Fundamentals of EU Regulatory Affairs 9th Edition

fundamentals of
EU REGULATORY
AFFAIRS Ninth Edition
Fundamentals of EU
Regulatory Affairs
Ninth Edition
Copyright ©2020 by the Regulatory Affairs Professionals Society.
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Dedication
This ninth edition of Fundamentals of EU Regulatory Affairs is dedicated to Pamela A. Jones, RAPS’
publications editor and longtime staff member who had a passion for editorial projects like this one. Pam
began work on this update before she passed away and it is with great admiration that we are dedicating
it to her memory. Pam was an extraordinary and wonderful person and dear member of the RAPS family.
The RAPS community benefitted greatly from Pam’s skilled work as an editor, but it is the loss of her wit,
humor and kindness that is felt most deeply by those who knew her. It was a genuine privilege to have Pam
in our lives. She was honest and direct and did not hesitate to share her opinions. Those of us who were
fortunate to have worked with her also know that beneath her tough, no-nonsense exterior beat an extremely
kind heart that cared deeply about her close friends, family and beloved pets. She is dearly missed.

Foreword
As work began on this ninth edition of Fundamentals of EU Regulatory Affairs, the healthcare product regulatory
landscape in the European Union (EU) was undergoing a significant transformation, including the impact of Brexit
and EMA’s move from London to Amsterdam.
New regulations for medical devices and in vitro diagnostic medical devices were adopted in April 2017 and will
transition into effect over the next three-to-five years, replacing the longstanding directives for these products. The
regulations will present consequential challenges for manufacturers and notified bodies. The medical device chapters
in this book provide an in-depth look at these changes and explain what they will mean for manufacturers, notified
bodies and competent authorities. At the time of publication, the EU MDR date of application was delayed to 26
May 2021, impact analysis is ongoing, and there is a move to review the date of application for EU IVDR as well.
The Clinical Trials Regulation also is in transition as it is intended to make the EU a more attractive location
for clinical trials. The regulation involves many modifications to the way trials have been conducted in the past and
the amount of trial information that will be available. And as the global pandemic demonstrated, disrupted access
to healthcare settings can hinder the commencement, continuation or completion of clinical trials, so adaptability is
critical to industry and regulators alike.
Other noteworthy updates in the ninth edition include:
• details on the latest EMA-EUnetHTA parallel consultation initiative
• guidance and current thinking on general safety and performance requirements (GSPR) compliance and
implementation
• implications of EU MDR and how medical device manufacturers need to reconsider their regulatory
strategy
• shift from medical devices directive to medical devices regulation classification
• impact of the in vitro diagnostic classification process including implementation of a rule-based system
• side-by-side tabular comparisons between the directive rules and regulation rules
• a narrative on specific devices and special rules
• addition of nonmedical devices to the legislative scope
• a new chapter outlining the regulatory framework for advanced therapy medicinal products (ATMPs) in the
EU, including how ATMPs are regulated and classified
• an overview of the main differences between the regulatory requirements for different types of ATMPs
• essential resources that developers and regulatory professionals can use to accelerate and de-risk their prod-
uct development plans
These impactful issues are presented throughout 43 chapters by thought leaders from diverse backgrounds, includ-
ing regulators, industry executives, consultants, scientists, manufacturers and academics representing nine different
countries.
Fundamentals of EU Regulatory Affairs, Ninth Edition is an excellent reference for regulatory professionals at all
levels and a valuable resource for anyone planning to take the RAC exam.
Gloria N. Hall
Senior Editor, Publications
Regulatory Affairs Professionals Society
The information in this publication is current to May 2020, including pending changes to legislation and website URLs.
Regulatory Affairs Professionals Society i

Acknowledgements
The Regulatory Affairs Professionals Society would like to express appreciation to the following subject matter
experts who shared their experience and knowledge with their colleagues by contributing to this book.
Sharry Arora, MPharm Kell Cannon Kate Dion

Manager 3D Communications 3D Communications
Novartis Healthcare Pvt. Ltd. US UK
India
Monique Carter, MS, RAC Tran Do
Yolanda García Barruso Director, Global Regulatory Affairs Senior Consultant
Regulatory Affairs Senior Manager Pfizer, Inc. Qserve Group US, Inc.
PharmaLex US US
Spain
Ashley Clark, MSc, RAC Daniela Drago, PhD, RAC
Frédéric Béard Senior Regulatory Affairs Specialist Senior Director Regulatory
Regulatory Officer R&Q, LLC Sciences
Biogecho Consulting GmbH US Biogen
Switzerland Adjunct Associate Professor
George Cusatis, MS, RAC George Washington University,
Nicole Béard, MSc, PhD Director School of Medicine and Health
Managing Director Merck and Co. Sciences
International Regulatory Affairs US US
Biogecho Consulting GmbH
Switzerland Ratinder Dhami, MSRA, RAC Karen Fan, MSc, PEng, RAC
Senior Director, Regulatory Affairs Manager, RA/QA
Gert Bos, MSc, PhD, FRAPS Network Partners Rostrum Medical Innovations Inc.
Executive Director and Partner US Canada
Qserve Consultancy BV
Netherlands Cindy DiBiasi Robert Falcone, PhD
3D Communications Senior Manager, Regulatory Affairs
Meredith Brown-Tuttle, FRAPS US Prestige Consumer Health
Principal Consultant US
Regulatorium
US
ii Regulatory Affairs Professionals Society

Anu Gaur, PhD, MBA, MSRA, James McBlane, PhD Siegfried Schmitt, PhD
RAC Preclinical Assessor, Biologicals Vice President Technical
Faculty, Regulatory Affairs Unit Parexel
Graduate Program Medicines and Healthcare products UK
College of Professional Studies Regulatory Agency (MHRA)
(CPS) UK Jan-Paul van Loon, MSc, PhD
Northeastern University Senior Consultant
US Darin Oppenheimer, DRSc, RAC Qserve Consultancy BV
Executive Director, Global Netherlands
Sabina Hoekstra-van den Bosch, Regulatory Affairs and Clinical
PharmD, FRAPS Safety, Devices and Digital Ruthanne Vendy, RAC
Regulatory Strategy Principal Health Senior Principal Specialist
TÜV SÜD Product Service Merck and Co. Regulatory and Quality Solutions
Netherlands US LLC (R&Q)
US
Karl-Heinz Huemer, PhD, MD Loes Pelgrim, MSc
Scientific Office / Austrian Senior Consultant Erik Vollebregt, LLM
Medicines and Medical Devices Qserve Consultancy BV Partner
Agency Netherlands Axon Lawyers
Austrian Agency for Health and Netherlands
Food Safety (AGES) Suraj Ramachandran, MS, RAC
Austria Director of Regulatory Affairs, Chauneen Leah Wood, MS, RAC
Device and Digital Health Associate Director, Regulatory
Florence Houn, MD, MPH Merck and Co. Affairs
Manager/Owner US IQVIA Biotech
Florence Houn MD MPH LLC US
US Azzurra Ravizza, MSc
Director Karen Zhou, JD, MS, RAC
Claudia Ising, FRAPS, RAC Pfizer Research and Development Senior Regulatory Affairs Specialist
Senior Consultant UK Limited Medtronic
viacuras consulting GmbH UK Canada
Germany
Manfred Ruthsatz, PhD, RAC,
Treena Jackson, MS, MA, CQA, FRAPS
CSSGB, RAC Executive Director
President Nutrition+HealthCARE
Quality Resource Consulting, Inc. Switzerland
US
Kathrin Schalper, PhD, RAC
Jocelyn Jennings, MS, RAC Senior Director, Regulatory Affairs
Senior Director, Regulatory Affairs Epizyme, Inc.
and Quality Assurance US
Mycovia Pharmaceuticals, Inc.
US
Regulatory Affairs Professionals Society iii

iv Regulatory Affairs Professionals Society
Table of Contents
Section I: General Information
Chapter 1 EMA and Other Regulatory Bodies.....................................................................................................1
Updated by Ratinder Dhami, MSRA, RAC
Chapter 2 History of Regulations........................................................................................................................13

Updated by Sabina Hoekstra-van den Bosch, PharmD, FRAPS
Chapter 3 Overview of Drug and Biologic Regulatory Pathways........................................................................31

Updated by Kathrin Schalper, PhD, RAC
Chapter 4 Preparing for EMA Meetings Prior to Submission of a Marketing Authorisation Application.........41
Updated by Kell Cannon, Kate Dion and Cindy DiBiasi
Chapter 5 Preparing for EMA Meetings During Review of a Marketing Authorisation Application................53
By Kell Cannon, Kate Dion and Cindy DiBiasi
Chapter 6 Pricing and Reimbursement................................................................................................................61

Updated by Anu Gaur, PhD, MBA, MSRA, RAC
Chapter 7 Health Technology Assessment (HTA)..............................................................................................77

Updated by Azzurra Ravizza, MSc and Monique Carter, MS, RAC
Chapter 8 The Paediatric Regulation...................................................................................................................93

Updated by Karl-Heinz Huemer, PhD, MD
Chapter 9 Advertising and Promotion...............................................................................................................103

Updated by Karen Zhou, JD, MS, RAC
Chapter 10 Enforcement and Competent Authorities........................................................................................115

Chapter 11 Falsified Medicines Directive: Requirements and Implications for

Multi-Stakeholder Healthcare Delivery...........................................................................................121
Updated by Yolanda García Barruso
Chapter 12 Regulatory Strategy..........................................................................................................................135

Updated by Karen Fan, MSc, PEng, RAC
Section II: Medical Devices

Chapter 13 The New Medical Devices Regulation and In Vitro Diagnostic Medical Devices Regulation.........141
Updated by Gert Bos, MSc, PhD, FRAPS and Erik Vollebregt, LLM
Chapter 14 The European Medical Devices Legal System..................................................................................151

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Chapter 15 Medical Devices: Legislation and Classification...............................................................................183
Updated by Ruthanne Vendy, RAC and Chauneen Leah Wood, MS, RAC
Chapter 16 In Vitro Diagnostic Medical Devices................................................................................................207

Updated by Erik Vollebregt, LLM
Chapter 17 General Safety and Performance Requirements and Technical Documentation

(EU MDR, EU IVDR)......................................................................................................................221
Updated by Darin Oppenheimer, DRSc, RAC, Suraj Ramachandran, MS, RAC and George Cusatis, MS, RAC
Chapter 18 Medical Device Preclinical Testing...................................................................................................229

Updated by Jan-Paul van Loon, MSc, PhD and Gert Bos, MSc, PhD, FRAPS
Chapter 19 Clinical Evaluation and Clinical Investigations................................................................................237

Updated by Loes Pelgrim, MSc and Gert Bos, MSc, PhD, FRAPS
Chapter 20 Medical Device Conformity Assessment Procedure.........................................................................243

Updated by Gert Bos, MSc, PhD, FRAPS
Chapter 21 Medical Device Compliance: Postmarket Requirements..................................................................257

Updated by Tran Do and Gert Bos, MSc, PhD, FRAPS
Chapter 22 Medical Device National Particularities............................................................................................271

Updated by Robert Falcone, PhD
Section III: Medicinal Products

Chapter 23 Overview of Authorisation Procedures for Medicinal Products........................................................277
Updated by Sharry Arora, MPharm
Chapter 24 Adaptive and Alternative Pathways..................................................................................................295

Chapter 25 Preclinical Testing and Good Laboratory Practice Regulations........................................................301

Chapter 26 Medicinal Product Clinical Trials.....................................................................................................309

Updated by Ashley Clark, MSc, RAC
Chapter 27 Registration Procedures for Medicinal Products...............................................................................341

Updated by Jocelyn Jennings, MS, RAC
Chapter 28 Quality Systems and Inspectorate Process—Pharmaceuticals..........................................................363

Updated by Treena Jackson, MS, MA, CQA, CSSGB, RAC and Siegfried Schmitt, PhD
Chapter 29 Generic Medicinal Products.............................................................................................................377

Updated by Nicole Beard MSc, PhD
Chapter 30 Biosimilar Medicinal Products..........................................................................................................393

Chapter 31 Nonprescription Medicinal Products................................................................................................403

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Chapter 32 Marketing Authorisations for Products Derived From Biotechnology.............................................413
Chapter 33 Pharmaceutical Postauthorisation Requirements and Compliance With the

Marketing Authorisation..................................................................................................................423
Chapter 34 Pharmacovigilance............................................................................................................................437
Chapter 35 Regulatory Framework for Advanced Therapy Medicinal Products .................................................451

By Daniela Drago, PhD, RAC, Florence Houn, MD, MPH and James McBlane, PhD
Chapter 36 Human Tissue Regulation................................................................................................................471

Updated by Nicole Beard, MSc, PhD
Chapter 37 Vaccines............................................................................................................................................489
Updated by Frédéric Béard
Section IV: Foods

Chapter 38 Food Supplements............................................................................................................................501
Updated by Manfred Ruthsatz, PhD, RAC, FRAPS
Chapter 39 Food for Special Medical Purposes...................................................................................................511

Section V: Other Product Classifications

Chapter 40 Products Manufactured From Human Blood or Plasma...................................................................519
Chapter 41 Orphan Medicinal Products.............................................................................................................529

Chapter 42 Combination Products......................................................................................................................543

Updated by Claudia Ising, FRAPS, RAC
Section VI: Resources

Chapter 43 Regulatory Information Resources....................................................................................................553
Updated by Meredith Brown-Tuttle, FRAPS and Gert Bos, MSc, PhD, FRAPS
Appendices
Comparative Matrix of EU Legislation Across Product Lines................................................................................575
Glossary ..........................................................................................................................................................623
Index ..........................................................................................................................................................643
Figures
Figure 1-1. EMA Mission.................................................................................................................................... 3
Figure 1-2. EMA Organisational Structure.......................................................................................................... 9
Figure 5-1. Approximate Representation of Key CHMP, CAT and PRAC Feedback and Meetings Based
on Standard Assessment Review Timeline....................................................................................... 55
Figure 5-2. Example Timeline for CHMP Meeting Preparation....................................................................... 57
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Figure 6-1. Factors Influencing Medicinal Product Pricing................................................................................ 62
Figure 6-2. Overview of ERP across Europe (2013)........................................................................................... 64
Figure 6-3. Summary of Economic Evaluation Methods................................................................................... 66
Figure 6-4. Types of Cost Containment Policies Adopted by Member States.................................................... 67
Figure 6-5. German Pricing for Medicinal Products Under AMNOG.............................................................. 70
Figure 7-1. Process Map for France.................................................................................................................... 85
Figure 7-2. Process Map for Germany................................................................................................................ 86
Figure 7-3. Mean Length of Time From EMA Authorisation to HTA Decision for Oncology Products......... 88
Figure 8-1. PIP Procedure.................................................................................................................................. 98
Figure 11-1. Comparison of EU FMD and Other Countries’ Falsified Medicines Legislation.......................... 123
Figure 11-2. Routes in the Medicinal Product Supply Chain by Which Falsified Active Substances may
Reach Patients................................................................................................................................ 125
Figure 11-3. An Example of the Common Logo Online Retailers of Medicines Must Display........................ 128
Figure 11-4. Flowchart Representing Product and Information Flow With Unique Product Identifiers and
Accompanying Verification and Repository Systems...................................................................... 131
Figure 13-1. Supply Chain Controls................................................................................................................... 143
Figure 13-2. Proposed EU IVDR Classification Rules........................................................................................ 145
Figure 13-3. Governance Structure for the EU MDR and EU IVDR.................................................................. 147
Figure 14-1. Simplified EU Legislative Process.................................................................................................. 153
Figure 14-2. Flow Chart for the Conformity Assessment Procedures in Directive 93/42/EEC on Medical
Devices........................................................................................................................................... 156
Figure 14-3. Flow Chart for the Conformity Assessment Procedures Provided for in Directive 90/385/EEC
on Active Implantable Medical Devices......................................................................................... 157
Figure 14-4. Flow Chart for the Conformity Assessment Procedures Provided for in Directive 98/79/EEC
on in Vitro Diagnostic Medical Devices......................................................................................... 158
Figure 14-5. Clinical Evaluation Cycle .............................................................................................................. 159
Figure 14-6. EU MDR and EU IVDR Governance Structure............................................................................ 176
Figure 20-1. Class III Device Conformity Assessment Procedure Options........................................................ 248
Figure 20-2. Class IIb Conformity Assessment Procedures................................................................................ 249
Figure 20-3. Class IIa Conformity Assessment Procedure.................................................................................. 249
Figure 20-4. Class I Device, Self-Declaration or Self-Certification.................................................................... 250
Figure 20-5. AIMDD Conformity Assessment Procedure.................................................................................. 250
Figure 20-6. IVD Conformity Assessment Procedure........................................................................................ 251
Figure 20-7. Self-Testing IVD Conformity Assessment Procedure.................................................................... 251
Figure 20-8. IVDD Annex II List B Conformity Assessment Procedures.......................................................... 252
Figure 20-9. High-Risk IVD Conformity Assessment Procedure...................................................................... 253
Figure 24-1. Product Eligibility for Adaptive Pathways Approach (Source: EMA, 2016).................................. 297
Figure 26-1. Clinical Trial Legislative Improvements......................................................................................... 312
Figure 26-2. Regulation (EU) 536/2014............................................................................................................. 313
Figure 26-3. Clinical Trial Authorization Procedure........................................................................................... 326
Figure 26-4. Clinical Trial Application Scientific Assessment............................................................................ 327
Figure 26-5. Clinical Trial Application: Part II Assessment............................................................................... 328
Figure 26-6. Serious Adverse Event Reporting................................................................................................... 332
Figure 27-1. Initial Marketing Authorisation Application Through the Centralised Procedure......................... 355
Figure 27-2. Initial Marketing Authorisation Application Through the Decentralised Procedure..................... 356
Figure 27-3. Initial Marketing Authorisation Application Through National Procedure and Mutual
Recognition Procedure................................................................................................................... 357
Figure 28-1. Drug Lifecycle Regulations............................................................................................................ 364
Figure 28-2. Assessors and Inspectors................................................................................................................. 365
Figure 28-3. EU Legal Instruments.................................................................................................................... 366
Figure 28-4. Inspections as Part of the Drug Approval Process.......................................................................... 367
Figure 30-1. Biosimilar Development................................................................................................................. 395
Figure 30-2. Stages of Development of a Biosimilar Medicine........................................................................... 396
Figure 30-3. Timeline for Development of a Biosimilar Medicine..................................................................... 397
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Figure 30-4. Biosimilar Product Development and Marketing Approval........................................................... 399
Figure 34-1. Pharmacovigilance System Master File.......................................................................................... 441
Figure 34-2. ICSR Expedited Submissions Requirements................................................................................. 445
Figure 34-3. Signal Management Lifecycle........................................................................................................ 447
Figure 35-1. Decision Tree for Potential Pathways and Expedited Evaluation Programs in the EU.................. 454
Figure 35-2. Decision Tree for Classification of TEPs and CTMPs................................................................... 458
Figure 35-3. Decision Tree for the Classification of GTMPs ............................................................................ 459
Figure 37-1. General Principles of VAMF Certification..................................................................................... 491
Figure 37-2. Procedure for Seasonal Influenza Vaccines in the EU (EMA/56793/2014)............................................................ 495
Figure 41-1. Simplified View of the Designation Criteria.................................................................................. 532
Figure 41-2. EMA Orphan Drug Designation Guide........................................................................................ 534
Tables
Table 3-1. Differences Between Conditional Marketing Authorisation and Marketing Authorisation
Under Exceptional Circumstances..................................................................................................... 36
Table 4-1. Overview of the Key EMA Advice Meetings and Their Goals......................................................... 43
Table 4-2. Overview of the Different Steps Required for Each Meeting........................................................... 45
Table 4-3. Timeline for Key Meeting Steps....................................................................................................... 46
Table 5-1. EMA Scientific Committees: Roles................................................................................................... 54
Table 6-1. Overview of Reference Pricing and Country Baskets in Europe....................................................... 65
Table 7-1. HTA and Associated Organisations in Select EU Member States.................................................... 82
Table 7-2. Comparison of HTA in Germany, France, UK, Italy and Spain........................................................ 83
Table 7-3. Summary of Time From EMA Authorisation to HTA Decision and Outcome............................... 87
Table 11-1. Definitions of Key Terms in This Chapter ...................................................................................... 124
Table 11-2. Worldwide Examples of SFFC Medicines From 2008 to Present................................................... 126
Table 11-3. Different Medicinal Product Supply Chain Stakeholder Requirements Under the FMD............... 127
Table 11-4. FMD Definitions of Active Substances and Excipients.................................................................. 128
Table 11-5. EU Initiatives Relevant to the FMD................................................................................................. 129
Table 11-6. Status of Third Country Listing Requests....................................................................................... 130
Table 12-1. Regulatory Key Questions During Development............................................................................ 137
Table 14-1. New Approach Areas....................................................................................................................... 154
Table 14-2. EU Member States and Affiliated Countries Competent Authorities............................................ 161
Table 14-3. European Commission Working Groups and Their Activities........................................................ 166
Table 14-4. European Industrial Trade Associations.......................................................................................... 167
Table 14-5. Comparison of MDD and EU MDR Definition of a Medical Device .......................................... 168
Table 14-6. MEDDEV Guidance Documents................................................................................................... 172
Table 14-7. European Commission Consensus Statements................................................................................ 174
Table 14-8. Informative Documents Issued by the European Commission........................................................ 174
Table 14-9. NBOG Documents (NBOG Best Practice Guides)........................................................................ 175
Table 15-1. MDR Annex VIII, Chapter III Classification Matrix..................................................................... 188
Table 15-2. MDR Classification Rules for Non-Invasive Medical Devices........................................................ 189
Table 15-3. MDR Classification Rules for Invasive Medical Devices................................................................. 190
Table 15-4. MDR Classification Rules for Active Medical Devices................................................................... 191
Table 15-5a. Special MDR Rules: Medical Devices............................................................................................. 192
Table 15-5b. Special MDR Rules: Medical Devices............................................................................................. 192
Table 15-6. Comparison of MDD and MDR Device Classification Rules......................................................... 194
Table 15-7. IVDR Annex VIII, I Classification Matrix ..................................................................................... 202
Table 15-8. Comparison of IVDD and IVDR Device Classification Rules......................................................... 204
Table 16-1. Examples of General Laboratory Use Products and IVD Medical Devices.................................... 210
Table 17-1. General Safety and Performance Requirements Checklist (Annex I of EU MDR and EU IVDR)... 223
Table 18-1. Basic Design Traceability Matrix (DTM) for Connecting Requirements to Test Results............... 231
Table 20-1. Conformity Assessment Procedures................................................................................................ 246
Table 20-2. AIMDD Conformity Assessment Documentation.......................................................................... 246
Table 20-3. MDD Conformity Assessment Documentation.............................................................................. 247
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Table 20-4. IVDD Conformity Assessment Documentation.............................................................................. 247
Table 20-5. Internal Production Control............................................................................................................ 254
Table 20-6. EC Type-Examination.................................................................................................................... 254
Table 20-7. Production Quality Assurance......................................................................................................... 254
Table 20-8. Product Quality Assurance.............................................................................................................. 254
Table 20-9. Product Verification......................................................................................................................... 254
Table 20-10. Full Quality Assurance System........................................................................................................ 254
Table 20-11. Authorised Representatives.............................................................................................................. 255
Table 21-1. Provisions for Providing Feedback about Medical Devices.............................................................. 259
Table 21-2. Eudamed Data Repository.............................................................................................................. 262
Table 21-3. Comparison of Safeguard Clause and Health Monitoring Measures.............................................. 267
Table 22-1. EU Outermost Regions................................................................................................................... 272
Table 22-2. Current Directives and New Regulations for Medical Devices, AIMDs and IVDs........................ 272
Table 22-3. Translation Requirements for Medical Devices, AIMDs and IVDs................................................ 273
Table 22-4. National Languages of the EU, Iceland, Liechtenstein and Norway............................................... 274
Table 23-1. Standard Timetable for Evaluation of a Centralised Application.................................................... 284
Table 23-2. Mutual Recognition Procedure Flowchart....................................................................................... 287
Table 23-3. Decentralised Procedure Flowchart................................................................................................. 290
Table 26-1. Summary of Selected Significant Changes Under Regulation (EU) No. 536/2014 (ECTR).......... 314
Table 26-2. Definitions of Selected Clinical Trials Directive and ECTR Terms.................................................. 316
Table 26-3. General Contents of Applications to Ethics Committees and National Competent Authorities..... 321
Table 26-4. Contents of Clinical Trial Application Dossier per the ECTR......................................................... 329
Table 26-5. Contents of DSUR.......................................................................................................................... 334
Table 27-1. EU Module 1 Contents................................................................................................................... 351
Table 27-2. EU eCTD Envelope Information................................................................................................... 352
Table 29-1. Legal Basis of EU Applications from Directive 2001/83/EC......................................................... 381
Table 30-1. Data Package Required for a Marketing Authorisation Application to EMA................................ 400
Table 31-1. Some Common Health Conditions Treated Using Nonprescription Medication........................... 405
Table 31-2. Comparison of EU MAA Procedure Advantages and Risks for Nonprescription Medicines......... 406
Table 34-1. Overview of Good Pharmacovigilance Practices............................................................................. 439
Table 34-2. Periodic Benefit-Risk Evaluation Report (PBRER), Development Safety Update Report
(DSUR) and Risk Management Plan (RMP) Interchangeable Modules........................................ 444
Table 35-1. EU Pathways and Expedited Evaluation Programs That Might Apply to ATMPs......................... 453
Table 35-2. ATMPs That Have Been Granted a Marketing Authorisation in the EU ...................................... 455
Table 35-3. Recent Examples of CAT ATMP Classifications............................................................................ 457
Table 36-1. Serological Donor Testing Requirements........................................................................................ 475
Table 36-2. Structure of the Single European Code........................................................................................... 476
Table 36-3. Qualifications and Responsibilities of the Responsible Person Under the EUTCD, Qualified
Person for Human Medicinal Products and Responsible Person for Regulatory Compliance
Under the EU MDR........................................................................................................................ 479
Table 36-4. Standard Timetable for Initial ATMP Marketing Authorisation Application Evaluation
Under the Centralised Procedure..................................................................................................... 481
Table 36-5. General Applicable Regulatory Framework for Medical Products Containing Human Tissue
Intended for Human Clinical use and its Interconnection with Directive 2004/23/EC
(Tissues and Cells Directive).............................................................................................................. 484
Table 40-1. Medicinal Products Derived From Human Plasma and Their Indications...................................... 521
Table 43-1. EMA’s Committees and Working Parties........................................................................................ 558
Table 43-2. National Competent Authorities..................................................................................................... 562
Table 43-3. Eligible Industry Stakeholder Organisations................................................................................... 565
Table 43-4. EDQM Databases........................................................................................................................... 567
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Chapter 1
EMA and Other

Regulatory Bodies
Updated by Ratinder Dhami, MSRA, RAC
OBJECTIVES □ Directive 2012/26/EU of the European

Parliament and of the Council of 25 October
□ Provide a background of the European 2012 amending Directive 2001/83/EC as re-
Medicines Agency and its relevance in Europe gards pharmacovigilance
□ Discuss the responsibilities and various activi- □ Directive 2004/24/EC of the European
ties being undertaken by EMA Parliament and of the Council of 31 March 2004
amending, as regards traditional herbal me-
□ Provide a summary of EMA’s organisational
dicinal products, Directive 2001/83/EC on the
structure
Community code relating to medicinal products
□ Review the different EMA committees and inter- for human use
national collaborations
□ Commission Directive 2003/94/EC of 8 October
□ Explain current activities around the UK’s exit 2003 laying down the principles and guidelines
from EU of good manufacturing practice in respect of
medicinal products for human use and investi-
gational medicinal products for human use
DIRECTIVES, REGULATIONS AND GUIDELINES □ Commission Directive of 23 July 1991 laying
COVERED IN THIS CHAPTER down the principles and guidelines of good
□ Directive 2001/82/EC of the European manufacturing practice for veterinary medicinal
Parliament and of the Council of 6 November products
2001 on the Community code relating to veter- □ Regulation (EC) No. 726/2004 of the European
inary medicinal products European Union (EU) Parliament and of the Council of 31 March 2004
Directive 2001/83/EC laying down Community procedures for the
□ Commission Directive 2010/83/EU of 30 authorisation and supervision of medicinal
November 2010 amending Council Directive products for human and veterinary use and
91/414/EEC to include napropamide as active establishing a European Medicines Agency
substance □ Regulation (EU) No. 1235/2010 of the European
□ Directive 2010/84/EU of the European Parliament and of the Council of 15 December
Parliament and of the Council of 15 December 2010 amending, as regards pharmacovigi-
2010 amending, as regards pharmacovigilance, lance of medicinal products for human use,
Directive 2001/83/EC on the Community code Regulation (EC) No. 726/2004 laying down
relating to medicinal products for human use Community procedures for the authorisation
and supervision of medicinal products for
Regulatory Affairs Professionals Society 1

Chapter 1
human and veterinary use and establishing a Regulation (EC) No. 726/2004 of the European
European Medicines Agency, and Regulation Parliament and of the Council
(EC) No. 1394/2007 on advanced therapy medic-
inal products
Introduction to EMA
□ Regulation (EU) No. 1027/2012 of the European The European Medicines Evaluation Agency (EMEA)
Parliament and of the Council of 25 October was founded in 1995, working across the EU to protect
2012 amending Regulation (EC) No. 726/2004 human and animal health by assessing medicines to rig-
as regards pharmacovigilance orous scientific standards and by providing partners and
stakeholders with independent, science-based informa-
□ Commission Implementing Regulation (EU) No.
tion on medicines.1 The agency’s name was changed to
520/2012 of 19 June 2012 on the performance
European Medicines Agency (EMA) in late 2009. The
of pharmacovigilance activities provided for in
agency cooperates with the European medicines regula-
Regulation (EC) No. 726/2004 of the European
tory network. The primary reason for establishing EMA
Parliament and of the Council and Directive
was to harmonise the work being done by the individual
2001/83/EC of the European Parliament and of
regulatory bodies in Europe. The agency’s primary func-
the Council
tion is to evaluate human and veterinary medicines. The
□ Regulation (EC) No. 1901/2006 of the European agency also is responsible for products developed in the
Parliament and of the Council of 12 December specialised areas of medicines for rare diseases, herbal
2006 on medicinal products for paediatric use medicines, medicines for children and advanced therapy
and amending Regulation (EEC) No. 1768/92, medicines. Up until 2020, the UK hosted the EMA.
Directive 2001/20/EC, Directive 2001/83/EC The UK withdrew from the European Union (EU) on
and Regulation (EC) No. 726/2004 31 January 2020 and is no longer an EU Member State.
The Netherlands now hosts EMA in Amsterdam.
□ Commission Regulation (EC) No. 2049/2005 The agency is a decentralised body responsible
of 15 December 2005 laying down, pursuant to for evaluating European Marketing Authorisation
Regulation (EC) No. 726/2004 of the European Applications (MAAs) for medicinal products
Parliament and of the Council, rules regard- (Centralised Procedure). Under the Centralised
ing the payment of fees to, and the receipt of Procedure, firms submit a single MAA to EMA.
administrative assistance from, the European Medicinal products for human and veterinary use
Medicines Agency by micro, small and medi- derived from biotechnology and/or other high-technol-
um-sized enterprises ogy, human medicines for HIV/AIDS, cancer, diabetes
or neurodegenerative diseases and all designated
□ Commission Regulation (EC) No. 1234/2008 of orphan medicines are to be approved by the Centralised
24 November 2008 concerning the examination Procedure. Veterinary medicines used to increase yields
of variations to the terms of marketing authori- from animals and performance-enhancing medicines
sations for medicinal products for human use to promote growth must go through the Centralised
and veterinary medicinal products Procedure as well. Any other products can be sub-
mitted as an application for a centralised Marketing
□ Regulation (EC) No. 726/2004 of the European
Authorisation (MA), provided the medicine is of sig-
Parliament and of the Council of 31 March 2004
nificant therapeutic value and a scientific or technical
laying down Community procedures for the
innovative product benefiting human or animal health.
authorisation and supervision of medicinal
EMA is a key component of the European regula-
products for human and veterinary use and
tory framework. EMA plays numerous roles, including
establishing a European Medicines Agency
facilitating development and access to medicines. EMA
□ Regulation (EC) No. 470/2009 of the European became responsible for monitoring medicines’ safety
Parliament and of the Council of 6 May 2009 throughout their lifecycles with the establishment of the
laying down Community procedures for the Pharmacovigilance and Risk Assessment Committee
establishment of residue limits of pharmacolog- (PRAC).2 Council Directive 65/65 3 was the first
ically active substances in foodstuffs of animal European pharmaceutical directive issued in response
origin, repealing Council Regulation (EEC) No. to the thalidomide tragedy. The early directive focused
2377/90 and amending Directive 2001/82/EC of on harmonising medicines approval standards within
the European Parliament and of the Council and the European Economic Community. Now, EMA
plays a key role in supporting medicines’ approval,
2 Regulatory Affairs Professionals Society

EMA and Other Regulatory Bodies
Figure 1-1. EMA Mission
Protect Human and Animal Health
Provide information on
Monitor the safety of
Facilitate development and Evaluate applications for human and veterinary
medicines across their
access to medicines marketing authorisation medicines to healthcare
lifecycles
professionals and patients
pharmaceutical research and innovation and promoting public health, patients, healthcare professionals and
the development of innovative novel medicines.4,5 EMA research (see Figure 1-1). EMA continuously reviews
collaborates with Member States in such areas as rare and improves its policies.
medical conditions. The clinical trial regulations and the EMA is committed to enabling timely patient
data protection directives support the entire EU popu- access to new medicines and plays a vital role in sup-
lation. The history of EMA is covered in Chapter 2 of porting medicine development.
this book. EMA uses multiple regulatory mechanisms to
EMA draws scientific resources from more than enable timely patient access to medicines8 while meet-
40 national competent authorities and a network of ing the agency’s goals. Medicines that would meet
more than 4,000 European experts.6 The agency partic- unmet medical needs are of major interest to the agency.
ipates in international activities through its work with It seeks to support the medicine development process
organisations such as the World Health Organization from an early stage by offering regulatory mechanisms
(WHO) and the International Council on Harmonisation to move promising molecules to the market sooner.
of Technical Requirements for Registration of Companies are taking advantage of these opportunities
Pharmaceuticals for Human Use (ICH). It also is that facilitate the development of such medicinal prod-
involved in referral procedures relating to medicinal ucts. Accelerated assessment reduces the review timeline
products that are approved or under consideration by for an MA for therapeutic innovations. The conditional
Member States. Since EMA was established, it has authorisation provision grants an MA before com-
maintained the highest standards in integrity, trans- plete data are available. The Committee for Medicinal
parency and independence. The agency has a code of Products for Human Use (CHMP)9 is authorised to
conduct by which its employees, management board, allow unapproved medicines for compassionate use.
scientific committees and expert staff must abide. They issue an opinion on criteria and conditions and the
Members of the management board and scientific type of patient access programmes that can be consid-
committees, experts and staff demonstrate integrity and ered for such products.
high standards of professional conduct, which are cru- The agency has a Priority Medicines (PRIME)10,11
cial for EMA’s role as an independent body. The code of scheme to enhance support for developing medicines
conduct and its active application help EMA perform that target unmet medical needs. This is a voluntary
its roles and responsibilities. scheme based on enhanced interaction and early dialogue
with developers of promising medicines, to optimise
EMA Mission development plans and speed up evaluation, so these
EMA’s mission is to foster scientific excellence in med- medicines can quickly reach the patient population. The
icines’ evaluation and supervision for the benefit of programme builds on the existing regulatory framework,
public and animal health.7 The agency is the EU body providing accelerated assessment to developers submit-
responsible for coordinating the scientific resources ting MAAs for these medicines. PRIME is aimed at
from the various Member States and their institutions. improving clinical trial designs, so the data generated
EMA is responsible for providing the best advice to are suitable for application evaluation. Early dialogue
Member States on any queries related to the quality, and scientific advice also will ensure parties, the devel-
safety and efficacy of medicinal products for human or oper and the agency use the best resources in a focused
veterinary use. EMA’s scientific evaluation and phar- manner. The programme focuses on medicines that offer
macovigilance roles and responsibilities have a major major therapeutic advantages over current treatments and
impact on human and animal health protection and was developed in consultation with the agency’s scientific
promotion. EMA plays an important role in supporting committees, the EC expert group on Safe and Timely

Chapter 1
Access to Medicines for Patients (STAMP)12 and the injury. The agency’s Committee for Advanced Therapies
European medicines regulatory network. (CAT) plays a central role in the scientific assessment of
EMA provides Scientific Advice and Protocol advanced therapy medicines. The medicines are autho-
Assistance to medicine developers. CHMP provides rised centrally by EMA, thus benefiting from a single
scientific advice and protocol assistance for human evaluation and authorisation process. EMA also is
medicines based on the Scientific Advice Working responsible for monitoring ATMPSs’ safety and efficacy.
Party’s (SAWP)13 recommendations. EMA advises the It is estimated 30 million people in the EU suffer from
sponsor on appropriate tests and studies for medicine a rare disease.16 The agency reviews sponsors’ applica-
development. This is to facilitate the development and tions for orphan medicine designation. EMA, therefore,
availability of high-quality, effective and safe medicines is in the forefront in facilitating orphan medicinal
for the patient population. The sponsor can request product development and market authorisation. In
Scientific Advice from EMA at any stage of a medi- addition, the agency encourages organisations by pro-
cine’s development. This ensures sponsors perform the viding incentives—administrative, procedural assistance
applicable tests and procedures and ensures no major and fee reductions—if they can be classified as micro-,
objections regarding test designs are raised during small- or medium-sized enterprises (SMEs).
MAA evaluation. Major objections can delay product CHMP prepares scientific guidelines in consul-
marketing significantly. Scientific Advice is provided by tation with EU Member States’ regulatory authorities,
virtue of answering the developer’s questions. It must including interpretation. This enables a harmonised
be noted the advice is always based on current scien- approach while examining requirements for the prod-
tific knowledge in response to information the sponsor uct’s quality, safety and efficacy. The guidances are
provides. Scientific Advice is focused primarily on intended to assist applicants preparing MAAs for
development strategies, not data evaluation. The advice human medicines. Any deviation from guidance require-
is not legally binding on the agency or the sponsor ments must be explained and justified in the submission.
regarding future MAAs. The guidance is available as a concept paper, draft
Protocol Assistance is a form of Scientific Advice guidance, overview of consultation comments and final
available to developers of designated medicines for version. EudraLex17 consists of only adopted guidances.
rare diseases or orphan medicines. Here, in addition One EMA goal is to nurture research and inno-
to Scientific Advice, sponsors receive answers to ques- vative methods in developing medicines in a timely
tions relating to orphan medicine authorisation criteria. fashion. The Innovation Task Force (ITF)18,19 is a mul-
Medicine developers can request Scientific Advice and tidisciplinary group that includes scientific, regulatory
Protocol Assistance either during the medicinal prod- and legal experts. The task force provides a forum for
uct’s initial development, before MAA submission or early dialogue with applicants. It is responsible for
during a later postauthorisation phase. Although vol- identifying any challenges or issues in emerging tech-
untary, the agency also encourages sponsors to obtain nologies and therapies proactively; addressing the new
scientific advice for postauthorisation safety study technology or therapy’s impact on current processes;
(PASS) protocols. determining the need for additional expertise; providing
EMA considers paediatric drugs important and advice on the eligibility to agency procedures relating to
has focused tasks and responsibilities oriented toward research and development in conjunction with CHMP,
facilitating development and marketing of these prod- the Committee for Medicinal Products for Veterinary
ucts. The responsibilities came from the EU Paediatric Use (CVMP), the European Commission and national
Regulation14 that enables the agency to stimulate competent authorities and increasing agency awareness
research into medicines use in children and pioneer of emerging technologies.
MAs for all age groups. The regulation and focus were EMA’s scientific committees provide indepen-
required because many products were not studied dent recommendations on medicines for human and
adequately or authorised for use in children. The new veterinary use based on comprehensive scientific data
regulation mandated a Paediatric Committee to pro- evaluation or submitted information and literature. The
vide objective scientific opinions on development plans evaluation and authorisation process provides the basis
for medicines used in children, paediatric investigation for critical decisions on medicines marketed in the EU.
plans (PIPs). The agency plans to add the views of chil- The agency conducts inspections in connection with
dren and young people by incorporating consultation MAA assessments or matters referred to its commit-
into the framework. tees. It monitors and supervises the safety of medicines
EMA supports Advanced Therapy Medicinal authorised in the EU to ensure benefits outweigh risks.
Products (ATMPs)15 based on genes or cells. The prod- It accomplishes this by developing guidelines, coor-
ucts offer newer opportunities for treating disease and dinating pharmacovigilance activities, contributing

to international pharmacovigilance activities and functions efficiently. The HMA meets four times per
informing the public on medicines’ safety aspects. year to address key strategic issues for the network, such
EMA publishes information about medicines and their as the exchange of information, IT development and
approved uses,20 including scientific assessment reports best practices, and to streamline Mutual Recognition
and summaries. and Decentralised Procedures.22,23 Members from the
The regulatory agency works with multiple stake- national authorities constitute EMA’s scientific commit-
holders on a broad range of topics. Stakeholders include tees, working parties and assessment teams. In addition
research institutions, universities and public-private to the European Commission, the network includes
initiatives. The agency aims at improving medicines’ EEA national authorities.
regulation science and process to encourage the devel- The national competent authorities for human
opment of medicines for unmet medical needs and to medicines include:24
optimise the surveillance and management of medicines • Austrian Agency for Health and Food Safety,
on the EU market. The agency roadmap underscores Spargelfeldstraße 191, 1220 Wien, Austria,
these activities and stresses the mission to foster scien- www.ages.at
tific excellence in medicines’ evaluation and supervision • Federal Agency for Medicines and Health
for the benefit of human and animal health. Therefore, Products, Eurostation Building, Block 2, Place
the agency and its members are keen to learn and Victor Horta, 40/ 40, 1060 Brussels, Belgium,
understand the latest scientific knowledge and methods www.fagg-afmps.be/
to support science in the relevant areas of their roles. • Bulgarian Drug Agency, 8 Damyan Gruev Str.,
Sofia 1303, Bulgaria, www.bda.bg
European Medicines Regulatory Network • Agency for Medicinal Products and Medical
The regulatory network in Europe is different than any Devices of Croatia, Ksaverska Cesta 4, 10 000
other in the world. The network includes European Zagreb, www.almp.hr
Economic Area (EEA) Member States’ competent • Ministry of Health—Pharmaceutical Services,
authorities.21 The competent authorities collaborate on Pharmaceutical Services Ministry of Health,
reporting medicines’ side effects, clinical trial oversight, 1475 Nicosia, Cyprus, www.moh.gov.cy/phs
medicinal product manufacturer inspections and Good • State Institute for Drug Control, Srobárova 48,
Clinical Practice (GCP), Good Manufacturing Practice 100 41 Praha 10, Czech Republic, www.sukl.cz
(GMP), Good Distribution Practice (GDP) and • Danish Medicines Agency, Axel Heides Gade
Good Pharmacovigilance Practice (GVP) compliance. 1, 2300 København S, Denmark, www.laegem-
They work in tandem with EMA and the European iddelstyrelsen.dk
Commission (EC). The EC is responsible for taking • State Agency of Medicines, 1 Nooruse Street,
decisions based on EMA scientific recommendations. 50411 Tartu, Estonia, www.ravimiamet.ee
The regulatory network is key to EMA’s organisational • Finnish Medicines Agency, PO Box 55,
success. EMA works in coordination with the numerous FI-00034 Fimea, Finland, www.fimea.fi
human and veterinary medicines’ competent authorities. • National Agency for the Safety of Medicine
EMA’s resources come from these competent and Health Products, 143-147 bd Anatole
authorities. Diversity of expert opinions from various France, 93285 Saint Denis Cedex, France,
agencies ensures the exchange of knowledge, ideas and www.ansm.sante.fr
best practices between the best scientists applying their • Federal Institute for Drugs and Medical
best approaches. EMA has an active list of experts, Devices, Kurt-Georg-Kiesinger-Allee 3, 53175
including details of their experience. EMA runs a pro- Bonn, Germany, www.bfarm.de
gramme for multinational experts who can be involved • Paul Ehrlich Institute, Paul-Ehrlich-Straße
in assessing human and veterinary medicines. This 51-59, 63225 Langen, Germany, www.pei.de
enables the agency to use the best in their fields. • National Organization for Medicines,
As noted earlier, the national authorities are respon- Messogion Avenue 284, 15562 Athens,
sible for the authorisation of medicines that do not go Greece, www.eof.gr
through the Centralised Procedure. The national compe- • National Institute of Pharmacy and Nutrition,
tent authorities are responsible for regulating human and Zrínyi U. 3, 1051 Budapest, Hungary, www.
veterinary medicines in the EU, coordinating their work ogyei.gov.hu
through the Heads of Medicines Agencies (HMA). The • Icelandic Medicines Agency, Vínlandsleið 14,
competent authority heads work closely with EMA and 113 Reykjavík, Iceland, www.ima.is
the European Commission to maximise cooperation • Health Products Regulatory Authority
and ensure the European medicines regulatory network (HPRA), Kevin O’Malley House, Earlsfort

Chapter 1
Centre, Earlsfort Terrace, Dublin 2, Ireland, • Austrian Agency for Health and Food Safety,
www.hpra.ie Spargelfeldstraße 191, 220 Wien, Austria,
• Italian Medicines Agency, Via del Tritone, 181, www.ages.at
00187 Roma, Italy, www.aifa.it • Federal Agency for Medicines and Health
• State Agency of Medicines, 15 Jersikas Street, Products, Eurostation Building, Block 2 Place
1003 Riga, Latvia, www.zva.gov.lv Victor Horta, 40/40, 1060 Brussels, Belgium,
• Office of Health/Department of www.fagg-afmps.be
Pharmaceuticals, Äulestr 512, 9490 Vaduz, • Bulgarian Food Safety Authority, 15A Pencho
Liechtenstein, http://www.llv.li/#/1908/ Slaveikov Blvd., 1606 Sofia, Bulgaria, www.
amt-fur-gesundheit babh.government.bg
• State Medicines Control Agency, Žirmūnų g. • Ministry of Agriculture, Veterinary and Food
139A, 09120 Vilnius, Lithuania, www.vvkt.lt Safety Directorate, Planinska 2a, 10 000
• Ministry of Health, Allée Marconi, 2120 Zagreb, Croatia, www.veterinarstvo.hr
Luxembourg, Luxembourg, www.ms.etat.lu • Veterinary Services, Ministry of Agriculture,
• Medicines Authority, 203 Rue DÁrgens, Natural Resources and Environment,
GZR 03 Gzira, Malta, www.medicinesauthor- Athalassa, 1417 Nicosia, Cyprus, www.moa.
ity.gov.mt gov.cy/moa/vs/vs.nsf
• Medicines Evaluation Board, Graadt van • Institute for State Control of Veterinary
Roggenweg 500, 3531 AH Utrecht, The Biologicals and Medicines, Hudcova Str. 56A,
Netherlands, https://english.cbg-meb.nl/ 621 00 Brno–Medlánky, Czech Republic,
• Healthcare Inspectorate, Stadsplateau 1, 3521 www.uskvbl.cz
AZ Utrecht, The Netherlands, www.igz.nl • Danish Health and Medicines Authority, Axel
• Norwegian Medicines Agency, Postboks 240 Heides Gade 1, 2300 København S, Denmark,
Skoyen, 0213 Oslo, Norway, www.legemid- www.laegemiddelstyrelsen.dk
delverket.no • State Agency of Medicines, 1 Nooruse Street,
• Office for Registration of Medicinal Products, 50411 Tartu, Estonia, www.sam.ee
Medical Devices and Biocidal Products, Al. • Finnish Medicines Agency, PO Box 55,
Jerozolimskie 181C, 02-222 Warsaw, Poland, FI-00034 Fimea, Finland, www.fimea.fi
www.urpl.gov.pl • National Veterinary Medicines Agency, 14 rue
• Chief Pharmaceutical Inspectorate, Senatorska Claude Bourgelat, Parc d’activités de la Grande
12, 00-082 Warsaw, Poland, www.gif.gov.pl Marche Javené, CS 70611, 35306 Fougères
• National Authority of Medicines and Health France, www.anses.fr
Products, Parque de Saúde de Lisboa, Avenida • Federal Office of Consumer Protection and
do Brasil, 53, 1749-004 Lisboa, Portugal, www. Food Safety, Rochusstraße 65, 53123 Bonn,
infarmed.pt Deutschland, www.bvl.bund.de
• National Authority of Medicines and Medical • Paul Ehrlich Institute, Paul-Ehrlich-Straße
Devices, 48, Av. Sanatescu, 011478 Bucharest, 51-59, 63225 Langen, Germany, www.pei.de
Romania, www.anm.ro • National Organization for Medicines,
• State Institute for Drug Control, Kvetná 11, Messogion Avenue 284, 15562 Athens,
825 08 Bratislava 26, Slovakia, www.sukl.sk Greece, www.eof.gr
• Agency for Medicinal Products and Medical • Directorate of Veterinary Medicinal Products,
Devices of the Republic of Slovenia, Szállás utca 8, 1107 Budapest 10.Pf. 318,
Slovenčeva ulica 22, 1000 Ljubljana, Slovenia, Hungary, www.portal.nebih.gov.hu
www.jazmp.si • Icelandic Medicines Agency, Vínlandsleið 14,
• Spanish Agency for Medicines and Health 113 Reykjavík, Iceland, www.imca.is
Products, Parque Empresarial, Las Mercedes • Department of Agriculture, Food and the
Edificio 8C/, Campezo, 1, 28022 Madrid, Marine, Kildare Street, Dublin, Ireland, www.
Spain, www.aemps.gob.es agriculture.gov.ie
• Medical Products Agency, Dag • Health Products Regulatory Authority
Hammarskjölds väg 42, Box 26, 751 03 (HPRA), Kevin O’Malley House, Earlsfort
Uppsala, Sweden, www.lakemedelsverket.se Centre, Earlsfort Terrace, Dublin 2, Ireland,
www.hpra.ie
The national competent authorities for veterinary med-
icines include:25

• Ministry of Health, Via Giorgio Ribotta 5, • Medical Products Agency, Dag

Angolo Viale Oceano Pacifico, 00144 Roma Hammarskjölds väg 42, Box 26, 751 03
EUR, Italy, www.salute.gov.it Uppsala, Sweden, www.lakemedelsverket.se
• Food and Veterinary Service, Peldu Street 30,
Riga 1050, Latvia, www.pvd.gov.lv EMA Organisation and Structure
• Office of Health, Äulestr 512, FL—9490 EMA is governed by an independent Management
Vaduz, Liechtenstein, www.llv.li Board26 composed of 36 independent members. The
• State Food and Veterinary Service, Siesiku Str. board’s role is to define EMA’s budget, develop the
19, 07170 Vilnius, Lithuania, www.vmvt.lt yearly work plan and ensure the agency works effec-
• National Food and Veterinary Risk tively with partnering organisations. The executive
Assessment Institute, J. Kairiukscio st. 10, director also is responsible for operations, EMA staff
08409 Vilnius, Lithuania, www.nmvrvi.lt and developing the annual work plan. Staff members’
• Ministry of Health, Allée Marconi, L - 2120 responsibilities include administrative and procedural
Luxembourg, Luxembourg, www.ms.etat.lu functions. The EMA administration and corporate
• Veterinary and Phytosanitary Regulation management group is responsible for budgeting, plan-
Department, Abattoir Street, Albertown, ning and human resource matters. Support services are
Marsa, MRS 1123, Malta, www.veterinary- responsible for policy development, revising legislation,
medicine@gov.mt emergency management, liaising with EU institu-
• Medicines Evaluation Board, Graadt van tions, supporting the management board, document
Roggenweg 500, 3531 AH Utrecht, The management, access management and management
Netherlands, www.cbg-meb.nl of publication of clinical data. (See Figure 1-2 EMA
• Healthcare Inspectorate, Stadsplateau 1, 3521 Organisational Structure.)
AZ Utrecht, The Netherlands, www.igz.nl
• Norwegian Medicines Agency, Postboks 240 EMA Committees
Skoyen 0213 Oslo, Norway, www.legemiddelv- The scientific committees evaluate medicines through-
erket.no out their lifecycles, from development to marketing
• Office for Registration of Medicinal Products, authorisation to pharmacovigilance monitoring. The
Medical Devices and Biocidal Products, Al. committees and bodies constitute European experts
Jerozolimskie, 181C, 02-222 Warsaw, Poland, who work with EMA and the European medicines
www.bip.urpl.gov.pl regulatory network. There are seven such committees
• Chief Pharmaceutical Inspectorate, Senatorska and multiple working groups under EMA. MAAs sub-
12, 00-282 Warsaw, Poland, https://www.gif. mitted via the Centralised Procedure are reviewed by
gov.pl/en the committees. The committees also work to develop
• National Authority for Animal Health, medicines regulations and provide Scientific Advice to
Lg. Academia Nacional de Belas Artes 2, companies on medicines’ research and development.
1294-105 Lisboa, Portugal, www.dgv.min-ag- Committees also are involved in harmonising the reg-
ricultura.pt ulatory requirements in the EU and internationally.
• Institute for Control of Biological Products Further details of individual committees follow.
and Veterinary Medicines, Str. Dudului 37,
Sector 6, 060603 Bucuresti, Romania, www. Committee for Medicinal Products for Human Use
icbmv.ro (CHMP)
• Institute for State Control of Veterinary CHMP plays a vital role in authorising medicines in the
Biologicals and Medicaments, Biovetská 34 EU. It is the EMA committee responsible for human
PO Box 52c, 949 01 Nitra, Slovakia, www. medicines.27 CHMP conducts the initial assessment of
uskvbl.sk EU-wide MAAs; assesses modifications or extensions
• Agency for Medicinal Products and Medical (variations) to existing MAs; considers PRAC recom-
Devices of the Republic of Slovenia, mendations on marketed medicinal products’ safety and,
Slovenčeva ulica 22, 1000 Ljubljana, Slovenia, when necessary, recommends changes to a medicine’s
www.jazmp.si MA or its suspension or withdrawal from the market to
• Spanish Agency for Medicines and Health the European Commission. CHMP also evaluates med-
Products, Parque Empresarial Las Mercedes icines authorised at the national level referred to EMA
Edificio 8C/, Campezo, 1, 28022 Madrid, for a harmonised position across the EU.
Spain, www.aemps.gob.es

Chapter 1
Pharmacovigilance Risk Assessment Committee focuses on establishing EU monographs covering the

(PRAC) well-established herbal substances and preparations’
PRAC28 is the EMA committee responsible for assessing therapeutic or traditional uses and safe conditions, and
and monitoring human medicinal products’ safety and drafting an EU list of herbal substances, preparations
assessing all aspects of human medicines’ risk manage- and combinations thereof for use in traditional herbal
ment. The committee detects, assesses, minimises and medicinal products.
communicates the risk of adverse reactions, while taking
the therapeutic effect of the medicine into account. It Committee for Advanced Therapies (CAT)
designs and evaluates postauthorisation safety studies CAT’s32 main responsibility is to prepare a draft opinion
and pharmacovigilance audits. PRAC provides recom- on each ATMP application submitted to EMA, before
mendations on pharmacovigilance and risk management CHMP adopts a final opinion on the concerned medi-
systems, including monitoring their effectiveness. cine’s MAA. CAT also participates in certifying quality
and nonclinical data for small and medium-sized enter-
Committee for Medicinal Products for Veterinary Use prises developing ATMPs; participates in providing
(CVMP) scientific recommendations on ATMPs’ classification;
CVMP plays a vital role in the authorisation of veter- and contributes to Scientific Advice, in cooperation
inary medicines in the EU. CVMP29 is responsible for with the SAWP. It also participates in any procedure
conducting the initial assessment of EU-wide veterinary delivering advice on the conduct of ATMPs’ efficacy
product MAAs; postauthorisation and maintenance follow-up, pharmacovigilance or risk-management
activities, including the assessment of any modifica- systems; advises CHMP on any medicinal product that
tions or extensions (variations) to an existing marketing may require ATMP expertise for the evaluation of its
authorisation; monitoring marketed veterinary med- quality, safety or efficacy; and assists scientifically in
icines’ safety and, when necessary, recommending developing any documents relating to the objectives of
changes to a medicine’s marketing authorisation or the ATMP Regulation. CAT provides scientific exper-
its suspension or withdrawal from the market to the tise and advice for any Community initiative related to
European Commission. CVMP evaluates veterinary the development of innovative medicines and therapies
medicines authorised at the national level and referred to requiring ATMP expertise and supports the CHMP
EMA for a harmonised position across the EU. CVMP working party programmes.
recommends safe limits for residues of veterinary med-
icines used in food-producing animals, and assesses Paediatric Committee (PDCO)
biocidal products used in animal husbandry, to establish The Paediatric Committee (PDCO)33 is the EMA scien-
maximum residue limits by the European Commission. tific committee responsible for activities on medicines
for children and supporting such medicines’ develop-
Committee for Orphan Medicinal Products (COMP) ment in the EU by providing scientific expertise and
COMP30 is responsible for evaluating applications for defining paediatric needs. PDCO’s main role is to assess
orphan designation. This designation is for medicines the content of PIPs, which determine the studies com-
developed for the diagnosis, prevention or treatment of panies must carry out in children when developing a
rare diseases that are life-threatening or very serious. medicine. This includes assessing applications for a full
In the EU, a disease is defined as rare if it affects fewer or partial waiver and for deferrals.
than five in 10,000 people across the Community. The The agency has a number of working parties and
European Commission decides whether to grant an related groups, which can be consulted by its scientific
orphan designation for the medicine based on COMP’s committees on issues relating to their particular fields of
opinion. An orphan designation allows a pharmaceu- expertise. The working parties’ members have expertise
tical company to benefit from such EU incentives as in a particular scientific field, selected from the agency’s
reduced fees and protection from competition once the list of European experts. Members are given tasks asso-
medicine is placed on the market. ciated with MAA scientific evaluation or drafting and
revising scientific guidance documents.
Committee on Herbal Medicinal Products (HMPC) The Coordination Group for Mutual Recognition
HMPC31 is the EMA committee responsible for com- and Decentralised Procedures—Human (CMDh)34
piling and assessing scientific data on herbal substances, was created in 2005. It examines questions relating to
preparations and combinations, to support the harmon- human medicines’ MAs in two or more EU Member
isation of the European market. HMPC is composed States in accordance with the Mutual Recognition
of scientific experts in the field of herbal medicines. It or Decentralised Procedure, and questions concern-
ing variations of these MAs. If there is disagreement

Figure 1-2. EMA Organisational Structure

Chapter 1
between Member States during the assessment of the information and quality defects. The EU has MRAs
submitted data based on the grounds of a potential in place with Australia, Canada, Israel, Japan, New
serious risk to public health, the CMDh considers the Zealand, Switzerland and the US. EMA also coop-
matter and strives to reach an agreement within 60 erates with the European Commission in the BRIC
days. If this is not possible, the Member State respon- countries. Activities with China, India and Russia are
sible for the product brings the case to the attention of through specific EU frameworks. EMA works with
the CHMP for arbitration. Each year, the CMDh iden- the International Council for Harmonisation (ICH),
tifies a list of medicines for which harmonised product International Coalition of Medicines Regulatory
information should be developed to promote the har- Authorities (ICMRA), Veterinary International
monisation of marketing authorisations across the EU. Conference on Harmonisation (VICH), International
CMDh is composed of one representative per Member Pharmaceutical Regulators Forum (IPRF), WHO,
State (plus Norway, Iceland and Liechtenstein), Council of Europe, Organisation for Economic
appointed for a renewable period of three years. Co-operation and Development (OECD), Codex
The Coordination Group for Mutual Recognition Alimentarius, Office International des Epizooties (OIE)
and Decentralised Procedures—Veterinary (CMDv)35 and the European Free Trade Association (EFTA).
was created in 2005. It examines questions relating to EMA is involved in multiple initiatives, such as:
veterinary medicines’ MAs in two or more EU Member • EU-US Mutual Reliance Initiative on GMP
States in accordance with the Mutual Recognition inspection36
or Decentralised Procedure. In particular, if there is • Increasing collaboration with China and India
disagreement between Member States during the • Reform of ICH governance and science
assessment on the grounds of a potential serious risk • Common FDA-EMA application form and
to human or animal health or to the environment, the annual report for orphan designation
CMDv considers the matter and strives to reach an • International Generic Medicines Assessment
agreement within a 60-day time period as set out in pilot
the legislation. CMDv is composed of one represen- • International cooperation on approaches to
tative per Member State (plus Norway, Iceland and Ebola treatment and prevention
Liechtenstein), appointed for a renewable period of • ICMRA37
three years.
The EMA Stakeholders and Communication EMA Innovation Support
Division is responsible for ensuring the agency has The Innovation Task Force (ITF)38 is a multidisciplinary
a coherent, coordinated and consistent approach to group that includes scientific, regulatory and legal
stakeholder and partner relations management and competences. Its goal is to ensure coordination across
communication. EMA and to provide a forum for early dialogue with
applicants. The network aims to facilitate the creation
EMA and International Collaboration of innovative methods and technologies in academic
EMA recognises the requirement for international environments and translate basic research into the med-
cooperation. It believes this will protect product qual- icine development process. It comprises a network of
ity and supply chain security, ensure data integrity to regulators focusing on innovation (innovation centers
support clinical trials and manufacturing, encourage or innovation-technology forums). ITF also supports
a global approach to authorisation and supervision the exchange of information and facilitates knowledge
of medicines and avoid unnecessary duplication of transfer for the benefit of public health.
efforts. EMA works efficiently with its partners to
promote effective global regulatory resources’ use. The UK Withdrawal from EU
current focus is on work-sharing. Bilateral activities The UK formally left the European Union (EU) on 31
are conducted through confidentiality arrangements January 2020 and became a third country. This move
or mutual recognition agreements. The agency and the has commonly been known as “Brexit.” A transition
European Commission work closely in all international period began on 1 February 2020, during which EU
activities. Confidentiality arrangements facilitate the pharmaceutical law remains applicable to the UK. This
exchange of confidential information between regula- is due to end on 31 December 2020. On 1 February
tors. Mutual recognition agreements (MRAs) on Good 2019, EMA and the European Commission published
Manufacturing Practice (GMP) allow EU authorities a Question and Answer (Q&A) document39 concerning
to rely on GMP inspections performed by other reg- company establishment requirements in the context of
ulators, waive batch testing of products on entry into the Centralised Procedure and certain activities. The
the EU and share information on inspection-related

Q&A provides further detail following the European areas of medicines for rare diseases, herbal medicines,
Commission/EMA notice of 1 February 2019,40 medicines for children and advanced therapy medicines.
intended to remind MAHs of centrally authorised EMA continues to promote innovation in the develop-
medicines of their legal obligations. ment of novel medicines.
EMA has made preparations to ensure it con-
tinues to deliver on its mission to protect public and References
1. About Us. EMA website. http://www.ema.europa.eu. Accessed
animal health throughout the Brexit process. One of 11 March 2020.
the consequences of Brexit was that EMA relocated to 2. Pharmacovigilance and Risk Assessment Committee (PRAC).
Amsterdam, the Netherlands, in March 2019. EMA EMA website. http://www.ema.europa.eu/ema/index.
continues to operate in accordance with the timelines jsp?curl=pages/about_us/general/general_content_000537.
jsp&mid=WC0b01ac058058cb18. Accessed 11 March 2020.
set by its rules and regulations throughout the Brexit 3. Council Directive 65/65/EEC of 26 January 1965 on the
process. The UK notified the EU of its intention to approximation of provisions laid down by Law, Regulation or
leave the EU on 29 March 2017. Administrative Action relating to proprietary medicinal prod-
EMA developed a business continuity plan to ucts. EUR-Lex website. https://eur-lex.europa.eu/legal-content/
EN/TXT/?uri=CELEX%3A31965L0065. Accessed 11 March
ensure operational continuity during its physical relo- 2020.
cation and readiness for Brexit. This enabled EMA to 4. Innovation Task Force. EMA website. http://www.ema.europa.
deliver its highest priority activities, temporarily scaling eu/ema/index.jsp?curl=pages/regulation/general/general_con-
back or suspending lower priority activities as required. tent_000334.jsp. Accessed 11 March 2020.
5. Mandate of the EMA Innovation Task Force. EMA website.
The agency is reinitiating its activities in 2020 and is no http://www.ema.europa.eu/docs/en_GB/document_library/
longer under business continuity measures. The agency Other/2009/10/WC500004912.pdf. Accessed 11 March 2020.
is still in the process of rebuilding its workforce after its 6. Op cit 1.
relocation. It will continue to monitor staff levels and 7. What we do. EMA website. http://www.ema.europa.eu/ema/
index.jsp?curl=pages/about_us/general/general_content_000091.
review and relaunch additional activities as appropriate. jsp. Accessed 11 March 2020.
In preparation for Brexit, the EU 27 Member 8. Essential Medicines and Health Products Information Portal.
States and EMA redistributed the UK’s portfolio of WHO website. http://apps.who.int/medicinedocs/en/d/
medicines to other EU Member States. This involve Js22187en/. Accessed 11 March 2020.
9. Committee for Medicinal Products for Human Use (CHMP).
transferring over 370 centrally authorised products to EMA website. http://www.ema.europa.eu/ema/index.
rapporteurs and co-rapporteurs from the 27 Member jsp?curl=pages/about_us/general/general_content_000094.jsp.
States plus Iceland and Norway. In September 2018, Accessed 11 March 2020.
the new (co)-rapporteurs received a knowledge transfer 10. PRIME—Priority Medicines. EMA website. http://www.ema.
europa.eu/ema/index.jsp?curl=pages/regulation/general/gen-
package for each product. This contained background eral_content_000660.jsp. Accessed 11 March 2020.
on the regulatory and evaluation history of each prod- 11. PRIME—Priority Medicines: Paving the way for Promising
uct, including the most recent benefit-risk assessment. Medicines for Patients. EMA website. http://www.ema.
The new rapporteurs and co-rapporteurs have been fully europa.eu/docs/en_GB/document_library/Leaflet/2016/03/
WC500202670.pdf. Accessed 11 March 2020.
responsible for these medicines since 1 July 2019. 12. Commission Expert Group on Safe and Timely Access
Answers to potential questions on the supply of to Medicines for Patients (STAMP). EC website. https://
medicines in the EU in the context of Brexit are avail- ec.europa.eu/health/documents/pharmaceutical-committee/
able in a question and answer document published on stamp_en. Accessed 11 March 2020.
13. The Scientific Advice Working Party (SAWP). EMA website.
26 March 2019, last updated on 2 April 2020, entitled http://www.ema.europa.eu/ema/index.jsp?curl=pages/contacts/
“European Authorities Working to Avoid Shortages of CHMP/people_listing_000022.jsp. Accessed 11 March 2020.
Medicines due to Brexit: Questions and Answers.”41 14. Paediatric Regulation. EMA website. http://www.ema.europa.eu/
ema/index.jsp?curl=pages/regulation/document_listing/docu-
ment_listing_000068.jsp. Accessed 11 March 2020.
Conclusion 15. Advanced Therapy Medicinal Products: Overview. EMA web-
Since its inception, EMA has evolved and proven site. http://www.ema.europa.eu/ema/index.jsp?curl=pages/
successful in protecting human and animal health by regulation/general/general_content_000294.jsp. Accessed 11
March 2020.
assessing medicines to rigorous scientific standards 16. Rajeev KB, Lodewijk B, Michael CG and Simon I. (2014). Rare
and by providing stakeholders with independent, Diseases in the age of Health 2.0, Springer Science and Business
science-based information on medicines. They have Media, pp. 4–7.
cooperated nationally and internationally.42 The 17. EudraLex—EU Legislation. EC website. https://ec.europa.eu/
health/documents/eudralex_en. Accessed 11 March 2020.
centralised review goal has been achieved with the har- 18. Op cit 4.
monised work being done among the regulatory bodies 19. Op cit 5.
in Europe. The agency’s primary function is to evaluate 20. Clinical Data Publications. EMA website. http://www.ema.
human and veterinary medicines. The agency also is europa.eu/ema/?curl=pages/special_topics/general/general_con-
tent_000555.jsp. Accessed 11 March 2020.
responsible for products developed in the specialised

Chapter 1
21. Fact Sheets on the European Union. European Parliament web- 33. Paediatric Committee (PDCO). EMA website. http://www.
site. http://www.europarl.europa.eu/atyourservice/en/displayFtu. ema.europa.eu/ema/index.jsp?curl=pages/about_us/general/gen-
html?ftuId=FTU_6.5.3.html. Accessed 11 March 2020. eral_content_000265.jsp. Accessed 11 March 2020.
22. Mutual Recognition Agreements. EMA website. http://www. 34. Coordination Group for Mutual Recognition and Decentralised
ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/ Procedures—Human (CMDh). EMA website. http://www.
general_content_001843.jsp&mid=WC0b01ac058005f8ac. ema.europa.eu/ema/index.jsp?curl=pages/about_us/general/gen-
Accessed 11 March 2020. eral_content_000310.jsp. Accessed 11 March 2020.
23. European and US Regulators Agree on Mutual Recognition 35. Coordination Group for Mutual Recognition and Decentralised
of Inspections of Medicines Manufacturers. EMA web- Procedures—Veterinary (CMDv). EMA website. http://www.
site. http://www.ema.europa.eu/ema/index.jsp?curl=pages/ ema.europa.eu/ema/index.jsp?curl=pages/about_us/general/gen-
news_and_events/news/2017/03/news_detail_002703. eral_content_000311.jsp. Accessed 11 March 2020.
jsp&mid=WC0b01ac058004d5c1. Accessed 11 March 2020. 36. Mutual Reliance Between the United States Food and
24. National Competent Authorities (Human). EMA website. Drug Administration and the European Union on Good-
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medi- Manufacturing-Practice Inspections. EMA website. http://www.
cines/general/general_content_000155.jsp. Accessed 11 March ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/
2020. events/2014/11/event_detail_001071.jsp. Accessed 11 March
25. National Competent Authorities (Veterinary). EMA website. 2020.
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medi- 37. ICMRA Membership Country/Region and Regulatory
cines/general/general_content_000167.jsp. Accessed 11 March Authority’s website. http://www.icmra.info/participating_regu-
2020. latory_authorities.html. Accessed 11 March 2020.
26. European Medicines Agency Organisation Chart ( June 2017). 38. Innovations in Medicine. EMA website. http://www.ema.
EMA website. http://www.ema.europa.eu/docs/en_GB/docu- europa.eu/ema/index.jsp?curl=pages/regulation/general/gen-
ment_library/Other/2009/12/WC500017948.pdf. Accessed 11 eral_content_000334.jsp. Accessed 11 March 2020.
March 2020. 39. Questions and Answers Related to the United Kingdom’s
27. Op cit 9. Withdrawal From The European Union With Regard to the
28. Pharmacovigilance Risk Assessment Committee (PRAC). Medicinal Products for Human and Veterinary use Within
EMA website. http://www.ema.europa.eu/ema/index. the Framework of the Centralised Procedure. EMA website.
jsp?curl=pages/about_us/general/general_content_000537.jsp. http://www.ema.europa.eu/docs/en_GB/document_library/
Accessed 11 March 2020. Other/2017/05/WC500228739.pdf. Accessed 11 March 2020.
29. Committee for Medicinal Products for Veterinary Use 40. Notice to Marketing Authorisation Holders of Centrally
(CVMP). EMA website. http://www.ema.europa.eu/ema/index. Authorised Medicinal Products for Human and Veterinary use.
jsp?curl=pages/about_us/general/general_content_000262.jsp. EMA website. http://www.ema.europa.eu/docs/en_GB/docu-
Accessed 11 March 2020. ment_library/Other/2017/05/WC500226603.pdf. Accessed 11
30. Committee for Orphan Medicinal Products (COMP). EMA March 2020.
website. http://www.ema.europa.eu/ema/index.jsp?curl=pages/ 41. European Authorities Working to Avoid Shortages of
about_us/general/general_content_000263.jsp. Accessed 11 Medicines due to Brexit: Questions and Answers. EMA
March 2020. website. https://www.ema.europa.eu/en/documents/other/
31. Committee on Herbal Medicinal Products (HMPC). EMA european-authorities-working-avoid-shortages-medi-
website. http://www.ema.europa.eu/ema/index.jsp?curl=pages/ cines-due-brexit-questions-answers_en.pdf. Accessed 11 March
about_us/general/general_content_000264.jsp. Accessed 11 2020.
March 2020. 42. International Affairs, International Cooperation. EMA website.
32. Committee for Advanced Therapies (CAT). EMA website. http://www.ema.europa.eu/docs/en_GB/document_library/
http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/ Leaflet/2015/05/WC500186919.pdf. Accessed 11 March 2020.
general/general_content_000266.jsp. Accessed 11 March 2020.

Chapter 2
History of Regulations
OBJECTIVES □ Council Directive 93/42/EEC of 14 June 1993

concerning medical devices
□ Learn why and when regulations for medicinal
products and medical devices were established □ Council Directive 98/79/EEC of 27 October 1998
in the European Union (EU) on in vitro diagnostic medical devices
□ Discover key historic developments influencing □ Directive 2007/47/EC of the European

today’s EU healthcare regulations Parliament and Council of 5 September 2007
amending Council Directive 90/385/EEC on
□ Understand the major EU regulations governing the approximation of laws of Member States
medicinal products, medical devices and in relating to active implantable medical devices
vitro diagnostics Council Directive 93/42/EEC concerning med-
ical devices and Directive 98/8/EC concerning
DIRECTIVES, REGULATIONS AND GUIDELINES placing biocidal products on the market
COVERED IN THIS CHAPTER
□ Regulation 1394/2007/EC of the European
□ Council Directive 65/65/EEC of 26 January 1965 Parliament and Council of 13 November 2007
on the approximation of provisions laid down by on advanced therapy medicinal products and
law, regulation or administrative action relating amending Directive 2001/83/EC and Regulation
to medicinal products, the first European medic- (EC) No. 724/2004
inal product Directive
□ Directive 2001/83/EC of the European Introduction

Parliament and of the Council of 6 November Every regulatory system’s history reflects circumstances
2001 on the Community code relating to medici- providing insight into legislators’ goals and intentions.
nal products for human use Compared to the US, where the first federal law on
medicines dates back to 1906,1 European medical
products regulation lagged behind and was not intro-
duced until the advent of the European Economic
Union (EEU) in 1957. The basic concept of the EEU,
constituted by the Treaty of Rome,2 was to create a
single European market, in which people, products
and services could move freely across national bor-
□ Council Directive 90/385/EEC on the approxima- ders. The EEU was renamed the European Union
tion of laws of Member States relating to active (EU) in 1992, reflecting the fact that it no longer was
implantable medical devices a purely economic union, but also a political one. The
EU evolved over the years as the treaty’s scope was

Chapter 2
extended and, consequently, the areas where national and effective products and treatments, without neces-
laws were replaced by EU laws increased as well. The sarily considering cost implications. Industry prefers a
number of Member States has grown from six in 1957 regulatory system enabling an “approved once, accepted
to 28 in 2017. In addition, EU laws also are applica- everywhere” approach to reduce the time and cost of
ble in Norway, Iceland, Liechtenstein (as Members multiple registrations under heterogeneous national
of the European Economic Area) and in Switzerland requirements, i.e., if a country approves a product on
(Member of the European Free Trade Association). the basis of its regulatory system, other countries should
In June 2016, UK citizens voted by referendum in accept the product without further testing or applica-
favour of terminating the UK’s EU membership; there- tion review.
fore, after completion of the so-called Brexit procedure This chapter simplifies the complex subject of EU
on 31 January 2020, the UK no longer is part of the EU. medical product regulations. After briefly describing the
During the transition phase, expected to last until 31 history and background of EU healthcare regulations, it
December 2020, there will be negotiations on what the summarises those governing today’s medicinal product
relationship between the UK and EU will exactly look and medical device industry.
like. In this transition phase, EU laws are still applicable
in the UK. EU Legislation
Currently, the EU’s population is the world’s third The basic piece of EU legislation is the EU Treaty,
largest after China and India, making EU laws applica- which is the constitution of the EU. The treaty is ‘pri-
ble to more than 500 million European citizens.3 mary legislation.’
A prerequisite for a single market is harmonised Directives and regulations are ‘secondary legisla-
legislation, because requirements on all sides of the bor- tion.’ A directive obliges Member States to implement
der need to be the same. The harmonisation of various its provisions into national laws. A regulation is directly
national laws into European legislation took decades. applicable in all Member States and obliges Member
European legislation has to be proportional, meaning States to remove any conflicting provisions from their
its implications have to be within the scope of the EU national legislation. Other forms of secondary legisla-
Treaty. National laws can never contradict EU legislation are decisions (binding on Member States or legal
tion. Countries wishing to become EU Member States entities, e.g., legal persons or companies), opinions and
must accept the ‘acquis,’ or all EU regulations. Their recommendations.
national laws must be in accordance with the acquis, In addition, there are notes of guidance in the
and any conflicting laws removed, before they can be pharmaceutical area and medical device guidance
accepted as new Member States. Such a process can documents (MEDDEVs) in the medical device and
take years. Currently, there are five candidate Member in vitro diagnostic area. These non-binding consensus
States (Albania, the former Yugoslav Republic of documents interpret and explain the legal texts, with the
Macedonia, Montenegro, Serbia and Turkey). purpose of helping manufacturers and other stakehold-
In general, product market access is regulated on ers fulfil their regulatory obligations.
the EU level, so a product has to meet EU require- Another category of regulatory documents is
ments. This also applies to medical products. For harmonised standards for medical devices and in vitro
medicinal products, this implies approval of the diagnostics. Harmonised standards are part of the “New
Marketing Authorisation Application (MAA) by Approach” legislative system and have a special legal
one national authority (national procedure), one status, as adherence to them provides a presumption of
national authority in conjunction with others (Mutual conformity with the directives’ requirements.
Recognition Procedure) or the European Medicines The EU Treaty has been updated several times. The
Agency (Centralised Procedure). For medical devices 1993 Maastricht Treaty brought public health into the
and in vitro diagnostics, the manufacturer has to EU’s competence areas.
perform conformity assessment of its product and, The European Commission’s mission was extended
subsequently, CE-Mark it. For higher risk classes, a to ensure a high protection level for consumers’ health,
notified body certificate is an obligatory part of the con- safety and economic interests, as well as public health.
formity assessment process.
Today, the single EU market has to meet the Historic Factors in the Development of
various interests of healthcare providers, industry and
consumers, although these stakeholders’ viewpoints Medical Product Regulations
may differ significantly. Providers and reimbursement Healthcare regulations have their beginnings in ethics.
bodies focus on minimising healthcare costs, whereas Originally, their main objective was to protect individ-
consumers demand easy access to a broad range of safe uals from unethical and unsafe human trials. The first

European healthcare regulations concerned ethical blood, leading to a major public scandal. A former
treatment of human subjects. health minister responsible for the National Blood
After World War II, the Allied Forces organised Transfusion Centre was convicted for failing to screen
a series of military tribunals in Nuremberg, Germany blood adequately, leading to five deaths from AIDS and
to prosecute prominent Nazi leaders who had partic- the contamination of two individuals. Two other gov-
ipated in the Holocaust and other war crimes. These ernment officials were sent to prison for continuing to
trials, known as the “Nuremberg Trials,” have had a allow old, unheated blood products to be used in 1985,
great influence on the development of international when a heated product was available. Allegedly, all
war law. The Nuremberg Trials also included the three politicians delayed the introduction in France of
“Doctors’ Trials,” in which Nazi physicians, who had a blood-screening test, produced in the US, until a rival
performed atrocious medical experiments on prisoners French test was ready to be sold on the market.
in concentration camps, were prosecuted. As a result, Awareness of potential Bovine Spongiform
a set of research ethics principles for human medical Encephalopathy (BSE or “mad cow disease”) transmis-
experiments, the Nuremberg Code, was drafted in 1947.4 sion and Transmissible Spongiform Encephalopathy
The Helsinki Declaration of 1964 further developed (TSE) to humans during the 1990s led to heightened
the Nuremburg Code’s principles, and tied them to legislative activity to regulate medicinal products and
the Declaration of Geneva (1948), an internationally medical devices containing bovine-derived materials. In
acknowledged statement of physicians’ ethical responsi- the early 1990s, BSE cases were reported in the UK, as
bilities. The Helsinki Declaration evolved over the years. were a growing number of new forms of Creutzfeldt-
Although not formal law, the Helsinki Declaration Jakob Disease (CJD), the human equivalent of TSE.
has influenced national laws on clinical research Suspicions that these cases were associated with con-
throughout the world deeply, including Europe, and suming BSE-infected beef led to dramatic export
continues to do so. restrictions on British beef, resulting in a significant
Subsequently, laws were drafted to regulate which economic impact on British farmers. The crisis led to
products could be placed on the market and the claims amended medicinal product and medical device reg-
manufacturers could make about them. Today, medi- ulations because many products contain constituents
cal product regulations target not only ethical, safety, derived from bovine material (e.g., lactose, gelatine and
efficacy and performance concerns, but also economic magnesium stearate).
issues, increased availability of information, continuing A more recent example is the PIP-case, where a
technological and product innovations, market structure fraudulent French manufacturer used cheaper indus-
changes and consumer protection. trial-grade silicon oil in breast implants instead of the
required medical grade, resulting in a high number of
Consequences of Unsafe Products post-implantation side effects and subsequent removal
Certain safety incidents have been catalysts for medical of the implants for thousands of European women. This
product regulations. The thalidomide scandal in Europe PIP-case became publicly known in 2010 and profoundly
and Canada was a milestone in the development of influenced the outcome of the legislative process, leading
pharmaceutical product regulations. to Regulation (EU) 2017/745 of the European Parliament
In the late 1950s, the German pharmaceutical and of the Council of 5 April 2017 on medical devices,
company Grünenthal launched Contergan, a sedative amending Directive 2001/83/EC, Regulation (EC) No.
containing thalidomide, used to treat morning sickness. 178/2002 and Regulation (EC) No. 1223/2009 and
Contergan was advertised by the company as “atoxic,” repealing Council Directives 90/385/EEC and 93/42/
“without danger” and “non-poisonous.” EEC (EU MDR)5 and Regulation (EU) 2017/746 of
Soon after the product was introduced, thousands the European Parliament and of the Council of 5 April
of babies were born with malformations, particularly 2017 on in vitro diagnostic medical devices and repealing
to their limbs. These typical deformities soon were Directive 98/79/EC and Commission Decision 2010/227/
associated with thalidomide. In 1961, Contergan sales EU (EU IVDR).6 EU MDR was planned to become
peaked at DM 1.3 million per day. The scandal broke applicable in May 2020, but this was postponed until May
in 1961–62, when the link to Contergan officially was 2021 because of the COVID-19 pandemic and EU IVDR
established. At the time, no premarket reproductive will become applicable in May 2022. See Chapter 13 for
toxicity testing was required by law, so new medicinal more information on these new regulations.
products’ teratogenic potential was unknown prior to
Marketing Authorisation (MA). Product Innovation
In the mid-1980s in France, thousands of hae- Tremendous technological advances have made many
mophiliacs received transfusions of HIV-infected novel therapies available. New developments in biologics,

Chapter 2
blood products, tissue engineering, nanotechnology, 3D website. Today, agendas, meeting minutes and high-
printing, in vitro diagnostics for new biomarkers, medical lights are published.10
apps and Artificial Intelligence (AI) did not exist when For medical devices, the EU MDR and the EU
the applicable regulatory system was designed. IVDR, both published in 2017, included several provi-
For example, the introduction of medicinal sions that will enhance transparency. Parts of the new
products based on recombinant products led to imple- EU database, Eudamed, will be publicly accessible. For
mentation of the Concertation Procedure in 1987, in certain high-risk devices, manufacturers must draft a
which Member States agreed to conduct a common Summary of Safety and Clinical Performance (SSCP).
MAA dossier assessment. This enabled Member States SSCPs need to be drafted in such a way that they will
to collaborate across national borders. This need to share be understandable to the general public.
expertise has driven both regulation development and
regulation harmonisation. Patient Advocacy and Involvement
Innovative product developers may benefit from Regulatory authorities consider safety to be of para-
and exploit the existence of a “regulatory gap,” as some mount importance. The agencies ensure that adequate
novel product areas still lack adequate regulations. On safety data are generated to support authorisation
the other hand, a lack of adequate regulation might and that data are monitored throughout the product’s
lead to uncertainty on which rules to apply and under postmarket lifecycle. They also promptly communicate
which conditions a product under development might any safety profile changes to the public when concerns
be allowed on the market. This might hamper or delay arise—all while ensuring products are available to
the market entry of innovative products for which there patients in a timely manner.
could be a clear medical need. Patients’ perceptions of health and healthcare have
changed over time. The economic prosperity of most
Information Availability and Transparency European countries has led to higher expectations of
Triggered by social media and supported by the inter- improved quality of life, improved survival rates and
net, all existing information on medical products is longevity, and a growing demand for not only illness
available almost immediately to virtually everyone. This treatment and prevention, but also improvements in
information overload no longer can be controlled by general well-being.
authorities or industry. For individuals without a med- This demand also drives new regulations.
ical education, it is virtually impossible to distinguish Healthcare professionals who direct healthcare products’
between reliable, trustworthy and accurate information use and these products’ consumers can have divergent
and ‘spam.’ For example, entering the word “Ritalin” interests. Providers focus on reimbursement, whereas
into a common search engine may provide numerous patients want to protect their health by using products
hits, including some from anti-Ritalin activist groups of maximum safety. Healthcare providers are subject
fighting the drug’s use in children with attention deficit to increased oversight by newly empowered patients.
hyperactivity disorder. Patients are increasingly well educated and informed
In view of the extensive and often inaccurate about health and health products and services, and are
material available, maintaining public confidence in not afraid to challenge medical professionals, companies
the healthcare system is crucial. To answer growing and regulatory and enforcement authorities. This all is
societal demands for information and transparency, the enhanced by the internet and social media.
European Medicines Agency (EMA) started publish- Patients’ and patient advocacy groups’ growing
ing European Public Assessment Reports (EPARs) for power and involvement were acknowledged by EMA
each approved pharmaceutical product on its website when it started a formal patients’ working group in
in the late 1990s. EPARs contain detailed information 2003,11 and the agency now cooperates with a wide
on the scientific grounds for approval or rejection of variety of patient organisations.12 Patient involvement
a pharmaceutical product.7. Member States followed in the regulatory process for medical devices is ‘lagging
with National Public Assessment Reports (NPARs) behind’ that for pharmaceuticals. This will change in
for pharmaceuticals approved on a national level. As the near future, as the EU MDR and EU IVDR, respec-
EPARs are quite difficult for the general public to tively, include provisions on patient representation in
understand, EMA decided in the first decade of the regulatory committees.
new century to introduce a public friendly summary.8
The next step on the ‘transparency path’ came in Economic Issues
2001, with the publication of ‘technical reports’ (sum- Although public health protection is the primary driver
maries) of scientific committee9 meetings on EMA’s of healthcare regulation, economic considerations also

began to have an impact in the second half of the 20th health. The risk of detection and prosecution is relatively
century. With the establishment of the first health low compared to other criminal activities, and poten-
insurance systems, the growing availability and number tial financial gains are high. Medical product internet
of healthcare products increased costs for EU Member sales contribute to the problem. The World Health
States due to higher medicinal product consumption. Organisation (WHO) has found more than 50% of
The transfer of healthcare costs from individuals to pri- medicines purchased on internet sites concealing their
vate or public insurance systems necessitated product real addresses are counterfeit.18
pricing policy, confirming limited economic resources “The” example of an attractive medical product for
had to be spent prudently. This was aggravated by sub- falsification and counterfeiting was Viagra (sildenafil)
sequent economic crises. The pressure to limit public in the late 1990s. This male erectile dysfunction product
expenditure led to stringent healthcare cost-cutting was very popular, also outside its medical indication. It
measures in several Member States. was not reimbursed, was quite expensive and because of
Medical products’ market access is controlled by the product’s nature, people were not inclined to buy it
EU regulations, but pricing and reimbursement are in their local pharmacy. So, internet sales were high, and
national responsibilities. This is a sensitive area. a large proportion (up to 77%)19 of the characteristic
The Transparency Directive (Council Directive blue tablets offered on the internet were falsified.
1989/105/EEC),13 adopted in 1989, included minimum The problem of falsification and counterfeit
procedural safeguards ensuring national cost-containment medicines is not limited to ‘lifestyle’ products.20 In
measures regulating the pricing of medicines were trans- 2007–2008, medicinal products for blood-thinning con-
parent and did not restrict the free movement of goods. taining counterfeit heparin reached patients in the US
The research-based pharmaceutical industry often and EU. The US Food and Drug Administration (FDA)
claims that divergent national prices and profit control reported at least 81potentially related deaths. In the EU,
regulations are a major obstacle for the single market, and only three side effects and no deaths were reported, but
the continued existence of parallel import of pharma- the EU could have been affected equally.21
ceuticals within the EU is a persistent concern for them. Counterfeit medical devices are a problem as well.
Member States are reluctant to surrender their sover- Counterfeit condoms, glucose test strips and insulin
eignty on pricing and profit controls, as this would imply needles have been seized on the EU market.22
that they would put an important part of their national Regulators recognised the importance of fighting
health budgets into the hands of European institutions. these criminal activities in the interest of public health.
Attempts to harmonise price control legislation at In 2011, the Council of Europe issued the
the European level were not successful, despite major Medicrime convention.23 This international convention
efforts for informal consensus-building, such as the makes any contribution to falsified medical products a
G10 Medicines Group (2002)14 and the High-Level criminal offence and provides a framework for national
Pharmaceutical Forum (2005–08).15 and international cooperation. Medicrime entered into
The Commission’s legal proposal to update and mod- force in 2016 in those jurisdictions that have signed it.
ernize the Transparency Directive, published in 2012 and In 2013, the new Directive 2011/62/EU of the
amended in 2013,16 was withdrawn in early 2015, because European Parliament and of the Council of 8 June 2011
European legislators (Commission, EU Parliament and amending Directive 2001/83/EC on the Community
EU Member States) could not find consensus. code relating to medicinal products for human use, as
However, since then, several initiatives enhancing regards the prevention of the entry into the legal supply
cross-country collaboration on pharmaceutical pricing chain of falsified medicinal products (also called the
have been developed, such as the BeNeLuxA Initiative. Falsified Medicines Directive or FMD)24 was introduced.
In BeNeLuxA, five Member States (Belgium, the New measures included an obligatory authenticity fea-
Netherlands, Luxemburg, Austria and Ireland) collab- ture on outer packaging; a common, EU-wide logo to
orate through sharing of information and experiences identify legal online pharmacies; tougher rules on con-
on past, current or expected reimbursement procedures, trols and inspections of active pharmaceutical ingredient
because collaboration on price negotiations on specific manufacturers; and strengthened recordkeeping require-
pharmaceuticals will improve their strategic position ments for wholesale distributors. (See also Chapter 11.)
toward the industry.17
Evolution of Current Regulations
Falsification and Counterfeiting Product Legislation in the EU
The increasing economic value of medical products has As explained in this chapter’s introductory paragraph,
made them attractive targets for falsification and coun- the EU’s basic goal was to create a single European
terfeiting, which represents a growing threat to public market. Harmonised product legislation is a prerequisite

Chapter 2
to achieve this single market. Harmonised product Contergan catastrophe was the driving force for the
legislation implies harmonisation of technical specifica- first European Medicinal Product Directive, Council
tions. There are two mechanisms to achieve this: Directive 65/65/EEC of 26 January 1965 on the
• The “Traditional Approach”—This approach approximation of provisions laid down by law, regu-
has been followed since the beginning of the lation or administrative action relating to medicinal
EU. It implies the inclusion of detailed techni- products.25 For the first time, detailed MA require-
cal specifications in the law. This often results ments for medicinal products for human use were
in highly detailed, inflexible and very extensive described and applied across the European Economic
legislation. Examples of this approach are cars, Community. Directive 65/65/EEC reflected many of
foodstuffs and pharmaceutical products. the requirements already established by FDA. In the
• The “New Approach”—In the 1980s, EU decades following the enactment of Directive 65/65/
legislators realised continuing the Traditional EEC, the EU adopted a highly sophisticated and
Approach could result in a substantial and detailed system of legal provisions dealing with medici-
increasing regulatory burden for EU indus- nal products.
try, which could have a negative impact on By the 1970s, Directive 65/65/EEC had been
industries’ competitiveness. This idea was implemented into the national laws of all Member
enhanced in the 1980s by some influential States, replacing the former national laws on medi-
Member States with political leaders from the cines’ registration and, thus, led to harmonisation of
right wing of the political spectrum (e.g., UK’s requirements across Europe. But differences between
Margaret Thatcher, Germany’s Helmut Kohl). the national implementations still existed. In addition,
manufacturers needed to request registration in each
An innovative regulatory technique was devel- Member State separately.
oped, which was called “New Approach to Product Council Directive 75/318/EEC of 20 May 1975
Legislation.” The basic concept of this New Approach on the approximation of the laws of Member States
is including Essential Requirements for safety and relating to analytical, pharmacotoxicological and clinical
performance in the core legal text and publishing the standards and protocols in respect of the testing of pro-
technical specifications in harmonised standards. Broad prietary medicinal products defined legal requirements
spectrum industrial products (pressure vessels, lifts, relating to MAAs for analytical, pharmaco-toxicological
toys, low voltage equipment, radio and telecommuni- and clinical documentation.
cation equipment, etc.) were regulated via this “New In 1991, Commission Directive 91/356/EEC of 13
Approach” principle, including medical devices. June 1991 laying down the principles and guidelines of
The New Approach product legislation is con- good manufacturing practice for medicinal products for
sidered to have contributed significantly to the human use described GMP principles, which Member
development and success of the EU single market. In States incorporated into their regulations over the next
the 1990s, the New Approach was refined and renamed 10 years.
“Global Approach,” but its principles were maintained. Subsequent directives were introduced on pre-
scription status (Council Directive 92/26/EEC of 31
Medical Product Legislation March 1992 concerning the classification for the supply
The goal of product legislation is to protect European of medicinal products for human use) and labelling
citizens against product risks. This maximum safety and package leaflets (Council Directive 92/27/EEC of
principle cannot be applied to medical products, 31 March 1992 on the labelling of medicinal products
because most medical products have inherent risks. for human use and on package leaflets). For the latter,
Citizens and governments accept this as long as these the national transition periods were rather long, e.g.,
risks are outweighed by medical benefits. A positive package leaflets were not mandatory in the UK and
balance between benefit and risk is a condition to be Denmark before 1995.
fulfilled before medical products can enter the market The next directive was on advertising (Directive
and European citizens are exposed to them. Both phar- 92/28/EEC). Advertising for prescription medication
maceutical and medical device regulations are based on was limited to physicians only. Advertising to the gen-
this ‘positive balance between benefit and risk’ principle. eral public was prohibited.
Medicinal Products for Human Use Centralisation of Market Access Authorisation

Early Development of Requirements Procedures
The first regulations governing medicinal products for In 1995, pursuant to Council Regulation (EEC) No.
human use were introduced in the early 1960s. The 2309/93 of 22 July 1993 laying down Community

procedures for the authorization and supervision of two mechanisms: the National Procedure and the
medicinal products for human and veterinary use and Decentralised or Mutual Recognition procedure.
establishing a European Agency for the Evaluation of An MA through the National Procedure is possible
Medicinal Products, the EU implemented a pan-Eu- only for medicinal products not qualified for centralised
ropean registration system known as the “Centralised approval and intended for marketing in only one EU
Procedure” and established the European Medicines Member State. If these conditions apply, require-
Evaluation Agency (EMEA) in London. Scientific ments, review procedures and timelines are governed
opinions on MAAs were entrusted to EMEA’s scien- by the individual Member State’s registration process.
tific Committee for Proprietary Medicinal Products Reference should be made to the specific country’s
(CPMP). Each Member State delegated two scientific agency website for further information.
experts as CPMP members. The preparatory work for If the intent is to market the product in more than
market access decisions still was done by the Member one Member State, the manufacturer should apply for
States. For each MAA, CPMP appointed one of its the Mutual Recognition or Decentralised Procedure.
members as rapporteur and one as co-rapporteur. The In essence, in both procedures, the MAA will be
rapporteur and co-rapporteur each made a draft scien- evaluated by one Member State (Reference Member
tific evaluation report on the MAA, and those reports State or RMS), chosen by the manufacturer, with sub-
were discussed in the plenary CPMP meetings. CPMP sequent recognition of the evaluation of the RMS by
formulated an opinion and, subsequently, CPMP draft other Member States (Concerned Member States).
opinions were converted into Commission decisions The company also chooses Concerned Member States,
in a dedicated legal procedure. A positive Commission depending on its wish to sell the product. Concerned
decision entitled a manufacturer to bring its product Member States are asked to “mutually recognise” the
onto the market in all EU Member States. This system Reference Member State’s approval. If the approval is
enabled a single medicinal product MA for the entire recognised, an MA will be granted in all the Concerned
EU. In those early days, the Centralised Procedure was Member States.
obligatory for recombinant DNA products, gene ther- The Decentralised Procedure applies if the appli-
apy and monoclonal antibodies, and was voluntary for cant seeks simultaneous authorisation in more than
innovative or therapeutically important products. one Member State. The Mutual Recognition Procedure
In 2004, Regulation (EEC) No. 2309/93 was applies if the applicant already has an MA in one EU
superseded by Regulation (EC) No. 726/2004 of the Member State.
European Parliament and of the Council of 31 March In 2004, all three procedures were revised by the
2004 laying down Community procedures for the adoption of Directive 2004/27/EC of the European
authorisation and supervision of medicinal products for Parliament and of the Council of 31 March 2004
human and veterinary use and establishing a European amending Directive 2001/83/EC on the Community
Medicines Agency, which aimed to improve the code relating to medicinal products for human use.
authorisation procedure, amending certain administra-
tive aspects. Further, the name of the European Agency Codification and Clarification of all Existing
for the Evaluation of Medicinal Products was changed Pharmaceutical Directives
to European Medicines Agency, while retaining the In 2001, Directive 2001/83/EEC of the European
acronym EMEA. The acronym was shortened to EMA Parliament and of the Council of 6 November 2001 on
in 2010. The option of submitting an MAA through the Community code relating to medicinal products for
the Centralised Procedure also was made available for human use was adopted. Directive 2001/83/EEC was
biotechnology-derived products and other products an act of codification, as the contents of all previous
considered highly innovative. Moreover, this regulation directives were fully preserved, and amendments were
expanded application of the Centralised Procedure to made only as far as required by the merger. This super-
orphan drugs (established by Commission Regulation seded all former directives. This huge project simplified
(EC) No. 141/2000 of the European Parliament and the existing directives, unified recommendations that
the Council of 16 December 1999 on orphan medicinal had diverged over time, clarified definitions and terms
products) and products with new active substances to and enabled the repeal of directives no longer neces-
treat acquired immune deficiency syndrome, cancer, sary. This made the regulatory environment clearer for
neurodegenerative disorders, diabetes and, from 20 May authorities and industry.
2008, autoimmune diseases and other immune dysfunc-
tions and viral diseases.
Medicinal products not meeting the Centralised
Procedure criteria may apply for MAs through

Chapter 2
Further Development of the EU Regulatory System to the terms of marketing authorisations for
for Pharmaceuticals medicinal products33 (M8)
After the codification and clarification under Directive • Commission Directive 2009/120/EC of 14
2001/83/EC, the EU system for pharmaceuticals kept September 2009 amending Directive 2001/83/
evolving to keep up with new developments. The direc- EC of the European Parliament and of the
tive has subsequently been amended by: Council on the Community code relating to
• Directive 2002/98/EC of the European medicinal products for human use as regards
Parliament and of the Council of 27 January advanced therapy medicinal products34 (M9)
2003 setting standards of quality and safety for • Directive 2010/84/EU of the European
the collection, testing, processing, storage and Parliament and of the Council of 15 December
distribution of human blood and blood com- 2010, amending, as regards pharmacovigilance,
ponents26 (M1) Directive 2001/83/EC35 (M10)
• Commission Directive 2003/63/EC of 25 June • Directive 2011/62 Directive 2011/62/EU of
2003 amending Directive 2001/83/EC of the the European Parliament and of the Council
European Parliament and of the Council on of 8 June 2011 amending Directive 2001/83/
the Community code relating to medicinal EC on the Community code relating to
products for human use (which established the medicinal products for human use, as regards
analytical, pharmaco-toxicological and clinical the prevention of the entry into the legal
standards and protocols for medicinal product supply chain of falsified medicinal products
testing)27 (M2) (M11)36
• Directive 2004/24/EC of the European • Directive 2012/26/EU of the European
Parliament and of the Council of 31 March Parliament and of the Council of 25 October
2004 amending, as regards traditional herbal 2012, amending Directive 2001/83/EC as
medicinal products, Directive 2001/83/EC28 regards pharmacovigilance37 (M12)
(M3)
• Directive 2004/27/EC of the European As some developments impacted the authorisation
Parliament and of the Council amending system via the Centralised Procedure, regulations
Directive 2001/83/EC on the Community amending Regulation (EC) 726/2004 were adopted,
code relating to medicinal products for human which can be considered the “centralised equivalent” of
use (M4)29 some of the above-mentioned directives.
• Regulation (EC) No. 1901/2006 of the The EU pharma legislation had its ‘golden jubilee’
European Parliament and of the Council of in 2015, as 50 years had been elapsed since Directive
12 December 2006 on medicinal products 65/65 had come into force. On this festive occasion, a
for paediatric use and amending Regulation dedicated part on EU Commission’s website published
(EEC) No. 1768/92, Directive 2001/20/EC, with the highlights of EU pharmaceutical legislation,38
Directive 2001/83/EC and Regulation (EC) including an interactive e-timeline.39 This e-timeline can
No. 726/200430 (M5) be consulted as illustration of the above list of legal texts
• Regulation (EC) No. 1394/2007 of the amending Directive 2001/83.
European Parliament and of the Council of 13
November 2007 on advanced therapy medicinal Variations to Human and Veterinary MAAs
products and amending Directive 2001/83/EC In the early 2000s, the need for handling variations and
and Regulation (EC) No. 726/200431 (M6) extensions to existing MAAs consistently resulted in
• Directive 2008/29/EC of the European drafting a dedicated registration procedure applicable
Parliament and of the Council of 11 March to pharmaceutical products for both human and vet-
2008 amending Directive 2001/83/EC on erinary use. It was based on a classification system of
the Community code relating to medici- minor Type IA and Type IB variations and major Type
nal products for human use, as regards the II variations. An example of a minor Type IA variation
implementing powers conferred on the is a change of the MAA holder’s address. Adding a
Commission32 (M7) new therapeutic indication or modifying an existing
• Directive 2009/53/EC of the European one is an example of a major Type II variation. Also, a
Parliament and of the Council of 18 June number of clearly defined, minor MAA extensions were
2009 amending Directive 2001/82/EC and addressed in this procedure’s scope. The procedure and
Directive 2001/83/EC as regards variations classification were laid down in Commission Regulation
(EC) No. 1084/2003 of 3 June 2003 concerning the

examination of variations to the terms of marketing subject to the above codification process and were inte-
authorisation for medicinal products for human use and grated into Directive 2001/83/EC.
veterinary medicinal products granted by a competent Directive 2001/18/EC of the European Parliament
authority of a member state for those registered via and of the Council of 12 March 2001 on the deliberate
national authorities, and in Commission Regulation release into the environment of genetically modified
(EC) No. 1085/2003 of 3 June 2003 concerning the organisms and repealing Council Directive 90/220/
examination of variations to the terms of a marketing EEC—Commission Declaration regulates the use of
authorisation for medicinal products for human use and genetically modified organisms (GMOs) and their
veterinary medicinal products falling within the scope deliberate release into the environment and replaced
of Council Regulation (EEC) 2309/93 for those regis- Council Directives 90/219/EEC and 90/220/EEC.
tered via EMEA. This directive was amended by Regulation (EC) No.
In 2008, both Variations Regulations were 1830/2003 of the European Parliament and of the
combined into Commission Regulation (EC) No. Council of 22 September 2003 concerning the trace-
1234/2008 of 24 November 2008 concerning the ability and labelling of genetically modified organisms
examination of variations to the terms of marketing and the traceability of food and feed products produced
authorisations for medicinal products for human use from genetically modified organisms and amending
and veterinary medicinal products.40 This Regulation Directive 2001/18/EC, establishing a clear EU system
was supplemented by a Commission Communication for tracking and labelling of GMOs.
with an extensive list of detailed variation subtypes and Biological medicinal product safety was increased
the required data and documentation to be submitted by Commission Directive 2003/63/EC of 25 June 2003
for each subtype.41 amending Directive 2001/83/EC of the European
However, most medicinal products for human or Parliament and of the Council on the Community code
veterinary use on the market had been authorised under relating to medicinal products for human use, amend-
purely national procedures and, as such, fell outside the ing Annex I of Directive 2001/83. Directive 2001/83
scope of the aforementioned Variations Regulations. This Annex I Part III now includes special requirements for
was corrected by Directive 2009/53/EC of the European biological pharmaceuticals. It established a new system
Parliament and of the Council of 18 June 2009 amend- to simplify approval and subsequent change proce-
ing Directive 2001/82/EC and Directive 2001/83/EC, dures for human plasma-derived medicinal products.
as regards variations to the terms for marketing authori- Moreover, it introduced a Vaccine Antigen Master File
sations for medicinal products,42 bringing variations to (VAMF), which allows the pooling of national expertise
marketing authorisations granted under national proce- and, through EMA coordination, a single evaluation of
dures under the scope of the Variations Regulations. the concerned vaccine antigen.
CHMP has established a dedicated working party,
Biological Medicinal Products the Biologics Working Party (BWP), providing rec-
Medicinal products of biological origin cover a diverse ommendations to EMA’s scientific committees on all
field and often result from innovative scientific or matters relating directly or indirectly to biological and
technical developments. They include vaccines, blood biotechnological medicines’ quality and safety aspects.
derivatives, allergens, somatic cells, gene therapies, tis- Several relevant BWP guidance documents can be
sues and recombinant therapeutic proteins. found on EMA’s website.44
In 1989, Council Directive 89/342/EEC of 3
May 1989 extending the scope of Directives 65/65/ Advanced Therapy Medicinal Products
EEC and 75/319/EEC and laying down additional (ATMPs)
provisions for immunological medicinal products con- In the mid-1990s, regulators began debating the best
sisting of vaccines, toxins or serums and allergens43 way to regulate so-called tissue engineered products on
defined requirements for those immunological prod- a European level. At that time, these products were reg-
ucts. A counterpoint to this directive was Council ulated by a spectrum of national regulations, with large
Directive 89/381/EEC of 14 June 1989 extending the variations in levels of scrutiny. A harmonized regulatory
scope of Directives 65/65/EEC and 75/319/EEC on approach for these complex and technologically sophis-
the approximation of provisions laid down by Law, ticated products was preferred.
Regulation or Administrative Action relating to pro- Different options were discussed, such as a dedi-
prietary medicinal products and laying down special cated ‘stand-alone’ regulation or expanding the scope of
provisions for medicinal products derived from human one of the existing medical product regimens to include
blood or human plasma. Both of these directives were

Chapter 2
these products, with pharmaceuticals, medical devices established. The legislation of veterinary medicines is
and human tissues and cells as obvious candidates. well developed and complex. Since consumer protection
Eventually the idea of a ‘stand-alone’ regulation from residue limits from pharmacologically active sub-
was abolished, and these products were, jointly with stances used in food-producing animals also needs to
the gene and cell therapy products, brought into the be ensured, veterinary medicines’ regulation essentially
scope of pharmaceutical regulation under the name addresses two areas: 1) veterinary medicines’ quality,
ATMPs, by means of Regulation (EC) No. 1394/2007 safety and efficacy, which largely mirror the require-
of the European Parliament and of the Council of ments for human medicines and 2) safety of residues
13 November 2007 on advanced therapy medicinal in treated animals’ foodstuffs, which was developed
products and amending Directive 2001/83/EC and according to Codex Alimentarius principles.
Regulation (EC) No. 726/2004.45 For almost 20 years, veterinary medicinal products
See Chapter 35 for more information on ATMPs.46 in the EU were regulated under Council Directive
81/851/EEC of 28 September 1981 on the approxi-
Biosimilars mation of the laws of the Member States relating to
The discussion on biosimilars’ approval and their ther- veterinary medicinal products and Council Directive
apeutic interchangeability arose in the late 90s, when 81/852/EEC of 28 September 1981 on the approxi-
the first ‘similar’ biological medicinal products were mation of the laws of the Member States relating to
developed. Directive 2004/27/EC of the European analytical, pharmacotoxicological and clinical standards
Parliament and of the Council amending Directive and protocols in respect of the testing of veterinary
2001/83/EC on the Community code relating to medicinal products.
medicinal products for human use47 introduced a new, In 1990, Council Regulation (EEC) No. 2377/90
dedicated article into Directive 2001/83 (art 10(4)) in of 26 June 1990 laying down a Community procedure
which additional requirements for an MAA based on for the establishment of maximum residue limits of
demonstration of similarity of two biological medical veterinary medicinal products in foodstuffs of animal
products were stipulated. origin entered into force, introducing the concept of
A period of intense debate followed, where man- maximum residue limits, later replaced by Regulation
ufacturers of the original biological medicinal products (EC) No. 470/2009 of the European Parliament and of
argued that the ‘uniqueness’ of their product could not the Council of 6 May 2009 laying down Community
allow similarity of other biological products to their procedures for the establishment of residue limits of
product. Regulators were concerned about the safety pharmacologically active substances in foodstuffs of
and efficacy of biosimilars, and healthcare insurers animal origin, repealing Council Regulation (EEC)
and payers were quite interested in the huge financial No. 2377/90 and amending Directive 2001/82/EC
advantages, as biologicals are by far the most expensive of the European Parliament and of the Council and
category of pharmaceuticals. Regulation (EC) No. 726/2004 of the European
EMA established a dedicated Biosimilar Medicinal Parliament and of the Council.
Products Working Party (BMWP)48 and issued numer- GMP was introduced by Commission Directive
ous scientific guidelines and other useful documents.49 91/412/EEC of 23 July 1991 laying down the principles
In 2006, the first biosimilar (a recombinant human and guidelines of good manufacturing practice for vet-
growth hormone) was registered. Since then, a constant erinary medicinal products. Directive 81/851/EEC and
stream of biosimilars has found its way to patients in Directive 81/852/EEC were supplemented by Regulation
the EU. (EEC) No. 2309/93 of 22 July 1993 laying down
The current requirements for an MAA for biosimi- Community procedures for the authorization and super-
lars are extensively discussed in Chapter 3. vision of medicinal products for human and veterinary use
and establishing a European Agency for the Evaluation of
Veterinary Medicinal Products Medicinal Products, which centralised Community proce-
The basic regulatory principles applied to human prod- dures for both human and veterinary medicines.
ucts also govern veterinary medicinal products. The In the late 1990s, codification of the existing vet-
European legal framework for veterinary medicinal erinary medicinal product regulation was conducted in
products started in 1965 with the adoption of Directive parallel with the codification of the human pharmaceu-
65/65/EEC, which required marketing authorisations tical regulations. Directive 81/851/EEC and Directive
to be issued before such products could be placed on 81/852/EEC were merged in the Community code of
the market. Since then, numerous other directives and Directive 2001/82/EC,50 which provided the legal envi-
regulations have been adopted to extend and refine the ronment for veterinary medicinal product authorisation,
rules, and a harmonised framework gradually has been manufacturing, marketing, distribution and use.

In 2004, a major framework revision was con- Traditional Herbal Medicinal Products
ducted by Regulation (EC) No. 726/2004 and Directive In 2004, Directive 2004/24/EC amended Directive
2004/28/EC of the European Parliament and of 2001/83/EC on traditional herbal medicinal products.
the Council of 31 March 2004 amending Directive Given the particular characteristics of these prod-
2001/82/EC on the Community code relating to veteri- ucts—especially their long tradition—the European
nary medicinal products.51 Commission established a special, simplified application
Commission Directive 2006/130/EC52 of 11 procedure for them. When this simplified procedure
December 2006 implementing Directive 2001/82/ was proposed, there was much resistance among phar-
EC of the European Parliament and of the Council as maceutical regulators, who did not consider these
regards the establishment of criteria for exempting cer- herbals ‘real’ medicinal products. Eventually, a compro-
tain veterinary medicinal products for food-producing mise was reached.
animals from the requirement of a veterinary prescrip- A dedicated scientific committee, the Herbal
tion amended Directive 2001/82/EC. Medicinal Product Committee (HMPC), was
Commission Directive 2009/9/EC of 10 February established within EMA. HMPC is responsible for
200953 amended Directive 2001/82/EC. It was introduced reviewing registry documents and providing scientific
primarily to simplify procedures for veterinary vaccines, opinions on traditional herbal medicines.
both for granting a first MA and subsequent changes due
to modifications to the manufacturing process and testing Medical Devices
of individual antigens involved in combined vaccines. A
New Approach
new system based on the concept of a VAMF was intro-
As described in in the Medical Product Legislation
duced for veterinary vaccines involving several antigens
section, medical device regulation in the EU is based on
concurrently with the VAMF for human vaccines (see
the New Approach product legislation.
section on Biological Medicinal Products.)
The New Approach directives describe a fast legis-
Regulation (EC) 1950/200654 of 13 December
lative pathway with defined content and structure. Their
2006 established a list of substances essential for treat-
legal basis is Article 95 of the EU Treaty, which enables
ment of equidae. It is allowed to apply these ‘essential
EU institutions to adopt measures intended to promote
substances’ to equidae in cases where no authorised
the internal market’s establishment and operations.
veterinary medicinal product would yield equally satis-
Products granted market access using the New
factory results.
Approach can be recognised by the Conformité
A last major revision was introduced by Regulation
Européenne (CE) or European conformity mark. CE
(EC) No. 470/2009 of the European Parliament and of
means the product complies with all applicable EU
the Council of 6 May 2009 laying down Community
legislation and can be considered the ‘passport’ to the
procedures for the establishment of residue limits of
EU single market. New Approach directives are har-
pharmacologically active substances in foodstuffs of
monised across the EU; the Member States must repeal
animal origin, repealing Council Regulation (EEC)
all contradictory national legislation and are not allowed
No. 2377/90 and amending Directive 2001/82/EC
to maintain or introduce more-stringent measures than
of the European Parliament and of the Council and
those in the directives. When Member States incorpo-
Regulation (EC) No. 726/2004 of the European
rate the New Approach requirements, they may include
Parliament and of the Council.55
additional provisions considered necessary to apply
In 2010, the European Commission announced the
the requirements more effectively. These harmonised
next revision of the veterinary medicinal product reg-
directives limit public authority intervention and enable
ulatory framework. Major problems in the availability
industry to meet its obligations in a manner suitable to
of registered veterinary medicines were identified by
the specific situation or device without the need for a
different stakeholders, including the Member States.56
cumbersome regulatory approval process. This decreased
A public consultation was issued, and in 2014, the
regulatory burden for both industry and public author-
Commission published a proposal for a new regulation
ities enabled approval processes to advance much more
on veterinary medicinal products. After intense debate
quickly than before.
among EU legislators, in which among others growing
An essential feature of the New Approach is the
concerns on Antimicrobial Resistance (AMR) played
distinction between the Essential Requirements for
a role, early 2019 a new Regulation57 was published,
safety and performance and the technical requirements.
which replaces Directive 2001/82. The new Regulation
The Essential Requirements are included in the legal
enters into force in 2022.
texts (such as in the Annex I of the Medical Devices

Chapter 2
Directive (Council Directive 93/42/EEC of 14 June gives a detailed description of New Approach and
1993 concerning medical devices). Global Approach directives.60 Although the EU
Technical specifications and requirements are Commission published new versions of the Blue Guide
described in standards. Standards are drafted via a in 2014 and 2016,61 the 2000 version still contains valu-
dedicated and complex process called ‘standardisation.’ able information, which is not included in the 2014 and
Standards can be drafted on an international, regional 2016 versions, such as detailed charts for conformity
(European) or national level. In principle, any company assessments under all New Approach directives.
or individual interested in a particular standard is wel-
come to participate in the drafting process. In practice, Harmonised EU Medical Device Regulation
the majority of participants in standardisation processes In contrast with pharmaceuticals, which were regu-
come from industry, but public authorities, academia lated in the mid-1960s by Directive 65/65/EEC, EU
and patients’ representatives also are involved. regulations relating to medical devices’ safety and per-
After a standard has been drafted and approved by formance were harmonised in the 1990s, following the
a recognised standardisation body on the international, New Approach legislative principles. Previously, medical
regional or national level, it has to be ‘harmonised’ devices were regulated only by the (divergent) national
before it can be used in the context of the New regulations of the Member States.
Approach directives. The harmonisation process was The core legal framework consists of three
described in Council Directive 83/189/EEC of 28 directives:
March 1983 laying down a procedure for the provision • Council Directive 90/385/ EEC of 20 June
of information in the field of technical standards and 1990 on the approximation of the laws of the
regulations58 and its ‘successor’ Directive 98/34/EC Member States relating to active implantable
of the European Parliament and of the Council of 22 medical devices (AIMDD)62
June 1998 laying down a procedure for the provision of • Council Directive 93/42/EEC of 14 June 1993
information in the field of technical standards and reg- concerning medical devices (MDD)63
ulations and of rules in information society services.59 • Directive 98/79/EC of the European
Harmonisation comes down to approval of a standard Parliament and of the Council of 27 October
to be suitable to provide ‘presumption of conformity.’ 1998 on in vitro diagnostic medical devices
Presumption of conformity means that if a product ful- (IVDD)64
fils a harmonised standard’s requirements, the product
is presumed by the Member States to be in conformity European legislators in the mid-1980s wanted the
with the Essential Requirements. The Commission regulation harmonisation process to start with medical
publishes updates to the list of harmonised standards in devices with the highest public health risks, e.g., pace-
the Official Journal on a regular basis. For industry, using makers and other active implantable devices. Then a
harmonised standards has proven to be an efficient way series of other categorical medical device directives (e.g.,
to comply with the Essential Requirements and, thus, orthopaedic implants, medical imaging) would follow,
with the New Approach directives. until the whole spectrum of medical devices would be
About 20 New Approach directives were intro- covered. Later, this plan was abolished, as they realised,
duced during the mid-1980s. The New Approach was it would take decades before such a stepwise harmon-
supplemented by the Global Approach, defining the isation process would be completed. It was decided
basis for Conformity Assessment Procedures (CAPs) all medical devices would be covered by one general
within the New Approach directives. The Global medical device directive. It was a major achievement for
Approach did not give conformity assessment details; the early legislators, having regulated such a large and
those were described in the directives themselves. diverse group of products successfully in one directive.
In 2008, the so-called New Legislative Framework More than 100,000 different medical devices were on
(NLF) was adopted. The NLF was a package of legal the market in Europe at that time, and these were regu-
texts and can be considered as an update of the Global lated by 60 pages of legal text.
Approach, especially in the area of market surveillance. Only in vitro diagnostics (IVDs) were covered by a
The Global Approach was updated again by Regulation separate directive, because of their very specific charac-
1025/2012, which entered into force in 2013. This teristics (IVDs are not applied to humans, but to human
Regulation included elaborate descriptions of the roles and specimens).
responsibilities of the actors in the standardisation process. The MDD was introduced in 1993, and its provi-
The guide to the implementation of directives sions became applicable in the Member States in 1998.
based on the New Approach and the Global Approach In line with the New Approach, the manufacturer
from 2000, called the Blue Guide after its blue cover, may choose among the various conformity assessment

procedure routes, which the MDD defined. The device’s period but, in general, stakeholders felt this harmonised
classification determines the routes from which a man- regulatory system functioned effectively.
ufacturer is allowed to choose. The classification rules The MDD (and, if applicable, the AIMDD and
are based on the human body’s vulnerability and take IVDD) was amended by:
into account potential risks associated with the device’s • Directive 2000/70/EC of the European
technical design and manufacture. This classification Parliament and of the Council of 16
system comprises 18 rules and, in principle, each medical November 2000 amending Council Directive
device risk class can be assigned by applying these rules. 93/42/EEC as regards medical devices incor-
There are four risk classes: Class I for low-risk, Class IIa porating stable derivatives of human blood
and Class IIb for medium-risk and Class III for high- or human plasma,65 which brought medical
risk devices. There is a special Annex (Annex VII) on devices incorporating stable human blood
risk classification. Medium- and high-risk class devices derivatives within the MDD’s scope.
require a design and manufacturing inspection by a • Directive 2001/104/EC of the European
notified body. Notified bodies are private organisations Parliament and of the Council of 7 December
with special legal status. They are designated by national 2001 amending Council Directive 93/42/EEC
competent authorities to check manufacturers’ confor- concerning medical devices,66 which clarified
mity assessment procedures and subsequently grant that stable human blood products as such (not
certificates according to the requirements of the applica- incorporated in a device) are not in the MDD’s
ble directive. They are supervised and monitored by the scope.
national competent authority of the Member State in • Commission Directive 2003/12/EC of 3
which they are located. Manufacturers, themselves, can February 2003 on the reclassification of breast
perform conformity assessment procedures for Class I implants in the framework of Directive 93/42/
devices. Class I devices are under the direct supervision EEC concerning medical devices,67 which
of the medical device authority of the Member State in classified breast implants in risk Class III.
which the manufacturer is established. However, Class I • Commission Directive 2005/50/EC of 11
devices sold in a sterile condition or having a measuring August 2005 on the reclassification of hip,
function require notified body involvement. knee and shoulder joint replacements in the
The manufacturer is free to select a notified body framework of Council Directive 93/42/EEC
designated for the applicable directive and must pay the concerning medical devices,68 which up-classi-
notified body a fee for its services. fied hip, knee and shoulder implants from risk
Once a manufacturer has completed a conformity class IIb to risk class III.
assessment procedure as described in the applicable • Commission Regulation (EU) No. 722/2012
directive, and has obtained a notified body certificate, of 8 August 2012 concerning particular
if the device is mid- or high-risk, or is a Class I sterile requirements as regards the requirements laid
device or one with a measuring function, the device down in Council Directives 90/385/EEC and
can be CE marked and placed on the market in all EU 93/42/EEC with respect to active implantable
Member States. medical devices and medical devices manufac-
Some medical devices fall within the scope of other tured utilising tissues of animal origin.69 The
EU regulations, e.g., the Low Voltage Directive and aim was to improve the protection against the
Electromagnetic Compatibility (EMC) Directive for elec- overall risk of transmitting animal spongiform
trical medical equipment and the EURATOM Directive encephalopathies (TSE/BSE).
for ionizing radiation-emitting medical imaging equip- • Commission Regulation (EU) No. 207/2012
ment. For those devices, the relevant requirements of of 9 March 2012 on electronic instructions for
other applicable regulations must be fulfilled before the use of medical devices, which allows instruc-
manufacturer is allowed to include the CE Mark on its tions for use for some medical devices (e.g., for
product and put the product on the EU market. professional use) to be delivered in electronic
format.70
Further Development of the EU Medical Device
Regulatory System All the above legal changes impacted isolated, very
The MDD was introduced in 1993, and its provisions specific MDD sections. The MDD obligated the
had to be implemented fully in 1998. The stakeholders Commission to evaluate its overall functioning and
(Member States, EU institutions, industry, notified bod- effectiveness within five years of its coming into force
ies, etc.) undertook major efforts during the transition and report to the Council. This evaluation exercise
resulted in a proposal for an update to the AIMDD

Chapter 2
and MDD in 2005, leading to adoption of Directive The IVDD includes special provisions for self-test-
2007/47/EC of the European Parliament and Council ing devices (e.g., pregnancy tests), which require
of 5 September 2007 amending Council Directive notified body involvement. Another difference is the
90/385/EEC on the approximation of laws of Member so-called ‘hospital exemption.’ Tests and reagents devel-
States relating to active implantable medical devices, oped in health institutions’ laboratories do not have
Council Directive 93/42/EEC concerning medical to comply with IVDD provisions before being used to
devices and Directive 98/8/EC concerning placing bio- make a medical diagnosis, as long as they are used only
cidal products on the market.71 within the same health institution and are not put on
This directive left the existing framework the market.
untouched; it was a technical revision. The main The most striking difference between the IVDD
changes included bringing software explicitly into the and MDD is the risk classification system. IVDD risk
definition of a medical device, adding obligatory checks classification is not rule-based, like the MDD. IVDD
of representative samples of the Class IIa and Class IIb Annex II includes two lists of diseases and biomarkers:
device design dossiers by notified bodies to the quality list A and list B. If an IVD is included in Annex II, a
system conformity assessment module (MDD Annex notified body’s intervention is required. List A includes
II) and extending clinical evaluation obligations. These reagents for determining blood groups, hepatitis and
provisions came into force in March 2010. For more HIV. List B has a variety of reagents for infectious and
information, see Chapter 14. congenital diseases. Annex II’s content can be consid-
In 2008, the Commission initiated the next revision ered a reflection of healthcare’s state-of-art in the early
by issuing a public consultation. This revision’s timing 1990s. Since it has not been updated since 1998, the
raised some questions. The vast majority of respon- Annex is outdated. Diagnostics for infectious diseases
dents to the public consultation (in particular Member emerging since 1998 (e.g., SARS, avian flu, Ebola,
States and industry) considered this to be premature, MRSA and COVID-19) have not been included in
since the previous revision by Directive 2007/47 still Annex II, so no notified body involvement legally is
was to come into effect in March 2010. Eventually, the required. This will be addressed in the new EU IVDR,
Commission published its proposal for a new Medical a proposal for which the Commission published in
Device Regulation in September 2012. In this proposal, September 2012. This regulation includes a major
the New Approach requirements, including the role of change in the risk classification system, as this evolves
notified bodies in the certification of mid- and high- from a list-based system, as described above, into a rule-
risk devices, were maintained. The subsequent legislative based system with obligatory involvement of a notified
procedure took more than four years and resulted in body in the certification of mid- and high-risk classes.
Regulation (EU) 2017/745 of the European Parliament The legislative process has run in parallel with the legis-
and of the Council of 5 April 2017 on medical devices, lative process for the new EU MDR and resulted in the
amending Directive 2001/83/EC, Regulation (EC) No. EU IVDR.74 For further information, see Chapters 13
178/2002 and Regulation (EC) No. 1223/2009 and and 14.
repealing Council Directives 90/385/EEC and 93/42/
EEC (EU MDR),72 and will become applicable in References
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publication/4f6721ee-8008-4fd7-acf7-9d03448d49e5. Accessed Lex website. https://eur-lex.europa.eu/LexUriServ/LexUriServ.
2 March 2020. do?uri=OJ:L:2012:212:0003:0012:EN:PDF. Accessed 2 March
61. The Blue Guide on the Implementation of EU Product Rules 2020.
(2016). EC website. http://ec.europa.eu/DocsRoom/docu- 70. Commission Regulation (EU) No. 207/2012 of 9 March 2012
ments/18027/. Accessed 2 March 2020. on electronic instructions for use of medical devices. EUR-
62. Council Directive 90/385/EEC of 20 June 1990 on the approx- Lex website. http://eur-lex.europa.eu/legal-content/EN/
imation of the laws of the Member States relating to active TXT/?uri=celex:32012R0207. Accessed 2 March 2020.
implantable medical devices. EUR-Lex website. http://eur-lex. 71. Directive 2007/47/EC of the European Parliament and
europa.eu/legal-content/EN/TXT/?uri=CELEX:31990L0385. of the Council of 5 September 2007 amending Council
Accessed 2 March 2020. Directive 90/385/EEC on the approximation of the laws of
63. Council Directive 93/42/EEC of 14 June 1993 concerning the Member States relating to active implantable medical
medical devices. EUR-Lex website. https://eur-lex.europa. devices, Council Directive 93/42/EEC concerning medical
eu/legal-content/en/ALL/?uri=CELEX%3A31993L0042. devices and Directive 98/8/EC concerning the placing of
Accessed 2 March 2020. biocidal products on the market. EUR-Lex website. http://
64. Directive 98/79/EC of the European Parliament and of the eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=O-
Council of 27 October 1998 on in vitro diagnostic medical J:L:2007:247:0021:0055:en:PDF. Accessed 2 March 2020.
devices. EUR-Lex website. http://www.legislation.gov.uk/ 72. Op cit 5.
eudr/1998/79. Accessed 2 March 2020. 73. Directive 98/79/EC of the European Parliament and of the
65. Directive 2000/70/EC of the European Parliament and Council of 27 October 1998 on in vitro diagnostic medical
of the Council of 16 November 2000 amending Council devices. EUR-Lex website. http://eur-lex.europa.eu/legal-con-
Directive 93/42/EEC as regards medical devices incorpo- tent/EN/TXT/?uri=CELEX:31998L0079. Accessed 2 March
rating stable derivates of human blood or human plasma. 2020.
https://op.europa.eu/en/publication-detail/-/publication/ 74. Op cit 6.

Chapter 2

Chapter 3
Overview of Drug and Biologic

Regulatory Pathways
OBJECTIVES □ Regulation (EC) No. 1901/2006 on medicinal

products for paediatric use
□ Present an overview of regulations and pro-
cesses related to developing and filing a drug □ Regulation (EC) No. 507/2006 of 29 March 2006
and biologic marketing application in the EU on the conditional marketing authorisation for
medicinal products for human use falling within
the scope of Regulation (EC) No. 726/2004 of
DIRECTIVES, REGULATIONS AND GUIDELINES the European Parliament and of the Council
□ Notice to Applicants, Volume 2B: Presentation
□ Directive 2001/83/EC of European Parliament and content of the dossier
and of the Council of 6 November 2001 on the
Community code relating to medicinal products □ Guideline on the scientific application and the
for human use (as amended) practical arrangements necessary to implement
Commission Regulation (EC) No. 507/2006 on
□ Directive 2001/20/EC of the European the conditional marketing authorisation for
Parliament and of the Council of 4 April 2001 medicinal products for human use falling within
the scope of Regulation (EC) No. 726/2004
□ Commission Regulation (EC) No. 1084/2003
concerning the examination of variations to the □ Guideline on procedures for the granting of
terms of a marketing authorisation for medic- a marketing authorisation under exceptional
inal products for human use and veterinary circumstances, pursuant to Article 14 (8) of
medicinal products granted by a competent Regulation (EC) No. 726/2004
authority of a Member State
□ Guideline on the scientific application and the
□ Regulation (EC) No. 726/2004 of the European practical arrangements necessary to imple-
Parliament and of the Council of 31 March 2004 ment the procedure for accelerated assessment
laying down Community procedures for the pursuant to Article 14(9) of Regulation (EC) No.
authorisation and supervision of medicinal 726/2004
establishing a European Medicines Agency □ Guidance for applicants seeking access to
PRIME scheme
Parliament and of the Council of 16 December □ Enhanced early dialogue to facilitate acceler-
1999 on orphan medicinal products ated assessment of PRIority MEdicines (PRIME)
□ Guideline of the investigation of bioequivalence

Chapter 3
Introduction must be authorised before they can be placed on the

The development of a medicinal product and the cho- market. Only entities that demonstrate a favourable
sen regulatory pathway are interrelated. The regulatory benefit-risk profile are considered for market access.
pathway determines the studies that will need to be The Medicinal Product Directive 2001/83/EC
conducted to demonstrate the safety, efficacy and quality forms the legal basis for submission of an MAA and
of the medicinal product and the type of regulatory fil- describes five different types of MAAs:1
ings that need to be submitted to the concerned health • Article 8(3): full or “full-mixed” application
authority (also referred to as competent authority). (complete dossier)
A regulatory pathway will typically be determined • Article 10: generic, hybrid or similar biological
by the following elements: application
1. What is the legal basis for the marketing • Article 10a: well-established use application
authorisation, e.g., will a full set of clinical • Article 10b: fixed combination application
and nonclinical studies be required, or can an • Article 10c: informed consent application
abbreviated application be filed?
2. Which authorisation procedure will be pro- It is highly recommended that applicants discuss the
posed, i.e., will the Marketing Authorisation legal basis for the MAA with the concerned competent
Application (MAA) be submitted via the cen- authority in advance, as the development program will
tralised, decentralised, mutual recognition or a largely depend on the proposed type of MAA. The dif-
national procedure? ferent types of applications are further described below.
3. What is the type of approval, i.e., will a stan-
dard or conditional marketing authorisation be Article 8(3): Full Application
sought? For full applications according to Article 8(3) of
4. Does the medicinal product intend to treat Directive 2001/83/EC, the results of pharmaceutical
a rare disease, i.e., is it eligible for orphan tests (physico-chemical, biological or microbiological),
designation? preclinical tests (pharmacological and toxicological) and
5. Is the medicinal product eligible for any des- clinical trials need to be submitted. Detailed require-
ignations and/or initiatives that will accelerate ments are given in Annex I to Directive 2001/83/EC.
the development program and regulatory Any deviation from these requirements needs to
approval pathway? be justified in the application. Annex I also specifies
6. Does the proposed indication occur in the a mandate to submit the application in the Common
paediatric population, i.e., will a paediatric Technical Document (CTD) format.
development program need to be considered? Regulatory requirements for various treatment
7. What is the proposed interaction strategy with modalities are further discussed in Chapter 27
the competent authority, e.g., at which stage of Registration Procedures for Medicinal Products,
the program will Scientific Advice be sought? Chapter 32 Marketing Authorisations for Products
8. Apart from the MAA, will any other regula- Derived From Biotechnology, Chapter 35 Regulatory
tory filings such as Clinical Trial Applications Framework for Advanced Therapy Medicinal
(CTAs) be required? Products and Chapter 37 Vaccines.
An initial determination of the regulatory pathway Article 8(3): “Full-Mixed” Application

will need to occur prior to initiating the development A “Full-Mixed” application allows submission of pub-
program to ensure design of an efficient program and lished literature either in support or in lieu of some of the
creation of robust evidence that will ultimately support nonclinical/clinical data to be presented in Module 4 and/
the MAA. The regulatory pathway will then be further or 5 of the Marketing Authorisation Application (MAA).
refined or modified when new information becomes This type of application is described in more detail in the
available throughout the course of development. section on ‘mixed’ marketing authorisation applications in
Part II of Annex I to Directive 2001/83/EC.
Marketing Authorisation Application
(MAA): Legal Basis and Dossier Article 10: Generic, Hybrid or Similar Biological
Requirements Applications
To guarantee the protection of public health and to Article 10 allows for a derogation from the require-
ensure the availability of high-quality, safe and effica- ments for a full marketing authorisation and for
cious medicines for European citizens, all medicines submission of an abbreviated application. The

Overview of Drug and Biologic Regulatory Pathways
development of a product authorised under Article 10 product and in part on new data generated by the appli-
will be conducted versus a reference medicinal prod- cant. Guidance on the appropriate additional studies
uct, which has been granted a marketing authorisation required in the cases described above is given in Annex
in the EU on the basis of a full dossier, i.e., in accor- IV of Chapter 1 of the Notice to Applicants.
dance with Articles 8(3), 10a, 10b or 10c of Directive Biosimilar applications described in Article 10(4)
2001/83/EC. of Directive 2001/83/EC apply to biological medicinal
The authorisation of an application under Article products, which are similar to a reference biological
10 is only possible once the applicable patents and data product, but do not meet the definition of a generic
protection period of the reference medicinal product medicinal products, e.g., due to differences related to
have expired. raw materials or manufacturing process of the similar
Article 10 distinguishes three different appli- biological medicinal product and the reference biologi-
cations: generic applications (Article 10(1)), hybrid cal medicinal product.
applications (Article 10(3)) and biosimilar applications Thus, for biosimilars submitted under Article 10(4),
(Article 10(4)). the results of appropriate preclinical tests and/or clinical
A generic medicinal product authorised under trials must be provided to establish similarity and to
Article 10(1) is defined as a medicinal product that has: demonstrate that no clinically meaningful differences
• the same qualitative and quantitative com- exist. The type and quantity of supplementary data to be
position in active substances as the reference provided must comply with the relevant criteria stated
product in Annex I to Directive 2001/83/EC and the related
• the same pharmaceutical form as the reference detailed guidelines. Further discussion on biosimilars is
medicinal product provided in Chapter 32 Marketing Authorisations for
• and whose bioequivalence with the reference Products Derived From Biotechnology.
medicinal product has been demonstrated As for the other two Article 10 applications dis-
by appropriate bioavailability studies, where cussed above, the chosen reference medicinal product
necessary must be a product authorised in the EU based on a
complete dossier
A biowaiver (i.e., a waiver of the requirement to con-
duct bioequivalence studies) may be possible for a Article 10a: Well-Established Use Application
generic medicinal product in line with the criteria In accordance with Article 10a of Directive 2001/83/
defined in the Guideline on the investigation of bio- EC, results of preclinical and clinical trials may be
equivalence. In addition, the Summary of Product replaced by detailed references to published scientific lit-
Characteristics (SmPC) should be consistent in all erature (i.e., information available in the public domain)
relevant respects with that of the reference medicinal if it can be demonstrated that the concerned active
product (except for patent-protected indications and substances have been in well-established medicinal use
dosage forms). Regulatory requirements for registration within the EU for at least 10 years, with recognised
of generic medicinal products are covered in more detail efficacy and an acceptable level of safety in terms of the
in Chapter 29 Generic Medicinal Products. conditions set out in Annex I of the Directive.
Hybrid applications under Article 10(3) of The following criteria for the demonstration of
Directive 2001/83/EC differ from generic applications such well-established use in the claimed therapeutic
in that the results of appropriate preclinical tests and indication should be considered:
clinical trials will be necessary in the following three • the time over which a substance has been used
circumstances: with regular application in patients
• where the strict definition of a ‘generic medici- • quantitative aspects of the use of the substance,
nal product’ is not met the extent of use on a geographical basis and
• where the bioavailability studies cannot be the extent to which the use of the substance
used to demonstrate bioequivalence has been monitored by pharmacovigilance or
• where there are changes in the active sub- other methods
stance(s), therapeutic indications, strength, • the degree of scientific interest in the use of
pharmaceutical form or route of administration the substance (reflected in the published scien-
of the generic product compared to the refer- tific literature) and the coherence of scientific
ence medicinal product assessments
These applications will thus rely in part on the results In addition, a positive benefit-risk balance will need to
of preclinical tests and clinical trials for a reference be demonstrated based on published scientific literature,

Chapter 3
which is available in the public domain, peer-reviewed Three different assessment procedures make use of the
and published by a reputable source. Assessment reports national route: the decentralised procedure, the mutual
(e.g., European Public Assessment Reports (EPARs)) recognition procedure and the national procedure. Both
are not acceptable for this purpose. Likewise, clinical the decentralised and mutual recognition procedure
studies are only accepted for bridging to literature and represent “concertation procedures,” which are based
cannot be used as evidence supporting a positive bene- on recognition of a first assessment performed by one
fit/ risk ratio. Member State by other national competent authorities.
Article 10a submissions are required to comply The centralised authorisation procedure allows
with the provisions of Annex I to Directive 2001/83/ applicants to submit a single MAA to the European
EC, as they are considered full and independent Medicines Agency (EMA).
applications. The scientific assessment of the application is
then carried out by EMA’s Committee for Medicinal
Article 10b: Fixed Combination Application Products for Human Use (CHMP) and overseen by a
In the case of medicinal products that contain a com- rapporteur, resulting in a recommendation (opinion)
bination of active substances, which have been used on whether the medicine should be marketed or not.
in authorised medicinal products individually but not EMA has no authority to permit marketing in the dif-
in combination, the results of new preclinical tests ferent EU countries under EU law. Thus, the European
or new clinical trials with the proposed combination Commission is the ultimate authorising body for all
need to be provided (Article 10b of Directive 2001/83/ centrally authorised product, who takes a legally bind-
EC). However, provision of scientific references and ing decision based on EMA’s recommendation and
data related to each individual active substance is not grants a centralised marketing authorisation valid in all
required. The combination of active substances within a 27 EU Member States as well as in the EEA countries
single pharmaceutical form is a so-called ‘fixed combi- Iceland, Liechtenstein and Norway.3
nation’ under this provision. Use of the centralised procedure may be mandatory
Applications for fixed combination medicinal prod- based on the route of manufacture of the product to be
ucts can be submitted under Article 10b, provided that the authorised and/or the proposed indication.
individual substances have been authorised as a medicinal The centralised procedure is compulsory for:
product in the European Economic Area (EEA). • human medicines containing a new active sub-
stance to treat:
Article 10c: Informed Consent Application o Human Immunodeficiency Virus
An informed consent application filed under Article (HIV) or Acquired Immune Deficiency
10c is based on a permission, which allows the appli- Syndrome (AIDS)
cant to make use of the quality, nonclinical and clinical o cancer
documentation contained in the dossier of another o diabetes
medicinal product. o neurodegenerative diseases
In order to qualify for an Article 10c application, o auto-immune and other immune
both medicines must have the same qualitative and dysfunctions
quantitative composition in terms of active substance(s) o viral diseases
and the same pharmaceutical form. In addition, the • medicines derived from biotechnology pro-
marketing authorisation holder of the reference product cesses, such as genetic engineering
needs to give their consent to reference the quality, pre- • advanced-therapy medicines, such as
clinical and clinical data (Modules 3, 4 and 5), and the gene-therapy, somatic cell-therapy or tis-
applicant of the informed consent application should sue-engineered medicines
have permanent access to this documentation. • orphan medicines (medicines for rare diseases)
Marketing Authorisation Application The centralised procedure is optional for other

medicines:
(MAA) Procedures • that contain new active substances for indica-
All medicines must be authorised before they can be tions other than those stated above
marketed and made available to patients in the EU. • that are a significant therapeutic, scientific or
There are two main routes for authorising medicines for technical innovation
commercial market access:2 • whose authorisation would be in the interest of
• a centralised route public health at the EU level
• a national route

Products authorised via the centralised route also may Application for Marketing Authorisation
benefit from an accelerated assessment if the CHMP (MAA): Types of Approval
decides the product is of major interest for public health For medicinal products that address highly unmet
and a therapeutic innovation. medical needs of patients, it may be possible to grant a
A medicinal product that has been granted accel- marketing authorisation on the basis of less complete
erated assessment follows a reduced assessment time data than normally required for a “standard approval.”
schedule for the MAA. The assessment period is In these cases, it is possible for EMA’s CHMP to rec-
reduced to 150 days or less (compared to standard 210 ommend granting of a marketing authorisation subject
days), not including clock-stops. An applicant who to certain obligations.
wishes to have their marketing authorisation application There are two types of “non-standard” marketing
reviewed under the accelerated assessment provision authorisations:4
should notify EMA of its intention to request acceler- 1. A conditional marketing authorisation, which
ated assessment six to seven months prior to submission is reviewed annually and will ultimately be
of the marketing authorisation application. A request converted to a standard marketing authorisa-
for accelerated assessment is then submitted two to tion based on provision of a “complete dossier.”
three months prior to submission and will be reviewed 2. A marketing authorisation granted under
by the rapporteurs. The final decision on whether exceptional circumstances, which is also
accelerated assessment is granted will be made by the reviewed annually but will normally not lead
CHMP based on the rapporteurs’ recommendations. to the completion of a full dossier and thus
While most new, innovative medicinal products are will never become a “standard” marketing
authorised via the centralised route, most generic med- authorisation.
icines and nonprescription medicines are assessed and
authorised at the national level in the EU. The authori- A conditional marketing authorisation may be issued
sation of nonprescription medicines is further discussed for medicinal products for human use that contain
in Chapter 31 Nonprescription Medicinal Products. new active substances, constitute significant therapeu-
In addition, many older medicines available today were tic and scientific innovations and are intended for the
authorised at a national level because they were mar- treatment, prevention or medical diagnosis of seriously
keted before the EMA was created in 1995. debilitating or life-threatening diseases.
For products to be authorised at a single Member A conditional marketing authorisation may
State level, each EU Member State has its own national be granted when EMA’s Committee for Medicinal
authorisation procedures. Information about these can Products for Human Use (CHMP) determines that,
be found on the websites of the national competent although comprehensive clinical data establishing the
authorities for each Member State. safety and efficacy of the medicinal product have not
If an applicant intends to obtain a marketing been supplied, all of the following requirements are met:5
authorisation in several EU Member States for a • the benefit-risk ratio of the medicinal prod-
medicine that is outside the scope of the centralised uct, as defined in Article 1(28a) of Directive
procedure, one of the following two routes can be used: 2001/83/EC, is favourable
• the mutual recognition procedure, which • it is likely that the applicant will be able to
provides for recognition of a marketing provide comprehensive data
authorisation granted in one Member State by • unmet medical needs of patients will be met
other EU Member States • the benefit of the immediate commercial avail-
• the decentralised procedure, which allows for ability of the medicinal product outweigh the
simultaneous authorisation of a medicine that risk inherent because additional data are still
has not yet been authorised in the EU in sev- required
eral EU Member States
Conditional marketing authorisations are valid for one
The centralised, decentralised and mutual recognition year and are renewed annually. The marketing authori-
procedures are discussed in more detail in Chapter 23 sation holder will be required to complete ongoing
Overview of Authorisation Procedures for Medicinal studies or to conduct new studies in order to confirm
Products. the positive benefit-risk ratio and long-term clinical
benefit. Other specific obligations, such as expanded
collection of pharmacovigilance data, may be imposed
as well. These specific obligations are reviewed annually
within the renewal procedure. In case the marketing

Chapter 3
Table 3-1. Differences Between Conditional Marketing Authorisation and Marketing Authorisation Under
Exceptional Circumstances
Conditional Marketing Authorisation Marketing Authorisation Under Exceptional

Circumstances
Authorisation before the availability of comprehen- Authorisation when comprehensive data on the efficacy
sive data in order to address unmet medical needs. and safety cannot be obtained, but it is still appropriate to
Comprehensive data are still being generated post grant the authorisation due to exceptional circumstances
authorisation in agreed timelines.
Medicinal products without comprehensive data intended Medicinal products without comprehensive data on
for the treatment, prevention or medical diagnosis of the efficacy and safety under normal conditions of use,
seriously debilitating or life-threatening diseases and because:
fulfilling the following criteria: • Indications encountered so rarely that the applicant
• favourable risk-benefit balance cannot reasonably be expected to provide compre-
• applicant likely to be able to provide comprehensive hensive evidence, or
data • In the present state of scientific knowledge, compre-
• fulfilment of unmet medical need hensive information cannot be provided, or
• benefits of immediate availability outweigh the risks • It would be contrary to generally accepted principles
related to additional data still being required of medical ethics to collect such information.
Authorisation valid for one year, to be renewed annually Authorisation initially valid for five years (renewable), but
based on review of specific obligations and reconfirma- the status of fulfilment of the specific obligations and the
tion of the benefit-risk balance impact of the specific obligations’ data on the benefit/risk
balance is to be reassessed annually
Once the comprehensive data are provided, it can become Will normally not lead to the completion of a full dossier
a “standard” marketing authorisation and therefore will not become a “standard” marketing
authorisation
authorisation holder has not complied with the specific discussion on the appropriateness of this approach
obligations imposed, the marketing authorisation can be should occur at the pre-submission meeting.
suspended in accordance with Article 20a of Regulation Authorisations that were granted conditionally or
(EC) No. 726/2004. under exceptional circumstances also will need to be
Applicants who consider requesting a conditional disclosed in the SmPC and patient insert of the con-
marketing authorisation should notify the EMA of cerned medicinal product.
their intention six to seven months prior to submission The differences between a conditional marketing
of the MAA. A request for a conditional marketing authorisation and a marketing authorisation under
authorisation is then presented at the time of submis- exceptional circumstances are summarised in Table 3-1.
sion of the MAA.
In contrast, a marketing authorisation under excep- PRIority MEdicines (PRIME)
tional circumstances (Article 14 (8) of the Regulation EMA launched the PRIME scheme in 2016 to
(EC) No. 726/2004) can be granted for products for enhance support for the development of medicines that
which the applicant can demonstrate that comprehen- target an unmet medical need.7 Like the Breakthrough
sive data under normal conditions of use cannot be Therapy designation in the US and the Sakigake
provided.6 This type of authorisation is also reviewed designation in Japan, this voluntary scheme foresees
annually to reassess the benefit-risk balance. The specific enhanced interaction and early dialogue between
obligations imposed as part of the marketing authorisa- EMA and sponsors of promising medicines, with the
tion under exceptional circumstances have the objective goal of optimising development plans and accelerating
to provide information on the safe and effective use evaluation. This will help patients to benefit as early as
of the product and will normally not lead to the com- possible from innovative therapies that may significantly
pletion of a full dossier. Applicants who consider their improve their quality of life.
product to be eligible for a marketing authorisation Key benefits of PRIME include:8
under exceptional circumstances should seek Scientific • early appointment of a rapporteur from
Advice from EMA as early as possible. Further CHMP or from the Committee on Advanced
Therapies (CAT) in case of an advanced

therapy to provide continuous support and (HTA) bodies in the EU to sponsors of medicines.10 It
allow to build knowledge ahead of an MAA gives the sponsor an opportunity to discuss and clarify
• organisation of a kick-off meeting with the their product development plan to ensure generation of
rapporteur and a multidisciplinary group robust evidence of a medicine’s benefits and risks, which
of experts, with the objective of providing will ultimately support marketing authorisation and
in-depth guidance on the overall development reimbursement. Scientific Advice focuses on develop-
plan and regulatory strategy ment strategies and study design rather than evaluation
• assignment of a dedicated contact point at of data. As part of this process, patient representatives,
EMA clinicians and experts may be invited to contribute to
• provision of Scientific Advice at key devel- the discussion.
opment milestones that may involve national The advice given is confidential and based on doc-
Health Technology Assessment (HTA) bodies umentation provided by the sponsor. It is not legally
to facilitate quicker access for patients to the binding and does not affect the sponsor’s responsibility
new medicine for developing their product.
• potential for accelerated assessment of the There are different options for obtaining Scientific
MAA Advice. In particular, Parallel Scientific Advice may be
sought from a range of agencies at the same time. This
To qualify for PRIME, a medicine has to offer a major may help to increase alignment across agencies and cre-
therapeutic advantage over existing treatments or pro- ate efficiencies in the medicine’s development process.
vide a benefit to patients without existing treatment Options for obtaining scientific advice include:
options. The potential to benefit patients with unmet • Scientific Advice given by EMA
medical needs will need to be demonstrated based on • Parallel Scientific Advice involving both
early clinical data. the EMA and the US Food and Drug
EMA offers special support to applicants from the Administration (FDA)11
academic sector and micro-, small- and medium-sized • Parallel Scientific Advice from EMA and
enterprises (SMEs). Entities that qualify as academic HTA bodies via the European Network
institution/SME can apply for PRIME earlier on the of Health Technology Assessment Bodies
basis of compelling nonclinical data and tolerability (EUnetHTA)12
data from initial clinical trials. • national scientific advice from a national
PRIME designation requests are reviewed by EMA’s competent authority (e.g., ANSM in France,
Scientific Advice Working Party (SAWP), with further AEMPS in Spain, BfArM in Germany)
participation by the CAT in case of Advanced Therapy • HTA national advice from individual national
Medicinal Products (e.g., gene and cell therapies). A final HTA bodies
decision is then adopted by CHMP based on the recom- • joint national HTA and regulatory advice
mendation from these committees. An updated timetable within one Member State, e.g., in Germany,
outlining deadlines for submission of PRIME eligibility joint G-BA and BfArM advice13
requests is published annually on EMA’s homepage.
Adoption of a decision by CHMP will usually occur National procedures for Scientific Advice from national
within 40 days of the start of the procedure. competent authorities and HTA bodies vary signifi-
Eligibility criteria and the procedure to request cantly, and it is recommended that sponsors consult the
PRIME designation are outlined in EMA’s Guidance for concerned authority’s homepage for further information.
applicants seeking access to PRIME scheme. Scientific Advice from EMA can be requested at
Since its launch in 2016, the PRIME scheme has any stage of a medicine’s development regardless of the
proven to be a powerful tool to accelerate patient access to medicine’s eligibility for the centralised procedure.
promising therapies. In 2019, the first medicinal products Scientific Advice is given by EMA’s Scientific
completed their journey through the PRIME scheme and Advice Working Party (SAWP), with participation
obtained marketing authorisation in the EU.9 from other EMA committees, if necessary.14 The
SAWP is a multidisciplinary group, which comprises
Agency Interaction Opportunities: a chairperson, 36 members, including three members
Scientific Advice, Protocol Assistance and of the Committee for Orphan Medicinal Products
(COMP), three members of the Paediatric Committee
MAA Presubmission Meeting (PDCO), three members of CAT and one member of
Scientific Advice is a fee-based service offered by com- the Pharmacovigilance Risk Assessment Committee
petent authorities and health technology assessment (PRAC). Patient groups may be invited to participate to

Chapter 3
provide a real-life perspective and their experience with designation. To qualify for orphan designation, a medi-
a specific medicine in relation to a specific disease area. cine must meet a number of criteria including:
Procedures and timelines vary according to the • it must be intended for the treatment, pre-
requested type of procedure (e.g., EMA-only Scientific vention or diagnosis of a disease that is
Advice; Parallel Scientific Advice with FDA or HTA life-threatening or chronically debilitating
bodies). An updated timetable outlining deadlines • the prevalence of the condition in the EU
for submission and procedure milestones is published must not exceed five in 10,000 or it must be
annually on EMA’s homepage. unlikely that commercialisation of the medi-
Scientific Advice is provided by responding to cine would generate sufficient returns to justify
specific questions posed by the sponsor. These ques- the investment needed for its development
tions can relate to any area pertaining to the medicine’s • no satisfactory method of diagnosis, preven-
development, e.g., quality aspects, nonclinical and clini- tion or treatment of the condition concerned
cal issues and methodological questions (e.g., statistical can be authorised, or, if such a method exists,
methods, data analysis). EMA bases their response on the medicine must be of significant benefit to
information provided by the sponsor in the form of a those affected by the condition
briefing package. A template for the briefing package is
available on the EMA homepage. Applications for orphan designation are reviewed by
EMA charges a fee for Scientific Advice, which EMA’s Committee for Orphan Medicinal Products
varies depending on the scope of the advice. (COMP). The evaluation process takes a maximum of
Reductions apply for certain types of medicines and 90 days from validation.
applicants, including a 75% fee reduction for medicines for Detailed information on orphan medicines can be
orphan medicines and a 90% fee reduction for SMEs.15 found in Chapter 41 Orphan Medicinal Products.
Protocol assistance is a special form of EMA
Scientific Advice available for sponsors of designated Paediatric Development Programs
orphan medicines for rare diseases. In addition to The Paediatric Regulation 1901/2006/EC came into force
Scientific Advice, protocol assistance provides for in 2007.18 It introduced sweeping changes into the regu-
answers to questions related to the authorisation criteria latory environment for paediatric medicines, designed to
of an orphan medicine, including the demonstration of better protect the health of children in the EU. The main
a significant benefit within the scope of the designated change was the requirement of an approved Paediatric
orphan indication and similarity or clinical superiority Investigation Plan (PIP) as a pre-requisite to obtain a
over other medicines. marketing authorisation in the EU,19 and the creation of
EMA also offers MAA Pre-Submission Meetings PDCO to provide objective scientific opinions on these
that are usually held six to seven months prior to sub- PIPs, which outline the development plan of a specific
mission of the MAA.16 These pre-submission meetings medicine for use in children.
provide applicants with information that will assist Laws, regulations and procedures pertaining
them in the finalisation of their upcoming MAA. to paediatric development are further discussed in
Such meetings typically address product-specific legal, Chapter 8 The Paediatric Regulation.
regulatory and scientific issues to facilitate subsequent
validation and assessment of the application. Pre- Clinical Trial Application (CTA)
Submission Meetings need to be requested at least six Prior to initiating clinical studies in humans, a sponsor
weeks prior to the intended meeting date. The meetings of an Investigational Medicinal Product (IMP) needs
typically start with a presentation given by the appli- to file a Clinical Trial Application (CTA) and obtain
cant, followed by a discussion on the presentation and approval from the competent authority.20 The authori-
the topics the applicant specified on the Pre-submission sation of clinical trials in the EU occurs at the national
Meeting Request Form. level by the competent authority of the Member State
in which the clinical trial will be conducted.
Orphan Medicinal Products In addition, EMA plays a key role in ensuring
EMA plays a central role in facilitating the develop- that the standards of Good Clinical Practice (GCP)
ment and authorisation of orphan medicinal products are applied across the EEA in cooperation with the
for treatment of for rare diseases.17 Sponsors of a des- Member States. It also manages EudraCT, a database of
ignated orphan medicinal product can benefit from a clinical trials carried out in the EU.
number of incentives in the EU. EMA is responsible The CTA dossier submitted to the compe-
for reviewing applications from sponsors for orphan tent authority of the Member State consists of

administrative information and the necessary demon- Authorisation.” Molecular Therapy: Methods and Clinical
stration of the IMP’s quality, safety and efficacy. Development. Volume 13 ( June 2019).
10. Scientific Advice and Protocol Assistance. EMA website.
Clinical Trial Applications are further discussed in https://www.ema.europa.eu/en/human-regulatory/research-de-
Chapter 26 Medicinal Product Clinical Trials. velopment/scientific-advice-protocol-assistance. Accessed 2
March 2020.
11. General Principles EMA-FDA Parallel Scientific Advice. EMA
Conclusion website. https://www.ema.europa.eu/en/documents/other/
The decision on which regulatory pathway to use will general-principles-european-medicines-agency-food-drug-ad-
depend on the nature of the active substance, the tar- ministration-parallel-scientific-advice_en.pdf. Accessed 2 March
get indication(s), the history of the product and/or the 2020.
12. Parallel Consultation With Regulators and Health Technology
marketing strategy. Tools like PRIME, conditional Assessment Bodies. EMA website. https://www.ema.
marketing authorisations and accelerated review have europa.eu/en/human-regulatory/research-development/
proven to be powerful means to accelerate regulatory scientific-advice-protocol-assistance/parallel-consultation-regu-
pathways in areas of highly unmet medical needs. lators-health-technology-assessment-bodies. Accessed 2 March
2020.
13. Joint Advice Through the BfArM and the Federal Joint
References Committee (G-BA). BfArM website. https://www.bfarm.de/
1. Pre-Authorisation Guidance. EMA website. https://www.ema. EN/BfArM/Organisation/Advice_Procedures/Request_for_
europa.eu/en/human-regulatory/marketing-authorisation/ consultation/_node.html. Accessed 2 March 2020.
pre-authorisation-guidance. Accessed 2 March 2020. 14. Scientific Advice Working Party. EMA website. https://www.
2. Authorisation of Medicines. EMA website. https://www. ema.europa.eu/en/committees/working-parties-other-groups/
ema.europa.eu/en/about-us/what-we-do/authorisation-med- chmp/scientific-advice-working-party. Accessed 2 March 2020.
icines#national-authorisation-procedures-section. Accessed 2 15. Fees Payable to the European Medicines Agency. EMA website.
March 2020. https://www.ema.europa.eu/en/human-regulatory/overview/
3. Obtaining an EU Marketing Authorisation, Step-by-Step. fees-payable-european-medicines-agency. Accessed 2 March
EMA website. https://www.ema.europa.eu/en/about-us/ 2020.
what-we-do/authorisation-medicines#national-authorisa- 16. Op cit 1.
tion-procedures-section. Accessed 2 March 2020. 17. Orphan Designation: Overview. EMA website. https://www.
4. Op cit 1. ema.europa.eu/en/human-regulatory/overview/orphan-designa-
5. Conditional Marketing Authorisation. EMA website. https:// tion-overview. Accessed 2 March 2020.
www.ema.europa.eu/en/human-regulatory/marketing-authori- 18. Paediatric Regulation. EMA website. https://www.ema.europa.
sation/conditional-marketing-authorisation. Accessed 2 March eu/en/human-regulatory/overview/paediatric-medicines/paedi-
2020. atric-regulation. Accessed 2 March 2020.
6. Op cit 1. 19. Paediatric Investigation Plans. EMA website. https://www.
7. Support for Early Access. EMA website. https://www.ema. ema.europa.eu/en/human-regulatory/research-development/
europa.eu/en/human-regulatory/overview/support-early-access. paediatric-medicines/paediatric-investigation-plans. Accessed 2
Accessed 2 March 2020. March 2020.
8. PRIME: Priority Medicines. EMA website. https://www. 20. Clinical Trials in Human Medicines. EMA website. https://
ema.europa.eu/en/human-regulatory/research-development/ www.ema.europa.eu/en/human-regulatory/research-develop-
prime-priority-medicines. Accessed 2 March 2020. ment/clinical-trials-human-medicines. Accessed 2 March 2020.
9. Detela G, et al. “EU Regulatory Pathways for ATMPs:
Standard, Accelerated and Adaptive Pathways to Marketing

Chapter 3

Chapter 4
Preparing for EMA Meetings Prior

to Submission of a Marketing
Authorisation Application
Updated by Kell Cannon, Kate Dion and Cindy DiBiasi
OBJECTIVES □ Guideline on the scientific application and the

practical arrangements necessary to imple-
□ Provide applicants an overview of the different ment the procedure for accelerated assessment
types of European Medicines Agency (EMA) pursuant to Article 14(9) of Regulation (EC) No
meeting procedures that support submission of 726/2004 (February 2016)
a Marketing Authorisation Application (MAA)1
□ Ensure regulatory teams understand the

Introduction
different steps and timelines involved in each
For companies seeking authorisation to market a
interaction and know how to prepare effectively
medication in the EU, effective communication with
for these meetings to increase their chances of
the EMA throughout product development is crucial.
success
Fortunately, there are a number of opportunities to
engage with, and receive valuable input from, EMA in
the months leading up to a Marketing Authorisation
DIRECTIVES, REGULATIONS AND GUIDELINES Application (MAA) submission.
COVERED IN THIS CHAPTER To maximise these opportunities, it is essential that
companies have a solid understanding of the different
□ European Medicines Agency guidance for appli-
types of meeting procedures, are clear on the specific
cants seeking scientific advice and protocol
steps that relate to them and know how to set clear
assistance (June 2017)
goals and prepare thoughtfully for these important
□ From laboratory to patient: the journey of a interactions.
centrally authorised medicine (2019) Meetings that occur after an MAA is submitted are
discussed Chapter 5.
□ Guidance for Parallel Consultation (July 2019)
□ General Principles EMA-FDA Parallel Scientific

Types of Communication
There are essentially two reasons why applicants would
Advice (Human Medicinal Products) (April 2017)
request to meet with EMA:
□ Parallel Scientific Advice (FDA-EMA) (July 2019) 1. to receive Scientific Advice as it develops their
product
□ European Medicines Agency pre-authorisation 2. to receive Regulatory Guidance that will sup-
procedural advice for users of the centralised port their MAA
procedure (April 2019)
There are nine key meeting types, highlighted in
□ Applying for EU marketing authorisation for Table 4-1, that fall into either the Scientific Advice or
medicinal products for human use (May 2015) Regulatory Guidance categories. Each has a specific goal
that defines the type of meeting sought by applicants.

Chapter 4
Common Procedural Steps for Obtaining requesting, the notification may enable EMA to sched-
Advice or Guidance that May Result in an ule a meeting date.
The notification step also applies to notification of
EMA Meeting intent to seek marketing authorisation. In this instance,
There are nine steps for which applicants may need to
applicants should notify EMA between seven and eight
be ready as they move through the process. An overview
months prior to submission.
of these steps is provided in Table 4-2. In most cases,
EMA tries to address applicants’ questions through writ-
ten communications and generally reserves meetings for
2. Presubmission
The presubmission phase begins once the LoI and draft
clarification purposes or to discuss unresolved issues.
briefing document have been sent to EMA. During the
1. Notification
presubmission phase, EMA will share the draft briefing
2. Presubmission
document with participating EMA members, allowing
3. Procedure Start
them to review and request clarification or additional
4. List of Issues
data. If necessary, the applicant or EMA may schedule a
5. Clarification Teleconference
presubmission meeting to clarify the process.
6. Written Responses
Applicants intending to submit an MAA may
7. Premeeting
request a presubmission meeting with the agency’s
8. Meeting
product team around this time. The MAA presubmis-
9. Postmeeting
sion request form gives applicants an overview of the
most relevant topics that they should consider as they
As applicants prepare for EMA interactions and a
prepare their submission. These topics also may be dis-
potential meeting, it is crucial that they understand each
cussed during the presubmission meeting.2
step and what is needed to support a successful meeting
request. Doing so will help them meet EMA’s require-
ments and optimise each stage of the regulatory process. 3. Procedure Start
Achieving this requires that applicants communicate as Once the applicant’s final briefing document has been
constructively as possible with EMA and engage with received, the clock starts for that given procedure. The
clarity, purpose and intent. EMA has issued numerous timeline will follow the review process outlined in the
guidance documents providing valuable information relevant guidance document for that meeting procedure.
on how to request a meeting, interact with the relevant (Note: the MAA procedure is addressed in the Chapter 5.)
committee and follow-up after the meeting.
This chapter provides a review of common goals 4. List of Issues
and actions, but specific EMA guidance should be Based on an applicant’s briefing document, the coor-
consulted for the requested meeting type listed above. dinator will prepare a list of outstanding issues that an
Timelines for each meeting procedure are provided in applicant must address.3
Table 4-3. In the case of scientific advice, the list of issues
An overview of three common scientific advice is divided into two categories: issues to be addressed
meetings is included at the end of this chapter. during the discussion meeting, and issues to be
addressed in writing by an applicant prior to the discus-
1. Notification sion meeting.4
In most cases, applicants will first need to send EMA
a Letter of Intent (LoI) informing the agency of their 5. Clarification Teleconferences
intention to seek advice or guidance. The notification Clarification teleconferences are set up in advance of
should outline the specific request and identify the face-to-face meetings to ensure applicants and EMA
desired meeting type (Table 4-1). Applicants should understand each other’s preliminary positions. These
send a draft briefing document to EMA that includes meetings also allow applicants to gain clarity on any
a list of consultation questions and background infor- information requests contained in the List of Issues,
mation, relevant scientific justification and data to along with guidance on recommended analyses to
support the applicant’s position. The briefing document address a given request.
with references and relevant annexes is usually sub-
mitted between 20 and 45 days before the start of the 6. Written Responses
procedure; it also can be part of the notification step. Applicants send written responses to address each ques-
Depending on what type of meeting an applicant is tion raised in the List of Issues, supported by relevant
scientific data, appropriate analyses and references. In

Preparing for EMA Meetings Prior to Submission of a Marketing Authorisation Application
Table 4-1. Overview of the Key EMA Advice Meetings and Their Goals
Meeting Description Goal

Procedure
Scientific Advice Applicants are To provide integrated, non-binding scientific advice related to the development and
Working Party given non-binding testing of medicinal, orphan medicinal and advance therapy medicinal products as well
Meeting scientific advice or as advice on thresholds for a clinically meaningful benefit and robust demonstration of
protocol assistance product quality, non-clinical, clinical safety and efficacy.
during clinical
development. Applicants will submit questions for feedback. Questions that cannot be quickly and
efficiently resolved with written communication will result in a face-to-face meeting with
the Scientific Advice Working Party (SAWP).
EMA guidance for applicants seeking scientific advice and protocol assistance (June
2017)
https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/
european-medicines-agency-guidance-applicants-seeking-scientific-advice-protocol-as-
sistance_en.pdf
Parallel Helps applicants To discuss issues of concern and critical divergences between EMA and Member States’
Consultation gain an understand- Health Technology Assessment Bodies (HTABs) related to an applicant’s proposal regard-
Meeting ing of the data needs ing major aspects of trial designs. To discuss potential solutions that could facilitate one
of EMA and local trial design or at least one development plan.
health authorities
EMA/EUnetHTA Guidance for Parallel Consultation (July 2019)
guidance-parallel-consultation_en.pdf
Parallel Scientific Provides a mech- To increase dialogue among the EMA, FDA and an applicant from the beginning of the
Advice Meeting anism for EMA lifecycle of a new product, provide a deeper understanding of the basis of regulatory
assessors and FDA divisions, optimise product development and avoid unnecessary testing replication or
reviewers to con- unnecessary testing methodologies.
currently exchange
views on develop- General Principles EMA-FDA Parallel Scientific Advice: Human Medicinal Products (April
ment issues with 2017)
applicants https://www.ema.europa.eu/en/documents/other/general-principles-european-medi-
cines-agency-food-drug-administration-parallel-scientific-advice_en.pdf
Parallel Scientific Advice: FDA/EMA(July 2019)

https://www.ema.europa.eu/en/documents/other/
timeline-european-medicines-agency-fda-parallel-scientific-advice_en.pdf
Clarification Provides clarifica- To gain an understanding of the rationale for regulators’ questions, objections and/or
Meeting tion and guidance other issues (e.g., List of Questions) and to discuss the applicant’s response strategy
on questions and and potential need to adjust timelines.
issues
Guidance on meetings with applicants on the responses to questions received from
European Medicines Agency Scientific Committees during the evaluation within the cen-
tralised procedure (January 2015)
guidance-meetings-applicants-responses-questions-received-european-medicines-agen-
cy-scientific_en.pdf
Innovation Task Applicants are given To obtain early guidance and information with relevant EMA scientific committees or
Force Meeting advice on topics working parties. To work toward complementing and reinforcing existing formal regula-
where there is no tory procedures that would support an MAA.
established experi-
ence or guidance HMA/EMA Mandate of the European Innovation Network (September 2016)
mandate-european-innovation-network_en.pdf

Chapter 4
Table 4-1. Overview of the Key EMA Advice Meetings and Their Goals (con’t.)
Meeting Description Goal

Procedure
Presubmission Delivers information To gain information that enables an applicant to submit applications that conform to EMA
Meeting necessary to finalise legal and regulatory requirements and speed up the validation process. Also, to enable
an MAA applicants to establish contact with the EMA staff closely involved with the application.
European Medicines Agency pre-authorisation procedural advice for users of the cen-
tralised procedure (February 2020)
european-medicines-agency-pre-authorisation-procedural-advice-users-centralised-pro-
cedure_en-0.pdf
Accelerated To obtain guidance To understand and align on the practical arrangements and legal provisions that an
Assessment on the thresholds applicant must fulfill to pursue the accelerated assessment procedure (commonly known
Meeting for requesting and as priority assessment).
obtaining a priority
150-day assessment Guidance on meetings with applicants on the responses to questions received from
European Medicines Agency Scientific Committees during the evaluation within the cen-
tralised procedure (January 2015)
guidance-meetings-applicants-responses-questions-received-european-medicines-agen-
cy-scientific_en.pdf
PRIME Kickoff To establish the To optimise development plans and speed up EMA’s evaluation of promising medicines
Meeting* interaction among using the PRIME scheme. This programme enhances interactions and early dialogue with
applicants, experts applicants of medicines with a high unmet need. It helps them tailor their programme by
from the EU reg- defining and planning technical and scientific assistance through scientific advice and/
ulatory network or other interactions with EU regulators.
and the CHMP/CAT
rapporteurs
*There is no specific guidance on the PRIME kickoff meeting process or data requirements. Each development is unique, initiated by the application for
PRIME that is the basis for the EMA designation. In general, EMA will identify and share discussion topics for the kick-off meeting, as well as milestones
before and after authorisation.
most cases, these responses are required approximately teleconference or videoconference, and some are face-
45 to 60 days following the start of the procedure. to-face meetings. The format is determined by EMA.
In most of these meetings, regulators will require
7. Premeeting that applicants answer explicit and precise questions.
Applicants are required to send their draft presentation The goal for applicants is to receive clear answers from
approximately seven days before the scheduled face-to- EMA. Questions should focus on:
face meeting, with the final presentation provided to • quality: questions on the manufacturing pro-
regulators before the meeting. cess and testing
• nonclinical: study design and results for phar-
8. Meeting macology, toxicology and biodistribution
Each meeting is an opportunity for applicants to gain • clinical: human study design, use of biomarkers
key advice from EMA on a wide range of topics. These if appropriate and the overall development
topics include procedural, regulatory and legal aspects. strategy
The meeting also allows applicants to establish con- • acceptability of data for an MAA
tact with the EMA staff who will be involved with an
eventual MAA submission. EMA uses the meetings to Key roles should be identified and assigned, including
discuss outstanding issues and raise any concerns it has the meeting moderator, presenter(s), functional area and
with an applicant’s data package (e.g., CMC, preclini- subject matter experts to respond to likely questions,
cal, clinical), proposed development plan and necessary and scribes.
regulatory documentation. The presentation time will be
agreed upon with the EMA coordinator. It is important
to note that some meetings are held remotely, either via

Table 4-2. Overview of the Different Steps Required for Each Meeting
Comparison of Key Meeting Steps*
Step Process Action A B C D E F G H I
The applicant notifies EMA of

their intent to request a meeting
1 Notification        **
and sends the draft briefing
document.
EMA collects and compiles mem-
ber requests for clarification or
2 Presubmission additional information related to        **
an applicant’s meeting request
and materials.
The applicant sends a revised,
final briefing document address-
ing EMA’s comments. The date
3 Procedure Start  
of receipt represents the start
of procedure and predefined
timeline.
The EMA coordinator consoli-
4 List of Issues     **
dates a List of Issues.
The applicant requests a pre
face-to-face call to discuss and
Clarification
5 understand preliminary EMA    **
Teleconference
positions on identified issues or
concerns.
If requested, an applicant sends
Written
6 any written responses to identi-     **
Responses
fied issues or concerns.
The applicant sends a final pre-
7 Premeeting sentation before the face-to-face     **
meeting.
The applicant and EMA discuss
8 Meeting major issues, concerns, or dis-        **
agreement with their proposal.
The applicant sends detailed
9 Postmeeting minutes of the face-to-face     **
meeting.
*Key to meeting procedure names:

A—Scientific Advice Working Party Meeting
B—Parallel Consultation
C—Parallel Scientific Advice Meeting
D—Clarification Meeting
E—Innovation Task Force Meeting
F—Presubmission Meeting
G—Accelerated Assessment Meeting
H—Name Review Group Meeting
I—PRIME Kickoff Meeting
**Likely step, recognising that there is no specific guidance on the PRIME kickoff meeting process or data requirements.

Chapter 4
Table 4-3. Timeline for Key Meeting Steps
Key Meeting Steps*

Step Process Action A B C D E F G H I
The applicant notifies
7–8 6–7 4–6
EMA of their intent to
Day Day ~Day Not months months months Not
1 Notification request a meeting and
-60 -60 -20 given before before before given**
sends the draft briefing
submission submission submission
document.
EMA collects and com-
piles member requests
for clarification or Day -20
Day Day Not Not
2 Presubmission additional information to
-30 -30 given given**
related to an applicant’s -45
meeting request and
materials.
The applicant sends a
revised, final briefing
document addressing
EMA’s comments. Day Day Not
3 Procedure Start
The date of receipt -2 -2 given**
represents the start
of procedure and pre-
defined timeline.
The EMA coordinator
~Day ~Day Day Day Not
4 List of Issues consolidates a List of
+32 +32 +30 +30 given**
Issues.
The applicant requests
a pre face-to-face call
Clarification to discuss and under- ~Day ~Day Day Not
5
Teleconferences stand preliminary EMA +32 +32 +30 given**
positions on identified
issues or concerns.
If requested, an appli-
Written cant sends any written Day Day ~ Day Not
6 Day +45
Responses responses to identified +45 +60 +45 given**
issues or concerns.
The applicant sends a 2 weeks
Day Day Day ~ Day Not
7 Premeeting final presentation before before
+56 +56 +60 +58 given**
the face-to-face meeting. meeting
The applicant and
6–7
EMA discuss major Within 60
~Day ~Day Day ~ Day months Not
8 Meeting issues, concerns, or days of
+60 +60 +60 +60 before given**
disagreement with their request
sub-mission
proposal.
The applicant sends
~Day ~Day ~ Day Within 2 Not
9 Postmeeting detailed minutes of the
+65 +65 +62 weeks given**
face-to-face meeting.
~8–5 6–7 6–7
~Day ~Day ~Day
~Day Not months months months Not
Total day range: -45– -60– +30–
-20–+70 given before before before given**
+70 +65 +70
submission submission submission
*Key to meeting procedure names:

A—Scientific Advice Working Party Meeting
B—Parallel Consultation
C—Parallel Scientific Advice Meeting
D—Clarification Meeting
E—Innovation Task Force Meeting
F—Presubmission Meeting
G—Accelerated Assessment Meeting
H—Name Review Group Meeting
I—PRIME Kickoff Meeting
**There is no specific guidance on the PRIME kickoff meeting process timeline.

9. Postmeeting Be clear on who will attend on the applicant’s

Applicants are required to send detailed minutes of the behalf and ensure all participants remain focused on
meeting to EMA. EMA will review and adapt to align that goal. Questions should be specific and aimed at
with meeting recommendations. helping the applicant reach this goal.
Strive for agreement on main issues. Try to gain
General Preparation for EMA Meetings clarity, direction and if possible, commitment, on these
Meticulous preparation and setting of clear goals for issues.
each interaction can often be the difference between
success and failure. The applicant’s goals are to gain Be Clear on the Company’s Position
clear advice, overcome potential concerns or objections Conduct a high-level messaging session before initiat-
for the development programme and ensure regulatory ing a meeting procedure request to ensure all functions
requirements are fulfilled. within the company and all outgoing communications are
Regardless of the meeting type, the product cate- aligned. This session should focus on the following steps.
gory for which a company may be requesting approval, • Scrutinise key data for gaps, weaknesses and
or any issues that may be playing out in the external alternative interpretation.
environment, all EMA meetings share the commonal- • Brainstorm and identify both strengths and
ities of needing to tell a clear story, setting the data or potential issues and concerns.
issue in context and providing a credible path forward • Develop high-level messages to provide the
that will adequately support MAA approval. basis for conversations with EMA.
Just as EMA has a process for determining thresh- • Make sure the team clearly understands, is
olds for whether a drug should be approved, a company aligned with, and can articulate, the company
needs a process to keep its team on track and to prepare position.
in the most efficient and effective way.
The best process will incorporate the following steps: Provide Pertinent Meeting Materials in a Timely
• Develop a strategy to attain company goals. Manner so EMA can Adequately Analyse the
• Understand the areas of interest for the Information
audiences. Send EMA materials and communications by the
• Prioritise data and other information. agreed upon deadline. Make sure each section of the
• Prepare speakers to articulate the information briefing document has a clear, key message that rein-
and answer questions effectively. forces what committee members will hear in the core
• Test and measure progress with well-organised presentation.
practices and rehearsals.
Anticipate Concerns and Interests; Be Prepared to
Prior to all communications with EMA, whether in Answer Likely Questions from EMA
writing, in person or by telephone, companies should Understand the potential risks that can arise from a
consider the following steps. difference in data interpretation or recommended data
requests, and proactively prepare acceptable contingency
Know the Audience scenarios to resolve them.
Anticipate what is important for the committee that Anticipate potential shifts in opinion or recom-
will provide advice or guidance, and tailor communica- mendations caused by recent publications and new
tions to their needs. marketing authorisations. In addition to any concerns
EMA may have on the specific product, proactively
Know the Issues address concerns or issues related to therapeutic area,
Focus communications to proactively address standard of care, class precedent and public perception.
known and likely concerns and differences in data Anticipate inter-agency communications that may
interpretation. influence data perception (e.g., concerns shared by FDA).
Set a Goal for Each EMA Communication or Be Organised

Meeting Manage the meeting time carefully to ensure an ade-
Determine the meeting objective or purpose, whether quate discussion and clear understanding of answers
it is to obtain guidance, present the development pro- and recommendations within the allocated time period.
gramme or obtain approval for the product.

Chapter 4
Bring the appropriate people to the meeting to Detailed Review of the Scientific Advice
discuss questions and provide any necessary clarification and Parallel Advice Meeting Procedures
to the committee.
Scientific Advice and Protocol Assistance
Non-binding scientific advice can be requested for
Adequately Prepare for the Meeting all medicines, as well as veterinary products. In addi-
Conduct “in-role” practice sessions to test the appli- tion, protocol assistance is available for medicines that
cant’s position on all essential meeting topics. Focus have received designated orphan drug status by the
on delivering concise, credible messages supported by Committee for Orphan Medicinal Products (COMP).
data that address known and potential objections. These This primarily covers the Centralised Procedure, but sci-
sessions should help establish boundaries for acceptable entific advice also can be obtained on the national level.
and unacceptable activities and parameters and provide The scope of scientific advice includes:
potential pathways for follow-up discussions. • acceptability of a development programme for
marketing authorisation, conditional market-
Listen Carefully to What EMA Actually Says ing authorisation, or a marketing authorisation
Carefully review written feedback, and gain clarification under exceptional circumstances
regarding vague or unclear issues, objections or questions. • clinical trial design to assess efficacy and safety
• During in-person meetings, pay attention to • paediatric development
body language, internal dynamics and offhand
remarks. Potential questions could focus on one or more of the
• During telephone meetings, listen to voice following topics:
tone. Immediately correct any misinterpreta- • quality (e.g., manufacturing process and
tions or misconceptions EMA might have. testing)
• nonclinical (e.g., pharmacology, toxicology and
Record Feedback biodistribution)
Strive for clear agreement on critical decisions and • clinical (e.g., study design, endpoints)
make sure they are clearly documented. • methodological (e.g., biomarkers)
• overall development strategy
Foster a Flexible, Collaborative and Non-
Adversarial Relationship Meeting Requests and Timing
Keep the lines of communication open. Do not take a The Scientific Advice Meeting is requested by submit-
divergent point of view personally. Always retain compo- ting an LOI using the LOI template and preparing
sure if EMA takes the opposite position. Listen to EMA’s a briefing document using the briefing document
requests and provide answers, where possible, before they template provided on the EMA website.5 Using this
become obstacles to approval. Be respectful but not meek. template helps applicants provide sufficient information
Be prepared to calibrate the communications strategy in on the medicinal product and frame the questions to
light of shifting issues, an evolving environment and any obtain the advice they are seeking.
changes within the EMA review team. The questions should be direct and focused to receive
Anticipate potential data requirements beyond the most useful information back from the agency.
those being articulated by EMA in case the agency The draft briefing document should be submitted
shifts direction or changes its mind. using Eudralink, as the agency accepts electronic sub-
missions only. These documents should be submitted
Be Clear About Timelines three weeks before the procedure’s intended start date
As applicants progress through the approval process, it is or seven weeks prior if a presubmission meeting is
essential that they have a good overview of the timelines required. The briefing document should also be sent to
for meetings, as these timelines will dictate how they will scientificadvice@ema.europa.eu.
prepare. An overview of the timelines associated with
the nine basic steps involved in the process is provided in Briefing Document
Table 4-3. Applicants should utilise the EMA guidance The briefing document introduction should cover the
as they define their explicit preparation steps. disease being treated and the product under develop-
The timelines are strict; applicants must make ment. Background information should provide context
sure that they do not miss out on valuable input or risk for the whole programme in addition to the quality,
alienating decision-makers by missing key dates and/or nonclinical and clinical questions being asked. The
milestones. scope, rationale and applicant position for each question

should be explained fully. Suggested templates for pre- • explicit authorisation of the agencies to
paring the briefing document and the LOI are provided exchange information relevant to the product,
on EMA’s website.6 including trade secret information
Other briefing document sections should include
the current regulatory status of marketing authori- Requesting a PSA does not guarantee one will be
sations, global clinical trial approvals and literature granted. One or both agencies may decline to partic-
references. If used, copies of literature references should ipate. If a request is declined, an applicant may elect
be included. to request scientific advice from each agency individ-
ually. If the PSA is granted by both agencies, each one
Meeting Presentation acknowledges the request and assigns a primary contact.
A face-to-face meeting is not convened for all products. The PSA process corresponds to the 70-day procedure
Should a meeting be scheduled, they generally last 90 timeline outlined in Table 4-1 and the timeline for an
minutes. A very brief presentation should be prepared, FDA Type B meeting. These timelines are generally
including a brief summary and a brief, systematic review aligned, and the meeting occurs at approximately Day
that addresses each question. Typically, agency feedback 60. The meeting is usually held by teleconference or
is provided in advance, and the company may decide not videoconference and is coordinated by the agencies’
to discuss a specific question if the agency’s response is primary contacts. PSA meetings are not under the man-
clear. New topics should not be introduced. date of the US Prescription Drug User Fee Act (PDUFA);
therefore, they are not subject to the PDUFA meeting
Parallel Scientific Advice (PSA) with the US Food performance goals.
Drug and Administration (FDA) After the PSA procedure concludes, each agency
The goal of Parallel Advice is to concurrently exchange retains individual authority regarding product develop-
EMA and FDA’s positions with applicants on scientific ment and marketing applications, and the advice may be
issues arising during new medicinal product devel- different from each agency, although they try to provide
opment. These interactions are aimed at increasing consistent PSA responses.
communication among the two agencies and the com- Both agencies strive to meet process and review
pany at the beginning of a new product development goals and timeframes, and the procedure should not
lifecycle. This has the potential to enable a faster product adversely impact either agency’s ability to meet its
development pathway and provide a deeper understand- performance expectations. Each agency commits to rec-
ing of the regulatory expectations from each agency. ognising the other’s domestic performance expectations
These procedures are voluntary and initiated at an and exhibiting flexibility when scheduling the meetings
applicant’s request. In special instances, EMA or FDA to enable them to meet their performance goals.
will initiate the process but with full cooperation from
an applicant. As with the scientific advice process, the Parallel Advice with Health Technology Assessment
Parallel Scientific Advice (PSA) request should focus Bodies
on specific product development questions where an Parallel EMA and Health Technology Assessment
applicant is seeking specific EMA and FDA input. (HTA) advice with Health Technology Assessment
The goal of harmonisation is increased insight on the Bodies (HTABs) is intended to advise applicants on the
agencies’ requirements and perspectives. If differences data and evidence required to determine a medicinal
exist, the reasons for them should be clarified. A PSA product’s benefit-risk ratio and value as efficiently as
is particularly relevant for those products that are not possible. It is a multi-stakeholder procedure with reg-
covered by existing guidelines or when EMA and FDA ulatory agencies and HTABs. The advice each agency
guidelines diverge. The number of PSA procedures is provides is not binding.
limited and may only occur once in a product’s develop- The meeting request should be specific as to the
ment lifecycle. desired date of the meeting and which HTABs are
To request a meeting, applicants need to send one being requested, the type of questions that will be put
letter to both EMA (emainternational@ema.europa.eu) forth and whether a presubmission teleconference is
and FDA (OC-OIP-Europe@fda.hhs.gov).The request being requested. Nonclinical and quality questions can
should include the following elements: be asked only of EMA.
• details of the product in development The European Network for Health Technology
• reasons why a joint discussion with EMA and Assessment (EUnetHTA) was established to create an
FDA reviewers would be beneficial effective and sustainable network to provide reliable
• specific questions and transparent HTA information across Europe. Early
• meeting’s goals dialogues with the EUnetHTA Secretariat will facilitate

Chapter 4
centralised HTA recruitment and determine whether • The exception option includes a telecon-
the consultation will follow a consolidated (i.e., full ference for either inexperienced applicants
participation) or the individual national HTA pathway. needing additional guidance or those with
An applicant should designate a single point of very complex programmes; this is requested
contact to interact with EMA and HTA representatives. by applicants in the notification letter. This
EMA will manage the administrative and logistical option takes approximately eight weeks. A
coordination, maintaining a contact sheet for all EMA teleconference will be scheduled approximately
participants. Scheduling will be in line with EMA four weeks after receipt of the briefing docu-
standard timetables, and the agency will send calendar ment. Applicants will provide a presentation
requests to all participants after the meeting is confirmed. covering the background, the questions and
EMA and participating HTABs may identify the the applicant’s positions at least four working
need for clinical experts from EMA, national author- days before the teleconference. Collated com-
ities and Healthcare Professionals (HCPs). Patient ments from the teleconference are shared with
experts may be identified through patient organisations. applicants within four days of the scheduled
EMA will inform an applicant via the draft list of par- teleconference.
ticipants. Conflicts of interest will be handled through
EMA standard policies. After receipt of collated comments, an applicant submits
A common briefing document is used, and each two versions of the finalised briefing document: one
question can be addressed to the regulatory agency or in track changes and one clean. These should include
the HTABs individually or jointly. All document sub- references and annexes that address all EMA and
missions will be handled through the secure Eudralink EUnetHTAB comments and points of clarification to
system. the EMA Scientific Officer and EunetHTA Secretariat.
Upon confirmation of validation, an applicant will send
Key Phases of the Parallel Process with HTABs the final briefing document directly to all EMA contacts
Simultaneous Notification (Early Engagement) via Eudralink. The procedure will formally begin one day
For all Parallel Consultations, applicants should simul- after sharing the final briefing document.
taneously notify the EMA Scientific Advice Secretariat
(scientificadvice@ema.europa.eu) and EUnetHTA ED Evaluation
Secretariat (eunethta-has@hassante.fr) by means of a The SAWP discusses the preliminary views and gen-
Letter of Intent using the available form for Parallel erates an EMA List of Issues. In parallel, HTABs will
Consultations. conduct their own assessment and draft a list of issues.
This notification allows the EUnetHTA Secretariat The EUnetHTA Secretariat will facilitate coordina-
to confirm completion of the selection criteria and tion of respective HTAB positions, and the Scientific
determine consolidated versus individual consultation. Coordinator will consolidate a draft HTA List of Issues.
This allows scheduling of face-to-face meetings Both the EMA and HTA’s List of Issues should be pre-
with HTABs. These meetings are scheduled during pared within 32 days; they are then exchanged.
the same week as a Scientific Advice Working Party At approximately Day 32 of the procedure, a
(SAWP) meeting. The pre-notification period ends once pre-teleconference meeting is held between EMA and
an applicant submits the LoI and draft briefing docu- EUnetHTABs to discuss positions and identify any
ment to EMA as well as the participating HTAB. This divergent issues or recommendations so that these can
LoI and draft briefing document should be sent in line be discussed in advance of the face-to-face meeting.
with EMA’s scientific advice timetable. EMA and the EUnetHTA Secretariat send the final
versions of the List of Issues to an applicant following
Presubmission the teleconference. These are also exchanged between
The presubmission phase is initiated once the LOI and EMA and the EUnetHTA Secretariat.
draft briefing document are sent to EMA (scientificad- Applicants should respond to the List of Issues that
vice@ema.eupropa.eu) and participating HTABs. There are will be shared with all EMA and HTAB participants at
two options: one with a teleconference and one without. least 12 working days before the scheduled face-to-face
• The standard option is based on written com- meeting.
ments without a teleconference. The draft There should be no major changes to the develop-
briefing document is sent at least 30 days ment plan unless it is in response to the List of Issues. If
prior to the start of the procedure, and col- changes are made, the amended development plan must
lected comments are sent to applicants within be submitted at least 12 days prior to the face-to-face
approximately 15 working days. meeting, with a table justifying any changes. Applicants

should submit an intent to amend the development plan A follow-up procedure is possible, and these pro-
as early as possible. Any changes to the development cedures should contain a table outlining the differences
plan after these dates will not be addressed in either the from the development plan along with justifications for
meeting or the minutes. all changes.
Applicants should submit their final presentation
and list of participants to all EMA participants and the Conclusion
EUnetHTA ED Secretariat four working days before The meeting procedures with EMA present an excellent
the face-to-face meeting. A final list of meeting partici- opportunity to establish strong and constructive rela-
pants will be shared two days before the meeting. tionships with the different committees involved in the
European regulatory process. Each interaction can provide
Discussion Meeting applicants with crucial insights throughout the develop-
The aims of the face-to-face meeting are to discuss: ment process that can lead to more efficient and effective
• issues of concern or disagreement from reg- regulatory and development pathways for medicines.
ulators and/or HTABs with an applicant’s One of the keys to success is ensuring that appli-
proposal regarding major aspects of trial cants approach the EMA process in a clear, structured,
designs and organised way, to increase the chances of achieving
• critical divergences between HTABs and regu- regulatory approval for innovative medicines.
lators on major aspects of trial designs
• potential solutions that could facilitate one References
trial design or at least one development plan 1. The Medicines and Healthcare products Regulatory Agency
(MHRA) has responsibility for marketing authorisations in
the UK following exit from the EU. Previously posted MHRA
The face-to-face meeting has two co-chairs: one from documents provided guidance on additional UK-specific steps
EMA and one from the HTABs. The meeting duration and alignment with European Medicines Agency (EMA) MAA
will depend on the range of issues to be discussed and procedures. However, these guidances and publications were
withdrawn on 31 January 2020. Updated guidances should
advice format; the maximum length of the meeting is be forthcoming via the MHRA website. https://www.gov.uk/
three hours. government/organisations/medicines-and-healthcare-prod-
Before an applicant enters the room, the EMA ucts-regulatory-agency. Accessed 13 March 2020.
regulators and the HTABs have the opportunity to 2. Pre-authorisation guidance: Steps prior to submitting
the application. EMA website. https://www.ema.europa.
have a closed session to align on any possible changes of eu/en/human-regulatory/marketing-authorisation/
position after an applicant’s responses and presentation. pre-authorisation-guidance#2.-steps-prior-to-submit-
The meeting with an applicant is interactive, focus- ting-the-application-section. Accessed 5 March 2020.
ing on the issues raised by the EMA and HTAB’s Lists 3. From laboratory to patient: the journey of a medicine assessed
by EMA. EMA website. https://www.ema.europa.eu/en/
of Issues. documents/other/laboratory-patient-journey-centrally-autho-
Following the face-to-face meeting, a closed rised-medicine_en.pdf. Accessed 5 March 2020.
debriefing between HTAB and EMA regulators is held 4. European Medicines Agency guidance for
to recap and resolve any outstanding divergences. If any applicants seeking scientific advice and
protocol assistance. EMA website. https://www.ema.
remaining differences cannot be resolved, possible ways europa.eu/en/documents/regulatory-procedural-guideline/
to address those issues should be considered. european-medicines-agency-guidance-applicants-seeking-scien-
tific-advice-protocol-assistance_en.pdf. Accessed 5 March 2020.
Postmeeting 5. Requesting Scientific Advice or Protocol Assistance From
EMA. EMA website. http://www.ema.europa.eu/ema/index.
Applicants should submit detailed meeting minutes to jsp?curl=pages/regulation/general/general_content_000057.
all participants within five working days. The minutes jsp&mid=WC0b01ac05800229bf. Accessed 5 March 2020.
should reflect each participant’s views as well as areas of 6. Scientific Advice and Protocol Assistance. EMA website. http://
agreement and divergent positions. An applicant’s min- www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/gen-
eral/general_content_000049.jsp&mid=WC0b01ac05800229b9.
utes are regarded as its record of the meeting and are Accessed 5 March 2020.
not adopted by EMA or HTAB participants.

Chapter 4

Chapter 5
Preparing for EMA Meetings

During Review of a Marketing
By Kell Cannon, Kate Dion and Cindy DiBiasi
OBJECTIVES □ Committee for Advanced Therapies (CAT) Rules

of Procedure (February 2014)3
□ Outline the key review meetings used by the
Committee for Medicinal Products for Human
Use (CHMP) and the Committee for Advanced Introduction
Therapies (CAT) during review of a Marketing Three EMA scientific committees are involved in the
Authorisation Application (MAA) evaluation of products seeking centralised marketing
authorisation in the EU (Table 5-1). Each of these
o Oral Explanation (OE)
committees is composed of members from each of the
o Scientific Advisory Group (SAG) 27 EU Member States and up to five co-opted mem-
bers who provide additional ad hoc scientific expertise.
o Ad Hoc Expert Group Iceland and Norway are also non-voting members.
For each of the three committees, the scien-
□ Explain the role of clarification/discussion tific review and evaluation is led by a rapporteur and
meetings with rapporteurs co-rapporteur appointed from among that committee
(collectively referred to as rapporteurs). The rapporteurs
□ Understand the role of the Pharmacovigilance
will prepare an assessment report and draft opinion,
Risk Assessment Committee (PRAC)
either positive or negative, for the entire committee to
□ Provide an overview of best practices for review and issue a majority decision. If an applicant
developing effective strategies that increase the and rapporteurs can resolve all important review issues
likelihood of success at these meetings through written responses, issue a positive opinion for
marketing authorisation and have it agreed upon by
the committee, no meetings with these committees are
DIRECTIVES, REGULATIONS AND GUIDELINES
necessary. Meetings with the rapporteurs during MAA
review are strongly advised.
□ Guidance on meetings with applicants on the However, there are frequently applications in which
responses to questions received from European the rapporteurs and applicant are unable to resolve
Medicines Agency Scientific Committees during important review issues. This can lead to major objec-
the evaluation within the centralized procedure tions that prevent a positive opinion. This results in
(January 2015)1 meetings between either an applicant and the rappor-
teurs, the full committee or an independent scientific
□ Procedural Advice for CHMP on the need to group. These meetings have rigorous requirements, rein-
convene a Scientific Advisory Group (SAG) or Ad forcing the need for meticulous preparation and practice.
Hoc Expert Meeting (July 2011)2 Face-to-face MAA-related committee meetings
take place at the CHMP building in Amsterdam and
are typically scheduled for one hour. Applicants are

Chapter 5
Table 5-1. EMA Scientific Committees: Roles
Committee Assessment Role

Committee for Medicinal • Preparation of final opinion regarding the benefit-risk of a human medicine
Products for Human Use based on a comprehensive scientific evaluation of the quality, safety and
(CHMP) efficacy
• While not addressed in this chapter, the CHMP also evaluates medicines autho-
rised at national level referred to EMA for a harmonised position across the EU
Committee on Advanced • Preparation of draft opinion regarding the benefit-risk of an Advanced Therapy
Therapies (CAT) Medicinal Product (ATMP, defined as a medicine based on genes, tissues or
cells) based on a comprehensive scientific evaluation of the quality, safety and
efficacy
• This opinion is used by the CHMP to adopt a final opinion on marketing
authorisation
Pharmacovigilance Risk • Provide recommendations to the CHMP and CAT regarding pharmacovigilance
Assessment Committee (PRAC) and risk management aspects of the product seeking authorisation
instructed to limit the number of meeting participants report can give some insights into important concerns
to 10 people, with others able to join in listen-only and issues.
mode by telephone.
Before applicants enter the room, the rapporteurs Five Types of Meetings During Marketing
brief the committee. After applicants leave the room, Authorisation Review
the CHMP deliberates and votes. The outcome of the The five types of face-to-face meetings that can occur
decision is based on a majority vote. during a marketing authorisation review are:
Should there be the need for independent advice 1. clarification and discussion meetings
on scientific and technical matters relating to prod- 2. Oral Explanation (OE) meetings
ucts under evaluation, the CHMP and CAT will seek 3. Scientific Advisory Group (SAG) meetings
non-binding advice from a Scientific Advice Group 4. Ad Hoc Expert Group meetings
or Ad Hoc Expert Group. For these advice meetings, 5. Pharmacovigilance Risk Assessment
applicants stay in the room when the rapporteurs com- Committee (PRAC) meetings
municate the data and requested guidance, but they do
not stay in the room for the deliberations, recommenda- A meeting could be signaled at several key time points
tions and final vote. during the regulatory process. These timepoints typically
Given what is at stake during these meetings and coincide with the sharing of important feedback from
the limited amount of time to address the objections, it the CHMP, CAT or PRAC to an applicant, as shown
is essential that applicants develop a strategic communi- in Figure 5-1. The decision to hold a meeting is usually
cations plan to deliver clear and convincing messages. communicated when the assessment report contained in
If applicants plan and prepare effectively, these the List of Outstanding Issues (LOI) is shared with the
meetings can offer an opportunity to: applicants. This is at Day 180 in the case of Standard
• resolve or ameliorate major objections that Assessment; however, applicants will often have already
have been raised received an indication of the likelihood of a meeting
• demonstrate a positive benefit-risk for their based on the draft review (e.g., Day 80 of Standard
product Assessment) and the List of Questions (LOQ) (i.e.,
• gain alignment on a potential path for obtain- Day 120 of Standard Assessment).
ing marketing authorisation
Clarification and/or Discussion Meeting Between
It is worth noting that these meetings are private, with
no public transcript. While CHMP minutes will note Applicants and Rapporteurs
the general discussion topics during MAA review, they Following receipt of the rapporteurs’ and CHMP’s
will omit key details related to CHMP objections and written feedback (e.g., draft assessment report, LOQ,
committee discussions. However, the final assessment LOI), applicants should request a clarification meet-
ing with the rapporteurs to gain further explanation

Preparing for EMA Meetings During Review of a Marketing Authorisation Application
Figure 5-1. Approximate Representation of Key CHMP, CAT and PRAC Feedback and Meetings Based on
Standard Assessment Review Timeline*
Day 180 Day 210

Day 80 Day 120 Oral
Opinion Final
Review LoQ** Explanation
Secondary & LoOl** Opinion
Evaluation
Extra
Advice
SAG or
Expert
Group
PRAC
*Actual timeline will depend on application review situation
**Clock stop until applicant submission
and interpretation regarding questions, comments or and co-rapporteur. Each member has one vote, except
concerns. In addition, applicants can propose potential the Chair and members from European Economic Area
strategies, actions or changes that might resolve poten- countries whose votes are not included when determin-
tial issues that improve the benefit-risk assessment and ing a majority result. The CHMP members are likely
help support authorisation. These meetings also provide to be familiar with an applicant’s product and the many
an opportunity for applicants to demonstrate a willing- issues discussed during the review; however, they will
ness to collaborate with the rapporteurs. not be as informed as the rapporteurs.
These meetings may be either by teleconference or The CHMP restricts the presentation to 20 min-
face-to-face, depending on timing, availability and need. utes, with approximately 40 minutes for Q&A.
Oral Explanation (OE) Meeting Scientific Advisory Group (SAG) Meeting

An OE may be called at the end of the review cycle SAG meetings provide independent scientific and clin-
when the opinion remains negative or the committee ical recommendations from pre-identified European
Chair determines that the vote may be “split” or nega- experts. There are eight established therapeutic area
tive. This is usually due to remaining major objections groups: anti-infectives, cardiovascular, diabetes/endo-
from one, or both, of the rapporteurs. As needed, the crine, HIV/viral, neurology, oncology, psychiatric and
Chair may take a trend vote the day before the sched- vaccines. Each group usually has 10 to 20 standing
uled meeting to gauge the committee opinion and the members from that therapeutic field, and one to three
need for an OE. Even so, applicants have the right to an experts on the specific disease. In addition, each SAG
OE before the CHMP takes a negative opinion. meeting will invite at least one biostatistician and at
Company teams are usually notified that they will least one patient representative. The meeting will be
be going to an OE following rapporteur review of an chaired by one of the SAG members.
applicant’s written response to the major and minor The CHMP can decide to involve a SAG for a
objections contained in the LOI document. The meet- number of reasons, including:
ing date typically occurs during the scheduled CHMP • a medicine that addresses a major public health
meetings one month after formal acceptance of the writ- interest and where public controversy might be
ten responses. Since applicants will often request a clock expected
stop in order to address all questions, this enables about • substantial disagreement within the committee
one to three months for the company team to prepare. on clinical aspects
An OE meeting will occur during regularly sched- • controversial issues that may be associated
uled CHMP meeting dates and is led by a rapporteur with the medicine, i.e., that might have a high

Chapter 5
impact on healthcare professionals, the public assessment report. As such, they may become discussion
and/or other stakeholders points at an OE, SAG or Ad Hoc Expert Group meeting.
• complex technical aspects that need to be While it is important to understand the impact of
addressed the PRAC opinion on the overall benefit-risk assess-
• a need to look at risk-minimisation measures ment, there is no formal presentation to the PRAC
that could affect clinical practice during an initial MAA review. However, applicants may
• questions regarding the design and feasibility be asked to present to the PRAC based on postapproval
of a post-authorisation efficacy trial pharmacovigilance. Meeting logistics are similar to an
• major postauthorisation safety issues OE meeting but are not addressed in this chapter.
In advance of the meeting, the rapporteurs will com- Meeting Preparation

municate the specific questions that will be addressed Be Ready and Proactive
by the SAG committee. During the meeting, applicants It is crucial that applicants prepare for a potential
can present data that support the application and can meeting as soon as it is apparent that there may be an
communicate their position regarding the specific ques- unresolved problem.
tions the CHMP would like the SAG to address. Applicants can increase their chances of success
The CHMP recommends a presentation of no more during these meetings by taking a few simple, but
than 30 minutes, with the remaining time for Q&A. highly effective steps.
The need for a SAG should be identified as early as 1. Understand the audience, their backgrounds
possible in order to allow adequate planning and meet- and the areas of interests pertaining to the
ing preparation, including the nomination of additional product’s issues.
SAG experts if necessary. Typically, a SAG meeting will 2. Conduct an honest and comprehensive assess-
occur after assessment of the responses to the LOI by ment of the data.
the applicant/MAH and before an OE or final opinion. 3. Develop messages that address major objec-
The EMA policy on conflicts of interests (EMA tions and communicate a positive benefit-risk.
POLICY/0044) and the EMA Code of Conduct on con- 4. Create clear slides with simple visuals that
fidentiality (Section 6) apply to all invited participants.4,5 focus on the most relevant data, as message
retention in these meetings is essential. The
Ad Hoc Expert Group Meeting ability to support each verbal response with a
These meetings play the same role as SAG meetings for visual is a critical component to help voting
other therapeutic areas or areas of interest that are not members remember the message after appli-
covered by one of the eight SAG committees. cants have been dismissed from the room.
The CHMP will attempt to recruit knowledgeable 5. Prepare and submit a concise briefing doc-
European experts for the clinical condition. For rare ument that addresses the issues, sets out the
indications, the CHMP may consult with applicants benefit-risk profile and highlights the key
to identify potential experts who are not conflicted per messages.
EMA policy. In addition, each SAG meeting will invite 6. Control the Q&A session by being prepared
at least one biostatistician and at least one patient rep- for the most likely questions based on the
resentative. This meeting will be chaired by a member of major objection(s). Practice giving concise
the CHMP or EMA. answers and bridging back to the key messages.
The SAG guidance and recommendations apply to Use a technology system that allows rapid
Ad Hoc Expert Group meetings. access to hundreds of backup slides to address
and resolve every conceivable question.
Pharmacovigilance Risk Assessment Committee 7. Conduct mock meetings to prepare. It is rec-
(PRAC) Communications ommended that one or two mock sessions with
The PRAC provides advice to the CHMP and CAT three or four mock panelists who are carefully
regarding the risk of products, both for new applications selected to be representative of the CHMP
and with ongoing pharmacovigilance. This includes members be conducted.
management and mitigation of known and potential 8. This is not the time to leave anything to
safety risks, Postauthorisation Safety (PAS) studies and chance. It is crucial that applicants make sure
pharmacovigilance audits. Most members are pharma- they have enough time to prepare and practice.
covigilance experts. To that end, applicants should implement a
Issues and concerns identified by the PRAC will planning timeline that allows them to effi-
typically be contained within the CHMP or CAT ciently and effectively prepare. This includes:

analysing the issues and objections, developing Figure 5-2. Example Timeline for CHMP Meeting
a strategy to prepare content that addresses Preparation
those issues, testing and evolving the strat-
egy and conducting final onsite practices in
Amsterdam prior to the actual meeting. Best Phase 1 Phase 2 Phase 3 Phase 4
practices support a two-month timeline as (Analyse) (Build Strategy (Test) (Execute)
and Content)
shown in Figure 5-2.
Prepare Early Month 1 Month 2

As applicants seek to prepare, manage and excel at CHMP
meetings, they should ensure they dedicate enough time Mock 1 Mock 2
to develop a compelling narrative that answers regulators’
concerns. Once they have done this, it is imperative that 1st Draft 2nd Draft
they practice delivery of their key messages. of Core of Core
Kickoff Final
A key part of the preparation for these meetings is Meeting Rehearsals
analysing the underlying concerns of the CHMP and Amsterdam
making sure that the content of the briefing documents,
Q&A Practice – Speaker Training
presentation and all answers given during the meeting
are relevant and to the point. Applicants should focus
on new analyses and actions that help address the major Preparing Briefing Materials, Main (Core)
objections and describe the favourable benefit-risk Presentation and Responses to Questions
profile of the medicine. It is important that they draw A well-constructed scientific story providing context
conclusions for each major objection so that the audi- for how the data and actions resolve the major objec-
ence is very clear about the significance of each piece of tions and support a positive benefit-risk profile are the
data and the takeaway message. backbone of an applicant’s presentation and optional
Due to the significant amount of preparation that briefing document.
is required, it is critical to select the right team, assign To ensure consistent messaging across all materials,
members to the correct roles and to set ground rules no content should be developed until a strategic mes-
and realistic expectations. A key starting point on team saging session is conducted. The messaging should drive
selection is identifying a senior research and develop- the content of the presentation script, slides, briefing
ment or regulatory person to champion the project and document and answers to key questions. This process
ensure that preparing for the CHMP meeting is the top should begin as soon as an applicant has selected and
priority for key team members. The ideal team should organised its team based on the key issues identified by
include European clinical experts and functional area the rapporteurs.
experts relevant to the major objections. Each selected There are key steps to creating, prioritising and
representative should bring individual expertise and harmonising content:
a unique perspective that can help secure a positive • Conduct a brainstorming session with key
majority vote. Orchestrating the team, considering and people from the applicant’s team. Set a goal for
weighing its input and selecting each team member’s the content. What needs to be communicated
specific role is as much an art as it is a science. to resolve the objections, and what is necessary
to demonstrate a positive benefit-risk profile.
Understand the Committee Members Focus on messages that best support a positive
Each of the 27-member nation committee members vote.
and alternatives has their own individual style and • Discuss and prioritise the data that succinctly
concerns. This impacts how they interpret the data, support key messages, with emphasis on
what questions they ask and ultimately how they vote. expanded analyses and new actions. Keep in
Understanding each member’s expertise and areas of mind that the rapporteurs are often seek-
interest can help frame a relevant presentation, predict ing iterative support to overcome concerns
questions and help prepare answers. rather than repeating what has already been
As needed, there may be up to five co-opted sci- considered.
entific experts. These typically have more knowledge of • Incorporate the data into a message grid that
the therapeutic area and will often influence how the serves as an outline for the narrative that will
committee interprets the data. underpin the presentation. It also aids in the
preparation for the questions and answers

Chapter 5
section of the meeting. The messages in the Consider Writing a Briefing Document
framework must be the same messages that A briefing document is optional, but a very brief
applicants want the committee to retain after summary of an applicant’s position can help frame
the team has left the room. the discussion among voting committee members. It
• Assign individual “owners” to issues by topic. is important to remember that the meeting is one of
Assign responsibility and accountability to dozens of other discussion topics that compete for the
specific team members for gathering data, attention of attending members. While the CHMP
drafting the first set of answers to questions recommends a briefing document no more than 40
and developing supporting documentation in pages, ideally it should be about 20 pages and presented
the form of charts, graphs or tables for slides. in a well-organised format that can be quickly read and
• Once the content has been determined, it is understood easily. The final briefing document is due to
time to develop the presentation and briefing the rapporteurs seven days prior to the meeting.
document flow. Write clearly and use a logical
structure. Applicants should make sure they Preparing for Q&A
signal or headline their main points succinctly, Since the meeting will focus on the issues cited in the
speak in short sentences and use words that LOI, the major objections will define the priority for
are readily understood by committee members Q&A preparation. However, applicants should be pre-
who are not native English speakers. pared to answer all potential committee questions and
support a positive benefit-risk.
Scripting and Developing the Core Presentation When developing answers to questions, it is import-
Message retention is critical during these meetings, and ant that applicants document and categorise questions in
it is enhanced by simplifying the message and support- a well-organised fashion. Answers should be developed
ing it with only the most essential information. Verbal with clear headlines, so the responses and messages
messages are better remembered when supported with are succinct and direct. In addition, companies should
a visual, so slides must reinforce the verbal message. document who will answer each question and prepare
Because this is not a typical scientific presentation, but a supportive slides that will reinforce the verbal message.
persuasive argument with a singular goal, every word is
important—and it is critical to control the story around Developing and Managing Slides
the data. The science does not speak for itself, and not Once the script is written, and as answers to questions
everyone will interpret the data the same way; therefore, are being crafted, PowerPoint slides should be devel-
context and clear explanation are essential components oped to reinforce the information visually. A slide’s
for success. purpose is to support the presenter’s message, not
Scripting every word of the presentation is a must, confuse it. As a result, the text on slides should follow
as this ensures the message’s precision and clarity and the same clear communication rules as in the presenta-
reduces the chance of “new ideas” or impromptu state- tion. To further support clear communications, choose
ments during the presentation. Outlining and scripting a simple, clear slide template with mid-to-dark blue
the presentation before developing slides allows messages backgrounds and a simple sans-serif font to reduce eye
to drive the presentation and will help applicants avoid strain. For graphs, ensure the x- and y-axes are thick
falling into the trap of providing data without context. and vibrant enough to be seen throughout the meeting
The core presentation is delivered orally rather than room and are labeled clearly with easy-to-find legends.
in writing; therefore, it is important to write the script Text slides should include the minimum number of
for the ear and not the eye. That means using short words necessary to answer the question succinctly. Any
sentences and an active voice. This will make it much slide’s goal is to pass the “glance test,” so that commit-
easier for the presenter to deliver and will significantly tee members immediately understand its message. Too
increase the chances that the non-native English- much information on one slide can be confusing and
speaking audience will understand it the first time they make the message less clear. With slides, as with writ-
hear it. The presentation’s goal is to have all voting ing, less is usually more.
members understand the data the same way. Companies typically hand over to the CHMP all
The draft core presentation is due seven days prior their slides, including their backup slides, at the start of
to the meeting and is forwarded to the meeting attend- the meeting. Understandably, this has often resulted in
ees. However, applicants can revise the presentation up applicants restricting the number of backup slides that
until the morning of the meeting. could help answer questions during the meeting.
Applicants should use a Q&A retrieval system that
allows access to all relevant support slides. This system

should allow responders to preview a slide on a moni- discussed, and those discussions should be fast, focused
tor that only they can see and, then, decide in real time and confidential.
whether to show that slide or call for another. This is cru- Whatever system is chosen, it must be decided in
cial since it furthers applicants’ ability to share data, helps advance and communicated to everyone involved. This
to augment credibility and reinforces memorable messages. includes everything from ensuring the availability of
enough meeting rooms with working computers, print-
Ensuring Perfect Practice Through Rehearsals ers, copiers and fax machines, etc. Whether a company
As the content is being developed, it also needs to be hires a professional meeting planning company, a secu-
tested. Applicant teams frequently wait too late in rity firm or handles these tasks internally, organisation
the process to begin testing. This is a lost opportunity and security are crucial components to ensuring the
because testing through practice is the best way to meeting runs smoothly.
refine content.
In addition to internal team rehearsals, applicants Conclusion
also should hold realistic rehearsals with external Every engagement with CHMP is a chance for appli-
experts role-playing the CHMP, SAG or PRAC mem- cants to resolve objections and reinforce the positive
bers. A mock meeting is an intentionally harsh rehearsal benefit-risk profile of the medicine. It is not always easy
where an applicant’s team gets its first taste of what it for applicants to ensure those voting on the product retain
is like to present to a potentially critical audience and the key messages that will support a positive vote due to
answer questions under pressure. If done correctly, this the limited access to the committee members, as well as
mock meeting will give an applicant a reality check. technology and time constraints. Fortunately, it is possible
The more realistic the mock members are, the better to overcome these challenges through careful preparation
prepared the presenters and other responders will be for and practice and systematic implementation of actions
the actual meeting. designed to make messages credible and memorable.
The best mock meetings are a dress rehearsal for
the real event. The room should be set up in a similar References
formation as on the actual meeting day. It is important 1. Guidance on meetings with applicants on the responses to
questions received from European Medicines Agency Scientific
for mock committee members to stay in role to provide Committees during the evaluation within the centralised
presenters with a realistic run-through. To maximise procedure. 25 January 2015. EMA website. https://www.ema.
the value of the mock meeting, applicants provide the europa.eu/en/documents/regulatory-procedural-guideline/
assessment report, list of relevant unresolved objections guidance-meetings-applicants-responses-questions-received-eu-
ropean-medicines-agency-scientific_en.pdf. Accessed 3 March
and the briefing document to mock members prior to 2020.
the rehearsal, so they come into the meeting with simi- 2. Procedural Advice for CHMP on the need to con-
lar preparation as the actual committee. vene a Scientific Advisory Group (SAG) or Ad
Following the rehearsal, the mock members can Hoc Expert Meeting. 21 July 2011. EMA website.
“break role” to provide a tough, insightful critique and procedural-advice-committee-medicinal-products-hu-
give honest feedback about the presenters and their man-use-need-convene-scientific-advisory-group-ad_en.pdf.
presentation. This feedback enables applicants to adjust Accessed 3 March 2020.
and enhance strategy, presentation messages and Q&A 3. Committee for Advanced Therapies (CAT) Rules of Procedure.
13 February 2013. EMA website. https://www.ema.europa.eu/
responses. en/documents/regulatory-procedural-guideline/committee-ad-
An applicant’s internal team should schedule a vanced-therapies-rules-procedure_en.pdf. Accessed 3 March
debrief immediately following each mock meeting and 2020.
document what worked well and what can be done dif- 4. European Medicines Agency policy on the handling of com-
peting interests of scientific committees’ members and experts.
ferently to prepare for the next mock meeting. 6 October 2016. EMA website. https://www.ema.europa.eu/en/
documents/other/policy-44-european-medicines-agency-poli-
Maximising Final Days Before the Meeting cy-handling-declarations-interests-scientific-committees_en.pdf.
Accessed 3 March 2020.
In the few days leading up to the meeting, applicant 5. The European Medicines Agency Code of Conduct. 16 June
teams should set up rehearsals in Amsterdam. 2016. EMA website. https://www.ema.europa.eu/en/docu-
Putting a logistics plan in place is essential to help ments/other/european-medicines-agency-code-conduct_en.pdf.
facilitate and control communications among team Accessed 3 March 2020.
members during the meeting. Given the pressure and
time constraints of the CHMP meeting day, communi-
cation discipline is critical. Only vital issues should be

Chapter 5

Chapter 6
Pricing and Reimbursement

OBJECTIVES activities for pharmaceutical products, the legal frame-

work still allows Member States to shape their own
□ Provide an overview of the EU pricing and reim- healthcare systems independently. This extends to
bursement legal developments national decisions on how drugs are priced, how they
are reimbursed by the healthcare system and the criteria
□ Enable an understanding of pricing and reim-
for selecting these drugs. For many branded products,
bursement relevance and key models used by
most patients rely on reimbursement to be able to afford
the EU healthcare systems
treatments. Thus, for a product to be launched success-
□ Provide case studies and examples to illustrate fully and be economically viable in a Member State,
the EU reimbursement models and how they are two hurdles need to be overcome: regulatory approval
interlinked with health technology assessments and reimbursement qualification. The processes gov-
erning pricing and reimbursement negotiations vary
greatly within the EU, which makes this a complex
DIRECTIVES, REGULATIONS AND GUIDELINES and time-consuming task. Pricing and reimbursement
COVERED IN THIS CHAPTER decisions often are supported by Health Technology
Assessments (HTAs), and it is vital that clinical, regula-
□ Council Directive 89/105/EEC of 21 December tory and market access teams work together throughout
1988 relating to the transparency of measures the development program to ensure a robust evidence
regulating the prices of medicinal products base is generated to support these assessments and
for human use and their inclusion in the ultimately the product’s value proposition. Decisions
scope of national health insurance systems regarding clinical and regulatory strategy, e.g., choice of
(Transparency Directive) comparator, trial design and incorporating patient-rele-
vant endpoints, will have profound implications for how
□ Communication from the commission on the the product will be evaluated by payers and providers
compatibility with Article 30 of the EEC Treaty of and how quickly the therapy will reach patients.
measures taken by Member States relating to An illustration of the importance of harmonis-
price controls and reimbursement of medicinal ing both regulatory and payer approval can be seen in
products (Notice number 86/C 310/08) the lengthy negotiations between GlaxoSmithKline,
Novartis and the UK Department of Health over the
cost of a meningitis B vaccine.1 Meningitis B is a dis-
Introduction abling infection affecting approximately 1,700 people in
Core pricing and reimbursement policies in the the UK annually, with a 10% mortality rate. The vaccine
European Union (EU) relate to the internal markets was approved in the EU in January 20132 and in the
and industrial competitiveness. Although a high level of US in January 2015,3 where it received a breakthrough
harmonisation has been achieved in the EU healthcare therapy designation. In March 2014,4 the UK’s Joint
sector with respect to regulatory pre- and postapproval Committee on Vaccination and Immunisation ( JCVI)

Chapter 6
Figure 6-1. Factors Influencing Medicinal Product Pricing
Funding Payer Product Type
Private: Differs by: Influenced by:

• Out-of-pocket payments Geographic hierarchy • Orphan drug designation
• Co-payments • national • Innovative/ATMP status
• Health Insurance • regional • Medical Device
• Employer benefits • local • Diagnostic
Point of delivery • Generic
Public: • hospital, specialist unit • Biosimilar
• Taxation • general practice, home • Vaccination
• National Insurance Organisations • Contraceptive
• state health insurance • Lifestyle
• private insurance • Complementary/alternative
• charitable foundation therapy
recommended the vaccine for distribution through states it is each Member State’s responsibility to create
the National Health Service. However, a disagreement health policies and organise, manage and fund health
between the original drug developer and the health services and medical care. Article 168 states:
authority over the price per dose (£75 versus £5 per “Union action shall respect the responsibilities of
dose) delayed a decision to roll out the vaccination the Member States for the definition of their health
program in the UK for a year.5 The health authority did policy and for the organisation and delivery of
not find the increased protection against Meningitis health services and medical care. The responsibilities
B warranted the price requested by the company; of the Member States shall include the manage-
resources were deemed better spent on other measures ment of health services and medical care and the
and products. While approximately 1,200 doses of the allocation of the resources assigned to them.”
vaccine were purchased privately in areas like London,
regional uptake was very low, with only about 243 doses The Transparency Directive is aimed at ensuring
sold in the Northeast UK.6 An agreement eventually increased levels of transparency in the way Member
was reached between the manufacturer and payer, and States control medicinal product pricing and reimburse-
the vaccine was approved for inclusion in a mass-vacci- ment. A series of procedures are designed to ensure
nation program, but not before precious time was lost. national pricing and reimbursement decisions do not
Increasingly, efficacy and safety data need to be adversely affect the free trade of pharmaceutical prod-
accompanied by evidence tailored to the relevant payers’ ucts within the EU. This directive’s aim is to ensure
requirements in each Member State to avoid delays pricing and reimbursement decisions are transparent
in getting new products to patients. Who, then, are and non-discriminatory within a precise timeframe. The
these payers, and how is a decision made on whether to directive was amended and adopted in 2013 to take the
include a product in a reimbursement program? Figure increasing complexity of national procedures for pric-
6-1 illustrates possible funding sources for medicines’ ing and reimbursement into account. Despite this legal
reimbursement as well as factors that may affect a prod- framework, and due to its complex implementation
uct’s reimbursement level. across Member States, one of the most common rea-
sons for marketing delays following regulatory approval
Development of Legal Framework remains price and reimbursement negotiations.
In 1986, the Commission issued Communication 86/C The European Commission has issued several
310/08 relating to medicinal product price controls and proposals to update the Transparency Directive but has
reimbursement. This was followed by the Transparency recommended the withdrawal of these proposals, as
Directive (Directive 89/105/EEC), which took effect no agreement on them is foreseeable. The proposals
in 1989. The cornerstones in the EU legal pricing and considered measures like revising pricing and reim-
reimbursement framework for pharmaceutical prod- bursement procedure time limits, including a statement
ucts are the Transparency Directive and the Treaty on that intellectual property rights should not interfere
the Functioning of the EU. Specifically, the treaty clearly with the procedures and proposing that there should

not be a need to reassess regulatory data. The proposals’ Two of these were the ‘High-Level Group on
withdrawal was formally published in March 2015.7 As Innovation and Provision of Medicines,’ launched in
a result of this withdrawal, the regulatory professional 2001, and the ‘Pharmaceutical Forum,’ which operated
remains integral to product development and launch between 2005 and 2008. The former was tasked with
teams, as regulatory data continue to be re-assessed by making recommendations on facilitating the access
payers, with a broader view than just quality, safety and and competitiveness of the European pharmaceutical
efficacy claims. industry.10 The Pharmaceutical Forum’s aim was to sup-
Key requirements outlined in Directive 89/105/ port the health system sustainability across Europe.11
EEC can be consolidated into three major points: As part of its final set of recommendations, the forum
1. Decisions must be made within a specific emphasised the need for Member States’ pricing and
timeframe: within 90 days of receipt of a valid reimbursement policies to ensure pharmaceutical
application and an additional 90 days if clarifi- expenditure control, promote equitable access to med-
cation is needed from the applicant. icines and provide incentives for innovative Research
2. Decisions must be communicated to the and Development (R&D).
applicant and contain a statement of decision
reasons based on objective and verifiable cri- Pricing and Reimbursement Models Used in the EU
teria. The applicant also should be informed Pricing
of permissible remedies and the response time Across the EU, different pricing models and approaches
limit. are applied in varying degrees, but the common goal is
3. Decisions must be open to judicial appeal at to ensure sustainable pharmaceutical expenditure in the
the national level. face of finite resources. The need for such sustainability,
even in wealthy countries, is increasing due to aging
An EU-level ‘Transparency Committee’ was established populations and new drugs and medical devices becom-
following the creation of the Transparency Directive, ing progressively more expensive. Below is a general
which is responsible for discussing issues relating to overview of different EU pricing models.
the directive’s implementation. The committee includes
representatives of all EU Member States and is chaired Reference-Based Pricing Model
by the European Commission. The European Court The price at which a medicine is reimbursed is based
of Justice8 has the final word on the Transparency on the prices of similar (and/or interchangeable)
Directive’s interpretation and implementation. and already marketed products, either within a given
Currently, the Commission is exercising alternative country (internal referencing) or in another country
ways to achieve the proposal’s objectives and to ensure (External Reference Pricing (ERP)). Figure 6-2 pres-
the transparency of pricing and reimbursement measures ents an overview of the ERP process. ERP is regarded
for medicinal products adopted by EU countries. This by many as a benchmark pricing policy, due to its ability
includes receiving feedback from stakeholders about the to significantly drive down pharmaceutical expenditure,
functioning and problems related to the implementation but sceptics point to the fact that it may well result
of the current Directive 89/105/EEC, which remains in in product-launch delays, particularly in countries
force via the transparency committee with EU countries with traditionally low medicine prices.12 This model is
and convening regular meetings to discuss the recent applied, in various forms, in most countries of the EU,
and forthcoming case-law. The Commission may launch with the notable exceptions of the UK and Sweden.
investigations and infringement proceedings whenever Table 6-1 demonstrates the myriad of approaches
appropriate to ensure that the current rules are fully countries take when compiling comparative baskets to
complied with and that the existing problems related to guide reference pricing strategies.
the regulatory framework in place on pricing and reim-
bursement are appropriately addressed.9 Cost-Based Pricing (CbP) Model
A product’s price is based primarily on its production
European Commission Initiatives on cost; in this context, production includes manufac-
Pricing and Reimbursement turing, marketing and R&D. The CbP model was
Following the creation of the Transparency Directive, the widely used in the past, particularly in Italy and Spain.
European Commission launched a number of initiatives Currently, this pricing model is not used commonly
specifically to provide support for EU pricing and reim- across the EU.13 The Pharmaceutical Price Regulation
bursement systems. Scheme (PPRS) is a closely related pricing model to
the CbP and continues to be used in the UK. In this
scheme, prices are re-negotiated after set periods and

Chapter 6
Figure 6-2. Overview of ERP across Europe (2013)
ERP as main criterion

ERP as supportive information
No ERP
Source: External reference pricing of medicinal products: simulation-based considerations for cross country coordination: Final Report (2014)
are designed to incentivise local R&D investment.14 countries that apply some form of managed-entry or
Plans to abandon this scheme in 2014 in favour of a risk-sharing approach to their pricing negotiations.
value-based pricing model appeared to have been halted
by the incumbent government. The PPRS is discussed Reimbursement
in more detail in the next section. To promote its citizens’ health, a Member State’s pur-
pose could be summarised in three obligations:
Value-Based Pricing Model 1. improving public access to therapies
This value-based pricing model allows a pharmaceutical 2. controlling health expenditures
product’s price to be set based on its added therapeutic 3. incentivising and rewarding drug development
value when compared with the existing standard of
care. This model has been promoted as a pricing policy These three goals are potentially conflicting. During
that directly links a product’s price to evidence-based the last decade, national growth has been lower than
value for end-users while at the same time incentivis- the increase in health expenditure; therefore, EU
ing innovation in drug development.15 In some cases, Member States have adopted a wide range of policies
a value-based pricing model can entail managed-entry and procedures to cap costs, yet still allow reimburse-
agreements. Here, agreements are made between a ment of therapeutically relevant medicinal products.20
given country’s relevant reimbursement authority and A reimbursement and pricing system goal is promoting
drug manufacturers to reimburse medicines (usually innovative research and discovery. However, perceptions
high-priced medicines) based on certain conditions the of innovation and added value differ greatly among
reimbursement authority sets.16,17 These conditions are Member States. Nevertheless, governments gener-
aimed primarily at managing uncertainties about the ally consider the following questions when deciding
medicine in question. This model increases the chances whether to reimburse a product:
a medicine will achieve reimbursement despite limited • Does it work?
evidence of its added therapeutic value,18 and it also • How does it compare to what exists already?
allows risk-sharing between the payer and the manufac- • Is it a reasonable cost to the public?
turer. Italy, France, Spain and the UK19 are among the • Does it add value to society?
• Is it the best way to deliver the outcome?

Table 6-1. Overview of Reference Pricing and Country Baskets in Europe
Source: European Commission: External reference pricing of medicinal products 2014

https://ec.europa.eu/health/sites/health/files/healthcare/docs/erp_reimbursement_medicinal_products_en.pdf
Health Technology Assessment (HTA) process. Collaboration between EMA and EUnetHTA
The World Health Organization (WHO) defines was announced in July 2017, which will enable manu-
HTA as the evaluation of health technologies’ medical, facturers to obtain coordinated scientific advice from the
social, economic, organisational and ethical properties two authorities: the so-called Parallel Consultation pro-
(including medicines and medical devices) for inform- cedure. Parallel Consultation provides a single gateway
ing policy decision making.21 The assessment process for the parallel discussion requests before starting pivotal
usually includes such criteria as the efficacy, safety, ease clinical trials and optimises opportunities for mutual
of use, comparative effectiveness (added therapeutic understanding and problem solving between regulators
value) and cost-effectiveness. Generally, the first step in and different HTA bodies, ultimately leading to more
the assessment process is to decide whether the product robust evidence generation.
is eligible for reimbursement. The next step is deciding EUnetHTA will facilitate the recruitment of
the extent to which the product will be reimbursed; in HTA bodies to participate in Parallel Consultation
other words, governments decide how much the payer and provide consolidated feedback from these bodies
is willing to pay and how much will be left for the throughout the procedure. Industry observers see this
non-governmental systems or patients to pay. as a major step toward simplifying HTA in Europe,
Pricing, reimbursement and HTA are interlinked and expectations for this new initiative are high.
and are often the integral parts of a Member State’s EUnetHTA defines HTA as a multidisciplinary process
healthcare system. However, although HTA is commonly in which medical, social, economic and ethical issues
used, each country applies it differently. Harmonising related to a health technology’s use are assessed in a
this process across the EU is the goal of the European systematic, transparent, unbiased and robust manner.
Network for HTA (EUnetHTA).22 EUnetHTA’s pur- HTA’s core is scientific evaluation of drugs’ relative effi-
pose is to create an HTA network across the EU and cacy. Economic evaluation often is part of an HTA, but
promote knowledge sharing, good practice, methods and decision making using HTA does not necessarily always
processes. EUnetHTA currently is exploring a common include economic evaluations.
‘Core Model’ for assessing new drugs seeking reimburse- HTA and the role of EUnetHTA are discussed in
ment in EU Member States. This is envisaged as leading more detail in Chapter 7.
to the development of an HTA mutual recognition

Chapter 6
Figure 6-3. Summary of Economic Evaluation Methods
Types of Economic Evaluation Methods
Cost-Effectiveness Analysis
Cost-Utility Analysis
Compares the relative costs
Cost-Minimisation Analysis Quantifies additonal cost of
and outcomes (effects)
Compares the cost per using a technology in relation Cost-Benefit Analysis
of different courses of
course of treatment when to additional health effects, Assesses all effects,
action. Health effects
alternative therapies have measured as quality-adjusted including health effects,
measured as life-years
demonstrably equivalent lifeyears (QALY). Parameter in monetary units
gained (LYG). Parameter of
clinical effectiveness of interest: Incremental
interest: Incremental cost-
cost-utility ratio (ICUR)
effectiveness ratio (ICER)
PERSPECTIVE
Societal/Economic
Health System
Social Insurance
Service Providers e.g., Hospitals
Economic Evaluations combines the time lived with the health-related quality
Economic evaluations are measured in costs and health of life, where one equals perfect health and zero equals
effect terms. By employing economic evaluations, the death. Therefore, one QALY can be interpreted as one
deciding body is trying to determine whether the new year of perfect health. Because this type of assessment
treatment merits the expenditure or if the money is is independent of disease and treatment, it is used
better spent elsewhere (on other treatments or health- widely to estimate health effects. Countries employing
care measures). Costs are taken into consideration QALY feed the result into reimbursement decisions.
from either a healthcare or a societal perspective. However, only the UK has expressed how much the
When applying a healthcare perspective, costs con- government is willing to pay per gained QALY (£20,
sidered include both the pharmaceutical itself and 000–£30, 000). Second and third thresholds have been
healthcare resource use, such as hospitalisation. In this proposed, namely a £50,000 QALY threshold for end-
case, the cost of a new treatment, which may reduce of-life treatments, and a £100,000 QALY threshold
healthcare resource use, is weighed against the current for medicines that treat very rare conditions or Highly
treatment and that therapy’s associated resource. A Specialised Technologies (HSTs), also known as
societal perspective includes consideration of health- ultra-orphan drugs.
care consumption costs, indirect costs, such as travel to Payers in most countries are reluctant to put an
healthcare providers and absence from work (leading to absolute figure on the willingness-to-pay threshold, mak-
patient and caregiver productivity loss). Thus, the societal ing it difficult for both applicants and assessors to predict
perspective encompasses and goes beyond the healthcare reimbursement decisions. Companies have been left to
perspective when calculating disease costs to society. estimate the price the market may be able to bear. In
Which method used tends to depend on the payer; a the UK, the reimbursement authority is trying to avoid
private health insurance organisation generally will use public criticism of its decisions by making it the compa-
the healthcare perspective, while the government usually ny’s responsibility to show why it is not able to offer the
will use the societal perspective. Figure 6-3 outlines the product at a price the government is willing to pay.
four types of economic evaluation methods.
Health effects commonly are measured using
Quality-Adjusted Life Year (QALY). A QALY

Figure 6-4. Types of Cost Containment Policies Adopted by Member States
Price Controls Volume Controls Revenue/Spending Value/Outcomes-

• Price cuts/freezes • Co-payments Controls Based Controls
• Discounts • Product volume caps • Product revenue caps • Pay for performance
• Tenders, bundling • Formularies, negative • Profit controls • Value-based pricing
• Therapeutic reference reimbursement list • Clawbacks • Pharmacoeconomic
pricing • Prescribing • Annuity vs. up front requirements,
• International refer- guidelines payments cost-effectiveness
ence pricing • Limits on number of • Deferred payments thresholds
• Mandatory generic cycles reimbursed • Money back guaran- • Accountable care,
substitution • Patient stratifica- tees, rebates targets
• Indication-specific tion, exclusion of • Commissioning • Risk-sharing
pricing subpopulations groups agreements
• Monitoring of out-
comes, RWE
Current Trends Generally, cost versus benefit for individual patients

EU Member States continue to move toward incor- and society will be estimated. This will include a com-
porating HTA and economic evaluations into their parison of the product’s quality, safety and efficacy with
reimbursement decisions and pricing policies. However, competing products. Based on these calculations and
in most countries, an external reference price remains considerations, governments will select which products
the predominant pricing policy (with one reference will be reimbursed. Thus, if a product is not selected to
estimating it is used by 24 of 27 Member States, with be included in the reimbursement program, the product
no data available for Croatia). Differences in execution will be available to patients only through private fund-
exist regarding procedures and reference countries.23 ing. In many cases, this would lead to a lower market
In practise, differential pricing is achieved through the share for two reasons:
widespread use of often confidential discounts and 1. patients need to pay the full cost
rebates. As a result, drug list prices in most EU coun- 2. patients may be unaware of the product due
tries, used for external price referencing, do not reflect to the strict EU direct-to-patient advertising
the actual prices. It is unlikely transparency will develop regulations
in this field, as there is limited incentive for companies
to offer lower prices to low-income countries, since Pricing and reimbursement models used in the EU-5
this subsequently would decrease the external refer- countries (i.e., France, Germany, Spain, Italy and
ence basket price. However, confidential discounts and the UK) are outlined below. These five countries are
rebates remain the most useful tools for countries to projected to continue to have the highest level of phar-
secure lower actual prices. The only countries currently maceutical expenditure into 202025 and are among those
employing value-based pricing are Sweden and the most often referenced by other countries that apply
UK, where a new product’s price is determined through external price referencing.
cost-effectiveness analysis and establishing added value.
However, many other countries employ some elements France
of value-based pricing in their decision-making proce- Healthcare System
dures.24 Figure 6-4 describes the key cost containment Most French citizens are covered by mandatory stat-
measures Member States adopt. utory social health insurance (the Universal Health
Coverage Act of 2010 (CMU)) funded by employee and
Link Between Reimbursement Models and employer contributions. In addition, approximately 25%
HTA—Case Studies of healthcare expenditures are out-of-pocket payments,
Governments are faced with an increasing challenge to taxation and voluntary health insurance. Healthcare is
provide healthcare solutions to their citizens. Treatment provided by a mixture of public and private practices
needs and costs are increasing, and budgets are finite. and hospitals.
This has led to systems through which governments
decide what price they are able to pay and, consequently,
which products will be available to patients through a
reimbursement system.

Chapter 6
Competent Authorities for Pricing, Reimbursement and • The price of a product must guarantee a sus-
HTA tainable budgetary impact for health insurance.
• The Transparency Committee (Commission de • All comparators are to be taken into account.
la Transparence, part of the French National • The additional cost of innovation should be
Authority for Health (HAS)), conducts HTA. controlled by performance clauses.
• The Commission for Economic Evaluation
and Public Health (CEESP) evaluates medi- Additionally, since 2012, CEESP conducts mandatory
cines’ cost-effectiveness. Cost-Effectiveness Analysis (CEA) for products rated
• The Health Products Pricing Committee ASMR 1–3 and predicted to exceed €20 million in annual
(Comité Economique des Produits de Santé revenue.27 The impact of such health economic assess-
(CEPS)) sets the prices for medicines through ments on pricing and reimbursement decisions is still an
negotiations with drug manufacturers and by evolving area in France28 and is not thought yet to have
using the cost effectiveness analysis results the same impact on reimbursement as ASMR ratings.29
from CEESP. UNCAM, representing third-party payers, decides reim-
• The National Health Insurance (UNCAM) bursement schemes, including co-payment levels based on
is in charge of reimbursement schemes and the Transparency Commission’s SMR determination.
determines levels of co-payment. Drugs are reimbursed at the following rates:
• The Ministry of Health makes the final deci- • 100%—life-threatening and incapacitating
sion on reimbursement. conditions; generally novel and particularly
expensive drugs
Pricing and Reimbursement Procedure • 65%—serious diseases
After a new drug is approved, manufacturers must apply • 30%—acute (less serious) illnesses
for the drug to be reimbursed by health insurance. The • 15%—low SMR drugs
criteria considered are: disease characteristics (e.g., • 0%—not reimbursed (e.g., Over-the-Counter
severity and frequency), alternative drug (comparator) (OTC) drugs)
availability, magnitude of effect, comparison of efficacy
with other available therapeutics, clinical trial results Once a reimbursement decision is made, drugs are
and real-life situations, target population and impact on added to one of the following reimbursement lists:
the healthcare system.26 Using these criteria, drugs are • Liste des Spécialités remboursables aux Assurés
rated in two ways: Sociaux—reimbursable drugs dispensed by
1. Actual medical benefit (service médical rendu retail pharmacies.
(SMR))—Drugs are rated from ‘insufficient’ • Liste des Spécialités agréées aux collectivités—
(and not recommended for inclusion in the hospital-only drugs; since 2004 this has been
reimbursement list) to ‘important’ (reimbursed split into:
at 100%), based on an assessment of illness a. drugs dispensed to outpatients (liste
severity and drug efficacy. This determines the retrocession)
reimbursement rate but does not affect pricing b. drugs dispensed to inpatients
recommendations.
2. Improvement in medical benefit (amélioration Excluded from the above lists are Disease-Related
du service médical rendu (ASMR)) compared to Group (DRG) payments for very expensive and inno-
existing therapies—Drugs are given an ASMR vative hospital-only drugs put on the T2A (Tarification
rating from I (major improvement) to V (no à l’activité) list where Social Security covers costs.
improvement). This is of greater significance to However, this system has been criticised, and the French
pricing negotiations than the SMR. government has indicated it is considering changes.30
CEPS is responsible for pricing reimbursed drugs
The Transparency Committee gives an opinion on SMR, within the current Framework Agreement (Accord
ASMR and target population for the reimbursement Cadre) negotiated with Les Entreprises du Médicament
scheme and recommends inclusion on a reimbursement (LEEM, a representative industry body). This agree-
list, reimbursement level and follow-up studies. This ment covers such items as market access, price setting,
advice is sent to CEPS for pricing and to UNCAM for economic regulation and industrial policy. There are
reimbursement. As part of its pricing assessment (which separate agreements for outpatient and hospital sectors,
is conducted indication-by-indication), CEPS ensures a and company registration is voluntary.
number of criteria are fulfilled, including: The reimbursable drug price varies depending on
ASMR ratings, comparator cost, ERP (most commonly

compared to prices in the UK, Germany, Italy and 4. the medicinal treatment’s net cost for Social
Spain), sales forecasts, target population size and likely Security when it is used concomitantly or
conditions of use. For instance: sequentially with other medicinal products
• Drugs assigned an ASMR of IV or V (typically 5. the amounts reimbursed, foreseen or estab-
retail pharmacy dispensed) are priced at a pro- lished by Social Security for the medicinal
portion of the comparator price with some use product concerned and those with the same
of ERP. therapeutic aim
• Retail pharmacy dispensed drug prices recom- 6. the existence of lower prices in other European
mended for reimbursement and assigned an countries with a comparable total market size
ASMR rating of I–III generally are negotiated (the list of which will be fixed by decree)
between manufacturers and CEPS. However,
there are provisions for companies to propose Germany
a price. Healthcare System
• Hospital-only drugs (Non-T2A) have manu- The main source of healthcare financing in Germany
facturer-declared prices to CEPS and, in most is statutory social health insurance (Gesetzliche
cases, CEPS chooses to accept these prices, Krankenversicherung (GKV)) funded predominantly by
which effectively become the reimbursement individual income-based premiums and employer contri-
prices. butions. Patients can choose the sickness fund in which
• Drugs on the T2A list are free priced. they enrol, and everyone receives the same level of cov-
erage no matter their contribution amount. Consumers
The SMR and ASMR are re-evaluated using real-world also are free to purchase private insurance instead.
data after five years, thus giving CEPS an opportunity
to review the prices. Competent Authorities for Pricing, Reimbursement
Sickness funds reimburse drug costs up to the and HTA
UNCAM recommended percentage; any balance is paid • HTA and reimbursement—The
through patient co-payments through supplementary Federal Joint Committee (Gemeinsamer
health insurance funds known as Mutuelles, which most Bundesausschuss—G-BA) and Institute for
French residents have. Patients taking medications for Quality and Efficiency in Health Care
certain chronic illnesses are exempt from co-payments. (Institut für Qualität und Wirtschaftlichkeit im
It also is common for manufacturers and wholesalers to GesundheitswesenIQ—WiG)
negotiate deals with hospitals and pharmacies on price • Pricing—Statutory Health Insurance
and volume agreements and discounts. (Gesetzliche Krankenversicherung-
The Social Security Financing Law (Loi de Spitzenverband—GKV-SV)
Financement de la Sécurité Sociale pour 2017) was adopted
in France in December 2016. Article 98 modifies Article Pricing and Reimbursement Procedure
L. 162-16-4 of the French Social Security Code regard- A manufacturer’s dossier, outlining the product’s effi-
ing the criteria for fixing and modifying a medicinal cacy, safety, target population, treatment costs and
product’s price. It now exhaustively lists the criteria that additional benefit over comparators, is submitted. This
guide the price negotiation. These criteria include: dossier is assessed by the Institute for Quality and
1. the date of the medicinal products’ registration Efficiency in Health Care (IQWiG). The Federal Joint
with the same therapeutic aim on the reim- Committee (G-BA) then makes a decision on a drug’s
bursed product lists or intellectual property value on the basis of advice from IQWiG. In addition,
rights’ expiration G-BA decides on an Appropriate Comparative Therapy
2. the medicinal product’s net price and those of (ACT), which can be a ‘new therapy’ or a ‘generic’.
other medicinal products with the same thera- Together, IQWiG and G-BA have one year to
peutic aim evaluate and rate the drugs according to the following
3. the medicinal product’s recorded purchase criterions:
price and that of other medicinal products a. Strength of evidence is rated on a four-point
with the same therapeutic aim by health estab- scale (proof, indication, hint or no proof ). This
lishments or wholesale or retail distributors, is based on the number and quality of clinical
considering discounts, rebates and similar trials and the end points used.
granted commercial and financial advantages b. Level of added benefit compared with the
of any kind ACT is rated on a six-point scale (major,
considerable/important, minor/slight,

Chapter 6
Figure 6-5. German Pricing for Medicinal Products Under AMNOG
Source: Gemeinsame Bundesausschuss (G-BA), EUCOPE presentation, March 2017
nonquantifiable, no added benefit or reduced manufacturers to set a price. Typically, there is a price
benefit). This is based on the assessment of premium over ACT, but it is likely to be lower than the
relative survival, health improvements, side free set price.31
effects, illness duration and impact on quality The implementation of AMNOG sought to reduce
of life. drug prices and control the healthcare budget, but
financial constraints remain, particularly when it comes
Drug pricing in Germany changed in 2011 under the to affording expensive novel agents in therapeutic cat-
Act on the Reform of the Market for Medical Products egories such as Hepatitis C and Oncology. As a result,
(Arzneimittelmarkt-Neuordnungsgesetz—AMNOG). in July 2016, the German Ministry of Health put for-
Figure 6-5 provides the German pricing for medic- ward a legislative proposal to improve the AMNOG
inal products under AMNOG. Under AMNOG, the process and extend patient access, Gesetz zur Stärkung
principle of free pricing was adopted. This implies that der Arzneimittelversorgung in der GKV (AM-VSG; Act to
a drug’s price can be set freely by the manufacturer for Strengthen Pharmaceutical Supply in the Statutory Health
the first year while the IQWiG and G-BA are assessing Insurance System). The proposal could lead to three
the pricing application. Following the price assess- important implications for manufacturers in Germany:
ment, the Federal Association of Statutory Health 1. patient subgroup exclusion
Insurance Funds (Gesetzliche Krankenversicherung- 2. a limit to free pricing in the first year
Spitzenverband—GKV-SV), representing the statutory 3. non-transparency of rebates
and private health insurance industry, sets the man-
ufacturer’s selling price. If G-BA decides a drug has Patient Subgroup Exclusion
no additional benefit, the new price is capped at the The proposed legislation allows G-BA to exclude patient
reference product price. However, if G-BA determines subgroups from reimbursement if the added benefit
there are additional benefits, GKV-SV negotiates with has not been demonstrated satisfactorily. While G-BA

analyses of subgroups has been commonplace in the sanctions for not prescribing the cheapest alternative, and
past (e.g., Fingolimod in RRMS and Kalydeco in CF), cost-cutting measures such as negotiating discounts and
excluding those subgroups from reimbursement has rebates or application of mandatory discounts.34
not been done before. Extensive subgroup analysis will
become essential for manufacturers hoping to achieve Spain
broad reimbursement for their products in the future. Healthcare System
Under these proposals, the principle of free pricing Healthcare in Spain is provided through the National
also contained a retrospective provision which suggested Health Service, SNS (Sistema Nacional de la Salud),
the following: which is funded mostly through public taxation.
“Once a revenue threshold of EUR 250 million Generally, healthcare is provided free of charge, but
is exceeded within the first 12 months, the price anyone under the age of 65 purchasing prescribed
negotiated between the manufacturer and the medicines pays a 40% co-payment. The Spanish
GKV-SV will apply retrospectively as of the first healthcare system was devolved to the regional level
month following the month in which the threshold in 2002, resulting in the establishment of 17 regional
was exceeded.” autonomous ministries of health, each with primary
jurisdiction over the organisation and delivery of health
However, this provision no longer applies since May services within their respective territories.35
2017, following a robust response from industry. There
is a counter-proposal under consideration to reduce the Competent Authorities for Pricing, Reimbursement and
duration of free pricing from one year to six months. HTA
Reimbursement agreements between manufactur- • Pricing decisions are made by The Directorate
ers and statutory health insurance will not be publicly General for Pharmacy and Health Care
disclosed. To protect the confidentiality of manufac- Products (DGFPS).
turers who have negotiated rebates and discounts to • HTA is conducted by the Spanish Network
achieve patient access, these terms will not be disclosed of Agencies for Assessing National Health
to third parties, and will be shared only with institutions System Technologies and Performance
requiring this information. This will prevent markets (RedETS) and the Interministerial
that reference German prices from using the negotiated Commission for Pricing (ICP).
price versus the list price, with all that that implies. • The Interministerial Commission of Price of
A manufacturer can choose to stop supplying a Medicines (within the Ministry of Health)
product if it deems the pricing decision as unfavourable, makes decisions regarding medicines’ inclu-
especially given the impact of the lower price on other sion on the national reimbursement list (and
countries that have implemented the popular ERP more broadly, the inclusion of services in the
strategy as a tool to constrain costs.32 An obligatory national basic benefit package).
Budget Impact Analysis (BIA) is required in the event • The 17 autonomous regional ministries or
a manufacturer does not accept G-BA’s decision with departments of health are responsible for
respect to premium pricing.33 decisions related to regional additions to the
Most registered prescribed drugs are covered auto- national catalogue of services.
matically (are reimbursable) under the statutory sickness
funds, with the exception of the following (which are Pricing and Reimbursement Procedure
placed on a ‘negative reimbursement list’): After marketing authorisation is granted, a drug man-
• drugs for ‘trivial diseases’ for insurant aged 18 ufacturer can seek reimbursement approval through
years or older the ICP. At this point, the DGFPS also advises the
• inefficient drugs (according to IQWiG’s benefit Commission regarding the medicine’s pricing. The
or cost-benefit assessment) process to determine whether a product is reimbursed
• drugs with limited indications (e.g., second- or runs parallel to the pricing process,36 thus eliminating
third-line treatment or a failed nonpharmaceu- the need for separate applications. This also implies that
tical treatment) once it is agreed, a product will be reimbursed, and a
regulated price is set.
The reimbursed price is the sum of the agreed manufac- Three reimbursement categories can be granted,37
turer’s selling price plus wholesale and pharmacy margins. depending upon the product type for which reimburse-
Reimbursement payments by sickness funds are reduced ment is sought:
by such measures as treatment cost caps, quotas (and • 100% reimbursement for pharmaceuticals
bonuses) for prescribing generics and parallel imports, administered in the hospital

Chapter 6
• 90% reimbursement for pharmaceuticals man- in the National Pharmaceutical Formulary

aging chronic illnesses (e.g., diabetes, asthma (PFN).
and epilepsy) • HTA is done by the Technical and Scientific
• 60% reimbursement for the majority of pre- Committee (Comitato Scientifico e Tecnico, part
scription-only pharmaceuticals of AIFA). The National Agency for Regional
Health Services (Agenzia Nazionale per i
If the product’s reimbursement application is unsuc- Servizi Sanitari Regionali, AGENAS) also sup-
cessful, the price is set by the manufacturer. Even ports the conduct of HTAs.
though pricing and reimbursement decisions are made • Pricing and Reimbursement Committee
nationally, the 17 EU regions retain the responsibility (CPR) (also part of AIFA) handles pricing
of managing services in their respective regions in ways negotiations with drug manufacturers.
that may impact medicines’ market access. These regions
are relatively free to conduct assessments, and in doing Pricing and Reimbursement Procedure
so, apply a variety of evidence-assessment techniques. Two pieces of legislation form the Italian legal frame-
However, the regions have certain common evidence work for medicines pricing and reimbursement—Law
parameters when conducting their respective assess- No. 326 of 24 November 2003 and Interministerial
ments.38 These include: Committee for Economic Planning (Comitato
• disease severity Interministeriale per la Programmazione Economia
• product price (CIPE)) Resolution of 1 February 2001.41 When
• Budget Impact Analysis (BIA) a reimbursement submission is received, the CPR
• patient well-being and Quality of Life (QoL) (through its Medicines Utilization Monitoring Centre
(OSMED)) conducts a medical and economic evalu-
Like most EU countries, Spain applies an ERP model; ation of the concerned product. At the national level,
however, particularly at regional level, a value-based and like Spain, Italy applies a joint process for pricing
model is widely adopted,39 e.g., with Price Volume and reimbursement assessments. A successful reim-
Agreements (PVAs) where the price of single new bursement application is followed immediately by price
products is linked to specific conditions. negotiations with the product manufacturer.
In July 2017, the governments of Spain and All medicines are placed in one of three categories,
Portugal signed an agreement for the joint procurement depending upon whether they have received reimburse-
of medicines and medical devices as well as for infor- ment.42 These categories are:
mation sharing. A pilot test using a selected medicine is 1. Class A medicines: these receive full reim-
planned and should provide the opportunity to evaluate bursement regardless of whether they are used
the impact of such cross-country collaboration on mar- in hospital or on an out-patient basis. This
ket access. concerns essential medicines and those for
chronic diseases.
Italy 2. Class H medicines: these receive full reim-
Healthcare System bursement but are for hospital use only.
Italy’s National Health Service (Servizio Sanitario 3. Class C medicines: all other medicines (i.e.,
Nazionale, (SSN)) provides free universal coverage to all those not reimbursed) belong to this class and
residents and emergency care to all visitors, regardless are purchased by the patient.
of their residency or nationality status. Healthcare is
funded primarily through national and regional taxes, However, in certain cases, a regional authority still may
supplemented by co-payments for pharmaceuticals and decide to reimburse a medicine in Class C (in other
outpatient care.40 words, include the medicine in the region’s own reim-
Healthcare delivery is decentralised into 20 regions, bursement scheme) that initially had not been granted
each of which receives annual allocations from the reimbursement through the national process. Medicines
national healthcare budget and, as such, is responsible that are not reimbursed are placed on a ‘negative list’
for the implementation of the healthcare plan in its and are subject to ‘free-pricing’ by the manufacturer.
respective region. To decide on the pricing and reimbursement condi-
tions for a product, the CPR takes into consideration:43
Competent Authorities for Pricing, Reimbursement and • therapeutic value (cost/efficacy analysis)
HTA • safety (pharmacovigilance)
• The Italian Medicines Agency (AIFA) assesses • degree of therapeutic innovation
new drugs for reimbursement and inclusion

• internal market forecasts (number of potential • The Department of Health (DH) decides
patients and expected sales) which products will be reimbursed based on
• price of similar products within the same or NICE recommendations.
similar therapeutic category
• External Reference Pricing (ERP) Pricing and Reimbursement Procedure
DH does not negotiate directly with manufacturers
In addition to the ERP model, Italy adopts a value-based when deciding whether to reimburse a product. Rather,
approach in managing new medicines’ pricing nego- this decision is based on prescription classification,
tiations. This is done by either risk-sharing with the efficacy, patient need and NICE recommendations. All
manufacturer in cases of non-response to a given treat- branded and generic drugs classified as Prescription-
ment (‘part-reimbursement’) or cost-sharing where the only Medicines (POMs) or Pharmacy (P) only will be
medicine is only reimbursed for a limited period (for reimbursed 100%, when prescribed through the NHS,
instance, limited cycles of treatment, particularly in the unless they fall into one of the following categories:
case of cancer therapy).44 The agreed price and reim- a. Black list: products like vitamins and diet pills,
bursement levels usually are re-evaluated annually. It is which cannot be prescribed under the NHS
argued that such a market entry agreement and risk-shar- system, so patients bear the full cost
ing approach is cost-effective and strengthens the link b. Grey list (selected list scheme): can be pre-
between reimbursement and actual patient outcome.45 scribed under the NHS but only for specific
A few of the regions conduct additional HTA and indications and patient groups, e.g., Viagra
region-specific tenders that impact their reimbursement (ineligible patients can still receive a prescrip-
decision making and pricing negotiations respectively. The tion but must bear the full cost.)
inevitable variations in HTA implementation and tenders c. Drugs sold directly to consumers (classified as
across the regions often have resulted in a given product P or General Sales List (GSL))
having different domestic prices at the same time.46 d. Drugs prescribed by private healthcare provid-
ers (even if they would be reimbursed by NHS
UK providers)
Healthcare System
Healthcare in the UK is delivered primarily through the The trade price paid to manufacturers for reimburs-
National Health Service (NHS), which covers health- able drugs is based on discussions between DH and
care for all UK residents. This is a public system funded the manufacturers, using the PPRS for branded drugs
mainly through general taxation with some National and Scheme M (for Category M generics) pricing
Insurance (NI) contributions and co-payments. Each frameworks. Alternatively, generic pricing can be deter-
UK country varies in the specifics of how drugs are mined through calculations done by the NHS Business
priced and reimbursed. The focus in this case study is Services Authority (NHSBSA) (Category A generics).
NHS England and its system for pricing and reim- PPRS is a framework negotiated between DH and
bursement. The UK government is responsible for NHS the Association of the British Pharmaceutical Industry
England. (ABPI) for reimbursable branded originator products and
With Brexit, the UK formally left the EU on seeks to control industry profits rather than prices. This is
31 January 2020, and a transition period began on 1 an interesting feature of the UK system, and the de facto
February 2020, during which EU pharmaceutical law criteria affecting price become profit, capital investment,
remains applicable to the UK. This transition is due to R&D and promotional costs. The UK does not use ERP.
end on 31 December 2020.47 If a manufacturer makes more profit than outlined in the
PPRS, it must either pay back the excess profit to NHS
Competent Authorities for Pricing, Reimbursement and or may choose to cut or freeze prices. Manufacturers can
HTA set their prices freely within the framework.
• In the UK, the National Institute for Health PPRS is a voluntary agreement, and those man-
and Care Excellence (NICE) performs HTA. ufacturers that do not participate are subject to an
• The National Coordinating Centre for Health alternative statutory scheme (the Health Service Branded
Technology Assessment (NCCHTA) man- Medicines (Control of Prices and Supply of Information)
ages the NHS HTA program. NHS entities (No. 2) Regulations 2008 (as amended)). Under this
are obligated to fund drugs recommended by scheme, there currently are mandatory 15% price cuts
NICE. for products launched before December 2013.
The Scheme M framework is negotiated between
DH and the British Generic Manufacturers Association

Chapter 6
(BGMA). Under this framework, participating compa- this to other treatments, medical devices and diagnos-
nies must provide sales information quarterly (used to tics over the next two years.48
inform reimbursement and drug tariffs) and then can In March 2017, NICE announced further changes
set generic prices in Category M. There is a similar sys- relating to drugs for rare diseases as well as drugs that
tem for generics wholesalers, known as Scheme W. cost more than £20m in any one of their first three years
Generics from nonparticipating companies are of approval. For the latter, discussions must be held
priced under Category A. Manufacturers can free set between the manufacturer and NHS England for the
generics’ prices in Category A but cannot exceed the purpose of mitigating the impact of the cost of such
originator price and are reimbursed only at the price drugs on the rest of the NHS.49
calculated by NHSBSA from a basket of prices pro- A sliding scale now will be used to evaluate drugs
vided by generic manufacturers and wholesalers. for rare diseases; this implies that for such drugs, the
The price NHS pays to pharmacists (NHS Price) higher the cost, the greater the health benefit that
comprises the Trade Price (what is paid to manufactur- would have to be demonstrated before they can be
ers) plus a wholesale mark-up. Dispensing fees also are approved by NICE for routine clinical use.
paid to pharmacies. PPRS outlines wholesale mark-ups Patient Access Schemes (PAS) are a common way
for branded pharmaceuticals, and Scheme W applies to for NICE to mitigate the risks associated with intro-
Category M generics. However, this mark-up is unreg- duction of high-cost treatments. The manufacturers of
ulated for other drug categories and non-reimbursed certolizumab pegol (UCB Pharma), golimumab (Merck
pharmaceuticals. Sharp and Dohme), abatacept (Bristol-Myers Squibb)
Although drugs funded by NHS England are and tocilizumab (Roche) have, for example, each agreed
100% reimbursed, patients in the UK pay a prescription a patient access scheme.50
fee. There are exemptions to this fee for some patient Under the schemes:
groups, and there is no fee on contraceptives. • The first 12 weeks of therapy (currently 10
NICE considers submissions from companies and preloaded syringes of 200 mg each) with cer-
other stakeholders (e.g., patients and healthcare provid- tolizumab pegol are free of charge.
ers) in its assessment and bases its recommendations on • The 100mg dose of golimumab will be avail-
clinical efficacy and cost effectiveness. It will not assess able to the NHS at the same cost as the 50mg
every newly registered drug, especially if there is already dose.
a good understanding of its anticipated benefit and cost. • Abatacept and tocilizumab will be available
There are three appraisal routes: with a discount; however, the discount level is
1. Single Technology Appraisal (STA): for held in confidence.
new drugs (‘technologies’) targeting a single
indication, or existing drugs targeting a new Conclusion
indication. NICE relies on submissions by This chapter introduces the regulatory professional to the
manufacturers that provide dossiers on clinical pricing and reimbursement aspects of placing a pharma-
evidence, cost effectiveness and impact on the ceutical product on the market in an EU Member State.
NHS. It highlights the fact that regulatory approval is not the
2. Multiple Technology Appraisal (MTA): for endpoint when securing market access. Reimbursement
disease areas or drug classes. It also could be and pricing are determined by the payer, and satisfying
used for a single drug with multiple indi- payer evidence requirements can be complicated, often
cations. The information NICE uses in its necessitating changes to the traditional development
assessments include post-launch findings, new programme (e.g., inclusion of different or additional
data analysis and evidence from a wider range endpoints or comparators). In contrast to regional reg-
of stakeholders. ulatory frameworks, the pricing and reimbursement
3. Highly Specialised Technologies (HST) processes have not been harmonised across the EU,
evaluations: for very rare conditions (sin- making securing reimbursement a major challenge for
gle technology for a single indication). pharmaceutical companies. The lack of predictability and
Manufacturers submit dossiers for assessment; seemingly inconsistent guidance industry receives makes
other interested stakeholders are encouraged to planning difficult, and some companies are choosing
submit comments. to avoid launching products in particularly challenging
markets. This reduces physician choice and may keep
A new fast-track appraisal process was approved in life-changing therapies from benefitting patients. On the
March 2017 that applies to drugs that cost less than other hand, the optimisation of reimbursement strategies
£10,000 per QALY. However, there are plans to extend creates a conundrum for payers around how to provide

innovative, safe, efficient, potent and high-quality phar- 14. Understanding the 2014 Pharmaceutical Price Regulation
maceutical products at prices society can support. During Scheme (2014). ABPI website. http://www.abpi.org.uk/
our-work/policy-parliamentary/Documents/understanding_
Brexit and the UK transition, the EU pharmaceutical pprs2014.pdf. Accessed 5 March 2020.
law remains applicable until 31 December 2020. Overall, 15. Sussex J, Towse A and Delvin N. “Operationalizing Value-Based
vast differences among Member States remain, and the Pricing of Medicines—A Taxonomy of Approaches.” Pharmaco
evolving legal frameworks and intricate maze of national Economics. 2013; 31 (1): 1-10. Springer website. https://link.
springer.com/article/10.1007%2Fs40273-012-0001-x. Accessed
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across Europe. Performance-Based Schemes in Italy Really Work? “Success
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2020. 2020.
8. Ibid. 26. Pricing and Reimbursement of Drugs and HTA Policies in
9. Transparency Directive. EC website. https://ec.europa.eu/ France (March 2014). Haute Autorité de Santé (HTA) web-
growth/sectors/healthcare/competitiveness/products-pricing-re- site. http://www.has-sante.fr/portail/upload/docs/application/
imbursement/transparency-directive_en. Accessed 5 March pdf/2014-03/pricing_reimbursement_of_drugs_and_hta_poli-
2020. cies_in_france.pdf. Accessed 5 March 2020.
10. High Level Group on Innovation and Provision of Medicines 27. Antonanzas F, Terkola R, Overton PM, Shalet N and Postma
Recommendations for Actions. EC website. http://ec.europa. M. “Defining and Measuring the Affordability of new
eu/health/ph_overview/Documents/key08_en.pdf. Accessed 5 Medicines: A Systematic Review.” Pharmaco Economics; doi:
March 2020. 10.1007/s40273-017-0514-4.
11. European Commission (EC). High Level Pharmaceutical 28. Toumi M, Remuzat C, El Hammi E, Millier A, Aballea S,
Forum 2005–2008 Conclusions and Recommendations. 20 Chouaid C and Falissard B. “Current Process and Future Path
April 2010. https://publications.europa.eu/en/publication-de- for Health Economic Assessment of Pharmaceuticals in France.”
tail/-/publication/4fddf639-47cc-4f90-9964-142757d2515a. Journal of Market Access & Health Policy Vol. 3. (2015).
Accessed 5 March 2020. 29. Angelis A, Lange A and Kanavos P. “Using Health Technology
12. Vogler S, Paris V, Ferrario A, et al. “How Can Pricing and Assessment to Assess the Value of new Medicines: Results of
Reimbursement Policies Improve Affordable Access to a Systematic Review and Expert Consultation Across Eight
Medicines? Lessons Learned from European Countries.” Appl European Countries.” Eur J Health Econ. 2017; doi: 10.1007/
Health Econ Health Policy. 2017; 15: 307-321. Doi: 10.1007/ s10198-017-0871-0.
s40258-016-0300-z. 30. Or Z. “Implementation of DRG Payments in France: Issues
13. Garattini L, Curto A and Freemantle N. “Pharmaceutical and Recent Developments.” Health Policy, Vol. 117; Issue 2. pp.
Price Schemes in Europe: Time for a ‘Continental’ One?” 146–150. (2014).
Pharmaco Economics. 2016; 34: 423-426. doi: 10.1007/ 31. Sackman JE and Kuchenreuther M. “Germany Post AMNOG:
s40273-015-0377-5.f. Insights for BioPharma.” BioPharm International. Vol. 27; No.
11. (2014).

Chapter 6
32. Hogan Lovells. Pricing and Reimbursement Schemes in 42. Value-Based Health Assessment in Italy: A Decentralised
Major European Countries. EU Pricing and Reimbursement Model (2015). The Economist website. https://www.eiuper-
Newsletter. November 2014. spectives.economist.com/sites/default/files/Value-based%20
33. Op cit 29. Health%20Assessment%20in%20Italy.pdf. Accessed 5 March
34. Op cit 32. 2020.
35. García-Armesto S, Abadía-Taira MB, Durán A, Hernández- 43. Op cit 28.
Quevedo C and Bernal-Delgado E. “Spain: Health System 44. Op cit 18.
Review. Health Systems in Transition.” 2010;12(4):1–295. 45. Op cit 15.
36. Prior M. “Review of Spanish Pricing and Market Access 46. Op cit 12.
Environment: Implications for Small and Medium Size 47. Brexit: The United Kingdom’s Withdrawal From the European
Companies.” Grifols Presentation Brussels. Presented on 31 Union. EMA website. https://www.ema.europa.eu/en/about-us/
May 2017. brexit-united-kingdoms-withdrawal-european-union. Accessed
37. Innovation Excellence (Inno AG). Analysis of the Impacts of 5 March 2020.
Dual Pricing in Spain (2014). Inno-group website. http://www. 48. Press Release: NICE Gets Go-Ahead to Fast-Track More Drug
inno-group.com/system/projects/attached_files/000/000/147/ Approvals. 15 March 2017. National Institute of Health and
original/Analysis_of_dual_pricing_in_Spain_final_ver- Care Excellence (NICE) website. https://www.nice.org.uk/
sion_20140701.pdf ?1427327440. Accessed 5 March 2020. news/article/nice-gets-go-ahead-to-fast-track-more-drug-ap-
38. Op cit 29. provals. Accessed 5 March 2020.
39. Ibid. 49. Ibid.
40. Op cit 32. 50. List of Technologies With Approved Patient Access Schemes.
41. Pricing and Reimbursement. The Italian Medicines Agency NICE website. https://www.nice.org.uk/about/what-we-do/
(AIFA) website. http://www.aifa.gov.it/en/content/pric- patient-access-schemes-liaison-unit/list-of-technologies-with-
ing-and-reimbursement. Accessed 5 March 2020. approved-patient-access-schemes. Accessed 5 March 2020.

Chapter 7
Health Technology
Assessment (HTA)
Updated by Azzurra Ravizza, MSc and Monique Carter, MS, RAC
OBJECTIVES knowledge and skills in the form of medicines, medical

devices, vaccines, procedures and systems developed to
□ Provide an overview of the history and legal solve a health problem and improve quality of life.1 The
framework for Health Technology Assessment Health Technology Assessment (HTA) is a multidisci-
(HTA) in the European Union (EU) plinary process to systemically evaluate the properties,
effects and impact of health technology from social,
□ Describe the role of HTA in health product mar-
economic, organizational and ethical perspectives. The
ket access
key goal of the HTA is to generate and/or synthesize
□ Compare various HTA models used across the appropriate level of evidence to inform policy deci-
health systems in the EU sion making about health technologies.2
The HTA concept was initially developed in a
□ Discuss the collaboration between the systemic manner by the US Office of Technology
European Medicines Agency (EMA) and the Assessment (OTA), established in 1972.3 This was in
European Network for Health Technology recognition of the growing importance of accurate,
Assessment (EUnetHTA) timely and independent information to enhance and
evaluate the impact of technological developments.4
Broader global HTA development began in the late
DIRECTIVES, REGULATIONS AND GUIDELINES 1980s,5 and in Europe, the Swedish Council on
COVERED IN THIS CHAPTER Technology Assessment in Health Care (Statensberedning
för medicinsk utvӓrdering) was established in 1987.6
□ Directive 2011/24/EU of the European In the 1980s and 1990s, the European Commission
Parliament and the Council of 9 March 2011 on (EC) funded several studies and meetings related to
the application of patients’ rights in cross-bor- HTA, such as the EUR-ASSESS project and the HTA-
der healthcare EUROPE project. The objective of these initiatives was
to improve coordination and publish recommendations
□ European Commission, Final Conclusions regarding HTA in the EU Member States.7 In 1993,
and Recommendations of the High-Level the International Network of Agencies for Health
Pharmaceutical Forum Technology Assessment (INAHTA) was established,
□ European Commission, High Level with Sweden as one of the founders, and 12 other HTA
Pharmaceutical Forum. Core Principles on institutions representing nine countries.8 From 2000 to
Relative Effectiveness 2002, the EC funded the European Collaboration on
Health Technology Assessment (ECHTA) to further
examine the possibilities to improve coordination of
HTA History and Legal Framework in the EU HTA in Europe.9
The World Health Organization (WHO) defines In 2004, the EC and Council of Ministers targeted
a health technology as the application of organized HTA as “a political priority,” recognising “an urgent

Chapter 7
need for establishing a sustainable European network evidence-based health policy decision making.20 The
on HTA.” A Commission call was answered in 2005 INAHTA currently represents 51 HTA member
by a group of 35 organisations throughout Europe, agencies in 32 countries in North and Latin America,
led by the Danish Centre for HTA (DACEHTA) Europe, Asia and Australia.21
in Copenhagen, which led to the activities of the Despite the efforts in harmonization, HTA Bodies
European Network for Health Technology Assessment (HTABs) provide recommendations on health tech-
(EUnetHTA) Project.10 Objectives of the EUnetHTA nologies that can be financed or reimbursed by the
Project included the following: healthcare system in a specific Member State or region
• promote efficient use of resources where the assessment criteria used differ in accordance
• increase the impact of HTA through decision with regional and national legislation, leading to differ-
making input ences in HTA recommendations between regions and
• strengthen the relationship between HTA and Member States.
EU healthcare policy making
• support countries within the EU with limited Role of HTA in Health Product Market
HTA experience11 Access in EU
Healthcare delivery in EU and globally depends largely
Further, in 2008, the EC issued a proposed directive on the technologies available at the point of care. In
entitled, A Community Framework on the Application of general, these health technologies can range from med-
Patients’ Rights in Cross-Border Healthcare, with an aim icines and medical devices, to clinical diagnostic and
to improve cooperation between Member States and treatment methodologies (e.g., surgical procedures), to
clarify patients’ rights to access safe and good quality disease prevention and rehabilitation methodologies, to
treatment across EU borders and be reimbursed accord- the organisational and support systems within which care
ingly.12 To that end, HTA was indicated as one of the is provided.22 These health technologies are constantly
directive’s major provisions and as a field in which col- evolving in response to the need for continuous improve-
laboration between Member States can yield relevant ment in the quality and delivery of care. Therefore,
added value.13 systematic evaluation of health technologies can be con-
Directive 2011/24/EU,14 adopted in 2011 and sidered essential to healthcare delivery. This evaluation
implemented with EC Decision of 26 June 2013,15refers can be broadly categorized via a three-phase process:
to the EUnetHTA Project as a basis for a perma- 1. market authorisation (MA)
nent EU structure of cooperation in the HTA field, 2. health technology assessment (i.e., HTA)
describing its objectives in Article 15.16 This article also 3. utilisation decision making
specifies EUnetHTA limitations so as not to interfere
with Member States’ competences in “deciding on the The first phase involves evaluating a given technology’s
implementation of health technology assessment con- safety and efficacy profile to support authorisation for
clusions and shall not harmonise any laws or regulations its use. For example, a medical device must undergo a
of the Member States.”17 This language connotes a rigorous evaluation process to confirm alignment with
balance between the reach of mandated collaboration product type-specific EU Directives regarding per-
and the limitations set forth under the Treaty on the formance standards, quality, safety and efficacy before
Functioning of the EU. Thus, the directive manages to receiving Conformitè Europëenne (CE) marking, which
indirectly increase HTA collaboration without imping- is required before the device may be marketed legally in
ing on Member States’ dominions. The EUnetHTA the EU. The CE marking process will change and must
Joint Action 3 (2016–2020) is now developing the comply with European Commission Regulation (EU)
final phase of establishing a permanent HTA working No. 2017/745, commonly known as the EU Medical
structure.18 The EUnetHTA collaboration has grown to Devices Regulation (EU MDR) in May 2020 (see
81 organisations from 29 countries, forming a network Chapter 13 for more details).23 Similarly, new surgical
of strong partners across Europe working together for procedures are subject to peer review and broader clin-
better access to health technologies.19 ical scrutiny before becoming adopted as the standard
The spread and global presence of HTA bodies was of care, and a medicine’s safety and efficacy profile is
largely facilitated by international organizations such as evaluated and reviewed by regulators before obtain-
the WHO and the World Bank as well as HTA mem- ing MA. However, simply demonstrating that a given
ber associations, including INAHTA. The INAHTA health technology is safe and effective in achieving its
network is a platform for these organizations to cooper- desired clinical goal and obtaining MA does not ensure
ate and share information regarding the production and that the technology is the optimal means by which to
dissemination of HTA reports to support appropriate

Health Technology Assessment (HTA)
achieve the clinical goal or that it will be adopted for implications is the Relative Effectiveness Assessment
use within all levels of a country’s national healthcare (REA), which can be generally defined as the extent
system or across the EU. Such utilisation decisions (the to which an intervention does more good than harm
third phase in the process) are influenced by numerous compared to one or more intervention alternatives
factors, including HTA outcome (the second phase). for achieving the desired results when provided under
In general, HTA is the systematic and multi- the usual circumstances of healthcare practice.30,31 As
disciplinary evaluation of health technologies, using HTABs evaluate medicines in local clinical context,
available data, to support their adoption and utilisation the scientific requirements of HTABs vary according
in the Member State or region. The EUnetHTA Project to local standard of care,32 and the HTA implementa-
defines HTA as: tion varies considerably across national settings.33 This
“[A] multidisciplinary process that summarises variability introduces uncertainty into drug develop-
information about the medical, social, economic ment decisions and can result in a potential mismatch
and ethical issues related to the use of a health of regulatory and HTA outcomes.34 For example, the
technology in a systematic, transparent, unbiased, HTAB in one Member State could restrict usage to
robust manner. Its aim is to inform the formulation patient groups or treatment settings where they believe
of safe, effective, health policies that are patient the product is most effective and/or most cost-effective
focused and seek to achieve best value. Despite its (e.g., the payer evidence standard), despite the indi-
policy goals, HTA must always be firmly rooted in cation in the product label.35A REA needs to convey
research and the scientific method.”24 whether the treatment has a clinically and statistically
significant effect on a relevant endpoint compared
HTA is an interactive process that follows some com- to some alternative under real-world conditions.36
mon steps. The first step is ”priority setting,” and once a Clinical endpoints to use for REA are “patient-relevant”
technology has been prioritized, the assessment phase endpoints reflecting how a patient feels, functions or
starts. A preparatory step (scoping) frames the decision survives;37 they broadly measure mortality, morbid-
problem and, based on the scope, a protocol is devel- ity and Health-Related Quality of Life (HRQoL).
oped to detail the method of the assessment and its In situations of “unmet medical need,” Conditional
reporting process. Evidence is collated, analysed and Marketing Authorization (CMA) can be granted by
interpreted to inform policy makers in their recom- EMA based on both clinical and surrogate endpoints.
mendations for use and reimbursement of the health Surrogate endpoints are biomarkers or intermediate
technology under evaluation (appraisal).25 There is a endpoints intended to substitute for and predict a clin-
clear distinction between assessment, which is con- ical outcome; they may be validated or non-validated,
sidered to be a scientific process, and the role of HTA depending on the evidence available. Both validated
and subsequent appraisal by policy makers.26 Therefore, and non-validated surrogate endpoints have been
HTA is generally accepted “as a bridge between research accepted in place of clinical endpoints by EMA to grant
and decision making” with a majority of EU Member CMA, with the requirement to conduct postmarketing
States using public sector HTABs to influence decision studies demonstrating the intended clinical benefit or
and policy making at regional and national levels.27 validating the endpoints in the case of non-validated
HTA is conducted by interdisciplinary groups, and surrogates.38 Clinical and patient relevant outcomes are
throughout the process, input and contributions are given priority in HTA, and surrogate outcomes are not
received from key stakeholders such as industry, health- preferred; these are considered less relevant for the deci-
care providers and professionals, third-party payers and sion making than clinical outcomes and are accepted
regulators. Public and patient involvement in all the only if considered clinically relevant and/or validated.39
stages of the HTA process is increasingly encouraged This is another common case of divergent approach
to maximize the relevance, acceptability and uptake of between regulators and HTABs.
related recommendations.28 While a regulatory agency The EC launched in 2001 a High-Level
grants MA based on the benefit-risk balance of a med- Pharmaceutical Forum (HLPF) intended to serve as
icine, usually through an evaluation of randomised a platform for the exchange of best practices and for
controlled trials, with high attention on internal valid- examining efficiency gains.40 HLPF adopted a report
ity, safety, efficacy and manufacturing, HTABs focus in October 2018 in which it recalls that evaluation
on effectiveness evaluation of the intervention under and the decision-making process leading to decisions
the general circumstance of clinical practice, including on the pricing and reimbursement of pharmaceutical
comparison with available treatments at the local level, products lie with the national competent authorities
clinical effectiveness and cost over time.29 A specific and strongly recommended that regulatory agencies
HTA element focusing on an intervention’s clinical and EMA be included in networks that deal with issues

Chapter 7
related to relative effectiveness, giving EMA a political 3. Safety (SAF): This domain’s purpose is to
mandate to interact with HTA agencies. The report also review unwanted or harmful effects caused by
acknowledged the distinction between scientific assess- using a health technology. Safety information,
ment of the relative effectiveness of medicinal products balanced with data on effectiveness, form
and health-economic assessments of their costs and the basis for further assessment on costs and
benefits and endorsed the aim of REA to compare organisational aspects. As the assessment of
healthcare interventions in daily practice and classifying the safety profile could be described in many
them according to their added therapeutic value. 41 ways, this domain should cover safety issues
important to patients and guide decisions of
HTA Models Used Across the EU healthcare providers and policy makers. Terms
In some countries, HTA is limited to clinical- and describing adverse effects have to be defined
cost-effectiveness. Other countries may extend the assess- and added to each search strategy. Information
ment more broadly into social and ethical impacts of an about new, serious, rare or long-term adverse
assessed technology. Differences in national implemen- effects typically are found in observational
tation and organisation present challenges to the global studies.
adoption of a technology.42 For example, operational 4. Clinical Effectiveness (EFF): The focus of
setting, funding, assessment type and scope and relation this domain is to determine the net benefit
to decision making are a few areas in which HTABs (benefit minus harm) caused by the technol-
may diverge or converge.43 These variations can create a ogy, the benefit-harm balance and the certainty
difficult environment for stakeholders involved in health of the evidence. The core of this domain is
technology development across different EU markets. traditionally the Randomised Controlled Trial
To enable collaboration in producing HTA infor- (RCT). While efficacy is the extent to which a
mation and efficient sharing of the results, EUnetHTA technology does more good than harm under
published the HTA Core Model so that redundant over- ideal circumstances (e.g., within the protocol
lapping work in different countries and regions could be of an RCT), effectiveness assesses whether
avoided.44 The HTA Core Model organises the informa- a technology does more good than harm
tion within an HTA by dividing it into nine domains:45 when provided under usual circumstances of
1. Health Problem and Current use of healthcare practice (e.g., by a physician in a
Technology (CUR): This domain describes the community hospital treating outpatients).
target conditions, target groups, epidemiology, 5. Cost and Economic Evaluation (ECO): The
the use and regulatory status of the technology aim of this domain is to inform value-for-
and its alternatives and the burden on individ- money judgements about the technology with
uals and society caused by the health problem. information about costs, health-related out-
It uses published epidemiological, prognostic comes and economic efficiency, often utilizing
and qualitative research as well as statistical evidence from the SAF and the EFF domains.
data and registries as sources of informa- The type of analysis and data collected for this
tion. Further, horizon scanning and ongoing domain will depend on the specific research
research using websites and databases often is question. Modelling is useful when economic
relevant. Both national and EU information and clinical data are missing. Sensitivity analy-
can be valuable. sis shows the decision maker the robustness of
2. Description and Technical Characteristic of an economic analysis’ conclusions. Ideally, the
Technology (TEC): This domain focuses on analysis is conducted from the broad societal
describing the purpose(s), features, information perspective instead of for one or two narrow
and training needed to use the technology in contexts or settings.
sufficient detail to differentiate it from its com- 6. Ethical Analysis (ETH): This domain consid-
parators. Terms and concepts should be used ers social and moral norms and values pertinent
in a manner that allows an overall understand- to the technology. This domain is an ongoing
ing by those unfamiliar with the technology. process by content experts, lasting throughout
Sources could include articles, textbooks and the HTA project. The analysis should never be
technical reports from governmental agencies a philosophical add-on by ethicists. The method
or scientific research groups and manufacturers’ should be tailored to suit the topic under study,
websites. A systematic review is not always the local culture, the healthcare system and the
needed; however, explicit documentation is HTA organisation itself.
required for transparency.

7. Organisational Aspects (ORG): This domain complemented by various “soft law” instruments,
considers how to mobilise and organise differ- agreements, documentation by the technology
ent kinds of resources (e.g., material artefacts, supplier and legal scientific literature.
human skills and knowledge, money, atti-
tudes, work culture) for the implementation It is important to note that some assessments under
of a technology and the consequences on a given domain may be context-dependent or con-
the organisation and the healthcare system. text-independent. A context-dependent domain will
This domain requires both qualitative and be limited in its application, whereas a context-inde-
quantitative research data. Registries and rou- pendent assessment may have broader implications,
tinely collected statistics often are useful for including those that span domains.46 The nine domains
this analysis. Comparing results from two or define a full comprehensive HTA, while the first four
more data collection methods (e.g., interview domains, which only concern clinical characteristics and
and observation) may reduce bias. Assessing testing, are defined as rapid REA.
organisational issues, in many cases, is context Several EU countries generally use an approach
dependent. At least two different views on consistent with the EUnetHTA core model in the
causality and transferability are used in the assessment of technologies, which implies there are
organisational research: the diffusion model similarities in the type of data required to demonstrate
and the translational model. The diffusion efficacy, safety and innovation. However, while HTA
model suggests that the establishment of an remains a local competency, it varies in scope, legality
organisational practice is evidence of diffusion and methodology between Member States, and there
by assuming that practice is reproduced locally are differences in the way certain HTA elements are
following a prototype. The translational model implemented in practice due to several factors includ-
emphasizes that not all ideas are translated ing, but not limited to, differences in country priorities,
locally and that each process requires careful healthcare budget and the perception of value.
analysis.
8. Patients and Social Aspects (SOC): This Comparison of HTA in EU Countries
domain aims to identify evidence from Table 7-1 lists the various HTA agencies in EU
patients, individuals, care-givers and social Member States.
groups about the burden of living with the Table 7-2 shows a comparison of how Germany,
condition being studied, experiences of current France, UK, Italy and Spain organise and conduct HTA.
technologies and experiences with and expec-
tations of the health technology being studied Organisation and Structure of EU HTA Bodies
(in particular, what would be valued most from EU HTAB recommendations are typically nonbind-
the technology and issues regarding managing ing,47 particularly with respect to final decisions on
technology administration and side-effects?). pricing and reimbursement. Nevertheless, HTA is
Qualitative studies are highly relevant, as are becoming an increasingly mandatory element of the
quantitative studies with various observational regulatory process.
designs. If no relevant studies are found, a A variety of different organisational forms and
primary study (e.g., an interview, survey or structures have been set up in the EU, ranging from
participant observation) should be considered. large single HTA bodies with formal singular remit to
A thematic synthesis, a thorough description develop HTA recommendations, to Working Groups
of relevant themes and sub-themes identified within the Ministry of Health, to models with two or
in literature or interviews (thematic mapping), more organisations performing various functions in the
is more important than finding every single national HTA processes.48 Bulgaria, Denmark, France,
study or opinion. Poland and Slovakia, for example, have a national
9. Legal Aspects (LEG): The objective of this HTAB exclusively focused on development of HTA
domain is to assist the HTA doers in detecting recommendations. In Finland and Hungary, the HTA
rules and regulations that need to be considered body combines regulatory and HTA functions, while in
when evaluating the implications and conse- the Netherlands, the HTA body combines pricing and/
quences of implementing a health technology. or reimbursement and HTA functions.49 In Portugal
Compulsory legal sources (e.g., international and Czech Republic, the same body has regulatory,
laws, EU laws and national legislation) form pricing and/or reimbursement and HTA functions.50
the regulatory framework of any given ques- In many EU countries, the HTAB also performs other
tion in this domain. These sources often are additional tasks such as development of guidelines and

Chapter 7
Table 7-1. HTA and Associated Organisations in Select EU Member States
Country Agency Name

Germany G-BA*/IQWIG
UK NICE*#/SMC /SHTG/AWTTC
France HAS*
Hungary NIPN*
Netherlands ZIN
Belgium RIZIV-INAMI*/KCE
Italy AIFA*, RER*, AGENAS
Spain AETS-ISCIII, AEMPS*, AETSA, AQuAS, IACS, SESCS, UETS, OSTEBA
Poland AOTMiT
Norway NMA*/Hdir/NIPH
Austria HVB/GOG/LBI-HTA
Portugal INFARMED
Sweden SBU/TLV*
Finland FIMEA/THL
*Member of Early Dialogue Working Party (EDWP)

#
As of February 2020; may change based on outcome of BREXIT
Source: Mapping of HTA national organisations, programmes and processes in EU and Norway. EC website. https://ec.europa.eu/health/sites/health/files/
technology_assessment/docs/2018_mapping_processes_annexes_en.pdf. Accessed 22 February 2020.
Abbreviations:
G-BA—The Federal Joint Committee (Gemeinsamer Bundesausschuss)
IQWIG—Institute for Quality and Efficiency in Health Care (Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen)
NICE—National Institute for Health and Care Excellence
HAS—French National Authority for Health (Haute Autorité de Santé)
AIFA—Italian Medicines Agency
RER—Regione Emilia-Romagna
NIPN—National Institute of Pharmacy and Nutrition
ZIN—Zorginstituut Nederland
RIZIV-INAMI—Rijksinstituut voor Ziekte- en Invaliditeitsverzekering/ Institut national d’assurance maladie-invalidité
AGENAS—Agenzia Nazionale per i Servizi Sanitari Regionali
AEMPS—Spanish Medicines Agency
AETS-ISCII—The Instituto De Salud Carlos III
AETSA—Andalusian HTA Agency
AOTMiT—Agency for Health Technology Assessment and Tariff System
AQuAS—Agency for Health Quality and Assessment of Catalonia
AVALIA-T—Galician Agency for HTA
AWTTC—All Wales Therapeutics and Toxicology Centre
GOEG—Gesundheit Osterreich GmbH, Austrian Health Institute
Hdir—Norwegian directorate of Health
HVB—Hauptverband der Österreichischen Sozialversicherungsträger (Association of Austrian Social Insurance Institutions)
IACS—Health Sciences Institute in Aragon
FIMEA—Finnish Medicine Agency
INFARMED—National Authority of Medicines and Health Products
LBI-HTA—Ludwig Boltzmann Institute for Health Technology Assessment
KCE—Belgian Health Care Knowledge Centre
NIPH—The Norwegian Institute of Public Health
NMA—Norwegian Medicines Agency
OSTEBA—Basque Office for Health Technology Assessment - Ministry for Health
SESCS—Evaluation and Planning Unit – Directorate of the Canary Islands Health Service
SBU—Swedish Agency for Health Technology Assessment and Assessment of Social Services
SHTG—Scottish Health Technologies Group
SMC—Scottish Medicines Consortium
SNHTA—Swiss Network for HTA
STAKES—The Finnish Office for Health Care Technology Assessment
THL—National Institute for Health and Welfare
TLV—Dental and Pharmaceutical Benefits Agency
UETS—Health Technology Assessment Unit, Madrid

Table 7-2. Comparison of HTA in Germany, France, UK, Italy and Spain
Germany France UK Italy Spain

HTA Main Role GBA (Develop HAS (develop and NICE, SMC, SHTG, AIFA (regulation, AEMPS, OSTEBA
Organisation and issue HTA issue HTA recom- AWTTC (develop and issue pricing and reim- (develop and issue HTA
and Structure recommen- mendations) HTA recommendations) bursement of HT) recommendations and
dations and AGENAS (develop regulation of HT)
reimbursement and issue HTA AETS-ISCIII, AETSA,
of HT) recommendations) AQuAS, IACS, SESCS,
IQWIG (develop Regional HTA agen- UETS (develop and issue
and issue HTA cies with varying HTA recommendations)
recommenda- HTA mandates and
tions ) remits (e.g., RER)
Other Tasks GBA (quality HAS (quality NICE (quality standards, AGENAS (quality AEMPS, AETSA, IACS,
standards, clin- standards, clin- clinical guidelines standards, clinical OSTEBA (quality stan-
ical guidelines ical guidelines development, health- guidelines devel- dards, clinical guidelines
development, development, care promotion, horizon opment, healthcare development, healthcare
early dialogues healthcare pro- scanning, registries, edu- promotion, hori- promotion, horizon scan-
and scientific motion, early cation, early dialogues zon scanning, ning, registries, education,
advice) dialogues and and scientific advice) education) early dialogues and scien-
IQWIG (quality scientific advice) SMC (quality standards, tific advice)
standards, horizon scanning) AETS-ISCIII (horizon scan-
education) SHTG (quality standards, ning, registries, education)
clinical guidelines AQuAS (quality standards,
development, horizon clinical guidelines devel-
scanning, early dialogues opment, registries,
and scientific advice) early dialogues and scien-
AWTTC (clinical guidelines tific advice)
development, horizon UETS (clinical guidelines
scanning, education) development, horizon
scanning, registries,
education)
Scope of HTA Type of HT GBA, IQWIG HAS (pharma, NICE (pharma, medical AIFA (pharma) AEMPS (pharma)
(pharma, medical medical devices, devices, other HT) AGENAS (medical AETS-ISCII (medical
devices, other other HT) SMC, AWTTC (pharma devices, other HT) devices, other HT)
HT) only) AETSA, AQuAS (pharma,
SHTG (medical devices, medical devices, other
other HT) HT)
IACS (pharma limited
to the regional context,
medical devices, other
HT)
UEATS (pharma - limited,
medical devices, other
HT)
REA Yes Yes No No No (AEMPS)
Yes (AETS-
ISCIII, AETSA, AQuAS,
IACS, UETS, OSTEBA)
REA and No (G-BA) Yes, as requested Yes No (AGENAS) No (AQuAS)
Economic Yes (IQWIG) Yes (AIFA) Yes (AEMPS, AETS-
Assessment ISCIII, AETSA, IACS,
UETS, OSTEBA)
Full HTA No Yes, as requested No (NICE, SMC, AWTTC) Yes (AGENAS) Possible (AEMPS)
Yes (SHTG) No (AIFA) No (AETS-ISCIII, UETS)
Yes (AQuAS, AETSA,
IACS, OSTEBA)
Use of HTA Core No Yes Yes (SHTG) Yes (AGENAS) No (AEMPS)
EUnetHTA Model No (NICE, SMC, AWTT) No (AIFA) Yes (AETS-
Tools ISCIII, AETSA, AQuAS,
IACS, UETS, OSTEBA)
Guidelines Yes Yes Yes (SHTG) Yes (AGENAS) No (AEMPS)
No (NICE, SMC, AWTT) No (AIFA) Yes (AETS-
ISCIII, AETSA, AQuAS,
IACS, UETS, OSTEBA)
Adapted from: Mapping of HTA national organisations, programmes and processes in EU and Norway. EC website. https://ec.europa.eu/health/sites/
health/files/technology_assessment/docs/2018_mapping_npc_annexes_en.pdf. Accessed 9 March 2020.

Chapter 7
quality standards, early dialogues and scientific advices, mandatory in Germany except in cases of failure to
registries and education.51 agree a price with a manufacturer due to an unfavour-
In Spain, a decision to include a product in the able early benefits assessment.
basic benefits package cannot be made without first In the UK, NICE appraisals are based on the
conducting HTA.52 Similarly, in France, the improve- review of clinical and economic evidence, mainly pro-
ment of medical benefit assessment (ASMR) and the vided by the company, supported by testimonies from
medical benefit (SMR) ratings, which impact pricing patients, healthcare professionals and commissioners;
negotiations, are intricately linked and require HTAs clinical evidence shows the health benefit, including
conducted by the Transparency Commission (Figure the impact on quality of life and effects on mortality;
7-1).53 The situation is different in Germany, where the and economic evidence shows how well the technology
Institute for Quality and Efficiency in Health Care works in relation to how much it costs to the National
(IQWIG) plays a much more advisory role in pro- Health Service (NHS) and whether it represents value
viding recommendations (based on its HTA) to the for money.61
Federal Joint Committee (Gemeinsamer Bundesausschuss) NICE uses Quality Adjusted Life Years (QALYs)
(G-BA) (Figure 7-2). Moreover, a manufacturer can to compare different drugs, devices and other technol-
set the price of a given product for the first 12 months ogies for different conditions. NICE’s ‘threshold,’ over
while the product is still being assessed by the G-BA which treatments are less likely to be recommended
and IQWIG. In the UK, although uncommon, it is for use in the NHS, is typically between £20,000 and
possible for an approved medicine to be available for £30,000 per QALY.62 Companies can submit proposals
prescription even though it has not yet been reviewed for patient access schemes, allowing patients to have a
and recommended for reimbursement by the National technology when NICE’s assessment of value is unlikely
Institute of Health and Care Excellence (NICE).54 to support the list price.63
HTA in Italy is largely advisory rather than mandatory; The organisation of the HTA process informing
even in cases where they are conducted, the outcome of reimbursement decisions also differs substantially from
such assessments seldom influences pricing and reim- country to country. For example, in France, Netherlands
bursement decisions directly.55 and Poland, the same HTA body informs and makes
reimbursement decisions, while Spain has a network
Scope and Role of HTA in Decision-Making in EU of regional HTA organisations (the Spanish HTA
Most EU countries use REA and economic evaluation Network) that, together with the Spanish Agency of
to assess health technologies, but not all. For example, Medicines and Medical Devices, has a specified role
in Germany, the HTA scope includes REA only.56 and a process to inform reimbursement decision-mak-
However, the G-BA Rules of Procedures has an option ing at the national level.64 The majority of EU countries
for including economic evaluation, despite it being also use HTA to inform pricing decisions on pharma-
applied only twice in practice.57 ceuticals, but only a minority on medical devices and
Assessing whether technologies are cost-effective other technologies. HTA organisations across EU use
is the ultimate scope of economic evaluations. HTA to inform decisions on capital investments, clini-
Full economic evaluations require a comparison cal guidelines and quality standards development.65
In principle, patients should have access to new and
of two or more alternatives and consider both the
innovative medicines as soon as possible, and it has been
costs and consequences associated with each of the described how differences in HTA agencies’ approaches
alternatives. There are three main types of full eco- across Europe have led to differences in market access
nomic evaluations: for some medicines (see Table 7-3 and Figure 7-3).66
1. Cost-Effectiveness Analysis (CEA)
2. Cost Utility Analyses (CUA), providing EU HTA Harmonisation
insight on whether the technology is more cost In recent years, the EU has recognised a “clear area
effective than any other alternative of European added-value (in harmonising HTA) to
3. Budget Impact Analysis (BIA)58 reduce overlap and duplication of efforts in this field
and hence promote the effective and efficient use of
CEA is an HTA requirement in Italy and the UK, resources.”67 However, harmonisation and a more col-
but it is optional in Spain.59 In France, cost-effective- laborative scheme have limitations under the Treaty on
ness analysis is mandatory for products that are rated the Functioning of the EU, which does not allow the EU
ASMR 1–3 and are predicted to exceed €20 million in to intervene directly in Member States’ healthcare pol-
annual revenue.60 There are variations regarding when icies. Opponents to EU-wide HTA collaboration argue
BIA is required as a part of HTA; for example, it is not that healthcare implementation and reimbursement

Health Technology Assessment
Figure 7-1. Process Map for France

FMA EU Commission
European Medicines Agency
1a
Regulator Market Authorisation
Ministry of Health
ANSM
French Agency for the safety of
Medicines and Health Products
1b
Regulator
Sponsor
HAS UNCAM
The French National National Union of
Authority for Health
Health Insurance Funds
CT
Transparency Committee
2a HTA
SA TV CED
$
Recommender
Recommender
2b
CEESP
Economic and Public Minister of Health
Healt Evaluation
Committee
SA TV EV CED
Decision Maker
CEPS Social Security

The Economic Committee on
system
Health Care Products National Health Insurance
2c Adoption committee
Price Authority Provider
Source: Allen N, Liberti L, Walker, Stuart R, Salek S. A comparison of reimbursement recommendations by European HTA agencies: Is there opportunity for
further
Source:alignment? Frontiers
Allen N, Liberti in Pharmacology
L, Walker, Stuart R,8;Salek
384,S.2017.
A comparison of reimbursement recommendations by European HTA agencies: Is there opportunity for
further alignment? Frontiers in Pharmacology 8; 384, 2017.
overlap and duplication of efforts in this field and hence ministries and regional health authorities to support an
promote the effective and efficient use of resources.”34 effective collaborative approach to bring added value at both
decisions harmonisation
However, are driven by distinct
and a moreCommunity and scheme
collaborative two-year
the project
national in 2006–08,
and regional with
levels.36 the following strate-
Based on that mission,
national
have standards
limitations andthe
under should
Treatynot
onadhere to an
the Functioning of the gic objectives:
EUnetHTA 70
undertook a two-year project in 2006–08 with
EU-wide
EU, whichset of not
does principles. 68
allow the EU to intervene directly in • reduce
the following overlap
strategic and duplication
objectives: 37 of effort and
Member TheStates’
underlying motivation
healthcare policies.for the establishment
Opponents to EU-wide promote
• reduce more and
overlap effective resource use
duplication of effort and
of EUnetHTA
HTA was to
collaboration bringthat
argue together national
healthcare health
implementa- • promote
increase HTA
more input to
effective decision
resource usemaking in
insurance
tion organisations, academia,
and reimbursement decisions aregovernment
driven byagen-
distinct Member
• increase HTA States
inputand the EU making
to decision and increase HTA
in Member
cies, health ministries
Community and nationalandstandards
regionalandhealth authorities
should not adhere impact
States and the EU and increase HTA impact
to an
to support
EU-widean effective collaborative
set of principles. 35 approach to bring • • strengthen
strengthen thethe link
link between
between HTAHTA andand health-
healthcare
addedThevalue at both motivation
underlying the nationalfor andthe
regional lev-
establishment of care making
policy policy making
in the EU in the
andEU and its Member
its Member States
els.69 Based on
EUnetHTA wasthat mission,
to bring EUnetHTA
together nationalundertook a
health insur- Statescountries with limited HTA experience
• support
ance organisations, academia, government agencies, health
RegulatoryAffairs
Regulatory AffairsProfessionals
ProfessionalsSociety
Society 85
81

Chapter 7
Chapter 6
Figure 7-2. Process Map for Germany
Figure 6-2. Process Map for Germany
EU Commission
European Medical Agency
1a Regulator Market Authorisation
Ministry of
BfArM PEI
Federal Institute for Drugs Federal Institute for Vac-
1b and Medical Devices cines and Biomedicines
Regulator Regulator
Sponsor
IQWIG
Federal Joint Commit- Institute for Quality and Ef-
ficiency in Health Care
Medicines Reimbursement
2 Commission HTA
SA TV $ TV EV
3
Decision Maker Recommender
GKV-Spitzenverband SHI
Federal Association of the Statutory Health Insurance
Statutory Health Insurance
Price Authority Provider
Source:Allen
Source: AllenNicola,
Nicola,Liberti
LibertiLawrence,
Lawrence, Walker
Walker Stuart
Stuart R.,
R., Salek
Salek Sam.
Sam. AA Comparison of reimbursement
comparison of Reimbursementrecommendations
RecommendationsbybyEuropean
EuropeanHTA
HTAagencies:
Agencies:IsIsthere
There
Opportunity for Further Alignment? Frontiers in Pharmacology 8; 384,
opportunity for further alignment? Frontiers in Pharmacology 8; 384, 2017.2017.
application of tools and approaches to cross-border HTA

• support
Adopting countriesand
the methods withtools
limited HTA
established by the • develop
collaboration. TheHTA tools
aim was and methods
to bring collaboration to a higher
2006–08experience
project and incorporating initiatives developed level,• resulting
field test and apply
in better developedby
understanding tools
the and
Commission
by the HLPF’s Working Group on Relative Effectiveness, and Member methods
States of ways to establish a sustainable EU
Adopting
EUnetHTA the initiated
methods EUnetHTA
and tools established by the
Joint Action 1 (2010– HTA structure. Specifically, the programme will develop a
2006–08 project
2012), with the and incorporating
following initiatives 38developed
specific objectives: The EUnetHTA
general Joint Action
strategy, principles 2 (2012–2015)
and an implementationwasproposal
by the
• HLPF’s
developWorking
a generalGroup
strategyonand
Relative Effectiveness,
a business model for initiated with theEuropean
for a sustainable general objective of strengthening
HTA collaboration according to
EUnetHTA initiated
sustainable the EUnetHTA
European Joint Action 1
HTA collaboration the
thepractical
requirementsapplication of toolsfor
of the directive and approacheshealthcare
cross-border to
(2010–2012),
• develop with
HTA the tools
following specific objectives:71
and methods cross-border
Article 15. HTA collaboration. The aim was to bring
•• field
develop a general
test and apply strategy
developedand a business
tools and methods collaboration to a higher level, resulting in better under-
model for sustainable European HTA standing by the Commission and Member States of
collaboration
The EUnetHTA Joint Action 2 (2012–2015) was initiated
with the general objective of strengthening the practical
86
82 Regulatory
RegulatoryAffairs
AffairsProfessionals
ProfessionalsSociety
Society
Table 7-3. Summary of Time From EMA Authorisation to HTA Decision and Outcome
Product Brand Germany France (HAS) UK (NICE) Italy (AIFA) Spain (AEMPS)
Name (Generic (IQWiG)
Name)
Xalkori (crizotinib) 113 d 162 d 327 d 153 d -
Added benefit Approved (ASMR III) Rejected Approved with
not proven conditions
Teysuno - 569 d 982 d -
(combination: Rejected Approved
tegafur, gimeracil
and oteracil)
Caprelsa 121 d 124 d - 497 d 644 d
(vandetanib) Added benefit Approved with restric- Approved with Approved
not proven tions (ASMR IV) conditions
Halaven (eribulin) 319 d 125 d 395 d 279 d 925 d
Added benefit Approved with Rejected Approved with Approved with
not proven restrictions conditions restrictions
(ASMR IV)
Jevtana 301 d 216 d 425 d 275 d -
(cabazitaxel) Proven Approved (ASMR IV) Rejected Approved with
conditions
Yervoy (ipilimumab) 289 d 154 d 521 d 590 d 590 d
Added benefit Approved (ASMR IV) Approved with PAS Approved Approved
Zelboraf 663 d 229 d 302 d 473 d 644 d
(vemurafenib) Added benefit Approved (ASMR II) Approved with PAS Approved Approved
Pixuvri (pixantrone 293 d 426 d 646 d 424 d -
dimaleate) No added Approved with Approved with Approved with
benefit restrictions restrictions conditions
(ASMR V)
Gilenya 305 d 125 d 365 d 236 d -
(fingolimod) Minor added Approved (ASMR IV) Approved with PAS Approved
benefit
Onbrez Breezhaler 380 d 247 d -
(indacaterol) Approved (ASMR V) Approved
Note: dates are taken from the product decision/publication date on the relevant country agency webpages. For Germany, the time is from EMA authorisa-
tion to IQWiG recommendation. For France, Italy and Sweden, the HTA decision date is also the date of reimbursement.
Source: Akehurst R, Abadie E, Renaudin N, Sarkosy F. Variation in Health Technology Assessment and Reimbursement Processes in Europe. Value in
Health 20 (2017) 67–76. https://www.valueinhealthjournal.com/article/S1098-3015(16)31305-5/pdf.
ways to establish a sustainable EU HTA structure, with requirements of Article 15 of the Directive for
the following specific objectives:72 cross-border healthcare
• strengthen the practical application of
tools and approaches to cross-border HTA The EUnetHTA Joint Action 3 (2016–2020) builds
collaboration on the lessons, success and products of earlier actions.
• bring collaboration to a higher level, result- This Joint Action aims to increase the use, quality and
ing in better understanding for the EC and efficiency of joint HTA work at the European level,
Member States of the ways to establish a sus- defining and implementing a sustainable model for the
tainable structure for HTA in the EU scientific and technical cooperation.73
• develop a general strategy, principles and an Despite the achievements of the current EU
implementation proposal for a sustainable cooperation, some challenges cannot be sufficiently
European HTA collaboration according to the addressed by continued project-based voluntary

Chapter 7
Chapter
Figure 67-3. Mean Length of Time From EMA EMA HTA Parallel Consultation
Authorisation to HTA Decision for Oncology In November 2017, EMA and EUnetHTA published a
Products
Figure 6-3. Mean Length of Time from EMA joint work plan for 2017–2020, outlining further oppor-
Summary
Authorisation to HTA Decision for Oncology Products tunities
This to harness
chapter reviews synergies
Healthbetween
Technology regulatory and
Assessment’s
HTA evaluation
current status and for a medicine.
likely future trends 81
Onein key area HTA
Europe. of col-is
laboration
here to stay,includes
but differentparallel consultation.
procedures and This procedure
approaches to
offers a single
determining valuepathway
have ledthrough
to wastefulwhich a sponsorofcan
duplication effort
request
and pre- and
unwieldly postauthorisation
complexity consultationRecently
for manufacturers. from
EMA, EUnetHTA
adopted and proposedmembers directives anddemonstrate
HTABs. This theoffers
EU is
several benefits,
committed including:82processes and working with
to harmonising
EMA •to support
convergent
more advice
efficientonevidence
development plansWhile
generation. for
medicines
it is impossible to explorefromallboth
the regulators and HTABs
nuances surrounding this
topic, •it ismutual
clear from inputthe onexamples
methodologicalprovided andthere is an
opportunity disease-specific
now to step back guidelines, evidence how
and re-evaluate require-
deci-
ments
sions are made, and publication
particularly in lightof of data relevant
the slew for
of disruptive
technologies orphan-designated
heading for the market. medicines These gene and cell
• will
therapies collaboration
require a new on study
way of registries
looking at healthcare
and new improved
• ways of paying coordination
for it. with and greater partic-
Source: Value in Health 20 (2017) 67-76: https://www.ispor.org/preference- References ipation of HTABs through EUnetHTA’s Early
based-assessment_hta_reimbursement_Europe.pdf. DatesF.are taken from
in the 1. Velasco Garrido M, Kristensen FB, Nielsen CPP and Busse R.
Source: Akehurst R, Abadie E, Renaudin N, Sarkosy
product
Variation Dialogue Working Party (EDWP) and the
Healthdecision/publication dateand
Technology Assessment on the relevant country
Reimbursement agencyinweb
Processes pages.
Europe, Health Technology Assessment and Health Policy-Making in Europe—
EUnetHTA
An introduction early
to objectives, roledialogue
of evidence,(ED) secretariat
and structure in Europe
Value in Health 20 (2017) 67-76. https://www.valueinhealthjournal.
com/article/S1098-3015(16)31305-5/pdf. Dates are taken from the prod- [hereinafter European Observatory HTA Policy Report]. 2008:
The concept of adaptive
uct decision/publication date on pathways is not agency
the relevant country the launch of a
web pages. EMA HTAHealth
34. World Parallel Consultation
Organization, European is Observatory
increasingly on Health
Systems and Policies. WHO website. www.euro.who.int/__data/
new pathway for achieving Marketing Authorisation and/or fostered by industry as an efficiency toward ultimate
assets/pdf_file/0003/90426/E91922.pdf. Accessed 3 October 2017.
reimbursement; rather, it utilises already existing approval 2.availability
Ibid, p. 80. of potential treatments for patients, reducing
cooperation on HTA; therefore, the EC adopted on 31
tools. 3.development
Ibid, p. 81. program uncertainty through awareness
January 2018Final
In EMA’s a proposal
Report for a new
on the regulation,
Adaptive strength-
Pathways Pilot, 4.of Ibid.
data requirements and likely market access outcomes
ening the EU cooperation beyond 2020.
published in 2016, it was shown that 18 of 62 applications
74 5. International Network of Agencies for Health Technology Assessment
allowing for optimal evidence generation in support
(INAHTA) website. www.inahta.net/. Accessed 3 October 2017.
received were selected for more in-depth consideration, 6.of Proposal
both regulator and payer
for a Directive of the decision
European making
Parliamenton bene-
and of the
which resulted in seven applications progressing to either fit-risk
Counciland value.
on the
83
application of patients’ rights in cross-border health-
Collaboration
formal Between
Scientific Advice the EMA
or parallel and
regulatory-HTA care (COM(2008) 414 final). Brussels; 2 July 2008. EC website.
EUnetHTA
http://ec.europa.eu/health/ph_overview/co_operation/healthcare/
Consultation. 43
EMA Initiatives to Facilitate Early Access for
docs/COM_en.pdf. Accessed 3 October 2017. (See also Europa Press
In the past two decades, several initiatives have been Essential Medicines Q&A: Patients’ Rights in Cross Border
Release (MEMO/11/32),
PRIME
established to address the disparities of regulatory and EMA has several
Healthcare. initiatives
(19 January through
2011). Europa which
website. it provides
http://europa.eu/
InHTA
2016,requirements.
EMA launched In PRIME
EMA’s Road (PRIority
MapMEdicines)—a
to 2015,75 there rapid/pressReleasesAction.do?reference=MEMO/11/32&format=H
developmental support and facilitates early access for
TML&aged=0&language=en&guiLanguage=en. Accessed 3 October
scheme aimed
is a vision foratcollaboration
medicines still in development
between EMA and(pre-mar-
HTABs, essential
2017. medicines, such as the Adaptive Pathways con-
keting authorisation),
concentrating which address
on improving an unmet medical
the information need
available on 7.cept and the PRIME scheme.
Ibid.
(taking
centrallyboth innovation
authorised and public
medicines; thishealth
is basedrelevance
on HLPF into 8. Directive 2011/24/EU of the European Parliament and the Council
of 9 March 2011 on the application of patients’ rights in cross-border
consideration).
recommendations Thisfrom
is particularly
2008.76 Since focused
2010,onEMAmedicines
has Adaptive Pathways
healthcare. EurLex website. http://eur-lex.europa.eu/LexUriServ/
for whichclosely
worked the relevant patient population
with EUnetHTA. 77 does not have
The collaboration’s In LexUriServ.do?uri=OJ:L:2011:088:0045:0065:EN:PDF.
a bid to reduce the ‘time-to-patient’ for highly Accessed 3
any existing
initial focustreatment
was a projectoption. 44
The assessment
examining how a medi-parameters innovative
October 2017.medicines, EMA introduced the Adaptive
that determine
cine’s benefit andwhether or not a medicine
risk information is accepted
in European into
Public 9.Pathways
Ibid. concept in 2014.84 This allows the MA and
the scheme include:
Assessment Reports (EPARs) could address HTABs 10. Ibid.
reimbursement processes to run parallel to each other,
11. HTA definition. “About.” EUnetHTA website. http://www.eunethta.
• degree
needs. 78
This of unmet was
program needstarted after European policy hence facilitating quicker
eu/about-us/faq#t287n73. access
Accessed to medicines
3 October 2017. that
• innovation
makers recommended level improvements be made to the address
12. very significant “unmet needs.” EMA defines
Op cit 11.
way• data
treatment
publishedeffect
bymagnitude
regulators contribute to HTABs the“JAadaptive
13. pathways
WP5: Relative as: Assessment (REA) of Pharmaceuticals,”
Effectiveness
• treatment
REAs. effect of
An evaluation duration
this collaboration with respect July 2011. EUnetHTA website. http://www.eunethta.eu/activities/
A prospectively planned, iterative approach to
JA-WP5/ja-wp5-relative-effectiveness-assessment-pharmaceuticals.
to •the observed clinical outcome
EPAR79 concluded that a relevance
revised proposed bringing
Accessed medicines
3 October 2017. to market…initially targeting the
template did indeed lead to a better understanding of development
14. High Level Group to ona innovation
well-defined groupofof
and provision patients
medicines that
recommenda-
PRIME designation
information providesaamore
needs. Further, manufacturer
harmonised access
regu-to a is likely
tions forto benefit
actions. most http://ec.europa.eu/health/ph_overview/
EC website. from the treatment. This is
multi-disciplinary
latory document (for teaminstance,
of advisors to support
in terms develop-
of efficacy data Documents/key08_en.pdf. Accessed 3 October 2017.
followed by iterative phases of evidence gathering and
15. Ibid.
ment strategy and
presentation) trial planning.
is expected to result Several HTAequipped
in better agencies are 16. Op cit 1, pp.licensing
progressive 31–32. adaptations, including to expand
represented in this team.
HTABs (particularly inEMA reported
the context of in February
rapid REA).2017
80
itsIbid,
17. use p.to21.
a wider patient population as more data
that 17 of 80 applications received were accepted into the become
18. Ibid, p. available.
33. 85
scheme, 45 the majority of which were oncology related. 19. Ibid, p. 32.
20. Ibid, p. 13.

The concept of adaptive pathways is not the launch and the design of confirmatory trials and postmarket
of a new pathway for achieving MA and/or reimburse- real-world data collection.99
ment; rather, it uses already existing approval tools.86
In EMA’s Final Report on the Adaptive Pathways Conclusion
Pilot, published in 2016, it was shown that 18 of 62 This chapter reviews the development of the field of
applications received were selected for more in-depth HTA and its role in health products market access.
consideration, which resulted in seven applications pro- It provides an overview of some of the differences in
gressing to either formal Scientific Advice or parallel HTA across EU Member States and how these might
regulatory-HTA Consultation.87 impact patients’ access to new health technologies.
Following the pilot project, EMA is exploring While the evaluation and the decision-making process
the adaptive pathways concept further in the context leading to decisions on the pricing and reimbursement
of parallel consultation with HTABs and additional of health technologies is undertaken within national
stakeholders, including patients. Additional support is and local contexts and lies with the national competent
available for sponsors via pre-submission meetings prior authorities, there are potential efficiencies to be gained
to the one anticipated by the parallel consultation pro- from enhanced collaboration around the collection of
cedure. Proposals can be submitted to EMA following evidence underpinning these decisions. There is also
guidance published in August 2016.88 an increased collaboration between EMA and HTA
bodies that has the potential to reshape the way clinical
PRIME development is designed and managed to harmonise
In 2016, EMA launched PRIority MEdicines regulatory and HTA expectations.
(PRIME), a scheme aimed at medicines still in devel-
opment (premarketing authorisation), which addresses References
an “unmet medical need” (taking both innovation and 1. World Health Organization (WHO) website. https://www.who.
int/health-technology-assessment/about/healthtechnology/en/.
public health relevance into consideration).89 This is Accessed 5 March 2020.
particularly focused on medicines for which the relevant 2. HTA 101: Introduction to Health Technology Assessment.
patient population does not have any existing treatment National Institute of Health (NIH) website. https://www.nlm.
option.90 The assessment parameters that determine nih.gov/nichsr/hta101/ta10103.html. Accessed 5 March 2020.
3. Ibid.
whether a medicine is accepted into the scheme include: 4. Ibid.
• degree of unmet need 5. Ibid.
• innovation level 6. International Network of Agencies for Health Technology
• treatment effect magnitude Assessment (INAHTA) website. SBU. http://www.inahta.org/
Members/SBU/. Accessed 5 March 2020.
• treatment effect duration 7. Banta D and Jonsson, E. “History of HTA: Introduction.”
• observed clinical outcome relevance International Journal of Technology Assessment in Health Care. 25:
Supplement 1 (2009), 1–6. https://www.cambridge.org/core/ser-
PRIME designation provides a manufacturer access to a vices/aop-cambridge-core/content/view/S0266462309090321.
multi-disciplinary team of advisors to support develop- 8. Co-Operation is Strength: Joint Achievements of the
ment strategy and trial planning. Several HTA agencies NordicHTA Centers. Det norske medicinske Selskab website.
are represented in this team. As of January 2020, EMA https://www.michaeljournal.no/i/2012/03/Co-operation-is-
has received and assessed a total of 281 requests for strength-Joint-achievements-of-the-Nordic-HTA-centers.
eligibility to PRIME, the majority of which were oncol- 9. Op cit 7.
ogy related.91 10. European Network for Health Technology Assessment
As of January 2020, five products (i.e., Zynteglo®,92 (EUnetHTA) website. https://eunethta.eu/eunethta-proj-
Yescarta®,93 Polivy®,94 Ervebo®,95 Kymriah®96) granted ect-2006-2008/. Accessed 5 March 2020.
11. Ibid.
PRIME designation have received marketing authori- 12. Proposal for a Directive of the European Parliament and of the
sation in the EU. Both Kymriah® and Yescarta® have Council on the application of patients’ rights in cross-border
successfully obtained reimbursement in their labelled healthcare (COM (2008) 414 final). Brussels. 2 July 2008. EC
indications in France, Germany, Italy and Spain.97 website. http://ec.europa.eu/health/ph_overview/co_operation/
healthcare/docs/COM_en.pdf. Accessed 5 March 2020.
The approval of Zynteglo® provides an example of the 13. Ibid.
advantages resulting from iterative scientific advice with 14. Directive 2011/24/EU of the European Parliament and the
involvement of HTABs in fostering patient access;98 Council of 9 March 2011 on the application of patients’
clinical issues were discussed with EMA, patients and rights in cross-border healthcare. EurLex website. http://
eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=O-
HTA bodies, including the suitability of the clinical J:L:2011:088:0045:0065:EN:PDF. Accessed 5 March 2020.
data set, the primary endpoint used to support approval 15. Commission Implementing Decision of 26 June 2013.
2013/329/EU. https://ec.europa.eu/health/sites/health/files/

Chapter 7
technology_assessment/docs/impl_dec_hta_network_en.pdf. wp-content/uploads/2018/01/Clinical-endpoints.pdf. Accessed

Accessed 5 March 2020. 5 March 2020.
16. Op cit 14. 37. Biomarkers Definitions Working Group. Biomarkers and
17. Directive 2011/24/EU of the European Parliament Surrogate Endpoints: Preferred Definitions and Conceptual
and the Council of 9 March 2011 on the application of Framework. ClinPharmacolTher. 2001; 69(3):89-95. Accessed 5
patients’ rights in cross-border healthcare. Article 15 – March 2020.
Cooperation of heath technology assessment. EurLex 38. Schuster BC, Brhlikova P, Heath J and McGettigan P. The use
website. https://eur-lex.europa.eu/legal-content/EN/TXT/ of Validated and Nonvalidated Surrogate Endpoints in two
HTML/?uri=CELEX:32011L0024&from=EN. Accessed 5 European Medicines Agency Expedited Approval Pathways:
March 2020. A Cross-Sectional Study of Products Authorized 2011–2018.
18. EUnetHTA Joint Action 3 (2012-2020).EUnetHTA website. PLoS Med. September 2019; 16(9). https://doi.org/10.1371/
https://eunethta.eu/ja3-archive/. Accessed 5 March 2020. journal.pmed.1002873. Accessed 28 February 2020
19. Ibid. 39. Kleijnen S, et al. “Relative Effectiveness Assessment
20. International Network of Agencies for Health Technology of Pharmaceuticals: Similarities and Differences in 29
Assessment (INAHTA) website. www.inahta.net/. Accessed 5 Jurisdictions.” Value in Health. Volume 15, Issue 6, September–
March 2020. October 2012, Pages 954-960. https://www.sciencedirect.com/
21. Velasco GM, Kristensen FB, Nielsen CPP and Busse R. science/article/pii/S1098301512016099#tbl1. Accessed 5 March
European Observatory Health Technology Assessment (HTA) 2020.
Policy Report. 2008:34. World Health Organization, European 40. High Level Group on Innovation and Provision of Medicines
Observatory on Health Systems and Policies. WHO website. Recommendations for Actions. EC website. http://ec.europa.
www.euro.who.int/__data/assets/pdf_file/0003/90426/E91922. eu/health/ph_overview/Documents/key08_en.pdf. Accessed 5
pdf. Accessed 5 March 2020. March 2020.
22. European Observatory Policy Brief. http://www.euro.who. 41. High Level Pharmaceutical Forum 2005-2008 Final Report.
int/__data/assets/pdf_file/0006/108960/E87922.pdf. Accessed http://www.rees-france.com/en/IMG/pdf/2008_High_level_
5 March 2020. Pharma_forum__en_final_report.pdf. Accessed March 2020.
23. EU MDR: The Challenge of Compliance by May 2020. 42. Op cit 21.
https://www.mddionline.com/eu-mdr-challenge-compli- 43. Op cit 21.
ance-may-2020. Accessed 5 March 2020. 44. EUnetHTA JA2 WP8 Deliverable. HTA Core Model Version
24. EUnetHTA Submission FAQs for Industry: Pharmaceuticals. 3.0. https://eunethta.eu/wp-content/uploads/2018/03/
https://eunethta.eu/frequently-asked-questions-for-the-phar- HTACoreModel3.0-1.pdf. Accessed 5 March 2020.
maceutical-industry/. Accessed 5 March 2020. 45. Ibid.
25. Ciani O and Federici C. Clinical Engineering Handbook 46. Ibid.
(Second Edition). Chapter 110: Introduction to Economic 47. European Network for Health Technology Assessment
Evaluation and Health Technology Assessment. Pages 789-794. (EUnetHTA) Guideline. Process of Information Retrieval for
Elsevier 2020. https://www.sciencedirect.com/science/article/ Systematic Reviews and Health Technology Assessments on
pii/B9780128134672001115. Accessed 5 March 2020. Clinical Effectiveness. December 2016. http://www.eunethta.eu/
26. Op cit 21. sites/default/files/Guideline_Information_Retrieval_V1-1.pdf.
27. Op cit 21. Accessed 5 March 2020.
28. Op cit 25. 48. Mapping of HTA National Organisations, Programmes and
29. Wang T, et al. “Building Synergy Between Regulatory and HTA Processes in EU and Norway. https://ec.europa.eu/health/sites/
Agencies Beyond Processes and Procedures: Can We Effectively health/files/technology_assessment/docs/2018_mapping_npc_
Align the Evidentiary Requirements?” A Survey of Stakeholder en.pdf. Accessed 5 March 2020.
Perceptions. Value in Health. Volume 21, Issue 6, June 2018, 49. Ibid.
Pages 707-714. https://www.sciencedirect.com/science/article/ 50. Ibid.
pii/S1098301517336689#ec0005. Accessed 5 March 2020. 51. Ibid.
30. “JA WP5: Relative Effectiveness Assessment (REA) of 52. Hogan Lovells. EU Pricing and Reimbursement: Pricing
Pharmaceuticals.” July 2011. EUnetHTA website. http://www. and Reimbursement Schemes in Major European Countries.
eunethta.eu/activities/JA-WP5/ja-wp5-relative-effectiveness-as- Published 2014. Hogan Lovells website. https://www.
sessment-pharmaceuticals. Accessed 5 March 2020. hoganlovells.com/~/media/hogan-lovells/pdf/publication/
31. Drummond MF, Schwartz JS, Jönsson B, Luce BR, et al. “Key eu-pricing--reimbursement-newsletter--november-2014_pdf.
Principles for the Improved Conduct of Health Technology ashx. Accessed 5 March 2020.
Assessments for Resource Allocation Decisions.” Int J Technol 53. “Pricing and Reimbursement of Drugs and HTA Policies in
Assess Health Care. 2008; 24:244–58. France.” March 2014. Haute Autorité de Santé (HTA) web-
32. Op cit 29. site. http://www.has-sante.fr/portail/upload/docs/application/
33. Op cit 21. pdf/2014-03/pricing_reimbursement_of_drugs_and_hta_poli-
34. Op cit 29. cies_in_france.pdf. Accessed 5 March 2020.
35. van Nooten F, et al. “Health Economics and Outcomes 54. Integlia D and Mazzoni E. Health Technology Assessment in
Research Within Drug Development: Challenges and the European Union: State of art and Future Scenarios. Institute
Opportunities for Reimbursement and Market Access Within for Competitiveness. February 2017. http://www.astrid-online.
Biopharma Research.” Drug Discovery Today. Volume 17, Issues it/static/upload/7787/7787e169a7f0afc63221153a6636c63f.pdf.
11–12, June 2012, Pages 615-622. https://www.sciencedirect. Accessed 5 March 2020.
com/science/article/pii/S1359644612000438?via%3Dihub. 55. Ibid.
Accessed 5 March 2020. 56. Op cit 48.
36. EUnetHTA Guideline, Endpoints Used for Relative 57. Ibid
Effectiveness Assessment of Pharmaceuticals: Clinical 58. Op cit 25.
Endpoints. February 2013. https://www.eunethta.eu/ 59. Angelis A, Lange Ansgar and Kanavos P. Using Health
Technology Assessment to Assess the Value of new Medicines:

Results of a Systematic Review and Expert Consultation Across 81. European Medicines Agency (EMA) website. https://www.
Eight European Countries. Eur J Health Econ. 2017. ema.europa.eu/en/partners-networks/health-technology-assess-
60. Antonanzas F, Terkola R, Overton PM, Shalet N and Postma ment-bodies. Accessed 5 March 2020.
M. “Defining and Measuring the Affordability of New 82. Ibid.
Medicines: A Systematic Review.” PharmacoEconomics. doi: 83. Khan S and Carter M. European Medicines Agency‐Health
10.1007/s40273-017-0514-4. Technology Assessment Parallel Consultation Platform: An
61. Armoiry X, Spath HM, Clarke A, Connock M, Sutcliffe P and Industry Perspective. Clinical Pharmacology and Therapeutics.
Dussart C. “Comparison of Health Technology Assessment for 29 February 2019. https://ascpt.onlinelibrary.wiley.com/doi/
new Medicines in France and England: An Example Based on abs/10.1002/cpt.1337. Accessed 5 March 2020.
Ixazomib for Patients With Relapsed or Refractory Multiple 84. European Medicines Agency (EMA). https://www.ema.europa.
Myeloma.” J Mark Access Health Policy. 2019; doi:10.1080/20016 eu/en/human-regulatory/research-development/adaptive-path-
689.2019.1648971. ways#. Accessed 5 March 2020.
62. National Institute for Health and Care Excellence. Carrying 85. European Medicines Agency (EMA). Final Report on the
NICE Over the Threshold. https://www.nice.org.uk/news/blog/ Adaptive Pathways Pilot. EMA/276376/2016. Published 28
carrying-nice-over-the-threshold. Accessed 5 March 2020. July 2016. EMA website http://www.ema.europa.eu/docs/
63. National Institute for Health and Care Excellence. Guide to the en_GB/document_library/Report/2016/08/WC500211526.pdf.
Processes of Technology Appraisal. https://www.nice.org.uk/ Accessed 5 March 2020.
process/pmg19/chapter/patient-access-schemes-commercial-ac- 86. Ibid.
cess-agreements-and-flexible-pricing. Accessed 5 March 2020. 87. Ibid.
64. Op cit 48. 88. European Medicines Agency (EMA). Guidance for
65. Ibid. Companies Considering the Adaptive Pathways Approach.
66. Akehurst R, Abadie E, Renaudin N and 2016. https://www.ema.europa.eu/en/documents/
Sarkosy F. Variation in Health Technology Assessment and regulatory-procedural-guideline/guidance-companies-consid-
Reimbursement Processes in Europe. Value in Health. 20 (2017) ering-adaptive-pathways-approach_en.pdf. Accessed 5 March
67-76. https://www.valueinhealthjournal.com/article/S1098- 2020.
3015(16)31305-5/pdf. Accessed 5 March 2020. 89. European Medicines Agency (EMA) website. https://www.
67. Op cit 21. ema.europa.eu/en/human-regulatory/research-development/
68. Policy Brief: Cross Border Health Technology Assessment. prime-priority-medicines. Accessed 5 March 2020.
Stockholm Network (2010). Stockholm network website. http:// 90. European Medicines Agency (EMA). Enhanced Early Dialogue
www.euro.who.int/__data/assets/pdf_file/0006/108960/E87922. to Facilitate Accelerated Assessment of PRIority MEdicines
pdf. Accessed 5 March 2020. (PRIME) EMA/CHMP/57760/2015. EMA website.
69. European Network for Health Technology Assessment http://www.ema.europa.eu/docs/en_GB/document_library/
(EUnetHTA). “Mission, Vision and Values.” EUnetHTA web- Regulatory_and_procedural_guideline/2016/03/WC500202636.
site. http://www.eunethta.eu/about-us/mission-vision-values. pdf. Accessed 5 March 2020.
Accessed 5 March 2020. 91. European Medicines Agency (EMA) website.https://www.
70. “EUnetHTA Project Reporting 2006–2008.” EUnetHTA ema.europa.eu/en/human-regulatory/research-development/
website. http://www.eunethta.eu/news/eunethta-project-report- prime-priority-medicines. Accessed 5 March 2020.
ing-2006-2008. Accessed 5 March 2020. 92. European Medicines Agency (EMA) website. Zynteglo
71. “EUnetHTA Joint Action 1 2010–2012.” EUnetHTA European Public Assessment Report. https://www.ema.europa.
website. http://www.eunethta.eu/activities/eunethta-joint-ac- eu/en/medicines/human/EPAR/zynteglo. Accessed 5 March
tion-2010-12/eunethta-joint-action-2010-12. Accessed 5 2020.
March 2020. 93. European Medicines Agency (EMA) website. Yescarta
72. “EUnetHTA Joint Action 1 2010–2012.” EUnetHTA website. European Public Assessment Report. https://www.ema.europa.
https://eunethta.eu/ja2-archive/. Accessed 5 March 2020. eu/en/medicines/human/EPAR/yescarta. Accessed 5 March
73. Op cit 18. 2020.
74. Proposal for a Regulation of the European Parliament and of 94. European Medicines Agency (EMA) website. Polivy European
the Council on Health Technology Assessment and Amending Public Assessment Report. https://www.ema.europa.eu/en/med-
Directive 2011/24/EU. https://ec.europa.eu/health/sites/health/ icines/human/EPAR/polivy. Accessed 5 March 2020.
files/technology_assessment/docs/com2018_51final_en.pdf. 95. European Medicines Agency (EMA) website. Ervebo European
Accessed 5 March 2020. Public Assessment Report. https://www.ema.europa.eu/en/med-
75. Roadmap to 2015—The European Medicines Agency’s icines/human/EPAR/ervebo. Accessed 5 March 2020.
Contribution to Science, Medicines and Health. EMA website. 96. European Medicines Agency (EMA) website. Kymriah
http://www.ema.europa.eu/ema/pages/includes/document/ European Public Assessment Report. EMA website. https://
open_document.jsp?webContentId=WC500101373. Accessed www.ema.europa.eu/en/medicines/human/EPAR/kymriah.
5 March 2020. Accessed 5 March 2020.
76. Op cit 41. 97. Jørgensen J, Hanna E and Kefalas P. Outcomes-Based
77. Berntgen M, Gourvil A, Pavlovic M, Goettsch W, Eichler Reimbursement for Gene Therapies in Practice: the Experience
HG and Kristensen FB. Policy Perspectives: Improving of Recently Launched CAR-T Cell Therapies in Major
the Contribution of Regulatory Assessment Reports to European Countries. Journal of Market Access and Health Policy.
HealthTechnologyAssessments: A Collaboration Between the 2020. 8:1. https://doi.org/10.1080/20016689.2020.1715536.
European Medicines Agency and the European Network for Accessed 5 March 2020.
Health TechnologyAssessment. https://www.valueinhealthjour- 98. Schuessler-Lenz M, Enzmann H, Vamvakas S. Commentary:
nal.com/article/S1098-3015(14)01836-1/pdf. Accessed 5 March Regulators’ Advice can Make a Difference: European Medicines
2020. Agency Approval of Zynteglo for Beta Thalassemia, Clinical
78. Ibid. Pharmacology and Therapeutics. Volume 107, Issue 3, 8
79. Ibid. November 2019. https://ascpt.onlinelibrary.wiley.com/doi/
80. Ibid. full/10.1002/cpt.1639. Accessed 27 February 2020

Chapter 7
99. Mezher M. EMA Officials: Regulatory, HTA Advice Sped Recommended Reading
Access to Bluebird’s Gene Therapy. Regulatory Focus. 12 • Europa Press Release (MEMO/11/32), Q&A: Patients’
November 2019. https://www.raps.org/news-and-articles/ Rights in Cross Border Healthcare. 19 January 2011.
news-articles/2019/11/ema-officials-regulatory-hta-ad- Europa website. http://europa.eu/rapid/pressReleasesAction.
vice-sped-access. Accessed 5 March 2020. do?reference=MEMO/11/32&format=HTML&aged=0&lan-
guage=en&guiLanguage=en. Accessed 5 March 2020.
• “About INAHTA.” INAHTA website. http://www.inahta.org/
about-inahta/). Accessed 5 March 2020.

Chapter 8
The Paediatric Regulation

Updated by Karl-Heinz Huemer, PhD, MD
OBJECTIVES assessing significant studies, Communication

from the Commission 2014/C 338/014
□ Understand key aspects of the Paediatric
Regulation □ Clinical investigation of medicinal products in
the paediatric population (January 2001) CPMP/
□ Identify the role of the European Medicines ICH/2711/99, ICH Topic E115
Agency (EMA) and its Paediatric Committee
(PDCO) in European paediatric drug
development Background and Scope
In October 2004, when the European Commission pro-
□ Become aware of other guidance applicable to
posed a regulation on medicines for paediatric use, the
European paediatric drug development
potential advantages and risks of dedicated European
legislation in this field had been under intense debate
for several years. A focal point for the discussion was
DIRECTIVES, REGULATIONS AND GUIDELINES how to strike the right balance between new require-
COVERED IN THIS CHAPTER ments and possible incentives and rewards for the
pharmaceutical industry. Second, if companies were to be
□ Regulation (EC) 1901/2006, as amended, of
rewarded in some way for paediatric research, how would
the European Parliament and of the Council
these rewards be delivered and what would they be?
of 12 December 2006 on medicinal products
Understandable ethical concerns about conducting clin-
for paediatric use and amending Regulation
ical trials in children had to be balanced against equally
(EEC) 1768/92, Directive 2001/20/EC, Directive
valid concerns about potential harmful effects of the con-
2001/83/EC and Regulation (EC) 726/20041
tinued practice of unlicensed and off-licence prescribing
□ Regulation (EC) 1902/2006 of the European of adult medicines for children. After public consultation
Parliament and of the Council of 20 December and review by EU institutions, a regulation was approved
2006 amending Regulation 1901/2006 on by the European Parliament and the Council in 2006
medicinal products for paediatric use2 European and entered into force on 26 January 2007.
Medicines Agency decision on class waivers in The stated overall policy objective of the Paediatric
accordance with Regulation (EC) No. 1901/2006 Regulation (Regulation (EC) No. 1901/2006),6 as
of the European Parliament and of the Council3 amended by Regulation (EC) No. 1902/2006,7 is to
improve the health of children in Europe. This goal is to
□ Guideline on the format and content of appli- be achieved by:
cations for agreement or modification of a • facilitating the development and accessi-
paediatric investigation plan and requests for bility of medicines for use in the paediatric
waivers or deferrals and concerning the opera- population
tion of the compliance check and on criteria for

Chapter 8
• ensuring medicines used to treat the paediatric • authorised products no longer covered by
population are subject to ethical high-quality patents or SPCs (Article 30 procedure related
research and are authorised appropriately for to a Paediatric Use Marketing Authorisation
use in the paediatric population (PUMA))
• improving the information available on the use
of medicines in the paediatric population A combination of incentives, obligations and rewards
• achieving the above objectives without sub- aims to increase pharmacological research and enhance
jecting children to unnecessary or duplicative paediatric labelling information for all three product
trials and without delaying medicinal products’ categories.
authorisation for other age groups (including Several product groups are exempted from the need
adults) to submit a PIP, depending on the selected licensing
route: products filed for Marketing Authorisation (MA)
Patient Population(s) as generic, biosimilar, hybrid, well-established use,
The Paediatric Regulation text defines “paediatric pop- homeopathic or herbal medicinal products (Article 9 of
ulation” as the population less than 18 years of age. A the Paediatric Regulation.11)
Commission guideline clarifies this definition as the
population ranging from pre-term neonates up to 18 Paediatric Investigation Plan (PIP)
years.8 This document also adapted the definitions for A PIP is a development plan aimed at ensuring the
different subsets of paediatric patients in accordance necessary data are obtained prior to filing a Marketing
with the ICH E11 guideline,9 i.e., pre-term neonates, Authorisation Application (MAA) for a product for
term neonates (0–27 days), infants (1–23 months), children. Measures to be agreed as an outcome of a
children (2–11 years) and adolescents (12–18 years— PIP procedure can include quality development (e.g.,
omitting the variability of the upper cut off, depending paediatric formulations), nonclinical studies or clinical
on the legal requirements in different geographic trials in children, but also include modelling or extrapo-
regions). However, these age subsets are proposed only lation exercises, literature reviews or any other activities
as guidance and can, based on medical or scientific that would help inform assessment for an MA, and
grounds, be adapted for a given condition if justified. ultimately provide information to prescribers on how
Foetuses and unborn children are outside the scope of to use a licensed medicinal product in any paediatric
this regulation. population subgroup. Data generated after paediatric
population licensing are, by definition, outside a PIP
Which products are concerned? agreement, even if such data might be of value and nec-
The regulation’s scope includes medicinal products for essary for long-term evaluation.
human use within the meaning of Directive 2001/83/ A PIP prepared by the applicant or Marketing
EC, as amended by Directive 2004/27/EC.10 In Authorisation Holder (MAH) and approved by EMA
other words, the legislation, in principle, describes the is expected to address the entire disease or condition,
requirements for marketing authorisations applica- encompassing each adult indication authorised or under
ble to all human medicinal products (including those development and should propose measures to assess the
used for treatment, prevention or diagnosis, but not medicine’s quality, safety and efficacy in all paediatric
medical devices) regardless of the registration pathway population subsets (unless a limitation can be justified).
(Centralised, Mutual Recognition, Decentralised or The PIP also should include a time schedule for all
purely national procedures) or prescription status. It agreed measures.
specifies how to generate information for the later use A PIP must cover all paediatric population subsets.
of medicines in paediatric populations. A paediatric This means if the whole range from 0 to <18 years is
drug development plan must be agreed in advance with not covered by the PIP, a waiver has to complement
the European Medicines Agency (EMA) in a Paediatric the proposed program (see below). For products already
Investigation Plan (PIP) procedure. For this purpose, authorised in the Community and still protected by an
medicines are subdivided into three main categories, SPC (or a patent qualifying for an SPC), any applica-
resulting in different regulatory requirements: tion for a new indication, new pharmaceutical form or
• products in development (unauthorised in the new route of administration will also trigger the need
EU) (Article 7 procedure) to agree on a PIP (the scope of which is not necessarily
• authorised products still covered by patents or limited to the newly proposed indication).
Supplementary Protection Certificates (SPCs) How to define an indication’s scope has been
(Article 8 procedure) discussed extensively, as proposed adult labels often
limit use to specific subsets that would exclude use in

paediatric patients. EMA has published a document already represented through the members
explaining the context in which a PIP submission appointed by CHMP).
should define a condition.12 This focuses basically on a • Three members and alternates representing
medicine’s mechanism of action, which also often has healthcare professionals are appointed by the
the potential to work in diseases similar, but not identi- EU Commission.
cal, to the adult indication. • Three members and alternates representing
There is one specific PIP procedure for products patient associations are appointed by the EU
already marketed but which no longer qualify for an Commission.
SPC (e.g., for generating efficacy data in children or
when proposing a new paediatric formulation). This A chair and vice-chair are elected from the committee
is linked to a PUMA. For such products, a PIP is not members (three-year terms, renewable once).
required but can be proposed as a voluntary commit- PDCO’s main tasks include:
ment. Different from Article 7 or 8 procedures, this • assessing PIP content, including full or par-
type of PIP is not required to cover the whole paediatric tial waiver and deferral requests and adopting
age range and is intended to provide a possible incen- opinions thereon
tive for off-patent medicines to generate supporting • assessing MA compliance with the agreed
paediatric data. The reward is 10 years of protection for PIP (in principle, this also can be performed
the generated data. Such a PUMA-related PIP can be by national competent authorities in non-cen-
proposed by the MAH of the initial product or other tralised procedures)
MAHs newly proposing an already available product • adopting opinions on a medicine’s quality,
for paediatric use. safety and efficacy for use in the paediatric
Detailed PIP preparation instructions are provided population—at the request of CHMP or a
in Communication from the Commission 2014/C 338/01— national competent authority (It must be
Guideline on the format and content of applications for emphasised PDCO is not the licensing body
agreement or modification of a paediatric investigation plan in MAAs. This remains the formal respon-
and requests for waivers or deferrals and concerning the sibility of CHMP or a national competent
operation of the compliance check and on criteria for assessing authority.)
significant studies.13 For instance, the PIP documentation
should describe disease or condition similarities and Among other tasks, PDCO also:
differences and the product’s anticipated effect among • regularly updates an inventory of paediat-
different age groups (adult and different paediatric sub- ric uses, therapeutic needs and priorities for
sets); paediatric prevalence and incidence (including the research; the inventory also is intended as an
earliest age of onset); current diagnosis, prevention or information source for physicians and patients
treatment methods; and whether the product might pro- and to help companies identify business devel-
vide a significant therapeutic benefit or fulfil an unmet opment opportunities
paediatric therapeutic need (comparing the product with • provides advice on any questions related to
the current standard of care). medicines used in the paediatric population—
at the request of the EMA executive director
Paediatric Committee (PDCO) or the EU Commission
One of the key Paediatric Regulation requirements • provides support and advice to a European
was establishing a Paediatric Committee (PDCO) to paediatric investigator network
provide expertise on multiple aspects of the research,
development, authorisation and use of medicines for Waivers
children. This committee can rely on administrative Many medicinal products are of limited value in the
and scientific support from EMA’s organisational paediatric population. Defining the scope of a pro-
framework. posed product developed for children requires detailed
The regulation also defines the composition of this discussions with PDCO. Waivers can be issued for
body (members are appointed for three-year, renewable indications, age ranges, formulations, genetic subtypes,
terms): weight ranges or any other suitable criteria, for which
• Five members with their alternates are it can be agreed paediatric development is not useful.
appointed by the Committee for Medicinal Hence, a (partial) waiver basically describes a popula-
Products for Human Use (CHMP). tion in more detail by exclusion criteria and can be a
• One member and one alternate are appointed complex mixture of such specifications. The regulation
by each Member State (except Member States defines three alternative criteria for granting waivers:

Chapter 8
• The product is likely to be ineffective or unsafe from academic studies), there is no need to repeat such
in part or all of the paediatric population. trials within a development program, and such spe-
• The disease or condition occurs only in adult cific trials would not be requested. This waiver is not
populations. straightforward and therefore is not assigned to any of
• The product does not represent a significant the above-mentioned regulatory grounds. Most likely,
therapeutic benefit over existing treatments for PDCO would use lack of significant benefit as grounds
paediatric patients. for the waiver (but this would rather limit a waiver to
specific measures, not the therapeutic benefit in total).
In practice, this opinion, which is the official PIP pro- Depending on available data or for other reasons, such a
cedure outcome, would list the scope of any waivers product-specific waiver might not be applicable to other
agreed. This opinion, including the underlying regu- similar products from another applicant.
latory justification listed above, also is published on Another argument often used by applicants for
EMA’s website, searchable by active substance, thera- requesting waivers is lack of sufficient safety or effi-
peutic area or keyword.14 cacy data in children to feel confident enough to start
Some other terms need to be understood: paediatric trials. This would not be in accordance with
• Product-specific waiver: a waiver as agreed on the first grounds for waiver, “likely to be…unsafe.” This
within a PIP procedure for a specific product would imply, e.g., juvenile animal data or adult data
in a specific condition, as discussed above. already have shown safety signals, or a mechanism of
Such a product-specific waiver can be a partial action could anticipate negative effects (e.g., interfer-
waiver or a full waiver (see below). ing with normal growth or organ development) in at
• Class waivers: a list of class waivers is main- least some age ranges. If this is not the case, this would
tained on EMA’s website15 and is updated strengthen the argument that the generation of such
regularly by PDCO. The current list includes data is needed.
mainly diseases clearly irrelevant to children, It is worth noting the Paediatric Regulation does
such as Alzheimer’s disease, age-related mac- not foresee explicitly granting waivers on the basis of
ular degeneration or several types of tumours. small patient numbers and/or geographic dispersion,
In practice, this often is limited to waiving because studies are impractical or because formula-
developments in specific medicinal products tion efforts have failed. However, including a robust,
or classes of products (e.g., for safety reasons). evidence-based explanation detailing why paediatric
Hence, class waivers are not the resulting out- clinical studies for a product in a given condition may
come of a PIP procedure but of more general not be feasible likely will be accepted. In such cases, the
considerations on paediatric therapeutic needs. outcome might determine activities other than clinical
• Partial waivers: any subsets within an agreed trials that could help support licensing in the popula-
PIP, e.g., the age range or a subset of a condition under discussion. This could include measures like
tion for which a development is waived. Such extrapolation exercises or modelling approaches.
partial waivers are an integral part of the final
outcome of most PIP procedures. Deferrals
• Full waivers: the outcome of a PIP procedure When the PIP is submitted, the applicant can request
for a specific product in a specific indication if a deferral of the initiation or completion of some (or
an applicant can justify why the product is not all) of the measures it sets forth. A deferral may be
useful or not needed in the paediatric popu- granted on scientific or technical grounds or be related
lation. Such a full waiver request is a shorter to public health. In any event, deferrals can (and should)
procedure of only 60 days (compare below). be granted whenever it is more appropriate to conduct
In case the full waiver is not granted, for sub- studies in adults before initiating studies in children,
sequent submission of a development plan, a and when studies in children will take longer than those
new PIP procedure must be planned. PDCO in adults. The deferral, nevertheless, must present a
also can grant a full waiver on its own motion deadline for the PIP’s initiation and/or completion.
in a PIP submission, even if the applicant did The most important aspect with regard to defer-
not request it. In this case, the opinion can be rals is postponing the completion of a product’s agreed
adopted at D60 or after the clock stop at D120. measures for a specific indication until after a planned
initial MA (often in adults only), as PIP compliance at
Product-specific waiver opinions sometimes are mis- this time will be a prerequisite to validate the (adult)
interpreted. If a company, for example, already can MAA (“partial compliance check”). Any unfinished
present some trial data when submitting a PIP (e.g.,

non-deferred PIP measures would result in blocking an the procedure’s start. Sixty days after the procedure’s
MAA due to lack of compliance with the PIP. start date (=D60), in principle, an opinion may be given;
Starting with the initial MA, annual progress however, this is rare. In the majority of cases, the D60
reports on deferred paediatric measures must be pro- outcome is a request for modification, which will raise
vided to EMA until all PIP measures are completed. questions and proposals to amend the submitted PIP.
When a deferral is requested, it is necessary to Following D60 is a clock stop, the duration of which
consider when initiating a clinical trial in children has not been specified in the regulation and, therefore,
is appropriate and ethically defensible. On the other can vary. It is preferable to reply comprehensively to
hand, if the unmet paediatric population medical need all raised points rather than reply within a short time.
is high, any delay in initiating trials in children would When the procedure restarts (after the applicant replies
be discouraged. Consideration also should be given to in writing to this request for modifications), possibilities
recruiting different age groups at different points in for negotiating substantial changes are limited further.
time; adolescents often are acceptable for inclusion in A request for a teleconference during the clock-stop
adult trials, while younger children can be recruited period between the applicant or MAH, EMA paedi-
later, in an age/subgroup-specific, step-wise manner. As atric coordinator and the assigned PDCO rapporteur
PIP outcomes also include quality and nonclinical mea- and peer reviewer usually is accepted and may be valu-
sures, it should be ensured that if these are postponed able for clarifying requested PIP modifications prior
(e.g., paediatric formulation development or juvenile to submitting responses. It also is possible to file a
toxicity data), they do not further delay any clinical pae- request for Scientific Advice (from CHMP’s Scientific
diatric studies. Therefore, deferrals for such measures are Advice Working Party (SAWP)) during the clock-stop,
handled rather restrictively. the outcome of which could further inform the D61
ICH E11 offers relevant reference,16 describing responses (EMA would liaise PDCO and SAWP to
a number of factors to consider when choosing the ensure consistency).17
best timing. These factors may include the condition’s After restart (=D61), the procedure takes another
prevalence and seriousness, availability of alternative 60 days and will result in an opinion. This written doc-
treatments, whether the product is novel or belongs to ument will be a detailed overview of the decisions taken
a known class of medicines, whether there are unique and indicate which waivers (age-range, indication, etc.)
paediatric subsets and the need to develop paediat- have been accepted and which measures have been
ric-specific endpoints. agreed. An abridged overview of this document (after
removal of any commercially sensitive information) will
Application Procedure be published on EMA’s website.18
Initial PIP Submission The outcome of such a PIP procedure is a written
At which stage should the PIP be submitted? The opinion containing:
Paediatric Regulation’s clear intention is a PIP (or • detailed key elements (e.g., study design,
waiver) application should be submitted early in clin- inclusion criteria, sample sizes, primary end-
ical development, “…except in duly justified cases, not points, etc.) for all requested trials or other
later than upon completion of the human pharmaco- measures to be performed, including timelines
kinetic studies in adults.” This might not be applicable by when these activities must be initiated and
to all drug developments, but the intention is to ensure completed
early dialogue between the sponsor and the Paediatric • measures that can be postponed to a later date
Committee. Further, early PIP submission, combined are listed as deferred
with submission of a deferral request, will avoid delay- • a list of all waived populations, age-ranges, etc.
ing authorisation for other populations. It should be
realised there is no requirement to start the paediat- This will be reviewed in detail during the later compli-
ric development at this time, but only to identify the ance check.
appropriate time in product development for initiation. There is one exception to the above-mentioned
The procedure’s duration can vary (Figure 8-1). timeline if a full waiver is requested. Such a proce-
This depends primarily on the validation period’s dure does not go into a clock stop (because no studies
duration and the length of the clock stop. At best, an have been proposed for which modifications could be
announced PIP currently can be submitted and is vali- requested), but there will be a (negative or positive)
dated by EMA staff within 30 days, before assessment opinion issued at D60.
by PDCO members officially starts (=D0). EMA may If an agreement cannot be reached within these
suspend the validation phase for an unspecified period procedural timelines, the applicant can withdraw the
(if the dossier is deemed incomplete), which will delay application without negative consequences. This would

Chapter 8
Figure 8-1. PIP Procedure
Figure 7-1. PIP Procedure
COMPANY PDCO/EMA
Day –70 Submission Letter of intent

Day –60 Nomination Rapp/Peer Rev
Validation
Day –30 PIP submission Phase
Day 0 Start PIP procedure
Assessment
SR & D30 minutes (for information) Day 30 1st PDCO discussion
Phase 1
Opinion or Request for modification Day 60 2nd PDCO discussion
Clock Stop on request optional TC with Applicant
Submission Responses to Request for

modification (triggers D61 at next PDCO) Day 61 Restart of procedure
Assessment
Draft opinion/D90 minutes Day 90 3rd PDCO discussion
Phase 2
Draft opinion comments Day 120 4th PDCO discussion
Opinion as adopted by PDCO Appeal

Window
Day 150 Opinion definitive (unless

reexamination requested)
Day 180 Start Re-Examination
Re-exam
phase
Day 210 PDCO decision after Re-Exam
Day 240 Opinion definitive

after reexamination
be possible at anyProcedure
Application time up to D120. If the likely opin- must be filed for
authorisation within
other30populations.
days after receiving
It shouldthe
be original
realised
ion
Initial PIP Submissionalso would be an option
is negative, withdrawal opinion. Therefore, in this case, no withdrawal would be
there is no requirement to start the paediatric development
to
Atprevent the negative
which stage should theopinion from beingThe
PIP be submitted? published
Paediatric possible,
at as this
this time, but blocks
only tothe opinion
identify thefrom being issued.
appropriate time in
on
Regulation’s clear intention is a PIP (or waiver) also
EMA’s website. In this case, the applicant has
application A new rapporteur and peer-reviewer
product development for initiation. will be nominated
the
should be submitted early in clinical development,its“…
right to an oral explanation meeting to defend and The
will procedure’s
re-evaluate duration
the initialcan
PIP, based
vary on additional
(Figure 7-1). This
case in in
except a direct dialoguecases,
duly justified withnotthelater
PDCO thanplenary. In
upon comple- applicant
depends arguments
primarily (but
on the not new
validation proposals).
period’s duration and the
most
tion ofcases, this will
the human involve a company
pharmacokinetic delegation.
studies in adults.” This length of the clock stop. At best, an announced PIP currently
Subsequent
might not betoapplicable
a negativetoopinion
all drugordevelopment,
withdrawal, abut newthe Modifications
can be submittedtoandanbeAgreed PIP
validated by EMA staff within 30
PIP procedure
intention is to can be early
ensure proposed.
dialogue between the sponsor days, before assessment by PDCO
Product development is a dynamic members
processofficially
with fre-starts
and The
PDCO.applicant has the
Further, right
early PIPtosubmission,
appeal a PDCO combined (=D0). EMA may suspend the validation phase for
quent changes. Due to the requirement to submit the an unspeci-
decision. In such of
with submission a case, a request
a deferral for awill
request, “re-examination”
avoid delaying fied period (if the dossier is deemed incomplete), which will

PIP proposal early, there also is a high likelihood the Rewards for Paediatric Research
initial opinion may need to be amended. Therefore, The Paediatric Regulation stipulates paediatric research
provision has been made for PIP modifications. This will be rewarded by granting a six-month SPC exten-
can be done at any time and as often as needed. Such sion subject to meeting all the following conditions:19
a modification can propose new measures, waivers or • compliance with all measures included in the
deferral requests. Amendments to the initial plan must approved PIP
be justified. • product protection by an SPC (or by a patent
Modification procedures are assessed within 60 qualifying for an SPC)
days (no clock stop). The outcome will be a modified • product authorisation in all EU Member
version of the opinion (accepting or refusing each of States and/or inclusion of relevant information
the suggested changes). If there are substantial changes on results generated in the PIP in the product
to an initial plan, a new full PIP procedure might be information (by means of a variation)
more appropriate (and would replace the initial PIP).
Modifications should be discussed prior to their imple- Since the patent restoration reward is for conducting
mentation in a study program or, at the latest, as soon clinical studies and not for demonstrating the product is
as problems become apparent. Retrospective changes safe and effective in the paediatric population, it will be
always risk not being acceptable to PDCO. granted even if the results are negative and no paediatric
indication is achieved. In this case, relevant information
Compliance Check for limitations of use in paediatric patients can be added
As mentioned above, confirmed compliance with to the product information
an agreed PIP is a prerequisite for an MAA unless Alternatively, the MAH can apply for a one-year
exempted, depending on the chosen licensing procedure extension of data protection on the grounds a new
or because it is waived. For centralised procedures, the paediatric indication “brings significant clinical benefit
compliance check is performed by the PDCO before in comparison with existing therapies” in accordance
submitting to CHMP. For other marketing authori- with EU Regulation (EC) No. 726/200420 or Directive
sation routes, the Competent Authority can perform 2001/83/EC, as amended. However, it is not possible
such a procedure in the Member State where the MA to combine one year of extra data protection and a six-
is submitted. Optionally, as foreseen in the regulation, month SPC extension for the same product.
this task can be delegated to PDCO, and this actu- For compliance with a PIP agreed under the pro-
ally is done concurrently, almost without exception in vision for a PUMA (Paediatric Regulation Article 30,21)
non-centralised MAAs. such as off-patent products, the SPC prolongation
A compliance check’s scope compares agreed mea- is not applicable. Therefore, another type of reward
sures with those actually completed. As such, this is is offered: a 10-year data protection period for the
an accurate, formal comparison without the option to information generated. This means only this product’s
assess whether changes made but not agreed would be MAH can get a label based on this information; other
acceptable scientifically. Therefore, if not in compliance manufacturers of the same drug substance can do so
with all details in the written opinion, it is strongly rec- only after 10 years. Theoretically, this would exclude,
ommended the applicant submits a PIP modification for example, the use of generics in the same indication
to reach agreement with the PDCO about accepting in children. If the PUMA was submitted by someone
changes prior to submitting the compliance check. other than the initial MAH, this would even exclude
Compliance normally is based on submitted final the originator from adding this use to the Summary of
study protocols or similar documents that show which Product Characteristics (SmPC). However, in practice,
measures have been performed. it is difficult to prevent such alternate products from
As PIPs often still are ongoing when the initial being used.
MAA is planned, a partial compliance check will Under EU orphan drug legislation, products des-
be performed, limited to the measures not deferred. ignated as orphan medicinal products gain 10 years of
Confirmed compliance is a requirement for validating market exclusivity when the orphan indication MA is
the initial MAA. For PIPs still running, beginning with granted.
this initial MAA, an annual report must be provided Frequently, these products no longer benefit
to continue checking compliance. A final compliance from intellectual property protection. The Paediatric
check will be performed after all PIP measures are com- Regulation, therefore, in return for compliance with
pleted. This final procedure is the prerequisite to qualify an approved PIP, provides a two-year extension of
for applicable rewards. the orphan market exclusivity. This extension applies
whether or not the orphan product is subject to

Chapter 8
intellectual property protection. Again, it is not possible Additional Points to Consider in Paediatric
to combine this market exclusivity reward with a six- Development
month SPC extension for the same product where still • Expanded clinical testing in children and
applicable. When an agreed PIP has led to the authori- adolescents offers a range of new challenges.
sation of a paediatric indication for a product already The Paediatric Regulation cross-references the
available for other (adult) indications, the MAH is ICH E11 guideline,25 which addresses several
obliged to implement labelling changes and market the important ethical considerations. Other issues
product accordingly in all EU Member States within of relevance to the paediatric population, e.g.,
two years. The applicant also must describe measures juvenile toxicology studies, organ maturity
to follow up on efficacy and possible adverse reactions and pharmacokinetics, trials in small patient
linked to the paediatric use. The obligation to market populations and issues specific to paediatric
within two years does not apply to products with a pharmacovigilance, are addressed in a series of
PUMA. If an MAH with a paediatric SPC extension dedicated EMA guidelines.26
decides to discontinue commercialisation, the MA will • A sometimes-overlooked aspect is the
be transferred, or a third party will be allowed to use the potential necessity to develop age-specific
pharmaceutical, preclinical and clinical documentation formulation(s). While solid tablets may be a
contained in the file. preferred dosage form for adolescents, they
are (as any parent surely has observed) of little
Other Measures or no use for very young children. Conversely,
The Paediatric Regulation also contains other measures, intravenous solutions may be convenient for
which cannot be covered in detail in this chapter. For administration to newborns but may not be
instance: the preferred form for older children. EU and
• MAHs are obligated to submit any existing global initiatives have been started in the last
data from paediatric trials completed by the few years. WHO’s campaign “Make medicines
date the regulation entered into force within child size”27 and the European Initiative for
one year of study completion and from any Paediatric Formulations (EuPFI)28 are two
other MAH-sponsored studies within six examples. It is within PDCO’s remit to request
months of study completion. the development of a new formulation for pae-
• EMA Scientific Advice for paediatric-only diatric use if needed.
development is available free of charge from • Paediatric research is a priority collaboration
SAWP.22 This can contain questions on quality, area as defined within the US Food and Drug
nonclinical and clinical safety or efficacy and Administration (FDA)-EMA confidentiality
risk management system methodology. Such agreement. The two agencies are committed to
a procedure can be requested at any time, i.e., a regular information exchange on:
prior to or after a PIP submission, during a o product-specific paediatric development
PIP clock-stop or prior to submitting a modi- (PIPs, written requests, deferrals) and
fication. However, parallel running procedures waivers from the obligations to perform
should be avoided. such paediatric development (which may
• EudraCT is a database of information on the include discussions on trial design issues)
content, commencement and termination of o general issues related to paediatric devel-
all clinical trials in the EEA from May 2004 opment (including sharing early-stage
onward. It was established in accordance with draft guidance documents of paediatric
Directive 2001/20/EC.23 The EMA-managed relevance)
EudraCT database for clinical trials contains o safety issues, particularly related to report-
information on all trials performed anywhere ing Adverse Drug Reactions (ADRs)
in the world with children, if the trial is part of occurring in children and exchange of
an agreed PIP or is sponsored by an MAH and ADR database statistics
involves the paediatric use of a medicine with • One Paediatric Regulation requirement (Article
an EU marketing authorisation. This require- 44) is EMA’s obligation to support establish-
ment is set out in Paediatric Regulation Article ing a European network of research networks,
46. Selected data fields concerning paediatric investigators and centres with recognised
protocols stored in the EudraCT database is expertise in performing clinical studies in
made accessible to the public.24 children to facilitate studies to increase the
availability of medicinal products authorised

for use in the paediatric population. This Potential paediatric needs must be examined fur-
network (Enpr-EMA)29 works by allowing ther for all adult indications and all paediatric subsets
networking and collaboration with members (i.e., premature neonates, term neonates, infants, chil-
from within and outside the EU, including dren and adolescents). An approved EU PIP includes
members from academia and the pharma- timelines for completing various elements and is con-
ceutical industry. Hence, this is not foreseen sidered an agreement between the company and the
to include drug companies as members, but agency. Companies failing to comply with the agreed
rather expert groups that coordinate research plan (at least if judged in bad faith) risk delays in mar-
activities in paediatric medicine. However, an keting access.
MAH can liaise with members of this network
to get support in coordinating and facilitating References
1. Regulation (EC) No 1901/2006 of the European Parliament
paediatric studies. and of the Council of 12 December 2006 on medicinal prod-
• There are several initiatives available at ucts for paediatric use and amending Regulation (EEC) No.
EMA, among them the Adaptive Pathway 1768/92, Directive 2001/20/EC, Directive 2001/83/EC and
Project,30 parallel procedures including Health Regulation (EC) No. 726/2004. EC website. http://ec.europa.
eu/health/files/eudralex/vol-1/reg_2006_1901/reg_2006_1901_
Technology Assessment (HTA) aspects31 en.pdf. Accessed 6 March 2020.
and accelerated assessment programs like 2. Regulation (EC) No. 1902/2006 of the European Parliament
PRIME.32 All of these also involve PDCO and of the Council of 20 December 2006 amending Regulation
and take specific paediatric medicines’ require- 1901/2006 on medicinal products for paediatric use. EC website.
http://ec.europa.eu/health/files/eudralex/vol-1/reg_2006_1902/
ments into account, where applicable. Hence, reg_2006_1902_en.pdf. Accessed 6 March 2020.
paediatric medicine is more and more consid- 3. European Medicines Agency decision CW/1/2015 of 23 July
ered an integral part of drug development. 2015 on a class waiver in accordance with Regulation (EC) No.
o Finally, as foreseen in the Paediatric 1901/2006 of the European Parliament and of the Council.
EMA website. http://www.ema.europa.eu/docs/en_GB/docu-
Regulation, this legal framework was ment_library/Other/2015/07/WC500190385.pdf. Accessed 6
re-evaluated 10 years after its launch. March 2020.
The EU Commission report was due in 4. Communication from the Commission 2014/C 338/01—Guideline
late 2017, and the outcome of a public on the format and content of applications for agreement or mod-
ification of a paediatric investigation plan and requests for
consultation on items highlighted by the waivers or deferrals and concerning the operation of the compli-
Commission was published.33 It has not ance check and on criteria for assessing significant studies. EUR-
been decided whether this will result in Lex website. http://eur-lex.europa.eu/legal-content/EN/
revision of some aspects of the regulation, TXT/PDF/?uri=CELEX:52014XC0927%2801%29&qid=
1430293224114&from=EN. Accessed 6 March 2020.
where deemed useful, or be used to align 5. CPMP/ICH/2711/99, ICH Topic E11, Clinical investigation of
with amendments in other regulations. medicinal products in the paediatric population ( January 2001).
ICH website. https://database.ich.org/sites/default/files/E11_
Conclusion R1_Addendum.pdf. Accessed 6 March 2020.
6. Op cit 1.
After public consultation and a review by the European 7. Op cit 2.
institutions, a regulation was approved by the European 8. Op cit 3.
Parliament and the Council of Ministers in 2006 and 9. Op cit 5.
10. Directive 2004/27/EC of the European Parliament
entered into force on 26 January 2007. The Paediatric and the Council of 31 March 2004 amend-
Regulation’s (Regulation (EC) No. 1901/2006) overall ing Directive 2001/83/EC on the Community code
objective is to improve the health of children in the EU. relating to medicinal products for human use. EUR-Lex
This regulation describes the requirements for market- website. http://eur-lex.europa.eu/legal-content/EN/TXT/
PDF/?uri=CELEX:32004L0027&qid=1430296239733&from=
ing authorisations for all human medicinal products EN. Accessed 6 March 2020.
(including those used for treatment, prevention or diag- 11. Op cit 1.
nosis, but not medical devices) regardless of registration 12. Policy on the Determination of the Condition(s) for a Paediatric
pathway. One of its key elements was the establishment Investigation Plan/Waiver (Scope of the PIP/Waiver). EMA
website. http://www.ema.europa.eu/docs/en_GB/document_
of a Paediatric Committee (PDCO) to provide exper- library/Other/2012/09/WC500133065.pdf. Accessed 6 March
tise on multiple aspects of the research, development, 2020.
authorisation and use of medicines for children. 13. Op cit 4.
The Paediatric Regulation specifies how information 14. Opinions and Decisions on Paediatric Investigation Plans.
EMA website. https://www.ema.europa.eu/en/medicines/
for use of medicines in paediatric populations must be ema_group_types/ema_pip. Accessed 6 March 2020.
generated. Paediatric drug development must be agreed 15. Op cit 12.
in advance with the responsible regulatory bodies in a 16. Op cit 5.
Paediatric Investigation Plan (PIP).

Chapter 8
17. Scientific Advice and Protocol Assistance. EMA website. http:// 25. Op cit 3.
www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/gen- 26. Scientific Guidelines. EMA website. http://www.ema.europa.
eral/general_content_000049.jsp&mid=WC0b01ac05800229b9. eu/ema/index.jsp?curl=pages/regulation/general/general_con-
Accessed 6 March 2020. tent_000043.jsp&mid=WC0b01ac05800240cb. Accessed 1
18. Op cit 14. March 2020.
19. Regulation (EC) No. 469/2009 of the European Parliament 27. Essential medicines for children. WHO website. http://www.
and of the Council of 6 May 2009 concerning the supplemen- who.int/childmedicines/en/. Accessed 6 March 2020.
tary protection certificate for medicinal products (replacing 28. European Paediatric Formulation Initiative (EuPFI) website.
Regulation (EEC) No. 1768/92). EUR-Lex website. http:// http://www.eupfi.org/ . Accessed 6 March 2020.
eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=O- 29. European Network of Paediatric Research at EMA (Enpr-
J:L:2009:152:0001:0010:en:PDF. Accessed 6 March 2020. EMA). EMA website. http://www.ema.europa.eu/ema/index.
20. Regulation (EC) No. 726/2004, as amended, of the European jsp?curl=pages/partners_and_networks/general/general_con-
Parliament and of the Council of 31 March 2004 laying down tent_000303.jsp&mid=WC0b01ac05801df74a. Accessed 6
Community procedures for the authorisation and supervi- March 2020.
sion of medicinal products for human and veterinary use and 30. Adaptive Pathways. EMA website. http://www.ema.europa.
establishing a European Medicines Agency. EUR-Lex website. eu/ema/index.jsp?curl=pages/regulation/general/general_con-
http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=O- tent_000601.jsp&mid=WC0b01ac05807d58ce. Accessed 6
J:L:2004:136:0001:0033:en:PDF. Accessed 6 March 2020. March 2020.
21. Op cit 1. 31. Parallel consultation with regulators and health technology
22. Op cit 17. assessment bodies. EMA website. http://www.ema.europa.
23. Directive (EC) 2001/20/EC of the European Parliament and eu/ema/index.jsp?curl=pages/regulation/general/general_con-
of the Council of 4 April 2001 on the approximation of the tent_001857.jsp&mid=WC0b01ac0580a11c96. Accessed 6
laws, regulations and administrative provisions of the Member March 2020.
States relating to the implementation of good clinical practice in 32. PRIME—Priority Medicines. EMA website. http://www.ema.
the conduct of clinical trials on medicinal products for human europa.eu/ema/index.jsp?curl=pages/regulation/general/general_
use. EUR-Lex website. http://eur-lex.europa.eu/LexUriServ/ content_000660.jsp&mid=WC0b01ac05809f8439. Accessed 6
LexUriServ.do?uri=OJ:L:2001:121:0034:0044:en:PDF. March 2020.
Accessed 6 March 2020. 33. The 2017 Commission Report on the Paediatric Regulation.
24. Public data from Article 57 database. EMA website. https:// EC website. https://ec.europa.eu/health/human-use/paedi-
www.ema.europa.eu/en/human-regulatory/post-authorisation/ atric-medicines/developments/2016_pc_report_2017_en.
data-medicines-iso-idmp-standards/public-data-article-57-da- Accessed 6 March 2020.
tabase. Accessed 6 March 2020.

Chapter 9
Advertising and Promotion

Updated by Karen Zhou, JD, MS, RAC
OBJECTIVES □ International Federation of Pharmaceutical

Manufacturers Association (IFPMA) Code of
□ Understand the aim of medicinal product adver- Practice (2019)3
tising and promotion as defined by EU Directive
2001/83/EC and applicable codes of conduct
Introduction
□ Become familiar with the basic principles laid
The advertising and promotion of healthcare prod-
down in EU Directive 2001/83/EC
ucts is one of the most regulated areas in the industry.
□ Understand the European Union (EU) legal Successfully advertising and promoting a product has
framework on medicinal product advertising implications for both the industry and the economy.
Strong sales and revenues can help recuperate the high
□ Understand EU’s current position on medical upfront cost of research and development and therefore
device advertising incentivise further investments in the industry. This
positive feedback spurs innovations and contributes to
□ Understand the differences between EU macroeconomic productivity. Because of the potential
Member State national rules on medicinal prod- risk to public health, advertising of healthcare products
uct promotion versus the EU Directive is subject to tighter regulatory controls across the world
than most other products, through a combination of
□ Understand the impact and aims of interna-
national regulations and self-regulatory mechanisms.
tional and European codes of conduct and their
The EU advertising regulatory framework has
implementation into national codes of conduct
its legal basis in Council Directive 2001/83/EC
via trade associations
on medicinal products for human use (Medicinal
Products Directive (MPD)), specifically in Title VIII
(Advertising) and Title VIIIa (Information and
DIRECTIVES, REGULATIONS AND GUIDELINES Advertising). The goal of the MPD is to remove barriers
COVERED IN THIS CHAPTER to trade between Member States. It is the position of
the European Court of Justice (ECJ) that the MPD sets
□ Directive 2001/83/EC of the European
out the maximum standard except where it specifically
Parliament and of the Council of 6 November
sets out circumstances where Member States are given
2001 on the Community code relating to medici-
flexibility to adopt stricter legislation.
nal products for human use, as amended1
Advertising of medicinal products is defined in
□ European Federation of Pharmaceutical Title VIII as any form of door-to-door information,
Industries and Associations (EFPIA) Code of canvassing activity or inducement designed to pro-
Practice (2019)2 mote the prescription, supply, sale or consumption
of medicinal products. However, the MPD exempts
certain activities from advertising regulations, such

Chapter 9
as correspondence required to answer specific ques- The Framework

tions about the product, informative announcements, General Principles of Advertising Under Directive
reference material relating to drug precautions, trade 2001/83/EC
catalogues and price lists that make no product claims The principles of advertising under Directive 2001/83/
and information relating to health or diseases, given EC can be summarised as follows:
that no reference is made to medicinal products. Article • medicines without a market authorisation shall
88 of the MPD prohibits advertising of prescription not be advertised
medicines to the general public. On the other hand, • off-label indications for an authorised medi-
Over-the-Counter (OTC) products may be directed at cine cannot be advertised
both healthcare practitioners and the general public. • advertising of a medicine must comply with
Member States have implemented the require- the specifics in the summary of product char-
ments of the MPD into national laws; however, the acteristcs (SmPC)
rules are not harmonised across the EU. Member States • advertising of a medicine shall encourage the
often go further than the MPD in some requirements. rational use of the product by an objective pre-
The pharmaceutical advertising space is comprised sentation and shall not be misleading
of not just national laws, but also a self-regulatory • prescription medicines may only be advertised
mechanism driven by industry associations. Advertising to HCPs with the qualifications to prescribe or
and promotion of prescription medicines to healthcare supply them
professionals (HCPs) requires that member compa- • OTC medicines may be advertised to the gen-
nies subscribe to codes of conduct. Known as soft law, eral public, subject to certain rules.
these codes of conduct arise out of ethical obligations
that underpin communications between the industry
Self-Regulation in the EU
and healthcare practitioners rather than any source of
The pharmaceutical industry is characterised by a
positive law. In the EU, the European Federation of
self-regulatory mechanism through which companies
Pharmaceutical Industries and Associations (EFPIA)
adhere to a set of ethical codes of conduct developed by
has an EU-wide Code of Practice. At the interna-
various trade associations. These codes of conduct are
tional level, members of the International Federation
informed by the EFPIA as well as IFPMA.
of Pharmaceutical Manufacturers and Associations
(IFPMA) also are encouraged to adhere to a Code of
EFPIA
Practice containing ethical guidelines for the advertising
The EFPIA is the representative body of pharmaceu-
and promotion of prescription medicines.
tical companies marketing products in the EU. The
Non-prescription pharmaceuticals or OTC
organisation’s core mission is to promote the technolog-
pharmaceuticals are regulated through the industry’s
ical and economic development of the pharmaceutical
own voluntary codes of conduct. The Global Self-
industry in Europe and to assist in bringing to market
Care Foundation (GSCF), of which the Association
medicinal products to improve health worldwide. The
Européenne des Spécialités Pharmaceutiques Grand
EFPIA is aware of providing accurate, fair and objective
Public (AESGP) is a member, supports the develop-
information about medicinal products so that ratio-
ment of industry associations globally to aid in the
nal decisions can be made as to their use. As such, the
understanding of responsible self-care and self-med-
organisation has adopted a set of ethical rules for the
ication. As part of its mandate, the GSCF requires
promotion of medicinal products to HCPs and inter-
member associations to develop voluntary codes of
actions with HCPs, healthcare organisations (HCOs)
advertising practice.
and patient organisations (POs), with the intent of
This chapter opens with an introduction to the
guaranteeing that these activities are conducted while
general advertising principles underlying the MPD
respecting the most stringent ethical principles of pro-
and the self-regulatory paradigm that characterises the
fessionalism and responsibility.
pharmaceutical industry. The second section reviews
These ethical rules had previously existed as three
the application of national rules and ethical codes
codes:
with respect to advertising to HCPs and the general
1. EFPIA Code on the Promotion of
public. The third section looks at several topics within
Prescription-Only Medicines and Interactions
the pharmaceutical advertising space. Throughout this
with Healthcare Professionals
chapter, the reader should pay special attention to the
2. EFPIA Code of Practice on Relationships
fine line between what is considered promotion and
between the Pharmaceutical Industry and
what is merely information. The final section focuses on
Patient Organisations
the current medical device regulatory framework.

3. EFPIA Code on Disclosure of Transfers of Advertising Medicinal Products to

Value from Pharmaceutical Companies to Healthcare Professionals
Healthcare Professionals and Healthcare Advertisements and documentation presented to HCPs
Organisations must include essential information compatible with the
summary of product characteristics (SmPC) and the
The Code on Disclosure of Transfers of Value requires supply classification of the medicinal product. Additional
companies to disclose transfers of value made to HCPs information may be required by various Member States,
or to HCOs either on the company’s website or on a such as the selling price or indicative price and the con-
central platform. ditions for reimbursement. Such essential information
In 2019, the EFPIA consolidated all three codes includes the name of the product, contact information of
into one volume for the purposes of simplification and the Marketing Authorisation Holder (MAH), marketing
clarification. authorisation number, classification, adverse effects, list of
active ingredients and composition.
IFPMA The mandatory essential information is defined
The IFPMA is a non-profit, non-government organ- more clearly by national regulations. In the UK, the list
isation representing research-based pharmaceutical of active substances, using their common names, must
companies and associations from both developed and be placed immediately adjacent to the most prominent
developing countries. It provides guidance and publi- display of the name of the product. In Norway, this
cations on health-related topics for its members and information must be presented in clear fonts and clearly
addresses key global health issues for pharmaceutical visible. The MPD allows national authorities the flexi-
companies. To support the ethical promotion of pre- bility to include reimbursement information. As such,
scription medicines, the IFPMA developed a code of many jurisdictions require advertising material to contain
conduct to cover promotion of pharmaceutical products a selling price and/or provision for reimbursement (e.g.,
and to help to ensure interactions with HCPs, medical France (reimbursement information), Netherlands (reim-
institutions, patient organisations and other stake- bursement information), Norway (both), UK (price)).
holders are appropriate. Member national and regional Some countries also regulate how this information
associations look to the IFPMA to craft their own is laid out: in Belgium, retail price information must be
codes of conduct with additional provisions for compli- presented in bold and located in the upper right-hand
ance with local requirements. The IFPMA Code serves corner of the advertisement, and selected information
as a default regulatory framework where there are no derived from the SmPC must comprise at least 50% of
local codes or relevant laws and regulations or where a the total advertisement space.
member company is not part of the local association.
The Code covers interactions with HCPs and other
Restrictions on Advertising Content
stakeholders, preapproval communications and off-label
Although the MPD forbids the inclusion of information
use, standards of promotional information, including
that is inconsistent with the SmPC, certain types of adver-
printed and electronic materials, control of samples,
tisements may include additional claims that confirm or
clinical research and transparency, company proce-
clarify the information in the SmPC. In Denmark, claims
dures and responsibilities with respect to compliance
not substantiated by the SmPC can be made only by refer-
with applicable codes and law and complaint handling
ence to scientifically substantiated research.
procedures. The latest IFPMA Code became effective
on 1 January 2019. In the 2019 version, the IFPMA
HCP Endorsements
departs from rule-based codes and adopts a culture
Regulations and industry codes throughout the EU
rooted in integrity, values, principles and patient trust.
unanimously prohibit recommendations by HCPs in
By having an ethos consisting of the four core values
pharmaceutical advertisements. Under Section 289 of
of care, fairness, respect and honesty underpinning the
the Human Medicines Regulations 2012, the UK bans
Code of conduct, the organisation believes its members
any endorsement by HCPs or scientists of any medicinal
will behave with integrity when faced with challenging
product featured in an advertisement. Pharma Industry
circumstances. Among the key changes are prohibition
Finland (PIF) requires that promotions must not con-
on gifts to HCPs, and a full ban on non-monetary
tain direct and active recommendations by HCPs to
promotional aids and reminder items in relation to the
use a product. In France, a special exception is made
promotion of prescription-only medicines.
where results of opinion surveys are consistent with the
marketing authorisation, the option of the Transparency
Commission and the proper use of the product. In

Chapter 9
any case, an individual HCP’s endorsement is not promoted. Sales representatives also must report all
allowed. Belgium’s approach to HCP endorsements is information related to the safety of a product that they
determined on a case-by-case basis. Endorsements are receive from HCPs directly. License holders must estab-
allowed in Belgium only if certain conditions are met (all lish a scientific service in charge of information about
information is compatible with the SmPC, the HCP did the medicinal products placed on the market.
not receive any premiums for the endorsement and the Free samples may be offered to HCPs for the pur-
information in the endorsement is objective, truthful and pose of gaining experience with the product under the
backed up by verifiable data). following conditions:
• the number shall be limited
Advertising Words and Expressions • supply should take place only on written
The regulations and codes of conduct in various request and must be adequately documented
Member States also have specific requirements and controlled
regarding the use of certain words and expressions in • the sample shall not be larger than the smallest
advertising material. In the Danish Promotion Code, marketed presentation, must be marked “free
words indicating that the product is “safe” may not be medical sample—not for sale” and must be
used to describe the product. In addition, words indi- accompanied by the SmPC
cating that the product is “new” may not be used to • no samples containing psychotropic or narcotic
describe a product or packaging that has been generally substances within the meaning of major inter-
available or for a therapeutic indication for which there national conventions are supplied
has been widespread use of advertising measures for
more than a year. The advertising material also must Member States may place further restrictions on distribu-
not state that a medicinal product has no side effects, tion of samples. The interpretation of the term “limited”
toxic hazards or risk of addiction or dependency. In the varies across jurisdictions. In the UK, guidance can be
Italian Farmaindustria Code, exaggerated declarations, found in self-regulatory codes of practice. The ABPI
universal and hyperbolic assertions such as “perfectly Code of Practice 2019 states that no more than four sam-
tolerated,” “fully safe,” “preferred medicines” are not ples of a particular medicine may be provided to an HCP
allowed. Aside from regulations, companies should over the duration of one year. Nevertheless, when a new
refer to codes of conduct for accepted industry usage of medicine is marketed that is an extension of an existing
advertising words and expressions. product (e.g., a new strength or dosage form), samples of
that new medicine can be provided. The German Drug
Abbreviated Advertisements or Reminders Act allows the manufacturer to supply no more than two
If the advertisement is intended solely as a reminder, more samples of one product over the course of one year,
Member States may allow some exemptions to advertis- and the voluntary code of conduct (FSA) provides that
ing requirements. These reminder advertisements usually the supplying of samples is limited to a period of two
consist of the medicinal product’s name or its interna- years after the initial request by an HCP.
tional non-proprietary name (INN) or trademark. The EFPIA interprets the MPD’s provision as
In the UK, abbreviated advertisements are defined allowing distribution of medicinal products to each
as advertisements no larger than 420 square centimetres HCP not to exceed more than four medical samples of
appearing in a publication sent or delivered wholly or a particular medicine he or she is qualified to prescribe
mainly to persons qualified to present or supply medic- for two years after first requesting samples. A pharma-
inal products. They must contain essential information ceutical company or member association must adhere to
compatible with the SmPC, and the majority of the this interpretation if it is an EFPIA member.
information required must be included in the adver-
tisement but can refer to a website for information on Gifts, Donations and Hospitality
adverse reactions, precautions, contraindications and The ban on promotion outside of its regulated bound-
methods of use. aries extends to gifts, cash and services that enrich
HCPs. MPD Article 94 prohibits the exchange of gifts
The Role of Medical Sales Representatives and when promoting to HCPs unless they are inexpensive
Distribution of Professional Samples and relevant to the practice of medicine or pharmacy.
As sales representatives’ visits are viewed as advertise- The EFPIA Code of Practice strictly prohibits gifts,
ments, pharmaceutical manufacturers must ensure cash or personal services for the benefit of HCPs,
these personnel are trained adequately and have suffi- healthcare organisations and purchasing organisations.
cient scientific knowledge to be able to provide precise Donations and grants in cash or in kind are permitted
and complete information about the products being only if they are made for the purpose of supporting

healthcare, research or education, are documented and Transfers of value over €10 granted to HCPs, POs
do not constitute an inducement to recommend and/ and healthcare organisations must be published on a
or prescribe, purchase, supply, sell or administer specific central platform. Moreover, any company manufactur-
medicinal products. In the updated IFPMA Code, the ing or commercialising health products or performing
ban on gifts now removes all exceptions carved out in related services in any part of the world is bound by this
the previous version of the Code (e.g., cultural courtesy requirement, provided they have a relationship with the
gifts) and aligns IFPMA to member association codes, aforementioned entities. Belgium also requires compa-
such as those of EFPIA and PhRMA, where a ban has nies to disclose transfers of value in its Sunshine Act. This
been in force for years. While promotional aids such as requirement applies to any company, whether Belgian or
non-monetary reminder items are no longer permit- foreign, to disclose any benefits granted to HCPs or POs
ted under the 2019 Code, exceptions are made for the on a public platform (www.betransparent.be).
promotion of OTC medicines if relevant to the HCP’s
practice, and for distribution of company-branded Advertising to the General Public
stationery of minimal value for the purpose of taking Advertising of prescription-only medicinal products
notes during a company-organised event. The purpose and those containing substances defined as psychotropic
is to avoid any perceived potential influence of an HCP or narcotic is generally forbidden. On the other hand,
while prescribing pharmaceutical products. advertising of over-the-counter medicines to the public
The UK has codified Article 94 of the MPD in is permitted. Vaccination campaigns can be carried out
Section 300 of the Human Medicines Regulations by the industry and approved by competent authorities.
2012. As a supplement, the industry codes of practice National regulations often go further than Article
ensure the promotion of medicines is conducted in a 88 of the MPD and have specific requirements with
transparent, responsible, ethical and professional man- respect to certain classes of medicinal products. In the
ner. The ABPI and PAGB Codes agree that gifts and UK, products used to procure an abortion may not be
benefits should not induce an HCP to recommend advertised. The Cancer Act 1939 prohibits any adver-
or use the company’s products. Hospitality offered to tisement to the public that offers to treat cancer or to
HCPs is limited to the main purpose of the event. For prescribe any remedy for its treatment. In Germany,
example, if hospitality is being offered at events for a advertising to the general public must not contain
purely professional and scientific purpose, it should advertising statements relating to diseases explicitly
be limited to the main scientific objective. Hospitality called out in the Heilmittelwerbegesetz (HWG), such
offered at meetings to promote medicines should be as epidemics, tumour diseases, blood diseases or diseases
restricted to the main purpose of the event. In general, of the metabolic system.
the codes of conduct (e.g., the UK’s PAGB and ABPI Generally, disease awareness campaigns are meant
Codes) require that events sponsored by companies to educate the public about a disease and should not
disclose their sponsorship. be used as an advertising vehicle for a specific product.
Information provided should not make product claims
Disclosure of Transfers of Value or use brand names in order to tread judiciously so as
Some countries have adopted the requirements of the not to violate the prohibition against advertising to the
EFPIA Disclosure Code into a self-regulatory system. general public. This is a grey area for a specific medic-
The UK’s ABPI Code requires that companies doc- inal product that is the only available treatment for an
ument and publicly disclose certain transfers of value underlying disease. In this case, the disease awareness
made to HCPs and HCOs in Europe, including dona- campaign may be interpreted as a mechanism to cir-
tions, grants and benefits in kind provided to various cumvent the rule against advertising to the general
organisations, and fees and expenses paid to HCPs and public, since a consumer may view the product as the
other relevant decision makers. Disclosures are made only treatment for the disease.
annually (six months after end of the calendar year) In some countries, a product or treatment may be
on the central platform for disclosure in the UK, and mentioned as long as the information is in line with the
companies also can disclose this information on their SmPC and all relevant treatments are mentioned (e.g.,
websites. Similarly, Germany has adopted the FSA Finland). In this case, information also can refer to pre-
Transparency Code based on the requirements of the scription products.
EFPIA Disclosure Code. The disclosure requirements
relate to research and development, donations (monetary Advertising Content
or in-kind), training events and consultancy services. Advertisements addressed to the general public must be
By contrast, in France, the requirement for com- identified clearly as such. There are two requirements
panies to disclose transfers of value has been codified. under MPD Article 89. First, advertisements to the

Chapter 9
general public must clearly identify the medicinal product. While advertising of OTCs to the French public
In addition, advertisements shall contain at minimum: is legal, companies advertising in France should be
1. the medicinal product’s trade name, as well aware that the presentations of such medicinal products
as the common name if it contains only one should not be reimbursed (consistent with MPD Article
active substance 88(3)) and that the marketing authorisation of the
2. information necessary for the product’s correct product does not contain any restriction or prohibition
use regarding advertising to the public due to a potential
3. an express, legible invitation to read the public health risk. French law also forbids certain alle-
instructions carefully on the package leaflet or gations, for example, that the effect of the medicinal
on the outer packaging product is guaranteed.
In the UK, the Proprietary Association of Great
Some countries’ national regulations fall in line with Britain Codes of Practice for Advertising OTC
Article 89 of the MPD (e.g., Germany), whereby it is Medicines (PAGB Code) provides guidelines on
mandatory to include in the advertisement the infor- acceptable standards in advertising. The PAGB has two
mation necessary for the medicinal product’s correct codes for OTC products: the PAGB Consumer Code
use. Consistent with Article 91(2), German law also and the PAGB Professional Code, the former covers
exempts reminder advertisements from the mandatory advertising to the general public, and the latter covers
information required by Article 89. Reminder adver- advertising to HCPs. Advertising material to consum-
tisements consist only of the name of the medicinal ers, which can include promotional scripts for telephone
product and the company’s name or trademark or hotlines and hot-air balloons, must be pre-vetted by
the active pharmaceutical ingredient. Any advertising PAGB before release. By contrast, advertising material
directed at the general public also must contain the for HCPs, such as promotional aids, samples, posters
statement “For further information on risks and side and oral representations to promote a brand, do not
effects, please read the package leaflet and consult your require preapproval.
physician or pharmacist.”
In other countries (e.g., Austria and Italy), this kind Topics in Advertising
of information is not required explicitly by law but must Press Releases
be defined and provided by the MAH. Additionally, Press releases may be interpreted as advertising and
mandatory text, e.g., instructing users to read the pack- therefore fall within the rules regarding advertising
age leaflet carefully, also might need to be incorporated toward HCPs or the general public. It is often permissi-
into an advertisement to the general public and is ble to inform the media about products in development
subject to local laws or codes. In Denmark, television that have not yet been authorised. In Germany, the
commercials must show not only the product’s name line between promotional material and information
and effects, but also significant side effects. is interpreted on a case-by-case basis. For example, a
press release that objectively provides information on
Advertising of OTCs an important research activity, such as the outcome
Advertising of OTCs is permitted under MPD Article of a clinical study, may qualify as non-promotional
88(2) as an exception to the general prohibition against information. Companies have legitimate reasons to
advertising to the public. A common understanding inform HCPs, investors and press and media about
among Member States is that the advertising of any important milestones. Press releases, if they do not
class of medicinal products, whether prescription or focus on product information, will not be interpreted
OTC, should encourage the rational use of the product as a recommendation to prescribe or use a medicine.
by presenting objective information. Advertising should Pharmaceutical companies should draft press releases
not be misleading. in an objective, non-promotional way. In the UK, press
In Germany, advertisements related to non-prescrip- releases to the general public and HCPs about unau-
tion products must comply with the general rules for thorised medicines and off-label use are permitted if
advertising. For example, advertisements shall not be mis- they have legitimate scientific interest (e.g., results of a
leading and must contain the same basic information as pivotal trial) and are not promotional. The trade name
for prescription medicines. Restrictions on OTC adver- should be used in moderation and sweeping claims
tising to the general public shall not be interpreted as should not be made. The press release’s tone and content
being more restrictive than the restrictions in the MPD. should be accurate, factual and balanced.
Reminder advertisements need not contain the same basic In Denmark, press releases are exempted by law
information or the invitation to seek HCP advice. from advertising rules as long as they are objective, pro-
vide brief information regarding a medicinal product,

contain value as general news, are targeted at the press takes the viewer to mandatory information. According
and are sent or made available to journalists, with a view to an ECJ verdict, information on prescription med-
to journalistic assessment prior to publication. Press icines can be released on a company website if such
releases are interpreted as being informational if these information is accessible only to those actively searching
requirements are met and they do not contain medicinal for it and if the information is an accurate presentation
product advertisements. However, if companies pay for of the product. The selective display or rearrangement of
the press release, the exemption does not apply. information on the website for the purpose of promo-
tion rather than informing the viewer is prohibited.
Internet Advertising In general, the onus is on the pharmaceutical
The internet is a platform widely used to provide infor- company to take every measure possible to secure
mation to both HCPs and the general public. As such, advertisements directed at HCPs cannot be accessed
countries have enacted national laws and self-regulatory by the general public. It is recommended that pharma-
codes that apply to advertising through digital commu- ceutical companies make certain sections of a website
nication channels. accessible only to HCPs through codes or unique log-in
In the UK, internet advertisements of prescription credentials. According to the UK’s Blue Guide, when
medicines directed at HCPs are acceptable, but access companies provide a link from the home country site
should ideally be restricted only to these individuals. to websites serving other countries, they should ensure
Where websites provide both information targeted at that users do not need to access non-UK parts of the
consumers and information for HCPs, the two sections website to obtain essential product information.
must be clearly demarcated to ensure the general public
is not directed to information that is not intended for Nonauthorised Products and Off-Label Information
them. According to the APBI Code of Practice, public Article 87(1) forbids any advertising of a medicinal
assessment reports (EU or UK), SmPC, package leaflets product for which a marketing authorisation has not
and other reference materials may be included on web- been granted in accordance with Community law.
sites and may be accessible to the general public if they Accordingly, the national laws and codes of conduct
are not presented in a promotional way. Advertising are unanimous in forbidding advertising for an unau-
of prescription medicines on social networks such as thorised product. “Off-label advertising,” which covers
Facebook and Twitter is also forbidden because these advertising for indications or dosage forms not within
are public sites. Service providers (e.g., online pharma- the scope of an existing marketing authorisation, also is
cies or clinics) linked to prescription medicines should forbidden. Regardless, providing information on unau-
be aware that any claims relating to prescription med- thorised medicines or indications is possible so long as
icines on social media, such as Twitter, would likely be the information is not promotional.
interpreted as advertisements for these drugs and may What is considered “off-label advertising” is sub-
lead the general public to seek treatments. The ABPI ject to interpretation. In Germany, this is determined
Code of Practice (Clause 28) further provides that by whether a claim advertises a separate indication
information or promotional material about medicines or whether it only promotes a certain new effect of a
directed to a UK audience that is placed on the internet product. The former is prohibited, since it amounts to
outside the UK will be considered covered by the Code promoting an unauthorised product. The latter is not
if the content was placed there by a UK company (or an considered advertising if the company clearly pres-
affiliate) or under its authority. ents the claim as a new effect, and not an off-label
The PAGB’s Consumer Code requires web-based indication. Information on off-label indications or
promotional material over which companies have edito- non-authorised medicines generally can be presented at
rial control to comply with the Code and to submit this scientific conferences. The exchange of scientific infor-
material to PAGB for approval. mation during development or marketing authorisation
Germany, which has no explicit legal provisions phases is permissible, given that these activities are not
regarding advertising on the internet or through considered to be part of product-related advertising.
social media, applies the general rules of advertising of Information presented at scientific meetings must
medicinal products to advertising on the internet. The avoid the use of trade names and instead mention the
legal rules governing internet advertising are derived non-proprietary name of active ingredients (INN).
from case law. Therefore, certain exemptions from the In France, medical press publishers can present
general rules of advertising are carved out for internet information at independent meetings in the form of
advertising. For example, it is not necessary for the special editions. These publications can contain research
advertisement to display the mandatory information data that have not been validated. They also can con-
upon first sight if it shows a visible link that directly tain advertisements, but not for medicinal products

Chapter 9
for which off-label information is provided. Similarly, recommended as the rationale for a comparative claim.
in Belgium, information on non-authorised medicinal Similarly, the UK’s MHRA does not require con-
products or off-label indications can be published in trolled head-to-head trials, but when results are used
scientific journals not affiliated with corporate interests; in comparative claims, statistical information should
however, such publications cannot be used as promo- be subjected to statistical appraisal. Also, if secondary
tional material by a pharmaceutical company. endpoints are being used to promote a product, primary
endpoint data and its limitations must be included so
Exemptions from Directive 2001/83/EC as not to mislead readers. Clinical trials used in com-
Article 5(1) of Directive 2001/83/EC allows an exemp- parative advertising also must be registered with results
tion to the MA requirements, where a doctor may disclosed, following regulatory guidelines.
decide, at his or her discretion and under his or her
responsibility, to recommend or prescribe use of a medic- Market Surveillance
inal product for that patient “to fulfil special needs,” even MPD Article 97 covers market surveillance of medic-
if the medicine has not been granted an MA. inal product promotion in the EU. It makes Member
States responsible for ensuring there are adequate
Comparative Advertisements and effective methods to monitor medicinal product
Comparative advertising refers to any advertising that advertising. Such surveillance might be established by
explicitly or by implication identifies a competitor or competent authority preapproval of material, but this is
goods or services offered by a competitor (Article 2, left to the Member States to decide and implement. The
Directive 2006/114/EEC). UK’s MHRA, for example, conducts a number of activi-
Comparative advertising must meet the following ties related to advertising control:
criteria under the Directive: 1. preapproving advertisements
• The advertising must not be misleading. 2. monitoring of published advertising
• The advertising should only compare products 3. handling of complaints
meeting the same intended purpose. 4. enforcement actions when materials are out of
• The advertising does not discredit or denigrate compliance
the trademarks, trade names and other distin-
guishing marks of a competitor. It is within the ambit of Member States to confer
upon courts or administrative authorities the powers to
Member States have codified these principles in their enforce the regulations. Measures can include orders for
national regulations. the cessation of misleading advertising, whether it has
Generally, comparative advertising of pharma- been published or not; for the latter, it is not necessary
ceuticals is legal if addressed to HCPs and must meet to show actual loss or damage or of intention or negli-
national requirements transposed from Directive gence on the part of the advertiser. Intentional breach of
2006/114/EEC. In addition to national laws, Member regulations is grounds for imprisonment or a fine.
States also impose additional requirements or guidance. Empowering national competent authorities to
The German courts require that promotional claims for take these actions does not exclude the possibility
a pharmaceutical product be substantiated by reliable of voluntary advertising control by self-regulatory
scientific evidence, which mean the comparison needs bodies, such as local trade associations. In general,
to be based on a clinical head-to-head study. A clinical national authorities come in where the issues implicate
study deemed to have enough evidence to support a a public health concern or require additional investi-
promotional claim must meet the “gold standard” of gation. In the UK, the MHRA has a Memorandum
clinical studies, i.e., a prospective randomised dou- of Understanding with self-regulated bodies in which
ble-blind trial with an adequate statistical analysis. In the two systems are regarded as complementary and
France, comparative advertising is regulated under the synergistic. Both bodies can hear complaints. The
Consumer Code. The ANSM also recommends that MHRA usually will refrain from investigating cases
comparison shall be as exhaustive as possible by includ- referred to one of the two self-regulating bodies, such
ing comparison of essential characteristics, benefit-risk as inter-company complaints and other complaints
ratio and useful details for HCPs, such as treatment with the consent of the complainant. Although the
periods. No pharmacological properties shall be detailed MHRA declines to investigate cases that are under
without validated clinical results. In the Netherlands, investigation by a self-regulatory body, it reserves the
comparative claims must be justified by at least one right to step in if serious public health concerns are
study published in a peer-reviewed journal. In Austria, raised or if self-regulation fails, for example, to deter
head-to-head trials, although not mandatory, are highly a company from violating rules of conduct. Therefore,

the MHRA monitors the Prescription Medicines Code In Italy, promotional material directed to the gen-
of Practice Authority (PMCPA) website for any cases eral public or HCPs is required to be preapproved by
where further investigations by the national authority the Italian Ministry of Health (MOH). Advertising
may be required. Similarly, the decisions of self-regula- material is deemed tacitly approved after 45 days from
tory bodies in Germany do not negate the authority of the date of application. Advertising material targeting
the national competent authority to further investigate HCPs is deemed approved after 10 days from filing
matters that require interpretation of both the law and with the AIFA (filing started 1 June 2018) without
the ethical code. In Spain, the Farmaindustria Code objections. Filing also includes gadgets.
states that claims against the advertising practices of Other jurisdictions do not require prior approval.
other companies must be brought before the Ethics Germany does not require companies to submit adver-
Committee of Farmaindustria before being raised with tising material under any circumstances. In Spain, prior
health authorities or the Courts. approval of advertisements is not required; however, a
copy of the advertisement must be sent to the health
Preapproval of Advertising Material authority. Since July 2013, advertising OTC drugs no
Some Member States have implemented processes for longer requires preapproval from the Spanish authority.
preapproval of promotional material in their local mar- An annual index listing all activities must be sent to
ket surveillance regulations. the Health Authority of the Autonomous Community
where the company is located. In Finland, while prior
The UK System approval is not required, the industry may voluntarily
The UK’s MHRA defines certain situations where vet- request an inspection by PIF for an advertisement
ting may be required, including: directed at consumers. As per PIF Code, TV and radio
1. where a newly authorised product subject to advertisements must be pre-approved.
additional monitoring is placed on the market
2. where a product has been reclassified, for Scientific Service
instance, from prescription-only to pharmacy The MPD states, “the Marketing Authorisation holder
3. where previous advertising for a product has shall establish, within his undertaking, a scientific
breached regulations service in charge of information about the medicinal
products which he places on the market.”
The vetting procedure normally takes two to three The MPD also states, “each undertaking which
months but no longer than six months. The period can manufactures or imports medicinal products should set
be reduced or extended, depending on material quality. up a mechanism to ensure that all information supplied
Discussions with MHRA on proposed advertising mate- about a medicinal product conforms with the approved
rial are possible, or the company may request a meeting conditions of use.” This includes more pharmaceutical
to discuss issues that occur during a vetting procedure. entrepreneurs into this scope than just MAHs.
Guidance from ABPI also can be sought prior to Once this scientific service is implemented, the
publication of advertising materials related to prescrip- MAH, according to the MPD, still is responsible for
tion only medicines. OTC promotion to the general keeping samples of all advertisements and information
public requires preapproval under the PAGB Consumer on the audience addressed, distribution dates and meth-
Code, while promotion to HCPs is governed by the ods, compliance with the MPD, adequate medical sales
PAGB Professional Code. representative training, support from authorities and
implementation of authorities’ decisions.
Other Jurisdictions Member States have implemented the scientific
In Belgium, preapproval/notification is dependent on service’s responsibilities differently.
whether the advertisement is directed to HCPs or the The IFPMA Code states “a designated employee
general public. Television and radio advertisements with sufficient knowledge and appropriate qualification
directed to the public require preapproval. All other should be responsible for approval of all promotional
forms of advertisement directed to the public should be communication.” If no such employee is available, it
notified 30 days prior to publication. Advertisements might be another senior employee who receives adequate
directed to the general public do not require a prior scientific advice from sufficiently qualified scientific
notification or approval by the Ministry of Health. personnel. Going further than the IFPMA, the EFPIA
In France, preapproval from ANSM is required Code requires a member company to establish a scien-
for advertising directed to both the general public and tific service in charge of both information on medicinal
HCPs. The approval is valid for two years. products and the approval and supervision of non-in-
terventional studies. Such service must include a doctor

Chapter 9
or a pharmacist responsible for approving promotional Article 4 of the EU Medical Devices Directive (93/42/
material before release. In addition, this person is EEC or EU MDD).
responsible for overseeing any non-interventional stud- Another provision in the EU MDR related to
ies. EU Member States’ laws and industry codes have advertising is Article 7:
also broadened the scientific service responsibilities to all In the labelling, instructions for use, making avail-
kinds of information including promotion. able, putting into service and advertising of devices, it is
Many countries (e.g., Belgium, Bulgaria, Denmark, prohibited to use text, names, trademarks, pictures and
Finland) require that the scientific service unit employ figurative or other signs that may mislead the user or
persons with sound scientific educations, such as physi- the patient with regard to the device’s intended purpose,
cians or pharmacists. In some countries like Denmark, safety and performance by:
companies are free to decide how to best establish such • ascribing functions and properties to the prod-
services (e.g., whether there is one service in charge of uct that the product does not have
both promotion review and non-interventional studies, • creating a false impression regarding treatment
or separate services). French law mandates that com- or diagnosis, functions or properties that the
panies must have a department in charge of advertising product does not have
under the responsibility of a pharmacist who is tasked • failing to inform of a likely risk associated with
with ensuring a company’s compliance with advertis- the use of the product in line with its intended
ing rules and the scientific accuracy of the information purpose
released. Instead of specifically requiring a pharmacist • suggesting uses of the product other than those
or a physician to oversee scientific service, the German declared in the intended purpose when the
Drug Act requires the appointment of an informa- conformity assessment was carried out
tion officer responsible for ensuring that promotional
material is in line with the content of the marketing Given the shifting regulatory landscape in the medical
authorisation. As an internal procedure, it is recom- technology space, manufacturers who are currently sell-
mended that a sign-off procedure be established for the ing in the EU market or planning to enter the market
purpose of document control. should conduct a gap analysis between their current
advertising and promotion practices and the guidelines
Medical Devices prescribed by the EU MDR. In addition to device-spe-
In contrast to the regulation of prescription medicines, cific regulations, companies also should keep in mind
there are no EU-level rules that provide an overarching instruments such as the EU Directive on Misleading
regulatory framework for the advertising and promotion and Comparative Advertising (Directive 2006/114/
of medical devices. MedTech Europe, a trade associ- EC).5 The goal of this directive is to protect traders
ation representing the medical technology industry, from misleading advertising and adverse consequences.
has published a code for ethical business practice that The World Health Organization (WHO) states that
sets out the minimum standards applicable to various advertisements should be factual, fair and capable of
types of activities carried out by its members, including substantiation. Misleading advertising is defined in this
being in compliance with key laws affecting the device directive as a type of presentation that deceives a person,
industry. The Code for Ethical Business Practice aims and by its deceptive nature, likely affects their economic
to provide guidelines by which industry interacts with behaviour or injures, or may injure, a competitor.
HCPs in a way that fulfils MedTech’s mission to make
safe, innovative and reliable technology. The code is Conclusion
informed by the principle that member companies shall Medicinal product advertising not only contributes to
respect the obligation of HCPs to make independent a pharmaceutical company’s revenue, but also serves as
decisions regarding treatment and ensure integrity in a source of information on the product’s correct use.
the interaction between companies and HCPs. Advertising is regulated by national implementation of
As per Article 21 of the EU Medical Devices an EU Directive. When undertaking business in areas
Regulation (EU 2017/745 or EU MDR), medical regulated by EU Directives, as is the case for medicinal
devices may be displayed at trade fairs, exhibitions, product promotion, it is recommended that compa-
demonstrations or similar events prior to receiving a CE nies consult national implementations of the Directive
Mark as long as a visible sign clearly indicates that such in advance to understand the underlying Directive’s
devices are intended for presentation or demonstration meaning and to gain practical information from any
purposes only. Devices without a CE Mark cannot additional or slightly modified interpretations. While
be made available until they have been brought into the advertising and promotion of medical devices is
compliance with the EU MDR.4 This is consistent with currently not captured in a fixed regulatory framework,

the device manufacturer is advised to keep up to date IFPMA_Code_of_Practice_2019_Webinar-3.pdf.

with the changing regulatory landscape as the EU Accessed 6 March 2020.
• MedTech Europe Code of Ethical Business Practice.
MDR officially begins to take effect throughout the https://www.medtecheurope.org/wp-content/
region in 2020 and not to lose sight of other regulatory uploads/2017/06/20190312_MedTech-Europe-Code-
frameworks that apply to advertising and promotion of of-Ethical-Business-Practice-QA-DG.pdf. Accessed 6
products in general. March 2020.
• Directive 2006/114/EC of the European Parliament
and of the Council of 12 December 2006 concern-
References ing misleading and comparative advertising. https://
1. Directive 2001/83/EC of the European Parliament and of the eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=O-
council of 6 November 2001 on the Community code relating J:L:2006:376:0021:0027:EN:PDF. Accessed 6 March
to medicinal products for human use. https://ec.europa.eu/ 2020.
health/sites/health/files/files/eudralex/vol-1/dir_2001_83_
cons2009/2001_83_cons2009_en.pdf. Accessed 6 March 2020.
2. European Federation of Pharmaceutical Industries and UK
Associations (EFPIA) Code of Practice (2019). https://www. • The Human Medicines Regulations 2012 Part
efpia.eu/media/413022/efpia-code-2019.pdf. Accessed 6 March 14 Advertising. http://www.legislation.gov.uk/
2020. uksi/2012/1916/part/14/made. Accessed 6 March 2020.
3. International Federation of Pharmaceutical Manufacturers • The Blue Guide: Advertising and Promotion of Medicines
Association (IFPMA) Code of Practice (2019). https://www. in the UK. https://assets.publishing.service.gov.uk/
ifpma.org/subtopics/new-ifpma-code-of-practice-2019/. government/uploads/system/uploads/attachment_data/
Accessed 6 March 2020. file/824778/Blue_Guide.pdf. Accessed 6 March 2020.
4. Regulation (EU) 2017/745 of the European Parliament and • ABPI Code of Practice. https://www.abpi.org.uk/
of the Council of 5 April 2017 on medical devices, amend- media/6655/abpi-code-of-practice-2019.pdf. Accessed 6
ing Directive 2001/83/EC, Regulation (EC) No. 178/2002 March 2020.
and Regulation (EC) No. 1223/2009 and repealing Council
Directives 90/385/EEC and 93/42/EEC. https://www.legisla- Germany
tion.gov.uk/eur/2017/745/contents. Accessed 6 March 2020. • Medicinal Products Act. https://www.gesetze-im-internet.
5. Directive 2006/114/EC of the European Parliament and of de/englisch_amg/englisch_amg.html. Accessed 6 March
the council of 12 December 2006 concerning misleading and 2020.
comparative advertising. https://eur-lex.europa.eu/LexUriServ/ • Code of Conduct on the Collaboration with Healthcare
LexUriServ.do?uri=OJ:L:2006:376:0021:0027:EN:PDF. Professionals (FSA Code of Conduct with Healthcare
Accessed 6 March 2020. Professionals). http://www.efpia-e4ethics.eu/usd/e4ethics.
nsf/_/2F5D5706083A641FC125806E0041D58D/%-
Useful Websites 24File/2018-05-02_Fachkreiskodex-engl_.002.pdf.
• Directive 2001/83/EC of the European Parliament and Accessed 6 March 2020.
of the Council of 6 November 2001 on the Community
code relating to medicinal products for human use. https:// International Sources
ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/ • Ethical Criteria for Medicinal Drug Promotion. https://
dir_2001_83_consol_2012/dir_2001_83_cons_2012_ apps.who.int/medicinedocs/documents/whozip08e/
en.pdf. Accessed 6 March 2020. whozip08e.pdf. Accessed 6 March 2020.
• EPIA Code of Practice. https://www.efpia.eu/ • The International Comparative Legal Guide to:
media/413022/efpia-code-2019.pdf. Accessed 6 March Pharmaceutical Advertising 2019, 16th Edition. A
2020. Practical Cross-Border Insight Into Pharmaceutical
• Code of Practice. https://www.ifpma.org/wp-content/ Advertising. https://iclg.com/practice-areas/pharmaceu-
uploads/2018/09/IFPMA_Code_of_Practice_2019.pdf. tical-advertising-laws-and-regulations. Accessed 6 March
Accessed 6 March 2020. 2020.
• IFPMA Code of Practic 2019 Q&A. https://www.ifpma. • Pharmaceutical Advertising 2019. https://practiceguides.
org/wpcontent/uploads/2018/09/QA_IFPMA_Code-_of_ chambers.com/practice-guides/pharmaceutical-adverti-
Practice_2019-2.pdf. Accessed 6 March 2020. sing-2019. Accessed 6 March 2020.
• Code of Practice: Key Changes. https://www.
ifpma.org/wp-content/uploads/2018/09/

Chapter 9

Chapter 10
Enforcement and Competent

Authorities
OBJECTIVES Regulation (EC) No. 1223/2009 and repealing

Council Directives 90/385/EEC and 93/42/EEC
□ Understand the role of the different authorities,
their enforcement methods and how these are □ MEDDEV 2.12/1 Rev. 8: Guidelines on a Medical
applied Devices Vigilance System
□ Understand how different authorities from the □ Directive 2001/83/EC of the European Parliament
EU Commission and Member States coordinate and of the Council of 6 November 2001 on the
with each other on enforcement methods Community code relating to medicinal products
for human use, as last amended by Directive
2012/26/EU of the European Parliament and of
DIRECTIVES, REGULATIONS AND GUIDELINES the Council of 25 October 2012
COVERED IN THIS CHAPTER:
□ Council Directive 93/42/EEC of 14 June 1993 Parliament and of the Council of 31 March 2004
concerning medical devices, as amended laying down Community procedures for the
by Directive 2007/47/EC of the European authorisation and supervision of medicinal
Parliament and the Council of 5 September 2007 products for human and veterinary use and
establishing a European Medicines Agency as
□ Council Directive 90/385/EEC of 20 June 1990 amended by Regulation (EU) No. 12235/2010 of
on the approximation of the laws of the Member the European Parliament and of the Council of
States relating to active implantable medical 15 December 2010
devices, as amended by Directive 2007/47/EC
of the European Parliament and the Council of 5 □ Commission Directive 2003/94/EC of 8 October
September 2007 2003 laying down the principles and guidelines
of good manufacturing practice in respect of
□ Directive 98/79/EC of the European Parliament medicinal products for human use and investi-
and of the Council of 27 October 1998 on in gational medicinal products for human use
vitro diagnostic medical devices, as amended
by Directive 2007/47/EC of the European □ Directive 2001/20/EC of the European
Parliament and the Council of 5 September 2007 Parliament and of the Council of 4 April 2001
on the approximation of the laws, regulations
□ Regulation (EU) 2017/745 of the European and administrative provisions of the Member
Parliament and of the Council of 5 April 2017 States relating to the implementation of good
on medical devices, amending Directive clinical practice in the conduct of clinical trials
2001/83/EC, Regulation (EC) No. 178/2002 and no medicinal products for human use, as last
amended by Regulation (EC) No. 596/2009 of

Chapter 10
the European Parliament and of the Council of Clinical Investigations and Clinical Trials
18 June 2009 In Europe, the term ‘clinical trial’ is used in the pharma-
ceutical regulation, while the Medical Devices Directive
□ Regulation (EU) No. 536/2014 of the European (MDD) and the Medical Devices Regulation (EU MDR)
Parliament and of the Council of 16 April 2014 use the term ‘clinical investigation.’
no clinical trials on medicinal products for By definition, the products to which human sub-
human use, and repealing Directive 2001/20/EC jects are exposed during clinical trials or investigations
have not passed all legally required checks for market
access and, therefore, a final conclusion on the balance
Introduction between risk and benefit cannot be drawn yet. As a con-
Competent Authorities sequence, clinical trials and investigations are subject to
As described in Chapter 2, Member States have a dedicated system of competent authority monitoring
delegated some of their powers to the European and control. The goal is to ensure every precaution is
Commission, in accordance with the EU Treaty. The reg- taken to protect human subjects’ health and safety. The
ulations on medical products’ market access are drafted ethical principles laid down in the Helsinki Declaration
at the EU level, at the Commission’s initiative and with and its successors (see Chapter 2) have to be respected.
involvement of Member States and the EU Parliament. Before the start of a trial or investigation, relevant com-
However, the Commission has neither direct petent authority(ies) permission is required. Competent
enforcement powers regarding medical product regulation authorities have the legal right to intervene at any
compliance nor a central police force. The Member States moment and may force the manufacturer to stop the
retain sovereignty with respect to their own markets. investigation or trial.
Each Member State has established one or more For medical devices, these provisions are included
dedicated regulatory bodies for market oversight and in MDD Article 15 and Section 2 Annex X and in EU
enforcement in their territory; these are called compe- MDR Articles 62–82 and Annex XV. See Chapter 14
tent authorities. for more information on medical devices.
EU regulations include specific mechanisms for For in vitro diagnostics, the new In Vitro Diagnostic
coordinating enforcement actions by national com- Medical Devices Regulation (EU IVDR) includes the
petent authorities (e.g., the medical device safeguard term ‘performance study.’ Performance studies, which
clause). In addition to enforcement powers based on will require subjects to undergo additional burdensome
EU regulations, competent authorities have specific and/or invasive procedures, will be subject to a similar
national powers based on their countries’ legislation. oversight mechanism by competent authorities as for
These powers differ among Member States, as do com- medical devices.
petent authorities’ organisation and structure. Penalties For medicinal products, these provisions are included
depend on the powers vested in a particular competent in Regulation (EU) No. 536/2014 of the European
authority. Some competent authorities can impose Parliament and of the Council of 16 April 2014 on
certain penalties directly (e.g., fines); others refer their clinical trials on medicinal products for human use, and
enforcement cases to a national court of justice. repealing Directive 2001/20/EC. See Chapter 26 for
As a result, there sometimes are discrepancies more information on medicinal product clinical trials.
among different competent authorities on how prod-
ucts are treated within their territories. These national
Coordination and Cooperation
variations make it especially important for regulatory
To achieve effective enforcement, coordination and
professionals to know what entity enforces what prod-
cooperation among all involved entities is required.
uct regulations and how. For example, in the majority
The EU regulations explicitly give competent authori-
of Member States, medicines and medical devices’
ties and the EU Commission or European Medicines
regulations are enforced by one competent authority
Agency (EMA) the obligation to cooperate with each
(e.g., ANSM in France, MHRA in the UK, BfArM in
other and exchange relevant information (MDD Article
Germany), while in other countries, two (or even more)
20a and Directive 2001/83 Articles 122–124).
competent authorities are involved (e.g., Italy and the
For medicinal products, the European Commission
Netherlands). A list of competent authorities for med-
has delegated its direct responsibilities to EMA.
ical devices is included in Chapter 14, Table 14-2. In
Consequently, cooperation and coordination between
most Member States, competent authorities for medical
competent authorities and EMA is needed in the phar-
devices and medicines operate under the Ministry of
maceutical sector.
Health’s direct responsibility.
For medical devices, Member States have des-
ignated conformity assessment checks for devices

Enforcement and Competent Authorities
in specific risk classes to third parties called notified State where the manufacturer is established) must “…
bodies. Consequently, in the medical device sector, com- take all appropriate measures to restrict or prohibit the
petent authorities, notified bodies and the European placing on the market of the product…or to ensure that
Commission need to coordinate and cooperate. it is withdrawn from the market.”
Various competent authorities and EU When the CE marking is affixed to products that
Commission or EMA forums have been established do not fulfil the definition of a medical device, this is
with the goal of enhancing coordination and coop- considered as “wrongly affixed CE marking” as well
eration, such as Competent Authorities for Medical (MDD Article 18).
Devices (CAMD)1 and Heads of Medicines Agencies
(HMA).2 HMA has a Human Medicines section and Safeguard Clause
a Veterinary Medicines section. These bodies have As “wrongly affixed CE marking” relates to non-
various subgroups and subcommittees. Examples compliant devices, the MDD includes an additional
of relevant groups are the Joint Action on Market ‘safety-valve’ that gives Member States the legal power
Surveillance ( JAMS)3 in the medical device sector, and to act without delay on conforming devices, which nev-
the Pharmacovigilance Risk Assessment Committee ertheless pose an unacceptable health risk for patients,
(PRAC)4 and EU Joint Audit Program ( JAP) in the users or other relevant persons. The safeguard clause
pharmaceutical sector. Some of these committees are is not applied frequently but can be an important tool
chaired by the Commission or EMA, while others are for quick action in exceptional cases. A Member State
chaired by a competent authority representative. In can take an interim measure immediately (e.g., device
addition to these European forums for cooperation, the withdrawn from the market, marketing prohibited or
European Commission participates in global cooper- restricted) on its own territory and must notify the
ation entities, such as the Pharmaceutical Inspection European Commission and other Member States of the
Convention (PIC) and International Council on interim measure taken. After consultation with other
Harmonisation (ICH) in the pharmaceutical sector and Member States, the Commission takes a formal deci-
the International Medical Device Regulators Forum sion on whether the interim measure was justified. If
(IMDRF)5 in the medical device sector. the measure is justified, legal procedures to consolidate
the measure in the directive (e.g., in the classification
Medical Devices rules) or harmonised standard will be initiated. If the
Member States want to ascertain that devices on the Member State’s interim measure was not justified, the
market do not endanger health, safety or any other EU Commission will inform the Member State and the
aspect of public health. The MDD states “Members involved manufacturer (MDD Article 8).
States shall take all necessary steps to ensure that
devices may be placed on the market and/or put into Particular Health Monitoring Measures
service, only if they comply with the requirements laid As the safeguard clause relates to specific medical
down in this Directive” (MDD Article 2), but does devices or device groups that pose a risk to patients or
not specify in detail how Member States should do users, the MDD also includes a provision under which
this. In addition, the MDD gives Member States the a Member State can act against more general threats to
following legal tools for their enforcement activities: public health in a similar procedure. This is called “par-
“Wrongly affixed CE-marking” (MDD Article 18), ticular health monitoring measures” (MDD Article 14b).
“Safeguard Clause” (MDD Article 8) or “Particular
health monitoring measures” (MDD Article 14b). The Market Surveillance, Postmarket Surveillance and
Active Implantable Medical Devices Directive, the In Vitro Vigilance
Diagnostic Medical Devices Directive and the new EU Market surveillance comprises executed activities and
MDR and EU IVDR include similar provisions. competent authorities’ measures to check and ensure
devices present within their national territories comply
Wrongly Affixed CE Marking with the directives’ requirements. MDD Article 10 gives
As explained in Chapter 2, when the CE marking is the general framework of how competent authorities
put on a medical device, this means the device is in should process information on incidents and which
conformity with the legal requirements. When the CE other parties should be involved (e.g., manufacturer,
marking is affixed to a device that is not in conformity healthcare professionals, other competent authorities
with the legal requirements, the manufacturer has the and/or the European Commission).
duty to remedy the issue causing the nonconformity. The manufacturer conducts postmarket surveillance
If the device continues not to conform, the competent (PMS), a systematic and proactive process to collect
authority (i.e., the competent authority in the Member

Chapter 10
and review experience gained from the manufacturer’s Eudamed will facilitate communication between com-
devices on the market. The manufacturer’s Quality petent authorities and notified bodies.
Management System (QMS) must include a PMS Unfortunately, Eudamed will not be operational
procedure. PMS’ purpose is to identify any need for before 2022. See Chapter 13 for more information on
corrective action. PMS needs to be systematic; the man- the new EU MDR and EU IVDR.
ufacturer needs to plan in advance. PMS is a continuous
process; the manufacturer must be able to feed PMS Notified Bodies’ Specific Enforcement Role
information back into its QMS. Notified bodies’ primary responsibility is to check
Vigilance reporting requires manufacturers to manufacturers’ medical device premarket conformity
notify the relevant competent authorities of serious assessments. However, the MDD includes some market
incidents and field safety corrective actions. It is a enforcement responsibilities resulting from notified
reactive process. The obligation to notify competent bodies’ ongoing medical device conformity assessment
authorities in relevant cases must be part of the manu- checks. MDD Article 16 gives notified bodies the
facturer’s PMS. power to withdraw or suspend certificates if they see
The MDD does not include very detailed provi- evidence a device or its manufacturer does not con-
sions on market surveillance, postmarket surveillance form to MDD requirements. Notified bodies also must
and vigilance. Over time, the need for more detail and inform their competent authorities about certificates
harmonisation in procedures arose, and the MEDDEV they issue, suspend and withdraw. Notified bodies’
2.12/1 Guidelines on a Medical Devices Vigilance System6 surveillance activities include continued conformity to
was drafted in early 2000s. This MEDDEV outlines regulatory requirements of the manufacturer, its quality
and details the steps manufacturers, competent authori- system and its devices.
ties and other entities need to take. Standardised forms Triggered by the PIP issue, the EU Commission
for information exchange are available as annexes to this and the Member States issued a Joint Immediate
MEDDEV. Action Plan7 in 2012. As part of this plan, notified bod-
MEDDEV 2.12/1 has been amended and updated ies were required specifically to perform unannounced
continuously; the eighth revision was adopted in 2013. audits on a regular basis at manufacturers’ and critical
An important addition in the seventh revision (in 2012) suppliers’ facilities. As it was not possible to grant noti-
was to require the manufacturer to recognise and report fied bodies direct access to vigilance reports due to data
significant increases or trends in incidents to the com- protection requirements, notified bodies were asked
petent authority, which on their own would be excluded to include the obligation to transmit vigilance reports
from the obligation to report. to them in their contracts with manufacturers, so the
notified body would be aware of any specific issues. A
Eudamed procedure, in which competent authorities provide noti-
To facilitate the exchange of information and commu- fied bodies with dedicated vigilance information, has
nication among competent authorities, the European been developed as well.8
Commission has established a central database called The EU MDR and EU IVDR further build on the
Eudamed. Eudamed is accessible only to competent ‘spirit’ of the Joint Immediate Action Plan, as men-
authorities and the EU Commission. It includes data tioned above. The EU MDR and EU IVDR extend the
on manufacturers and Authorised Representatives postmarket enforcement role by making notified bodies
and contains information on device certificates, vig- de facto an ‘extended arm’ of the competent authorities,
ilance procedures and clinical investigations (MDD especially for the higher risk classes. Notified bodies
Article 14a). Eudamed has contributed to coordinating will assess the postmarket surveillance plans of the
enforcement activities among competent authorities. manufacturers before certification. Furthermore, they
The EU MDR and EU IVDR include provisions on will assess the PSURs for Class III and implantable
an entirely renewed and extended Eudamed. This new devices and decide if there are any consequences for the
Eudamed will be the ‘backbone’ of the new legal system. validity of the certificate. They will share their PSUR
It will include modules with information on economic evaluations with the competent authorities through
operators, products and certificates, postmarket surveil- Eudamed. For other devices, manufacturers shall make
lance and clinical investigations. the PSURs available to the notified body and on request
Eudamed will be used to report and track inci- to the competent authorities.
dents and will help competent authorities (and the EU
Commission) to coordinate and exchange information
on their market surveillance activities. In addition,

Enforcement and Competent Authorities
Medicinal Products the Coordination Group for Mutual Recognition

Good Manufacturing Practices (GMP) Compliance and Decentralised Procedures—Human (CMDh)11
GMP describes the minimum standards a medicinal if it concerns a nationally authorised medicine. The
product manufacturer must meet in its production Member State competent authorities are responsible
processes. EU good manufacturing practice (GMP) for ensuring manufacturers adhere to these PRAC
requirements are included in Commission Directive recommendations.
2003/94/EC of 8 October 2003 laying down the prin-
ciples and guidelines of good manufacturing practice Recalls
in respect of medicinal products for human use and A recall is the classic enforcement action competent
investigational medicinal products for human use. See authorities use to police and withdraw medicinal prod-
Chapter 28 for more information on GMPs. ucts from the market. Recall mechanisms actually are
Member States’ competent authorities conduct required by good manufacturing practice; the MAH is
GMP inspections when the manufacturer and its required to have a mechanism for handling unplanned
Marketing Authorisation Holder (MAH) apply for product conformance deviations. Usually, a designated
Marketing Authorisation (MA), and they grant the individual (e.g., the manufacturer’s Qualified Person)
manufacturer a GMP certificate if all requirements should be involved in the recall decision, and the deci-
are met. In addition, the competent authority retains sion to implement a recall should be independent from
the ability to inspect the manufacturer periodically sales and marketing.
throughout the MA’s duration. Competent authorities also are involved in recalls
and withdrawing marketing authorisation for medici-
Pharmacovigilance nal products on their own markets. Directive 2001/83/
Pharmacovigilance is the process of monitoring EEC Article 117a obliges Member States’ competent
medicinal products’ use after they have entered the authorities to have systems for governing recalls and
market. The information resulting from this process is withdrawing medicinal products from the market. In
incredibly important for patient safety in the postap- addition, the system should have mechanisms in place
proval phase. See Chapter 34 for more information on to notify other Member States’ competent authorities in
pharmacovigilance. the event a medicinal product is suspected of presenting
The primary legal basis for pharmacovigilance a serious public health risk. These systems include the
requirements in the EU is found in Regulation (EC) ability to issue urgent public announcements within 24
No. 726/2004 Article 57 and Directive 2001/83/EC hours to facilitate the recall and protect patients and
Title IX. In 2010 and 2012, the EU introduced new other users’ health.
directives and regulations amending its pharmacovigi-
lance requirements, which are known collectively as the Advertising and Promotion
New Pharmacovigilance Legislation; these were partly EU medicinal product advertising regulations are
consolidated in Directive 2001/83 and Regulation strongly enforced in the EU Directive 2001/83/EC
726/2004. The more operational aspects were included of the European Parliament and of the Council of 6
in Commission Implementing Regulations (EU) No. November 2001 on the Community code relating to
520/2012 of 19 June 2012 on the performance of phar- medicinal products for human use includes detailed
macovigilance activities provided for in Regulation provisions on advertising and other forms of promo-
(EC) No. 726/2004 of the European Parliament and tion toward prescribers and toward the general public
of the Council and Directive 2001/83/EC of the (Articles 87–100).
European Parliament and of the Council.9 In contrast with the US, where direct-to-consumer
One of the changes was the establishment of a new prescription medication advertising is widespread, and
EMA committee, Pharmacovigilance Risk Assessment one can see ads containing statements like “Ask your
Committee (PRAC). PRAC consists of Member State doctor about prescription medication X” on television
representatives, supplemented by scientific experts and every five minutes, any direct promotion to consumers
patients’ and healthcare professionals’ representatives. It for prescription medication is prohibited in the EU,
has the authority to give recommendations for regula- with the exception of vaccination campaigns approved
tory actions (e.g., extra product information warnings or by the health authorities (Article 88).
restriction of the indication, removal from the market). Direct-to-consumer advertising for non-prescrip-
PRAC recommendations for regulatory action tion medication is bound to an extensive set of rules
are submitted for endorsement to the Committee (Articles 89 and 90).
for Medicinal Products for Human Use (CHMP)10 The directive also includes detailed rules on hospi-
if it concerns a centrally authorised medicine or to tality (limited to professional and scientific purposes),

Chapter 10
free samples (only allowed in small quantities and with eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=O-

a lot of restrictions) and other inducements manufac- J:L:2012:159:0005:0025:EN:PDF. Accessed 27 April 2020.
10. Committee for Medicinal Products for Human Use (CHMP).
turers are allowed to offer prescribers. EMA website. https://www.ema.europa.eu/en/committees/
The directive requests Member States to have a committee-medicinal-products-human-use-chmp. Accessed 27
dedicated system to control medicinal product advertis- April 2020.
ing and promotion on their markets and to enforce the 11. Coordination Group for Mutual Recognition and Decentralised
Procedures—Human (CMDh). EMA website. http://www.
applicable rules. These systems are operational in most hma.eu/cmdh.html. Accessed 27 April 2020.
Member States. The directive gives Member States
room to impose additional rules on their territories, Recommended Reading
so some Member States have more granular national • EMA website. “What we do.” http://www.ema.europa.eu/ema/
regulations and restrictions, some of which are enforced index.jsp?curl=pages/about_us/general/general_content_000091.
jsp&mid=WC0b01ac0580028a42. Accessed 27 April 2020.
quite rigorously. • Council Directive 93/42/EEC of 14 June 1993 concerning
medical devices, as amended by Directive 2007/47/EC of the
References European Parliament and the Council of 5 September 2007.
1. Competent Authorities for Medical Devices (CAMD) website. EUR-Lex website. http://eur-lex.europa.eu/LexUriServ/
http://www.camd-europe.eu/. Accessed 27 April 2020. LexUriServ.do?uri=CONSLEG:1993L0042:20071011:en:PDF.
2. Heads of Medicines Agencies website. http://www.hma.eu/. Accessed 27 April 2020.
Accessed 9 March 2020. • MEDDEV 2.7/4 Guidelines on Clinical investigations: a guide for
3. Joint Action on Market Surveillance. CAMD website. https:// manufacturers and notified bodies. EC website. http://ec.europa.
www.camd-europe.eu/joint-action-projects/market-surveil- eu/consumers/sectors/medical-devices/files/meddev/2_7_4_
lance-of-medical-devices-jams/. Accessed 27 April 2020. en.pdf. Accessed 27 April 2020.
4. Pharmacovigilance Risk Assessment Committee (PRAC). • MEDDEV 2.12/1 Rev. 8 Guidelines on a Medical Devices
EMA website. http://www.ema.europa.eu/ema/index. Vigilance System. EC website. https://ec.europa.eu/docsroom/
jsp?curl=pages/about_us/general/general_content_000537. documents/15506. Accessed 27 April 2020.
jsp&mid=WC0b01ac058058cb18. Accessed 27 April 2020. • European Commission Information 2010/C 82/01
5. International Medical Device Regulators Forum website. http:// Communication from the Commission—Detailed guidance on
www.imdrf.org/. Accessed 27 April 2020. the request to the competent authorities for authorization of a
6. MEDDEV 2.12/1 Rev. 8 Guidelines on a Medical Devices clinical trial on a medicinal product for human use, the notifica-
Vigilance System. EC website. http://ec.europa.eu/DocsRoom/ tion of substantial amendments and the declaration of the end
documents/15506/attachments/1/translations. Accessed 27 of the trial (CT-1). EUR-Lex website. http://eur-lex.europa.eu/
April 2020. legal-content/EN/TXT/?uri=CELEX%3A52010XC0330(01).
7. Action Plan for Immediate Actions under Existing Medical Accessed 27 April 2020.
Devices Legislation. EC website. http://ec.europa.eu/growth/ • Guidelines on Good Pharmacovigilance Practices (GVP). EMA
sectors/medical-devices/pip-action-plan. Accessed 27 April website. http://www.ema.europa.eu/docs/en_GB/document_
2020. library/Other/2015/04/WC500186216.pdf. 27 April 2020.
8. Commission Staff Working Document Implementation of the • Good Manufacturing Practice and Good Distribution Practice
Joint Plan for Immediate Actions under the existing Medical Compliance. EMA website. http://www.ema.europa.eu/ema/
Devices legislation. EC website. http://ec.europa.eu/transpar- index.jsp?curl=pages/regulation/document_listing/document_
ency/regdoc/rep/10102/2014/EN/10102-2014-195-EN-F1-1. listing_000154.jsp. Accessed 27 April 2020.
Pdf. Accessed 27 April 2020. • The Rules Governing Medicinal Products in the European Union—
9. Commission Implementing Regulation (EU) No. 520/2012 Volume 4: EU Guidelines for Good Manufacturing Practice for
of 19 June 2012 on the performance of pharmacovigilance Medicinal Products for Human and Veterinary Use, Part 1 Chapter
activities provided for in Regulation (EC) No. 726/2004 of 8: Complaints, Quality Defects and Product Recalls (13 August
the European Parliament and of the Council and Directive 2014). EU website. https://ec.europa.eu/health/documents/
2001/83/EC of the European Parliament and of the Council eudralex/vol-4_en. Accessed 27 April 2020.
(Text with EEA relevance). EUR-Lex website. http://

Chapter 11
Falsified Medicines Directive:

Requirements and Implications for
Multi-Stakeholder Healthcare Delivery
Updated by Yolanda García Barruso
OBJECTIVES amending Directive 2001/83/EC on the

□ Introduce the problem of falsified medicines for human use, as regards the prevention of
the entry into the legal supply chain of falsified
□ Define substandard, falsified and counterfeit
medicinal products
medicines
□ Commission Implementing Regulation (EU)
□ Define active substances and excipients
No. 699/2014 of 24 June 2014 on the design of
□ Explain the aims and scope of the Falsified the common logo to identify persons offering
Medicines Directive (FMD) 2011/62/EU and medicinal products for sale at a distance to the
Delegated Regulation (DR) (EU) 2016/161 public and the technical, electronic and cryp-
tographic requirements for verification of its
□ Identify requirements for different stakeholders authenticity
in the medicines supply chain arising from the
FMD □ Commission Delegated Regulation (EU) No.
1252/2014 of 28 May 2014 supplement-
□ Discuss challenges in implementing FMD ing Directive 2001/83/EC of the European
requirements Parliament and of the Council with regard to
principles and guidelines of good manufactur-
□ Identify relevant existing EU initiatives ing practice for active substances for medicinal
products for human use
□ Provide a list of third countries
□ Falsified Medicines Directive (FMD) and
□ Describe the timelines for implementation of
Delegated Regulation (DR) (EU) 2016/161
the FMD
□ Describe the European Medicines Verification

System (EMVS) Introduction
Falsified medicines, as defined by the European
□ Evaluate potential developments in detecting Medicines Agency (EMA), “are fake medicines that pass
and managing falsified diagnostics themselves off as real, authorised medicines.”1 Such med-
icines pose a significant public health risk, as they may
lack active ingredients, contain dangerous contents, con-
DIRECTIVES, REGULATIONS AND GUIDELINES tain incorrect doses or be inappropriately labelled.2 In the
COVERED IN THIS CHAPTER past, the World Health Organization (WHO) used the
term “Spurious/Falsely-Labelled/Falsified/Counterfeit
□ Directive 2011/62/EU of the European (SFFC)” medicines to refer to these products. As of May
Parliament and of the Council of 8 June 2011 2017, WHO had changed its definitions and now refers

Chapter 11
to these products as Substandard and Falsified (SF) Greater nomenclature clarity and consistency was
medicines.3 These medicines comprise up to 1% of mar- required internationally, and the advent of the new
ket value in the developed world, with the global figure WHO term “SF medicines” has in some ways provided
rising to 10%4,5 of a pharmaceuticals market worth more this clarity. Despite this improvement, there still is not
than $300 billion per year.6 Remarkably, estimates of consensus in defining counterfeit and falsified drugs in
the global market value for fake medicines are as high as every country,18 which continues to create difficulty in
$75 billion.7 Pioneering attempts to address this import- global discussions. WHO has attempted to standardise
ant global health issue, the European Parliament and the terminology, and the author recommends the
Council of the European Union adopted the Falsified WHO definitions used herein (Table 11-1) be adopted
Medicines Directive (FMD), Directive 2011/62/EU, worldwide to help facilitate standardisation in both
Delegated Regulation (DR) (EU) 2016/1618 and dele- discussion and policy.
gated acts and regulations.9,10 FMD adoption has been
described as the single largest change in the pharma- Problem Scope
ceutical industry in the last 40 years,11 and resulted from SF medicines are not a new concept; however, the
recognition of the issue’s significance (Figure 11-1).12 advent of the internet and e-pharmacies has augmented
Parallel international efforts include the US Drug Supply their threat. SF medicines’ appearance in international
Chain Security Act (DSCSA). FDA’s requirements, devel- commerce was mentioned first in 1985 at the WHO
opment of standards and the system for product tracing Conference of Experts on Rational Drug Use in
will continue to be phased in until 2023. FDA will Nairobi, Kenya.19,20 Increasing international trade and
continue working with trading partners and other stake- the growth in online pharmaceutical sales has facilitated
holders to effectively implement the requirements.13 entry of SF medicines into the complex supply chain,21
This chapter provides an overview of this signif- eventually leading WHO to establish the International
icant policy, outlines anticipated requirements and Medical Products Anti-Counterfeiting Taskforce
means of execution and discusses implications for mul- (IMPACT) in 2006.22 More than 50% of medicines
tiple stakeholders involved in healthcare delivery. purchased online from illegal sites, which do not reveal
their physical addresses, have been found to be SF med-
Defining Falsified Medicines icines.23 However, SF medicines also may reach patients
Understanding the meaning of “falsified medicines” is via the legal supply chain (Figure 11-2).24
critical to understanding the FMD’s scope. The terms SF medicines often are perceived as a problem
“counterfeit” and “falsified” medicine are often con- largely affecting less economically developed countries
fused and applied incorrectly; counterfeit medicines and high-cost drugs (e.g., the 1985 WHO Conference
“do not comply with intellectual-property rights or Report suggested only high-cost drugs were affected).
infringe trademark law,” whereas falsified medicines are However, the problem actually affects high- and low-
“fake medicines designed to mimic real medicines.”14 cost products, including branded and generic drugs in
This difference and the need for explicit definitions more and less economically developed countries (Table
is emphasised by EMA.15 The FMD defines falsified 11-2). For example, falsified vials of the relatively high-
medicinal products as: cost breast cancer drug Herceptin were confirmed in
“Any medicinal product with a false representation Germany and suspected in Finland, Austria and Sweden,
of: (a) its identity, including its packaging and label- following their theft in Italy. In 2013, 1.2 million doses
ling, its name or its composition as regards any of of the common drug aspirin were seized in France.
the ingredients including excipients and the strength The presence of SF medicines has a straightfor-
of those ingredients; (b) its source, including its ward impact on public health. Some examples of the
manufacturer, its country of manufacturing, its coun- negative implications are the increase in mortality and
try of origin or its marketing authorisation holder; or morbidity, higher disease prevalence, loss of confidence
(c) its history, including the records and documents or progression of antimicrobial resistance. In addition, it
relating to the distribution channels used.” is important to mention that SF medicines also have a
socioeconomic effect, triggering issues such as lost pro-
Note: The definition “does not include unintentional ductivity or economic loss.25
quality defects and is without prejudice to infringe- To attempt to address the problem of falsified med-
ments of intellectual property rights.” Confusingly, icines, the EU adopted the FMD in 2011.
although the two terms clearly are distinct, SF medi-
cines often are referred to collectively as “counterfeits,”
and those producing falsified medicines may be termed
“counterfeiters” (e.g., WHO).16,17

Falsified Medicines Directive: Requirements and Implications for Multi-Stakeholder Healthcare Delivery
Figure 11-1. Comparison of EU FMD and Other Countries’ Falsified Medicines Legislation
EU
1998—A pharmaceutical industry Green US/Worldwide
Paper is published on counterfeiting in
the single market. 1998—Prescription Drug Marketing Act
1980s provides a legal basis for combatting
2000—In Italy, the “Bollini” Law counterfeit medicines.
requires drugs to be tracked to the 1990s
point of sale using two bar codes. 2004—FDA’s Counterfeit Drug
Taskforce sets a framework for rollout
2005—New laws in Greece and Belgium 2000
of an ePedigree scheme by 2007.
compel drug manufacturers to adopt
mass Serialisation. 2001 2005—Despite assurances, market
players make slow progress toward
2006—European Commission warns 2002 deploying tracking technology.
about fake drugs on the internet
and issues resolution on counterfeit 2006—Pfizer works on a proprietary
2003
medicines mass serialisation system, while EPC
looks for an industry standard.
2007—Industry associations, such as 2004
EFPIA, look for standardisation and the 2006—WHO launches the International
adoption of second technology. 2005 Medical Products Anti-Counterfeiting
Taskforce (IMPACT).
2008—European Commission launches 2006
a public consultation on anti-counter- 2007—FDA declares itself disappointed
feiting measures. with ePedigree progress and targets
2007 adoption by 2010.
2008—Responses to the public
consultation are made public. 2008 2008—California publishes
“E-Pedigree Requirements,” which are
2008—Adoption of the proposal for scheduled to go into effect in a phased
2009
the Commission for a Directive of the approach between 2015–2017.
European Parliament and of the Council
2010 2008—FDA looks at technologies for
amending Directive 2001/83/EC.
the ID, validation, track and trace and
2011—Directive 2011/62/EU introduces 2011 authentication of prescription drugs.
EU-wide rules for the importation of
active substances. 2012 2011—California also extends the
deadline for roll-out of its state-level
2011—Commission Implementing scheme from 2007 to 2011.
2013
Decision of 23 January 2013 on the
assessment of a third country’s regula- 2012—Switzerland, Israel, Australia,
2014 Singapore, Brazil and Japon request to
tory framework.
be listed as third countries.
2013—New EU legislation becomes 2015
Aplicable. 2013—US and New Zealand request to
2016 be listed as third countries.
2014 —Good manufacturing and
distribution practices (GMP and GDP) 2015—South Korea request to be listed
2017 as third country.
are to be adopted.
2014—Common logo design for 2018 2018—Canada request to be listed as
legally operating online websites is third country.
implemented. 2019 2019—List of adopted third countries:
2016—Delegate Regulation 2016/161 is Switzerland, Israel, Australia, Brazil,
published. Japon, US and South Korea.
2019—Delegate Regulation 2016/161

becomes aplicable.

Chapter 11
Table 11-1. Definitions of Key Terms in This Chapter
Term Definition Source

Substandard Authorised medical products that fail to meet either their quality stan- World Health
dards or specifications, or both Organization1
Falsified Medicine Medical products that deliberately/fraudulently misrepresent their World Health
identity, composition or source Organization
Counterfeit Any medicinal product that does not comply with intellectual property European Medicines
Medicine rights and/or infringes on trademark law Agency2
1. WHO. Substandard and falsified medical products (http://www.who.int/mediacentre/factsheets/fs275/en/).

2. European Medicines Agency, Falsified Medicines Webpage (http://www.ema.europa.eu/ema/index.jsp?curl=pages/special_topics/general/
general_content_000186.jsp).
Falsified Medicines Directive regulated: medicinal product brokers, who do not han-
Aims and Scope dle products physically. Further, it provides definitions
The FMD amended Directive 2001/83/EC on the for active substances and excipients (Table 11-4) and
Community code related to medicinal products for introduces Good Manufacturing Practice (GMP)
human use26 and aims to tighten medicinal product guidelines for active substances.
distribution chain control and protect consumers from Not all medicines are subject to the FMD’s rules.
falsified medicines. The FMD addresses problems The directive states prescription medicines must bear
arising from the medicines supply chain’s increasing the safety features mentioned above, whereas those
complexity, with the internet being one of the most not subject to prescription shall be exempt from the
significant threats. Controls and checks throughout the requirements. There are exceptions: if risk assessment
supply chain are to be strengthened, including active excludes them, prescription medicines will not require
substances (sometimes also called Active Pharmaceutical safety features and, conversely, nonprescription med-
Ingredients (APIs)) sourced from non-EU countries and icines deemed particularly vulnerable to falsification
the point at which patients receive medication from a will require the features. Risk assessment to determine
pharmacist or delivery via the internet. exceptions include considerations of price, sales volume,
Similar to other introduced legislation in the previous falsification cases in the EU or third coun-
EU, such as the Advanced Therapy Medicinal Products tries, implications of falsification for public health and
(ATMP) Regulation (Regulation (EC) No. 1394/2007), severity of the condition to be treated. Any excepted
one of the FMD’s central aims is harmonisation of fal- medicines must be listed in a delegated act.
sified medicines regulation across the EU. Delegated
acts ensure each Member State implements regulations Directive Implementation
uniformly, ensuring consistency throughout the EU. The Perhaps the most significant regulation imposed in
directive also emphasises falsified medicines are a global the FMD is the requirement for new safety features
problem, and in the interests of global health, coopera- for medicinal product packaging to verify whether the
tion with international bodies is essential with regard to packaging has been tampered with (‘tamper-evidence’),
falsified medicines. to verify the product’s authenticity and to identify an
individual product pack (‘unique identifier’). In a con-
Requirements cept paper released for public consultation in 2011,27
The FMD introduces new requirements for various the European Commission outlined expected require-
stakeholders in medical supply chains, who can be ments for these features, subsequently codified in the
broadly categorised as manufacturers, brokers, whole- FMD Delegated Regulation (DR) (EU) 2016/161.
salers and retailers. These requirements are outlined in For tamper-evidence, the technical specification
Table 11-3. Introducing safety features—mandatory choice is left to the manufacturer, and specific guidance
tamper-evident seals and unique pack identifica- is not given, although CEN standard EN 16679:2014
tion—on packaging provide assurance of medicines’ Tamper verification features for medicinal product packag-
authenticity. The FMD substantially has changed the ing is available for manufacturers to consider. However,
European framework for the supply of medicines, for the unique identifier, specific technical guidance is
and also includes businesses traditionally not directly provided: the only way to uniquely identify a pack is to
label it with a randomised serialisation number affixed

code related to medicinal products for human use25 and from a pharmacist or delivery via the Internet.
aims to tighten medicinal product distribution chain Similar to other recently introduced legislation in
control and protect consumers from falsified medicines. the EU, such as ATMP Regulation (Regulation (EC) No
FMD addresses
Falsified problems
Medicines arisingRequirements
Directive: from the medicines 1394/2007),
and Implications forone of the FMD’s centralHealthcare
Multi-Stakeholder aims is harmonisation
Delivery
supply chain’s increasing complexity, with the Internet of falsified medicines regulation across the EU. Delegated
being one of the most significant threats. Controls and acts ensure each Member State implements regulations
checks throughout the supply chain are to be strengthened, uniformly, ensuring consistency throughout the EU. The
Figure 11-2. Routes in the Medicinal Product Supply Chain by Which Falsified Active Substances may Reach
Patients
Figure 10-2. Routes In the Medicinal Product Supply Chain by Which Falsified Active Substances May Reach Patients
Pharmaceutical Ingredient
Legitimate pharmaceutical Illegitimate manufacturers

manufacturers
Illegal suppliers Illegal online

Wholesalers sales
Retail Legal online

Hospitals pharmacies pharmacies
Key:
Legal route
Illegal route
PATIENTS

to the package by a carrier holding the number. This requirements, and some existed prior to the FMD’s
carrier is a 2-D data matrix, although radio-frequency publication (Table 11-5).
identification also has been proposed previously. The
serialisation number then is checked against its entry in Third Countries
EU Fund 8th ed 10.indd 116 11/6/17 1:26 PM
the repository system, which verifies its authenticity. Under the FMD, countries outside the EU are obliged
For this system to be successful, a reliable veri- to provide written confirmation that active substances
fication system must be in place. Since randomised exported from their country adhere to GMP standards
numbers could be reproduced easily, the serialisation equivalent to those in the EU. Third countries can be
number must be ‘checked in’ to a repository system and added to a ‘white-list’ if the country’s “regulatory frame-
after its final use, removed or ‘checked out’ of the system work applicable to active substances exported to the EU
(Figure 11-3). Such a system would have various ben- and the respective control and enforcement activities
efits, for example, allowing recall of medicines, safety ensure a level of protection of public health equivalent to
messaging, notification of expired or suspicious medi- the [EU].”28 So far, Australia, Switzerland, Japan, the US,
cine and information on previously dispensed medicine, Brazil, Israel and South Korea have been added to the list,
all based on information stored in the serial number and other countries are at various stages in the process
and/or verification system. (Table 11-6). In particular, the assessment will consider:
In addition to those covered in Table 11-3 and 1. GMP rules in the country
made explicit in the FMD, the introduction of unique 2. regularity of GMP compliance inspections
product identifiers may elicit new stakeholders in the 3. effectiveness of GMP enforcement
medicinal product supply chain: those who establish 4. regularity and rapidity of provision of informa-
and maintain the verification systems and reposito- tion regarding noncompliant active substance
ries. Several organisations address unique identifier production29

Chapter 11
Table 11-2. Worldwide Examples of SFFC Medicines From 2008 to Presenta,b
SFFC Medicine Country/Year Report

Meglumine (for Iran and Pakistan, The results of laboratory analysis indicate that the product
leishmaniosis) 2019 was not manufactured in accordance with Good Manufacturing
Practices.
Hepatitis B vaccine Uganda, 2018 The stated manufacturer confirmed that some batches of the
product were falsified based on label inconsistencies.
Penicillin V (antibiotic) Cameroon, 2017 Product being sold in a street market. The stated manufacturer
did not exist, and the label contained spelling mistakes. The
analyses revealed that the tablets did not contain any penicillin
but contained paracetamol instead.
Phenobarbital (for Liberia, 2016 Lack of efficacy (patients treated had increased recurrence of sei-
epilepsy) zures during the course of their treatment with these products)
Meningitis vaccine Niger, 2015 Lot of vaccines and diluent with false batch number, manufactur-
ing date or expiry date
Herceptin (for breast Finland, Germany, Vials initially labelled Herceptin thought to have labels and pack-
cancer) Austria, Sweden, aging tampered with, following theft of vials in Italy. Product not
2014 identified at hospital level, but suspected wholesalers in several
countries.c
Omeprazole (for gastro- Germany, 2013 Fake drugs supplied to wholesale drug distributors that reached
esophageal reflux disease) patients.d
Aspirin (multiple clinical France, 2013 1.2 million doses of fake aspirin seized. Largely consisting of
indications) glucose and containing no active ingredient.
Avastin (for cancer US, 2012 Affected 19 medical practices in the US. Drug lacked active
treatment) ingredient.
Viagra and Cialis (for erec- UK, 2012 Smuggled into the UK. Contained undeclared active ingredients
tile dysfunction) with possible serious health risks to the consumer.
Truvada and Viread (for UK, 2011 Seized before reaching patients. Diverted authentic product in
HIV/AIDS) falsified packaging.
Zidolam-N (for HIV/AIDS) Kenya, 2011 Nearly 3,000 patients affected by falsified batch of their antiret-
roviral therapy.
Alli (weight-loss US, 2010 Smuggled into the US. Contained undeclared active ingredients
medicines) with possible serious health risks to the consumer.
Glibenclamide (anti-dia- China, 2009 Contained six times the normal dose. Two people died, and nine
betic medicine) people were hospitalized.
Seretide Evohaler (asthma) UK, 2009 Batch recalled after information from EU customs office indicated
product was falsified.
Metakelfin (antimalarial) United Republic of Discovered in 40 pharmacies. Drug lacked sufficient active
Tanzania, 2009 ingredient.
Enbrel (rheumatoid UK, 2008 Diverted authentic product in falsified packaging was seized
arthritis) before reaching patients.
a. WHO. Standard and falsified medicines (http://www.who.int/mediacentre/factsheets/fs275/en/).

b. Royal Pharmaceutical Society Policy Statement: Falsified Medicines Directive (http://www.rpharms.com/promoting-pharmacy-pdfs/falsi-
fied-medicines-sept-2013.pdf ).
c. European Medicines Agency alerts EU healthcare professionals after vials of falsified Herceptin identified (http://www.ema.europa.eu/docs/
en_GB/document_library/Press_release/2014/04/WC500165501.pdf ).
d. Jack A. “Teva Discovers Sophisticated Fakes of Popular Drug.” Financial Times (http://www.ft.com/cms/s/0/bd988804-afed-11e2-8d07-
00144feabdc0.html#axzz3Ys9GLBhw).

Table 11-3. Different Medicinal Product Supply Chain Stakeholder Requirements Under the FMD
Multiple • Packagers, repackagers, wholesale distributors, pharmacies/retailers and possibly others must be able to verify
the medicinal product’s authenticity, uniquely identify individual packs and maintain a repository system in
which to store identification data. They must be able to determine whether the outer packaging has been tam-
pered with.
• Active substance importers, manufacturers and distributors established in the EU must register their activity
with the competent authority of the Member State in which they are established.
• Each Member State must ensure the import of active substances from outside the EU, intended for use in the
manufacture of a medicinal product, is accompanied by a written confirmation from the competent authority of
the non-EU country stating standards of manufacture at the active substance manufacturing site are equivalent
to EU requirements.
• The competent authority of the Member State shall ensure legal requirements for manufacturers are met by
inspection of facilities, which may be unannounced. Manufacturers and wholesale distributors are subject to
repeated inspections.
Manufacturer • Any actor in the supply chain that packages medicinal products must hold a manufacturing authorisation.
• Manufacturing authorisation holders who are not the original manufacturers must only remove, replace or
cover the original safety features under strict conditions; if the product is repackaged, safety features must be
replaced by equivalent safety features.
• Manufacturers must inform the competent authority and marketing authorisation holder immediately should the
manufacturer obtain information that medicinal products (manufactured under the scope of the manufacturing
authorisation) may be falsified, regardless of whether those products are being distributed through the legiti-
mate supply chain or by illegal means.
• Active substance manufacturers should be subject to inspections on the basis of risk-analysis, as well as on the
grounds of suspected noncompliance.
• Regardless of whether an active substance is manufactured inside or outside the EU, its manufacture should be
subject to good manufacturing practice (GMP). A legally binding act regarding GMP for active substances has
been introduced.
Broker • Introduction of the brokering concept for finished medicinal products and provision of a new definition for brok-
ering: “All activities in relation to the sale or purchase of medicinal products, except for wholesale distribution,
including physical handling and consisting of negotiating independently and on behalf of another legal or natu-
ral person.”
• Brokers must register with the competent authority of the EEA Member State in which they are established.
Wholesaler • Wholesale distributors should verify their supplying wholesale distributors are holders of a wholesale distribu-
Distributors tion authorisation.
• A person exporting medicinal products from the EU, including those with the sole purpose of exporting medic-
inal products, are considered wholesale distributors and are, as such, subject to relevant provisions and Good
Distribution Practices.
• A list of wholesale distributors complying with EU regulations based on inspection by a competent authority in a
Member State will be published in a database established at the EU level.
Retailers • Companies selling medicines online to members of the public must be authorised and require a common logo to
(Suppliers to the be displayed on their websites (Figure 11-3), which should be linked to the website of the competent authority
Public) for the country in which the retailer is established. Websites of all Member States and of the EMA should explain
use of the logo, and all of those websites should be linked to provide comprehensive information to the public.
• Member States are allowed discretion regarding conditions for the supply of medicines to the public on their
territory.
• Given risks of online retail, Member States may, in principle, restrict sale of medicinal products to pharmacists
alone. However, these restrictions should not unduly restrict functioning of the internal market.
• A list of compliant retailers selling medicinal products at a distance should be provided to the public by each
Member State.
Community • Pharmacies will be required to authenticate medicines at the point of dispensing with an approved
Pharmacies FMDcompliant authentication service to ensure medicines supplied are from legitimate sources with clear distri-
(Independent bution histories.
and Multiple) • In keeping with their role in the community as the medicines experts, they also will be responsible for providing
patient advice concerning queries relating to falsified and counterfeit medicines.
Hospital • Hospital dispensaries may be given special dispensations in certain circumstances with regard to FMD compli-
Dispensaries/ ance, but it generally is understood they, too, will be expected to comply with the majority of FMD requirements.
Pharmacies • Hospital pharmacies may encounter problems with authentication of medicines issued within the hospital and
returned to stock as some medication packs are used for multiple patients and, therefore, multiple pack authen-
tications, which is a problem not experienced by community pharmacies.

Chapter 11
Table 11-4. FMD Definitions of Active Substances and Excipients
Term EU FMD Definition

Active Any substance or mixture of substances intended to be used in the manufacture of a medicinal prod-
Substance uct and when used in its production, becomes an active ingredient of the product intended to exert a
pharmacological, immunological or metabolic action with a view to restoring, correcting or modifying
physiological functions or to make a medical diagnosis.
Excipient Any constituent of a medicinal product other than the active substance and packaging material.
With this legislation, the EU aims to protect its Broadly summarising the regulation:
Member States, but also supports recognising equiva- • Personnel and equipment in the manufactur-
lent science-based standards worldwide, helping protect ing area’s vicinity must be sanitary.
the public better and providing a greater level of protec- • To prevent cross-contamination when produc-
tion on a wider international scale. ing active substances harmful to human health,
those substances should be manufactured
GMP for Active Substances only in separate areas; for active substances
Commission Delegated Regulation (EU) No. with potential to be harmful to human health
1252/2014 supplements Directive 2001/83/EC of the due to potency, toxicity or infectiveness, risk
European Parliament and the Council with regard to assessment must be undertaken to evaluate the
principles and guidelines of GMP for active substances potential need for separate production areas.
for medicinal products for human use.30 Continuing • Detailed written records of production pro-
with one of the FMD’s central aims, the regulation cesses must be kept, and any changes affecting
strives to promote use of harmonised standards at the active substance’s quality should be com-
a global level, developing guidelines aligning with municated to manufacturers using the active
those established by the International Council on substance.
Harmonisation (ICH). • Procedures must be in place allowing product
recall and investigation of concerns over active
substance quality.
Figure 11-3. An Example of the Common Logo Online • If the manufacture of any part of an active
Retailers of Medicines Must Display substance is entrusted to another party, respon-
sibilities of the other party in terms of GMP
quality compliance must be clarified in writing.
• GMP must be applied to the repackaging and
relabelling process.
Description of the Implementation Process

The FMD was published in the Official Journal of the
European Union (OJ) 1 July 2011. This mandated all
Member States to transpose legislation into national law
by the end of January 2013, with full compliance man-
dated within three years of the publication of the FMD
delegated acts in the OJ.31 Delegated acts were expected
in mid-2015; however, they were delayed. Although they
have been published and were slated for discussion, the
delay between publication of the FMD and the dele-
gated acts was criticised.32,33. The Delegate Regulation
2016/161 was published in the OJ on 9 February 2016
The flag corresponds to the Member State in which the retailer is reg-
istered. Only EU Member State national flags are allowed, as well as and became applicable on 9 February 2019.
those of Norway, Iceland and Lichtenstein. By clicking on the image, Safety features introduced required substantial
the purchaser is directed to the entry of the retailer on the national medicinal product packaging manufacturing process
list. Commission implementing regulation (EU No. 699/2014 details adaptations. As such, the FMD stated the timeline for
the requirements for the logo. (Image Source: http://ec.europa.eu/
health/human-use/eu-logo/index_en.htm). implementing provisions relevant to safety features must

Table 11-5. EU Initiatives Relevant to the FMD
European Stakeholder Model

European Stakeholder Model (ESM) is a partnership of organisations involved in the pharmaceutical supply chain,
overseen by a not-for-profit stakeholder organisation called the European Medicines Verification Organisation (EMVO).
The ESM’s aim is to develop a safe, cost-effective and partnership-based pan-European medicines verification system
using 2-D barcodes to address FMD needs. ESM partners are establishing a coding and serialisation system to be
implemented by Europe’s research-based manufacturers, licensed parallel distribution companies, wholesalers and
pharmacists. Their approach was tested at a national level in Sweden.
eTACT: Anti-Counterfeiting Traceability Service for Medicines

eTACT is the European Directorate for the Quality of Medicines and Healthcare (EDQM) anti-counterfeiting traceability
service for medicines. The project has been developed in parallel to the FMD and is part of the Council of Europe’s
global strategy to combat SFFC medicines. eTACT’s aim is to ensure traceability of individual packs of medicines using
mass serialisation.Similar to safety features introduced by the FMD (mandatory seals and unique pack identification),
it is based on the principle of generating a Unique Medicine Identifier (UMI) at the manufacturing stage. UMI allows
traceability and verification by different stakeholders in the legal supply chain. It is designed in accordance with the
FMD’s requirements and its future delegated acts.
ASOP EU
Alliance for Safe Online Pharmacy (ASOP EU) comprises patient organisations, internet intermediaries, healthcare
providers, pharmaceutical companies and supply chain stakeholders united in a campaign to make the internet a safer
place to obtain medicines. It aims to become a trusted partner of the authorities in combatting the illegal sale of medi-
cines online.
be sufficiently long to allow manufacturers to adapt in particular regarding internet sales. As such, Member
their manufacturing processes effectively. Some Member States and the European Commission are encourag-
States had authentication or verification systems in ing cooperation and supporting ongoing international
place, and they were given additional time to adapt efforts on falsified medicines. In line with this, and “to
to the harmonised EU system. Several EU initiatives promote the use of harmonized standards at a global
emerged or exist already with relevance to various FMD level,” a delegated regulation regarding GMP for active
components, including the unique identifier and, more substances35 adopted guidelines in agreement with
generally, combatting illegal drug sales via the internet. those established by ICH. If other worldwide regulatory
With the aim to facilitate the implementation of bodies act similarly and standardise terminology as sug-
the delegated regulation, the European Commission gested above, the battle against falsified medicines will
Directorate published “Safety features for medicinal prod- be greatly accelerated and facilitated.
uct for human use-question and answers.” Despite these positive steps, many perceive FMD
Additionally, as stated above, some Member implementation as a challenge. Costs for affected
States—including Belgium, Italy and Greece—were actors in the medical product supply chain likely will
given the option to defer the application of the rules be considerable, particularly regarding new safety fea-
until February 2025. However, Belgium formally ture requirements and accompanying systems; some
renounced using this option. have expressed concerns these costs will make some
Currently, Member States are continuing to medicines unaffordable and could impact parallel trade
develop additional guidance to reinforce and provide negatively, particularly given they often are repack-
instruction on different aspects of implementation of aged.36 Complex information transfer required for
the directive. Guidance at the national level is continu- FMD compliance will necessitate substantial changes
ally emerging. For example, the UK published guidance to current system infrastructures, and ensuring these
for the implementation of the FMD as it applies to changes are harmonised throughout the EU will be
vaccines in July 2019.34 essential to successful implementation.
This chapter has discussed implications for multi-
Implications and Challenges ple stakeholders in the medicinal product supply chain
Addressing falsified medicines ultimately requires global affected by the FMD. However, ultimately, the most
cooperation. The FMD recognises the need for con- important stakeholder affected by the directive is the
certed international effort against falsified medicines, patient, and issues with implementation costs likely

Chapter 11
Table 11-6. Status of Third Country Listing Requests
Country Request Date Status, Publication Date in the Official Journal of the European Union
(if adopted)
Switzerland 4 April 2012 Adopted 22 November 2012
Israel 9 May 2012 Adopted 1 July 2015
Australia 18 September 2012 Adopted 24 April 2013
Singapore 17 September 2012 No listing for the moment (relevant Singapore legislation provides for a
non-mandatory GMP certification scheme). Contacts ongoing. In the mean-
time, Singapore has issued written confirmation.
Brazil 4 October 2012 Adopted 1 July 2015
Japan 6 December 2012 Adopted 4 June 2013
US 17 January 2013 Adopted 11 June 2013
New Zealand 26 June 2013 Assessment on hold pending clarification of scope of existing MRA
South Korea 22 January 2015 Adopted 14 May 2019
Canada 1 October 2018 Equivalence assessment ongoing
Source: https://ec.europa.eu/health/international_cooperation/pharmaceuticals/Importation_activesubstances_en
will be outweighed by patient benefits. Beyond the particularly in primary and secondary care pharmacies,
clear benefits of reducing the prevalence of falsified initially may be burdensome, generation of primary bene-
medicines, there is considerable scope for wide-reach- fits—reduction in falsified medicines and reimbursement
ing impact. In particular, adopting unique identifiers fraud and tighter control of active pharmaceutical ingre-
and verification/repository systems could allow other dients—likely will be swift. Secondary benefits, including
health-related issues to be addressed: data generated reduced dispensing errors, opportunity for patient
could be used to measure and characterise patient engagement, providing information about medicines
behaviour with regard to medicine, aid communication and supporting optimal adherence, electronic informed
between pharmacy and patient and allow development consent, real-time pharmacovigilance and business intel-
of tools to communicate with and support patients ligence, are trackable and impactful.
directly (Figure 11-4). Preventing falsified medicines and realising the
Although other legislation aims to combat falsi- FMD’s secondary benefits are not just legal require-
fied medicines’ trade worldwide (e.g., the Drug Quality ments; they are healthcare professionals’ responsibilities
and Security Act, H.R. 3204 in the US), with the FMD, at all stages of the lifecycle37 to safeguard patient safety
the EU is leading an ambitious attempt to develop a and improve patient outcomes.
harmonised approach to tracking and labelling safe And last but not less it is remarkable the contin-
medicines and ensuring falsified medicines do not reach uous efforts made, and the role played by WHO at
patients by authentication at the dispensing point. The worldwide level in this instance. The WHO Global
FMD applies directly to the EU; however, by promot- Surveillance and Monitoring System (GSMS) for
ing standardisation more broadly, patients throughout substandard and falsified medical products is a collab-
the world may benefit. While inevitably introducing orative system in which any suspicion of SF medicines
costs and challenges to the medicinal product supply is systematically reported to the National Medicines
chain, this historic regulation is an essential step toward Regulatory Authorities. The NMRAs assess the infor-
a world free of falsified medicines and should be per- mation and through nominated contacts (referred to as
ceived as such. NMRA Focal Points) reports to WHO’s surveillance
Ultimately, the problem of falsified medicines is and monitoring database.
a major risk to patient safety, damaging public trust in Immediate technical assistance, alerts, validated
healthcare and the pharmaceutical industry—reduc- reports, procedures, processes, etc., are provided. This sys-
ing revenue available to reinvest in R&D efforts to tem improves the quality of reporting of SF and ensures
address unmet medical needs. While investment in data are collected and analysed properly.38 During 2019,
requisite manufacturing and distribution infrastructure, there were 11 alerts of falsified medical products.39

medicines. It aims to become a trusted partner of the authorities in combatting the illegal sale of medicines online.
Switzerland, Japan, the US, Brazil and Israel have been 2. regularity of GMP compliance inspections
Falsified Medicines
added to the Directive:
list, and other countries Requirements
are at various stagesand Implications for Multi-Stakeholder
3. effectiveness of GMP enforcement Healthcare Delivery
in the process (Table 10-6). In particular, the assessment 4. regularity and rapidity of provision of informa-
will take into account: tion regarding noncompliant active substance
1. GMP rules in the country production29
Accompanying Verification and Repository Systems
Figure 10-4. Flowchart Representing Product and Information Flow With Unique Product Identifiers and Accompanying
Verification
Accompanyingand Repository Systems
Verification and Repository Systems
Direct to Pharmaist Messaging
1. Recall
2. Safety messaging
3. Expired medicine
4. Suspicious medicine
5. Medicine dispensed previously KEY
Patient Related Messages
1. Adherence support Product transfer
2. Patient information
Parallel Trader(s)
Supply Chain Inputs Distributor(s) 3. Electronic Informed constant Information transfer
(Re-packages)
1. (Bio) Pharmaceutical Com- 4. Cross selling
panies
2. Generic Manufacturing
3. Tools and Technology Suppliers
4. Contract Manufacturing
Organizations
5. Parallel trader (Re-packages) Pharmacies
1. Hospital
2. Community/retail
Manufacter(s) Wholesaler(s) 3. Independent Patient(s)
4. Dispersing clinicians
5. Inherent
Serial Number Verification

Potential Direct to Patient Messaging
(Using Pharmiscist to sign up)
1. Health communication organization
2. Commuity health provider
3. Disease specific foundations
4. Patient advocates
5. Payers
Unique partialization of tamper Serial Number Upload Serial Number

Authentication and “check out”
resistant packaging with random “Check-In” National Authentication
of serial number after dispersing
numbers Medicines Verification Resposi-
to patients
tory
Regular meetings are held by the WHO Member European Medicines Verification Organisation
State mechanism on substandard and falsified medical (EMVO)
products to continuously develop mechanisms to the EMVO is a nonprofit organisation representing stake-
EU Fund prevention,
8th ed 10.indd 120 detection and response to substandard and 11/6/17 1:26 PM
holders united in securing the legal supply chain from
falsified medical products. During the October 2019 falsified medicines. EMVO is primarily responsible
meeting, a variety of activities and initiatives were out- for setting up and running the European Hub, where
lined and discussed.40 pharmaceutical companies upload the unique identifier
for each pack. The European Hub serves as the central
The European Medicines Verification database and router for the EMVS and connects all
System (EMVS) national systems together.
This chapter has widely discussed the requirements, EMVO also assists with connecting On-Boarding
implications and challenges of the FMD. However, it Partners (OBPs) to the European Hub. The OBPs
is important to highlight the necessity of developing are pharmaceutical companies and parallel importers
and building a complex system to ensure the practical who upload their data to the European Hub. Thus, the
implementation of all the precepts in the FMD. European Hub serves as a gateway for the transmission
The European Medicines Verification System of manufacturers ‘and parallel distributor’s data to the
(EMVS) is in place in the EU to prevent falsified national systems.’
medicines entering the legal supply chain. This system It is important to address the difference between
connects 28 EEA countries and guarantees medicines’ a Marketing Authorisation Holder (MAH) and an
authenticity by an end-to end verification. OBP. Under the architecture of the EMVS, an MAH
The structure of the EMVS is divided into or a group of MAHs can connect to the European Hub
the European level, represented by the European via OBP. An OBP is a legal entity, set up in order to
Medicines Verification Organisation (EMVO) and the connect with and upload data to the European Hub, on
national level, represented by each national Medicines behalf of a single/more than one MAH(s).
Verification Organization (NMVO).

Chapter 11
National Medicines Verification Organisations to potential legislation to identify and control falsified
(NMVOs) devices are ongoing among international regulators,
NMVOS are responsible for establishing and operating positive synergies between the FMD and the forthcom-
a national system in their territory, which connect to the ing EU Falsified Device Directive (EU FDD) should not
Hub on one end, and to all the end-users (pharmacies, be overlooked, nor should potential complexity in their
hospital, etc.) on the other end.41-43 parallel implementation and enforcement.
References
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peutic. Finally, and more futuristically, combinational fied medicinal products. Off J Eur Union. 8 June 2011. EUR-Lex
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11. Elvidge S. “The Falsified Medicines Directive—What Does It
Really Mean?” Life Science Leader. Life Science Leader website.
Companion Diagnostics http://www.lifescienceleader.com/doc/the-falsified-medi-
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Stergachis A. “Technologies for Detecting Falsified and
trial pipelines. Presently, only the therapeutic compo-
Substandard Drugs in Low- and Middle-Income Countries.”
nent of the treatment will be protected against SFFC PloS One. 2014;9(3):e90601.
by FMD-mandated safety features. However, there 13. https://www.fda.gov/drugs/drug-supply-chain-security-act-
is an incentive to falsify the companion diagnostic— dscsa/are-you-ready-drug-supply-chain-security-act. Accessed
27 April 2020.
which can command a high reimbursement level akin
14. European Medicines Agency. Falsified Medicines. EMA web-
to some high-cost small molecules—both to generate site. http://www.ema.europa.eu/ema/index.jsp?curl=pages/
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also potentially by generating a deliberate false posi- April 2020.
15. Ibid.
tive to stimulate sales of legitimate and/or counterfeit
16. Op cit 4.
therapeutics. Therefore, while discussions pertaining

17. WHO. General Information on counterfeit medicines. WHO 33. O’Donnell P. EU Patients Will Wait Years for Counterfeit Med
website. http://www.who.int/bulletin/volumes/88/4/10-020410/ Fix. Politico 2015. Politico EU website. http://www.politico.
en/. Accessed 27April 2020. eu/article/eu-patients-will-wait-years-for-counterfeit-med-fix/.
18. Ibid. Accessed 27 April 2020.
19. Ibid. 34. Guidance for recipients of PHE supplied vaccines and other
20. WHO. The Rational Use of Drugs: Report of the Conference of medicines under the EU Falsified Medicines Directive 2011/60/
Experts, Nairobi, 25–29 November 1985. WHO website. http:// (FND) and Delegated Regulation ((EU) 2016/161), July 2019.
apps.who.int/medicinedocs/documents/s17054e/s17054e.pdf. 35. Op cit 30.
Accessed 27 April 2020. 36. Op cit 11.
21. Op cit 4. 37. Black N. “The Cooksey review of UK health research funding.”
22. WHO International Medical Products Anti-Counterfeiting BMJ. 2006;333(7581):1231.
Taskforce—IMPACT. WHO website. http://apps.who.int/med- 38. WHO Global Surveillance and Monitoring System for
icinedocs/en/d/Js20967en/. Accessed 27 April 2020. Substandard and Falsified Medical Products
23. Op cit 4. 39. Full List of WHO Medical Product Alerts. WHO website.
24. Op cit 6. https://www.who.int/medicines/publications/drugalerts/en/.
25. WHO. A Study on the Public Health and Socioeconomic Accessed 27 April 2020.
Impact of substandard and falsified medical products. WHO 40. WHO. Report of the eighth meeting of the Member State
website. https://www.who.int/medicines/regulation/ssffc/publi- mechanism on substandard and falsified medical prod-
cations/SE-Study_EN_web.pdf ?ua=1. Accessed 27April 2020. ucts. WHO website. https://apps.who.int/gb/SF/pdf_files/
26. Directive 2001/83/EC of the European Parliament and of the MSM8/A_MSM8_4-en.pdf. Accessed 27 April 2020.
Council on the Community code relating to medicine products 41. The European Medicines Verification System (EMVS)
for human use. Off J Eur Union (Internet), 2001. EC website. explained: The European Medicines Verification Organisation
http://www.ema.europa.eu/docs/en_GB/document_library/ (EMVO). EMVO website. https://emvo-medicines.eu/new/
Regulatory_and_procedural_guideline/2009/10/WC500004481. wp-content/uploads/The-European-Medicines-Verification-
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27. Directive 95/46/EC of the European Parliament and of the 42. EMVO press release: The European Medicines System (EMVS)
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1995. EUR-Lex website. http://eur-lex.europa.eu/LexUriServ/ EMVS-1-year-press-release_07022020.pdf. Accessed 27 April
LexUriServ.do?uri=CELEX:31995L0046:en:HTML. Accessed 2020.
27April 2020. 43. The European Medicines Verification Organisation:
28. European Commission. Commission Implementing Decision: Organisation and Structure. EMVO website: https://
on the assessment of a third country’s regulatory framework emvo-medicines.eu/mission/emvo/. Accessed 27 April 2020.
applicable to active substance of medicinal products for human 44. Brindley DA, Rakhi R, Fuerstenau-Sharp M, Kantoff P,
use and of the respective control and enforcement activities pur- Hollander G, Smith JA, et al. “The Potential Application
suant to Article 111b of Directive 2001/83/EC of the European of Real-Time Release Testing for the Biomanufacture of
Parliament and of the Council. Off J Eur Union (23 January Autologous Cell-Based Immunotherapies.” BioProcess Int.
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29. Op cit 8.
30. Commission Delegated Regulation (EU) No. 1252/2014 sup- Recommended Reading
plementing Directive 2001/83/EC of the European Parliament • Regulation (EC) No. 1394/2007 of the European Parliament
and of the Council with regard to the principles and guidelines and of the Council of 13 November 2007 on advanced therapy
of good manufacturing practice for active substances for med- medicinal products and amending Directive 2001/83/EC and
icine products for human use. Off J Eur Union, 28 May 2014. Regulation (EC) No. 726/2004 (Text with EEA relevance).
EC website. http://ec.europa.eu/health/files/eudralex/vol-1/ http://www.legislation.gov.uk/eur/2007/1394/contents#.
reg_2014_1252/reg_2014_1252_en.pdf. Accessed 27 April Accessed 27 April 2020.
2020. • European Committee for Standardization (CEN) EN
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32. Taylor NP, European Regulatory Roundup: Commission Under product packaging.” https://standards.globalspec.com/std/9892212/
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RAPS website. http://www.raps.org/Regulatory-Focus/ • European Commission Directorate. “Safety features for medic-
News/2015/07/02/22832/European-Regulatory-Roundup- inal product for human use-question and answers.” Questions and
Commission-Under-Fire-for-Delay-in-Implementing- Answers Version 17. February 2020. https://ec.europa.eu/health/
Falsified-Medicines-Legislation-2-July-2015/. Accessed 27 sites/health/files/files/falsified_medicines/qa_safetyfeature_en.pdf.
April 2020. Accessed 27 April 2020.

Chapter 11

Chapter 12
Regulatory Strategy
Updated by Karen Fan, MSc, PEng, RAC
OBJECTIVES Introduction
In the definitive Harvard Business Review article on
□ Learn how to define regulatory strategy strategy, Michael E. Porter defines strategy as the
□ Understand how to develop and implement a creation of a unique and valuable position involving a
regulatory strategy specific set of activities.1 It involves not only creating
a high-level plan to achieve one or more goals under
□ Get to know the information available to help conditions of uncertainty but also creating “fit” and
develop a regulatory strategy alignment among a company’s activities. Strategy is
important because the resources available to achieve the
□ Understand which key considerations need to necessary competitive advantage are usually limited.
be addressed during development and lifecycle
management Regulatory Strategy
Regulatory strategy specifically aligns the regulatory
activities required with the business strategy, to bring
DIRECTIVES, REGULATIONS AND GUIDELINES a new or modified product to market in the desired
COVERED IN THIS CHAPTER regions within the desired timeframes. It also provides
overall direction to the project team by defining the key
□ Regulation (EU) 2017/745 of the European
regulatory components and proactively identifies the
Parliament and of the Council of 5 April 2017
challenges as well as alternative approaches to the cho-
on medical devices, amending Directive
sen development pathway.
2001/83/EC, Regulation (EC) No. 178/2002 and
In addition, regulatory strategy anticipates issues
Regulation (EC) No. 1223/2009 and repealing
and concerns with regulatory authorities and stake-
holders. It defines key programme milestones, often
□ Regulation (EU) 2017/746 of the European considered business catalysts driving both investor
Parliament and of the Council of 5 April 2017 interest and financing.
on in vitro diagnostic medical devices and
repealing Directive 98/79/EC and Commission Regulatory Strategy—Market
Decision 2010/227/EU Considerations
Regulatory professionals need to understand what the
□ Rules governing medicinal products in the company wants to achieve before developing the regu-
Europe Union: Medicinal Products for Human latory strategy. Questions such as the following should
and Veterinary Use list both pharmaceutical be asked:
legislation (Volumes 1 and 5) and various guid- • What is the business objective?
ance documents (Volume 2–4 and 6–10) • What business problem will the product solve?
• What are the competitor products?

Chapter 12
• Upon which regulatory pathways have com- and performance requirements checklist at the end of
petitor products embarked? the medical device development process only to find
that additional nonclinical or clinical studies need to be
This regulatory intelligence data will help key stake- conducted to support the product claims; the company
holders and decision-makers identify the product should plan early and consider all its options before
features and attributes on which they want to focus in proceeding with the programme.
the project scope. In the long run, developing a strategy and imple-
Another key aspect of the regulatory strategy is the menting it will save time and money and focus the
assessment of the marketplace opportunities. development or project team.
• What are the specific needs in each of the 27 Good regulatory strategy cannot not be created
EU Member States? in a vacuum and often requires balancing competing
• How big is the market in the remaining priorities; a cross-functional project team should be
European Economic Area (EEA), such as assembled, representing regulatory, marketing, medical/
Iceland, Liechtenstein or Norway? clinical, engineering, usability, reimbursement, man-
• What are the specific considerations in ufacturing, quality and/or other functions within the
Switzerland, which is neither an EU nor an company. Outside experts may be needed from partner
EEA member?2 companies, key suppliers or consultants.
• What are the implications of Brexit on the Table 12-1 depicts key questions from a product
UK? The Medicines and Healthcare products development perspective. Additional operational, com-
Regulatory Agency (MHRA) provides current pliance and promotional considerations are detailed
guidance and publications3 on the situation below.
and indicates the new transition rules will take • Major regulations and directives
effect on 1 January 2021.4 o What are the key regulations that apply?
o Does the product meet the definition of a
The EU MDR (2017/745) refers to national law and medical device, medicinal product, combi-
provisions in multiple places, including the role of nation product or another type of product?
national competent authorities. o Are there timelines that may differ
• What national requirements will impact depending on the product functionality?
product development (e.g., requiring instruc- For medical devices, for example, a four-
tions for use or software interfaces in specific year exemption in the application of the
languages)? EU MDR may apply even though the EU
• What are the regulatory application fees? MDR (2017/745) entered into force on 26
• Have translation costs been factored in? May 2020.5
• What are the reimbursement strategies for • Conformity assessment
each country and/or region? o Is a notified body required to be involved?
• Do any of the countries require another o Has the notified body been designated
country’s prior approval, which could impact under the required legislation? A list
approval staging or timing? of the bodies designated under the EU
• Is the potential revenue in a target market sig- MDR (2017/745), for example, can be
nificant enough to justify the costs of pursuing found on the New Approach Notified and
regulatory approval for that country/region? Designated Organisations (NANDO)
Information Systems website.6
Developing and Implementing a o Is the desired notified body accepting new
Regulatory Strategy clients?
As the old adage says, “If you fail to plan, you can plan o Does the notified body have auditors
to fail.” Implementing a strategy allows a company to available to approve technical documen-
map its path forward and examine the potential pitfalls tation and assess the quality management
and mitigate any risks, challenges or issues the new or system within the desired time to market
revised product might face. timelines?
Small companies tend to plan to fail by not recog- • Economic operators
nising the value of strategic planning. They may claim o Have manufacturers, authorised represen-
to be “too busy” to put together an overall strategic plan. tatives, importers and distributers been
For example, a company may prepare the general safety identified?
o Have formal agreements been put in place?

Regulatory Strategy
Table 12-1. Regulatory Key Questions During Development
Key Area Considerations for EU Development Program

Intended Use • What are the proposed indications for use?
• What is the target patient population(s) and/or anatomical site(s)?
• What is the use environment (e.g., ICU, surgical suite, office setting, home)?
• Is it intended for prescription or over-the-counter use?
• Could the product qualify for expedited review or humanitarian use designation?
Description • What features are proposed for marketing?
• Which characteristics could be significant from a regulatory perspective?
• Are there any device accessories, and will they require approval/clearance?
Claims • Are there unique claims for which regulatory approval is required (or desirable)?
• It often is possible to secure a competitive advantage by carefully planning and obtaining
the data necessary to support desired claims.
Lifecycle Issues • What short- and long-term changes are anticipated?
• How might these changes impact the regulatory strategy, e.g., require a staged approach,
with approval of one generation of device building off another?
• Will older generations of the device be removed from the marketplace?
Device Classification • How does the device meet the definition of a medical device?
• Is the device invasive?
• Is the device an active device?
• Is the device software?
• Will the device be supplied sterile?
• Are there special classification rules for specific types of products?
• Is the product for prescription use only?
Harmonized • What are the harmonized standards and common specifications applicable to the
Standards product?
and Common • Are there other ways to demonstrate compliance with the applicable legal obligations?
Specifications
Clinical Evaluation • For medical devices, consider:
and Clinical o What are requirements for literature review and analysis?
Investigations o Will equivalence be demonstrated for existing CE-marked devices?
o Is clinical investigation required?
o What are the requirements for informed consent?
• For drugs, consider:
o What are the requirements for informed consent?
o What are the roles of the ethics committees?
o What is required for regulatory approval and notification for trial initiation, trial con-
duct, and trial suspension?
o Have clinical supply manufacturing been considered?
o What are the requirements for adverse event reporting and serious adverse reaction
notification?
Packaging and • Device labelling on the outer package and instructions for use must meet certain require-
Labelling ments. Also, all medical devices must contain a statement about any time limitations on
their safe use.
• For drugs, labelling requirements are controlled at the national level.
Technical • Have the general safety and performance requirements been considered?
Documentation • Have the clinical evaluation requirements been considered?
• Have substantially equivalent devices been identified?
• Have the clinical investigation requirements been considered?
Technical • Have the postmarket surveillance plan requirements been considered?
Documentation— • Have the Periodic Safety Update Report (PSUR) requirements been considered?
Postmarket • Have the postmarket clinical follow-up (PMCF) requirements been considered?
Surveillance

Chapter 12
• Quality management system Once the basics are established, the team should “peel
o Has a person responsible for regulatory the onion” to make sure it understands any subtleties
compliance been identified? that may have regulatory impact.
o Has a quality plan been established for
both premarket activities and postmarket Information Available to Help Regulatory Strategy
activities? Development
o Have standard operating procedures been The European Commission provides a range of guid-
defined? ance documents adopted by the Medical Device
o How will economic operators communi- Coordination Group (MDCG) to assist stakeholders
cate required information to EU Member implementing the EU MDR (2017/745).8 These legally
States? Consideration should be given to non-binding guidance documents have the objective of
device registration, clinical investigations ensuring uniform application of the relevant provisions
and postmarket surveillance requirements of the regulations within the EU. The guidance docu-
for medical devices, in light of the news ments include documents pertaining to Unique Device
that the European database on medical Identifiers (UDI), qualification and classification of
devices (Eudamed) will not be launched software, cybersecurity and summary of safety and clini-
until May 2022.7 cal performance.
• Marketing Authorisation procedure While the MDCG continues to work on new
o For medical devices, CE marking is the guidance documents, the MEDDEVs can be considered
only prerequisite to placing products on for their background information on the most recent
the market. It is necessary to communi- consensus reached on various matters. The MEDDEVs
cate with the national authorities when were developed for the now repealed Council Directives
placing medical devices on the market, 90/385/EEC and 93/42/EEC. Details can be found on
as additional requirements like local the European Commission website.9
language requirement, etc., might be While the European Committee for
applicable. Please see Chapter 14 The EU Standardisation (CEN) and the European Committee
Medical Devices Legal System for more for Electrotechnical Standardization (Cenelec) draft
information. revisions to their existing standards, adapt others and
o For medicinal products, there are issue newly harmonised standards in support of EU
four marketing authorisation routes: MDR (2017/745) and EU IVDR (2017/746),10 the
the National, Mutual Recognition, current list of harmonised standards published in the
Decentralised and Centralised Procedures. Official Journal of the European Union can be found on
For more details on these procedures, the European Commission website.11 These harmonised
please refer to Chapter 3 Overview of standards provide insight into the current thinking on
Drug and Biologic Regulatory Pathways. the matter and the state-of-the-art.
• Promotion and advertising The European Medicines Agency’s (EMA)
o Most regulated countries do not allow website12 provides information on the regulation of
advertising until products are registered. medicines for human and veterinary use in the EU
o Marketing claims must match those in the to help applicants prepare marketing authorisation
clinical trial and technical documentation. applications. The legal framework governing medicinal
o For drugs, this is controlled at the products for human use in the EU13 is based on the
national level. International Federation principle that the placing on the market of medicinal
of Pharmaceutical Manufacturers products is subject to a competent authority granting a
Association and European Federation of marketing authorisation.
Pharmaceutical Industries and Association
codes cover advertising and promotion to Documenting Regulatory Strategy
healthcare professionals, behavior of sales “If it isn’t documented, it doesn’t exist.” There are many
representatives, supply of samples, spon- reasons to document a strategy in a sort of “playbook”
sorship of meetings and participation by for the team. The team is being asked to think critically
healthcare professionals including travel about all the factors that go into medical device or
expenses. For more details, please refer to medicinal product development, not just their small seg-
Chapter 9 Advertising and Promotion. ments of the process. By seeing the whole picture, people
understand how their portions affect the strategy.

Regulatory Strategy
Constructing a formal written analysis of the reg- • externally driven changes, such as new regu-
ulatory strategy provides a reference to why a decision latory requirements or guidance or competent
was made at a particular juncture in the development authority action on similar products
timeline, so new team members understand the whole
picture. In addition, it can serve as the foundation docu- Conclusion
ment for any future updates. A solid regulatory strategy is one of the foundations
Thus, the process of putting together a regulatory upon which successful medical product development is
strategy does not need to take months or a year to based. The company should start by asking a broad range
complete. Regulatory can provide the research, infor- of questions to ensure it has a solid understanding of the
mation and intelligence, and come to the table with a product and marketing plans, especially any subtleties
reasonable working draft for team discussion (which that may have regulatory impact. Regulatory intelligence
might take a month or two), but once the initial draft should be used to obtain as much information as possi-
is done, the team can sit down and focus on the task at ble about the regulation of similar or related products.14
hand and leave competing interests outside the room Being practical and realistic when developing the
to develop the first team draft strategy. Participating in strategy helps attain the “must haves,” but strategies to
strategy development also requires the team to act and stretch for the “nice to haves,” too, is important. The
agree, so everyone can stand behind the decisions made. strategy should be validated by internal and external
stakeholders, and where appropriate, notified body and
Confirming the Strategy regulatory authority personnel. Finally, it is critical to
It is almost always prudent to confirm the proposed watch product development and the regulatory envi-
strategy is sound (likely to be effective), practical (rea- ronment closely and be ready to revise the strategy as
sonable and efficient) and addresses company objectives. necessary.
The draft strategy should be circulated for cross-func-
tional team review. Despite care taken up front to References
1. Porter M P. Chapter 1: What is Strategy? HBR’s 10 Must
fully understand the programme, it is possible a key Reads On Strategy. Harvard Business School Publishing
point was missed or perhaps more likely, a change has Corporation. 2011.
emerged since the initial meetings. Feedback from oth- 2. Countries in the EU and the EEA. UK Government website.
ers in the company, trusted colleagues or advisors can https://www.gov.uk/eu-eea. Accessed 18 March 2020.
3. Medicines and Healthcare products Regulatory Agency Services
further vet the strategy. and Information. UK Government website. https://www.gov.
Finally, for many programmes, particularly if the uk/government/organisations/medicines-and-healthcare-prod-
product is novel or the data required are expected to ucts-regulatory-agency/services-information. Accessed 18
be extensive, it is wise to contact the notified body or March 2020.
4. The UK has Left the EU: Transition Period. UK Government
the regulatory authority to refine and/or redirect the website. https://www.gov.uk/transition. Accessed 18 March
strategy as appropriate. In general, contact is desirable 2020.
as soon as there is enough information available for a 5. Second Corrigendum to Regulation (EU) 2017/745 of the
meaningful discussion but before the company moves European Parliament and of the Council of 5 April 2017 on
medical devices. European Commission website. https://data.
too far ahead or commits significant resources. consilium.europa.eu/doc/document/ST-13081-2019-INIT/en/
pdf. Accessed 18 March 2020.
Be Prepared for Changes 6. Notified Bodies designated to Regulation (EU) 2017/745
on medical devices. European Commission website. https://
Even the most diligently developed strategy is almost ec.europa.eu/growth/tools-databases/nando/index.cfm?fuse-
certain to change in at least some respect during the action=directive.notifiedbody&dir_id=34 Accessed 18 March
course of product and regulatory development. A 2020.
schedule should be established to review and update 7. European database on medical devices (Eudamed). European
Commission website. https://ec.europa.eu/growth/sectors/
the strategy periodically with the team. If the product medical-devices/new-regulations/eudamed_en. Accessed 18
development cycle is short but intense, weekly checks March 2020.
might be needed; but for most products, a quarterly 8. Medical Device Coordination Group (MDCG) Endorsed
review probably will suffice. A keen eye should be kept Documents. European Commission website. https://ec.europa.
eu/growth/sectors/medical-devices/new-regulations/guidance_
for new information that may influence the regulatory en. Accessed 18 March 2020.
strategy. This may include: 9. Medical Device (MEDDEV) Guidance Documents. European
• internally driven changes, such as company Commission website. http://ec.europa.eu/growth/sectors/medi-
plans for new or revised indications or claims, cal-devices/guidance_en. Accessed 18 March 2020.
10. Standardisation request to the European Committee
device modifications or new markets for Standardisation and the European Committee for
Electrotechnical Standardisation as regards medical devices

Chapter 12
in support of Regulation (EU) 2017/745 of the European Recommended Reading

Parliament and of the Council and in vitro diagnostic med- • Kramer MD. “Developing an Effective Regulatory
ical devices in support of Regulation (EU) 2017/746 of Strategy.” Regulatory Focus. Regulatory Affairs
the European Parliament and of the Council. European Professionals Society. 2012.
Commission website. https://ec.europa.eu/docsroom/docu- • Fan K and Falcone R. Chapter 10 Regulatory Strategy.
ments/36104?locale=en. Accessed 18 March 2020. Fundamentals of US Regulatory Affairs, 11th Edition.
11. Harmonised Standards. European Commission website. https:// Regulatory Affairs Professionals Society. 2019.
ec.europa.eu/growth/single-market/european-standards/har-
monised-standards_en. Accessed 18 March 2020.
12. Human Medicines: Regulatory Information. European
Medicines Agency website. http://www.ema.europa.eu/ema/
index.jsp?curl=pages/regulation/landing/human_medicines_reg-
ulatory.jsp&mid. Accessed 18 March 2020.
13. Legal Framework Governing Medicinal Products for Human
use in the EU. European Commission website. https://ec.eu-
ropa.eu/health/human-use/legal-framework_en. Accessed 18
March 2020.
14. Brown-Tuttle M. Regulatory Intelligence 101, Second Edition.
Regulatory Affairs Professionals Society. 2016.

Chapter 13
The New Medical Devices

Regulation and In Vitro Diagnostic
Medical Devices Regulation
OBJECTIVES a series of implementing and delegated acts that will

allow them to be revised and fine-tuned in almost every
□ Gain insight into the revised European medical detail. In this way, the future will mainly see incremen-
devices and IVD legislation tal legislation rather than another massive regulatory
overhaul. The first additional legislative pieces have
□ Understand the major changes in these new
already been implemented. One key change could bring
regulations
up a future full rewrite, and that is if the system were to
□ Become aware of the transitional regime and move towards more involvement of a central agency for
preparatory requirements for companies in the devices. Far away, but the debates have started.
medical device and IVD industries The proposals were initiated in 2007 and finalised
in 2012, after which a number of years of political and
technical debates followed until their final publication
DIRECTIVES, REGULATIONS AND GUIDELINES in Q2 2017.
COVERED IN THIS CHAPTER The EU MDR replace the existing Medical
Devices Directive (MDD, Directive 93/42/EC) and
□ Regulation (EU) 2017/745 of the European Active Implantable Medical Devices Directive (AIMDD,
Parliament and of the Council of 5 April 2017 on Directive 90/385/EEC), while the EU IVDR will
medical devices, amending Directive 2001/83/ replace the IVD Directive (Directive 98/79/EC).
EC, Regulation (EC) No. 178/2002 and Regulation Besides a transition period that is rapidly being used up,
(EC) No 1223/2009 and repealing Council a grace period will exist where under specific circum-
Directives 90/385/EEC and 93/42/EEC (EU MDR) stances manufacturers may for a while continue to ship
products under the old certificates; however, essential
□ Regulation (EU) 2017/746 of the European parts of the new legislation would be applicable to such
Parliament and of the Council of 5 April 2017 legacy products in this grace period.
on in vitro diagnostic medical devices and Essential in the legislative reform is that it will
repealing Directive 98/79/EC and Commission form a clearing house for all legacy products and oper-
Decision 2010/227/EU (EU IVDR) ators. As such, there intentionally is no grandfathering
for products already CE-marked, and there will be
no grandfathering for notified bodies either: notified
Introduction body designations are fresh, and all products need to
The EU has spent the last decade on a radical over- be reviewed again. As such, the same product may be
haul of its medical device legislation. The new Medical CE-marked under say MDD/IVDD and EU MDR/EU
Devices Regulation (EU MDR) and In Vitro Diagnostic IVDR for a period at the same time; the notified body
Medical Devices Regulation (EU IVDR) will provide a and/or manufacturer in this case will need to assess
new regulatory framework for medical devices in the conformity against EU MDR/EU IVDR and separately
EU for the coming decade. They are constructed with against MDD/IVDD.

Chapter 13
Why a new EU MDR and EU IVDR? medical devices’ accessories that are classified in their
The revision of EU medical devices law began in own right. This integration ends the old adage in which
2007 with informal interactions between the EU the original intent was to write a series of product
Commission and selected stakeholders, followed by two category-specific laws on active implants, orthopaedic
more formal consultations in 2008 and 2010 that aimed implants, cardiovascular implants, etc.
to make mid-life updates to the existing directives for The EU MDR also includes a borderline decision
medical devices, active implantable medical devices and mechanism to allow the Commission, through the new
IVDs. The oldest of the three directives dates back to Medical Device Coordination Group (MDCG), to take
1990 and never has been changed substantially. binding decisions on product qualification, which the
In 2012, when the Commission made its legislative Commission presently cannot do under the directives.
proposals, it felt compelled to amend them significantly Products manufactured utilising nonviable human
following an additional impact assessment related to tissues or cells (and their derivatives) will be regulated
several highly publicised issues with medical devices in under the EU MDR, which has been a longstanding reg-
the EU market, such as the PIP breast implants, met- ulatory gap under the MDD. This will end the era where
al-on-metal hip implants, leadless pacemakers, pelvic such products’ manufacturers had to negotiate the mar-
floor meshes, etc., which sparked a political wish for keting approval path separately with each EU country.
more centralised and premarket controls on higher-risk
medical devices. These issues impacted the EU MDR EU IVDR
proposal debates heavily and led to much divergence on The EU IVDR features the same borderline decision
subjects among both the involved political institutions mechanism as the EU MDR.
and Member States. The EU IVDR includes a new regime for lab-
The EU IVDR proposal was influenced less by oratory-developed tests (home brew tests) and for
external issues, but in many respects followed the EU companion diagnostics.
MDR path. The EU IVDR provides specific definitions and reg-
ulatory requirements for ‘devices for self-testing,’ ‘devices
Scope of the New EU MDR and EU IVDR for near-patient testing,’ ‘single-use devices’ and ‘kits.’
Since both regulations are intended to account for
technological developments, they both feature a con- Accessories
siderable extension of scope compared to the directives The definition of accessory changes to incorporate
they will replace. In addition, in many places, the phrase devices that ‘assist’ a medical device in both regulations.
‘state of the art’ is used, sometimes in comparison to the This is expected to expand the scope of accessories
practice of medicine. In this way, the interpretation of covered by the regulations significantly, for example,
acceptable risks will ensure gradual replacement of older with respect to networked or connected equipment and
products with more-modern medical devices. modular software.
Products specifically intended for cleaning, disin-
EU MDR fecting or sterilising medical devices, and devices for
The EU MDR extends its scope not only to devices controlling or supporting conception are treated sepa-
currently not regulated as medical devices. It also rately as though they were medical devices, rather than
includes devices for which the manufacturer does not as the accessories often claimed today.
claim an intended medical purpose but have a risk pro-
file similar to medical devices, such as non-correcting Implementation of the MAID Goods
contact lenses, cosmetic implants and invasive laser Package
equipment used for cosmetic purposes. These devices The MAID acronym refers to the medical device
will be included on the so-called Annex XVI list, which manufacturer, authorised representative, importer and
the Commission may amend over time to include addi- distributor, i.e., the economic operators covered by
tional devices. EU MDR will kick in for these devices the new supply chain regime. Both regulations will
only once a Common Specification document on them implement the supply chain controls (Figure 13-1)
is formally released. developed in 2008 for CE-marked products set out
The EU MDR will absorb the AIMD. Active in Commission Decision 2008/768 and since imple-
implantable devices currently regulated under that mented in other EU new approach regulations. The
directive will fall within the EU MDR’s highest med- regulatory logic behind this has been described in detail
ical device risk class, including their accessories that in the European Commission’s Blue Guide.1
automatically will be Class III, in contrast to other

The New Medical Devices Regulation and In Vitro Diagnostic Medical Devices Regulation
The New Medical Device Regulation and In Vitro Diagnostic Device Regulation
Figure 13-1. Supply Chain Controls
Figure 12-1. Supply Chain Controls
Su
pp
lie
r
Supplier
Manufacturer Importer Distributor
s
or
End
ct
tra
User
on
Postmarket surveillance and vigilance

bc
Su
Regulatory compliance of device
Unannounced Notified Body

inspections
be
Thepart of the
supply Eudamed
chain system,
controls providethe independent
overarching EU IT (UDIs) Thetoregulation
all medical proposals
devices provide
placed on onlythegeneral UDI
EU market,
architecture for administrating medical devices under the requirements. The Commission will complete the modalities
regulatory responsibility of the respective MAID sup- except custom-made and investigational devices. The
new regulations. and procedural aspects to ensure harmonised application of
ply chain actors regarding device compliance and an system will be part of the Eudamed system, the over-
The regulations call for the Commission to promote the UDI System via implementing acts.
obligation to check the previous supply chain link’s
interoperability among different UDI assignment entities
arching EU IT architecture for administrating medical
A provision is in place on how to comply with the
compliance.
and to minimise financial and administrative burdens for devices under
new transparency the rules
new regulations.
if the new Eudamed system is not
Under theoperators
economic current andsystem,
healthonly the manufacturer
institutions. Currently, the The regulations
operational in time. It callincludes
for theaCommission
period in which to manu-
has regulatory
EU’s UDI policy is to ensure the Member Statesofdo not set
obligations. The new obligations promote interoperability between different UDI
facturers retrospectively can fill the database once it goes
importers and that
up systems distributors willwith
may conflict necessitate
the system an contemplated
update to assignment
live. That meansentities and to minimise
manufacturers financial
will need to startand
the UDI
existing distribution and supply agreements.
under the regulations, and to ensure the finally agreed administrative burdens for economic operators
implementation at the specified times from 2021 onwards, and
With regard
system under the to authorised representatives,
regulation proposals the reg-
is not incompatible health institutions.
and store Currently,
all information until itthe
canEU’s UDI policy
be embedded into is
theto
ulations
withincorporate the requirements
other UDI systems from
already in use in the
other existing
countries. ensure
new EU thedatabase.
Member States do not set up systems that
MEDDEV
However,guidance
althoughon authorised legislation
more-detailed representatives 2
is expected to may conflict with the system contemplated under the
and be
feature prescriptive
published minimum
in late 2017 requirements
or early 2018, severalon EU thecoun- Notified Bodies
regulations, and to ensure that the finally agreed system
authorised representative
tries already have startedmandate’s
to demandcontents.
use ofAlso, theUDI
specific under
The EU thewillregulation proposals changes
make considerable is not incompatible
in Notified Bodywith
systems include
regulations for selected product categories
an independent as offor
liability summer 2018.
defective oversight,
other UDImany systemsof which
already stem
in from
use inthe Jointcountries.
other Action Plan
The manufacturer
devices within the scope ofmust assign a UDI
the authorised prior to placing
representative’s currently being implemented
The manufacturer to improve
must assign a UDI Notified Bodies’
prior to
the device
mandate, which onin thethe
market. The UDI
early phase will be used for report-
of implementation quality.the
placing
3
Notified
device onBodies not onlyThe
the market. willUDIneedwill
to employ
be used
ing serious incidents and field safety
is indicated to be hard to insure. This might corrective
wellactions
mean and more
for expertiseserious
reporting rather than hiringand
incidents contractors, theycorrec-
field safety also will
that companies might establish legal entities within theto a
shall be included in the information to be provided play a role in enforcement by conducting
tive actions and shall be included in the information unannounced
patient implanted
EU instead with a medical
of using authorised device.
representatives to ensure toinspections
be provided of manufacturing processes and
to a patient implanted withtaking a strong
a medical
Under the new regulations, Member States may require supporting role in following up vigilance reporting.
compliance with the new regulations. device. To assist in this work, also a basic-UDI should
healthcare professionals and institutions to store and keep When the new regulations enter into force, all Notified
be assigned, which serves as flag in the Eudamed data-
the UDIs of the devices with which they have been supplied. Bodies will need to re-apply for accreditation under stricter
Traceability base to link products to their certificate, clinical trial
rules, and the Commission also will play a role in the
The EU will set up a traceability system under the new approval, periodic safety reports, summary of safety and
regulations that will assign unique device identifiers clinical performance and vigilance data.

Chapter 13
Under the new regulations, Member States may Because of the political outrage over the PIP case,
require healthcare professionals and institutions to store there has been a movement to increase premarket
and keep the UDIs of the devices with which they have assessment of higher-risk medical devices. A clinical
been supplied. ‘scrutiny’ mechanism (notified bodies had to elevate the
The regulation proposals provide only general review of certain high-risk devices to specialized EU
UDI requirements. The Commission will complete the review committees) as been brought in place under the
modalities and procedural aspects to ensure harmonised EU MDR and EU IVDR alike.
application of the UDI System via implementing acts. The market access system for low- and medium-risk
A provision is in place on how to comply with the medical devices stays the same and see little change.
new transparency rules if the new Eudamed system is For IVDs, there will be a quantum leap in all
not operational in time; the first delay of 2 years has requirements. Currently, 10–20% of all IVDs in the EU
already been announced, and further delays are possi- are CE-certified; self-certification applies to the rest.
ble. The provision regarding Eudamed delay includes a Under the new regime, 80–90% of all IVDs will need to
period in which manufacturers retrospectively can fill be CE-certified by a notified body, and self-certification
the database once it goes live. The assignment of UDI will be possible only in limited cases for low-risk devices.
is not delayed together with Eudamed, as they are sepa- This is resulting from IVD classification rules being
rate requirements. introduced in the EU IVDR (see Figure 13-2) and dis-
continuing the current list-based classification system.
Notified Bodies An additional challenge is that current IVD notified
The EU will make considerable changes in notified body staff have been selected based on their qualifi-
body oversight, many of which stem from the Joint cation for current list A and list B devices. With the
Action Plan currently being implemented to improve much broader scope, notified bodies will need to hire
notified bodies’ quality.3 Notified bodies not only will additional staff with the relevant product design or pro-
need to employ more expertise rather than hiring con- duction experience, as they might well lack sufficient
tractors, they also will play a role in enforcement by regulatory knowledge to get started directly on con-
conducting unannounced inspections of manufacturing formity assessments. Availability of EU IVDR notified
processes and taking a strong supporting role in follow- body resource will even hit industry harder than it hits
ing up vigilance reporting. the medical devices industry. At the time of writing
When the new regulations entered into force, all (half February 2020) only three notified bodies had been
notified bodies needed to re-apply for accreditation notified under the EU IVDR, two of which BSI notified
under stricter rules; however, the majority did not. bodies, belonging essentially to the same organisation.
There will be no grandfathering of notified bodies into
the new system, except for the notified bodies that will Clinical Evidence, Clinical Trials and
continue surveillance of existing certificates under the Regulatory Compliance
(AI)MDD and IVDD during the respective transitional Clinical evidence is one of the core themes in both reg-
periods after the date of application of the EU MDR ulations due to the political wish to increase the amount
and EU IVDR. While these notified bodies lose their of clinical evidence required to support a medical
notifications under the directives, they will remain device’s safety and performance.
responsible for surveillance of the certificates granted Both regulations contain comprehensive and
under the directives with validity beyond the dates of detailed regimes for collecting clinical evidence (both
application of the regulations until their expiry or 26 pre- and postmarket) using the existing MEDDEV
May 2024 at the latest. guidance documents (e.g., the MEDDEV on post-
Currently, a minority of the notified bodies in the market clinical follow-up.)4 The new regulations will
market are expected to be able to meet the new accredi- require manufacturers to collect more clinical evidence
tation requirements with their current designated scope. than currently is needed, meaning manufacturers will
This is expected to affect manufacturers, since they may need to start preparing for increased clinical evidence
need to change their notified bodies as a result. Given requirements for devices to be CE-marked under the
the pressure on the capacity, it appears to be virtually new regulations. However, since the regulations will not
impossible at this stage to still shift notified body. ‘grandfather’ existing devices, manufacturers also must
plan to collect additional clinical evidence for devices
Market Access Mechanism already CE-marked because they will need to be recer-
The market access mechanism in general terms will tified under the new requirements. And even existing
largely stay the same, but the details will change radically. data from clinical trials performed by the manufacturer

Chapter 12
Figure
Figure 13-2.
12-2. Proposed EUIVDR
Proposed EU IVDR Classification
Classification RulesRules
Figure 12-2. Proposed EM IVDR Classification Rules
Rule 1 Rule 2 Rule 3 Rule 4 Rule 5 Rule 6 Rule 7
Infectious
disease
Specific
Cancer IVD
Self-testing reagents
Blood Blood testing
screening or tissue None of Controls
High risk Instruments
compatability Comparison the other no
High risk N N diagnostics N near N N rules assigned
patient Speciment
disease values
tests receptacles
Genetic
testing
Congenial
screening
Y Y
Y High risk Y Self tests for Y Y Y
blood non critical
groups conditions
D C Y C C Y A B B
D B
accreditation decision. There will be no grandfathering of Drug Administration’s (FDA), supervised by the European
Notified Bodies into the new system. Currently, a minor- Medicines Agency (EMA). The Council proposed leaving
itself under the MDD and AIMD will need to be
ity of the Notified Bodies in the market are expected to
between the final regulations and the GCP standard
the system as it is but adding the option of a scientific advice-
re-evaluated
be able to meetto confirm
the new the data haverequirements
accreditation been collected with likeappeared
proceduretobymake the EUEU
a specialised a less attractivewhere
committee, clinical
theinves-
and analysed consistent with the new EU
their current designated scope. This is expected MDR to affect tigation location; fortunately, the ISO
manufacturer can validate in advance the clinical evidencestandard has been
requirements.
manufacturers,ForsinceIVDs clinical
they may needperformance
to change theirdata must
Notified revised to match the new EU expectations.
required for market access. These are very different solutions
beBodies
addedas to existing
a result. analytical validity and scientific The problem
for the same regulations
duringaimthetotrilogue
increase companies’ regula-
negotiations.
validity data.
Uncertainties about the Brexit negotiations’ outcome tory awareness levels by obliging their
The market access system for low- and medium-risk organisations to
Both regulations
in terms implement to
of the UK continuing a centralised
be part of clinical
the EU havedevices
medical at leastwill
onestay
available
the same‘person
and seeresponsible
little change.for regula-
trial regime
single market formeans
covered devices, modelled
manufacturers on theBritish
now utilising EU tory
For compliance.’
IVDs, there will This
be will apply to
a quantum leapboth
in allmanufacturers
require-
Notified Bodies
medicinal productmight have totrial
clinical change twiceThis
regime. over:includes
first to the ments.
and Currently,
authorised10–20% of all IVDs
representatives, except in micro-enterprise
the EU are
EU-based counterpart
notification of theirdatabase
in a centralised Notifiedthat
Bodywill
(still
beunder
part CE-certified;
manufacturersself-certification
of custom-made applies devices.
to the rest.TheUnder
respon-
ofcurrent directives)system.
the Eudamed and secondly to move
Initially, to EUcontinue
this will MDR and/ the sible
new persons’
regime, 80–90% of allrequirements
qualification IVDs will need to be
are set out in
or EU
with IVDR certification. approval on clinical trial
a country-by-country CE-certified by a Notified
the regulations. Body, and self-certification
This individual is, among otherwill things,
be possible only in limited cases for low-risk devices. This
initiation, but from 2027 onward, a central approval of responsible for managing technical files, the Declaration
Market Access Mechanism is resulting from IVD classification rules being introduced
a The
multi-country clinical trial will be in place. Until then,
market access mechanism in general terms will largely
of Conformity and reporting obligations. This indi-
in the EU IVDR (see Figure 12-2) and discontinuing the
countries
stay the same, but the detailswith
may experiment multi-country
will change radically. approvals, vidual
current is not required
list-based to be
classification an employee but must be
system.
following the details laid out for the 2027
Because of the political outrage over the PIP system.
case, there ‘available to the organisation,’
An additional challenge is that currentand, inIVD specific circum-
Notified
Due to the political desire to synchronise
has been a movement to increase premarket assessment regulatory Body staff have been selected based on their qualification the
stances such as is the case with large manufacturers,
concepts pertaining to clinical investigation between
of higher-risk medical devices. Initially, the Commission the for assignment
current list A may beBdistributed
and list devices. With over theseveral people.
much broader
medicinal product and medical device regulatory
proposed a ‘scrutiny’ mechanism (Notified Bodies had frame- scope, Notified Bodies will need to hire additional staff with
works, the legislative
to elevate the review process hashigh-risk
of certain introduced important
devices to spe- the Postmarket
relevant productSurveillance
design or production andexperience,
Vigilance as
concepts inconsistent
cialized EU with the current
review committees). EU harmonised
Parliament proposed a theyEffectively
might well starting
lack sufficient regulatory knowledge
in 2013, national competent author- to get
premarket
Good assessment
Clinical program
Practice (GCP)similar to thefor
standard USmedical
Food and started
itiesdirectly on conformity
have begun to increaseassessments.
and coordinate market
devices (EN ISO 14155:2011). For example, the EU surveillance activities as part of the Commission’s Joint
MDR’s
132 proposed definition of ‘sponsor’ is much broader Action Plan.5 Regulatory
In addition, notified
Affairs bodies have
Professionals been
Society
than under EN ISO 14155:2011. Inconsistencies obliged to start performing unannounced audits of

EU Fund 8th ed 12.indd 132 145
11/6/17 1:27 PM

Chapter 13
manufacturers’ production processes, a process that took up-classify substance-based medical devices consider-
until sometime in 2014 to start, but now is in full swing.6 ably (e.g., creams) absorbed by or locally dispersed in
The proposed regulations build on this develop- the human body. If they are intended to be introduced
ment and introduce the following: into the human body via a body orifice, they will be in
• incorporating the MEDDEV 2.12 Rev 8 vigi- Class III or IIb, and if applied on skin, they will be in
lance system in regulation Class IIa. For such substances, a special consultation
• vigilance reporting of serious incidents and with drug agencies might be needed.
field safety corrective actions in the Eudamed A second example of key reclassification is in the
system special article of software, rule 11. Also, software sees a
• requiring manufacturers to adopt a lifecycle stratified classification system, where most standalone
concept based PMS plan for their devices, software will be Class IIa or higher.
which includes a mandatory postmarket clini- Thirdly, following earlier reclassification of selected
cal or performance follow-up plan orthopaedic implants, the new rules change most ortho-
• Periodic Safety Update Reports (PSURs), an paedic implants into Class III now. Exceptions exist for
inheritance from the EU pharma legislation a list of long available ‘simple’ products, where clinical
• centralised evaluation of the same or similar data is not required.
incident occurrences, or where more than one In addition, for the first time elected active medical
Member State has had to take a corrective devices will be classified in Class III.
action As a last example, reusable surgical tools are being
• Member State cooperation under the reclassified to a new Class Ir. As many such tools are
Commission’s auspices (MDCG) to coordi- made available by the manufacturer as a service, getting
nate enforcement activities in a new electronic them certified, including the processes of returning,
surveillance system and draw up ‘strategic sur- cleaning, sterilisation and redistribution, will have a
veillance plans’ to which the Commission may significant impact.
recommend changes
• binding procedure for dealing with noncom- EU IVDR
pliant and compliant devices, both in national The IVD conformity assessment system will not change
and cross-border situations; the Commission radically, but the IVD classification system will. The
will function as an arbitrator between Member current list-based system will be discontinued in favour
States with respect to provisional measures of GTHF’s proposed system7 of four risk classes (A–D).
taken Therefore, the classification rules will require around
90% of IVDs to be CE-certified by a notified body
Classification and Conformity Assessment because all except those in Class A will require notified
A new aspect of both regulations is the Common body CE certification. This means an initial CE certi-
Specification adoption mechanism for general safety fication for most products, and secondly it follows that
and performance requirements, technical documen- these products currently on the market under self-dec-
tation, clinical evaluation and post-market clinical laration of conformity will not be able to use the grace
follow-up or clinical investigation requirements for spe- period, which is reserved for those products already CE
cific devices or device groups. Common Specifications certified under the IVDD.
may be adopted by an implementing act if no harmon-
ised standards exist or if relevant harmonised standards Own-Brand Labelling Consequences,
are deemed to be insufficient to meet EU requirements. Reprocessing
Adopting similar measures (common technical specifi- The regulations will have far-reaching consequences
cations) already is possible to a certain degree under the for three capita selecta, own-brand labelling single-use
existing directives but, in practice, has been used only device reprocessing and in-house produced devices.
rarely under the IVDD. The Commission is expected
to rely on Common Specifications much more under Own-Brand Labelling (OBL)
the new regulations. In addition, a new system of prod- The widespread practice of own-brand labelling is heav-
uct-specific guidance documents is considered. ily impacted by the new regulations. Each manufacturer
will be obliged to have a full technical file available
EU MDR for the authorities, while the current legislation only
The EU MDR classification and conformity assessment requires an abbreviated technical file referencing the
procedures are staying largely the same, but details underlying original device’s technical file to be available
will be updated. An example is new rule 21, which will

Figure 12-3. Governance StructureThe

forNew
theMedical
EU MDR and Regulation
Device EU IVDR and In Vitro Diagnostic Device Regulation
Figure 12-3. Governance Structure for the EU MDR and EU IVDR
Figure 13-3. Governance Structure

DG GROW-Policy & for the EU MDR and EU IVDR
implementing legislation
Competent
Competent Competent
DGSANTE
DG GROW-Policy &
Unit F–Notified Authorities
Authorities Authorities
implementing
Body Joint legislation
Assessment
Competent
Competent Competent
DG DG JRCUnit
SANTE – Joint Research
F–Notified Authorities
Centre
Body Joint Scientific
Assessment
and technical aspects
DG JRC – Joint Research
Centre Scientific
Medical Device Competent
Coordination Authorities for
Group Medical Devices
Working Group Medical Devices
Group
Working
Group Working Working Working
Group Group Group
Working Working Working
Group Group Group
the Annex XVI list of nonmedical devices regulated under MDR, and five years for the EU IVDR, although a soft
the EU MDR and the EU model of the certificate of free transition scheme to prolong to a maximum of seven years
sale.
thethe
to Annex Also,XVI
authorities. thelistCommission
of nonmedical
Existing OBL is entitled
devices to
schemes change
regulated
will the
haveunderto regu- MDR,
The ishealthcare
foreseen;
and fivehowever,years forinthe
institution such
must a IVDR,
case, the
EUjustify significant
use of EU
although MDR
a soft
lations’
theupdated
be EU MDR technical
and theeach
to enable aspects
EU and via
model delegated
everyof the acts if it
certificatelabel
own-brand of freenot
does elements
transitiondeveloped
in-house already will
scheme to devices be
prolongby required, and
to demonstrating the
a maximum of seven soft-transition
that the years is
deem international
sale. Also, the to
manufacturer Commission standards
have full access compliant
is entitled
to thetoentire with
change EU
the law,
underlying regu-e.g., available
is foreseen;
specific needs only
however, to products
in such group
of the patient with an ongoing
a case,concerned MDD,
significantcannot EU MDR AIMD
be or
the
technical essential
lations’ technical safety
file and will aspects and
need performance
viatodelegated
be structured requirements
acts ifalongit does in EU
the not IVD
elements
met certificate
at analready
appropriate that remains
will belevel
required, under
and
of performance the oldby equiva-Body’s
Notified
soft-transition is
MDR and
deemofinternational
lines EU
the so-called IVDR
standardsAnnex I, the conformity
compliant withmodel.
‘virtual manufacturer’ assessment
EU law, e.g., scrutiny;
available
lent no significant
only to products
CE-marked changes
with an ongoing
device available will be allowed
MDD, AIMD
on the market. in this or time.
the procedures
essential safety and common specifications
and performance to providein
requirements technical
EU IVDBoth regulations
certificate will feature
that remains under a so-called sunshineBody’s
the old Notified compli-
requirements. ance regime, meaning companies, from the date of entry
MDR and EU IVDR Annex I, the conformity assessment
Reprocessing Governance
scrutiny; no significant changes will be allowed in this time.
procedures
Single-use Currently,
and common
medical itdevice
is unclear whethertoEU
specifications
reprocessing law
provide
has been permits
one com-
technical into force,
Bothgovernance may
regulationsmodel comply
will feature with the new rules
a so-called sunshine beforecompli-end
the
The is a combination of the various
the most hotly debated EU MDR item, since it acts at the
panies
requirements.
of to challenge implementing and delegated of the
ance regime,
proposals
transitional
the meaning
period.
three EUcompanies,
Prospective
institutionsfrom
compliance
the date
involved in the
may be
of pro-
entry
European is notGeneral
Currently,
currently itharmonised Court,
is unclear evenEU
whether
under if
EUthese acts affect
law(apart
law permits fromcom-them difficult
into have however,
force,proposed: as the Commission
may comply with the new rules before the end is expected to be in
cess
directly.
panies tolabelling
challenge implementingand andisdelegated acts at the the
of the process of adopting delegated and implementing acts
limited requirements) left to Member • transitional
A Medicalperiod. DeviceProspective
Coordination compliance
Group may be
European Generaldecisions.
Court, even Also,ifcountries
these actshave affectverythem during the
difficult however, transitional period.
States’ individual (MDCG)ashas thebeenCommission
established, is expected
composed to beof in
Timeline
directly.
different for Adopting
perceptions, based on scientificthe Regulations views and eco- the processWhat ofwill
Member
happendelegated
adopting with existing
State delegates with and CE certificates after the
implementing
medical deviceacts
nomicandandthe Transitional
social-cultural Regime
arguments. regulations
during theand
enter into
transitional
IVD expertise
force? Certificates issued under the
period. and chaired and supported
Timeline
Many
After many for arguments
companies Adoptingback
are under the
theand Regulations
impression
forth, thethe new regu- existing
Whatbywilldirectives
thehappen
remain
Commission,
valid until
with existing whichCE
the end ofafter
certificates
decides on consen-
the period
the
and theregulations
lations’
European Transitional
entry into allow Regime
force will not
national decision affect devices
makersalready indicated
regulations on
susenter
the certificate,
into force?
or majority
except
voteCertificates
basis.
certificates
issued under issued
the for
Many CE-marked.
companies But beware,
are under the
the but regulations
impression purposely
thedecide
new regu- to do conformity
existing assessment pursuant to EC verification (Annex
to continue with their practice, once they • directives
The MDCG remain hasvalid
certain until the related
tasks end of the to theperiod
allownot
lations’ allow
reprocessing any
entry intoofforcegrandfathering,
will not
single-use which
affect they
devices, means
devices all
mustalready devices
fol- 4 Directive
indicated on MDR 90/385,
the Annexexcept
certificate, IV Directive
certificates93/42 and Annex
issued for
EU and EU IVDR centralised compe-
CE-marked
CE-marked.
low a commonBut before the date
beware,
conformity the
path. of entry into purposely
regulations force of thedonew VI Directive
conformity 98/79 pursuant
assessment respectively); to EC these will be void,
verification (Annex at the
tences, e.g., assessing applicant notified bodies
notregulations
allow any will need to be CE-marked
grandfathering, which means again under the
all devices latest,
4 Directive two years
and90/385,
after
Annex IV
their periodic
the transitional
Directive 93/42
accreditation
period ends.
and Annex
renewals;
new regulations’
CE-markedProduced requirements.
before theDevices This means,
date of entry into force of the new among other CE certificates
VI Directive issued by Notifiedwill
98/79 respectively); Bodies after atthetheregu-
In-House involvement in high-riskthese be void,
device conformity
things,
regulations a company
will need may need
to aberegime to
CE-marked produce additional
again under clinical lations’ entry into force (i.e., during the transitional period)
Both regulations feature for in-house pro- the latest, twoassessments;
years after the transitional
developing period to
guidance ends.ensure
newevidence
duced regulations’ and have to redraft This
devices thatrequirements.
its technical
make in-house produced means, among files to meet
devicesother
the also
CEwill be void,issued
certificates
effective and
at the by latest,
harmonised
two years
Notified Bodiesafter
regulation
thethe
after
imple-
transitional
regu-
technical
things, a company documentation
may format prescribed under the new period ends (EU IVDR) or four years after (EU MDR).
essentially subject to theneedsame to substantive
produce additional requirements clinical lations’ entry into force
mentation; (i.e., during
overseeing the transitional
expert panels and period)expert
regulations.
evidence and have to redraft itsthe
technical filesproduced
to meet the also willSelf-declared
be void, at theCE marking
latest, two is not
aftersubject to the tran-
as CE-marked devices. While in-house laboratories advising theyears
MDCG; the
and transitional
devel-
technicaldo The transitional period between
documentation the regulations’ entry sitional regime for Notified Body-issued CE certificates.
devices not need to beformat CE-marked, prescribed the under
healthcarethe new period ends oping(EUthe IVDR) or four surveillance
EU market years after (EU MDR).
program.
regulations.must undertake post market surveillance for EU
into
institution
force and date of application is three years for the Manufacturers
•Self-declared
The MDCG
of self-certified
CE marking devices
is not subject
will be consulted
will
on many
need
to the to update
of tran-
The transitional
the devices and is subjectperiodtobetween
nationalthe regulations’
competent entry
author- sitional regime for Notified
the delegated Body-issued CE
and implementing actscertificates.
the
intooversight.
ity force and date of
Furthermore, application
the
Regulatory Affairs Professionals Society is
devices three can years
only for betheusedEU ManufacturersCommissionof self-certified
will takedevices will needthe
to implement to update135
in the legal entity in which they were manufactured.

EU Fund 8th ed 12.indd 135 147 11/6/17 1:27

Chapter 13
regulations on such details as UDI and the grace period. However, in this grace period, significant
Eudamed database. EU MDR elements already will be required, and the
• The MDCG will be consulted on applying EU soft-transition is available only to products with an
procedures to deal with noncompliant devices. ongoing MDD, AIMD or IVD certificate that remains
under the old notified body’s scrutiny; no significant
The above makes it clear, whatever the governance changes will be allowed in this time. Both regulations
model may be, EU medical device policy governance will feature a so-called sunshine compliance regime,
will be much more centralised and coordinated. meaning companies, from the date of entry into force,
An overview of the governance structure can be may comply with the new rules before the end of the
found in Figure 13-3. transitional period. Prospective compliance may be
difficult however, as the Commission is expected to be
Delegated and Implementing Acts in the process of adopting delegated and implementing
The EU MDR and EU IVDR rely heavily on the acts during the transitional period.
Commission finalizing details by delegated competence What will happen with existing CE certificates
to adopt so-called delegated and implementing acts. after the regulations enter into force? Certificates issued
These acts are intended to enable the Commission to under the existing directives remain valid until the end
propose detailed implementing regulation on nonessen- of the period indicated on the certificate, except cer-
tial elements. In practice, however, these acts concern tificates issued for conformity assessment pursuant to
many important elements where the draft regulations EC verification (Annex 4 Directive 90/385, Annex IV
lack considerable detail, such as the notified bodies’ Directive 93/42 and Annex VI Directive 98/79 respec-
designation detail, the UDI and Eudamed systems, the tively); these will be void, at the latest, two years after
Annex XVI list of nonmedical devices regulated under the transitional period ends.
the EU MDR and the EU model of the certificate of CE certificates issued by notified bodies after the
free sale. Also, the Commission is entitled to change regulations’ entry into force (i.e., during the transitional
the regulations’ technical aspects via delegated acts if period) also will be void, at the latest, two years after the
the Commission does not deem international standards transitional period ends (EU IVDR) or four years after
compliant with EU law, e.g., the essential safety and (EU MDR).
performance requirements in EU MDR and EU IVDR Self-declared CE marking is not subject to the
Annex I, the conformity assessment procedures and com- transitional regime for notified body-issued CE certif-
mon specifications to provide technical requirements. icates. Manufacturers of self-certified devices will need
Currently, it is unclear whether EU law permits to update their declarations of conformity by the tran-
companies to challenge implementing and delegated sitional period’s end but are allowed to do so as of the
acts at the European General Court, even if these acts date of entry into force.
affect them directly.
*This period was initially three years, but has been
Timeline for Adopting the Regulations and extended with one year pursuant to Regulation (EU)
2020/561 of the European Parliament and of the Council
the Transitional Regime of 23 April 2020 amending Regulation (EU) 2017/745
Many companies are under the impression that the on medical devices, as regards the dates of application of
new regulations’ entry into force will not affect devices certain of its provisions. OJ 2020 L 130/18.
already CE-marked. This in correct: the regulations pur-
posefully do not allow any grandfathering, which means
that all devices CE-marked before the date of entry into Conclusion
force of the new regulations will need to be CE-marked • The EU MDR and EU IVDR will change EU
again under the new regulations’ requirements. This medical devices regulation profoundly in many
means, among other things, a company may need to areas, such as an enlarged scope of devices
produce additional clinical evidence and have to redraft included under the rules, amended confor-
its technical files to meet the technical documentation mity assessment procedures and increased
format prescribed under the new regulations. postmarket clinical follow-up and surveillance
The transitional period between the regulations’ requirements.
entry into force and date of application is four years* for • Companies will need to plan to generate more
the EU MDR, and five years for the EU IVDR from 25 clinical evidence for medical devices and for
May 2017, although a soft transition scheme to prolong new approval pathways for high-risk devices.
to a maximum of seven years is in place – the so-called

• Devices already CE-marked cannot be grand- 3. Action Plan for Immediate Actions under Existing Medical
fathered and must be recertified under the new Devices Legislation (PIP Action Plan). EC website. http://
ec.europa.eu/growth/sectors/medical-devices/pip-action-plan/
requirements. index_en.htm. Accessed 10 April 2020.
• Notified bodies are not grandfathered in, so 4. MEDDEV 2.12/2 rev. 2 Post Market Clinical Follow-up stud-
manufacturers need to ensure they are working ies, January 2012. EC website. http://ec.europa.eu/DocsRoom/
with a notified body that will obtain designa- documents/10334/attachments/1/translations. Accessed 10
April 2020.
tion status under the new regulations for their 5. Op cit 3.
product categories. 6. See Commission Implementing Regulation (EU) No 920/2013
• The EU MDR and EU IVDR will include a on the designation and the supervision of notified bodies
centralised EU governance system to oversee under Council Directive 90/385/EEC on active implantable
medical devices and Council Directive 93/42/EEC on medical
medical devices, using a single IT system for devices (OJ L253 of 25 September 2013) and Commission
collecting and sharing information; companies Recommendation on the audits and assessments performed by
will need to interact with the system for regis- notified bodies in the field of medical devices (OJ L 253 of 25
trations and notifications. September 2013).
7. Principles of IVD Medical Devices Classification. February
• The EU MDR and EU IVDR will provide a 2008. IMDRF website. http://www.iEU-MDRf.org/docs/
centralised clinical investigation system for ghtf/final/sg1/procedural-docs/ghtf-sg1-n045-2008-princi-
medical devices and IVDs. ples-ivd-medical-devices-classification-080219.pdf. Accessed 10
• The EU IVDR will require approximately April 2020.
80–90% of all IVDs to be CE-certified by a
Recommended Reading
notified body, compared to 10–20% under the • Medicaldeviceslegal.com articles on EU MDR and EU
current IVDD. IVDR developments. Accessed 10 April 2020.
• European Commission webpage on EU MDR and EU
References IVDR Framework: https://ec.europa.eu/growth/sectors/
1. The ‘Blue Guide’ on the implementation of EU product rules medical-devices/regulatory-framework_en. Accessed 10
– Version 1.1. EC website. http://ec.europa.eu/DocsRoom/docu- April 2020.
ments/11502. Accessed 23 March 2020. • European Commission webpage on Joint Action Plan
2. MEDDEV 2.5/10 Guideline for Authorised Representatives (PIP): http://ec.europa.eu/growth/sectors/medical-de-
( January 2012). Global Spec website. http://standards.global- vices/pip-action-plan/index_en.htm. Accessed 10 April
spec.com/std/1513265/eu-ec-meddev-2-5-10. Accessed 10 April 2020.
2020.

Chapter 13

Chapter 14
The European Medical

Devices Legal System
OBJECTIVES lawfully marketed in another Member State and

repealing Decision No. 3052/95/EC
□ Gain insight into the European legislative
process □ Council Directive 90/385/EEC of 20 June 1990
on the approximation of the laws of the Member
□ Understand the basic legal requirements for States relating to active implantable medical
medical devices devices
□ Become aware of available guidance concerning □ Council Directive 93/42/EEC of 14 June 1993
medical device requirements concerning medical devices
□ Directive 98/79/EC of the European Parliament

DIRECTIVES, REGULATIONS AND GUIDELINES and of the Council of 27 October 1998 on in vitro
COVERED IN THIS CHAPTER diagnostic medical devices
□ Consolidated versions of the Treaty on European □ Regulation (EU) 2017/745 of the European
Union and the Treaty on the Functioning of the Parliament and of the Council of 5 April 2017 on
European Union, both last revised 26 October medical devices, amending Directive 2001/83/
2012 EC, Regulation (EC) No. 178/2002 and
Regulation (EC) No. 1223/2009 and repealing
□ Decision No. 768/2008/EC of the European Council Directives 90/385/EEC and 93/42/EEC
Parliament and of the Council of 9 July 2008 on a (EU MDR)
common framework for the marketing of prod-
ucts, and repealing Council Decision 93/465/EEC □ Regulation (EU) 2017/746 of the European
□ Regulation (EU) No. 1020/2019 of the European on in vitro diagnostic medical devices and
Parliament and of the Council of 20 June 2019 repealing Directive 98/79/EC and Commission
on market surveillance and compliance of Decision 2010/227/EU (EU IVDR)
products and amending Directive 2004/42/EC
and Regulations (EC) No. 765/2008 and (EU) No. □ Commission Decision of 19 April 2010 on
305/2011 the European Databank on Medical Devices
(Eudamed) (2010/227/EU)
Parliament and of the Council of 9 July 2008 lay- □ Commission Decision of 7 May 2002 on
ing down procedures relating to the application common technical specifications for in vitro
of certain national technical rules to products diagnostic medical devices (2002/364/EC)

Chapter 14
□ Commission Decision of 27 November 2009 of European law can be found in a consolidated version
amending Decision 2002/364/EC on common of the Treaty on European Union and the Treaty on the
technical specifications for in vitro diagnostic Functioning of the European Union,1 hereafter the “Treaty,”
medical devices (2009/886/EC) as amended by the Treaty of Lisbon. The last revision of
both documents dates from 26 October 2012.
□ Commission Directive 2005/50/EC of 11 August Although the EU has many institutions similar to
2005 on the reclassification of hip, knee and those of a sovereign state, its legal nature is very different.
shoulder joint replacements in the framework of Its Member States retain much more sovereignty than
Council Directive 93/42/EEC concerning medi- in a federation such as the US. These differences can be
cal devices understood best in the context of the European legis-
lative process and the interplay between European and
□ Commission Directive 2003/12/EC of 3 February
national law, a system where, in recent years, the balance
2003 on the reclassification of breast implants
is shifting toward more central regulations than the older
in the framework of Directive 93/42/EEC con-
directives, operating in a more decentralised manner.
cerning medical devices
□ Commission Implementing Regulation (EU) No. Legislative Process

920/2013—OJ L 523 of 25-09-2013 on notified Treaty Article 288 defines the EU’s legal acts.
bodies Regulations, directives and decisions are legally binding,
whereas recommendations and opinions are not.
□ Commission Regulation (EU) No. 722/2012—OJ A “regulation” is directly applicable in all Member
212/3 of 09-08-2012 on medical devices manu- States.
factured utilising tissues of animal origin A “directive” must be transposed into national law
and administrative provisions. Each Member State
□ Commission Regulation (EU) No. 207/2012 of 9
is free to decide on the nature and contents of texts
March 2012 on electronic instructions for use of
adopted nationally, but it must achieve the directive’s
medical devices, 10.3.2012, OJ 2012 L 72/28
intended results. Failure to do so may result in an
□ Commission Directive 2011/100/EU—OJ infringement procedure against the Member State,
L341/50 of 22-12-2011 on Variant Creutzfeld- which may lead to a judgment against it in the Court of
Jakob Decision 2009/886/EC—OJ L 348/94 of Justice of the European Union (CJEU).
29-12-2009 A “decision” applies to those to whom it is
addressed.
□ Commission Notice The ‘Blue Guide’ on the Normally, regulations, directives and decisions
implementation of EU products rules 2016 OJ are adopted jointly by the European Parliament and
2016/C 272/01, 26 July 2016 Council, based on a proposal from the European
Commission in the “co-decision procedure.” This leg-
□ Commission Recommendation of 24 September islative procedure is defined in Treaty Article 294.
2013—OJ L 253/27 of 25-09-2013 on the audits These joint acts can be used to delegate power to the
and assessments performed by notified bodies Commission, in specific cases, to adopt legally binding
in the field of medical devices acts. In such cases, legislative texts are called commis-
sion directives instead of council directives.
□ Guidance from the Commission in the form of
Ordinary legislative procedure is illustrated in
MEDDEV documents, consensus statements and
Figure 14-1.
interpretative documents on MDD, AIMD and IVDD
The basis upon which the Council makes its deci-
□ Guidance from the Notified Body Operations sions was subject to a transitional period that ended in
Group (NBOG) March 2017.2 Initial parts of the old system have been
eliminated.
□ Guidance from the MDCG on the EU MDR and EU From 1 November 2014, a qualified majority is
IVDR defined as at least 55% of Council members, comprising
at least 15 who represent Member States comprising at
least 65% of the EU population. A blocking minority
Introduction must include at least four Council members, or the
Successive treaties have changed the European legal sys- qualified majority shall be deemed attained.
tem over the years. The most recent, the Treaty of Lisbon,
came into force on 1 December 2009. The basic principles

The European Medical Devices Legal System
1
Figure 14-1. Simplified

Figure EU Legislative
13-1. Simplified Process
EU Legislative Process
Figure 13-1. Simplified EU Legislative Process
Proposal by the
Commission
European Parliament Council approves EP’s EP’s position adopted as

(EP) adopts its position position law
disagrees,
Council disagrees,
adopts a different
adopts different
position, EP agrees with Council’s Council’s position
position,informs
informs EP
EP
position or has not acted adopted as law
Within three months EP rejects by a majority No text adopted

of its constituent
members
EP proposes amendments by a
majority of its constituent members
Within three months Commission issues

opinion
Qualified majority in Amended text adopted

Council does not
not Council approves EP as law
approve the
approve the amendments
amendments
amendments (unanimously for
amendments where
Joint conciliation
conciliation Commission issued a
Joint
committee of negative opinion)
committee of EP
EP and
and
Council
Council
Agree on a joint text Fail to agree on a joint No text adopted

within six weeks text within six weeks
Text is voted by EP by a
majority of its
constituent members
and by Council by a
qualified majority within
six weeks
Vote is not successful No text adopted
Vote is successful
Text adopted as law
The “New Approach” Regulatory good example of such an approach and one still used as
Philosophy a tool in drug legislation, mainly for well-known drugs.4
Medical devices directives and the new EU MDR and Similar regulations later were instituted for food and
EU IVDR regulations (the “Regulations”) are based on cosmetics. Premarket approval and/or market surveil-
the “NewRegulatory
Approach” regulatory
Affairs philosophy.
Professionals Society In the early
lance are conducted by authorities, initially by national
139
days of the European Communities, product-related authorities, with more and more work conducted at a
directives contained much technical detail. The first central level by Commission agencies.
directive on medicinal products (drugs)3 in 1965 is a

Chapter 14
Table 14-1. New Approach Areas
Directive/Regulation Subject Directive/Regulation Reference

Cableway installations 2000/9/EC
Chemical substances (REACH) (EC) 1907/2006
Construction products (CPD) 89/106/EEC
Construction products (CPR) (EU) 305/2011
Cosmetics (EC) 1223/2009
Ecodesign—hot-water boilers 92/42/EEC
Ecodesign and energy labelling 2010/30/EU
Ecodesign and energy labelling 2009/125/EC
Eco-management and audit scheme (EMAS) (EC) 1221/2009
Electromagnetic compatibility (EMC) 2004/108/EC
Equipment for explosive atmospheres (ATEX) 94/9/EC
Explosives for civil uses 93/15/EEC
Gas appliances (GAD) 2009/142/EC
Inspection of pesticide application equipment 2009/128/EC
Lifts 95/16/EC
Low Voltage (LVD) 2006/95/EC
Machinery (MD) 2006/42/EC
Measuring instruments (MID) 2004/22/EC
Medical devices (MDD) 93/42/EEC
Medical devices: active implantable 90/385/EEC
Medical devices: in vitro diagnostic 98/79/EC
New legislative framework (NLF) (EC) 765/2008
Non-automatic weighing instruments (NAWI) 2009/23/EC
Packaging and packaging waste 94/62/EC
Personal protective equipment (PPE) 89/686/EEC
Pressure equipment (PED) 97/23/EC
Pyrotechnic articles 2007/23/EC
Radio and telecommunications terminal equipment (RTTE) 1999/5/EC
Rail system: interoperability 2008/57/EC
Recreational craft 94/25/EC
Restriction of the use of certain hazardous substances (RoHS) 2011/65/EU
Simple Pressure Vessels 2009/105/EC
Toy safety 2009/48/EC
Construction products (CPD) 89/106/EEC
When 1993 was selected as the date for creating a backed by a line of case law from the European Court
single market, a key challenge was drafting product-ori- of Justice obligating Member States to recognise prod-
ented directives to eliminate technical barriers to trade ucts mutually complying with their Member State of
hindering free movement of goods in the newly estab- origin’s technical requirements—it was decided to aban-
lished single market. Indeed, if products were required don the detailed technical legislation approach for the
to conform to different technical standards and regula- so-called ‘New Approach.’
tions in each EU Member State, selling products in the Table 14-1 illustrates the New Approach areas.5
EU would be a very expensive and complicated prop- More-recent additions include several directives on
osition. To speed up creation of a single market—and eco-design and energy labelling, eco-management and

audit scheme, pesticide application equipment inspec- Compliance Verification9

tion and restriction of the use of certain hazardous • The manufacturer conducts conformity
substances. The New Approach established the follow- assessment following its choice of procedures
ing principles for legislative harmonisation: provided in applicable medical devices direc-
• Legislative harmonisation is limited to tive (technical file, quality systems).
Essential Requirements that products placed • Depending on their risk classification, some
on the Community market must meet if they products and/or quality systems are evaluated
are to benefit from free movement within the and certified by a third-party, notified body.
Community.
• Technical specifications for products meeting Compliance is confirmed by affixing a CE Mark and by
the directive’s Essential Requirements are laid issuing a Declaration of Conformity once the manufac-
down in harmonised standards. turer is convinced it has achieved compliance with the
• Application of harmonised or other standards directive, with a technical file adequately demonstrating
remains voluntary, and the manufacturer conformity to the Essential Requirements and a quality
always may apply other technical specifications system appropriate for the device’s risk profile. Schematic
to meet the requirements. overviews of the procedures for arriving at a medical
• Products manufactured in compliance with device’s Declaration of Conformity (“conformity assess-
harmonised standards benefit from a presump- ment”) are provided in the Blue Guide 2016’s Chapter
tion of conformity with the corresponding 5 and Annex 4 and are useful tools for determining a
Essential Requirements. specific case’s requirements. Conformity assessment is
addressed in detail in Chapter 15 of this book. The orig-
All key medical devices directives and regulations inal Blue Guide 2000’s conformity assessment flowcharts
are included in Table 14-1, and some may be jointly still are useful (Figures 14-2, 14-3 and 14-4.)
applicable (e.g., machinery for medical devices also No EU Member State can oppose a CE-marked
falling within the scope of the Machinery Directive). product from being placed on its market unless it has
The European Commission has issued guidance on reason to believe the device is unsafe (principle of safe-
dealing with devices falling within the scope of two guard), is a threat to health and safety (precautionary
New Approach directives with respect to overlap with principle) or the CE marking is wrongly affixed (failure
the Personal Protection Equipment Directive6 and the to comply with legal requirements).
Machinery Directive.7 It is important to understand achieving CE mark-
ing, in many cases, is just the beginning of compliance,
Key Principles of the “New Approach” not an endpoint. The medical devices directives impose
a cyclical clinical evaluation process on the manu-
Applied to Medical Devices facturer (Figure 14-5), aimed at continuous device
The New Approach principles discussed above
improvement and clinical substantiation in its technical
are applied in the medical devices directives and
file. This recently was clarified further in the MEDDEV
Regulations as follows.
2.12/2 Rev. 2 guideline, Post Market Clinical Follow-up
Studies, which discusses EU guidance on postmarket
Compliance With Essential Requirements8 clinical follow-up studies and how the manufacturer
• Manufacturer must demonstrate its products and notified body should work together toward the
comply with Essential Requirements (first common goal of improving a device’s clinical substanti-
annex of each directive). Key objectives are to
ation.10 This process is now explicitly made mandatory
prove devices perform as intended and patient
in the EU MDR and EU IVDR.
benefits outweigh risks.
Annex X, point 1.1 of Council Directive 93/42/
• Essential Requirements are very general in
EEC, the Medical Devices Directive (MDD), Annex
content, but detailed technical explanations are
VII, point 1.1 of Council Directive 90/385/EEC, the
found in voluntary harmonised standards.
Active Implantable Medical Devices Directive (AIMDD),
• Demonstrated compliance with a harmonised
Article 61 and EU MDR Annex XIV and Article 56
standard creates a presumption of com-
and EU IVDR Annex XIII describe the clinical eval-
pliance with the corresponding Essential
uation process. Generally, clinical evaluation requires
Requirements.
the collection of clinical data to establish the device’s
conformity with Annex I’s Essential Requirements
or General Safety and Performance Requirements
concerning its characteristics and performance under

Chapter 14
Chapter 8 The European Medical Devices Legal System

Figure 14-2. Flow Chart for the Conformity Assessment Procedures in Directive 93/42/EEC on Medical Devices
Figure 13-2.
Figure 8-2. Flow
Flow Chart
Chart forConformity
for the the Conformity Assessment
Assessment ProceduresProcedures Provided
Provided for in Directivefor In Directive
93/42/EEC 93/42/EEC
on Medical Devices
on Medical Devices
No
EC declaration (*)
of conformity EC verification (Annex IV)
Product (Annex VII) + Products NB verifies and certifies that products conform
class I technical file in Annex with the technical file
VII.5
MODULE A MODULE F
Yes
(*)
Production quality assurance (Annex V)
EC declaration NB assesses and monitors the manufacturer’s
of conformity quality system. Manufacturer declares that
Manu- products conform with the technical file
(Annex VII) + facturer’s
technical file choice MODULE D
MODULE A
(*)
Production quality assurance (Annex VI)
Manu- NB assesses and monitors the manufacturer’s
Product
Product Full quality assurance system quality system. Manufacturer declares that
facturer’s
ClassIIIIA
class B (Annex II) NB assesses and products conform with the technical file
choice
monitors the manufacturer’s quality
system EC design verification by NN MODULE E
(Annex II.4) not applicable
MODULE H
EC verification (Annex IV)

Product Manu- NB verifies and certifies that products
Product
class facturer’s conform with the type
class II
II B choice
MODULE F
Type of
MANUFACTURER
product
EC type-examination Manu- NB assesses and monitors the
(Annex III) facturer’s manufacturer’s quality system
choice
MODULE B
MODULE D

NB assesses and monitors the
manufacturer’s quality system
MODULE E

NB verifies and certifies that products conform
EC type-examination Manu- with the technical file
(Annex III) facturer’s
choice MODULE F
MODULE B
Manu-
facturer’s Production Quality Assurance (Annex V)
choice NB assesses and monitors the manufacturer’s
quality system. Manufacturer declares that
products conform with the type
Product
Product
class MODULE D
Class III
II B
Full quality assurance system (Annex II)

NB assesses and monitors the manufacturer’s
quality system. NB verifies and certifies the
design conformity
MODULE E
Devices for clinical Statement concerning devices for
investigations and special purposes (Annex VIII) No CE
custom-made devices The manufacturer declares that products marking
conform with essential requirements
NB verifies and certifies that products conform
with the type
MODULE F

Manu- NB assesses and monitors the manufacturer’s No
facturer’s quality system complementary
Medical devices, bearing Manufacturer choice CE marking
the CE marking, marketed declaration Sterile MODULE D
as systems or procedure according to devices
packs (Art. 12) Art. 12. 2
NB assesses and monitors the manufacturer’s
quality system
(*) Third party assessment relates to MODULE E
(a) obtention of sterile device,
(b) metrological aspects.
Regulatory
68 Affairs Professionals Society 141


Figure 14-3. Flow Chart for the Conformity Assessment Procedures Provided for in Directive 90/385/EEC on
Figure 8-3.
13-3.Flow
FlowChart
Chartfor
forthe
theConformity
ConformityAssessment
AssessmentProcedures
ProceduresProvided
Providedfor
forinInDirective
Directive90/385/EEC
90/385/EECononActive
Active
Active Implantable Medical Devices
Implantable Medical Devices
Custom-made devices Manufacturer’s declaration

and devices for clinical (Annex 6) No CE marking
investigations + technical file
EC declaration of conformity
Type of
(complete quality assurance system
MANUFACTURER product
+ product design file (Annex 2) NM
Art. 9
issues an EC design examination
certificate (Annex 2, para. 4)
NB assesses and monitors the
manufacturer’s quality system EC declaration of conformity
to type (production quality
Manu- MODULE Hbis (*) assurance (Annex 5))
All other
facturer’s NB assesses and monitors the
devices
choice manufacturer’s quality system
MODULE D (*)
EC type- Manu-
examination facturer’s
(Annex 3) choice
MODULE B (*)
EC verification (Annex 4)
NB verifies and certifies that
products conform to the type
MODULE F (*)
• Legislative harmonisation is limited to Essential Compliance with Essential Requirements

Authority” consists of some 80 different administrative
Requirements NB will examine the product design and audit the quality
normal conditions of use, that products
evaluation of itsplaced on the
side-effects •Manufacturers
Manufactureraremust obligated to monitor
demonstrate its and collect
products
units. Community market must meet if they are to benefit system. An NB will not get involved in a Class I device
and acceptability of its benefit-risk profile. Clinical information
comply onwithexperience
Essentialgained with a (first
Requirements device’sannexuseof
Therefromarefree
27 movement
Member States. within To this
thetaking total must be
Community. unless it is sterile and/or has a measuring function, and then
evaluation
added
involves,
the
where appropriate,
three countries of the forEuropean
any rele-
Economic Area
and may
eachneed to conduct
directive). Key postmarket
objectives areclinical
the NBs scrutiny is1 limited to those aspects.
to provefollow-up
devices
•
vant(Iceland,Technical
harmonised specifications
standards into account,products
a meeting
defined andthe perform as 1intended and patient benefits outweigh
Liechtenstein and Norway) that apply thedown
medical (PMCF)
Member studies
States’ascontrol
part of postmarket
over the NBs surveillance
has gradually
directive’s
methodologically Essential
sound procedure(s) based on a criticalin
Requirements are laid risks.
devices harmonised
directives. Switzerland obligations. Adverse eventsevident
must be in reported as part of
standards. and Turkey have specific tightened. This is particularly
• Essential Requirements are part
the New Approach
very general in content,
evaluation
agreementsof either:
with the EU that impact medical vigilance
laws issuedobligations, which are specificofrequirements
the overarching
• Application of harmonised or otherdevice regu-
standards in 200815 that
but detailed
set out
technical explanations
for
• relevant
latory compliance. scientific literature currently available
remains voluntary, and the manufacturer always postmarket
NB accreditation. surveillance obligations. Moreare found in
importantly,
voluntary harmonised standards.
A on
list
maythe device’s
of these
apply safety,
countries
other performance,
and
technical their relevantdesign
specifications Competent
to meet manufacturers must evaluate
There are approximately 80 this
NBs usage
in the experience
EU. Many also by
• Demonstrated compliance with a harmonised stan-
characteristics
Authorities as well as their website addresses iswhere:
the requirements. and intended purpose, provided assessing
have officeswhether
outside the earlier
Europe (e.g.,benefit-risk
in the US) that profile
carrydeter-
out
dard creates a presumption of compliance with the
• o Products
in Table there
8-3 (theis demonstration
information
manufactured is in of the
given device’s
in English
compliance andhar-
with the mination
audit tasksisand stillsales
corresponding valid, for example,
promotion.
Essential
Mostby initiating
have
Requirements. PMCF
prior histories
country’s equivalence
official to
language(s)). the device to
monised standards benefit from a presumption which data as independent
12 testing houses, and
studies. If it is not, and no corrective action a few are government
is taken,
Several relate
countries are
of conformity with being
the considered
corresponding for member-
Essential institutions.
the CE marking would be invalid, and the device would
ship ino Requirements.
thedata
EU:adequately
Bosnia-Herzegovina,
demonstrate Croatia, FYROM
compliance Compliance
Thethe
CommissionVerificationmaintains a list of all NBs that also
be on market illegally.
(Former Yugoslav RepublicEssential
with relevant of Macedonia), Kosovo, Serbia
Requirements. includes
• Theinformation
manufacturer on their areas of
conducts competence
conformity (http://
assessment
and Turkey.
or key
All Candidate
medical devicescountries
directivesoften adopt regulations
are included in Table ec.europa.eu/enterprise/newapproach/nando/).
following its choice of procedures provided in appli-
similar to those
New Legislative Framework (NLF)
• results
13-1, and of in
some allthe
may EU.jointly
clinical
be investigations
applicable conducted
(e.g., machin- To
Thecable
NBs medical
improve
have setdevices
the internal
up a collective
market
organisation
directive (technical
for goods
file, known
quality
and the role
• forcombined
ery clinical
medical devices data
also falling within the scope of the as NB-MED.
systems). The Commission website describes
strengthen
of NB-MED: the
16 conditions for placing a wide range of
Notified Bodies The
Machinery Directive). (NBs)
European Commission has issued • Depending on their risk classification, some
products
• to on the EU market,
share experience
products and/or andNLF
quality wasare
exchange
systems adopted
views on in
evaluated 2008.
appli-
and
ForNBs are certification
guidance
implantable on dealing organisations.
deviceswith
anddevices
Class III They
falling owe their
within
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clinicalscope
It is a package of measures aimed at improving mar-
name
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fact that cation
certifiedofbyconformity
a third-party assessment procedures with
Notified Body.
investigations be they
Approach are notified
directives
performed by the
with
unless Member
respect
reliance States
toonoverlap
ket surveillance
to theclinical
Commission. They the aim ofand boosting conformity
contributing assessment
to a better understanding
with
existing the Personal can be operate
dataProtection on a mandate
Equipment
justified. Directive6from
and the
quality. It also clarifies the use of CE
Member
Machinery State that notifies
7 them to the Commission and and consistent
Compliance is confirmed application CE Mark and
marking
by affixingofarequirements andandby
The termsDirective.
“clinical evaluation” and “clinical inves- creates aaDeclaration
toolbox of of
issuing procedures measures
Conformity for use
onceinthe product legis-
manufacturer
must fulfil the requirements of MDD Annex XI.
tigation” should be clarified. Clinical evaluation is, lation.
• Within
to draft
is convinced theachieved
it technical
has NLF, the fundamentals
recommendations
compliance of directive,
on the
with the relat-
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KeyNBs
essentially,
are responsible for assessing manufacturers’ com-
Principles
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of evaluating Approach”
evidence Approach ing tohave
with a technical been
conformity
file revised following
assessment
adequately threeaconformity
and build
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consensus
pliance with the requirements of European medical device
Applied
to support to
safety Medical
and Devices
performance. Clinical investiga-
law, attesting to compliance by granting certificates and legal• texts:
to advise
13–15 the Commission, at its request, on sub-
tionthen
refers
The New toApproach
clinical
monitoring trials,
that which
principles
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discussed
throughbeabove
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periodic as
are applied
audits. • jects related to(EC)
Regulation application
765/2008 of the medical
setting outdevices
the
partThe
inofthe
the clinical
medical evaluation
devices to
directivessubstantiate
as follows.
nature of an NB’s involvement depends on the prod-safety and directives
requirements for accreditation and the market
performance aspects
uct’s class. For not corroborated
instance, in the case of aby reference
Class to an
III device, surveillance of products, recently amended by
literature. Clinical evaluation is described in more detail Regulation (EU) 2019/1020 of the European
in Chapter 19. Parliament and of the Council of 20 June 2019
142
Regulatory Affairs Professionals Society Regulatory Affairs Professionals Society
71
EU Fund 8th ed 13.indd 142

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Chapter 14
Figure 14-4.
Figure
Figure 8-4.Flow
13-4. FlowChart
Flow Chart
Chart forforthe
for Conformity
theConformity
the Assessment
ConformityAssessment
Assessment Procedures
Procedures
Procedures Provided
Provided
Provided for in Directive
forinInDirective
for Directive 98/79/EEC
98/79/EEC
98/79/EC In Vitroon in
on on
VitroIn Vitro Diagnostic
Diagnostic
Diagnostic Medical
Medical
Medical Devices Devices
Devices
Intended for Procedure Statement

performance according to drawn up by the
evaluation Annex VIII manufacturer
EC declaration of conformity/
full quality assurance + design
examination + verification of
manufactured products (Annex IV)
Manu-
Referred to in facturer’s
Yes MODULE Hbis +
List A of Annex II choice
EC declaration of conformity/
production quality assurance/
EC type-examination (Annex V)
verification of manufactured
products (Annex IV)
MODULE B
Manu- MODULE D +
Device covered Referred to in facturer’s
MANUFACTURER
by Annex II list B of Annex II choice EC declaration of conformity/
full quality assurance (Annex IV,
except points 4 and 6)
MODULE H
EC verfication (Annex V)
Manu- EC type-examination (Annex V)
facturer’s MODULE F
choice
MODULE B
Manu-
facturer’s
choice EC declaration of conformity/
production quality assurance
Yes EC declaration of conformity (Annex IV, except point 5)
+ examination of design
(Annex III) MODULE D
Intended for MODULE A +

No
self testing
EC declaration of conformity
No (Annex III, except point 6)
MODULE A
Intended for Procedure Statement

performance according to drawn up by the
evaluation Annex VIII manufacturer
to the Essential Requirements and a quality system appro- 13-5), aimed at continuous device improvement and
priateon formarket surveillance
the device’s risk profile. andSchematic
compliance of
overviews of • substantiation
clinical improving market surveillance
in its technical file. Thisrules to better
recently was
• products
to consider,
the procedures and
for and if necessary,
amending
arriving draft
Directive
at a medical reports on ethical
2004/42/EC
device’s Declaration • design
clarified further dossier
protect thereviews
in both MEDDEV
consumers 2.12/2 Rev. 2 guideline,
and professionals from
andaspects
of Conformity of NBs’ activities
Regulations
(“conformity (EC)assessment”)
No. 765/2008 and (EU)in
are provided Post•Market
rules for subcontracting
Clinical
unsafe Follow-up
products, Studies, which
including thosediscusses
imported EU
the •Blue to ensure consistency
No. 305/2011 Chapter
Guide 2014’s with5standardisation
and Annex 4 and workareat • rules
guidance on for outside
certification
postmarket
from the decisions
clinical
EUfollow-up studies and how
useful a European
tools for level
determining a specific case’s requirements. the manufacturer and Notified Body should workfor
together
• Decision 768/2008 on a common framework • setting clear and transparent rules con-
• to keep
Conformity informed of harmonisation activities at a The authoring
toward the commonNBs aimgoal to address the current
of improving weaknesses
a device’s in
clinical
for theassessment
marketingisofaddressed products, inwhich
detail in Chapter
includes formity assessment bodies’ (notified bodies)
European
15 of reference
this book. The leveloriginalto Blue the NB system
substantiation. with
8 this code, particularly by ensuring “a har-
provisions beGuide 2000’s conformity
incorporated when- monised accreditation
quality of work
assessment flowcharts still are useful (Figures 13-2, 13-3 Annex X, point 1.1 amongst
of CounciltheDirective
participating Notified
93/42/EEC,
A core ever product legislation
group of NBs (BSI, DEKRA/KEMA, LNE/G-is revised. In effect, it •
Bodies, toboosting
gain trustquality
in this of andinconfidence
work public in product
and 13-4.) the Medical Devices Directive (MDD), andperception
Annex VII, as
MED, is a template for future product harmonization conformity assessments throughtostronger and
NoTÜV EU Rheinland
Member State and TÜVcan opposeSÜD) has adopted a
a CE-marked well
pointas1.1
from ofpolitical
Counciland policy stakeholders,
Directive 90/385/EEC, contribute
the Active
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being code
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its market unless theitMDD and the
has reason to to ensure the
Implantable clearer rules on requirements
trustworthiness
Medical Devices of the system
Directive for conformity
amongst
(AIMDD), inter-
describe
•
AIMDD. Regulation
In addition(EC) to a764/2008
general laying
statement
believe the device is unsafe (principle of safeguard), is a down
and pro-
principles national assessment
partners of the bodies’
European notification
Union and to
the clinical evaluation process. As a general rule, clinical support the
threat cedures
of conduct,
to healththerelating
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contains
and safety application
rules of certain
on: principle)
(precautionary or the • clarifying
reputation meaningNotified
of the participating of CE Bodies.”
marking and
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implementation
is wrongly rules
and
affixed to products
monitoring
(failure of lawfully
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legal enhancing its credibility
marketed
Conduct in another EU country
requirements). • establishingOrganisations
Standardisation a common legal framework for
•It isqualification
important toand assignment
understand of NBCE
achieving assessment
marking, There areindustrial
three mainproducts in the form
standardisation of a toolbox
organisations in of
Their personnel
in practical
many cases, implication
is just the for the medical
beginning device indus-
of compliance, not an Europe: measures for use in future legislation (includ-
• minimum
try isendpoint.
tightening Thenotifiedtime body
medical for NB
devices assessments
accreditation
directives impose and creating
a cyclical • The ingEuropean
definitions of terms commonly
Committee used in
for Standardization
• sampling
clinical
special evaluation
requirements offorClass
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operators (CEN) develops
product standards
legislation, related to togeneral
and procedures allow
(distributors, importers and authorised representatives). future sectorial legislation to become more
Reinforcement of the application and enforcement of consistent and easier to implement)
Regulatory
internal
72 market Affairs Professionals
legislation Society
is achieved by: 143
158
EU Fund 8th ed 13.indd 143 Regulatory Affairs Professionals Society 11/6/17 1:27 PM

Figure 14-5. Clinical Evaluation Cycle
Technical Specs
Bench Testing/Prototyping
Development Technology,
Clinical Assumptions and
Intended Purpose
Post Market Surveillance Study

Verify Performance in Real Life
Clinical Trial
Verify Risk Management
Close Identified Clinical Gaps
Assumptions Identify
Underpin Benefit-Risk Profile
Improvements
Vigilance/Recall
In 2016, the European Commission re-issued its guid- EU Member States and Other Relevant Countries
ance document explaining the European legal framework EU Member States must transpose directives’ require-
in greater detail: The Blue Guide on the implementation of ments into their national laws and enforce them. For
EU product rules 2016, still called the Blue Guide, after the example, the MDD states:
colour of the original 2000 print publication.16 “Member States shall take all necessary steps to
Much of the 2000 edition of the Blue Guide is still ensure that devices may be placed on the market
valid but required updating to cover new developments and/or put into service only if they comply with the
and ensure broadest possible common understanding on requirements laid down in this Directive when duly
implementation of NLF (detailed above) for market- supplied and properly installed, maintained and
ing products. Changes introduced by the Lisbon Treaty used in accordance with their intended purpose.”17
(explained at the start of this Chapter) must be taken
into account with regard to legal references and termi- This enforcement also breaks down into specific
nology applicable to EU-related documents, procedures, responsibilities:
etc., taken into account first in the 2014 Blue Guide, • register manufacturers or their authorised
which was updated again in 2016. representatives
This new version of the Blue Guide includes • assess clinical trial applications
detailed guidance on the obligations of economic • act as a competent authority for notified bodies
operators or accreditation, standardisation and market • centrally evaluate adverse events
surveillance. The guide’s title reflects the fact the NLF
is to be used, at least in part, by all types of EU har- The EU MDR and EU IVDR are regulations, which
monisation legislation in the field of goods, not only are different from directives in the sense that they have
by the so-called “New Approach” directives. The new direct effect in Member States, and Member States
EU MDR and EU IVDR, described in more detail in are not allowed to implement them further, except to
Chapter 12, rely heavily on the Blue Guide’s content, the extent specifically provided for in the Regulations.
especially regarding supply chain regulation. Under the EU MDR and EU IVDR, the enforcement
responsibilities remain the same in substance, but the
Stakeholders Regulations contain additional obligations of coop-
Several agencies and other stakeholders constitute the eration and centralisation of market surveillance in
players in the EU regulatory arena. The introduction of Chapters VII, Section 3, Chapter VIII and Chapter
the EU MDR and EU IVDR has changed the system IX. For example, the EU MDR and EU IVDR provide
of expert groups and governance under the directives for a market surveillance module of the Eudamed, in
to a more centralised model operating under the new which Member States will cooperate for the purposes
Medical Devices Coordination Group (MDCG), in of enforcement and market surveillance. In the context
which the EU Member States and the Commission of the MDCG, Member States will coordinate market
take part. surveillance activities.

Chapter 14
Member States typically have a national competent grants the EU and UK more or less access to
authority enforce these responsibilities. Currently, 21 each other’s markets.
Member States have a common authority for medici- • The EU and UK agree to prolong the transi-
nal products (drugs) and devices (e.g., France’s Agence tional period in which EU law applies in the
nationale de sécurité du médicament et des produits de santé UK for two years as is provided for in the sep-
(ANSM) and Ireland’s Health Products Regulatory aration agreement.
Authority (HPRA)), although the organisation may be • The EU and UK do not manage to agree to a
split internally along drug and device lines. post 31 December 2020 arrangement and do
There are significant differences among Member not prolong the transitional period, effecting a
States due to resource availability and historic expe- hard Brexit.
rience. A small country like Malta or Luxembourg
typically will embed competent authority function in an A list of these countries in which EU medical devices
institution with much wider responsibilities than just law applies and their relevant competent authorities and
those related to medical devices, whereas larger coun- website addresses are provided in Table 14-2 (infor-
tries will have more specialised teams for medical device mation is given in English and the country’s official
supervision and control. language(s)).
Many countries delegate some competent authority Several countries are being considered for EU
responsibilities to a regional level. Often, this is due membership: Albania, Montenegro, Serbia, Former
to a pre-existing federalist approach to administra- Yugoslav Republic of Macedonia (FYROM) and
tion (e.g., system of Länder in Germany, Autonomous Turkey. In the future, this list also may include Bosnia
Communities in Spain and cantons in Switzerland). and Herzegovina, and Kosovo. Candidate countries are
Probably the most complex situation exists in Germany, required to start a process of alignment of regulations to
where the 16 Länder (states) may assign responsibili- those of the EU.
ties further to district level. It is estimated the German
“competent authority” consists of some 80 different Notified Bodies
administrative units. Notified bodies are certification organisations. Their
There are 27 Member States now after the UK left name derives from the fact they are notified by their
the EU on 31 January 2020. Added to this total are respective Member States to the Commission after first
the three European Economic Area countries (Iceland, being designated by the Member State. They operate
Liechtenstein and Norway) applying the medical on mandates from their Member States after their
devices directives. Switzerland and Turkey have specific compliance with requirements of MDD Annex XI is
agreements with the EU, which impact medical device confirmed. Initial and renewal reviews currently are
regulatory compliance. These countries together make up done in a joint assessment by various Member States
the “Union” referred to in the EU MDR and EU IVDR. together with Commission representation.
As a result of the UK leaving the EU (“Brexit”), a Notified bodies are responsible for assessing
transitional regime applies that also concerns medical manufacturers’ compliance with the requirements of
devices and IVD regulation. As of 31 January 2020, the EU medical device law, attesting to such compliance
UK is not a formal EU Member State anymore and by granting certificates and monitoring compliance
will no longer participate in EU institutions. EU law through periodic scheduled and unannounced audits.
will continue to apply in the UK until 31 December The nature of a notified body’s involvement depends on
2020, and all legislation in place will apply as normal the product’s class. For instance, in the case of a Class
until that date. As of that date, EU law will no longer III device (highest risk category), a notified body will
apply, and the relationship between the EU and the examine product design and audit the quality system. A
UK will be governed by newly negotiated rules, unless notified body will not get involved in a Class I device
negotiations are unsuccessful and the EU and UK will (lowest risk category) unless it is sterile and/or has a
be in a situation of a ‘hard Brexit.’ This would mean that measuring function; then, the notified body’s scrutiny is
the UK will have the status of any third country and limited to those aspects.
will not enjoy any privilege access to the EEA market Member States’ control over notified bodies has
and (likely) vice versa. Companies are advised to study tightened gradually. This is particularly evident in the
the potential effects of a hard Brexit for their own sit- New Approach laws issued in 200819 setting out specific
uation.18 At the time of writing (February 2020), three requirements for notified body accreditation.
options for after 31 December 2020 are on the table: In February 2020, there are approximately 55
• The UK and EU agree on their relationship notified bodies in the EU that are active in the field
going forward, in the form of a treaty that of medical technology. Many also have offices outside

Table 14-2. EU Member States and Affiliated Countries Competent Authorities
Member State Competent Authority

Austria Federal Ministry of Health, Department of Pharmaceuticals and Medical Devices
Österreich Bundesamt für Sicherheit im Gesundheitswesen
www.bmgfj.gv.at
Belgium MDD AIMDD
België/Belgique Federal Agency for Medicines and Health Products
Federaal Agentschap voor Geneesmiddelen en Gezondheidsproducten/ Agence Fédérale des Médicaments et des
Produits de Santé
http://www.health.belgium.be/eportal
IVDMD
Scientific Institute Public Health,
Wetenschappelijk Instituut Volksgezondheid/Institut scientifique de Santé Publique
www.wiv-isp.be
Bulgaria Bulgarian Drug Agency Department Medical Devices
България Изпълнителна Агенция по Лекарствата
www.bda.bg
Czech Republic Ministry of Health, Department of Pharmacy, Medical Devices Unit
Česká republika Ministerstvo zdravotnictví
https://www.mzcr.cz/en/
Croatia Agency for Medicinal Products and Medical Devices
HalMed
www.halmed.hr
Cyprus Cyprus Medical Devices Competent Authority
Κύπρος Αρμόδια Αρχή για τον Ιατροτεχνολογικό Εξοπλισμό
www.moh.gov.cy
Denmark Danish Medicines Agency
Danmark Sundhedsstyrelsen
http://sundhedsstyrelsen.dk
Estonia Health Board, Medical Devices Department
Eesti Terviseamet
www.terviseamet.ee
Finland Valvira—National Supervisory Authority for Welfare and Health
Suomi Valvira—Sosiaali- ja terveysalan lupa-ja valvontavirasto
www.valvira.fi/
France French Health Products Safety Agency
Agence nationale de sécurité du médicament et des produits de santé (ANSM)
http://ansm.sante.fr/
Germany Federal Institute for Drugs and Medical Devices
Deutschland Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM)
www.bmg.bund.de
For some IVD aspects

Paul-Ehrlich-Institute
Paul-Ehrlich-Institut
www.pei.de
Greece National Organization for Medicines
Ελλάδα Εθνικός Οργανισμός Φαρμάκων
www.eof.gr/
Hungary Health Registration and Training Centre, Department of Medical Devices
Magyarország Egészségügyi Nyilvántartási és Képzési Központ
www.enkk.hu
Ireland Health Products Regulatory Authority
Éire An tÚdarás Rialála Táirgí Sláinte
www.hpra.ie

Chapter 14
Table 14-2. EU Member States and Affiliated Countries Competent Authorities (cont.)
Italy Ministry of Health, Directorate General of Medicines and Medical Devices

Italia Ministero della Salute
Direzione Generale dei Farmaci e Dispositivi Medici
http://www.salute.gov.it
Latvia State Agency of Medicines
Latvija Zāļu valsts aģentūra
www.zva.gov.lv
Lithuania State Healthcare Accreditation Agency under the Ministry of Health
Lietuva Valstybinė akreditavimo sveikatos priežiūros veiklai tarnyba prie Sveikatos apsaugos ministerijos (VASPVT)
www.vaspvt.gov.lt
Luxembourg Health Ministry, Division for Therapeutic Medicine
Ministère de la Santé, Division de la Santé
www.ms.public.lu
Malta Malta Competition and Consumer Affairs Authority
Awtorita’ Maltija Dwar L-Istandards
http://mccaa.org.mt/
Netherlands CIBG Farmatec-BMC (e.g., device registrations)
Nederland www.farmatec.nl
Health Care Inspectorate (e.g., clinical investigations, vigilance)

Inspectie voor de Gezondheidszorg (IGZ)
www.igz.nl
Poland Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
Polska Urząd Rejestracji Produktów Leczniczych, Wyrobów Medycznych i Produktów Biobójczych
www.urpl.gov.pl/en/office
Portugal Infarmed—National Authority of Medicines and Health Products
INFARMED-Autoridade Nacional do Medicamento e Produtos de Saúde
www.infarmed.pt
Romania National Agency for Medicines and Medical Devices
România Ministerul Sănătăţii
www.ms.ro
Slovak Republic State Institute for Drug Control, Medical Devices Section
Slovenská Štátny ústav pre kontrolu liečiv, Sekcia zdravotníckych pomôcok
republika www.sukl.sk
Slovenia Agency for Medicinal Products and Medical Devices of the Republic of Slovenia
Slovenija Javna agencija Republike Slovenije za zdravila in medicinske pripomočke (JAZMP)
www.jazmp.si
Spain Spanish Agency for Medicines and Medical Devices
España Agencia Espaňola de Medicamentos y Productos Sanitarios
www.aemps.gob.es
Sweden Medical Products Agency
Sverige Läkemedelsverket
www.lakemedelsverket.se/
UK Medicines and Healthcare products Regulatory Agency (MHRA)
www.gov.uk/government/organisations/medicines-and-healthcare-products-regulatory-agency
EEA Countries
Iceland Icelandic Medicines Agency
Island Lyfjastofnun
www.lyfjastofnun.is
Liechtenstein Office of Public Health
Amt für Gesundheit
www.ag.llv.li/
Norway Health Directorate
Norge Helsedirektoratet
www.helsedirektoratet.no

Table 14-2. EU Member States and Affiliated Countries Competent Authorities (cont.)
Countries With Agreements With the EU With Implications for Medical Devices
Switzerland Swissmedic – Swiss Agency for Therapeutic Products
Suisse-Schweitz- Institut suisse des produits thérapeutiques
Swizzera Schweizerisches Heilmittelinstitut
Istituto svizzero per gli agenti terapeutici
www.swissmedic.ch
Turkey Ministry of Health
Türkiye General Directorate of Pharmacy and Pharmaceuticals
Sağlık Bakanlığı
İlaç ve Eczacılık Genel Müdürlüğü
www.titck.gov.tr
Europe (e.g., in the US or Asia) that carry out audit • take part in interim action—regulation and
tasks, dossier reviews and public training. Most noti- recommendation guidelines
fied bodies have prior histories as independent testing • improve stakeholder perception of responsible
houses or standardisation bodies, and a few are govern- notified bodies
ment institutions. • update the code of conduct to be in line with
The Commission maintains a list of all notified best practices
bodies, including information on their areas of com- • inform its members on trends concerning new
petence (http://ec.europa.eu/growth/tools-databases/ regulations and guidelines
nando/index.cfm?fuseaction=directive.pdf&refe_
cd=93%2F42%2FEEC&requesttimeout=900). The association has adopted a self-regulatory code for
Currently, the number of notified bodies is declining its work under the MDD, AIMDD and IVDD. In addi-
slowly due to increased oversight demands. tion to a general statement and principles of conduct,
There is a collective notified body organization the code contains rules on:
Notified Body Coordination Group (NBCG), previ- • implementation and monitoring of the code of
ously known as NB-Med:20 conduct
• to share experience and exchange views on the • qualification and assignment of notified body
application of conformity assessment proce- assessment personnel
dures, with the aim of contributing to a better • minimum time for notified body assessments
understanding and consistent application of • sampling of Class IIa and IIb technical files
requirements and procedures • design dossier reviews
• to draft technical recommendations on matters • unannounced visits
relating to conformity assessment and build a • rules for subcontracting
consensus • rules for certification decisions
• to advise the Commission, at its request, on
subjects related to application of the medical With the code of conduct, the association aims to
devices directives address weaknesses identified in the notified body sys-
• to consider, and if necessary, draft reports on tem. This is further enhanced by performing supervisory
ethical aspects of notified body activities audits of association members to verify implementation
• to ensure consistency with standardisation of the code and adherence to its details. The goal is
work at a European level to ensure “a harmonised quality of work amongst the
• to keep informed of harmonisation activities at participating notified bodies, to gain trust in this work
a European level in public perception as well as from political and policy
stakeholders, to contribute to ensure the trustworthi-
In addition, there is an association of notified bodies, ness of the system among international partners of the
TEAM-NB (www.team-nb.org). The association, which European Union and to support the reputation of par-
currently has 23 members, aims to: ticipating notified bodies.”
• support the finalisation of the new medical In conformity assessment of particular high-risk
devices regulations devices, notified bodies must consult drug agencies
• demonstrate commitment of Team NB mem- (drug-device combination products), European med-
bers in improving public health icines agencies (product with human blood/plasma

Chapter 14
derived components), national animal tissue experts not mention importers and distributors; however, these
(TSE-susceptible materials) and EU testing facilities are identified in requirements defined in the NLF texts.
(IVD blood grouping and specific high-risk IVDs).
Importers and Distributors
European Medicines Agency Under the directives, European medical device law
The European Medicines Agency (EMA)21 is respon- neither defines importers and distributors nor attri-
sible for scientific evaluation of medicines, thus playing butes any role in the compliance system to them. NLF
a central role in the approval of pharmaceutical prod- texts and the Regulations identify them as economic
ucts in the EU. It is responsible for the Committee for operators with specific responsibilities, especially in the
Advanced Therapies (CAT), which deals with Advanced area of market surveillance, and provide the following
Therapy Medicinal Products (ATMPs), e.g., tissue-en- definitions:
gineered products. It may deal with medical devices • “Importer’ shall mean any natural or legal per-
when these are combined with medicinal products, or son established within the Community who
for ATMPs requiring EMA evaluation. Under the EU places a product from a third country on the
IVDR, EMA will have a role with respect to companion Community market.”22
diagnostics (see Chapter 15). Some medical devices will • “‘Distributor’ shall mean any natural or legal
need a positive EMA review of human blood deriva- person in the supply chain, other than the
tives’ safety and quality before the notified body may manufacturer or the importer, that makes a
complete the conformity assessment. product available on the market, up until the
point of putting into service.”23
Standardisation Organisations
There are three main European standardisation The Regulations make importers and, to a lesser extent,
organisations: distributors, responsible for verifying products they
• The European Committee for Standardization handle are in compliance with EU requirements (EU
(CEN) develops standards related to general MDR Article 13 and EU IVDR Article 14). The new
compliance and specific non-active (non-pow- EU MDR and EU IVDR discussed elsewhere in this
ered) medical devices (www.cen.eu). book borrow heavily from the NLF texts, e.g., the sup-
• The European Committee for Electrotechnical ply chain regime in the new Regulations is modelled on
Standardization (CENELEC) develops stan- them.
dards for electromedical devices (www.cenelec.
eu). Healthcare Establishments
• The European Telecommunications Standards The medical devices directives do not assign any clear
Institute (ETSI) develops standards for infor- responsibilities to healthcare establishments. This area
mation and communications technologies still is regarded as a Member State’s prerogative. As
(www.etsi.org). medical technology becomes more complex, users have
an increasing burden of responsibility to learn how to
To the extent possible, standards of the International operate, maintain and integrate modern devices into
Organization for Standardization (ISO) and healthcare establishment systems. Another trend is
International Electrotechnical Commission (IEC) are healthcare establishments manufacturing devices for
adopted in Europe. their own use. New national regulations are emerging
The Commission publishes lists of harmonised in these areas, and some elements have been included in
standards providing a presumption of conformity with the new EU MDR and EU IVDR discussed in Chapter
directives’ or the Regulations’ requirements in the 13, e.g., with respect to in-house produced medical
EU Official Journal (http://ec.europa.eu/growth/sin- devices and IVDs and shared responsibilities around
gle-market/european-standards/harmonised-standards/ implant cards.
medical-devices/index_en.htm).
Institutional Cooperation and Consensus
Economic Operators Building
Manufacturers and Authorised Representatives The national competent authorities for Medical Devices
The medical devices directives and Regulations define (CAMD) meet at least twice a year under chairman-
manufacturers and Authorised Representatives as well ship of the Member State currently holding European
as for both, as discussed in more detail below. They do Council presidency (changes every six months).

The Regulations have added the MDCG as the • Regulation (EU) 2017/745 of the European
governing structure for the application of the EU MDR Parliament and of the Council of 5 April
and EU IVDR and provide signification detail on how 2017 on medical devices, amending Directive
the Commission and the Member States cooperate for 2001/83/EC, Regulation (EC) No. 178/2002
the purpose of the various aspects of the Regulations. and Regulation (EC) No. 1223/2009 and
The CAMD will continue to exist as a parallel structure. repealing Council Directives 90/385/EEC and
93/42/EEC
Working Groups Established by the • Regulation (EU) 2017/746 of the European
Commission Parliament and of the Council of 5 April
The Commission has established several working 2017 on in vitro diagnostic medical devices
groups that develop guidance on European compliance and repealing Directive 98/79/EC and
requirements and related areas (Table 14-3).24 Commission Decision 2010/227/EU
The regulations will be supplemented by implementing

Industry Representation: European Trade acts, delegated acts and guidance (see https://ec.europa.
Associations eu/growth/sectors/medical-devices/new-regulations/
Many trade associations exist in Europe; some are more guidance_en.)
active than others in developing consensus among
the Commission, Member States, notified bodies and Scope of Medical Devices Directives
industry on interpreting regulatory requirements. Table The medical devices directives’ and regulations’ scope
14-4 lists European industrial trade associations. is determined by a number of important concepts, dis-
MedTech Europe is the largest of these trade asso- cussed in the following.
ciations and represents all medical device technology
areas except health IT and imaging technology. Its Medical Devices and Active Implantable Medical
members are corporations, European product-specific Devices
associations and national associations. (https://www. The definitions of the products they regulate may be
medtecheurope.org). the most important concepts to discuss in terms of the
Trade association COCIR represents the health IT MDD’s and Regulations’ scope. A correct definition
and imaging devices companies. of the product is important from the start because it
The European Federation of Precision, Mechanical determines the regulatory strategy a manufacturer will
and Optical Industries’ (EUROM) membership extends pursue to bring a product to market. An incorrect prod-
beyond medical device manufacturers, which are placed uct classification can be very costly and delay a product’s
in a sub-group—the EUROM VI committee. market entry significantly.
The core concept for the three medical devices
Medical Device Laws directives and Regulations is the concept of “medical
Key EU medical devices directives are: device” in the lex generalis Directive 93/42 and its suc-
• Council Directive 90/385/EEC of 20 June cessor, the EU MDR. If a product falls within the scope
1990 on the approximation of laws of Member of that definition, it falls within the scope of one of the
States relating to active implantable medical three medical devices directives, or for the Regulations,
devices (AIMD)25 in the scope of the other regulation, the EU IVDR. The
• Council Directive 93/42/EEC of 14 June 1993 next step is to determine whether a lex specialis applies
concerning medical devices (MDD)26 because the medical device falls within the scope of the
• Directive 98/79/EC of the European AIMDD because it is an active implantable medical
Parliament and of the Council of 27 October device or of the IVDD because it is an in vitro diag-
1998 on in vitro diagnostic medical devices nostic medical device. This step does not apply to the
(IVDD)27 EU MDR, as it covers both active implantable medical
devices and general medical devices.
These are supplemented by several additional The definitions of medical device in Article 1(2)
Commission directives and decisions (see the sum- (a) of Directive 93/42/EEC and Article 2 (1) of the EU
mary below and http://ec.europa.eu/growth/sectors/ MDR differ, as the scope of the definition is broader
medical-devices/regulatory-framework/index_en.ht- that under the MDD (See Table 14-5).
m#current_legislation for formal documentation). The MDD definition contains a number of defining
The regulations are: elements:

Chapter 14
Table 14-3. European Commission Working Groups and Their Activities
Closed Groups: European Commission services and national competent authorities participate (industry and notified bodies are
normally excluded)
Competent Authority (CAMD) Meetings
Chair: Member State holding the EU presidency
The Member State holding the rotating EU presidency traditionally organises a meeting at which the Member States’ national
competent authorities, candidate countries and EFTA and the European Commission discuss policy issues.
Compliance and Enforcement Group (COEN)
Chair: Austria
COEN focuses on the scope and coordination of Member States’ enforcement activities and considers how to make communications
and cooperation among Member States more effective.
Notified Body Operations Group (NBOG)
Chair: Germany
NBOG aims to improve the overall notified bodies’ performance, primarily by identifying and promulgating examples of best practice
to be adopted by both notified bodies and organizations responsible for their designation and control.
It reviews recommendations issued by the NB-MED group (in which all the EU notified bodies participate) and acts as a “Mirror
Group” following GHTF work on certification bodies.
A Notified Body representative can be invited to participate as appropriate, depending on the issue.
Open Groups: Members are national Competent Authorities, industry (trade associations), notified bodies, standardization bodies
and Commission services.
Medical Devices Expert Group (MDEG)
Chair: European Commission
Umbrella group for other working groups in the field coordinating and overseeing their activities. It adopts MEDDEV guidance
documents.
MDEG also meets in closed session (with only Commission representatives and Member State competent authorities) to discuss all
issues relating to the implementation of the medical devices directives with National competent authorities.
Vigilance (adverse incidents)
The group exchanges guidance, discusses actual cases, reviews current reporting practices and prepares input for the Eudamed
database. The vigilance group also acts as the IMDRF Mirror Group.
Classification and Borderline
The group discusses borderline (is a specific product a medical device?) and classification cases. Often, this results in an entry in the
Commission’s Manual on Borderline and Classification.
The group typically uses an “Enquiry Template” to communicate questions to all Member States and gather responses. Responses
are collated and presented at the meeting by the Member State originator, including its proposed consensus opinion based upon the
responses.
IVD Technical Group
Chair: UK
The group supplies technical and specific input, for example by drafting CTS documents to the Commission, MDEG and other working
groups, and also provides input on the interpretation and uniform implementation of the IVDD.
Working Group on Clinical Investigation and Evaluation (CIE)
Chair: Austria
The group develops and promotes homogenous interpretation and implementation of EU requirements on clinical evaluation and
investigation, including Postmarket Clinical Follow-Up (PMCF). It monitors the EU and international regulatory environment and
technical standardization in the clinical area.
It serves as the European Mirror Group for GHTF SG 5.

Table 14-3. European Commission Working Groups and Their Activities (cont.)
Electronic Labelling Working Group

The group prepares guidance on the circumstances and manner in which Instructions for Use (IFU) and other information required for
medical devices’ safe and proper use can be provided, including any limitations and safeguards to be applied. Such guidance will
form the basis for possible Community measures on e-labelling.
New and Emerging Technologies (NET) Working Group
Chair: Netherlands and UK
NET identifies new and emerging technologies challenging existing regulatory requirements’ adequacy for devices. Where
shortcomings are identified, the group makes recommendations to MDEG about addressing these challenges by guidance or by
regulatory changes. It also informs MDEG about relevant scientific trends.
Eudamed Working Group
The group advises on all issues related to the implementation of the Eudamed database.
• “instrument, apparatus, appliance, software, according to the data supplied by the manu-
material or other article”—Basically, anything facturer on the labelling, in the instructions
can be a medical device, including software. and/or in promotional material.” Advertising
Software can constitute a medical device by or using the device outside the scope of the
itself if it does not come pre-installed on a intended purpose as expressed in the CE
medical device (e.g., on an MRI scanner). A Declaration of Conformity and the underly-
MEDDEV is in place to assist in determining ing technical file would constitute off-label
whether standalone software falls within the advertising and off-label use. Placing a medical
scope of the medical devices directives.28 device on the market for anything other than
• “intended by the manufacturer […] for the intended use is illegal.
the purpose of ”—This denotes the device’s • “for human beings”—Veterinary medical
“intended purpose,” one of the core concepts devices (unlike veterinary medicinal products)
of the medical devices directives. The device’s are not regulated as medical devices.
intended purpose determines the scope of • “which does not achieve its principal intended
the conformity assessment and Essential action in or on the human body by pharmaco-
Requirements it has to meet, much like the logical, immunological or metabolic means, but
indications for a medicinal product. The which may be assisted in its function by such
intended purpose is defined in the directive means”—This element determines the border-
as “the use for which the device is intended line between medicinal products and medical
Table 14-4. European Industrial Trade Associations
Trade Association Acronym Website

European Coordination Committee of the Radiological, Electromedical COCIR www.cocir.org
and Healthcare IT Industry
European Association of Authorized Representatives EAAR www.eaarmed.org
MedTech Europe http://www.medtecheurope.org/
European Hearing Instrument Manufacturers Association EHIMA www.ehima.com
Medical Technologies Industry in Europe EUCOMED www.eucomed.be
European Federation of Precision Mechanical and Optical Industries EUROM/EUROM VI www.eurom.org
European Federation of National Associations and International EUROMCONTACT www.euromcontact.org
Companies of Contact Lens (and Lens Care) Manufacturers
Federation of the European Dental Industry FIDE www.fide-online.org

Chapter 14
Table 14-5. Comparison of MDD and EU MDR Definition of a Medical Device
MDD Definition EU MDR Definition (bold text indicates added or altered element)
“any instrument, apparatus, appliance, software, material “any instrument, apparatus, appliance, software, implant,
or other article, whether used alone or in combination, reagent, material or other article intended by the manufacturer
including the software intended by its manufacturer to to be used, alone or in combination, for human beings for one or
be used specifically for diagnostic and/or therapeutic more of the following specific medical purposes:
purposes and necessary for its proper application, intended • diagnosis, prevention, monitoring, prediction, prognosis,
by the manufacturer to be used for human beings for the treatment or alleviation of disease,
purpose of: • diagnosis, monitoring, treatment, alleviation of, or
compensation for, an injury or disability,
• diagnosis, prevention, monitoring, treatment or alleviation • investigation, replacement or modification of the anatomy
of disease, or of a physiological or pathological process or state,
• diagnosis, monitoring, treatment, alleviation of or • providing information by means of in vitro examination of
compensation for an injury or handicap, specimens derived from the human body, including organ,
• investigation, replacement or modification of the anatomy blood and tissue donations,
or of a physiological process, and which does not achieve its principal intended action
• control of conception, by pharmacological, immunological or metabolic means,
in or on the human body, but which may be assisted in its
and which does not achieve its principal intended action in function by such means.
or on the human body by pharmacological, immunological
or metabolic means, but which may be assisted in its The following products shall also be deemed to be medical
function by such means” devices:
• devices for the control or support of conception;
• products specifically intended for the cleaning, disinfection
or sterilisation of devices as referred to in Article 1(4) and of
those referred to in the first paragraph of this point.
devices; the principle intended action of a highly relevant,31 as the scope of these concepts
medical device must not be that of a medicinal positively determines not only what is a medic-
product (action in or on the human body by inal product, but also negatively determines
pharmacological, immunological or meta- what constitutes a medical device.
bolic means are the core elements from the
definition of medicinal product in Directive An additional scope of the EU MDR includes:
2001/83/EEC). However, a medical device • “products specifically intended for the cleaning,
may be assisted in its function by such means. disinfection or sterilisation of devices” – the
For example, bone cement containing antibi- EU MDR also applies to products for cleaning,
otics has a mechanical/chemical primary mode disinfection or sterilisation of devices.
of action (harden to keep a prosthesis in place),
and that function is assisted by pharmacolog- MDD Article 1(5), in addition to medicinal products,
ical means (antibiotics to prevent infection). further excludes from the directive’s scope:
MEDDEV 2.1/3 Rev. 3, Borderline products, • human blood, blood products, plasma or blood
drug-delivery products and medical devices cells of human origin, or devices incorpo-
incorporating, as integral part, an ancillary rating, at the time of placing on the market,
medicinal substance or an ancillary human blood such blood products, plasma or cells, with the
derivative29 and the Commission’s Manual on exception of devices incorporating a medicinal
Borderline and Classification in the Community product derived from human blood or human
Regulatory Framework for Medical Devices30 plasma
both contain important and practical guidance • transplants or tissues or cells of human origin
on how to decide whether a specific product or products incorporating or derived from
is a medical device or a medicinal product. In tissues or cells of human origin, with the
addition, CJEU’s case law on pharmacological, exception of devices incorporating a medicinal
immunological or metabolic means concepts is

product derived from human blood or human Once a product is deemed a medical device, it is nec-
plasma essary to determine whether it is an active implantable
• transplants or tissues or cells of animal ori- medical device or an in vitro diagnostic medical device.
gin, unless a device is manufactured utilising The definition of active implantable medical device
animal tissue that is rendered nonviable or consists of two partial definitions, the first of which is
nonviable products derived from animal tissue nested in the second:
• “Active medical device”’ means any medical
Other MEDDEVs addressing the MDD’s scope can device relying for its functioning on a source of
be found in Section 2.1, “Scope, field of application, electrical energy or any source of power other
definition,” on the European Commission’s MEDDEV than that directly generated by the human
guidance page.32 body or gravity.
EU MDR Article 1(6) excludes from its scope: • “Active implantable medical device” means
a. in vitro diagnostic medical devices covered by any active medical device that is intended to
Regulation (EU) 2017/746 be totally or partially introduced, surgically or
b. medicinal products as defined in point 2 of medically, into the human body or by medical
Article 1 of Directive 2001/83/EC. In decid- intervention into a natural orifice, and which is
ing whether a product falls under Directive intended to remain after the procedure.
2001/83/EC or under this regulation, partic-
ular account shall be taken of the principal A typical example of an active implantable medical
mode of action of the product device is a pacemaker. However, suppose a company
c. advanced therapy medicinal products covered invented an implantable pacemaker powered by body
by Regulation (EC) No. 1394/2007 heat alone. This would not constitute an active implant-
d. human blood, blood products, plasma or blood able device, but rather an implantable device covered by
cells of human origin or devices which incor- the MDD, the general medical devices directive. Section
porate, when placed on the market or put into 2.1 on the European Commission’s MEDDEV guid-
service, such blood products, plasma or cells, ance page contains specific MEDDEVs clarifying the
except for devices referred to in paragraph 8 of scope of the AIMDD’s application.
this Article The definition of an in vitro diagnostic medical
e. cosmetic products covered by Regulation (EC) device is:
No. 1223/2009 “any medical device which is a reagent, reagent
f. transplants, tissues or cells of animal origin, product, calibrator, control material, kit, instrument,
or their derivatives, or products containing or apparatus, equipment or system, whether used
consisting of them; however, this Regulation alone or in combination, intended by the manu-
does apply to devices manufactured utilising facturer to be used in vitro for the examination of
tissues or cells of animal origin, or their deriv- specimens, including blood and tissue donations,
atives, which are non-viable or are rendered derived from the human body, solely or principally
non-viable for the purpose of providing information:
g. transplants, tissues or cells of human origin, or • concerning a physiological or pathological
their derivatives, covered by Directive 2004/23/ state or
EC, or products containing or consisting of • concerning a congenital abnormality or
them; however, this regulation does apply to • to determine the safety and compatibility with
devices manufactured utilising derivatives potential recipients or
of tissues or cells of human origin which are • to monitor therapeutic measures”
non-viable or are rendered non-viable
h. products, other than those referred to in points The directive considers specimen receptacles to be in
(d), (f ) and (g), that contain or consist of viable vitro diagnostic medical devices. Specimen receptacles
biological material or viable organisms, includ- are those devices, whether or not they use vacuum sys-
ing living micro-organisms, bacteria, fungi tems, specifically intended by their manufacturers for
or viruses in order to achieve or support the the primary containment and preservation of specimens
intended purpose of the product derived from the human body for the purpose of in
i. food covered by Regulation (EC) No. vitro diagnostic examination. Furthermore, products
178/2002 for general laboratory use are not in vitro diagnos-
tic medical devices unless such products, in view of
their characteristics, are specifically intended by their

Chapter 14
manufacturers to be used for in vitro diagnostic exam- stocks of the manufacturer or has not been released by
ination. In vitro diagnostics devices are discussed in customs. However, in certain circumstances, a device
more detail in Chapter 12. IVDD’s scope of application still physically in the manufacturer’s warehouse can
is clarified in MEDDEV 2.14/1 Rev. 2, Borderline issues, be considered as placed on the market. For example,
of January 2012, which can be found on the European this may be the case when the product’s ownership or
Commission website’s MEDDEV page.33 another right already has been transferred to a distrib-
utor or an end user, but the product still is stored by
Accessory the manufacturer on their behalf. In addition, the Blue
The MDD defines an accessory as “an article which Guide clarifies that a device really must have left the
whilst not being a device is intended specifically by manufacturer’s production process for it to be placed
its manufacturer to be used together with a device to on the market, and is not yet placed on the market if it
enable it to be used in accordance with the use of the is “transferred to a manufacturer for further measures
device intended by the manufacturer of the device.” (for example assembling, packaging, processing or label-
Directive Article 1(1) states “for the purposes of this ling).”36 A device displayed at trade fairs, exhibitions or
Directive, accessories shall be treated as medical devices demonstrations is not placed on the market either,37,38
in their own right.” An accessory also may be a dis- which explains why these devices are not allowed to
posable made by a manufacturer other than the device bear CE marking.39
manufacturer. In that case, the accessory, even if it is not
a medical device in itself, still needs to comply with all Putting Into Service
the medical device requirements under the directive. Putting into service is another core concept, similar to
This definition of accessory is broadened under placing on the market or having a valid CE Mark; it
the EU MDR, with the addition of the element of ‘to is a condition for a device to be put into service. It is
assist’: “an article which, whilst not being itself a med- defined as “the stage at which a device has been made
ical device, is intended by its manufacturer to be used available to the final user as being ready for use on the
together with one or several particular medical device(s) Community market for the first time for its intended
to specifically enable the medical device(s) to be used purpose.”40 The Blue Guide clarifies that putting into
in accordance with its/their intended purpose(s) or to service “takes place at the moment of first use within
specifically and directly assist the medical functionality the Community by the end user.”41 This concept applies
of the medical device(s) in terms of its/their intended to a device not placed on the market as a fully func-
purpose(s)” in EU MDR Article 2(2). tional device, but assembled in the place where it will be
used, e.g., a bigger device like an MRI scanner.
Placing on the Market
One of the core concepts of the medical devices direc- Custom-Made Devices
tives is “placing on the market.”34 Placing a device Two medical device categories are exempt from the full
on the market is allowed only after CE marking has conformity assessment requirements underlying CE
been affixed lawfully on the device, based on a valid marking: custom-made devices and devices intended
Declaration of Conformity. Placing on the market is for clinical investigation. Both these device categories
defined as “the first making available in return for pay- are made in small volumes and often constitute mature
ment or free of charge of a device other than a device prototypes. While these devices do not have to undergo
intended for clinical investigation, with a view to distri- full conformity assessment, they must fulfil the require-
bution and/or use on the Community market, regardless ments set out in MDD Annex VIII and may not bear
of whether it is new or fully refurbished.” CE marking.
This concept begs the question of when a device A custom-made device is any device specifically
actually is placed on the market, particularly whether made in accordance with the written prescription of a
a medical device may be considered as already being duly qualified medical practitioner or any other person
placed on the market when the manufacturing process authorised by virtue of his or her professional qualifi-
is finished, or whether additional steps need to be taken cations to provide, under the prescriber’s responsibility,
prior to its distribution or use. The latter is the case. The specific design characteristics and intended for a partic-
Commission clarified this in an interpretative notice, ular patient’s sole use.42
to the effect “placing on the market takes place when Mass-produced devices adapted to meet the med-
the product is transferred from the stage of manufac- ical practitioner or other professional user’s specific
ture with the intention of distribution or use on the requirements are not considered custom-made devices
Community market.”35 This transfer does not happen
merely when the device is placed in the warehouse or

(see additional information under the definition of 1. Access to investigational devices shall be
“manufacturer” below). controlled, and the investigational devices
Custom-made devices must comply with MDD shall be used only in the clinical investigation
Annex I’s Essential Requirements or EU MDR Annex and according to the Clinical Investigation
I’s General Safety and Performance Requirements , Protocol (CIP).
and be manufactured under a quality system ensuring 2. The sponsor shall keep records documenting
the devices are manufactured in accordance with the physical location of all investigational devices
device’s description as set out in Annex VIII, point 2.1 from the devices’ shipment to investigation
of the MDD and Annex XIII of the EU MDR. This sites until return or disposal.
description consists of:
• manufacturer’s name and address Under the MDD, clinical investigations were addition-
• data allowing identification of the device in ally controlled under national clinical trial regulations;
question however, the EU MDR adds a new centralised regime
• statement the device is intended for a partic- for clinical investigation in Articles 62–82 and Annex
ular patient’s exclusive use, together with the XV that replaces most national clinical trial legisla-
patient’s name tion for medical devices in the Union. This regime is
• medical practitioner or other authorized modelled after the new clinical trials regulation for
person’s name who wrote the prescription medicinal products.
and, where applicable, the name of the clinic
concerned Manufacturer
• specific product characteristics as indicated by The manufacturer is an important entity under the MDD,
the prescription because this individual or company must comply with
• statement the device in question conforms regulatory obligations in the current EU medical device
to Annex I’s Essential Requirements of the legal framework. The manufacturer is defined as “the
MDD or General Safety and Performance natural or legal person with responsibility for the design,
Requirements under Annex I of the EU manufacture, packaging and labelling of a device before
MDR and, where applicable, indicating which it is placed on the market under his own name, regardless
Essential Requirements have not been met of whether these operations are carried out by that person
fully, with the grounds himself or on his behalf by a third party.” Essentially, this
definition means the manufacturer is the party placing
The manufacturer must retain documentation indi- devices on the EU market under its own name. If the
cating the manufacturing site(s) and allowing an manufacturer has no EU presence, it must appoint an
understanding of the product’s design, manufacture Authorised Representative (see below) to function as the
and performance, including the expected performance, contact point for the authorities in its stead.
to allow assessment of conformity with the directive’s In addition to this definition, which covers the
requirements. traditional Original Equipment Manufacturer (OEM),
Procedural aspects of ensuring compliance manufacturer obligations also apply to certain post-sale
with rules for a custom-made device are defined in commercial activities with a risk profile similar to that
detail in the consensus statement, Guidance Note for of manufacturing a device. Therefore, the individual
Manufacturers of Custom-Made Medical Devices.43 At who assembles, packages, processes, fully refurbishes
this point, there is no new guidance for custom-made and/or labels one or more ready-made products and/or
devices under the EU MDR. assigns an intended purpose to a device with a view to
it being placed on the market under its own name must
Device Intended for Clinical Investigation meet the same obligations as a manufacturer.
As explained above, device clinical evaluation as Assembling or adapting the intended purpose of
described in MDD Annex X or EU MDR Annex XIV marketed devices for an individual patient does not
may include clinical investigation. Further, as is true constitute assembly regulated like manufacturing.
for custom-made devices, devices intended for clinical Typical examples are opticians assembling glasses and
investigation do not have to meet the requirements for dentists fitting dental implants. The device’s intended
full conformity assessment but are not allowed to bear purpose is the line of demarcation: if the adaptation
CE marking, as they might be confused with devices takes the device outside its original intended pur-
that have undergone full conformity assessment. pose, the party assembling or adapting it constitutes
ISO 14155:2011 Section 6.9 details the require- a manufacturer. For example, if a hospital configures
ments for devices for clinical investigation: software provided for a specific intended purpose (e.g.,

Chapter 14
Table 14-6. MEDDEV Guidance Documents
Code Title Date

2.1. Scope, Field of Application, Definition
MEDDEV 2.1/1 Definitions of “medical devices,” “accessory” and “manufacturer” April 1994
MEDDEV 2.1/2 Rev. 2 Field of application of directive “active implantable medical devices” April 1994
MEDDEV 2.1/2.1 Field of application of directive “active implantable medical devices” February 1998
Borderline products, drug-delivery products and medical devices incorporating, as an integral part, an
MEDDEV 2.1/3 Rev. 3 December 2009
ancillary medicinal substance or an ancillary human blood derivative—December 2009
Interface with other directives—Medical devices/Directive 89/336/EEC relating to electromagnetic
compatibility and Directive 89/686/EEC relating to personal protective equipment. (For the relation
MEDDEV 2.1/4 March 1994
between the MDD and Directive 89/686/EEC concerning personal protective equipment, please see the
Commission services interpretative document of 21 August 2009).
MEDDEV 2.1/5 Medical devices with a measuring function June 1998
MEDDEV 2.1/6 Qualification and Classification of standalone software July 2016
2.2 Essential Requirements
MEDDEV 2.2/1 Rev. 1 EMC requirements February 1998
MEDDEV 2.2/3 Rev. 3 “Use by” date June 1998
Conformity assessment of In Vitro Fertilisation (IVF) and Assisted Reproduction Technologies (ART)
MEDDEV 2.2/4 January 2012
products
2.4 Classification
MEDDEV 2.4/1 Rev. 9 Classification of medical devices June 2010
2.5 Conformity Assessment Procedure
General Rules
MEDDEV 2.5/3 Rev. 2 Subcontracting quality systems related June 1998
MEDDEV 2.5/5 Rev. 3 Translation procedure February 1998
MEDDEV 2.5/6 Rev. 1 Homogenous batches (verification of manufacturers’ products) February 1998
Conformity Assessment for Particular Groups of Products
MEDDEV 2.5/7 Rev. 1 Conformity assessment of breast implants July 1998
MEDDEV 2.5/9 Rev. 1 Evaluation of medical devices incorporating products containing natural rubber latex February 2004
MEDDEV 2.5/10 Guideline for Authorised Representatives January 2012
2.7 Clinical Investigation, Clinical Evaluation
MEDDEV 2.7/1 Rev. 3 Clinical Evaluation: Guide for Manufacturers and Notified Bodies June 2016
Appendix 1: Appendix 1: Clinical Evaluation on Coronary Stents December 2008
MEDDEV 2.7/2 Guide for Competent Authorities in making an assessment of clinical investigation; notification September 2015
MEDDEV 2.7/3 Clinical investigations: serious adverse event reporting and SAE reporting form May 2015
MEDDEV 2.7/4 Guidelines on Clinical Investigations: A Guide for Manufacturers and Notified Bodies December 2010
2.10 Notified Bodies
Designation and monitoring of Notified Bodies within the framework of EC Directives on Medical Devic-
MEDDEV 2.10/2 Rev. 1 April 2001
es and Annexes 1–4
2.11 Products Using Materials of Biological Origin
withdrawn
2.12 Market Surveillance
MEDDEV 2.12/1 Rev. 8 Medical devices vigilance system

January 2013
Manufacturer Incident Report; how to use the MIR, Field Safety Corrective Action
MEDDEV 2.12/2 Rev. 2 Clinical Evaluation—Postmarket Clinical Follow-Up Studies January 2012
2.13 Transitional Period
Commission communication on the application of transitional provision of Directive 93/42/EEC relating
MEDDEV 2.13 Rev. 1 to medical devices. (As regards the transitional regime of Directive 2007/47/EC, see the Interpretative August 1998
Document of the Commission’s services of 5 June 2009).

Table 14-6. MEDDEV Guidance Documents (cont.)
2.14 IVD
MEDDEV 2.14/1 Rev. 2 Borderline and Classification Issues: A Guide for Manufacturers and Notified Bodies January 2012
MEDDEV 2.14/2 Rev. 1 Research use only products February 2004
MEDDEV 2.14/3 Rev. 1 Supply of Instructions for Use (IFU) and other information for In-vitro Diagnostic (IVD) Medical Devices January 2007
Form for the registration of manufacturers and devices In Vitro Diagnostic Medical Devices Directive,
January 2007
Article 10
CE marking of blood based in vitro diagnostic medical devices for vCJD based on detection of abnormal
MEDDEV 2.14/4 January 2012
PrP
2.15 Other Guidances
MEDDEV 2.15 Rev. 3 Committees/Working Groups contributing to the implementation of the Medical Devices Directives December 2008
monitoring all cardiac monitors in a ward) to make it MEDDEV 2.5/10, Guideline for Authorised
suitable for monitoring other devices not included in Representatives44 ( January 2012) sets out the mutual
the intended purpose (e.g., infusion or food pumps), responsibilities and clarifies medical devices direc-
this configuration would make the hospital the manu- tives’ requirements. This MEDDEV contains useful
facturer, provided the other requirement of “placing on guidance on the agreement between the Authorised
the market under its own name” is met. Representative and the manufacturer and supervision of
The EU MDR contains a number of new articles its implementation by the manufacturer’s notified body.
under which a market party is considered to act as a It emphasises Member State authorities’ expectations
manufacturer, and thus must have the device concerned that an authorised representative takes an independent
CE-marked under his responsibility, including changing position toward its manufacturer and actively reports
the intended purpose of a device after it has been placed persistent nonconformities to the authorities and
on the market (Article 16 (1) (b)), modifying a device rescinding its agreement with a manufacturer.45
already placed on the market or put into service in such The definition of authorised representative under
a way that compliance with the applicable requirements EU MDR Article 2(32) is slightly different, because
may be affected (Article 16 (1) (c)), reprocessing a sin- it lacks the requirement for the representative to be
gle use device (Article 17) and making available on the ‘explicitly designated’ by the manufacturer. However,
market an item that is intended specifically to replace Article 11 makes it explicit that the authorised repre-
a part or component of a device and that significantly sentative must be mandated, what the minimum scope
changes the performance or safety characteristics or the of the mandate is and what manufacturer responsi-
intended purpose of the device (Article 23 (2)). bilities may not be in the mandate. The independent
position of the authorised representative has been clar-
Authorised Representative ified and laid down in law in EU MDR Article 11 in
Under MDD Article 14 and EU MDR Article 11, the requirement that the authorised representative must
where a manufacturer placing a device on the market terminate the mandate and inform the notified body of
under its own name does not have a registered place the manufacturer and the authorities in case the manu-
of business in a Member State, it shall designate a sin- facturer is not compliant. The authorised representative
gle EU authorised representative. MDD Article 1(2) is jointly and severally liable for damage as a result of
(j) defines authorised representative as any natural or defect devices under EU MDR Article 11(5).
legal person established in the Community who, explic-
itly designated by the manufacturer, acts and may be Improved Elements
addressed by authorities and bodies in the Community The three basic medical device directives have been
instead of the manufacturer with regard to the latter’s modified by various additional legal documents, inter-
obligations under the directive. Some authorised repre- pretative documents and recommendations.
sentative responsibilities include informing its Member The implementing legislation is approved at the
State’s competent authority it has its registered place of European Commission level, where all Commission
business and providing a description of the concerned sectors are consulted to check the legislation’s consis-
Class I devices and custom-made devices, systems and tency. However, the key legislators (EU Parliament and
procedure packs’ composition and systems and/or pro- Council) are not involved, as this process only aims to
cedure packs’ sterilization. tweak the legislation’s implementation without radically

Chapter 14
Table 14-7. European Commission Consensus The EU MDR and EU IVDR have incorporated
Statements unannounced audits and have made them mandatory
for notified bodies to perform periodically.47
Guidance Notes for Manufacturers of Class I Medical Devices
(December 2009) Medical Device Law Interpretation
Guidance Notes for Manufacturers of Custom-Made Medical Interpretation by Courts
Devices (June 2010) The CJEU provides the ultimate interpretation of
Guidance Document on Directive 2005/50/EC (December European law. There is a growing body of case law pro-
2006) viding significant interpretation in the field of medical
IVD Trisomy 21 (December 2006) devices, for example, with regard to the interpretation of
IVD Rare Blood Groups (December 2003) the definition of medical device, quality system require-
ments for repacking or translation of IFUs of medical
devices that have been placed on the market.
National courts also may interpret national and
changing its requirements. Occasionally, some revisions
European medical device law because the medical
do change basic requirements relating to specific risk-
devices directives must be implemented in national law,
based reclassifications.
and regulations are directly applicable in the Member
Several years ago, the Commission initiated a new
States. Courts in different Member States possibly
soft legislation tool, a Commission recommendation.
could come to different conclusions on similar issues.
The first of these was issued in 2013 in the medical
For example, courts in respective Member States may
device arena.
decide differently about whether a particular product
Under the EU MDR and EU IVDR, tweaking the
is a medical device or a medicinal product, as was con-
legislation will happen by means of so-called delegated
firmed by the CJEU in the Lycocentre case.48
and implementing acts. The EU MDR and EU IVDR
If the national court is uncertain about a point of
define what elements of the regulation can be amended
European law, it can request a preliminary ruling from
or changed by means of a delegated or implementing
CJEU. For example, the first request for a preliminary
act. The Commission prepares a proposal for a delegated
reference about the medical devices’ borderline with
or implementing act, which is subsequently routed
medicinal products occurred in 2012, when CJEU con-
through a so-called comitology procedure under which
cluded “the third indent of Article 1(2)(a) of Council
the Parliament and the Council have different levels of
Directive 93/42/EEC of 14 June 1993 concerning
influence over the proposal.
medical devices, as amended by Directive 2007/47/EC
of the European Parliament and of the Council of 5
Commission Recommendation September 2007, must be interpreted as meaning that
In 2013, the European Commission issued a recom- the concept of ‘medical device’ covers an object con-
mendation on conformity assessment procedure details, ceived by its manufacturer to be used for human beings
on both dossier reviews and audits. A special section for the purpose of investigation of a physiological pro-
was devoted to the concept of unannounced audits to be cess only if it is intended for a medical purpose.”49
performed by notified bodies.46
Table 14-8. Informative Documents Issued by the European Commission
Interpretation document of the Commission Services—Placing on the market of medical devices (16 November 2010)
Interpretation of the Customs Union Agreement with Turkey in the field of medical devices (11 February 2010)
Decision No. 1/2006 of the EC-Turkey Association Council of 15 May 2006 on the implementation of Article 9 of Decision No. 1/95 of
the EC-Turkey Association on implementing the final phase of the Customs Union
Statement of Turkey-EC Customs Union Joint Committee on the implementation of Article 1 of Decision 1/2006
Interpretation of the relation between the revised Directives 90/385/EEC and 93/42/EEC concerning (active implantable) medical
devices and Directive 2006/42/EC on machinery (21 August 2009)
Interpretation of the relation between the revised Directive 93/42/EEC concerning medical devices and Directive 89/686/EEC on
personal protective equipment (21 August 2009)
Interpretative document of the Commission’s services implementation of Directive 2007/47/EC amending Directives 90/385/EEC,
93/42/EEC and 98/8/EC (5 June 2009)
Interpretation of the medical devices directives in relation to medical device own brand labellers (4 February 2008)

Table 14-9. NBOG Documents (NBOG Best Practice Guides)
NBOG Best Practice Guides

Number Title Publication
NBOG BPG 2006-1 Change of Notified Body November 2008
NBOG BPG 2009-1 Guidance on Design-Dossier Examination and Report Content March 2009
NBOG BPG 2009-2 Role of Notified Bodies in the Medical Device Vigilance System March 2009
NBOG BPG 2009-3 Guideline for Designating Authorities to Define the Notification Scope of a March 2009
Notified Body Conducting Medical Devices Assessment
NBOG BPG 2009-4 Guidance on Notified Body‘s Tasks of Technical Documentation Assessment on July 2009
a Representative Basis
NBOG BPG 2010-1 Guidance for Notified Bodies auditing suppliers to medical device manufacturers March 2010
NBOG BPG 2010-2 Guidance on Audit Report Content March 2010
NBOG BPG 2010-3 Certificates issued by Notified Bodies with reference to Council Directives March 2010
93/42/EEC, 98/79/EC, and 90/385/EEC
NBOG BPG 2014-1 Renewal of EC Design-Examination and Type-Examination Certificates: November 2014
Conformity assessment procedures and general rules
NBOG BPG 2014-2 Guidance on the Information Required for Notified Body Medical Device November 2014
Personnel Involved in Conformity Assessment Activities
NBOG BPG 2014-3 Guidance for manufacturers and Notified Bodies on reporting of Design November 2014
Changes and Changes of the Quality System
NBOG Checklists
NBOG CL 2010-1 Checklist for audit of Notified Body’s review of Clinical Data/Clinical Evaluation March 2010
NBOG Forms
NBOG F 2009-1 Notification form—Directive 93/42/EEC December 2009
NBOG F 2009-2 Notification form—Directive 90/385/EEC August 2009
NBOG F 2009-3 Notification form—Directive 98/79/EC August 2009
NBOG F 2010-1 Certificate Notification to the Commission and other Member States March 2010
NBOG F 2014-1 Application form to be submitted when applying for designation as a notified November 2014
body
NBOG F 2014-2 Qualification of personnel November 2014
therefore, generally accept compliance with MEDDEV

Commission Guidance guidance as indicating compliance with the directives.
The Commission provides interpretation in the form Table 14-6 lists MEDDEV guidance documents
of guidance (MEDDEV) documents, consensus state- from the Commission’s website.51 The Commission also
ments and informative documents.50 has issued statements endorsed by MDEG, listed in
The MEDDEV guidance documents are adopted Table 14-7.52 Table 14-8 lists interpretative documents
by the Medical Devices Expert Group (MDEG), which issued by the Commission.53 Additional guidance may
is chaired by the Commission and whose members are be found in specific MDEG working group websites.
representatives of national competent authorities, stan- The Notified Body Operations Group (NBOG)
dardisation bodies, European trade associations and issues guidance on notified bodies (Table 14-9).54
notified bodies. MEDDEV documents are not legally Under the EU MDR and EU IVDR, the gover-
binding but represent MDEG members’ consensus. Often, nance structure to support the Regulations is renewed
they are prepared by working groups composed of vari- (Figure 14-6). The Commission and the Member States
ous MDEG members. National competent authorities, cooperate in the Medical Devices Coordination Group

Chapter Figure
14 12-3. Governance Structure for the EU MDR and EU IVDR
Figure 12-3. Governance Structure for the EU MDR and EU IVDR

Figure 14-6. EU MDR and EU IVDR Governance Structure
DG GROW-Policy &
implementing legislation
Competent
Competent Competent
DG SANTE
DG GROW-Policy &
Unit F–Notified Authorities
implementing
Body Joint legislation
Assessment
Competent
Competent Competent
DG JRCUnit
DG SANTE – Joint Research
F–Notified Authorities
Centre
Body Joint Scientific
Assessment
DG JRC – Joint Research
Centre Scientific
Group Medical Devices
Working Group Medical Devices
Group
Working
Group Working Working Working
Group Group Group
Working Working Working
Group Group Group
the Annex XVI list of nonmedical devices regulated under MDR, and five years for the EU IVDR, although a soft
the EU MDR and the EU model of the certificate of free transition scheme to prolong to a maximum of seven years
the sale.
Annex Also,
XVIthelistCommission
of nonmedical is entitled
devices to change under
regulated the regu- MDR,is foreseen;
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the process of will happendelegated
adopting with existing and
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CE certificates after
implementing acts the
and the Transitional Regime regulations
during enter into
the transitional force? Certificates issued under the
period.
b. to advise the Commission, at its request, in in directives
particularremain in thevalid fields of the
classification and
Timeline for Adopting
Many companies are underthe Regulations
the impression the new regu- existing
What will happen with existing until end ofafter
CE certificates the theperiod
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the EU
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Affairs Professionals Society
notified bodies and vigilance activities h. to contribute to harmonised administrative
d. to contribute to the continuous monitoring of practice with regard to devices in the Member
technical progress and assessment of whether States
the general safety and performance require-
ments laid down in the EU MDR and EU

The Commission as an Arbitrator regulations as well as guidance and often adverse inci-
The Commission does not have clear powers to make dent- and enforcement-related information. The vast
decisions in conflicts of interpretation. However, it does majority of available information is in the Member
provide a forum for building consensus. MEDDEVs and State’s national language, but English language content
consensus statements are one way of achieving this. The is increasing. The European Commission maintains a
Commission also holds closed meetings with national list of national competent authorities, including links
competent authority representatives to discuss interpreta- to most of their websites.60 However, there is no guar-
tion issues. These meetings are confidential, so discussion antee that other Member States’ national competent
outcomes usually do not reach the public domain. authorities always would agree with other Member
Under a quasi-informal process called the States’ competent authorities because they are not
“Helsinki procedure,” a national competent authority obliged to do so, as was confirmed by the CJEU in the
can request other national competent authorities to Lycocentre case (case C-109/12). The increased central-
provide opinions on specific borderline or classifica- isation and attribution of additional competence to the
tion issues. If consensus is not reached in this manner, Commission for ensuring uniform application of EU
which frequently is the case, the matter is passed for medical devices law under the EU MDR and EU IVDR
consideration to the Commission’s Working Group is expected to increase coherence of interpretation of
on Classification and Borderline. This group draws EU medical devices law.
its members from MDEG, so it also has industry and
other stakeholder representatives. When consensus is Technical Standards’ Significance
achieved within this group, results are published in the Essential Requirements and some other directive
Manual on Borderline and Classification.55 requirements are very general, but for many of them,
Under EU MDR Article 4 and EU IVDR Article 3, solutions have been provided in harmonised technical
the Commission has been given the competence to make standards. Compliance with such standards represents
decisions in conflicts of interpretation, after consulting a presumption of compliance with the corresponding
the MDCG, to determine by means of implementing directives’ requirements.
acts whether or not a specific product, or category or The general trend is to adopt international stan-
group of products, falls within the definitions of ‘medical dards from ISO61 and IEC.62
device’ or ‘accessory for a medical device’ under the EU European technical standards are adopted by
MDR or within the definitions of ‘in vitro diagnostic CEN63 and Cenelec,64 possibly based on international
medical device’ or ‘accessory for an in vitro diagnostic standards and otherwise based purely on European
medical device’ under the EU IVDR. The Commission work. These standards are made available through these
can exercise this competence only by its own initiative organisations’ national member organisations.
or upon request of a Member State, which means that
there is no direct possibility for private parties to file a National Enforcement
request for determination with the Commission. The European Commission does not have enforcement
powers regarding compliance with the medical devices
Guidance From Other Sources directives or the Regulations. Member States are
Many European stakeholders provide guidance. responsible for enforcement, as stated, for instance, in
Notified bodies are grouped in TEAM-NB, which MDD Article 2:
issues guidance relevant to notified body operations. “Article 2 Placing on the market and putting into
TEAM-NB provides its own position papers,56 further service Member States shall take all necessary steps
documents, such as press statements and surveys,57 and to ensure that devices may be placed on the market
external guidance documents, e.g., from the NBCG/ and/or put into service only if they comply with the
NB-MED forum.58 requirements laid down in this Directive when duly
Trade associations often issue position papers that, supplied and properly installed, maintained and
in a sense, can be considered guidance, although there used in accordance with their intended purpose.”
are no guarantees competent authorities would accept
such opinions. MedTech Europe is the most prolific Each Member State is free to carry out enforcement in
publisher of documents, providing an interesting per- the medical device area as it deems best. The texts trans-
spective on EU medical device law.59 posing the EU directives’ requirements into national law
often set out enforcement methods and the penalties for
Guidance From Member States violations of the law.
All national competent authorities have their own
websites, which provide links to national laws and

Chapter 14
In practice, it is clear many national competent technologies, such as optogenetics, synthetic biology
authorities have limited resources for market surveil- and 3D-printing of medical implants.
lance and enforcement; for instance, Luxembourg The EU recently adopted the new Medical Devices
cannot expend the same effort as France. Even the Regulation68 (EU MDR) and the IVD Regulation69 (EU
major Member States do not have unlimited resources. IVDR), which will replace the AIMDD/MDD and
Therefore, market surveillance and enforcement efforts IVDD respectively. These two new Regulations entered
tend to be more reactive than systematic. Adverse into force on 26 May 2017 and are described in more
incidents and complaints by competitors tend to trig- detail in Chapter 13.
ger action by national competent authorities. New There will be a period of concurrent application
information released by FDA or other non-European of the AIMDD, MDD and the EU MDR and of the
authorities also may elicit a response. In addition, there IVDD and the EU IVDR during the transitional regime,
is increased interaction among the Member States, e.g., which is described in Chapter 13.
monitoring one another’s websites and profiting from The governance model will change drastically under
contacts made at European competent authority and the EU MDR and EU IVDR. See Chapter 13 for a
expert meetings. description of the new governance model.
After the Poly Implant Prothèse (PIP) scandal The EU MDR and EU IVDR will make a number
involving breast implants in 2011, there was a call for of, sometimes radical, legal changes to the EU medical
more centralised enforcement of medical devices law, devices legal system, some of which are discussed below.
which is reflected in the new Regulations. Interim mea- Other changes are discussed in Chapter 13.
sures have been taken in a concerted manner and are
having a huge impact on the current system’s interpreta- Claims Regulation
tion and functioning.65 Article 7 of the EU MDR and EU IVDR covers mar-
Under the EU MDR and EU IVDR Chapter VII, keting and advertising regulation for medical devices
Section 3, a system has been set up that encourages and IVDs for the first time at the EU level. However,
cooperation in market surveillance matters and pro- the article targets not only marketing and advertising
vides for a Eudamed module on market surveillance materials, but any documentation, practice and/or state-
for information exchange. The competent authorities ment related to the devices concerned, including: device
shall draw up annual surveillance activity plans and labelling, instructions for use, making available, putting
allocate a sufficient number of material and competent into service and advertising. It prohibits the use of text,
human resources in order to carry out those activities, names, trademarks, pictures and figurative or other signs
taking into account the European market surveillance that may mislead the user or the patient regarding the
programme developed by the MDCG.66 The competent device’s intended purpose, safety and performance by:
authorities shall prepare an annual summary of the a. ascribing functions and properties to the prod-
results of their surveillance activities and make it acces- uct that the product does not have
sible to other competent authorities by means of the b. creating a false impression regarding treatment
market surveillance module of Eudamed.67 or diagnosis, functions or properties the prod-
uct does not have
Legal System Evolution c. failing to inform of a likely risk associated with
The MDD was amended five times between 1993 and the use of the product in line with its intended
2007. Most significant changes have been based on purpose
a better understanding of medical device safety and d. suggesting product uses other than those
compliance dynamics. For instance, the role of clinical declared in the intended purpose when the
evaluation has increased considerably, and more pressure conformity assessment was carried out
has been put on notified bodies to be stricter in their
certification and periodic audits. These standards apply to the whole supply chain for the
More effort has been expended trying to device concerned, i.e., manufacturer, importer, distrib-
understand the impact of accelerating technolog- utor and any other reseller. Member States can enforce
ical development on the regulatory framework. them at the national level.
The Commission has set up a New and Emerging
Technology Working Group to scan developments that Product Liability
might challenge the regulatory framework. The initial The two Regulations will implement significant changes
focus was on nanotechnology, but more recently, there with respect to medical devices and IVDs’ product lia-
has been a new focus on other potentially revolutionary bility in the EU:

• Manufacturers must have measures in place to user.73 This provision likely will lead to a steep
provide sufficient financial coverage for their increase in requests to competent authorities
potential liability under Directive 85/374/EEC to intervene in product liability claim scenarios
“in a manner that is proportionate to the risk where the injured party or its representatives
class, type of device and the size of the enter- or subrogated parties (e.g., insurance company)
prise.”70 Member States are allowed to enact has difficulty obtaining information from the
more protective measures under national law,71 manufacturer and tries to enlist the competent
but these measures cannot concern no-fault authority. If the competent authority inter-
product liability as governed by Directive venes, national procedural law will be the basis
85/374/EEC. There is room for national fault- to determine whether it can use the informa-
based liability measures. There currently are tion, the transmission of which facilitates its
no guidelines as to what kind and amount of own enforcement purposes.
coverage is considered “proportionate to the
risk class, type of device and the size of the Prescribed Authorised Representative
enterprise.” Agreement Contract Forms
• If the manufacturer is not established in an EU Article 11 of the EU MDR and EU IVDR contains
Member State and has not complied with the specific requirements for the authorised representa-
manufacturer obligations set out in Article 10 tive agreement and scope of its mandate. Strangely
of the EU MDR or EU IVDR, the Authorised enough, the same requirements apply to manufactur-
Representative is legally liable for defective ers with their own ‘internal’ authorised representative
devices on the same basis as, and jointly and (usually a subsidiary established in the EU), while the
severally with, the manufacturer.72 This shared requirements appear to be aimed at external authorised
product liability is very likely to significantly representatives. It is hard to see how an internal autho-
increase the amount of due diligence authorised representative, for example, would terminate the
rised representatives do for their customers, mandate if the manufacturer acts contrary to its obliga-
both at the beginning of a mandate and while tions, or how it would notify the competent authority
fulfilling that mandate, because manufacturer and notified body of that termination and the reasons
noncompliance may lead to full product lia- for it.
bility for the authorised representative. The In any event, the requirement means all manu-
relationship between the authorised repre- facturers and authorised representatives revise their
sentative and the manufacturer will change agreements to bring them in compliance with the new
considerably as a result. Also, it is expected requirements.
many of the smaller authorised representatives The EU MDR and EU IVDR also provide for
will cease activities under the new Regulations. a new handover regime of authorised representative
• As explained in Chapter 13, the EU MDR mandates in Article 12, requiring a handover preferably
contains a regime for reprocessing single-use should be laid down in a three-party agreement, which
devices. EU MDR Article 17(2) provides that must contain at least the elements set out in Article 12.
the device reprocessor shall be considered
to be a producer for the purpose of Article
3(1) of Directive 85/374/EEC. This means Additional Supply Chain Vigilance
the reprocessor, not the Original Equipment Obligations
Manufacturer (OEM), is product-liable for the Each link in the supply chain is responsible for check-
reprocessed device. ing compliance of the chain’s previous link regarding
• Competent authorities have a facilitation role the elements set out in EU MDR and EU IVDR
with respect to product liability claims. If a Articles 13 and 14, such as:
competent authority considers or has rea- • verifying the device’s compliance
son to believe a device has caused damage, it • informing the competent authority of device
shall, upon request, facilitate the provision of noncompliance
compliance-related information and docu- • implementing corrective action
mentation to the potentially injured patient or
user and, as appropriate, the patient’s or user’s This will impact not only the agreements that var-
successor in title, the patient’s or user’s health ious parties have with one another, but also create
insurance company or other third parties compliance risks for new parties in the supply chain,
affected by the damage caused to the patient or

Chapter 14
depending on the Member State. Some Member States health/documents/eudralex/vol-1/index_en.htm. Accessed 3

already regulate distributors. April 2020.
5. New Approach to Standardisation in the Internal Market. EC
website. https://healthmanagement.org/c/it/issuearticle/new-ap-
Conclusion proach-to-standardisation-in-the-internal-market. Accessed 9
European laws are proposed by the Commission and April 2020.
6. Interpretation of the relation between the revised Directive
debated and adopted by the Council (representing 93/42/EEC concerning medical devices and Directive
the Member State governments) and the European 89/686/EEC on personal protective equipment. Quality First
Parliament (representing the citizens). They are directly International website. http://www.qualityfirstint.com/interdoc2.
applicable decisions and regulations, and directives that pdf. Accessed 3 April 2020.
7. Interpretation of the relation between the revised Directives
must be transposed into Member States’ national laws. 90/385/EEC and 93/42/EEC concerning (active implantable)
Medical devices are regulated primarily by means medical devices and Directive 2006/42/EC on machinery (21
of New Approach directives or regulations. These August 2009). Quality First International website. http://www.
contain general requirements, which are elaborated in qualityfirstint.com/interdoc1.pdf. Accessed 3 April 2020.
8. European Commission Blue Guide. Section 4.1. EC website.
detail in harmonised technical standards. Compliance http://ec.europa.eu/DocsRoom/documents/11502. Accessed 3
is denoted by CE marking, which allows the device to April 2020.
be placed on the market in all EU Member States and 9. Ibid, Chapter 5.
some other countries that have specific agreements with 10. MEDDEV 2.12/2 Rev. 2. Guidelines on Medical Devices—Post
Market Clinical Follow-Up Studies – A Guide for Manufacturers
the EU, which together make up the ‘Union.’ Final and Notified Bodies ( January 2012). EC website. http://ec.eu-
responsibility for placing medical devices on the market ropa.eu/docsroom/documents/10334?locale=en. Accessed 3
belongs to the legal manufacturer whose name is on the April 2020.
label and on the Declaration of Conformity. Under the 11. Ibid.
12. Ibid.
EU MDR and EU IVDR, importers and distributors 13. Regulation (EC) No. 765/2008 of the European Parliament
also are responsible for ensuring compliance of devices and Council of 9 July 2008 setting out the requirements for
in the supply chain. For medium- and high-risk prod- accreditation and market surveillance relating to the marketing
ucts, the legal manufacturer must undergo a conformity of products and repealing Regulation (EEC) No. 339/93. EUR-
Lex website. https://eur-lex.europa.eu/LexUriServ/LexUriServ.
assessment by a notified body whose scope includes the do?uri=OJ:L:2008:218:0030:0047:EN:PDF. Accessed 9 April
specific product to be marketed. 2020.
Significant guidance has been issued by the 14. Decision No. 768/2008/EC of the European Parliament and
Commission and other key players. Member States’ Council of 9 July 2008 on a common framework for the market-
ing of products, and repealing Council Decision 93/465/EEC.
competent authorities are responsible for enforcing EUR-Lex website. http://eur-lex.europa.eu/legal-content/EN/
compliance. These enforcement actions and national TXT/?uri=CELEX%3A32008D0768. Accessed 3 April 2020.
court decisions provide further legal interpretations. 15. Regulation (EC) No. 764/2008 of the European Parliament and
Ultimate responsibility for interpreting the law rests Council of 9 July 2008 laying down procedures relating to the
application of certain national technical rules to products law-
with CJEU. fully marketed in another Member State and repealing Decision
No. 3052/95/EC. EUR-Lex website. http://eur-lex.europa.eu/
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Accessed 3 April 2020. 50. European Commission. Overview of MEDDEVs, guidance
30. Manual on Borderline and Classification in the Community, and informative documents. EC website. http://ec.europa.
Regulatory Framework for Medical Devices, Version 1.11, eu/growth/sectors/medical-devices/guidance/index_en.htm.
December 2011. SCRIBD website. https://www.scribd.com/ Accessed 3 April 2020.
document/92246814/Manual-Borderline. Accessed 3 April 51. Ibid.
2020. 52. Ibid.
31. BIOS Naturprodukte (Case C-27/08 BIOS Naturprodukte 53. Ibid.
GmbH v Saarland. EUR-Lex website. http:// 54. Notified Body Operations Group website. www.nbog.eu.
eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=O- Accessed 3 April 2020.
J:C:2009:153:0010:0011:EN:PDF) and Hecht Pharma 55. Op cit 30.
(C-140/07 HechtPharma v Bezirksregierung Lüneburg. EUR- 56. TEAM-NB. Position papers of TEAM-NB. TEAM-NB
Lex website. http://eur-lex.europa.eu/LexUriServ/LexUriServ. website. http://www.team-nb.org/team-nb-position-papers.
do?uri=CELEX:62007CJ0140:EN:HTML). Court of Justice of Accessed 3 April 2020.
the European Communities. Accessed 3 April 2020. 57. TEAM-NB. Other documents of TEAM-NB. TEAM-NB
32. Index of MEDDEV guidance documents. EC website. http:// website. http://www.team-nb.org/documents. Accessed 3 April
ec.europa.eu/growth/sectors/medical-devices/guidance/index_ 2020.
en.htm. Accessed 3 April 2020. 58. TEAM-NB. External documents, such as documents from
33. Ibid. NB-MED. TEAM-NB website. https://www.team-nb.org/
34. MDD Article 1(2)(h). EUR-Lex website. http:// nb-med-documents. Accessed 3 April 2020.
eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=CONS- 59. Medtech Europe website. https://www.medtecheurope.org/.
LEG:1993L0042:20071011:en:PDF and AIMDD Article 1(2) Accessed 3 April 2020.
(h). EUR-Lex website. http://eur-lex.europa.eu/LexUriServ/ 60. List of Contact Points Within the National Competent
LexUriServ.do?uri=CELEX:31990L0385:en:HTML, Authorities. EC website. http://ec.europa.eu/growth/sectors/
and IVDD Article 1(2)(i) in the IVDD (http:// medical-devices/contacts/index_en.htm. Accessed 3 April 2020.
eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=CONS- 61. International Organization for Standardization website. www.
LEG:1998L0079:20031120:en:PDF. Accessed 3 April 2020. iso.org. Accessed 3 April 2020.
35. Interpretative document of the Commission’s services on placing on 62. International Electrotechnical Commission website. www.iec.ch.
the market of medical devices (16 November 2010). EC website. Accessed 3 April 2020.
https://ec.europa.eu/docsroom/documents/10265/attach- 63. European Committee for Standardization website. www.cen.eu.
ments/1/translations/en/renditions/pdf. Accessed 3 April 2020. Accessed 3 April 2020.
36. Op cit 10. 64. European Committee for Electrotechnical Standardization
37. Article 4(3) MDD. EUR-Lex website. http:// website. www.cenelec.eu. Accessed 3 April 2020.
eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=CONSLE- 65. PIP-action plan. EC website. http://ec.europa.eu/growth/sec-
G:1993L0042:20071011:en:PDF. Accessed 3 April 2020. tors/medical-devices/pip-action-plan/index_en.htm. Accessed 3
38. Ibid. April 2020.
39. Article 1(2)(i) MDD. EudraLex website. http:// 66. Article 93(2) EU MDR; Article 88(2) EU IVDR.
eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=CONS- 67. Article 93(5) EU MDR; Article 88(5) EU IVDR.
LEG:1993L0042:20071011:en:PDF. Accessed 3 April 2020. 68. Regulation (EU) 2017/745 of the European Parliament and
40. Ibid. of the Council of 5 April 2017 on medical devices, amend-
41. Op cit 10. ing Directive 2001/83/EC, Regulation (EC) No. 178/2002
42. Article 1(2)(d) MDD. EudraLex website. http:// and Regulation (EC) No. 1223/2009 and repealing Council
eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=CONSLE- Directives 90/385/EEC and 93/42/EEC (EU MDR). EUR-
G:1993L0042:20071011:en:PDF. Accessed 3 April 2020. Lex website. http://eur-lex.europa.eu/legal-content/EN/
43. Guidance Note for Manufacturers of Custom-Made Medical TXT/?uri=CELEX%3A32017R0745. Accessed 3 April 2020.
Devices (November 2009). file:///C:/Users/ghall/Downloads/ 69. Regulation (EU) 2017/746 of the European Parliament
notes-for-manufactures-custom-made-md_en.pdf. Accessed 9 and of the Council of 5 April 2017 on in vitro diagnos-
April 2020. tic medical devices and repealing Directive 98/79/EC and

Chapter 14
Commission Decision 2010/227/EU (EU IVDR). EUR-

Lex website. http://eur-lex.europa.eu/legal-content/EN/
TXT/?uri=CELEX%3A32017R0746. Accessed 3 April 2020.
70. Op cit 68, Ibid. Article 10(16) EU MDR; Article 10(15) EU
IVDR.
71. Ibid. Article 10(16) EU MDR; Article 10(15) EU IVDR.
72. Ibid. Article 11(5) EU MDR and EU IVDR.
73. Ibid. Article 10(14) EU MDR; Article 10(13) EU IVDR.

Chapter 15
Medical Devices: Legislation

and Classification
Updated by Ruthanne Vendy, RAC and Chauneen Leah Wood, MS, RAC
OBJECTIVES □ Commission Directive 2003/12/EC of 3 February

□ Overview of the European Union (EU) Legislative in the framework of Directive 93/42/EEC con-
Framework cerning medical devices
□ Understand the differences between classes, □ Commission Directive 2005/50/EC of 11 August
categories, special devices and devices without 2005 on the reclassification of hip, knee and
a medical purpose shoulder joint replacements in the framework of
Council Directive 93/42/EEC concerning medi-
□ Gain insight into basic concepts and application
cal devices
of classification rules
□ Council Directive 90/385/EEC of 20 June 1990
□ Provide sources for related guidance
□ Become aware of nuances relating to States relating to active implantable medical
classification devices (End of validity: 25 May 2020)

concerning medical devices
COVERED IN THIS CHAPTER** □ Directive 98/79/EC of the European Parliament
and of the Council of 27 October 1998 on in vitro
□ Report on the functioning of the Medical diagnostic medical devices
Devices Directive 93/42/EC of 14 June 1993;
Medical Devices Experts Group, 5 June 2002 □ Directive 2007/47/EC of the European
Parliament and of the Council of 5 September
□ Regulation (EU) 2017/745 of the European 2007 amending Council directives 90/385/EEC;
Parliament and of the Council of 5 April 2017 93/42/EEC and Directive 98/8/EC
2001/83/EC, Regulation (EC) No. 178/2002 and □ Manual on Borderline and Classification in the
Regulation (EC) No. 1223/2009 and repealing Community Regulatory Framework for Medical
Council Directives 90/385/EEC and 93/42/EEC Devices, Version 1.22 (05-2019)
□ Regulation (EU) 2017/746 of the European □ MEDDEV 2.1/3 Rev. 3: Borderline products,
Parliament and of the Council of 5 April 2017 drug-delivery products and medical devices
on in vitro diagnostic medical devices and incorporating, as integral part, an ancillary
repealing Directive 98/79/EC and Commission medicinal substance or an ancillary human
Decision 2010/227/EU blood derivative (December 2009)

Chapter 15
□ MEDDEV 2.1/5: Medical devices with a measur- confirm the appropriate regulatory controls and confor-
ing function (June 1998) mity assessment procedures are in place.
To ensure conformity assessment under the med-
□ MEDDEV 2.1/6: Qualification and classification ical device legislation works effectively, manufacturers
of stand-alone software (July 2016) should determine their products’ classification as early
in the development process as possible. The classifi-
□ MEDDEV 2.4/1 Rev. 9: Classification of medical
cation of medical devices, in general, is a risk-based
devices (June 2010)
system taking the potential risks to patient or public
□ MEDDEV 2.14/1 Rev. 2: IVD Medical Device safety into consideration if products fail to function.
Borderline and Classification Issues (January This approach uses criteria that can be combined in
2012) various ways to determine classification.
The current medical device directives were recently
□ Factsheet for manufacturers of in vitro diag- reviewed and transposed into two new regulations.
nostic medical devices (European Commission While this chapter is based on the new regulations, it
website: https://ec.europa.eu/docsroom/ also provides a comparative overview of the medical
documents/31202) device landscape in light of the current directives.
The Medical Devices Directives and the

EU Legislation and Regulatory Framework Medical Devices Regulation
The EU legislative framework incorporates a system of
Council Directive 93/42/EEC, known as the Medical
governing laws aimed to promote health, maintain pub-
Devices Directive (MDD), together with the Active
lic safety and enable the circulation of free trade. This
Implantable Medical Devices Directive (AIMDD)
framework includes various binding and non-binding
(Directive 90/385/EEC) and the In Vitro Diagnostics
legal acts that may or may not be applied throughout
Medical Devices Directive (IVDD) (Directive 98/79/
the European Economic Area.
EC) constitute the legal framework for medical devices
• A Regulation is a binding legislative act that
in the EU. These directives have been supplemented by
is immediately enforceable across all EU
several modifying directives, including the last technical
Member States.
revision brought about by Directive 2007/47/EC.
• A Directive is a binding legislative act that
These directives have been transposed into national
must be adopted/transposed into national law.
legislation by each EU Member State. Although the
Although the national transpositions largely
national transpositions largely follow the directives, they
follow the directives, they also contain spe-
also contain specific requirements with which devices in
cific requirements with which devices in their
their respective national territories must comply. These
respective national territories must comply.
three directives govern pre and postmarket requirements
• A Recommendation is a non-binding act
compulsory for consumer access to the technology.
that allows the EU Commission, Council or
In May 2017, European Parliament published two
Parliament to suggest a course of action with-
new device regulations in the EU Official Journal.
out imposing legal obligation.
• Regulation (EU) 2017/745 of the European
• An Opinion is another means by which the
Parliament and of the Council of 5 April
EU Commission, Council or Parliament may
2017 on medical devices amending Directive
make statements in a non-binding fashion.
2001/83/EC, Regulation (EC) No. 178/2002
and Regulation (EC) No. 1223/200 repeals the
Introduction Medical Device Directive 93/42/EEC (MDD)
Europe is the second largest market for medical devices, and the Active Implantable Medical Device
after the US. Medical devices represent a critical seg- Directive 90/385/EEC (AIMDD)
ment of evolving healthcare systems, covering an array • Regulation (EU) 2017/746 of the European
of products. It’s been noted there are 10,000 different Parliament and of the Council of 5 April
families of medical device types, suggesting that there 2017 on in vitro diagnostic medical devices
are more than 400,000 devices and/or accessories on repeals the In Vitro Diagnostic Medical Devices
the EU market.1 These products represent varying lev- Directive 98/79/EC (IVDD). It is important to
els of risk to patients and users in practice; therefore, note that Regulation (EU) 2017/745 (MDR)
they require different levels of regulatory control. The replaces the MDD and the AIMDD and there-
medical device classification system was developed to fore covers both medical devices and active
evaluate the risk profile of a device, and by extension to

Medical Devices: Legislation and Classification
implantable medical devices. Although the EU fraudulent production of non-medical grade silicone in
MDR and the EU IVDR are already entered breast implants highlighted weaknesses in the legislative
into force, transition provisions apply. This system in place at the time. These issues damaged the
means that the MDD, AIMDD and the EU confidence of patients, consumers and healthcare pro-
MDR are all active and applicable during the fessionals in the safety of medical devices. Public outcry
period of transition. and consumer demand to ensure the safety of medical
devices available in the EU had to be strengthened.
The transition timeframe allows device manufacturers Moreover, revision to the legislative framework was
three years to comply with the EU MDR (May 2020) necessary to confirm the EU’s role as a global leader in
and five years to comply with the EU IVDR (May 2022). healthcare over the long-term, considering the techno-
Transition periods allow manufacturers adequate time to logical and scientific developments in this sector.
plan and implement changes to ensure compliance with The implementation of the EU MDR represents a
the new legislation (i.e., updates to quality management paradigm shift from a generalized approach to a high
systems). Transition timeframes also aim to prevent dis- level of control. The EU MDR is much more prescrip-
ruption of medical device availability to market. tive with increased requirements for the regulation
The new medical devices regulations contain of medical devices. It also introduces more stringent
a series of important improvements to the current standards for notified bodies. In addition, some of the
legislation: stand-alone guidance documents or MEDDEVs, which
• a more stringent process for the designation were not legally binding, have now been incorporated
and oversight of notified bodies into the regulation. The new regulations are designed to
• inclusion of select non-medical devices that ensure a level of health and safety protections for EU
present similar characteristics and risk profiles citizens by strengthening medical device safety require-
as analogous medical devices under the scope ments across member states. The legislation framework
of these regulations supports the significant technological and scientific
• introduction of a new risk classification system progress that occurred in the European sector over the
for in vitro diagnostic medical devices past two decades.
• improved transparency through the expansion
of a comprehensive European database on Guidance Documents: MEDDEVs, MDCG
medical devices (Eudamed) which includes and NBOG Guidance
a device traceability system based on Unique The European commission in collaboration with
Device Identification (UDI) industry, professional associations and notified bod-
• reinforcement of the clinical evidence rules, ies issue guidance documents that can be used to aid
including an EU-wide coordinated proce- in the implementation of medical device legislation.
dure for authorizing multi-centre clinical Guidelines that support the current MDD, AIMDD
investigations and the IVDD are active and still relevant. Those meant
• improved coordination of vigilance and market to compliment the EU MDR and EU IVDR are cur-
surveillance mechanisms among EU countries rently under revision. These guidance documents remain
useful in the application of medical device legislation, it
The impetus for change of the current directives (MDD, is important to remember that guidance documents are
AIMDD and IVDD) to the EU MDR and EU IVDR not legally binding.
regulations is to improve consumer safety and transpar-
ency, while enabling consistent free trade. The Medical
Scope and Definitions
Device Directives have been the subject of evaluation
since the directives first entered into force. The Medical The EU MDR and the MDD apply to not only
Devices Experts Group (MDEG) in “A Report on the medical devices, but also their accessories, which
Function of the Medical Devices Directive (93/42/EC are considered medical devices. The new regulations
of 14 June 1993),”2 evaluated the functionality of the provide rather comprehensive definition of a medi-
directive, and outlined areas of potential improvement. cal devices, and their accessories.
This working group had been making tremendous
strides in their evaluation the directives under the “New Medical Device
Approach.” Unfortunately, the work being done on the A ‘medical device’ is defined in Article 2 of the EU
functionality of the directives was overshadowed by MDR as “any instrument, apparatus, appliance, software,
public tragedy. Problems with diverging interpretation implant, reagent, material or other article intended by
of the current directives and an incident concerning the manufacturer to be used, alone or in combination,

Chapter 15
for human beings for one or more of the following spe- This definition was revised from the original MDD
cific medical purposes: text to clarify that prescribers of custom-made devices
• diagnosis, prevention, monitoring, prediction, must be qualified professionals must be authorized by
prognosis, treatment or alleviation of disease national law.
• diagnosis, monitoring, treatment, alleviation of,
or compensation for, an injury or disability In Vitro Diagnostic Medical Device
• investigation, replacement or modification of Article 2 of the EU IVDR defines an in vitro diagnos-
the anatomy or of a physiological or pathologi- tic medical device as “any medical device which is a
cal process or state reagent, reagent product, calibrator, control material, kit,
• providing information by means of in vitro instrument, apparatus, piece of equipment, software or
examination of specimens derived from the system, whether used alone or in combination, intended
human body, including organ, blood and tis- by the manufacturer to be used in vitro for the examina-
sue donations and which does not achieve its tion of specimens, including blood and tissue donations,
principal intended action by pharmacological, derived from the human body, solely or principally for
immunological or metabolic means, in or on the purpose of providing information on one or more of
the human body, but which may be assisted in the following:
its function by such means.”3 • concerning a physiological or pathological
process or state
The definition noted above has been expanded from the • concerning congenital physical or mental
MDD, to now include “prediction and prognosis” of a impairments
disease or health condition. This expanded definition also • concerning the predisposition to a medical
incorporates devices that do not have a medical purpose. condition or a disease
An example of devices that do not have a medical • to determine the safety and compatibility with
purpose (now categorized as medical devices) include: potential recipients
• devices for the control or support of concep- • to predict treatment response or reactions
tion products specifically intended for the • to define or monitoring therapeutic measures”6
cleaning, disinfection or sterilisation
The in vitro diagnostic medical device accessory defi-
Accessories nition in Article 2 of the EU IVDR is identical to the
Article 2 of the EU MDR defines a medical device medical device accessory definition in the EU MDR,
accessory as “an article which, whilst not being itself a with the addition of “in vitro diagnostic” references.
medical device, is intended by its manufacturer to be used
together with one or several particular medical device(s) Specimen Receptacles
to specifically enable the medical device(s) to be used in Specimen receptacles also shall be deemed to be in vitro
accordance with its/their intended purpose(s) or to spe- diagnostic medical devices. Article 2 of the EU IVDR
cifically and directly assist the functionality of the medical defines a specimen receptacle as a “device, whether of a
device(s) in terms of its/their intended purpose(s).”4 vacuum-type or not, specifically intended by its manu-
facturer for the primary containment and preservation
Custom-Made Devices of specimens derived from the human body for the pur-
The definition of custom-made devices per Article 2 of pose of in vitro diagnostic examination.”7
the EU MDR are those “specifically made in accordance
with a written prescription of any person authorised by Intended Purpose
national law by virtue of that person’s professional qual- ‘Intended purpose’ means the use for which a device is
ifications which gives, under that person’s responsibility, intended according to the data supplied by the man-
specific design characteristics, and is intended for the ufacturer on the label, in the instructions for use or in
sole use of a particular patient exclusively to meet their promotional or sales materials or statements or as spec-
individual conditions and needs. ified by the manufacturer in the performance evaluation.
However, mass-produced devices which need to
be adapted to meet the specific requirements of any Summary of Requirements
professional user and devices which are mass-produced The implementation of the medical device directives in the
by means of industrial manufacturing processes in 1990s marked a significant shift in the regulatory frame-
accordance with the written prescriptions of any autho- work beyond the emphasis on harmonizing trade among
rised person shall not be considered to be custom-made Member States. The MDD aimed to standardize the
devices.”5 movement of medical devices throughout the EU, placing

said devices on the market, and bringing them into service. conformity assessment, which is required for certain
The Directives “New Approach” acknowledged evolving Class I devices and all Class IIa, IIb and III devices, the
medical technology, the complexity of new product devel- notified body’s identification number is placed next to
opment and the criticality of bringing products to market (or under) the CE Mark.
that meet safety and performance standards. Devices CE-marked under MDD or AIMDD
Under the current MDD, AIMDD and IVDD, certificates may continue to be placed on the market as
design and manufacturing of medical devices are subject long as these certificates are valid. However, despite the
to a conformity assessment of Essential Requirements expiry date, all MDD certificates will become void on
(ER). ERs are the requirements for the safety and per- 26 May 2024. Notified bodies accredited per the EU
formance of a device, as outlined in the directives. MDR before the date of application can start issuing
The European Commissions’ adoption of the certificates under the EU MDR.
EU MDR and EU IVDR established a more robust
regulatory framework; restructured to ensure greater General Classification Principles
protection of public health and patient safety. Once the The classification principles remain essentially the same
transition period has lapsed, the MDD, AIMDD and under the new regulations; however, a thorough assess-
the IVDD will be repealed. The EU MDR and the EU ment of a device is required. Although the classification
IVDR will be the only two regulations to which medical process is still a rule-based system, the classification
devices must comply. Medical device manufacturers schemes are more detailed in the EU MDR and EU
must then demonstrate compliance with confor- IVDR. Some rules have been combined with other
mity assessment via General Safety and Performance rules. The classification scheme that may have applied
Requirements (GSPR) prescribed in the new regula- prior to the adoption of the new regulations may have
tions. The GSPR expands the scope of the ERs outlined an impacted relative to device class and conformity
in the original directives, on topics relative to risk, assessment route. Table 15-1 is a classification matrix
labelling and the use of harmonized standards. A man- demonstrating the new and amended rules in Annex
ufacturer utilizes the GSPR to verify compliance to the VIII, Chapter III.
conformity assessments routes. The routes to medical The first step in the classification process is deter-
device compliance depend on the device’s classification. mining whether the product falls within the definition of
A recommended method of compliance with a medical device; this includes active implantable medical
safety and performance requirements is by using EU device or an in vitro diagnostic medical device. Evaluating
harmonised standards. A harmonised standard is a the product’s characteristics, especially its intended use,
European standard developed by a recognised European indications for use and mode of action are significant
Standards Organisation: CEN, CENELEC or ETSI. considerations (in addition to respective regulation). Once
Economic operators and conformity assessment bodies the product is confirmed to be a medical device and its
use harmonised standards to demonstrate that prod- regulation identified, its class can then be determined.
ucts, services, or processes comply with EU legislation.
as well as demonstrate safety and performance. In Rule-Based Approach for Classification
addition to compliance to the harmonised standards, The EU MDR, similar to the MDD, utilizes a rule-
notified bodies may also require compliance to state- based classification system, which is outlined in Annex
of-the-art standards. It is recommended to consider VIII. The rules take into account multiple variables,
both the European harmonised standards as well as all such as intended purpose, invasiveness, contact type
state-of-the-art and international standards. The list of (e.g., skin surface, injured skin, etc.), anatomical location
published harmonised standards is available at the stan- (e.g., body orifice, central nervous system, central circu-
dardisation website.8 latory system, etc.), energy source and length of contact
Once the regulatory obligations of the medical (e.g., transient, short-term or long-term).
device directives or regulations have been fulfilled, the The manufacturer determines the device’s appro-
manufacturer or its authorised representative must sign priate class using the classification principles and rules,
a Declaration of Conformity (DoC). A Declaration based on the device’s intended purpose and mode of
of Conformity is document written and executed by a action. As per the MDD, the EU MDR also classifies
manufacture that attests that their product (which is the medical devices, taking into account their intended
subject of the DoC) meets the safety and performance purpose and inherent risks in accordance with the
standards of EU legislation. The DoC is part of the provisions of MDR Annex VIII, which includes classifi-
evidence package maintained by the manufacture, and/ cation rules subdivided into four groups as follows:
or submitted to a notified body in consideration of a • non-invasive devices
CE Mark. If a notified body has been involved in the • invasive devices

Chapter 15
Table 15-1. MDR Annex VIII, Chapter III Classification Matrix
Non- Rule 1 Rule 2 Rule 3 Rule 4

Invasive
Devices For non- Non-invasive devices Non-invasive devices modifying Non-invasive devices
invasive that channel or store biologic/chemical of body fluids or that come into
devices where blood, cells, tissues, other liquids incorporating substances contact with injured
another rule liquids or gases to be used in vitro skin or mucous
does not apply membrane
Invasive Rule 5 Rule 6 Rule 7 Rule 8

Devices
Devices Devices that are Devices that are Devices that are surgically invasive
invasive via a surgically invasive for surgically invasive for for long-term use and/or those that
body orifice transient use short-term use are implantable devices
Active Rule 9 Rule 10 Rule 11 Rule 12 Rule 13

Devices
Active devices Active devices Software Active devices For active devices
intended to intended for intended to administer where Rules 9, 10,
administer diagnosis and or remove drugs, body 11 or 12 do not apply
or exchange monitoring liquids and substances (was MDD Rule 12)
energy or to/from the body (was
emit ionizing MDD Rule 11)
radiation
Special Rule 14 Rule 15 Rule 16 Rule 17 Rule 18
Rules
Devices Devices intended Devices Devices intended to Devices
incorporating for contraception or intended record or diagnose manufactured using
a medicinal prevention of STDs to clean, x-ray images (was MDD non-viable tissues
product (with (was MDD Rule 14) disinfect and Rule 16) and cells
ancillary rinse other
action) medical
devices
Rule 19 Rule 20 Rule 21 Rule 22
Devices that Devices intended to Devices that are Devices that are active therapeutics
incorporate administer drugs via composed of substances with a diagnostic function that
nanomaterials inhalation to be introduced into the determines the patient management
human body
Note: The rules in bold italics indicate a new or amended rule. In some cases, only minor clarifications were made to the rule. These were still
captured as an amended rule, even if the intent of the rule didn’t change.
• active devices • Custom-made device: “any device specifically

• special rules made in accordance with a duly qualified med-
ical practitioner’s written prescription which
Devices That are not Classified gives, under his responsibility, specific design
Special device categories fall outside the classification characteristics and is intended for the sole use
system. Device regulations and directives recognise of a particular patient”
certain device categories are subject to requirements • Investigational device: device intended for
different from those intended for CE marking or plac- clinical investigation
ing on the market. These special categories are defined • Device authorised by the national competent
as follows: authority “in the interest of protection of

Table 15-2. MDR Classification Rules for Non-Invasive Medical Devices
Class I All other non-invasive In contact with

devices that do not fall injured skin or
under another rule mucous membrane
for compression or
absorption
Class IIa For channeling or storing To modify composition of In contact with injured
substances or body blood or liquids intended skin or mucous
tissue to be introduced for infusion using only membrane to manage
to the body connected to filtration, centrifugation the micro-environment
active Class IIa or higher or gas/heat exchange
Class IIb Blood bags In contact with injured In contact with injured
skin or mucous skin or mucous
membrane to manage membrane with
the micro-environment breached dermis or
mucous membrane
Class III To modify composition
of blood or liquids in
vitro in direct contact
with human cells, tissue,
organs or embryos
before implant or
administration into the
body
health”: this category is not defined but usu- body assessments are required for Classes B, C and D.
ally is understood to be a situation where the Similarly, the EU IVDD also divides IVDs into four
device is not CE-marked, but there is a real groups. General are the lowest risk devices under the
clinical need for it on compassionate grounds. IVDD; these do not require notified body involvement.
In this case, the competent authority may The self-test IVDs and Annex II (List A and B) IVDs
authorise placing the device on the market require notified body assessment.
within its territory. Some of these devices may The IVDD took more of a “list-based approach” to
be orphan devices. assigning risk classes, while the EU IVDR is a “rule-
based approach” focusing more on risk class. This shift
In Vitro Diagnostic Regulation effected how the process for conformity assessment
This rule-based classification system is new for the is determined. Thus, it is expected that approximately
EU IVDR. Previously, IVDs were classified by type or 85% of all IVDs will need some level of notified body
medical conditions. Now, intended use and risk are con- oversight.9
sidered for classification, using the rules in Annex VIII. See Table 15-7 for IVDR Annex VIII, I
Similar to the EU MDR, if more than one rule is appli- Classification Matrix and Table 15-8 for a comparison
cable, the highest classification takes precedence. of IVDD and IVDR Device Classification Rules
The EU IVDR and IVDD differentiate between
products for professional and patient use, defining Basic Principles of Application
the latter, a “device for self-testing,” as “any device The manufacturer must consider all the classification
intended by the manufacturer to be used by lay per- rules. Often, due to the nature of the device, two or
sons.” According to the EU IVDR, considering devices’ more rules may apply to the device. In such a case,
intended purposes and inherent risks, in vitro diag- the highest possible classification applies. The same
nostic devices now are classified into four classes (A, principle applies to devices that can be used on differ-
B, C and D), with Class A being the lowest risk IVDs ent parts of the body or have multiple purposes, i.e.,
and Class D being the highest risk IVDs. Notified the application resulting in the highest possible class

Chapter 15
Table 15-3. MDR Classification Rules for Invasive Medical Devices
Class I Transient via a body orifice Reusable, surgical

not connected to an active instruments
device or to a Class I active
device
Short-term invasive used in
the mouth, ear or nose
Class IIa Used short-term invasively Surgically invasive for Surgically invasive for Implantable and long-term
except oral, nasal or in the transient use short-term use surgically invasive in the
ear teeth
Long-term, non-absorbable
used in the mouth, ear or
nose
Used in body orifice
connected to an active
Class IIa or higher
Class IIb Long-term invasive except Surgically invasive for Surgically invasive short- Implantable and long-term
used in the mouth, ear, or transient use supplying term supplying ionising surgically invasive
nose ionising radiation radiation
Surgically invasive for Surgically invasive short-
transient use that gets term with chemical change
absorbed or has another in the body
biological effect
Surgically invasive for Surgically invasive for
transient use to administer short-term use that
medicinal products in a administer medicine
potentially hazardous way
Class III Surgically invasive for Surgically invasive for direct Implantable and long-term
direct transient use with the short-term use with the surgically invasive for direct
heart, central circulatory heart, central circulatory short-term use with heart,
system or central nervous system or central nervous central circulatory system
system system or central nervous system
Surgically invasive for Implantable and long-
short-term use that gets term surgically invasive
absorbed or has another that gets absorbed, has
biological effect another biological effect,
undergoes a chemical
change in the body,
administers medicine,
active implantables, breast
implants, surgical meshes,
joint replacements and/or
come into contact with the
spinal column
applies. Individual devices used in a system—e.g., an Key Classification Concepts

extracorporeal blood circulation system containing an The EU classification system is based on an understand-
oxygenator, a pump and tubes—can be classified in their ing of key device characteristics and the following use
own right or the system can be classified as a whole, in scenarios:
which case the item in the highest classification is the 1. time period
class for the entire system. 2. degree of invasiveness
3. energy use

Table 15-4. MDR Classification Rules for Active Medical Devices
Rule 9 Rule 10 Rule 11 Rule 12 Rule 13

Class I Devices intended Software, if no other Active medical devices
to illuminate the rule applies where no other rule
patient’s body in the applies
visible spectrum
Class IIa Active devices used Software intended to Active devices
for diagnosis and provide information intended to
monitoring that is used for administer/remove
diagnosis or medicinal products,
Active devices
therapeutic purposes body liquids or other
that supply energy
substances to/from
absorbed by the
the body
human body
Active devices used
to image in vivo
radio-pharmaceutical
distribution
Class IIb Active devices used to Active devices used Software intended to Active devices
administer/ exchange to diagnose/ monitor provide information intended to
energy in a hazardous vital physiological that is used for administer/remove
way parameters that could diagnosis or medicinal products,
result in immediate therapeutic purposes body liquids or
danger to the patient that may cause other substances to/
Active devices used or used for diagnosis serious deterioration from the body in a
to control/ monitor in situations where of health or need for potentially hazardous
active therapeutic the patient is in surgical intervention way (considering the
Class IIbs immediate danger substance involved,
part of the body
Active devices used to Active devices
concerned and mode
emit ionizing radiation intended to emit
of application)
for therapeutic ionizing radiation
purposes and intended
for diagnostic or
therapeutic radiology
Class III Active devices used Software intended to
to control/ monitor provide information
active implantables that is used for
diagnosis or
therapeutic purposes
that may cause
death or irreversible
deterioration of health
4. biological activity and/or incorporation of • long-term use: normally intended for continu-
drugs ous use more than 30 days
These concepts related to safety and/or hazards are crit- Manufacturers should consider known industry proce-
ical for determining the risk profile of the device. dural standards. For example, a specific type of device
may be intended for use by the manufacturer in medical
Time Period treatments for transient use. However, if the manufac-
The device’s duration of use is categorised as follows: turer becomes aware (for example, through literature,
• transient use: normally intended for continu- postmarket surveillance, clinical data, etc.) that their
ous use for less than 60 minutes device is being used in short-term procedures lasting
• short-term use: normally intended for contin- more than 60 minutes, the manufacturer should recon-
uous use between 60 minutes and not more sider the device’s duration of use.
than 30 days

Chapter 15
Table 15-5a. Special MDR Rules: Medical Devices
Rule 14 Rule 15 Rule 16 Rule 17 Rule 18

Class I
Class IIa Devices intended Devices that record
specifically for diagnostic images via
disinfecting or x-ray radiation
sterilizing medical
devices
Class IIb Contraceptives and/ Devices used
or devices used for for disinfection/
the prevention of cleaning/rinsing/
sexually transmitted hydrating contact
diseases lenses
Disinfecting
solutions and
washer-disinfectors
for invasive device
processing/
reprocessing
Class III Devices incorporating Implantable or long- Devices using non-
a medicinal product term contraceptives viable human or
with an ancillary and/or devices used animal tissues or
action to the device for the prevention of derivatives
sexually transmitted
diseases
Table 15-5b. Special MDR Rules: Medical Devices

Class I
Class IIa Devices incorporating Invasive devices with Devices made of substances
nanomaterial with respect to body orifices, that are absorbed by or
negligible potential for other than surgically dispersed in the nasal or
internal exposure invasive devices, which oral cavities
are intended to administer
medicinal products by
inhalation (inhalers)
Class IIb Devices incorporating Invasive devices intended Devices made of substances
nanomaterial with low to administer medicinal that are absorbed by or
potential for internal products by inhalation dispersed in the human
exposure in a way that impacts body if no other rule applies
the efficacy/safety of the
administered product
or used to treat life-
threatening conditions
Class III Devices incorporating Devices made of substances Active therapeutic devices
nanomaterial with high intended to be introduced with an integrated or
potential for internal into the human body via incorporated diagnostic
exposure a body orifice or applied function which significantly
to the skin and that are determines the patient
systemically absorbed management by the device

Invasiveness Energy Use

A device which, in whole or in part, penetrates inside Energy is a risk factor because of its potential for sys-
the body, either through a body orifice or through the temic effects and the difficulty in restricting it to a
surface of the body is considered an invasive device. specific location. Thus, the concept of “active device” is
There is a significant difference between invasiveness defined as “any device, the operation of which depends
through a body orifice and surgical invasiveness, which on a source of energy other than that generated by the
involves piercing the body surface. human body for that purpose, or by gravity, and which
“Body orifice” is defined as “any natural opening in acts by changing the density of or converting that
the body, as well as the external surface of the eyeball, or energy. Devices intended to transmit energy, substances
any permanent artificial opening, such as a stoma.” or other elements between an active device and the
“Surgically invasive device” is defined as “an inva- patient, without any significant change, shall not be
sive device which penetrates inside the body through deemed to be active devices.”
the surface of the body, with the aid or in the context of This definition’s critical element is the concept of
a surgical operation, or as a device which produces pen- energy conversion, which must produce a significant
etration other than through a body orifice.” change. Such a significant change is understood to occur
A surgically invasive device does not necessarily when the energy’s nature, level and/or density changes.
involve surgery. For example, needles used for injections The effect of a wire’s resistance is not regarded as a sig-
are regarded as surgically invasive. Surgically inva- nificant change. The conversion can occur in the device
sive devices may be introduced through a temporary, itself (e.g., electrical energy converted to thermal energy)
surgically created opening. Surgical gloves also are con- or at the interface between the device and tissue (e.g.,
sidered to be invasive devices. the conversion produced by an electrical scalpel blade).
The classification system recognises two specific Rules 6, 7, 9 and 10 are the rules in the EU MDR
surgically invasive device subtypes: implants and reus- which address devices intended to supply energy.
able surgical instruments. This distinction clarifies Devices that utilize or deliver ionizing radiation are
that implants, which are thought to be high-risk and classified as Class IIb. Other active therapeutic devices
in Class II or III, from reusable surgical instruments, intended to administer or exchange energy are classified
regarded as low-risk and therefore Class I. as Class IIa or IIb, depending on how the energy is
An “implantable device” is defined as any device, administered/exchanged, as well as the nature, the den-
which is intended to be totally introduced into the sity and site of application of the energy.
human body or to replace an epithelial surface or the
surface of the eye, by clinical intervention and which is Biological Effect
intended to remain in place after the procedure. If a device has a biological effect or is absorbed, it will
Any device intended to be partially introduced generally carry a higher classification (Class IIb or III).
into the human body through surgical intervention and A material is considered to have a biological effect if it
intended to remain in place after the procedure for at actively and intentionally induces, alters or prevents a
least 30 days also is considered an “implantable device.” response from the tissues that is mediated by specific
MEDDEV 2.4/110 further explains “invasiveness” with reactions at a molecular level. Classification rules have
practical examples. been added for devices having a biological effect or
The MDD did not account for level of invasive- composed of substances that are absorbed by or locally
ness. However, the EU MDR classification rules were dispersed in the human body. Classification is impacted
designed to address this by considering where in the by where the device performs its action in or on the
body the device is introduced, the type of contact (e.g., human body, where it is introduced or applied and
intact skin, mucous membrane, etc.) and how long whether a systemic absorption of those substances occurs.
the device remains in the body. For example, invasive The term “absorption” refers to a material’s degrada-
devices introduced via a body orifice are generally Class tion within the body and the metabolic elimination of
I or IIa unless they are used long-term. Surgically the resulting degradation products from the body.
invasive devices are IIa, IIb or III with the exception
of reusable surgical instruments. All implantable and Drug/Device Combinations
long-term surgically invasive devices are Class IIb or Drug-device combination products (DDCs) are medici-
III with the exception of those intended to be placed nal product(s) with medical device/device component(s)
in the teeth. Generally, devices used in the ear, nose or necessary for administration, correct dosing or use of
oral cavity (as far as the pharynx) have a lower-risk clas- the medicinal product.
sification than devices of similar intended use that are Integral DDCs incorporate, as an integral part, a
indicated for other parts of the body. substance that, if used separately, would be considered

Chapter 15
Table 15-6. Comparison of MDD and MDR Device Classification Rules
Rule MDD Device Classification MDR Device Classification

1 All non-invasive devices are classified as Class I, unless one No Change from the MDD
of the rules set out hereinafter applies.
2 All non-invasive devices intended for channeling or storing All non-invasive devices intended for channeling or storing
blood, body liquids, cells or tissues, liquids or gases for the blood, body liquids, cells or tissues, liquids or gases for the
purpose of eventual infusion, administration or introduction purpose of eventual infusion, administration or introduction
into the body are classified as Class IIa: into the body are classified as Class IIa:
• if they may be connected to a Class IIa, Class IIb or • if they may be connected to a Class IIa, Class IIb or
Class III active device Class III active device
• if they are intended for use for channeling or storing • if they are intended for use for channeling or storing
blood or other body liquids or for storing organs, parts blood or other body liquids or for storing organs, parts
of organs or body cells and tissues, except for blood of organs or body cells and tissues, except for blood
bags; blood bags are classified as Class IIb bags; blood bags are classified as Class IIb
In all other cases, such devices are classified as Class I. In all other cases, such devices are classified as Class I.
Blood bags moved to MDR Rule 2 from Rule 18 of MDD.

3 All non-invasive devices intended for modifying the biologi- All non-invasive devices intended for modifying the biologi-
cal or chemical composition of blood, other body liquids or cal or chemical composition of human tissues or cells, blood,
other liquids intended for infusion into the body are in Class other body liquids or other liquids intended for implantation
IIb, unless the treatment consists of filtration, centrifugation or administration into the body are classified as Class IIb,
or exchanges of gas, heat, in which case they are in Class IIa. unless the treatment for which the device is used consists of
filtration, centrifugation or exchanges of gas, heat, in which
case they are classified as Class IIa.
All non-invasive devices consisting of a substance or a

mixture of substances intended to be used in vitro in direct
contact with human cells, tissues or organs taken from the
human body or used in vitro with human embryos before
their implantation or administration into the body are classi-
fied as Class III.
4 All non-invasive devices which come into contact with in- All non-invasive devices which come into contact with in-
jured skin: jured skin or mucous membrane are classified as:
• are in Class I if they are intended to be used as a • Class I if they are intended to be used as a mechanical
mechanical barrier for compression or for absorption of barrier, for compression or for absorption of exudates
exudates • Class IIb if they are intended to be used principally
• are in Class IIb if they are intended to be used princi- for injuries to skin which have breached the dermis
pally with wounds or mucous membrane and can only heal by secondary
• which have breached the dermis and can only heal by intent
secondary intent • Class IIa if they are principally intended to manage
• are in Class IIa in all other cases, including devices the micro-environment of injured skin or mucous
principally intended membrane
• to manage the micro-environment of a wound
Class IIa in all other cases.

Table 15-6. Comparison of MDD and MDR Device Classification Rules (cont.)

5 All invasive devices with respect to body orifices, other than No Change
surgically invasive devices, which are not intended for con-
nection to an active device or which are intended for connec-
tion to a Class I active device are classified as:
• Class I if they are intended for transient use

• Class IIa if they are intended for short-term use, except
if they are used in the oral cavity as far as the pharynx,
in an ear canal up to the ear drum or in the nasal cavity,
in which case they are classified as Class I
• Class IIb if they are intended for long-term use, except
if they are used in the oral cavity as far as the pharynx,
in an ear canal up to the ear drum or in the nasal cavity
and are not liable to be absorbed by the mucous mem-
brane, in which case they are classified as Class IIa.
All invasive devices with respect to body orifices, other than

surgically invasive devices, intended for connection to a
Class IIa, Class IIb or Class III active device are classified as
Class IIa.
6 All surgically invasive devices intended for transient use are All surgically invasive devices intended for transient use are
in Class IIa unless they are: classified as Class IIa unless they:
• intended specifically to control, diagnose, monitor or • are intended specifically to control, diagnose, monitor
correct a defect of the heart or of the central circulatory or correct a defect of the heart or of the central circula-
system through direct contact with tory system through direct contact with those parts of
• these parts of the body, in which case they are in Class the body, in which case they are classified as Class III
III • are reusable surgical instruments, in which case they
• reusable surgical instruments, in which case they are are classified as Class I
in Class I • are intended specifically for use in direct contact with
• intended specifically for use in direct contact with the the heart or central circulatory system or the central
central nervous nervous system, in which case they are classified as
• system, in which case they are in Class III Class III
• intended to supply energy in the form of ionising radia- • are intended to supply energy in the form of ionising
tion in which case radiation in which case they are classified as Class IIb
• they are in Class IIb • have a biological effect or are wholly or mainly
• intended to have a biological effect or to be wholly or absorbed in which case they are classified as Class IIb
mainly absorbed in which case they are in Class IIb • are intended to administer medicinal products by
• intended to administer medicines by means of a deliv- means of a delivery system, if such administration
ery system, if this of a medicinal product is done in a manner that is
• is done in a manner that is potentially hazardous taking potentially hazardous taking account of the mode of
account of the application, in which case they are classified as Class
• mode of application, in which case they are in Class IIb IIb

Chapter 15

7 All surgically invasive devices intended for short-term use • All surgically invasive devices intended for short-term
are in Class IIa unless they are intended: use are classified as class IIa unless they:
• are intended specifically to control, diagnose, monitor
• either specifically to control, diagnose, monitor or or correct a defect of the heart or of the central circula-
correct a defect of the heart or of the central circulatory tory system through direct contact with those parts of
system through direct contact with the body, in which case they are classified as Class III
• these parts of the body, in which case they are in Class • are intended specifically for use in direct contact with
III, or specifically for use in direct contact with the cen- the heart or central circulatory system or the central
tral nervous system, in which case they are in Class III, nervous system, in which case they are classified as
• or to supply energy in the form of ionizing radiation in Class III
which case they • are intended to supply energy in the form of ionizing
• are in Class IIb radiation in which case they are classified as Class IIb
• or to have a biological effect or to be wholly or mainly • have a biological effect or are wholly or mainly
absorbed in absorbed in which case they are classified as Class III
• which case they are in Class III, • are intended to undergo chemical change in the body in
• or to undergo chemical change in the body, except if which case they are classified as class IIb, except if the
the devices are devices are placed in the teeth
• placed in the teeth, or to administer medicines, in • are intended to administer medicines, in which case
which case they are in they are classified as Class IIb
• Class IIb
8 All implantable devices and long-term surgically invasive All implantable devices and long-term surgically invasive
devices are in Class IIb unless they are intended: devices are classified as Class IIb unless they:
• to be placed in the teeth, in which case they are in • are intended to be placed in the teeth, in which case
Class IIa they are classified as Class IIa
• to be used in direct contact with the heart, the central • are intended to be used in direct contact with the heart,
circulatory system the central circulatory system or the central nervous
• or the central nervous system, in which case they are system, in which case they are classified as Class III
in Class III • have a biological effect or are wholly or mainly
• to have a biological effect or to be wholly or mainly absorbed, in which case they are classified as Class III
absorbed, in which • are intended to undergo chemical change in the body in
• case they are in Class III which case they are classified as Class III, except if the
• or to undergo chemical change in the body, except if devices are placed in the teeth
the devices are • are intended to administer medicinal products, in
• placed in the teeth or to administer medicines, in which which case they are classified as Class III
case they are classified in Class III • are active implantable devices or their accessories, in
which cases they are classified as Class III
• are breast implants or surgical meshes, in which cases
they are classified as Class III
• are total or partial joint replacements, in which case
they are classified as Class III, with the exception of
ancillary components such as screws, wedges, plates
and instruments
• are spinal disc replacement implants or are implantable
devices that come into contact with the spinal column,
in which case they are classified as class III with the
exception of components such as screws, wedges,
plates and instruments


9 All active therapeutic devices intended to administer or ex- All active therapeutic devices intended to administer or
change energy are in Class IIa unless their characteristics are exchange energy are classified as class IIa unless their
such that they may administer or exchange energy to or from characteristics are such that they may administer energy to
the human body in a potentially hazardous way, taking ac- or exchange energy with the human body in a potentially
count of the nature, the density and site of application of the hazardous way, taking account of the nature, the density
energy, in which case they are in Class IIb. and site of application of the energy, in which case they are
classified as Class IIb.
All active devices intended to control or monitor the perfor-
mance of active therapeutic devices in Class IIb, or intended All active devices intended to control or monitor the perfor-
directly to influence the performance of such devices are mance of active therapeutic class IIb devices or intended
classified as Class IIb. directly to influence the performance of such devices are
classified as Class IIb.*
All active devices intended to emit ionizing radiation for

therapeutic purposes, including devices which control or
monitor such devices, or which directly influence their per-
formance are classified as Class IIb.
All active devices that are intended for controlling, monitor-

ing or directly influencing the performance of active implant-
able devices are classified as Class III.*
10 Active devices intended for diagnosis are in Class IIa: Active devices intended for diagnosis and monitoring are
classified as Class IIa:
• if they are intended to supply energy which will be
absorbed by the • if they are intended to supply energy which will be
• human body, except for devices used to illuminate the absorbed by the human body, except for devices
patient’s body, in intended to illuminate the patient’s body, in the visible
• the visible spectrum spectrum, in which case they are classified as Class I
• if they are intended to image in vivo distribution of • if they are intended to image in vivo distribution of
radiopharmaceuticals radiopharmaceuticals
• if they are intended to allow direct diagnosis or moni- • if they are intended to allow direct diagnosis or moni-
toring of vital toring of vital physiological processes, unless they are
• physiological processes, unless they are specifically specifically intended for monitoring of vital physiolog-
intended for monitoring of vital physiological parame- ical parameters and the nature of variations of those
ters, where the nature of variations is parameters is such that it could result in immediate
• such that it could result in immediate danger to the danger to the patient, for instance variations in cardiac
patient, for instance performance, respiration, activity of the central nervous
• variations in cardiac performance, respiration, activity system, or they are intended for diagnosis in clinical
of CNS in which situations where the patient is in immediate danger, in
• case they are in Class IIb which cases they are classified as Class IIb
Active devices intended to emit ionizing radiation and in- Active devices intended to emit ionizing radiation and in-
tended for diagnostic and therapeutic interventional radiolo- tended for diagnostic or therapeutic radiology, including
gy including devices which control or monitor such devices, interventional radiology devices and devices which control
or which directly influence their performance are classified or monitor such devices, or which directly influence their
in Class IIb. performance are classified as Class IIb.

Chapter 15

11 All active devices intended to administer and/or remove Software intended to provide information which is used to
medicines, body liquids or other substances to or from the take decisions with diagnosis or therapeutic purposes is
body are in Class IIa, unless this is done in a manner: classified as Class IIa, except if such decisions have an im-
pact that may cause:
• that is potentially hazardous, taking account of the
nature of the • death or an irreversible deterioration of a person’s
• substances involved, of the part of the body concerned state of health, in which case it is in Class III
and of the • a serious deterioration of a person’s state of health or
• mode of application in which case they are in Class IIb a surgical intervention, in which case it is classified as
class IIb.
• Software intended to monitor physiological processes
is classified as class IIa, except if it is intended for
monitoring of vital physiological parameters, where the
nature of variations of those parameters is such that
it could result in immediate danger to the patient, in
which case it is classified as Class IIb
All other software is classified as Class I.
New Rule
12 All other active devices are in Class I. All active devices intended to administer and/or remove
medicinal products, body liquids or other substances to or
from the body are classified as class IIa, unless this is done
in a manner that is potentially hazardous, taking account of
the nature of the substances involved, of the part of the body
concerned and of the mode of application in which case they
are classified as Class IIb.
No change, formerly Rule 11

13 All devices incorporating, as an integral part, a substance All other active devices are classified as Class I.
which, if used separately, can be considered to be a medici-
nal product, as defined in Article 1 of Directive, and which is
liable to act on the human body with action ancillary to that
of the devices, are in Class III.
All devices incorporating as an integral part, a human blood

derivative are classified as Class III.
No change, formerly Rule 12
14 All devices used for contraception or the prevention of the All devices incorporating, as an integral part, a substance
transmission of sexually transmitted diseases are in Class which, if used separately, can be considered to be a medic-
IIb, unless they are implantable or long term invasive devic- inal product, as defined in point 2 of Article 1 of Directive
es, in which case they are in Class III. 2001/83/EC, including a medicinal product derived from
human blood or human plasma, as defined in point 10 of
Article 1 of that Directive, and that has an action ancillary to
that of the devices, are classified as Class III.
Formerly Rule 13
15 All devices intended specifically to be used for disinfecting, All devices used for contraception or prevention of the trans-
cleaning, rinsing or, when appropriate, hydrating contact mission of sexually transmitted diseases are classified as
lenses are in Class IIb. class IIb, unless they are implantable or long term invasive
devices, in which case they are classified as Class III.
All devices intended specifically to be used for disinfecting
medical devices are in Class IIa. Unless they are specifically Formerly Rule 14
to be used for disinfecting invasive devices in which case
they are in Class IIb.
This rule does not apply to products that are intended to

clean medical devices other than contact lenses by means of
physical action.


16 Devices specifically intended for recording of X-ray diagnos- All devices intended specifically to be used for disinfecting,
tic images are in Class IIa. cleaning, rinsing or, where appropriate, hydrating contact
lenses are classified as Class IIb.
All devices intended specifically to be used for disinfecting

or sterilising medical devices are classified as class IIa,
unless they are disinfecting solutions or washer-disinfectors
intended specifically to be used for disinfecting invasive
devices, as the end point of processing, in which case they
are classified as Class IIb.
17 All devices manufactured utilizing animal tissues or deriv- Devices specifically intended for recording of diagnostic im-
atives rendered non-viable are Class III except where such ages generated by X-ray radiation are classified as Class IIa.
devices are intended to come into contact with intact skin
only. No change, formerly Rule 16
18 By derogation from other rules, blood bags are in Class IIb. All devices manufactured utilising tissues or cells of human
or animal origin, or their derivatives, which are nonviable or
rendered non-viable, are classified as class III, unless such
devices are manufactured utilising tissues or cells of animal
origin, or their derivatives, which are non-viable or rendered
non-viable and are devices intended to come into contact
with intact skin only.
19 No existing rule All devices incorporating or consisting of nanomaterial are
classified as:
• Class III if they present a high or medium potential for

internal exposure
• Class IIb if they present a low potential for internal
exposure
• Class IIa if they present a negligible potential for inter-
nal exposure
Change from the MDD

New Rule
20 No existing rule All invasive devices with respect to body orifices, other than
surgically invasive devices, which are intended to administer
medicinal products by inhalation are classified as class IIa,
unless their mode of action has an essential impact on the
efficacy and safety of the administered medicinal product
or they are intended to treat life-threatening conditions, in
which case they are classified as Class IIb.
21 No existing rule Devices that are composed of substances or of combinations
of substances that are intended to be introduced into the
human body via a body orifice or applied to the skin and that
are absorbed by or locally dispersed in the human body are
classified as:
• Class III if they or their products of metabolism, are

systemically absorbed by the human body in order to
achieve the intended purpose
• Class III if they achieve their intended purpose in
the stomach or lower gastrointestinal tract and they,
or their products of metabolism, are systemically
absorbed by the human body
• Class IIa if they are applied to the skin or if they are
applied in the nasal or oral cavity as far as the pharynx,
and achieve their intended purpose on those cavities
• Class IIb in all other cases

Chapter 15

22 No existing rule Active therapeutic devices with an integrated or incorpo-
rated diagnostic function which significantly determines
the patient management by the device, such as closed loop
systems or automated external defibrillators, are classified
as Class III.
as a medicinal product or they are single-use devices • Classification rules are applied to each device
that administer a medicinal product. Some examples and each accessory separately in their own
would be pre-filled syringes, disposable injectors with right.
pre-filled cartridges, and non-refillable inhalers. • Software embedded in or operating a device is
Non-integral DDCs have two or more separate classified the same as the device.
components that are not sold physically integrated but • Software independent of a device shall be clas-
where the medicinal component and device(s) are used sified in its own right.
together for administration. The device(s) and medicinal
component may be packaged together or sold separately. MDD Annex IX and EU Annex VIII contain cer-
Some examples would be refillable injectors, reusable tain basic principles that must be understood before
inhalers, and nebulisers. applying the classification rules. The device’s intended
Integrating a drug into a medical device for an purpose must be achieved by a describable mode of
ancillary purpose categorises the drug/device combina- action supported by scientific evidence. All modes of
tion as Class III in most cases (EU MDR Annex VIII, action present must be considered. The manufacturer
Rule 14). cannot ignore a specific device mode of action con-
tributing to its intended purpose in order to claim the
Classification Rules Explained device falls into a lower class.
EU MDR and MDD classification rules are grouped
into sections: Software
• Rules 1–4: non-invasive devices Software is classified in the same way as any other
• Rules 5–8: invasive devices medical device or accessory, except for the following
• Rules 9–13: active devices (MDD Rules 9–12) principles:
• Rules 14–22: special rules (MDD Rules • Software (stand-alone or embedded) is consid-
13–18) ered an active medical device.
• Software that drives a device or influences its
MEDDEV 2.4/17 (guidance document) on classifica- use automatically falls into the same class as
tion of medical devices as of medical devices is written the device. This can be true for both embedded
per the MDD rules (not yet updated to EU MDR and standalone software.
rules). Tables 15-1 through 15-5b provide a simplified,
tabular version of Annex VIII, Chapter III. Table 15-6 General purpose software used in healthcare settings
outlines the medical device classification rules specified or intended for lifestyle and well-being purposes is not
in the MDD, and those implemented with the transi- considered a medical device. The qualification of soft-
tion to the EU MDR. The italicized text in Table 15-6 ware, either as a device or an accessory, is independent
highlights key changes or updates to the classification of the software’s location or the type of interconnection
rules. In addition, Chapter II of Annex VIII provides between the software and a device.
implementing rules related to classification. The imple- The European Commission issued a guidance doc-
menting rules are summarized as follows: ument on standalone software classification, MEDDEV
• Intended purpose the primary consideration 2.1/6, July 2016.11 Similarly, the EU MDR has a rule
in and device shall be classified according to specific to software that did not exist in the MDD.
most critical use. Similarly, if several rules or
sub-rules apply to a device, the highest classifi- Borderline Products
cation shall apply. In some instances, it is not always clear whether a prod-
uct falls under the EU MDR or EU IVDR. There are

medical devices that are excluded from the scope of the • Class IIa if they are applied to the skin or if
regulations, and there are products, such as those listed they are applied in the nasal or oral cavity as
in Annex XVI (List of Groups of Products Without an far as the pharynx and achieve their intended
Intended Medical Purpose), which are regulated by the purpose on those cavities
EU MDR. The European Commission and Member • Class IIb in all other cases
States have agreed on some interpretations, which are
outlined in the Manual on Borderline and Classification Equipment intended to be used to reduce, remove or
in the Community Regulatory Framework for Medical destroy adipose tissue, such as equipment for liposuc-
Devices (borderline manual). The borderline manual tion, lipolysis or lipoplasty is considered to be an active
includes determinations regarding both borderline medical device and should follow the active device rules
medical devices and their accessories and includes spe- for classification determination.
cific medicinal products, biocides, cosmetics, software High intensity electromagnetic radiation (e.g.,
and mobile applications.12 The guidance provided in infra-red, visible light and ultra-violet) emitting equip-
this manual is not legally binding because only the ment intended for use on the human body, including
European Court of Justice can give an authoritative coherent and non-coherent sources, monochromatic
interpretation of Community law. However, this manual and broad spectrum, such as lasers and intense pulsed
can be useful in documentation supporting manufactur- light equipment, for skin resurfacing, tattoo or hair
ers’ classification determinations. removal or other skin treatment is an active therapeutic
device and should follow the active device rules for clas-
Annex XVI Products Without an Intended Medical sification determination.
Purpose Equipment intended for brain stimulation that
There are products addressed in the borderline man- apply electrical currents or magnetic or electromagnetic
ual that may conflict with EU MDR Annex XVI. For fields that penetrate the cranium to modify neuronal
example, the manual states that non-corrective contact activity in the brain would likely be classified as Class
lenses without medical claims regarding prevention, IIa or Class IIb under EU MDR Rule 9, depending on
monitoring, treatment or alleviation of a disease are how the electrical/magnetic currents are applied.
not medical devices. However, contact lenses or other
items intended to be introduced into or onto the eye In Vitro Medical Device Classification
are within the scope of the EU MDR. In such cases, Process
where there seems to be a discrepancy between the bor- To be qualified as an IVD, the product first must fulfil
derline manual and the EU MDR, the EU MDR takes the definition of a medical device and, therefore, must
precedence. be intended by its manufacturer to be used for a medical
Based on the definition of a “medical device” alone, purpose, but the demarcation between the EU IVDR
it makes sense that products intended to be totally or and IVDD and EU MDR and MDD is fundamentally
partially introduced into the human body through sur- important because the EU MDR and MDD do not
gically invasive means for the purpose of modifying the apply to IVDs.
anatomy or fixation of body parts (with the exception of Following EU IVDR Article 2(2) an “in vitro diag-
tattooing products and piercings), would fall under the nostic medical device” means any medical device that is
EU MDR scope regardless of whether or not the prod- a reagent, reagent product, calibrator, control material,
uct has a medical purpose. kit, instrument, apparatus, piece of equipment, soft-
Substances, combinations of substances or items ware or system, whether used alone or in combination,
intended to be used for facial or other dermal or intended by the manufacturer to be used in vitro for the
mucous membrane filling by subcutaneous, submucous examination of specimens, including blood and tissue
or intradermal injection or other introduction (exclud- donations, derived from the human body, solely or prin-
ing those for tattooing) are classified according to cipally for the purpose of providing information on one
administration route. Devices that are composed of sub- or more of the following:
stances or combinations of substances that are intended • concerning a physiological or pathological
to be introduced into the human body via a body orifice process or state
or applied to the skin and that are absorbed by or locally • concerning congenital physical or mental
dispersed in the human body are classified under Rule impairments
21 of the EU MDR, meaning they are: • concerning the predisposition to a medical
• Class III if they are systemically absorbed condition or a disease
by the human body in order to achieve the
intended purpose

Chapter 15
Table 15-7. IVDR Annex VIII, I Classification Matrix
Class D Rule 1 Rule 1

Highest Risk
Devices used in detecting a transmissible agent in Devices used in detecting a

blood, blood components, cells, tissues or organs, transmissible agent that causes a
or derivatives to assess suitability for transfusion, life-threatening disease likely to
transplantation or cell administration propagate
Rule 1 Rule 2
Devices used in determining infectious load of Devices used to determine markers

a life-threatening disease where monitoring is for ABO, Rhesus, Kell, Kidd or Duffy
critical in patient management systems
Class C Rule 2 Rule 3
Devices used for blood grouping or tissue typing Devices used in detecting sexually
to ensure the immunological compatibility transmitted agents, cerebrospinal
of blood, blood components, cells, tissue or fluid, blood of infectious agents,
organs that are intended for transfusion or infective disease status, immune
transplantation or cell administration status
Devices used in screening Devices to be used Devices used Devices used for
for pre-natal immune status as companion for disease human genetic
toward transmissible agents, diagnostics staging testing
cancer and congenital
disorders in foetuses and
babies
Rule 3 Rule 3 Rule 4
Devices used for Devices used for Devices for self-testing except
monitoring levels of management of patients those identified in Class B
medicinal or biological with life-threatening
components disease or condition
Class B Rule 4 Rule 6 Rule 7
Self-testing devices Devices not covered by Devices which are controls

for pregnancy, fertility, Rules 1 through 5 without a quantitative or
cholesterol, glucose, qualitative value
erythrocytes, leucocytes
and urine bacteria
Class A Rule 5 Rule 5 Rule 5 Rule 5
General laboratory Buffer solutions, In vitro Specimen

use products washing solutions, diagnostic receptacles
with no critical general culture media, procedural
Lowest Risk
characteristics and histological stains instruments

for in vitro diagnostic
procedures

• to determine the safety and compatibility with IVD classification is based on a positive list-
potential recipients ing. First, the manufacturer determines whether the
• to predict treatment response or reactions product is an IVD. Then, the manufacturer verifies its
• to define or monitor therapeutic measures classification.
IVDR Annex VIII now includes seven rules
Specimen receptacles also shall be deemed to be in vitro divided into four classes—A, B, C and D—considering
diagnostic medical devices. the devices’ intended purposes and their inherent risks.
According to the definition in EU IVDR Article Classification shall be carried out in accordance with
2(2) and MEDDEV 2.14/1,13 an IVD’s essential char- Annex VIII. Prior to placing a device on the market,
acteristics are: manufacturers shall undertake an assessment of that
1. The IVD’s principal intended purpose is to device’s conformity, in accordance with the applicable
provide information on one or more of the conformity assessment procedures set out in Annexes
following medical purposes: IX–XI. Manufacturers of Class B, C and D devices,
o information concerning a physiological other than devices for performance studies, shall be
process or state (e.g., menopause assay, subject to a conformity assessment. Manufacturers of
ovulation assay, pregnancy test) Class A devices, other than devices for performance
o information concerning a pathological studies, shall declare the conformity of their products by
process or state (e.g., HIV assay) issuing the EU Declaration of Conformity referenced
o information concerning a congenital in Article 17, after drawing up the technical documen-
abnormality (e.g., evaluation of the risk of tation set out in IVDR Annexes II and III.
trisomy 21) Under the IVDD both Annex II devices and
o to determine safety and compatibility with self-testing devices require notified body involvement.
potential recipients (e.g., determination of All other IVDs, require the manufacturer to fulfil the
blood groups of the ABO system) applicable IVDD requirements before affixing the CE
o monitoring therapeutic measures (e.g., Mark, and no notified body involvement is required.
digitoxin assay)
2. The IVD may provide this information either Classification Disputes
alone or in combination with other devices or The manufacturer initially determines the device’s class
products. using the classification rules. If the conformity assess-
3. The IVD is used in vitro to examine a spec- ment procedure requires notified body involvement, the
imen derived from the human body, where two parties must agree on the classification. Although the
such specimen is never reintroduced into the classification rules are descriptive and well-defined, there
body. Note, if no specimen is involved, or the are situations that may arise when the rules do not pro-
examination takes place in or on the human duce a definitive classification result. If they cannot agree
body (in vivo), the devices intended to be used on classification, the notified body normally will go to its
for this examination are not IVDs. Example: a competent authority to request a solution. The competent
pulse oximeter emitting light through the fin- authority shall notify the Medical Device Coordination
gertip and absorbing infrared light to measure Group (MDCG) and the Commission of its decision.
the oxy/deoxyhemoglobin ratio is not an IVD. The decision shall be made available upon request.
4. The IVD is used in vitro to examine a spec- At the request of a Member State, the Commission
imen derived from the human body. Note, shall, after consulting the MDCG, decide by means of
devices for detection of, e.g., pathological implementing acts, on the following:
agents in the environment, are not IVDs. • application of Annex VIII to a given device, or
category or group of devices, in determining
Depending on the manufacturer’s intended use, similar the classification of such devices
products may be considered as IVDs. Products for gen- • a device or category or group of devices shall
eral laboratory use are not IVDs unless, in view of their for reasons of public health based on new scien-
characteristics, they specifically are intended by their tific evidence or based on any information that
manufacturer to be used for in vitro diagnostic exam- becomes available in the course of the vigilance
ination. MEDDEV 2.14/1 includes examples of general and market surveillance activities be reclassified,
laboratory products and IVDs. For example, while a by way of derogation from Annex VIII
general centrifuge is a product for general use, a haema-
tocrit centrifuge is an IVD.

Chapter 15
Table 15-8. Comparison of IVDD and IVDR Device Classification Rules
IVDD Classification IVDR Device Classification

IVDD does not utilize classification rules.
Annex II, List A Rule 1

• reagents and reagent products, including related Devices intended to be used for the following purposes are classified as
calibrators and control materials for determining the Class D:
following blood groups: ABO system, rhesus (C, c, D, • detection of the presence of, or exposure to, a transmissible agent in
E, e) anti-Kel blood, blood components, cells, tissues or organs or in any of their
• reagents and reagent products, including related derivatives in order to assess their suitability for transfusion, trans-
calibrators and control materials for the detection, plantation or cell administration
confirmation and quantification in human specimens • detection of the presence of, or exposure to, a transmissible agent
of markers of HIV infection (HIV 1 and 2), HTLV I and II, that causes a life-threatening disease with a high or suspected high
and hepatitis B, C and D risk of propagation
• determining the infectious load of a life-threatening disease where
monitoring is critical in the process of patient management
Annex II, List A Rule 2

• reagents and reagent products, including related Devices intended to be used for blood grouping or tissue typing to ensure
calibrators and control materials for determining the the immunological compatibility of blood, blood components, cells, tissue
following blood groups: ABO system, rhesus (C, c, D, or organs that are intended for transfusion or transplantation or cell admin-
E, e) anti-Kell istration are classified as Class C, except when intended to determine any
• reagents and reagent products, including related of the following markers:
calibrators and control materials for the detection, • ABO system [A (ABO1), B (ABO2), AB (ABO3)]
confirmation and quantification in human specimens • Rhesus system [RH1 (D), RHW1, RH2 (C), RH3 (E), RH4 (c), RH5 (e)]
of markers of HIV infection (HIV 1 and 2), HTLV I and II, • Kell system [Kel1 (K)]
and hepatitis B, C and D • Kidd system [JK1 (Jka), JK2 (Jkb)]
• Duffy system [FY1 (Fya), FY2 (Fyb)]
in which case they are classified as Class D.
IVDD does not utilize classification rules. Rule 3
Devices are classified as Class C if they are intended:
Annex II, List B • for detecting the presence of, or exposure to a sexually transmitted
• reagents and reagent products, including related agent
calibrators and control materials for determining the • for detecting the presence in cerebrospinal fluid or blood of an infec-
following blood groups: anti-Duffy and anti-Kidd tious agent without a high or suspected high risk of propagation
• reagents and reagent products, including related cali- • for detecting the presence of an infectious agent, if there is a sig-
brators and control materials for determining irregular nificant risk that an erroneous result would cause death or severe
anti-erythrocytic antibodies disability to the individual, foetus or embryo being tested, or to the
• reagents and reagent products, including related individual’s offspring
calibrators and control materials for the detection • for pre-natal screening of women in order to determine their immune
and quantification in human samples of the following status toward transmissible agents
congenital infections: rubella, toxoplasmosis • for determining infective disease status or immune status, where
• reagents and reagent products, including related there is a risk that an erroneous result would lead to a patient man-
calibrators and control materials for diagnosing the agement decision resulting in a life-threatening situation for the
following hereditary disease: phenylketonuria patient or for the patient’s offspring
• reagents and reagent products, including related • to be used as companion diagnostics
calibrators and control materials for determining • to be used for disease staging, where there is a risk that an erroneous
the following human infections: cytomegalovirus, result would lead to a patient management decision resulting in a
chlamydia life-threatening situation for the patient or for the patient’s offspring
• reagents and reagent products, including related • to be used in screening, diagnosis or staging of cancer
calibrators and control materials for determining the • for human genetic testing
following HLA tissue groups: DR, A, B, • for monitoring of levels of medicinal products, substances or biologi-
• reagents and reagent products, including related cal components, when there is a risk that an erroneous result will lead
calibrators and control materials for determining the to a patient management decision resulting in a life-threatening situa-
following tumoral marker: PSA tion for the patient or for the patient’s offspring
• reagents and reagent products, including related • for management of patients suffering from a life-threatening disease
calibrators, control materials and software, designed or condition
specifically for evaluating the risk of trisomy 21 • for screening for congenital disorders in the embryo or foetus
• the following device for self-diagnosis, including its • for screening for congenital disorders in new-born babies where fail-
related calibrators and control materials: device for ure to detect and treat such disorders could lead to life-threatening
the measurement of blood sugar situations or severe disabilities

Table 15-8. Comparison of IVDD and IVDR Device Classification Rules (cont.)
IVDD Classification IVDR Device Classification

Self-Testing IVDs and Rule 4

(a) Devices intended for self-testing are classified as Class C, except
Annex II, List B for devices for the detection of pregnancy, for fertility testing and
• the following device for self-diagnosis, including its for determining cholesterol level, and devices for the detection of
related calibrators and control materials: device for glucose, erythrocytes, leucocytes and bacteria in urine, which are
the measurement of blood sugar. classified as Class B.
(b) Devices intended for near-patient testing are classified in their own
right.
General IVDs Rule 5

IVDs other than those covered by Annex II and IVDs for The following devices are classified as Class A:
self-testing. (a) products for general laboratory use, accessories which possess no
critical characteristics, buffer solutions, washing solutions, and
Specimen receptables are considered in vitro diagnostics general culture media and histological stains, intended by the man-
under IVDD. ufacturer to make them suitable for in vitro diagnostic procedures
relating to a specific examination;
General laboratory use products are not considered in vitro (b) instruments intended by the manufacturer specifically to be used
diagnostics under IVDD. for in vitro diagnostic procedures;
(c) specimen receptacles.
All other devices not captured by Annex II List A, List B, or Rule 6

self-testing devices are grouped with General IVDs. Devices not covered by the above-mentioned classification rules are classi-
fied as Class B.
There are no requirements specified for controls without a Rule 7

quantitative or qualitative assigned value. Devices which are controls without a quantitative or qualitative assigned
value are classified as Class B.
To ensure the uniform application of Annex VIII, and the safety profile of new products on the market, and
taking account of the relevant scientific committees’ consumer confidence of healthcare products shipped
opinions, the Commission may adopt implementing and sold in the EU. Transition periods have been
acts to the extent necessary to resolve issues of divergent applied to aid industry partners in implementing
interpretation and practical application. the respective EU regulation of medical and in vitro
If it is resolved, the solution will be included in devices. The new EU MDR and EU IVDR will repeal
the next revision of the Manual on Borderline and and replace the MDD and IVDD. There are notewor-
Classification in the Community Regulatory Framework for thy changes from the medical device directives to the
Medical Devices. medical device regulations. Although public scandal
Manufacturers can challenge competent authori- was catalyst for these changes, the EU welcomes a new
ties’ classification decisions in the national courts. If the legislative system with a renewed focus on patient and
national court feels the matter involves interpretation user safety, consistency relative to requirements, and
of a point of European law that should be resolved first, transparency. Conformity assessments and classification
it can request a preliminary ruling from the Court of schemes are critical to the functionality of this regula-
Justice of the European Union. There were no known tory landscape.
cases at the time of publication. The EU medical device classification system rep-
resents the first step for a manufacturer in their pursuit
Conclusion to market a medical device. Device classification is
The adoption of the EU MDR and EU IVDR represent based on rules and the application principles prescribed
a significant change to the EU regulatory framework. in the applicable medical device directive or regulation.
The impact of new medical device legislation highlights The manufacturer must assess the product they intend

Chapter 15
to market in the EU, taking into account the device’s GROW_IVD_manufacturers_factsheet_EN. Accessed 18
intended purpose, contact type, duration of use, level March 2020.
10. MEDDEV 2.4/1, Rev. 9, June 2010. Medical Devices Guidance
of invasiveness and use of energy. The medical device Document—Classification of Medical Devices. European
classification is essential in determining the available Commission website. http://ec.europa.eu/DocsRoom/docu-
conformity assessment options. ments/10337/attachments/1/translations. Accessed 9 February
While the medical device classification, which now 2020. Accessed 18 March 2020.
11. MEDDEV 2.1/6, July 2016. Qualification and Classification
includes active implantable medical devices, has been of standalone software. European Commission website. http://
changed slightly under the regulations, the IVD classi- ec.europa.eu/DocsRoom/documents/17921/attachments/1/
fication system is considerably different under the EU translations. Accessed 18 March 2020.
IVDR. The EU IVDR adopted a risk-based classification 12. Manual on Borderline and Classification in the Community
Regulatory Framework for Medical Devices Version 1.17
system following the Global Harmonization Task Force (September 2015). European Commission website. http://
(GHTF) classification rules, with four classes of vary- ec.europa.eu/consumers/sectors/medical-devices/files/wg_min-
ing risk, from Class A (lowest risk) to Class D (highest utes_member_lists/version1_9_borderline_manual_en.pdf.
risk). The majority of IVDs currently self-certified will Accessed 18 March 2020.
13. MEDDEV 2.14/1, Rev. 2, Jan 2012. Guidelines on Medical
require notified body involvement in the Conformity Devices: IVD Medical Device Borderline and Classification
Assessment Process to ensure the safety and perfor- issues. A Guide for Manufacturers and Notified Bodies.
mance of IVDs placed on the EU market. European Commission website. http://ec.europa.eu/DocsRoom/
The regulations will be fully in effect in May 2020 documents/10322/attachments/1/translations. Accessed 18
March 2020.
for medical devices and May 2022 for in vitro diagnos-
tic devices. Links to the Council Directives
1. Council Directive 93/42/EEC of 14 June 1993 Concerning
References Medical Devices. EUR-Lex website. http://eur-lex.europa.
1. Report on the functioning of the Medical Devices Directive eu/legal-content/EN/TXT/PDF/?uri=CELEX:01993L0042-
93/42/EC of 14 June 1993; Medical Devices Experts Group, 5 20071011&from=EN. Accessed 18 March 2020.
June 2002. 2. Council Directive of 20 June 1990 on the Approximation
2. Ibid. of the laws of the Member States Relating to Active
3. Regulation (EU) 2017/745 of the European Parliament Implantable Medical Devices (90/385/EEC). EUR-Lex
and of the Council of 5 April 2017 on medical devices, website. http://eur-lex.europa.eu/legal-content/EN/TXT/
amending Directive 2001/83/EC, Regulation (EC) No. PDF/?uri=CELEX:01990L0385-20071011&from=EN.
178/2002 and Regulation (EC) No. 1223/2009 and repealing Accessed 18 March 2020.
Council Directives 90/385/EEC and 93/42/EEC. EUR- 3. Directive 98/79/EC of the European Parliament and of the
Lex website. https://eur-lex.europa.eu/legal-content/EN/ Council of 27 October 1998 on In Vitro Diagnostic Medical
TXT/?uri=CELEX:02017R0745-20170505. Accessed 18 Devices. EUR-Lex website. http://eur-lex.europa.eu/legal-con-
March 2020. tent/EN/TXT/PDF/?uri=CELEX:01998L0079-20120111.
4. Ibid. Accessed 18 March 2020.
5. Op cit 3.
6. Regulation (EU) 2017/746 of the European Parliament and **As of the date of this publication, The Official Journal of the European
of the Council of 5 April 2017 on in vitro diagnostic medical Union issued a one-year postponement to the implementation of the
devices and repealing Directive 98/79/EC and Commission Medical Devices Regulation, (EU MDR) 2017/745. The new imple-
Decision 2010/227/EU. https://eur-lex.europa.eu/legal-content/ mentation date is 26 May 2021. The Medical Devices Directive, 93/42/
EN/TXT/?uri=CELEX:02017R0746-20170505. Accessed 18 EEC and the Active Implantable Medical Devices Directive, 90/385/
March 2020. EEC remain valid until said date. There is no scheduled delay to the
7. Ibid. In Vitro Diagnostic Medical Devices Regulation, (EU IVDR) 2017/746.
8. Harmonised Standards. European Commission website. The EU IVDR will come into effect on 26 May 2022. The In Vitro
https://ec.europa.eu/growth/single-market/european-standards/ Diagnostic Directive, 98/79/EC remains valid until said date.
harmonised-standards. Accessed 18 March 2020.
9. Factsheet for Manufacturers of in vitro Diagnostic Medical
Devices. European Commission website. 201118_DG

Chapter 16
In Vitro Diagnostic
Medical Devices
Updated by Erik Vollebregt, LLM
OBJECTIVES □ MEDDEV 2.12/1 Rev. 6. Medical Devices—

Guidelines on a medical devices vigilance
□ Summarise the European In Vitro Diagnostic system, 2009
Medical Devices Directive (IVDD) and EU In Vitro
Diagnostic Medical Devices Regulation (EU IVDR) □ Summary Technical Documentation (STED) for
Demonstrating Conformity to the Essential
□ Describe the regulatory process to be followed Principles of Safety and Performance of In Vitro
by IVD manufacturers Diagnostic Medical Devices, GHTF
□ Focus on the specific elements in this directive □ MEDDEV 2.14/3 Rev. 1. 2007. IVD Guidances:
and regulation Supply of Instructions For Use (IFU) and other
information for In Vitro Diagnostic (IVD) Medical
Devices
COVERED IN THIS CHAPTER □ MEDDEV 2.14/4. Guideline for the CE marking of
blood based in vitro diagnostic medical devices
□ Regulation 746/2017 of the European for vCJD based on detection of abnormal PrP, 2012
on in vitro diagnostic medical devices and
repealing Directive 98/79/EC and Commission Introduction
Decision 2010/227/EU (EU IVDR) Directive 98/79/EC of the European Parliament and of
the Council of 7 December 1998 on in vitro diagnostic
□ Directive 98/79/EC of the European Parliament medical devices (IVDD) became the third in the series
and of the Council of 7 December 1998 on of directives on medical devices.1 It laid out pan-Euro-
in vitro diagnostic medical devices (In Vitro pean requirements for in vitro diagnostic (IVD) medical
Diagnostic Medical Devices Directive (IVDD)) devices, replacing national regulations where they
existed. Since 7 December 2003, the end of the transi-
□ Directive 93/42/EEC of the European Parliament
tion period, all IVDs in the European Economic Area
and of the Council of 14 June 1998 concerning
(EEA) and Switzerland also must comply with the
medical devices (Medical Devices Directive (MDD))
requirements of the IVDD and carry the CE Mark.
□ MEDDEV 2.14/2 Rev. 1, IVD Guidance: Research The IVDD has been transposed into the national
use Only Products, 2004 legislation of each Member State. Although the
national transpositions largely follow the IVDD, they
□ MEDDEV 2.14/1 Rev. 2. IVD Guidances: do contain specific elements with which devices in each
Borderline issues, 2012 respective national territory must comply. The language
requirements for IVDs for professional use are a good
example of these national differences. Another is the

Chapter 16
requirement for self-testing IVD labels to be in the This definition includes four types of IVDs:
local language(s) of the Member State in which the end 1. higher-risk IVDs to diagnose the indications
user resides. in Annex II list A
To gain a full understanding of European IVD 2. IVDs to diagnose the lower-risk indications in
regulatory requirements, other important documents Annex II list B
should be consulted: harmonised standards, guidance 3. self-tests
documents and, if applicable, the Common Technical 4. all other IVDs diagnosing indications not in
Specifications. either of the Annex II lists
The IVDD shares many features with Directive
93/42/EEC of the European Parliament and of the Products for general laboratory use are not in vitro
Council of 14 June 1998 concerning medical devices diagnostic medical devices unless such products, in
(MDD). For example, the definition of medical device view of their characteristics, are intended specifically by
is identical in both directives, and the IVD conformity their manufacturers to be used for in vitro diagnostic
assessment method is like that for medical devices. The examination.3
MDD is treated in more detail in other chapters of this The MEDDEV on IVD borderline and classifi-
book. This chapter focuses on the IVDD’s particularities. cation issues lists a number of illustrative examples of
The EU In Vitro Diagnostic Medical Devices devices that are IVDs or general laboratory equipment,
Regulation (EU IVDR) has been entered into force for depending on their intended use (see Table 16-1).
some years already and will replace the current IVDD The IVD definition also includes kits. Although
with a profoundly changed regulatory space for IVDs in “kit” is not further defined in the IVDD, the IVD
the EU. After a five-year transition period that started borderline MEDDEV clarifies that a kit consists of
26 May 2017, the EU IVDR will become fully applica- more than one component, made available together
ble on 26 May 2022. During this period, manufacturers and intended to be used to perform a specific IVD
of IVDs need to start planning for the transition, since examination. A kit whose intended purpose as a com-
the new regulation will not grandfather in currently bined set falls within the IVDD’s scope is regulated
marketed IVDs. This revision is treated in detail in under the directive. The intended purpose for the
Chapter 13. As a result of the transitional regime, the combination must be classified and assessed for its
IVDD and the EU IVDR will be applicable in parallel conformity to IVDD requirements, according to the
for a limited period of time. While the EU IVDR allows product combination’s principal intended purpose, and
IVDs that comply with the EU IVDR2 to be placed on must be CE-marked and labelled under the IVDD.4
the market, this does not really happen in practice yet. A kit can consist of a combination of IVDs already
This chapter will point to several EU IVDR CE-marked or medical device/IVD combinations not
requirements, with the aim to indicate gaps between the yet CE-marked, as long as the kit is CE-marked for its
IVDD and EU IVDR that manufacturers must bridge to intended purpose. The kit must fulfil the requirements
become compliant under the new regulation. regarding the “information supplied by the manufac-
turer” separately from the information supplied with
IVDD and EU IVDR Scope CE-marked IVDs and/or included medical devices.5 In
Currently, under the IVDD (Art. 1.2.b), an IVD is addition, the kit shall not bear an additional CE Mark
defined as follows: on the outer packaging for the medical devices included
“‘in vitro diagnostic medical device’ means any in the kit; only the kit itself will be marked.
medical device which is a reagent, reagent product,
calibrator, control material, kit, instrument, appa- The EU IVDR broadens the scope and introduces the
ratus, equipment, or system, whether used alone or following new definition of an IVD in Article 2(2):
in combination, intended by the manufacturer to “’in vitro diagnostic medical device’ means any
be used in vitro for the examination of specimens, medical device which is a reagent, reagent prod-
including blood and tissue donations, derived from uct, calibrator, control material, kit instrument,
the human body, solely or principally for the pur- apparatus, piece of equipment, software or system,
pose of providing information: whether used alone or in combination, intended by
• concerning a physiological or pathological the manufacturer to be used in vitro for the exam-
state ination of specimens, including blood and tissue
• concerning a congenital abnormality donations, derived from the human body, solely or
• to determine the safety and compatibility with principally for the purpose of providing informa-
potential recipients, tion on one or more of the following:
• to monitor therapeutic measures

In Vitro Diagnostic Medical Devices
a. concerning a physiological or pathological Examining Specimens, Including Blood and Tissue

process or state Donations, Derived From the Human Body
b. concerning congenital physical or mental The IVD definition states in both the IVDD and the
impairments EU IVDR that the devices are “intended by the man-
c. concerning the predisposition to a medical ufacturer to be used in vitro for the examination of
condition or a disease specimens, derived from the human body.” Therefore, if
d. to determine the safety and compatibility with no sample is “derived from the human body,” the device
potential recipients is not considered an IVD. Such products shall be qual-
e. to predict treatment response or reactions ified as medical devices. An example is a non-invasive
f. to define or monitoring therapeutic measures medical device for detecting blood glucose by energy
emission (e.g., near infra-red energy). This is not an
Specimen receptacles also shall be deemed to be in vitro IVD because no specimen derived from the human
diagnostic medical devices. body is involved, but it is a medical device within the
The EU IVDR has changed a significant number MDD’s scope.
of definitions, which may result in products currently Devices for detecting pathological agents in the
not classified as medical devices or accessories under environment, for example, are not IVDs, and neither are
the IVDD being included in the scope of the EU IVDR. devices for examining specimens derived from animals.
Examples are products falling within the enlarged scope
of the definition of accessory, products for (predictive) Specimen Receptacles
genetic testing and the inclusion of several new defini- Specimen receptacles and IVD accessories also are
tions, such as “companion diagnostic,” “kit,” “device for included in the IVDD’s and the EU IVDR’s scope.
near-patient testing” and “device for self-testing.” Specimen receptacles are those devices, whether util-
ising a vacuum system or not, specifically intended by
Medical Device their manufacturers for the “primary” containment and
An assay first must meet the medical device definition. “preservation” of specimens derived from the human
This excludes a number of assays, e.g., those intended body for in vitro diagnostic examination.9 This defini-
by their manufacturers to be used for forensic purposes, tion of “specimen receptacles” remains the same under
like detecting biologic agents used in weapons, or alco- the EU IVDR.
hol tests used for law enforcement purposes. The word “primary” in relation to containment does
In addition, the device has to be used for exam- not necessarily refer to the initial or first container of
ination. This excludes general purpose laboratory the specimen, but rather to the container’s intended use.
equipment, unless such products, in view of their char- A container is regulated as a specimen receptacle if its
acteristics, are intended by their manufacturer to be manufacturer intended it mainly to come into direct
used specifically for in vitro diagnostic examination.6 contact with the specimen, which could, therefore, affect
the specimen.
To be Used In Vitro The word “preservation” does not imply the recep-
An IVD is used for the in vitro examination of a speci- tacle has to contain a specimen preservative, but that it
men derived from the human body, where the specimen is intended to protect the specimen, for example, from
never is reintroduced into the body. If no specimen is temperature fluctuations, light, physical breakage, etc. If
involved, or if the examination takes place in or on the this is the intended use, it must be indicated clearly on
human body (in vivo), the devices for this examination the product labelling and any associated promotional
are not IVDs.7 For example, a pulse oxymeter, emitting literature. The manufacturer also must have evidence and
light through the fingertip and absorbing infrared light, technical documentation to support this product use.
to measure the oxy/deoxyhemoglobin ratio is not an If more than one specimen receptacle is involved
IVD; neither is a continuous blood glucose monitoring in an individual specimen’s collection, transport and
system where the analytical function is contempora- storage, each must have evidence of IVDD or EU IVDR
neous with continuous specimen collection. Both of compliance.
these examples are diagnostic medical devices. Devices Other receptacles in which the specimen may be
involving (invasive) contact with the human body to placed at some point during the analytical process (by
obtain continuous specimen collection are not consid- aliquoting or otherwise) are not considered “specimen
ered IVDs.8 receptacles,” but rather general laboratory equipment
under the IVDD10 and EU IVDR.
Products used to obtain specimens from the human
body usually are not IVDs if they are used to transfer a

Chapter 16
Table 16-1. Examples of General Laboratory Use Products and IVD Medical Devices
Laboratory Use Product Covered by IVDD

Centrifuges General centrifuges, cytospin Hematocrit centrifuge
Pipettes General purpose pipettes (e.g., single or multiple Blood coagulation pipettes with automatic timing
pipettes, plastic pipettes, Pasteur pipettes) (accessory of coagulometer)
Tubes and flasks Erlenmeyer flasks, plastic tubes Blood collection tubes, urine sample containers
Plates Empty ELISA plates, empty Petri dishes Coated microtiter plates for the diagnosis of Lyme
disease
Nucleic acid extraction DNA and RNA extraction kits that only provide a speci- DNA and RNA extraction kits intended to provide
products men without an intended IVD detection combination a specimen to be used with an IVD device (valida-
tion for at least one combination is to be provided)
General equipment Scales, balances, microtomes, incubators, steril-
isers for laboratory equipment, paraffin embedding
machine
HPLC products Size-exclusion HPLC columns HPLC columns for IVD purposes (e.g., HbA1c)
Detection equipment Mass spectrometer, spectrophotometers, ELISA read- McFarland bacteria density testing
ers providing raw data that is not readily readable and
understandable by the user (e.g., peaks, OD)
Others Foetal calf serum, cell culture media, fixation solution,
mounting media, buffers (e.g., PBS), chemicals (e.g.,
sulphuric acid, formol, water)
sample from the body rather than primary containment human body are not considered IVD accessories, but
(e.g., plastic pipettes to transfer blood drops from fin- are medical devices within the scope of the MDD (e.g.,
gers to rapid tests). needles, lancets, lancing devices, mouth tubes, swabs
and urine collection bags for babies).
Accessories
The accessories rule applicable to IVDs is identical IVDs for Performance Testing
to the one for medical devices, meaning the defini- IVDs introduced in European laboratories to establish
tion under the IVDD matches with the one under the their performance characteristics also are subject to the
MDD, and the definition under the EU IVDR matches IVDD and EU IVDR. Such products cannot carry the
with the one under the EU MDR. Under the EU IVDR, CE Mark because their performance characteristics have
an accessory is redefined as an “article which, whilst not been established yet, but otherwise should meet all
not being itself an in vitro diagnostic medical device, directive requirements. EU IVDR and IVDD Annex
is intended specifically by its manufacturer to be used VIII further detail performance evaluation documenta-
together with one or several particular in vitro diagnos- tion and notification requirements for these devices.
tic medical device(s) to specifically enable the in vitro
diagnostic medical device(s) to be used in accordance Research-Only IVDs
with its/their intended purpose(s) or to specifically Assays intended for research purposes are not subject
and directly assist the medical functionality of the in to the IVDD or EU IVDR. These assays lack a clinical
vitro diagnostic medical device(s) in terms of its/their application and, therefore, are not medical devices.
intended purpose(s).”11 According to Article 1(3)(a) of the EU IVDR, devices
The wording “to specifically and directly assist the intended for research use only are not subject to the
medical functionality of the in vitro diagnostic medical requirements of the regulation, unless such products,
device(s) in terms of its/their intended purpose(s)” gives in view of their characteristics, are specifically intended
the definition a wider scope, by including accessories by their manufacturer to be used for in vitro diagnos-
that assist the clinical purpose of the device but are not tic examination. The EU IVDR and IVDD neither
necessarily needed to enable it. define “Research Use Only” explicitly nor define any
EU IVDR Article 1(2)(b) and the current IVDD requirements for such products. Manufacturers of these
Article 1(2)(c) state that invasive sampling devices or reagents should not undertake conformity assessment
devices for obtaining specimens directly applied to the nor apply the CE Mark, but clearly label them as

“Research Use Only” and ensure all the labelling is con- a. identify, before and/or during treatment,
sistent with the devices’ nonclinical purpose. Guidance patients who are most likely to benefit from
documents for the IVDD on “Research Use Only”12 and the corresponding medicinal product; or
borderline products13 further clarify these subjects. b. identify, before and/or during treatment,
patients likely to be at increased risk of serious
In-House Developed IVDs adverse reactions as a result of treatment with
It is not unusual for clinical laboratories to develop the corresponding medicinal product.”
and produce their own reagents. These so-called “home
brew” tests are not subject to the IVDD. However, to be The EU IVDR contains a new regime on companion
exempt, these reagents must be manufactured and used diagnostics, which places them standard in the new
within the same legal entity and in the same geographic risk Class C and requires consultation with a Member
location. Moreover, the tests can be run only on spec- State-designated competent authority or with EMA in
imens from patients from the same health institution. accordance with Directive 2001/83/EC.
Preamble 11 clearly brings home brew assays “intended
to be used in a professional and commercial context” Manufacturer Process
within the IVDD’s scope. As a consequence, biotech Short Overview of the Steps
companies that, for example, are commercialising their An IVD manufacturer wishing to place a product on
often-innovative assays as a testing service instead of the European market must do the following:
selling the reagents to other laboratories also will have • define the product’s classification using Annex
to comply with the IVDD. II under the IVDD or Annex VIII under the
In-house developed IVDs are subject to a new EU IVDR
regime under the EU IVDR, set out in Article 5 (5), • ensure the product meets the Essential
that subjects in-house developed IVDs largely to the Requirements under the IVDD, preferably
same requirements as CE-marked IVDs. Among other complying with harmonised standards and,
things, the EU IVDR provides for technical docu- for Annex II List A products only, complying
mentation, production quality system, a declaration of with the Common Technical Specifications,
conformity-like documentation, postmarket surveillance or ensure the device meets the General Safety
and vigilance requirements for the development and and Performance Requirements (GSPRs)
subsequent deployment of such tests. In addition, it under Annex I of the EU IVDR (for which
imposes extra controls: the devices may not be trans- no harmonised standards or Common
ferred to another legal entity, and the health institution Specifications currently exist).
must justify in its documentation that the target patient • ensure its organisation meets the quality sys-
population’s specific needs cannot be met or met appro- tem requirements, which have increased under
priately by an equivalent CE-marked test available on the EU IVDR compared to the IVDD
the market. • implement vigilance procedures, which have
As a result, the EU IVDR changes the requirements increased under the EU IVDR compared to
for in-house developed IVDs profoundly, aligning the the IVDD
requirements for in-house developed tests materially • establish technical documentation, demon-
with those for CE-marked tests. Since in-house pro- strating compliance with the Essential
duced IVDs did not fall under the scope of the IVDD, Requirements and the applied harmonised
health institutions must remediate their full installed standards under the IVDD or compliance
base of in-house produced devices to comply with the with GSPRs under the EU IVDR and apply
EU IVDR in order to be able to continue to use them. harmonised standards and/or Common
Specifications when available, as well as estab-
Companion Diagnostics lish technical documentation on postmarket
The IVDD does not define or mention companion surveillance.14
diagnostics, which means the IVDD treats them as any • draft labelling meeting target countries’
other IVD, and companion diagnostics generally are national language requirements
self-certified. However, the EU IVDR defines a com- • appoint an Authorised Representative, if the
panion diagnostic as a “device which is essential for manufacturer is located outside the EEA,
the safe and effective use of a corresponding medicinal Turkey or Switzerland
product to: • execute an appropriate conformity assessment
procedure, including notified body certifica-
tion, if applicable

Chapter 16
• sign the Declaration of Conformity and apply List A

the CE Mark to the device • reagents and reagent products, including
• notify its product to the competent author- related calibrators and control materials, for
ities in one of the Member States where determining the following blood groups: ABO
the product will be placed on the market15 system, rhesus (C, c, D, E, e), anti-Kell
(if the manufacturer is located outside • reagents and reagent products, including
Europe, this must be done by the Authorised related calibrators and control materials, for
Representative) the detection, confirmation and quantifica-
tion in human specimens of markers of HIV
These points are described in more detail in this chapter infection (HIV 1 and 2), HTLV I and II and
and in other chapters of this book. hepatitis B, C and D
• variant Creutzfeldt-Jakob disease (vCJD)
IVD Classification assays for blood screening, diagnosis and
An IVD’s classification determines the appropriate con- confirmation
formity assessment procedure to be followed and, hence,
whether a notified body will be involved in the prod- List B
uct’s approval and certification and the quality system. • reagents and reagent products, including
The procedure impacts both cost and time to market. related calibrators and control materials, for
The current classification system is risk-based, but determining the blood groups anti-Duffy and
instead of defining classification rules, as is the case in anti-Kidd
the MDD, the IVDD literally lists the high-risk prod- • reagents and reagent products, including
ucts in Annex II. This annex contains two lists, List A related calibrators and control materials,
and List B. List A mentions the highest-risk products. for determining irregular anti-erythrocytic
List B mentions the products considered high-risk but antibodies
less so than those in List A. • reagents and reagent products, including
The IVDD does not classify products using ter- related calibrators and control materials, for
minology such as “Class I, Class II,” etc., resulting detecting and quantifying congenital infec-
in rather awkward IVD class designations. Based on tions: rubella, toxoplasmosis in human samples
Annex II and Articles 1 and 9, the following categories • reagents and reagent products, including
are defined: related calibrators and control materials, for
• “Annex II List A-products,” covering the diagnosing phenylketonuria
highest-risk products, mainly used in blood • reagents and reagent products, including
transfusion, for the prevention of transmission related calibrators and control materials, for
of HIV and certain types of hepatitis determining cytomegalovirus, chlamydia
• “Annex II List B-products,” covering products • reagents and reagent products, including
with somewhat less risk related calibrators and control materials, for
• “devices for self-testing,” covering prod- determining HLA tissue groups: DR, A, B
ucts to be used by lay persons in their home • reagents and reagent products, including
environments related calibrators and control materials, for
• “non-Annex II–products for professional use,” determining the tumour marker PSA
covering all products not mentioned in the • reagents and reagent products, including
previous classes related calibrators, control materials and soft-
ware, designed specifically for evaluating the
Both the classification system and the actual classi- risk of trisomy 21
fications badly need modification to bring them into • self-diagnosis device, including its related
alignment with technological and medical advances and calibrators and control materials, for the mea-
also to accommodate future evolutions. surement of blood sugar
Assays for variant Creutzfeldt-Jakob Disease
(vCJD) were integrated into List A of Annex II in the The EU IVDR classifies IVDs based on the Global
IVDD’s last revision in 2011. Harmonization Task Force’s (GHTF) proposed model
Following are lists of the highest- and high-risk of risk Classes A, B, C and D,16 with A being the lowest
products, as defined in IVDD Annex II. risk-class and D the highest and abandons the Annex II
lists. As a result, all IVDs on the market will need to be
reclassified when the EU IVDR applies, as is explained

in more detail in Chapter 13. The new classification management decision resulting in a life-threat-
system under the EU IVDR has as a consequence that ening situation for the patient or for the
self-certification becomes the exception rather than the patient’s offspring
general rule as is currently the case under the IVDD, • to be used as companion diagnostics
and most IVD manufacturers will need their products • to be used for disease staging, where there is
certified by a notified body. With the low number of a risk that an erroneous result would lead to
EU IVDR-accredited notified bodies currently available, a patient management decision resulting in a
this requires careful planning in order for the manufac- life-threatening situation for the patient or for
turer not to miss the 26 May 2022 deadline by which the patient’s offspring
IVDs must either have an EU IVDR CE Mark or a • to be used in screening, diagnosis or staging of
valid IVDD CE certificate issued by a notified body. cancer
Devices in Classes D, C and B must obtain a CE certif- • for human genetic testing
icate from a notified body. • for monitoring of levels of medicinal products,
The four classes of IVD devices in the new clas- substances or biological components, when
sification regime are set out in Annex VIII to the EU there is a risk that an erroneous result will lead
IVDR as follows: to a patient management decision resulting in
Class D covers devices intended to be used for the a life-threatening situation for the patient or
following purposes: for the patient’s offspring
• detection of the presence of, or exposure to, • for management of patients suffering from a
a transmissible agent in blood, blood com- life-threatening disease or condition
ponents, cells, tissues or organs, or in any of • for screening for congenital disorders in the
their derivatives, in order to assess their suit- embryo or foetus
ability for transfusion, transplantation or cell • for screening for congenital disorders in new-
administration born babies where failure to detect and treat
• detection of the presence of, or exposure to, a such disorders could lead to life-threatening
transmissible agent that causes a life-threaten- situations or severe disabilities
ing disease with a high or suspected high risk
of propagation Class B is the default class that covers all IVDs that
• determining the infectious load of a cannot be brought under any of the other classification
life-threatening disease where monitoring is rules. In addition, Class B covers self-testing devices for
critical in the process of patient management the detection of pregnancy, fertility testing and for deter-
mining cholesterol level, and devices for the detection of
This class also specifically covers devices intended to glucose, erythrocytes, leucocytes and bacteria in urine.
determine the following blood groups: ABO system, Class A covers the following devices:
Rhesus system, Kell system, Kidd system and Duffy • products for general laboratory use, accessories
system. which possess no critical characteristics, buffer
Class C, besides self-testing devices in general, solutions, washing solutions, and general cul-
covers also the devices intended for the following: ture media and histological stains, intended by
• for detecting the presence of, or exposure to, a the manufacturer to make them suitable for in
sexually transmitted agent vitro diagnostic procedures relating to a spe-
• for detecting the presence in cerebrospinal cific examination
fluid or blood of an infectious agent without a • instruments intended by the manufacturer
high or suspected high risk of propagation specifically to be used for in vitro diagnostic
• for detecting the presence of an infectious procedures
agent, if there is a significant risk that an • specimen receptacles
erroneous result would cause death or severe
disability to the individual, foetus or embryo Class A remains the only group of devices that do not
being tested or to the individual’s offspring need to be assessed by a notified body.
• for pre-natal screening of women in order to
determine their immune status toward trans- Essential Requirements, Harmonised Standards
missible agents and Common Technical Specifications
• for determining infective disease status or Before signing the Declaration of Conformity and
immune status, where there is a risk that affixing the CE Mark, the manufacturer must ensure
an erroneous result would lead to a patient

Chapter 16
its product meets the Essential Requirements of IVDD The Common Technical Specifications (CTS)20 are
Annex I or the GSPRs in Annex I of the EU IVDR. a specific set of requirements published in the Official
Under the IVDD and the EU IVDR, Annex I Journal of the European Union and currently apply only
comprises general requirements that must be met, if to Annex II List A products. The document’s name is
applicable.17 The wording often is rather broad, but many misleading, since it really contains performance spec-
essential requirements are intended to be supported ifications, not technical specifications. For this reason,
by harmonised standards. These standards describe in the EU IVDR refers to CTS as Common Specifications
more detail how the requirements may be met with (CS), which are defined as a “set of technical and/or
state-of-the-art solutions and define the gap between clinical requirements, other than a standard, that pro-
the lack of harmonised standards and the Essential vides a means of complying with the legal obligations
Requirements under the IVDD or the GSPRs under applicable to a device, process or system.” The EU IVDR
the EU IVDR. This means that even if the harmonised is expected to rely on these more than currently is the
standard is applied, any gaps defined in the harmon- case, and the adoption process under the EU IVDR
ised standard must be closed as well. A manufacturer has been simplified compared to the IVDD, enabling
should identify which Essential Requirements (under the MDCG to adopt them by implementing act.21 CS
the IVDD) or GSPRs (under the EU IVDR) apply to its under the EU IVDR also have a wider scope than under
product carefully and whether any harmonised standards the IVDD. They do not only concern the GSPRs set
or CS have been published to support these require- out in Annex I, the technical documentation set out
ments. Compliance with the harmonised standards in Annexes II and III, the performance evaluation and
leads to a presumption of conformity with the Essential postmarket performance follow-up set out in Annex
Requirements or GSPRs in the respective field.18 XIII or the requirements regarding performance studies
Applying harmonised standards to IVDs are set out in Annex XIII. Common Specifications must
equally important as those for medical devices, as be met under the EU IVDR’s requirements unless the
described elsewhere in this book. In this light, the lack manufacturer can justify that it has adopted a solution
of harmonised standards under the EU IVDR as a that is at least equivalent to the CS concerned.22
result of a troubled EU harmonisation process for the The IVDD CTS strictly define minimum perfor-
EU MDR and EU IVDR at this point is disconcerting. mance requirements for the various products in Annex
The first harmonised standards for the EU IVDR are II List A and also describe, in detail, how they should
expected to be available in 2020. be established. In addition, they include batch release
Several Essential Requirements, the GSPRs and criteria for these products, as they must be applied by
harmonised standards are generic and apply to both the manufacturer and the notified body in charge of
IVDs and other medical devices. A typical and import- batch release.
ant example is the requirement to manage the risks The CTS’ purpose is to ensure notified bodies
associated with the device’s use, supported by the har- assess the performance of these highest-risk devices and
monised standard ISO 14971.19 the individual batches’ quality consistently. The IVDD
Other Essential Requirements, GSPRs and associ- allows CTS also to be established for Annex II List B
ated harmonised standards are specific for some IVDs, products, but they have not been developed.
e.g., those for stability testing, calibration traceability for
quantitative assays, devices for self-testing and labelling. Quality System Requirements and Vigilance
The Essential Requirements and GSPRs cover Procedures
a variety of subjects, all safety related. They include The IVDD imposes quality system requirements on all
risk management, analytical and clinical performance, IVD manufacturers, including those placing only non-An-
stability, chemical and physical properties, infection nex II products for professional use on the market.
and microbial contamination, manufacturing and envi- ISO 1348523 is the harmonised standard that
ronmental properties, measuring functions, radiation, should be used as the quality system model. However,
electronic safety and electromagnetic compatibility, certification to this standard is not mandatory. At the
protection against mechanical and thermal risks, risk same time, an ISO 13485-certified quality system may
for devices for self-testing and information supplied show major nonconformities versus the IVDD and EU
by the manufacturer (labelling). The GSPRs under IVDR requirements.
the EU IVDR differ in comparison to the Essential The quality system should include adequate pro-
Requirements. Although a number of requirements cedures for handling field safety corrective actions and
have been specified in more detail, Annex I of the EU managing and reporting incidents and other postmar-
IVDR is not significantly different from the Essential keting surveillance activities in accordance with the
Requirements of IVDD Annex I.

IVDD and the applicable guidance document and the surveillance, setting out the elements for the mandatory
EU IVDR’s vigilance provisions as part of PMS.24 postmarket surveillance plan required under Article 79
The EU IVDR imposes specific, mandatory quality of the EU IVDR.
management system elements, which overlap with ISO
13485 on several core obligations. The expectation is Labelling, e-Labelling and Language Requirements
that ISO 13485 also will be harmonised for the EU Annex I.B.8 spells out IVD labelling requirements,
IVDR. The quality management system of the EU further specified in the ISO 18113 series of harmonised
IVDR covers all parts of a manufacturer’s organisation standards.26 Both sources focus primarily on labelling
and not only those that are directly related to the prod- and contents of the Instructions for Use (IFU).
uct’s realisation. As the requirements under the EU The IVDD explicitly requires the user informa-
IVDR are much more detailed than under the IVDD tion for self-testing devices be provided in the national
and apply across the board to all risk classes, the manu- language(s) of the end-user’s market.27 This provision’s
facturer must comply with many different requirements, application remains problematic because not all Member
and manufacturers with currently self-certified devices States have implemented it and instead rely on the
under the IVDD will find that they have to significantly general language requirement for IVDs to be labelled
amend their IVDD-compliant quality system. in their national language(s).28 However, for IVDs for
professional use, the IVDD’s provisions let individual
Technical Documentation and Design Dossier Member States determine which languages to use.
The manufacturer must be capable of making techni- Member States published their language requirements in
cal documentation available for all CE-marked IVDs, their national transpositions of the IVDD. The majority
regardless of their class. This technical documentation decided to impose their national language(s) for pro-
must demonstrate compliance with the applicable fessional IVDs, too. In practice, an IVD manufacturer
Essential Requirements, GSPRs, CS and applied har- selling products in all 32 countries covered by the IVDD
monised standards. IVDD Annex III lists items that must make IFU available in about 26 languages.
should be included in the technical documentation. To overcome some of the practical language
Not all items are applicable to each device; conversely, requirement problems, the European Commission pub-
an IVD’s technical documentation also may need to lished a guidance document29 defining the conditions
include information not explicitly listed in Annex III. for providing IFU by other means than sending them
For Annex II List A IVDD products, a design dos- physically with the product itself. Instructions now can
sier must be submitted to the notified body when the be posted on a website. However, strict conditions apply
Annex IV conformity assessment procedure is chosen. to this “e-labelling” solution. The website must meet
While technical documentation is not required to be certain requirements, and the manufacturer must make
submitted in one physical file, the design dossier is a a free telephone number available, so users can request a
single document addressing all items required for an mailed or faxed copy of IFU.
effective notified body assessment. A notified body may Devices for self-testing and point-of-care testing
make a proposal on a design dossier’s contents. The are excluded from e-labelling. Special requirements
Summary Technical Documentation (STED) format, apply to instrument manuals.
developed by GHTF’s Study Group 1,25 may become The language requirements also apply to labels.
a model in the future, but it currently is used less fre- Using the symbols in harmonised standard EN 98030
quently for IVDs than for medical devices. mitigates the problem.
In practice, manufacturers applying for a notified The EU IVDR changes the labelling requirements
body certificate for Annex II List A or Annex II List B and, more importantly, introduces Unique Device
devices, or devices for self-testing according to an Annex Identifiers (UDI) for IVDs (see Chapter 13 for more
V conformity assessment procedure, also may submit details). Annex I Chapter III concerning requirements
technical documentation structured as a design dossier. regarding information to be supplied with the device
The EU IVDR establishes a mandatory format for contains significantly amended requirements for infor-
technical documentation in its Annexes II (technical mation to be placed on the label and in the IFU. The
documentation) and III (technical documentation on EU IVDR does not contain an e-labeling regime, and
PMS), which is intended to align with the STED for- it is not certain whether the IVDD e-labeling guidance
mat). This means, for all existing IVDs, the technical discussed above will be carried over to the EU IVDR.
documentation must be revised to conform to the new The languages regime does not change in logic
format as a condition for CE marking under the EU under the EU IVDR but contains additional require-
IVDR. Annex III is a new annex with technical doc- ments. The EU IVDR provides that manufacturers
umentation requirements specifically for postmarket shall ensure that the device is accompanied by the

Chapter 16
information set out in Section 20 of Annex I in an Chapter 20 is dedicated to conformity assessment

official Union language(s) determined by the Member procedures, and an overview of the EU IVDR confor-
State in which the device is made available to the user mity assessment procedure.
or patient.31 In addition, the information supplied with
devices for self-testing or near-patient testing shall be Authorised Representative, Declaration of
easily understandable and provided in the official Union Conformity and Registration
language(s) determined by the Member State in which Other chapters in this book describe the Authorised
the device is made available to the user or patient. The Representative’s role and the Declaration of
EU IVDR also contains language requirements for the Conformity. Significant changes in the EU IVDR
declaration of conformity, which is to be translated into include the provision that Authorised Representatives
an official Union language or languages required by the are jointly and severally liable with the manufacturer for
Member State(s) in which the device is made avail- product liability.36
able.32 The EU IVDR also specifies that CE certificates After signing the Declaration of Conformity and
of conformity shall be in an official Union language before placing the product on the market, the manufac-
determined by the Member State in which the notified turer and devices must be registered. Under the IVDD,
body is established or otherwise in an official Union the manufacturer or its Authorised Representative
language acceptable to the notified body.33 Finally, the for non-European companies informs the competent
EU IVDR specifies that field safety notices shall be authority in the country in which it is based about plac-
edited in an official Union language or languages deter- ing the device(s) on the market.
mined by the Member State in which the field safety IVD registration is different from medical device
corrective action is taken.34 registration.
The IVD registration requirement applies to all
Conformity Assessment Procedures classes, not just those that do not require notified body
The IVD manufacturer must assess the conformity of involvement. Since the Eudamed database’s entry
its products and quality system prior to signing the into force37 in May 2011, the notification need not
Declaration of Conformity and affixing the CE Mark. be repeated in every country in which a product is
In the case of non-Annex II products for professional placed on the market. It is sufficient to notify only the
use, the manufacturer has sole responsibility for this. country in which the manufacturer or its Authorised
For other devices, the conformity assessment involves a Representative is based.
third-party notified body review. Only general information is requested for
For Annex II products, the notified body will non-Annex II products for professional use; however,
inspect the product’s quality and the quality system’s performance information, notified body certificates and
conformity. For Annex II List A products, the notified labelling must be provided for devices in other classes.
body also must release each batch. In practice, most countries accept the “Form for
Self-testing devices can be certified by the notified the registration of manufacturers and devices, In Vitro
body based on product documentation alone, although Diagnostic Medical Devices Directive, Article 10,”38
the manufacturer also can opt for conformity assess- available on the European Commission’s website for this
ment procedures, including quality system inspections. purpose. However, differences exist among countries
The EU IVDR does not change the conformity with respect to the information to be provided and costs.
assessment procedures radically in their basic logic, Under the EU IVDR, economic operators and
except that they are now linked to the risk class of the devices will be registered in the Eudamed database.39
IVD, a specific conformity assessment procedure has
been added for companion diagnostics and special The IVDD’s Revision
requirements apply for self-tests and near-patient testing The IVDD will be replaced by the EU IVDR. Details
IVDs. However, as a result of the changes to the classi- of this revision are discussed in detail in Chapter 13,
fication system, almost all currently self-certified devices including a detailed description of the process and
need to undergo conformity assessment by a notified changes. The EU IVDR entered into force on 26 May
body, because Class A remains the only class of devices 2017 and provides for a five-year transition period.
not subject to notified body scrutiny. Given the currently Those five years will be necessary because all IVDs on
limited capacity for certification of IVDs by notified the market will have to be reclassified, with the vast
bodies, it will be a challenge to recertify the majority majority ending up in a risk class requiring notified
of IVDs on the market in a timely manner during the body scrutiny and the collection of significant addi-
IVDR’s transitional period. Class D devices are subject tional clinical data for most current self-certified IVDs.
to additional scrutiny by an EU reference laboratory.35

The transitional regime is described in more detail in personal data and on the free movement of such data,
Chapter 13. and repealing Directive 95/46/EC (GDPR). The EU
Important changes will take place in: IVDR explicitly refers to data protection compliance in
• IVD classification and conformity assessment several instances, such as in relation to the use of left-
• scope of the accessory concept over samples,43 and in relation to performance studies.44
• “home brew” or “in-house” tests Other regulations and directives also may apply.
• companion diagnostics
• genetic testing Conclusion
• supply chain controls, labelling and UDI • The IVDD and its successor regulation, the EU
• demonstrating clinical validity and utility IVDR, share many features with the MDD and
• IVD clinical trials (performance evaluation its successor regulation, the MDR, respectively.
studies) The regulations’ general concept, its conformity
• vigilance reporting assessment procedures and its requirements
• market surveillance and unannounced audits for postmarketing surveillance, vigilance, risk
• own brand labelling management and technical documentation
are identical or very similar. The manufacturer,
It is important to note the EU IVDR will not grandfa- competent authorities, notified bodies and
ther in IVDs currently on the market; these will need Authorised Representatives’ responsibilities are
to be phased into the regulation’s framework during very similar to those defined in the MDD and
the transitional period. IVDs that are not CE-marked the MDR.
under the EU IVDR by the end of the transitional • Device classification is risk-based. The IVDD
period can no longer be placed on the EU market. literally lists Annex II’s high-risk products.
This annex contains two lists—List A and
Other Regulations List B. Self-testing devices are in a separate
IVDs are exempt from other directives, such as those on category. Under the EU IVDR, devices are
biocides, machinery, electric safety and electromagnetic classified in four risk classes (A–D), with com-
compatibility, often because the IVDD itself defines panion diagnostics, near patient testing devices
requirements addressing the safety issues in these and self-testing devices as special categories
directives. of devices. An additional layer of scrutiny has
However, other regulations may apply, including: been added for Class D devices.
• regulations on dangerous substances and • Before signing the Declaration of Conformity
preparations, which may impact labelling and affixing the CE Mark, the manufacturer
and require the availability and distribution must ensure its product meets the Essential
of material safety data sheets, such as the Requirements and, preferably, the associated
REACH regulation40 harmonised standards’ requirements. The CTS
• transport regulations are additional requirements, applicable only
• Directive 2002/96/EC of the European to Annex II List A products. Under the EU
Parliament and of the Council of 27 January IVDR, CS can apply to every product.
2003 on waste electrical and electronic • The IVDD will be replaced when the EU
equipment IVDR takes effect in 2022, bringing significant
• Directive 2011/65/EU of the European changes, e.g., in device classification.
Parliament and of the Council of 8 June 2011
on the restriction of the use of certain haz- References
1. Directive 98/79/EC of the European Parliament and
ardous substances in electrical and electronic of the Council of 27 October 1998 on in vitro diagnos-
equipment (RoHS) tic medical devices (IVDD). EUR-Lex website. http://
• LVD41 and EMC42 directives eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=CONS-
• radioactive materials’ regulations LEG:1998L0079:20031120:en:PDF. Accessed 8 April 2020.
2. EU IVDR Article 110 (5). https://eur-lex.europa.eu/legal-con-
tent/EN/TXT/PDF/?uri=CELEX:32017R0746&from=NL.
Since IVD tests usually entail processing patient data, Accessed 8 April 2020.
parties applying IVDs have to comply with the EU 3. IVDD Article 1(2)(b). EUR-Lex website. http://
rules on personal data protection. These are laid down in eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=CONS-
LEG:1998L0079:20031120:en:PDF. Accessed 8 April 2020.
Regulation (EU) 2016/679 of the European Parliament 4. Ibid.
and of the Council of 27 April 2016 on the protection 5. Ibid.
of natural persons with regard to the processing of 6. Ibid.

Chapter 16
7. European Commission. MEDDEV 2.14/1 Revision 2. Conformity to the Essential Principles of Safety and
Guidelines on Medical Devices: IVD Medical Device Performance of In Vitro Diagnostic Medical Devices (March
Borderline and Classification issues—A Guide for 2011). IMDRF website. http://www.imdrf.org/docs/ghtf/
Manufacturers and Notified Bodies ( January 2012) p. 5. EC archived/sg1/technical-docs/ghtf-sg1-n063-2011-summa-
website. https://ec.europa.eu/docsroom/documents/10322?lo- ry-technical-documentation-ivd-safety-conformity-110317.pdf.
cale=nl. Accessed 8 April 2020. Accessed 8 April 2020.
8. IVDD Article 1(3)(b). EUR-Lex website. http:// 26. ISO 18113:2009 (Part 1–5). In vitro diagnostic medical
eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=CONS- devices—Information supplied by the manufacturer (labelling).
LEG:1998L0079:20031120:en:PDF. Accessed 8 April 2020. (5 parts have been published).
9. IVDD Article 1(2)(a). EUR-Lex website. http:// 27. IVDD Annex I.B, section 8.1, last paragraph. EUR-Lex website.
eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=CONS- http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=CON-
LEG:1998L0079:20031120:en:PDF. Accessed 8 April 2020. SLEG:1998L0079:20031120:en:PDF. Accessed 8 April 2020.
10. Op cit 7. 28. IVDD Article 4(4). EUR-Lex website. http://
11. EU IVDR Article 2(4). EUR-Lex website. https:// eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=CONS-
eur-lex.europa.eu/legal-content/EN/TXT/ LEG:1998L0079:20031120:en:PDF. Accessed 8 April 2020.
PDF/?uri=CELEX:32017R0746&from=NL. Accessed 8 April 29. European Commission. MEDDEV 2.14/3 Rev. 1. Guidelines
2020. on Medical Devices: IVD Guidances: Supply of Instructions
12. European Commission. MEDDEV 2.14/2 Rev. 1. Guidelines For Use (IFU) and other information for In-vitro Diagnostic
on Medical Devices: IVD Guidance: Research Use Only (IVD) Medical Devices: A Guide for Manufacturers and
Products: A Guide for Manufacturers and Notified Bodies Notified Bodies. EC website. https://ec.europa.eu/docsroom/
(February 2004). CE Partner 4 U website. http://www. documents/10293/attachments/1/translations/en/renditions/pdf.
cepartner4u.com/wpdm-package/meddev-2-14_2-rev-1-re- Accessed 8 April 2020.
search-use-only/. Accessed 8 April 2020. 30. European Committee for Standardization. EN
13. Op cit 7. 980:2008. Symbols for use in the labelling of medi-
14. EU IVDR Annex III. Technical Documentation cal devices. BSI website. https://shop.bsigroup.com/
on Postmarket Surveillance. EUR-Lex website. ProductDetail/?pid=000000000030122247. Accessed 8 April
https://eur-lex.europa.eu/legal-content/EN/TXT/ 2020.
PDF/?uri=CELEX:32017R0746&from=NL. Accessed 8 April 31. EU IVDR Article 17. EUR-Lex website. https://
2020. eur-lex.europa.eu/legal-content/EN/TXT/
15. Since the entry into force of the Eudamed decision, IVD PDF/?uri=CELEX:32017R0746&from=NL. Accessed 8 April
manufacturers no longer have to notify the IVD in each 2020.
Member State in which the IVD is placed on the market, 32. Ibid.
see Commission Decision of 19 April 2010 on the European 33. EU IVDR Article 51(1). EUR-Lex website. https://
Databank on Medical Devices (Eudamed), OJ 2010 L102/45. eur-lex.europa.eu/legal-content/EN/TXT/
EUR-Lex website. http://eur-lex.europa.eu/LexUriServ/ PDF/?uri=CELEX:32017R0746&from=NL. Accessed 8 April
LexUriServ.do?uri=OJ:L:2010:102:0045:0048:EN:PDF. 2020.
Accessed 8 April 2020. EU IVDR Article 26 contemplates a 34. EU IVDR Article 84 (8). EUR-Lex website.
central notification in the Eudamed database, after central regis- https://eur-lex.europa.eu/legal-content/EN/TXT/
tration of the manufacturer in Eudamed (EU IVDR Article 27). PDF/?uri=CELEX:32017R0746&from=NL. Accessed 8 April
16. GHTF/SG1/N045:2008 Principles of In Vitro Diagnostic 2020.
(IVD) Medical Devices Classification. IMDRF website. 35. EU IVDR Article 48 (3). EUR-Lex website.
http://www.imdrf.org/docs/ghtf/final/sg1/procedural-docs/ https://eur-lex.europa.eu/legal-content/EN/TXT/
ghtf-sg1-n045-2008-principles-ivd-medical-devices-classifica- PDF/?uri=CELEX:32017R0746&from=NL. Accessed 8 April
tion-080219.pdf. Accessed 8 April 2020. 2020.
17. IVDD Article 3, EU IVDR Article 5(2). 36. EU IVDR, Article 11 (5). EUR-Lex website.
18. IVDD Article 5(1), EU IVDR Article 8(1). https://eur-lex.europa.eu/legal-content/EN/TXT/
19. ISO 14971:2012. Medical Devices—Application of risk man- PDF/?uri=CELEX:32017R0746&from=NL. Accessed 8 April
agement to medical devices. 2020.
20. Commission Decision of 20 December 2011 amend- 37. Commission Decision 2010/227/EU of 19 April 2010 on the
ing Decision 2002/364/EC on common technical European Databank on Medical Devices (Eudamed). OJ 2010
specifications for in vitro-diagnostic medical devices L102, 23.4.2010. EUR-Lex website. http://eur-lex.europa.eu/
(2011/568/EU), OJ 2011 L341/63. EUR-Lex website. legal-content/EN/TXT/?uri=CELEX:32010D0227. Accessed
http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=O- 8 April 2020.
J:L:2011:341:0063:0064:EN:PDF. Accessed 8 April 2020. 38. IVDD Article 10, Form for the registration of manufactur-
21. EU IVDR Article 9 (1) and (3). EUR-Lex website. ers and devices. EUR-Lex website. http://eur-lex.europa.eu/
https://eur-lex.europa.eu/legal-content/EN/TXT/ legal-content/en/ALL/?uri=CELEX:31998L0079. Accessed 8
PDF/?uri=CELEX:32017R0746&from=NL. Accessed 8 April April 2020.
2020. 39. EU IVDR Articles 26 and Article 28. EUR-Lex web-
22. Ibid. site. https://eur-lex.europa.eu/legal-content/EN/TXT/
23. ISO 13485:2016. Medical Devices—Quality management PDF/?uri=CELEX:32017R0746&from=NL. Accessed 8 April
systems—Requirements for regulatory purposes. 2020.
24. European Commission. MEDDEV 2.12/1 Rev. 6. 40. Regulation (EC) No. 1907/2006 of the European Parliament
Guidelines on a medical devices vigilance system (December and of the Council of 18 December 2006 concerning the
2009). EC website. http://www.meddev.info/_docu- Registration, Evaluation, Authorisation and Restriction of
ments/2_12_1-rev_6-12-2009_en.pdf. Accessed 8 April 2020. Chemicals (REACH), establishing a European Chemicals
25. Global Harmonization Task Force, Study Group 1. Summary Agency, amending Directive 1999/45/EC and repealing Council
Technical Documentation (STED) for Demonstrating Regulation (EEC) No. 793/93 and Commission Regulation

(EC) No. 1488/94 as well as Council Directive 76/769/EEC of the Member States relating to electromagnetic compatibility,
and Commission Directives 91/155/EEC, 93/67/EEC, 93/105/ OJ 2014 L 96/79.
EC and 2000/21/EC, OJ L 396, 30.12.2006, p. 1–849. OSHA 43. EU IVDR Article 57(3). EUR-Lex website. https://
Europe website. https://osha.europa.eu/en/legislation/directives/ eur-lex.europa.eu/legal-content/EN/TXT/
regulation-ec-no-1907-2006-of-the-european-parliament-and- PDF/?uri=CELEX:32017R0746&from=NL. Accessed 8 April
of-the-council. Accessed 8 April 2020. 2020.
41. Directive 2014/35/EU of the European Parliament and of the 44. EU IVDR Article 68(30). EUR-Lex website.
Council of 26 February 2014 on the harmonisation of the laws https://eur-lex.europa.eu/legal-content/EN/TXT/
of the Member States relating to the making available on the PDF/?uri=CELEX:32017R0746&from=NL. Accessed 8 April
market of electrical equipment designed for use within certain 2020.
voltage limits, OJ L 96, 29.3.2014, p. 357–374.
42. Directive 2014/30/EU of the European Parliament and of the
Council of 26 February 2014 on the harmonisation of the laws

Chapter 16

Chapter 17
General Safety and Performance

Requirements and Technical
Documentation (EU MDR, EU IVDR)
Updated by Darin Oppenheimer, DRSc, RAC, Suraj Ramachandran, MS, RAC and George Cusatis, MS, RAC
OBJECTIVES The Historical Foundation of the Medical

□ Understand the technical requirements that
Device Regulations’ General Safety and
must be met to demonstrate conformity with the Performance Requirements
General Safety and Performance Requirements The previous Medical Devices Directives (MDD) are
as outlined in Annex I Regulation 2017/45 EU based on treaty provisions regarding the EU internal
Medical Devices Regulation and Regulation market establishment and functioning (now Article
2017/746 In Vitro Diagnostic Medical Devices 114 of the Treaty on the Functioning of the European
Regulation (EU IVDR) Union (TFEU). The Lisbon Treaty added a legal basis
for the adoption of public health measures, setting high
□ Understand the role of European and interna- medical product quality and safety standards (Article
tional standards in the conformity assessment 168(4)(c) TFEU). Both policies are shared competences
process and expectations with respect to market- between the EU and the Member States.3 The new
ing medical devices in the European Union (EU) EU MDR and EU IVDR, which integrate the Lisbon
Treaty’s public health modification, can be achieved
□ Understand technical documentation require- only at the EU level. This will prevent Member States
ments covered in Annex II and III from adopting varying product regulations that would
fragment the internal market further.
On 5 April 2017, the European Commission pub-
DIRECTIVES, REGULATIONS AND GUIDELINES lished two new regulations. The publication of these
COVERED IN THIS CHAPTER regulations, in lieu of previously published directives,
demonstrated a greater approach to mandatory action
□ Regulation (EU) 2017/745 of the European across the EU and was intended to mitigate the risk
Parliament and of the Council of 5 April 2017 of diverting interpretations of previous directives.4 The
on medical devices, amending Directive EU MDR and EU IVDR, repealed the Medical Devices
2001/83/EC, Regulation (EC) No. 178/2002 and Directive 93/42/EEC, Active Implantable Medical
Regulation (EC) No. 1223/2009 and repealing Devices Directive 90/385/EEC and In Vitro Diagnostic
Council Directives 90/385/EEC and 93/42/EEC1 Medical Devices Directive 98/79/EC. The Commission
□ Regulation (EU) 2017/746 of the European has communicated that the importance of these
Parliament and of the Council of 5 April 2017 changes outlined in the above-referenced regulations
on in vitro diagnostic medical devices and were implemented to modernise the current system
repealing Directive 98/79/EC and Commission and address opportunities for improvements, such as
Decision 2010/227/EU2 strengthening postmarket surveillance, reinforcing the
rules of clinical evidence, introduction of implant cards,
increased transparency, new risk classification system
for IVD products, inclusion of certain aesthetic devices,

Chapter 17
reinforcement of notified body oversight and increased By demonstrating how each requirement has been met,
control of high-risk devices.5 a manufacturer can declare conformity and affix the
These regulations build upon the foundation CE Mark. Similarly, when a manufacturer draws up a
of what was previously established in the applicable compliance statement prior to commencing a clinical
directives and add further clarification where needed investigation (as specified in Annex XV, Chapter II
by the creation of 23 General Safety and Performance Documentation Regarding the Application for Clinical
Requirements (GSPRs) for medical devices, with mul- Investigation, point 4.1), the GSPR checklist specified
tiple subsections (20 for in vitro diagnostic devices) in in EU MDR Article 62 Point 4(1a-c) for aspects that
Annex I, compared to the previous version’s 13 sub- can be demonstrated only after the study is complete
sections. The GSPRs, spanning three chapters of the provides confidence the declaration is truthful. At an
EU MDR and EU IVDR, are categorised into general even earlier phase, the checklist is a valuable tool for gap
requirements, requirements regarding design and man- analysis during design verification.
ufacturer and requirements regarding the information A GSPR checklist should not include technical
supplied with the device. Another significant proposed details (only references to where such documentation
change is that manufacturers will be required to update exists); however, standards to which compliance has
technical documentation, declarations of conformity and been claimed should be cited, and all documents pro-
labelling. The technical documentation is a set of living viding evidence of conformity should be referenced.
documents that evolves with the lifecycle of the product. Such documents must be available in the technical doc-
umentation supporting CE conformity. Table 17-1 is
General Safety and Performance an example of a partial GSPR checklist.
Requirements The basic principles on which the regulations are
GSPRs for medical device design and manufacture based are summarised within the Chapter I general
ensure patient, end user and third party’s health and requirements of EU MDR and EU IVDR Annex I.
safety are protected. These requirements stipulate the These principles are:
safety principles that should be integral to the prod- • Devices must not compromise the patient’s or
uct’s design and suitability for its intended purpose. user’s clinical condition or safety.
The Essential Principles concept was developed by • The device’s risks must be acceptable when
the Global Harmonization Task Force (GHTF) and weighed against its benefits.
further implemented into the leading practices of • Risks must be eliminated or minimised in line
the International Medical Device Regulators Forum with the state of the art.
captured in the Essential Principles of Safety and • Devices must perform as intended by the
Performance of Medical Devices and IVD Medical manufacturer.
Devices guidance on best practices. It is intended to
encourage convergence in the evolution of medical These concepts are difficult to quantify, but the manu-
device regulatory systems.6 The GSPRs develop further facturer must demonstrate its device’s risks and benefits
requirements concerning risk management, combination have been assessed and are balanced appropriately.
products, software, labeling, etc., in addition to the exist- The remaining GSPRs are permutations on this
ing Medical Devices Directive’s essential requirements. theme and relate to the following specific circumstances
Conformity with all relevant GSPRs contained in or device attributes:
Annex I of the applicable regulation must be demon- • chemical, physical and biological properties
strated prior to CE marking a medical device. Notified • infection and microbial contamination
bodies review a checklist provided by the manufacturer, • devices incorporating a medicinal product and
listing all GSPRs and, for each requirement, an expla- devices composed of substances or of combi-
nation of how conformity has been demonstrated or nations of substances that are absorbed by or
why it is not applicable based on the product’s intended locally dispersed in the human body
use and functionality. A checklist also is required for • devices incorporating materials of biological
self-certified devices, e.g., some Class I medical devices; origin
in such cases, the list provides the assurance needed to • construction of devices and interaction with
underpin the declaration of conformity. The GSPRs their environment
have been devised carefully and result from a systematic • devices with a diagnostic or a measuring
approach to specifying necessary and appropriate reg- function
ulatory requirements. Therefore, manufacturers use an • protection against radiation
equally ordered approach to demonstrate compliance. • active devices and devices connected to them
• active implantable devices

General Safety and Performance Requirements and Technical Documentation (EU MDR, EU IVDR)
Table 17-1. General Safety and Performance Requirements Checklist (Annex I of EU MDR and EU IVDR)
Method of
Conformity
General Safety and Performance Requirements of the Applicability Justification Evidence of
(Standard/
Medical Devices Regulation 2017/745 (Yes or No) (if No) Conformity
Regulation/
Guidance)
Chapter I GENERAL REQUIREMENTS
Devices shall achieve the performance intended by their
manufacturer and shall be designed and manufactured
Design
in such a way that, during normal conditions of use, they
Requirements
are suitable for their intended purpose. They shall be
ISO Specification,
safe and effective and shall not compromise the clinical
13485:2016 PRO-XXXXXX
condition or the safety of patients or the safety and
1 Yes ISO Device Risk
health of users or, where applicable, other persons, pro-
14971:2019 Management
vided that any risks which may be associated with their
Report,
use constitute acceptable risks when weighed against
PRO-XXXXXX
the benefits to the patient and are compatible with a
high level of protection of health and safety, taking into
account the generally acknowledged state of the art.
The requirement in this Annex to reduce risks as far as
2 possible means the reduction of risks as far as possible
without adversely affecting the benefit-risk ratio.
Manufacturers shall establish, implement, document
and maintain a risk management system.
Risk management shall be understood as a continuous
iterative process throughout the entire lifecycle of a
device, requiring regular systematic updating. In carry-
ing out risk management manufacturers shall:
establish and document a risk management plan for
each device
identify and analyse the known and foreseeable hazards
associated with each device
estimate and evaluate the risks associated with, and
3 occurring during, the intended use and during reason-
ably foreseeable misuse
eliminate or control the risks referred to in point (c) in
accordance with the requirements of Section 4
evaluate the impact of information from the production
phase and from the postmarket surveillance system,
on hazards and the frequency of occurrence thereof, on
estimates of their associated risks, as well as on the
overall risk, benefit-risk ratio and risk acceptability
(f) based on the evaluation of the impact of the informa-
tion referred to in point (e), if necessary, amend control
measures in line with the requirements of Section 4
Risk control measures adopted by manufacturers
for the design and manufacture of the devices shall
conform to safety principles, taking account of the gen-
erally acknowledged state of the art. To reduce risks,
Manufacturers shall manage risks so that the residual
risk associated with each hazard as well as the overall
residual risk is judged acceptable. In selecting the most
appropriate solutions, manufacturers shall, in the fol-
lowing order of priority:
4
eliminate or reduce risks as far as possible through safe
design and manufacture
where appropriate, take adequate protection measures,
including alarms if necessary, in relation to risks that
cannot be eliminated
provide information for safety (warnings/precautions/
contra-indications) and, where appropriate, training to
users
Manufacturers shall inform users of any residual risks.
Continued on p. 224

Chapter 17
Table 17-1. General Safety and Performance Requirements Checklist (Annex I of EU MDR and EU IVDR) (cont.)
Method of
Conformity
General Safety and Performance Requirements of the Applicability Justification Evidence of
(Standard/
Medical Devices Regulation 2017/745 (Yes or No) (if No) Conformity
Regulation/
Guidance)
In eliminating or reducing risks related to use error, the
manufacturer shall:
reduce as far as possible the risks related to the ergo-
nomic features of the device and the environment in
which the device is intended to be used (design for
5 patient safety)
give consideration to the technical knowledge, experi-
ence, education, training and use environment, where
applicable, and the medical and physical conditions of
intended users (design for lay, professional, disabled or
other users)
The characteristics and performance of a device shall
not be adversely affected to such a degree that the
health or safety of the patient or the user and, where
applicable, of other persons are compromised during
6 the lifetime of the device, as indicated by the manufac-
turer, when the device is subjected to the stresses which
can occur during normal conditions of use and has been
properly maintained in accordance with the manufactur-
er’s instructions.
Devices shall be designed, manufactured and packaged
in such a way that their characteristics and performance
during their intended use are not adversely affected
7 during transport and storage, for example, through fluc-
tuations of temperature and humidity, taking account
of the instructions and information provided by the
manufacturer.
All known and foreseeable risks, and any undesirable
side-effects, shall be minimised and be acceptable when
8 weighed against the evaluated benefits to the patient
and/or user arising from the achieved performance of
the device during normal conditions of use.
For the devices referred to in Annex XVI, the general
safety requirements set out in Sections 1 and 8 shall be
understood to mean that the device, when used under
the conditions and for the purposes intended, does
9
not present a risk at all or presents a risk that is no
more than the maximum acceptable risk related to the
product’s use which is consistent with a high level of
protection for the safety and health of persons.
• protection against mechanical and thermal the predecessor, GHTF, viewed international con-
risks sensus standards as a tool for harmonising regulatory
• devices supplying energy or substances processes to ensure medical devices’ safety, quality
• information supplied by the manufacturer and performance. The International Organization
for Standardization (ISO) defines a “standard” as a
Using Standards and Common document, established by consensus and approved by
Specifications to Support Regulatory a recognised body, which provides for common and
repeated use, rules, guidelines or characteristics for
Requirements activities or their results aimed at the achievement of
A standard is a consensus document. The International the optimum degree of order in a given context.
Medical Device Regulators Forum (IMDRF) and

To ensure the essential principles are met, a man- regulations. Inherent in the new approach is the expecta-
ufacturer may use consensus standards. Such standards tion that compliance with these specifications provides a
provide a greater level of detail than the essential princi- presumption of conformity with the GSPRs.
ples. Equally, regulators may find the essential principles In practice, this means the European Commission
and their related standards useful in the context of med- “mandates” the European Standardization Committee
ical device regulatory systems.7 (CEN) or Electrotechnical Commission (CENELEC)
It is good practice to consider objectively the extent to develop standards necessary to demonstrate
to which a standard’s use complies with the GSPRs and GSPR compliance in one or more of the directives.
to identify any conformity assessment aspects that need CENELEC develops a relevant document, normally
to be addressed by other means. This chapter presents through cooperation with ISO. Typically, an inter-
some general observations about the nature of standards national standard is developed by a working group
and the way they are generated. However, it first is within an ISO technical committee and published
important to consider the critical role standards play in by European national standards bodies as a dual EN/
the EU medical device regulatory system. ISO standard. However, not all European standards
Standards used to address the essential principles are harmonised. Once a standard has been approved
should be based on: for publication as a European standard, CEN advi-
• a close relationship of the standard’s scope to sors review it to verify it adequately demonstrates
one or more essential principles conformity assessment. If it is found to be adequate,
• the clarity and completeness of the standard’s a reference to the standard is published in the Official
technical requirements Journal of the European Communities (OJ). This is “har-
• methods for determining compliance with monisation,” and the resulting document is known as
each of the standard’s applicable technical a harmonised European standard. Lists of harmonised
requirements standards are available from the European Commission
• clear criteria for determining whether techni- website (www.europa.eu) and are published periodically
cal requirements are met, or why an exclusion in the OJ.8
is justified An annex in the European version of each har-
monised standard indicates the GSPRs for which the
In parallel to the standards, the Common Specifications standard is deemed relevant. By referencing such infor-
(CS) published by the European Commission and mation and showing compliance with the standard’s
referenced in the EU MDR and EU IVDR Article 9, requirements, a manufacturer can claim conformity with
will have to be applied to support conformity with specific GSPRs. This should not merely be a box-check-
GSPRs for specific product groups typically without an ing exercise, as it is necessary to confirm the standard
intended medical purpose. CS refers to technical and/ is, indeed, appropriate and adequate for demonstrating
or clinical requirements, other than a standard, that full compliance. This process is set out in EU MDR
provide a means of complying with the legal obligations Article 8. In summary, a harmonised standard is deemed
applicable to a device, process or system. When applica- necessary and sufficient to carry the presumption of con-
ble, CS needs to be listed in the GSPR checklist. formity with the relevant European regulation’s GSPRs.
Using harmonised standards to demonstrate
Regulatory Status of European Standards compliance with the GSPRs is not obligatory. A
Standards’ nature and role in the regulatory process manufacturer may show compliance through other
is explained in the EU MDR preamble. Because the appropriate avenues. Manufacturers may choose to use
GSPRs are designed to cover a wide variety of safety an ISO standard where no harmonised CEN standard
and performance aspects for a wide variety of products, exists. Alternatively, national or in-house standards (e.g.,
they cannot provide the level of technical detail required Standard Operating Procedures (SOPs)) can be used.
to address everything relevant to conformity assessment. SOPs should justify the methods chosen and include
Standards in turn can provide this level of detail. The references to applicable standards, indicating the degree
basis for this arrangement lies in the “New Approach” to which compliance with each standard is required.
to European regulation adopted in 1985, based on the If alternative routes to harmonised standards are used,
principle of establishing an internal European market questions from competent authorities and notified bod-
with free movement of goods and services. This new ies may arise, and the departure from the norm needs
approach is critically dependent upon technical harmon- to be justified. The authority shall assess whether the
isation. European standards bodies were given the task risk-minimisation solution provides a level of protection
of drawing up technical specifications to meet the essen- equivalent to that provided by harmonised standards
tial principles of the various new approach directives and (EU MDR Article 71 Assessment by Member States

Chapter 17
3(b)). The justification should include the reasons a standards in the GSPR checklist should clearly indicate
harmonised standard was not used and why the selected any aspect of noncompliance with a standard, and justi-
methods are appropriate and adequate. fication for the noncompliance and alternative measures
taken to ensure full GSPR compliance.
Identifying and Referencing Applicable
Standards Technical Documentation
Generic standards, relevant to all devices or a wide Prior to the EU MDR and EU IVDR entering into
range of product types, are termed “horizontal” (Level force, manufacturers can use recommendations from
1) standards. Examples are standards on quality systems the European Association of Medical Device Notified
(ISO 13485), risk management (ISO 14971), biologi- Bodies (NB-MED)10 to structure the technical file.
cal safety (ISO 10993) and sterilization (ISO 11737). Both regulations provide the content description
“Semi-horizontal” (Level 2) standards contain require- regarding the technical documentation that sub-
ments applicable to a range of similar products, such as stantiates the device’s CE declaration of conformity
endovascular devices or surgical instruments. “Vertical” throughout its lifecycle.
(Level 3) standards apply to single product types or a Technical documentation is described in EU MDR
range of closely related products, such as vascular stents and EU IVDR Annex II and III and should cover the
or surgical scalpels. device’s design, manufacture and performance. The min-
National standards bodies, from which standards imal technical documentation retention period for the
can be purchased, provide searchable listings on their legal manufacturer is 10 years after the last device being
websites. These generally provide enough informa- placed on the market (15 years for implantable devices)
tion to determine the cited standard’s scope. A list of (EU MDR and EU IVDR Article 10).
harmonised standards can be found on the European The EU MDR includes notified body assessment of
Commission’s website (not yet available for EU MDR technical documentation as part of the CE conformity
and EU IVDR at the time this chapter was written).9 A assessment process for most devices; the exception being
search of these sources should reveal all standards that Class I devices that are non-measuring and non-ster-
may be applicable to a product. ile. The assessment’s extent depends on the device’s
Technical documentation has several deliverables classification. The manufacturer and its Authorised
in which standards applied to the product, in full or Representative must make technical documentation
in part, must be documented. Examples include the available to competent authorities, and under many cir-
Investigator’s Brochure (IB) for a premarket clinical cumstances, the notified body may request the same.
investigation and the GSPR checklist. This requirement The EU MDR defines the technical documen-
often is applied as an afterthought and interpreted as tation’s minimum requirements and its post-market
a simple list of all relevant standards to which some updates. The EU IVDR has similar requirements and
degree of compliance can be shown. However, a casual includes details of analytical and clinical performances
approach can lead to significant problems or delays in the product verification and validation (Annex II,
in regulatory approval. This regulatory requirement’s point 6). The documents comprising the technical
objective is to allow a precise indication of the extent documentation are relevant to regulatory compliance
to which GSPR conformity can be presumed via the and, thus, are considered critical to product quality.
use of harmonised standards. Unless the extent of com- Therefore, they need to be part of the manufactur-
pliance with a standard is specified clearly, conformity er-controlled documentation system (i.e., quality
cannot be established in this manner. management system). The manufacturer can compile
Mapping out how conformity will be established full technical documentation or a summary, the latter
early in the product development process can be very derived from the Summary Technical Documentation
beneficial to the success of the project, and the GSPR (STED) developed by GHTF. Technical documenta-
checklist is a great starting place. Potentially relevant tion contents include:
standards can be mapped against the checklist and 1. device description and specification, including
reviewed to establish whether they indeed are appli- variants and accessories
cable or whether alternative or additional conformity 2. labelling (including information supplied with
assessment means are necessary. Whenever a standard the device)
is used for presumption of conformity, any departure 3. design and manufacturing information
from complete compliance should be documented and 4. general safety and performance requirements
its significance to compliance with the relevant GSPRs 5. benefit-risk and risk management
considered. Any reports that reference the applicable 6. product verification and validation

In addition to premarket efforts to compile techni- state-of-the-art device bearing CE marking to support
cal documentation, the manufacturer shall update it compliance with the GSPRs.
according to EU MDR Article 83, point 3. Technical
documentation on postmarket surveillance (PMS) Conclusion
is defined in Annex III. This is in line with the New This chapter discusses:
Legislative Framework11 to ensure product safety via • EU MDR and EU IVDR expectations for
proactive market surveillance. The technical documenta- Annex I and II
tion on PMS includes: • GSPR checklist
1. PMS plan • relationship between the GSPRs, harmon-
2. Periodic Safety Update Report (PSUR) and ised standards and other publicly available
PMS report documents
• technical documentation contents
No Predicate Device • no comparison to predicate devices in the EU
It is important to underscore the fact that the EU med- regulatory process
ical device regulatory review process does not require
a substantially equivalent comparison to a predicate References
1. Regulation (EU) 2017/745 of 5 April 2017 on medical devices.
device. The data provided in each new submission EUR-Lex website. http://eur-lex.europa.eu/legal-content/EN/
must demonstrate “independent” conformity with the TXT/PDF/?uri=CELEX:32017R0745&from=EN. Accessed 22
GSPRs, often based on clinical evaluation data (EU March 2020.
MDR Article 61). Data demonstrating the “new” device 2. Regulation (EU) 2017/746 of 5 April 2017 on in
vitro diagnostic medical devices. EUR-Lex web-
has the same or better characteristics than a device site. http://eur-lex.europa.eu/legal-content/EN/TXT/
already on the market generally are not accepted. PDF/?uri=CELEX:32017R0746&from=EN. Accessed 24
There are two reasons for this approach. First, no March 2020.
one knows what devices are on the market in the EU, 3. Regulatory Framework for Medical Devices. EC website. http://
ec.europa.eu/growth/sectors/medical-devices/regulatory-frame-
as there is no publicly accessible database available yet. work_en#new_regulations. Accessed 24 March 2020.
This makes it impossible to find a predicate device. The 4. Op cit 1.
second reason for this approach is it mandates a return 5. Op cit 1.
to essential principles for each device, thereby pre- 6. ISO/TR 16142: 2006. Medical devices—Guidance on the selection
of standards in support of recognized essential principles of safety and
venting ‘drift’ where Device B is just slightly different performance of medical devices.
from Predicate A; Device C is slightly different from 7. Ibid.
Predicate B, etc. 8. Harmonised Standards. EC website. http://ec.europa.eu/
This approach’s advantage is it makes it easier to growth/single-market/european-standards/harmonised-stan-
dards/index_en.htm. Accessed 24 March 2020.
place new devices on the market. The disadvantage is 9. Ibid.
for “me-too” devices, where, despite being equal in every 10. NB-MED Technical Documentation: 2.5.1 Conformity assess-
way, the new device must undergo the same testing pro- ment procedures; General rules. MEDDEV website. www.
cedures. This can be very difficult, especially in relation meddev.info/_documents/R2_5_1-5_rev4.pdf. Accessed 25
February 2020.
to preclinical work, where governments place limits on 11. New Legislative Framework. EC website. https://ec.europa.eu/
repeating animal studies. growth/single-market/goods/new-legislative-framework_nl.
In some cases, the term “comparator device” Accessed 24 March 2020.
refers to an established device bearing the CE Mark 12. 2009/886/EC: Commission Decision of 27 November 2009
amending Decision 2002/364/EC on common technical
that is used as the reference in a clinical investigation. specifications for in vitro diagnostic medical devices. EUR-
For example, the overall performance of some blood Lex website. http://eur-lex.europa.eu/legal-content/EN/
screening IVD devices12 may be tested against that of a TXT/?uri=CELEX:32009D0886. Accessed 24 March 2020.

Chapter 17

Chapter 18
Medical Device Preclinical

Testing
Updated by Jan-Paul van Loon, MSc, PhD and Gert Bos, MSc, PhD, FRAPS
OBJECTIVES □ NBOG BPG 2009-4 Guidance on notified body’s

tasks of technical documentation assessment
□ Provide an overview of preclinical testing on a representative basis
and its role in medical device design and
development □ GHTF SG1/N011 2008: Summary Technical
Documentation (STED)
□ Discuss the objectives of the different types of
preclinical testing
Introduction
□ Provide examples of preclinical testing of
The purpose of preclinical testing is to ensure the device
devices
meets all its requirements, including user requirements,
regulatory requirements, requirements from (har-
monised/recognised) standards and risk management
DIRECTIVES, REGULATIONS AND GUIDELINES requirements. During the preclinical testing process,
COVERED IN THIS CHAPTER the product design might have to be modified to meet
these requirements. Both the US Food and Drug
□ Medical Devices Regulation (EU MDR) 2017/745
Administration (FDA) and the latest version of ISO
of the European Parliament and of the Council
134851,2 require that design outputs meet design inputs.
of 5 April 2017 on medical devices, amending
Preclinical testing covers both the in vitro and in
Directive 2001/83/EC, Regulation (EC) No.
vivo tests to ensure a device’s safety and efficacy. This
178/2002 and Regulation (EC) No. 1223/2009
chapter discusses the regulatory aspects of the preclin-
and repealing Council Directives 90/385/EEC
ical studies required before a device proceeds to the
and 93/42/EEC
clinical trial stage or achieves marketing approval.
□ Medical Devices Directive (EU MDD) 2007/47/EC
of the European Parliament and the Council of Preclinical Test Plan
5 September 2007 amending Council Directive During design, the manufacturer’s selection of mate-
90/385/EEC on the approximation of the laws rials to be used to produce the device should to fit the
of the Member States relating to active implant- device’s purpose, i.e., mechanical, physical, chemical and
able medical devices, Council Directive 93/42/ toxicological.
EEC concerning medical devices Current literature and other available information
should be reviewed to determine what standard testing,
□ Manual on borderline and classification in the purity data or biocompatibility studies associated with
Community regulatory framework for medical the (raw) materials already exists. The manufacturer’s
devices (only for the Medical Devices Directive) choice of materials should depend partly on the steril-
isation method, as some materials and some intended
uses are more suited for certain sterilisation methods.

Chapter 18
As stated above, inputs for the preclinical test plan the EU MDR has introduced “common specifications,”
include specific performance requirements in relation which can be considered similar to FDA’s guidances.
to the intended use of the device, requirements from
regulatory bodies and requirements identified during Requirements from Standards
the risk management process. These requirements are One of the first steps in the preclinical testing plan-
not fixed but can change as a result of the outcome of ning process as well as in the development process is
preclinical testing. to determine and evaluate the current relevant industry
Table 18-1 shows how the design traceability standards. In the EU, many International Organization
matrix connects the requirements to the test results by for Standardization (ISO) and International Electrical
listing the requirements on the y-axis and the design Commission (IEC) standards have been adopted, and
inputs and outputs in the columns in the x-direction. these have been published as EN-ISO and EN-IEC
standards, e.g., the ISO 10993-X (biocompatibility)
User Requirements series and the IEC 60601-1-X3 (electrical safety) series.
User requirements, or customer requirements, should However, only a limited number of these standards has
meet the needs of the user. The user is by default the been incorporated into the EU MDD’s harmonised
patient, but depending on the type of the device, the standards list, which can be confusing for non-EU
medical professional also can be a user. User require- companies. In practice, there is little difference between
ments are closely related to the device’s intended use, the EU MDD and FDA-recognised standards, although
actual use and are often performance requirements. FDA is quicker to recognise new standards and pro-
User requirements are often described in a “soft” vides specific mandatory standards per product type
way but need to be measurable to become a testable (code), while the EU does not.
requirement. For example, “widening the trachea” can Apart from the very limited list of harmonised
be translated into a testable minimum percentage of standards, there are many additional industry standards
diameter increase. In the preclinical phase, device perfor conducting both in vivo and in vitro experiments,
formance can be tested through patient simulations. which could be considered “best practices.”
A discussion of the clinical trial process for medical
devices falls outside the scope of this chapter. Risk Management Requirements
Risk management should follow the EN ISO 149714
Regulatory Requirements standard (2019 version), starting with a risk manage-
In Europe, the main regulatory requirements are con- ment plan, followed by the risk assessment process and
tained in the General Safety and Performance Checklist finally the report. The risk management file (including
(EU MDR Annex I), replacing the well-known EU the risk assessment) is updated during the development
MDD Essential Requirements. The manufacturer must process, and new requirements may become known
determine which of these general requirements are during the process.
applicable to its device. The list does not contain any During the risk assessment process, uncertainties
link to standards, so the manufacturer also must deter- are identified, which need to be mitigated by risk-re-
mine which standards are applicable. This is different ducing measures. This often involves testing, so these
from the system in the US, where FDA provides guid- requirements will appear in the preclinical test plan and
ance on the standards that apply to each type of device. preferably also in the design traceability matrix.
The EU MDD lists mandatory “harmonised stan- Increasingly, standards are explicitly requiring risk
dards.” A similar list will be available in the EU MDR. management assessments to be conducted prior to set-
As the list of harmonised standards in the EU MDD ting up the test plan, including those contained in the
has not been updated in the last three years, notified Electrical Safety and EMC standards (EN IEC 60601
bodies will require manufacturers to begin using the lat- series) and the new main biocompatibility standard (EN
est version of the applicable standards one year after the ISO 10993-1).5 The output of the risk management
standard has been published. In addition, manufacturers assessment is the input for the preclinical test plan.
will need to comply with a longer list of mandatory
standards compared to the EU MDD’s list of harmon- Nonclinical Studies
ised standards. A nonclinical laboratory study is an in vivo or in vitro
Further, under the EU MDD, compliance with test in which samples of the medical device are studied
MEDDEV guidances also were considered mandatory. prospectively in test systems to determine whether the
Currently, the Medical Device Coordination Group is device meets all requirements as determined during the
working to publish a new set of guidances. In addition, planning phase.

Medical Device Preclinical Testing
Table 18-1. Basic Design Traceability Matrix (DTM) for Connecting Requirements to Test Results
Design Input
Requirement Design Output Proof PASS?
(Measurable Specifications)
Target + Verification (ISO/IEC/Other) Result
Specification Report ID PASS/FAIL
Tolerances Method Standard (X, sd)
Depending on the type of device, preclinical testing • pyrogenicity testing

will contain one or more of the following tests:
• biocompatibility studies according to the Special attention must be given to the possible influence
EN ISO 10993-X series (and device-specific of the production and sterilisation methods. It is not
standards) possible to leverage data from competitors because this
• performance testing information is often proprietary. Also, it is often not possi-
• packaging validation and transport studies ble to use datasheets of raw materials as evidence because
• sterilisation validation production methods and sterilisation of the device may
• electrical safety and electrical magnetic distur- alter its biological properties. However, it is possible to
bance testing (EN IEC 60601-X and -X-X leverage data from the company’s similar products, in case
series) the type of contact, the production methods and the steril-
• shelf life (aging) studies isation methods are (nearly) identical.
• software verification The EN ISO 10993-X series is not the only source
• usability (human factors) studies for determining the type of tests to be performed. For
some devices, e.g., ventilation tubes and transfusion
These test types will be discussed in more detail below. sets, product standards require specific biocompatibility
testing.
Biocompatibility Testing If the product is made of a new material that has
All devices that are expected to have direct contact with a not been used in healthcare applications before, a full
patient and/or user require a biocompatibility evaluation suite of testing may be required. Some of these tests are
according to EN ISO 10993-1. This standard requires an lengthy and may take considerable numbers of devices
analysis of the device type, the contact and the duration to run, so proper planning for this segment is essential
of the contact, and a risk assessment to determine the to meeting timelines. Even when a device is made of
possible risks to the patient and/or user. Data can then well-known materials, biocompatibility testing may be a
be sought from toxicological databases and literature. If long and costly process.
existing information is not sufficient to address concerns
about the biological safety of the device, as is often the Performance Testing
case, preclinical biocompatibility testing may be needed. Each medical device will have to meet its intended
The EN ISO 10993-1 standard addresses the different performance, which will have to be proven by testing.
test types that should be considered. For some device types, specifically for devices used
These tests are described in detail in the EN ISO on a large scale, there are specific product standards
10993-X series. Examples are: with predefined performance criteria. For example, for
• cytotoxicity testing intravascular catheters, the EN ISO 10555-X6 series of
• sensitisation and irritation studies standards describes performance requirements, includ-
• acute, subchronic, chronic studies ing test set ups. Other devices with specific product
• carcinogenicity studies standards are transfusion sets for single use (EN ISO
• genotoxicity testing 1135-4)7 and x-ray equipment (EN IEC 60601-2-54).8
• implantation
• hemocompatibility testing

Chapter 18
Packaging Validation Sterilisation Validation

The product packaging should be made of robust Manufacturers of sterile devices or of devices that will
materials to protect the product under all shipping be cleaned and sterilised between uses, must validate
and temperature conditions because a compromised the sterilisation method to be used. Just as the mate-
product may have unintended functionality and safety rials chosen to build a product can affect its safety and
effects. Packaging material selection should be based on efficacy, so can sterilisation methods. Whether the man-
a few key areas: product integrity, sterilisation method ufacturer sterilises the product or provides instructions
and product functionality. The objective is to design a to the end-user, the chosen method must be demon-
packaging system that will allow the user ease of access strated to be safe and effective. A manufacturer’s choice
while also protecting the product from internal or exter- of materials should depend partly on the sterilisation
nal breaches in sterility. method used. Some materials and some intended uses
Sterile products are a special case, for which there are more suited for certain sterilisation methods.
are several standards addressing packaging for these Steam sterilisation is the most common sterilisa-
products, starting with the EN ISO 11607-1 and -2 tion method, because hospitals use this method for their
standards.9,10 The pouch or blister needs to keep the routine sterilisation processes; however, it is not popular
product sterile during the product’s whole lifetime; among medical device manufacturers. Manufacturers
therefore, the integrity of the packaging must be tested. commonly use Ethylene Oxide (EO) gas sterilisation
These tests consist of seal strength of the packaged because almost all materials are EO product friendly.
product and integrity of the complete pouch or blister, Exceptions are materials that cannot withstand 100%
i.e., determining whether there are any leaks in the humidity at 40oC, e.g., cyanoacrylate glues (superglues).
packaging. EN 868-511 provides requirements regard- Gamma-irradiation also is commonly used, but the
ing the required seal strength. Often, sterile packaging radiation can cause material degradation (cracks) and
testing is performed along with shelf life testing, as the discoloration. Although there are other methods (e.g.,
packaging needs to remain intact until the end of the E-beam sterilisation), these play a marginal role.
product’s shelf life. The (harmonised) EN 556-114 standard requires
that the chance that a device is not sterile as one device
Transport Studies in one million or better. Therefore, sterilisation valida-
In the EU, there are no harmonised standards for tion should prove the Sterility Assurance Level (SAL)
transport studies, although EN ISO 11607-1 provides is 10-6 or that there is less than one in a million chance
some general requirements. This may be the reason that the product is not sterile.
transport study requirements have not been addressed For EO sterilisation, the most applied validation
as thoroughly as other studies. However, recently, noti- method is the “overkill” method (Annex B of EN ISO
fied bodies have become much stricter in their review of 11135).15 The basis of this method is to prove that half
transport studies. the EO sterilisation cycle is sufficient to already achieve
Transport studies are conducted to ensure the a SAL of 10-6. For this test, test-strips (biological indi-
packaging system (inner and outer packaging) will cators) containing a million EO resistant bacteria are
maintain the product’s integrity until it reaches the placed inside the product in a difficult-to-reach area.
end user. For this reason, several harsh tests should be This is considered a worst-case situation. Then, the
performed, ranging from drop tests to extensive vibra- product with the test strips is exposed to a half cycle,
tion tests with a range of vibration frequencies. The two which according to the requirement, is already sufficient
most commonly applied test standards/methods are to kill a million bacteria. The full cycle will then always
ISTA 2 series and ASTM D4169.12,13 result in a 10-6 SAL or better. The second test during
In addition, there is more emphasis on study- this sterilisation method is performance qualification
ing possible temperature influences on the product. (PQ). PQ will determine whether the product meets its
Some companies place their products in temperature performance requirements after the sterilisation process.
test chambers and simulate a range of temperatures, Often, product performance is tested after two
from cold weather in winter to high temperatures and sterilisation cycles so that if something went wrong
humidity in hot climates. Whether this has any added during the first cycle, the product can be sterilised a
value should be analysed in the risk assessment phase. second time. In addition, the residuals of the EO gas
For example, when shelf life tests are performed at sterilisation process need to be determined after the
elevated temperatures, performing temperature tests sterilisation process because these remnants could be
during transport may not offer added value. detrimental to the patient.
In contrast to the EO sterilisation validation, the
gamma-irradiation sterilisation validation is based on

a theoretical model. The basis is a table in the EN ISO and efficacy after aging. As such, shelf life studies are
11137-2 standard16,17 showing the relationship between impractical, as they can take several years before they
the bioburden of the device and the required SAL. The are completed. Fortunately, it is commonly accepted to
consequence is the bioburden must be closely moni- speed up the process by elevating the temperature, using
tored, in number and gamma-irradiation resistance. the Arrhenius equation. The general rule is that every
For gamma-sterilisation, the most applied valida- 10-degree increase will double the aging process (see
tion method is the VDmax method (EN ISO 11137-2). the ASTM F1980 standard.)19 Thus, a 30oC tempera-
In this method, 10 products are exposed to the (low) ture increase would shorten the waiting time by a factor
gamma-irradiation dose corresponding to a 10% chance of eight. In this way, a shelf life test of several years can
(SAL 10-1) that the product is not sterile. This dose is be performed in a few months.
based on the average bioburden of three batches. In case Although the accelerated aging test method is gen-
9 out of the 10 products are sterile, the test is a pass. erally accepted when starting with a product, it is only
By applying a table from EN ISO 11137-2, the corre- accepted by notified bodies in combination with a plan
sponding SAL 10-6 can then be found. for real-time aging. Thus, a shelf life test plan should
Since this is a theoretical model, the resistance of contain both accelerated aging and real-time aging tests.
the contamination of the product needs to be tested
every quarter (quarterly dose audits) to determine Software Verification and Validation
whether the original sterilisation validation is still valid. Software can be a medical device if it is embedded
in the device. Many devices today contain software.
Electrical Safety and Electrical Magnetic Software verification is different from the other pre-
Disturbance Testing clinical tests described, as this is usually part of the
Testing of active (electrical) devices is one of the most development process and is performed by the manufac-
complicated subjects in medical device testing. The basic turer itself.
requirements are described in the General Electrical Software development, including verification, is
Safety Standard (EN IEC 60601-1) and in the corre- described in detail in the specific standard for medical
sponding collateral standards (EN IEC 60601-1-X). software, the EN IEC 62304.20
In addition, several device-related standards (EN IEC The software validation method used depends on
60601-2-X) contain electrical safety requirements that the type of device. Standalone software is usually vali-
are device-specific. dated in a simulated user environment, e.g., a hospital,
The general requirements applicable to medical or with possible users. Embedded software is usually
electrical devices address their safety and impact on validated as part of the complete device validation.
other medical electrical devices. If the device (or a part
of the device) contacts the patient, the device is consid- Usability (Human Factors) Studies
ered to have an “applied part,” and the general standard The usability of devices continues to receive increased
for electrical safety applies (IEC 60601-1). If there is no attention. The usability standard (EN IEC 62366-1),21
contact with the patient, this standard is in principle not although an IEC standard, is applicable to all medical
applicable, and the general low-voltage standards are devices.
applicable. However, even if there is no contact with the Usability testing should focus on safety, as the
patient (e.g., a medical power supply), manufacturers EN IEC 62366-1 explicitly states that medical device
often choose to test according to the general standard to usability testing relates to safety, only under normal use.
provide assurance of safety to their customers. The standard is risk based, so in principle, the analysis
The influence on other devices is covered in the can focus on the safety risks during all steps described
electrical magnetic disturbance (EMC) standard (EN in the instructions for use.
IEC 60601-1-2).18 Although there are some exceptions, The two main steps in the usability process are the
all electrical devices must meet this standard. formative evaluation and the summative evaluation.
Interestingly, electrical safety tests are usually During the formative evaluation, different designs or
performed on one device, which is considered to be parts of the design can be tested before a final design
representative for serial produced devices. has been reached. In the summative evaluation, the final
design is tested by a representative user group and set
Shelf Life (Aging) Studies up. In addition to EN IEC 62366-1, Part 2 of the stan-
Shelf life studies basically involve putting the device dard provides guidance on the application of usability
on the shelf, waiting until the expiry date of the device engineering to medical devices.
and conducting tests to determine the device’s safety

Chapter 18
Statistical Methods the manufacturer to write the test plans, including the
For every preclinical test, the sample size and accep- test method.
tance criteria need to be defined and explained in the Today, devices like the humidifier contain software
test report. In general, the number of samples is higher to drive the device and a display to create an appealing
for attribute sampling (pass/fail) than for variable sam- user-interface. Although the software is embedded in
pling (measured value). the device and not a device on its own, it must comply
For attribute sampling, a standard table with the with the medical device software lifecycle standard (EN
number of samples based on the required confidence IEC 62304).
and reliability level is often used. For variable testing, an
assumption of the required number of samples can only Nonclinical Evaluation: Biocompatibility
be made when there is an idea of the average value and Since the device has indirect and possibly direct contact
standard deviation. The closer the average to the limit, with the patient, it (specifically, the tube) must comply
and the wider the standard deviation, the more samples with the EN ISO 10993-1 standard and the applicable
will be required. parts of the EN ISO 10993-X series. In addition, for sleep
apnea devices, a specific series of biocompatibility test
Case Study 1: Heated Sleep Apnea Device (Active requirements are listed in the EN ISO 18562-X series.25
Device, Class IIa) Although the test-house usually writes the test pro-
Like many medical devices, a continuous positive airway tocol, the manufacturer must carefully review the set-up.
pressure (CPAP) device falls in risk Class IIa. Although For example, the inside of the sleep apnea tube is the
Class IIa devices are medium-risk devices, the amount specific area to be tested. Thus, the test-house should
of testing can be extensive, as this example will show. create a special set-up instead of the whole device being
CPAP devices are intended to deliver air with placed in the container with the extraction fluid. These
a slight over-pressure to the user (patient) to keep customised tests are expensive.
the throat open during sleep. The device consists of a
humidifier (driving-unit) to which the heated tube is Usability Testing
connected. At the patient side, the heated tube is con- Depending on its intended use, the CPAP device
nected to a face-mask (left out for this example). The may be operated by professional users and/or lay users
humidifier vaporises water so the air is humidified to (home use). Usability tests will have to address all steps
prevent the patient’s throat from becoming very dry. The involved in using the device, starting with unpacking
heated tube prevents condensation of the humid air to the device, operating the device, maintaining the device
the wall of the tube. and cleaning the heated tube. Determining whether the
At first glance, the device seems straightfor- user can understand the manual is part of the testing.
ward and not too complicated. However, there are For lay use, the amount of testing will need to be more
several product-specific standards with a long list of extensive than for professional use.
requirements.
Case Study 2: Preclinical Testing of a Drug-Eluting
Bench Testing Stent (Class III Implant and Combination Device)
As stated above, this active device can contact the For products that also contain a medicinal substance,
patient and therefore must comply with the basic safety the benefits and risks of this substance need to be eval-
standard (EN IEC 60601-1) and EMC standard (EN uated in addition to those of the medical device alone.
IEC 60601-1-2). As this device is used in the home As an example, the preclinical testing of a drug-eluting
environment, the standard for home use (EN IEC stent is discussed.
60601-1-11)22 also applies. Because sleep apnea devices The combination of a Drug Eluting Stent (DES)
are used widely, there are specific product standards and an ancillary medicinal substance creates the
applicable to this type of device (EN ISO 80601-2-70 potential for both local and systemic effects not seen
and EN ISO 80601-2-74).23,24 On the positive side, previously with bare metal stents (BMS). Although it
once the device meets all applicable requirements of is recognised that the total medicinal product amount
these standards, the manufacturer can claim that the incorporated in the DES is substantially lower than
device is safe and performs as intended. used systemically in other clinical applications, local
Detailed knowledge of the standards, test methods safety aspects are a major point of concern and should
and specific test equipment is required. Therefore, these be taken into account in the (non-) clinical evaluation
tests are usually outsourced to test-houses specialised in program. The medicinal substance’s benefit-risk profile
electrical safety testing. Note that the test-houses expect in the context of a DES is linked with the chosen stent
platform, the surface coating and drug carrier system (if

present) and any interaction among these. Evaluating Preclinical Toxicity Studies
the medicinal substance’s safety and clinical risk-benefit Because efficacy prediction from current animal mod-
profile in the context of a DES in coronary stenting is els is not reliable, animal testing is limited primarily
complicated by the fact that in case of adverse events to safety evaluation. The proposed clinical medicinal
(e.g., Major Adverse Cardiac Events (MACE)), the substance dose and release characteristics should be
medicinal substance and device component’s influence justified by nonclinical data. Preclinical dose range find-
cannot be separated easily. ing studies are strongly recommended, showing effects
across ranges from sub-therapeutic to toxic levels, where
Bench Testing practicable. A multiple-dose study should be performed
The manufacturer is expected to perform a series of in an animal model to establish safety margins and
bench tests on the integrity of the device component toxicity in choosing a dose for clinical trials. The dosing
of the investigational combination product. It must be studies will establish a performance margin between
demonstrated that the ancillary medicinal substance the sub-therapeutic dose and the therapeutic dose, and
and device neither chemically nor physically interact a safety margin between the therapeutic dose and the
adversely with each other. In addition, it is important toxic dose.
for the manufacturer to elucidate how the medicinal
substance and drug carrier’s application to the device Testing an Unapproved Medicinal Substance
may affect its fatigue and corrosion properties, coating Additional animal toxicity studies are expected to be
integrity, durability and any other relevant combination conducted if the medicinal substance is not approved
product-specific components. for use in a stent.
Nonclinical Evaluation: Biocompatibility Conclusion

The manufacturer must submit biocompatibility testing Preclinical testing is a critical part of the medical device
results of the bare stent platform to support the initi- lifecycle, as it is the stage in which the product design
ation of a human clinical study. The biocompatibility is fixed. Preclinical testing is proof the device meets
testing should provide results on all relevant materials, all requirements, except for the clinical evaluation.
including carrier and stent material. Preclinical testing is usually not a one-way process but
can be conducted in phases in case the device has to be
Nonclinical Pharmacodynamics (Proof of Concept) re-tested because a test failed or design changes were
Testing made during the development process. Preclinical test-
The manufacturer should elucidate the medicinal pro- ing showing the device meets its requirements, together
duct(s)’s mechanism of action, justified by relevant data. with clinical evaluation, is the basis for a market
approval application or a clinical trial application.
Nonclinical Pharmacokinetic Testing
Drug-eluting coronary stents present major challenges Acknowledgment
for in vivo pharmacokinetic (PK) characterisation. The The authors want to thank Sharad Mi. Shukla, RAC and Rajaram
Balasubramanian for providing case study 2.
devices are designed to release the medicinal substance
locally, with the intent of maximising or controlling References
bioavailability within local vascular tissue. The develop- 1. Design Control Guidance for Medical Device Manufacturers.
ment of a suitable in vivo local pharmacokinetic testing Guidance for Industry. March 1997. FDA website. https://www.
model is complicated by the lack of an animal model fda.gov/regulatory-information/search-fda-guidance-docu-
ments/design-control-guidance-medical-device-manufacturers.
equivalent to human atherosclerotic disease. DES Accessed 19 April 2020.
pharmacokinetic testing consists of local, regional and 2. EN ISO 13485:2016 Medical Devices: Quality Management
systemic assessments. Systems—Requirements for Regulatory Purposes.
3. EN IEC 60601-1:2006 Medical Electrical Equipment—Part
1: General Requirements for Basic Safety and Essential
Testing Multiple Overlapping Stents Performance.
Treatment of large vascular lesions requires multiple 4. EN ISO 14971:2019 Medical Devices: Application of Risk
stent implantations. At sites of stent overlap, the load Management to Medical Devices.
and release of the medicinal substance(s) are increased, 5. EN ISO 10993-1:2009 Biological Evaluation of Medical
Devices—Part 1: Evaluation and Testing Within a Risk
and substantial deposition of the medicinal substance(s) Management Process.
could occur because of altered flow. Within the clinical 6. EN ISO 10555-1:2013 Intravascular Catheters—Sterile and
practice context of implanting multiple overlapping Single-use Catheters—Part 1: General Requirements.
stents, the effect of stent overlap on vascular healing 7. EN ISO 1135-4:2011 Transfusion Equipment for Medical
use—Part 4: Transfusion sets for single use.
should be evaluated.

Chapter 18
8. EN IEC 60601-2-54:2009 Medical Electrical Equipment— 17. EN ISO 11137-2:2015 Sterilization of Healthcare Products—
Part 2-54: Particular Requirements for the Basic Safety and Radiation Part 2: Establishing the Sterilization Dose.
Essential Performance of X-ray Equipment for Radiography 18. EN IEC 60601-1-2:2015 Medical Electrical Equipment—
and Radioscopy. Part 1-2: General Requirements for Basic Safety and
9. EN ISO 11607-1:2009 Packaging for Terminally Sterilized Essential Performance—Collateral Standard: Electromagnetic
Medical Devices—Part 1: Requirements for Materials, Sterile Disturbances—Requirements and Tests.
Barrier Systems and Packaging Systems. 19. ASTM F1980-16 Standard Guide for Accelerated Aging of
10. EN ISO 11607-2:2006 Packaging for Terminally Sterilized Sterile Barrier Systems for Medical Devices.
Medical Devices—Part 2: Validation Requirements for Forming, 20. EN IEC 62304:2006 Medical Device Software—Software
Sealing and Assembly Processes. Lifecycle Processes.
11. EN 868-5: 2019 Packaging for Terminally Sterilized Medical 21. EN IEC 62366-1:2015 Medical Devices—Part 1: Application
Devices—Part 5: Sealable Pouches and Reels of Porous of Usability Engineering to Medical Devices.
Materials and Plastic Film Construction—Requirements and 22. EN IEC 60601-1-11:2010 Medical Electrical Equipment—
Test Methods. Part 1-11: General Requirements for Basic Safety and Essential
12. ISTA 2 Series: Partial Simulation Performance Tests. Performance—Collateral Standard: Requirements for Medical
13. ASTM D4169 - 16 Standard Practice for Performance Testing Electrical Equipment and Medical Electrical Systems Used in
of Shipping Containers and Systems. the Home Healthcare Environment.
14. EN 556-1:2001 Sterilization of Medical Devices— 23. EN ISO 80601-2-70:2013 Medical Electrical Equipment—Part
Requirements for Medical Devices to be Designated “Sterile” 2-70: Particular Requirements for Basic Safety and Essential
Part 1: Requirements for Terminally Sterilized Medical Devices. Performance of Sleep Apnea Breathing Therapy Equipment.
15. EN ISO 11135:2014 Sterilization of Healthcare Products: 24. EN ISO 80601-2-74:2020 Medical Electrical Equipment—Part
Ethylene Oxide—Requirements for the Development, 2-74: Particular Requirements for Basic Safety and Essential
Validation and Routine Control of a Sterilization Process for Performance of Respiratory Humidifying Equipment.
Medical Devices. 25. EN ISO 18562-1:2020 Biocompatibility Evaluation of
16. EN ISO 11137-1:2015 Sterilization of Healthcare Products— Breathing gas Pathways in Healthcare Applications—Part 1:
Radiation Part 1: Requirements for Development, Validation Evaluation and Testing Within a Risk Management Process.
and Routine Control of a Sterilization Process for Medical
Devices.

Chapter 19
Clinical Evaluation and

Clinical Investigations
Updated by Loes Pelgrim, MSc and Gert Bos, MSc, PhD, FRAPS
OBJECTIVES Regulation (EC) No. 1223/2009 and repealing

□ Understand current and future requirements for (EU MDR)
clinical evaluations in the EU
□ Clinical Evaluation: A Guide for Manufacturers
□ Understand the steps to be taken (stages) in and Notified Bodies (MEDDEV 2.7/1 Rev. 4, June
clinical evaluation 2016)
□ Learn how to determine a clinical strategy □ Guidelines on Clinical investigations: A Guide
for Manufacturers and Notified Bodies (MEDDEV
□ Review considerations in setting up and per-
2.7/4, December 2010)
forming clinical trials
□ Guidelines for Competent Authorities for making
□ Learn differences between the MDD and AIMDD
a validation/assessment of a clinical inves-
and implementation of the new EU MDR
tigation application, MEDDEV 2.7/2 Rev. 2,
□ Key directives and guidance to consult September 2016
□ Clinical Investigations: Serious Adverse Event

Reporting (MEDDEV 2.7/3 Rev. 3, May 2016)
COVERED IN THIS CHAPTER □ Postmarket Clinical Follow-Up Studies: A Guide
for Manufacturing and Notified Bodies (MEDDEV
□ Council Directive 90/385/EEC of 20 June 1990 2.12/2 Rev. 2, January 2012)
States relating to active implantable medical □ ISO 14155:2011: Clinical Investigation of Medical
devices, Article 10 and Annexes 6 and 7 (Active Devices for Human Subjects—Good Clinical
Implantable Medical Devices Directive (AIMDD)); Practice
recent Amendment M4 2007/47/EC
□ ISO 14971:2012: Medical Devices—Application
□ Council Directive 93/42/EEC of 14 June 1993 of Risk Management to Medical Devices
concerning medical devices, Article 15 and
Annexes VIII and X (Medical Devices Directive
(MDD)); recent Amendment M5 2007/47/EC Introduction
Clinical evaluation is an important and increasingly
□ Regulation (EU) 2017/745 of the European prominent part of the medical device technical docu-
Parliament and of the Council of 5 April 2017 mentation. Undeniably, the new EU Medical Devices
on medical devices, amending Directive Regulation (EU MDR) focuses on clinical data and the
2001/83/EC, Regulation (EC) No. 178/2002 and necessity to develop sufficient clinical evidence both

Chapter 19
in quality and quantity, encouraging manufacturers to Clinical Evaluation

reconsider the basis of their current clinical evaluations. Clinical evaluation typically is described as a method-
In practice, writing a Clinical Evaluation Report ologically sound ongoing procedure to collect, appraise
(CER), collecting contributable clinical data, setting-up and analyse clinical data pertaining to a medical device
a good clinical strategy and performing a qualitative and to analyse whether there is sufficient clinical evi-
clinical trial can be difficult. It requires a good under- dence to confirm compliance with relevant essential
standing of the regulations’ meaning and the available requirements for safety and performance when using
guidance, and knowing how to apply them to specific the device according to the manufacturer’s Instructions
situations. Practical experience helps. Objectivity in For Use (IFU).
discussing and addressing benefits and favourable out- This means the manufacturer should set up a sound,
comes, as well as risks and unfavourable data, is key. transparent, non-biased method, to be documented in
Before a notified body can CE Mark a medical a protocol or plan, on how and where to collect clinical
device and it can get on the market, the manufacturer data, for example, throughout a literature search, clinical
should demonstrate the device meets the Essential investigation, PMCF study, complaint trend analysis (as
Requirements (Annex 1 of the Active Implantable part of PMS). By analysing and appraising the collected
Medical Devices Directive (AIMDD) and Annex I information about the medical device under evaluation,
of the Medical Devices Directive (MDD). Essential the manufacturer needs to confirm the device is in com-
Requirements specifically addressed by clinical eval- pliance with all relevant Essential Requirements (ER)
uation are: MDD Annex I Sections 1, 3 and 6 and under MDD and/or General Safety and Performance
AIMDD Annex 1 Section 1, 2 and 5. The EU MDR Requirements (GSPR) under the EU MDR. It is
uses slightly different terminology: General Safety important to make sure all information is aligned with
and Performance Requirements (GSPR) instead of the IFU, e.g., claims made in marketing information.
Essential Requirements (ER), available under Annex I Only sufficiently supported claims can be made. If the
(to the EU MDR) as well. clinical evaluation outlines new or other risks in the
A clinical evaluation is required for every device IFU, an update of the risk management plan might
(Class I through III; AIMDD, MDD/MDR); the CER be required. If a contraindication is clearly outlined in
must be updated actively throughout the device’s life- the literature but not yet part of the current IFU, this
cycle as an ongoing process. In contrast, the MDD does should be updated. If some claims cannot be supported
not specify the clinical evaluation update frequency. with sufficient clinical data, the manufacturer needs
Updates should be made with data obtained from to consider removing the claim or initiating a clinical
postmarket surveillance (PMS). The current guidance, activity to provide sufficient evidence for the claim. In
MEDDEV 2.7/1 Rev. 4, clarifies these instructions; the short, performing a clinical evaluation is not just a paper
manufacturer should define and justify the frequency at exercise to meet the requirements. It is an ongoing pro-
which the clinical evaluation needs to be updated. The cess of becoming and staying up to date about products
clinical evaluation is actively updated: placed on the market.
• when the manufacturer receives new infor- A clinical evaluation is based on a critical evalua-
mation from PMS that has the potential to tion of the following:
change the current evaluation • relevant scientific literature relating to safety,
• if no such information is received, then: performance, design and intended purpose,
o at least annually if the device carries sig- where:
nificant risks or is not yet well established o there is demonstration of the device’s
or equivalence to the device from which the
o every two to five years if the device is not data was collected
expected to carry significant risks and is o the data adequately demonstrate com-
well established, a justification should be pliance with the relevant Essential
provided Requirements
• results of all clinical investigations performed
For Class III and implantable devices, the EU MDR • combination of both
(Chapter VI, Article 61 Section 11) specifies that
the Post Market Clinical Follow-up (PMCF) report, The EU MDR adds another bullet to this list (Chapter
and if indicated, the Summary of Safety and Clinical VI, Article 61, Section 3):
Performance (SSCP) shall be updated at least annually. • consideration of currently available alternative
The PMCF report is an input document for the CER. treatment options for that purpose, if any

Clinical Evaluation and Clinical Investigations
This last bullet introduces the necessity for clinical eval- clinical evidence primarily from the literature. If a
uations, under the EU MDR, to provide more rationale manufacturer can show its device is equivalent to a
for the product. Why should patients use this product? device for which clinical evidence is published, the
Are there alternatives, and if so, what are they? Do they manufacturer can use the published outcomes as clinical
introduce more risk? Do they have a lower benefit? evidence for its device as well. Therefore, demonstrating
technical, biological and clinical equivalence is required.
Clinical Investigation As equivalent devices are produced by competitors, it
If, as a result of the scientific literature evaluation, the is hard to demonstrate full equivalence on all aspects
conclusion does not provide justification for relying on (clinical, technical and biological).
existing clinical data, a clinical investigation has to be If a manufacturer can collect clinical evidence from
performed, with the objective of: the literature based on a critical evaluation of scientific
• verifying that, under normal conditions of literature, a clinical investigation is not required.
use, the device’s performance conforms to the The equivalence route under the EU MDR will
Essential Requirements referenced in Section become much more difficult, specifically for Class III
3 of Annex I and implantable devices. Chapter VI, Article 61 Section
• determining any undesirable side-effects, 5 explains that if a manufacturer demonstrates equiva-
under normal conditions of use, and assessing lence to an already marketed device, not manufactured
whether they constitute risks when weighed by itself, to avoid performing a clinical investigation,
against the device’s intended performance the two manufacturers need to have a contract in
place that explicitly allows full access to the marketed
The EU MDR extends the necessity for clinical inves- device’s technical documentation on a continuous basis,
tigations by stating that clinical investigations shall be including PMS, covering both Annex II and Annex III
performed in case of implantable and Class III devices, technical documentation.
unless:
• the device has been designed by modifications Performing a Clinical Evaluation
of a device already marketed by the same Knowing why and when a clinical evaluation is required
manufacturer does not mean it is easy to perform one. The MDD
• the modified device has been demonstrated by and new EU MDR do not directly provide practical
the manufacturer to be equivalent to the mar- tools. MEDDEV 2.7/1 Rev. 4 gives hands-on guid-
keted device or ance and a step-by-step description on performing a
• the clinical evaluation of the marketed device clinical evaluation. A frequently asked question is what
is sufficient to demonstrate conformity of the is the difference between MEDDEV 2.7/1 Rev. 4? In
modified device with the relevant safety and general, there is no difference. The EU MDR described
performance requirements some details, like having a Clinical Evaluation Plan
(CEP), but a fully MEDDEV-compliant CER is EU
Other exceptions include implantable and Class III MDR-ready.
devices placed on the market under the MDD or IVD, The first step will be to plan the clinical evaluation.
with a clinical evaluation including sufficient clinical Which sources will be used in the clinical evaluation?
data and complying with relevant product-specific Equivalence, risk management, current state-of-the-
Common Specifications (CS). art, introduced changes (for a CE-marked device) and
This implies manufacturers of Class III and data sources (including clinical concerns and PMS
implantable devices will need to critically review their aspects for CE-marked devices) all need to be described.
current clinical evaluations and the amount and quality Considering and documenting all the topics of stage 0,
of clinical data included. If the device was placed on as indicated in MEDDEV 2.7/1 Rev. 4 in a clinical eval-
the market with a clinical evaluation with very limited uation plan, can help to focus and guide your evaluation.
clinical data, the manufacturer might consider initiating The next phase (stage 1) is identifying the data
PMCF activities to collect clinical data to address the that can be used. These might be data the manufac-
gap in data requirements. turer holds, including relevant preclinical data, clinical
trial data, PMCF data, PMS data, complaints or Field
Equivalence Safety Corrective Actions (FSCA). If the manufacturer
Under the MDD, demonstrating a device’s equiva- does not have these data, this is the time to start collect-
lence to a competitor device for which clinical data are ing them to become EU MDR-compliant.
available is a common pathway for collecting sufficient Literature searches can be used to identify other
data not held by the manufacturer. Relevant data would

Chapter 19
include the device, current state-of-the-art, standards, Procedural details in the manufacturer’s QMS
guidance documents, justification for equivalence, etc. will be helpful to demonstrate how the evaluation was
It is important at this stage to be objective and conducted.
include both favourable and unfavourable data to be able
to make a good, balanced and transparent benefit-risk Setting up a Clinical Strategy
analysis. Several literature searches with different search To make sure currently MDD CE-marked products
strings in several search engines are preferred. This will be EU MDR-compliant, and to determine how to
should be covered by a search protocol and the search collect clinical data for a new (pre-CE) product, setting
itself documented in the CER, so it can be reproduced. up a clinical strategy can be very helpful for a manufac-
The manufacturer should remember to document the turer. It takes time to consider which product standards
engines used, exact search strings and filters and the and regulations are applicable, and how to implement
search date. Under the EU MDR, these strategies would them in the most efficient way but creating a focused
be best compiled in a clinical evaluation procedure plan will pay off in a smooth and fast (re)certification in
within the Quality Management System (QMS). the end.
After determining which data to use, they should Setting up a clinical strategy includes:
be appraised to determine their value (stage 2), i.e., the • determining which standards are applicable
extent to which they contribute to the clinical evaluation. (including clinical requirements)
Again, the manufacturer should document its appraisal • identifying the regulations that apply to the
to ensure a systematic and transparent way of working. product type, group or class
Setting up a plan before starting the appraisal is advisable • selecting appropriate clinical data sources
and helpful. MEDDEV 2.7/1 Rev. 4 provides useful (clinical investigation, literature, PMCF, PMS,
information for designing a good search protocol and registry)
guidance document; GHTF SG5 Clinical evaluation • determining whether data already available are
(2007) for performing an objective data appraisal. of high enough quality
In stage 3, the clinical data need to be analysed, • deciding how to set up a high-quality clinical
after which the clinical evaluation should be put on investigation, PMCF study or registry
paper as the CER (stage 4). • identifying the number of necessary resources
Common mistakes in performing clinical evalua- and their availability
tions include: • learning whether the notified body has signif-
• unclear or too little planning, resulting in a icant comment on the approach (request for
large amount of data, with unknown relevance clinical pathway review/assessment)
to the clinical evaluation
• valuable data sources not included (e.g., com- Performing Clinical Investigations
plaints, FSCA) When a manufacturer is developing a new, pre-CE
• no planned approach (e.g., lack of evaluation device or as a result of the scientific literature evalua-
plan, search protocol, appraisal plan) tion, it must determine whether it can rely on existing
• no transparent appraisal clinical data or conduct a clinical investigation. For
• too little attention to unfavourable results some (mostly smaller) medical device manufacturers,
• no conclusion about benefits vs. risks conducting clinical investigations might be challenging
• literature search includes only the actual regarding resources. It is an important and valuable
device; no broader relevant information (e.g., part of product design and development, but may be
current state-of-the-art, alternative treatments, resource consuming as well. However, the investment
etc.) will be worthwhile if good preparation methods and
• data provided does not cover all subpopula- compliant regulatory strategies are implemented.
tions and indications in scope sufficiently MDD Annex X Section 2 (AIMDD Annex 7
Section 2) describes clinical investigation elements. The
The clinical evaluation should be conducted by a suit- MDD has one page on clinical investigations discussing
ably qualified individual or a team. MEDDEV 2.7/1 the objectives, ethical considerations and methods. This
Rev. 4 describes how to determine this suitability. To is amplified further in the harmonised standard ISO
show the individual or team’s suitability, the clinical 14155:2011 Clinical Investigation of Medical Devices for
evaluation should include author, evaluator and/or Human Subjects—Good Clinical Practice.
reviewer CVs. A declaration of interest of each evalua- EU MDR Articles 62–82 cover information on
tor also should be provided. clinical investigation necessity and implementation, and

Clinical Evaluation and Clinical Investigations
Annex XV provides general requirements, including • Case Report Forms (CRFs)—instructions

additional guidance emphasising the importance and available in ISO 14155 Annex C
value of a good investigation and limiting nonbinding • Electronic Data Capture (EDC) system
instructions. • safety reporting procedures
While the new EU MDR describes in detail when • Clinical Investigation Report (CIR)—require-
clinical investigations are required and what requirements provided in EU MDR Annex XV,
ments must be followed, practical implementation Chapter 3 Point 7 and ISO 14155 Annex D.
might be a struggle. Smooth clinical investigations
are those that are well-planned and well-managed, Quality and Good Clinical Practice
in most cases by experienced staff. The following sec- ISO 14155 and EU MDR requirements are imple-
tion provides guidance on how to plan and perform mented to:
high-quality clinical investigations. • protect the rights, safety and well-being of
human subjects
Plan and Clinical Pathway Review • ensure the scientific conduct of the clinical
If the clinical evaluation strategy includes conducting investigation and the credibility of the clinical
a clinical trial, planning would be the next step. The investigation results
manufacturer must decide how to design a proto- • define the responsibilities of the sponsor and
col, what to include and how to assure quality. Most principal investigator
hands-on instructions can be found by following and • assist sponsors, investigators, Ethics
implementing EU MDR Annex XV and ISO 14155. It Committees, regulatory authorities and other
might be worthwhile to hire experienced clinical staff bodies involved in the conformity assessment
or outsource the clinical investigation to an experienced of medical devices
Contract Research Organization (CRO), to overcome
national regulation hurdles for Ethics Committee (EC) However, due to a variety of reasons like inexperience,
submission and approval, comply with documentation lack of resources, insufficient preparation or planning,
requirements and ensure proper site management. mistakes do happen that endanger these intentions.
During clinical trial planning and strategy devel- Examples of frequent mistakes are provided, which may
opment, a notified body review of the clinical pathway help manufacturers prevent similar pitfalls.
can be valuable. Although the notified body is unable to
advise the manufacturer directly, its feedback (reading Ethical Considerations, Common Mistakes
between the lines) will reveal if its attitude toward the • bribing vulnerable people to participate in a
selected approach is positive or negative. trial
• no informed consent process or form in place
Clinical Trial Essentials • Ethics Committee had not approved informed
Some regulatory requirements call for steps to be taken consent form used
and documents designed before and during a clinical • illiterate, therefore vulnerable, patient
investigation. Some important ones include: • using an emergency situation as an excuse to
• Clinical Investigation Protocol (CIP)— skip informed consent procedures
requirements provided in EU MDR Annex XV • Informed Consent Form use without a pro-
Section 3 and ISO 14155 Annex A cedure for discussion, or insufficient time to
• site agreements decide or answer questions
• CRO and vendor agreements • Informed Consent Form not completed
• Investigator’s Brochure (IB)—requirements are correctly, wrong chronology, signed by unau-
provided in EU MDR Annex XV Section 2 thorised site staff
and ISO 14155 Annex B • subject was not provided a copy of the signed
• Ethics Committee (EC) approval—procedures ICF
depend primarily on national and hospital or
site requirements Clinical Investigation Planning, Common Mistakes
• Competent Authority (CA) application (where • anticipated adverse device effects not clearly
applicable) identified based on risk management
• Informed Consent Form—requirements pro- • unclear endpoints; not really measurable or
vided in EU MDR Article 63 objective

Chapter 19
• CIP does not include all ISO 14155 Annex A Principal Investigator Responsibilities, Common
topics Mistakes
• agreements do not state responsibilities clearly • lack of, or outdated, GCP training
• unclear protocol traceability (versioning, sign- • insufficient resources (e.g., staff )
ing, etc.) • lack of awareness of role’s responsibilities
• contradictions within or among documents • inadequate safety reporting
(e.g., protocol vs. CRF) • insufficient oversight
• ambiguous wording or insufficient clarification • insufficient protocol knowledge
and site guidance
Conclusion
Clinical Investigation Conduct, Common Mistakes Considering the amount of EU MDR text dedicated to
• incomplete site, sponsor and CRO training, clinical evaluation and investigation (one chapter out
qualification and delegation records of 10, and one annex out of 15), clinical data’s impor-
• incorrect, incomplete or delayed safety tance is increasing. Currently, under the MDD, clinical
reporting strategies and data also are important and valuable, but
• documentation not Attributable, Legible, notified bodies and regulators’ focus on these aspects
Contemporaneous, Original and Accurate might be less so. These changes will occur and, mov-
(ALCOA) ing forward, will be necessary for every manufacturer
• names, addresses, photos (patient identifiers) regardless of the device type.
shared with sponsor (data protection) Some key messages are:
• missing device stock or incorrect storage • Keep the clinical evaluation updated.
conditions MEDDEV 2.7/1 Rev. 4 compliance is the
• no (solid) monitoring latest requirement.
• The clinical evaluation should be assessed criti-
Clinical Investigation Suspension, Termination and cally. Is it fundamentally solid?
Close-out, Common Mistakes • Keeping in mind the upcoming EU MDR
• no significant and/or documented reasons for implementation, does the manufacturer need
termination to consider collecting and owning more clini-
• no CIR cal data, limiting dependence on equivalence?
• sites not closed • If more data are required, collected in a clinical
• inadequately informing the Ethics Committee trial or PMCF study, the manufacturer should
make sure the trial is worth the effort by
Sponsor Responsibilities, Common Mistakes ensuring quality.
• blaming problems on a site or CRO instead of • The manufacturer should ask for help from
taking responsibility experienced colleagues, staff or vendors where
• inadequate task outsourcing its own knowledge is limited. No one is an
• lack of clarity about procedures or QMS used expert on everything, especially the upcoming,
• inadequate safety evaluation complex and detailed EU MDR.

Chapter 20
Medical Device Conformity

Assessment Procedure
Updated by Gert Bos, MSc, PhD, FRAPS
OBJECTIVES distribution of human blood and blood compo-

nents and amending Directive 2001/83/EC
□ Understand conformity assessment in the
CE-marking process □ Commission Directive 2003/12/EC of 3 February
□ Describe procedures a manufacturer may use to in the framework of Directive 93/42/EEC con-
demonstrate a device’s safety and performance cerning medical devices
□ Understand different conformity assessment □ Commission Directive 2005/50/EC of 11 August
elements applicable to each device class 2005 on the reclassification of hip, knee and
shoulder joint replacements in the framework of
Council Directive 93/42/EEC concerning medi-
DIRECTIVES, REGULATIONS AND GUIDELINES cal devices
□ Council Directive 90/385/EEC of 20 June 1990 Parliament and of the Council of 5 September
on the approximation of the laws of the Member 2007 amending Council Directive 90/385/EEC
States relating to active implantable medical on the approximation of the laws of the Member
devices States relating to the active implantable medi-
cal devices Council Directive, Council Directive
□ Council Directive 93/42/EEC of 14 June 1993 93/42/EEC concerning medical devices and
concerning medical devices Directive 98/8/EC concerning the placing of
□ Directive 98/79/EC of the European Parliament biocidal products on the market
and of the Council of 27 October 1998 on in vitro □ Decision 93/465/EEC Council Decision of 22 July
diagnostic medical devices 1993 concerning the modules for the various
□ Directive 2000/70/EC of the European phases of the conformity assessment proce-
Parliament and of the Council of the 16 dures and the rules for the affixing and use of
November 2000 amending Council Directive the CE conformity marking, which are intended
93/42/EEC as regards medical devices incor- to be used in the technical harmonization
porating stable derivates of human blood or directives
human plasma □ Decision 768/2008/EC of the European
□ Directive 2002/98/EC of the European Parliament and of the Council of 9 July 2008 on a
Parliament and of the Council of 27 January common framework for the marketing of prod-
2003 setting standards of quality and safety for ucts and repealing Council Decision 93/465/EEC
the collection, testing, processing, storage and

Chapter 20
□ EN ISO 13485 Medical Devices—Quality (EU MDR) and EU In Vitro Diagnostic Medical Devices
Management Systems—Requirements for Regulation (EU IVDR).
Regulatory Purposes (2012)
CE Marking Process—Description
□ ISO 13485 Medical Devices—Quality National competent authorities, notified bodies, import-
Management Systems—Requirements for ers and distributors, as well as European authorised
Regulatory Purposes (2016) representatives all are involved in the CE-marking pro-
□ New Blue Guide (2016) cess. Competent authorities in every EU Member State
are nominated by their governments to monitor and
□ Guidelines for conformity assessment of In Vitro ensure compliance with medical devices directives’ pro-
Fertilization (IVF) and Assisted Reproduction visions. The competent authority may designate one or
Technologies (ART) products, MEDDEV 2.2/4 more notified bodies to ensure conformity assessment
(January 2012) procedures are completed according to the relevant
criteria. The authorised representative, designated by
□ Guideline for Authorised Representatives a manufacturer, is legally responsible for compliance
MEDDEV 2.5/10 (January 2012) with regulations and is the first point of contact for EU
authorities. Under the new regulations, they also are
□ Commission Regulation (EU) No. 207/2012 of 9 liable for defective products in the postmarket phase.
March 2012 on electronic instructions for use of In addition, in the new system, they need to perform
medical devices spot-checks on the conformity assessment process and
□ Regulation (EU) 2017/745 of the European documentation; importers and distributors have similar
Parliament and of the Council of 5 April 2017 on additional tasks to verify the manufacturer’s compliance.
medical devices, amending Directive 2001/83/ It is the manufacturer’s responsibility to ensure
EC, Regulation (EC) No. 178/2002 and Regulation its product complies with the relevant EU legislation’s
(EC) No. 1223/2009 and repealing Council essential requirements or similarly, in the new regu-
Directives 90/385/EEC and 93/42/EEC (EU MDR) lations, the essential principles. Following is a general
overview of the CE-marking process:
□ Regulation (EU) 2017/746 of the European • check which medical devices directives and
Parliament and of the Council of 5 April 2017 regulations and annexes apply
on in vitro diagnostic medical devices and • choose conformity assessment procedure or
repealing Directive 98/79/EC and Commission route
Decision 2010/227/EU (EU IVDR) • prepare the technical documentation (depend-
ing on the device’s risk class)
• prepare declaration of conformity
Introduction • submit to notified body, if applicable, for cer-
Medical devices placed on the EU market must bear tification and for continuous monitoring upon
the CE Mark. Before the CE Mark is affixed, medical certification
devices are subject to a risk and conformity assessment • register with competent authority (manufac-
procedure to approve and establish compliance with the turer or authorised representative)
provisions of the European medical devices directives • apply CE marking and market product
and national medical device laws. The key conformity • implement vigilance and postmarket sur-
assessment procedure issue is demonstrating a medi- veillance by monitoring safety and efficiency
cal device meets the essential requirements regarding and reviewing use experience and any action
quality, safety, performance, user and environmental required
protection over its entire lifespan. Properly implement-
ing the conformity assessment procedure with the Regardless of class, all devices must:
respective measures and documentation is a prerequisite • meet essential requirements or principles,
for CE marking and successfully passing third-party including requirements regarding information
inspections by notified bodies (medium and high-risk to be supplied by the manufacturer
products) and regulatory authorities (low-risk products, • evaluate clinical performance and any side
special products such as combination products and effects, if applicable, via a preclinical and clini-
animal-derived devices) and clinical scrutiny (high-risk cal evaluation
products) under the EU Medical Devices Regulation • be subject to the medical device vigilance sys-
tem’s reporting requirements

Medical Device Conformity Assessment Procedure
• be CE-marked (except accepted exemptions) Therefore, conformity assessments’ importance

• be registered with the competent authority arises from users’ expectations for a product’s perfor-
where the manufacturer (or the authorised rep- mance and use and EU competent authorities’ concerns
resentative) has a registered place of business for their citizens’ safety, health and well-being. Such
• be registered in selected other countries where concerns extend to design, manufacturing and use, but
local legislation requires this also include the product’s disposal and recycling.
A CE-marked medical device must fulfil the EU
Role of Conformity Assessment in the CE-Marking medical device legislation essential requirements or
Process principles on safety and performance, which must be
Medical devices intended to be sold in the EU must documented in writing as part of the conformity assess-
comply with EU medical devices directives’ provisions ment procedure.
applicable to them and will need to comply with the The conformity assessment procedure type to be
new EU MDR and EU IVDR on or before May 2021 conducted and the extent to which an independent
and 2022, respectively. Manufacturers need to prove testing and certification body (notified body) is required
their devices comply with these requirements, which depends on the product’s potential risk. While no
may take a form in the next few years where some distinction is made among active implantable devices
products are compliant with the old directives, whereas according to risk levels, Directive 93/42/EEC differen-
others already comply with the new regulations. tiates devices into four risk classes (I, IIa, IIb and III).
A very large range of products, medical devices The product classification and conformity assessment
included, are covered by EU “new approach” legislation, procedure are chosen from criteria in Directive 93/42/
which specifies the essential requirements and principles EEC Annex IX and are summarised in Table 20-1.
with which products must comply and the conformity Current documentation records for conformity assess-
assessment route to be followed. The selected route ment procedures are outlined in Tables 20-2–4. The
includes product design and manufacturing stages, new regulations continue with a somewhat restructured
and depending on the product risk class, may include but similar system.
manufacturer self-assessment (for low-risk devices), As there is no grandfathering foreseen in the com-
type approval (for medium-risk products) or systematic plete legal overhaul into the regulations, the notified
follow-up by external conformity assessment bodies bodies’ designation to perform conformity assessment
(notified bodies) or a combination of these elements. procedures also is to be revised, and all notifications
The new approach regulatory framework favours under the current directives will stop at the end of the
the “conformity” principle, which means a product’s transition period. Meanwhile, the transition has been
conformity with the harmonised EU standard pro- extended to include another four-year grace period,
visions confirms a device meets the presumption of which allows parallel certification under the old MDD/
conformity with the applicable EU medical devices AIMDD and the new EU MDR. Hence, the conformity
directive’s essential requirements. Lists of harmonised assessments will continue for legacy products during
standards are published in the Official Journal of the EU these additional four years as if the notified bodies are
and updated irregularly. Manufacturers using harmon- still designated under the MDD/AIMDD regime. These
ised standards to confirm compliance with the essential audits and reviews will be taking place on top of the
requirements must check the Official Journal of the EU new EU MDR conformity assessment procedure.
regularly and update product files and testing to meet
the most current harmonised standards’ versions. A new Conformity Assessment and Product Risk
listing of harmonisation regarding the new regulations Class
is foreseen for 2020; manufacturers should be aware a Medical device classification rules in MDD Annex IX
standard harmonised with the current directives is not address an approach based on risk, invasiveness, tech-
automatically harmonised with the new regulations. nology and intended use without mandating a specific
The new approach legislation’s primary goal is to product “coding” before classification. This gives man-
create a single, unified, free EU market across the 27 ufacturers a certain degree of flexibility in selecting the
Member States and those other countries aligned with technical pathway to meet health and safety require-
EU legislation. However, this single market also should ments, i.e., essential requirements.
guarantee citizens’ safety and health. The general legisla- Depending on device class, manufacturers may
tive framework of EU Regulation 765/2008 and the EU choose from a range of conformity assessment proce-
medical devices directives regulating medical devices dures to demonstrate compliance with the directive.
and IVDs, and the upcoming EU MDR and EU IVDR, Manufacturers do not need to consider any specific
help achieve this goal.

Chapter 20
Table 20-1. Conformity Assessment Procedures
Conformity Assessment
Classes
Procedures
Annexes I I Sterile I Measuring IIa IIb III
II (+ Sect. 4) x
II (- Sect. 4) x x x x x
III x x
IV x x x x
V x x x x
VI x x x x
VII x x x x
Table 20-2. AIMDD Conformity Assessment Documentation
Conformity Assessment Documentation

90/385/EEC (AIMDD)
Annex 2 Section 6.1. For at least 15 years from the last date of manufacture of the product, the manufacturer or his authorized repre-
sentative shall keep available for the national authorities:
• Declaration of conformity
• Documentation referred to in the second indent of Section 3.1, and in particular the documentation, data and records referred to
in the second paragraph of Section 3.2
• Amendments referred to in Section 3.4
• Documentation referred to in Section 4.2
• Decisions and reports of the notified body referred to in Sections 3.4, 4.3, 5.3 and 5.4
Annex 3 Section 7.3. The manufacturer or his authorized representative shall keep with the technical documentation a copy of the EC
type—examination certificates and the supplements to them for a period of at least 15 years from the manufacture of the last product.
Annex 4 Section 6.5. The manufacturer or his authorized representative shall ensure that he is able to supply the notified body’s
certificates of conformity on request.
Annex 6 Section 3. The manufacturer shall undertake to keep available for the competent national authorities:
3.1. For custom—made devices, documentation, indicating manufacturing site(s) and enabling the design, manufacture and perfor-
mances of the product, including the expected performances, to be understood, so as to allow conformity with the requirements
of this directive to be assessed. The manufacturer shall take all necessary measures to see the manufacturing process ensures the
products manufactured conform to the documentation referred to in the first paragraph.
3.2 For devices intended for clinical investigations, the documentation shall also contain:
• A general description of the product and its intended use
• Design drawings, manufacturing methods, in particular as regards sterilization and diagrams of parts, sub-assemblies, circuits,
etc.
• The descriptions and explanations necessary for understanding the drawings and diagrams and product operation
• The results of the risk analysis and a list of the standards laid down in Article 5, applied in full or in part, and a description of the
solutions adopted to satisfy the essential requirements of the directive where the standards in Article 5 have not been applied
• If the device incorporates, as an integral part, a substance or human blood derivative referred to in Section 10 of Annex 1, the
data on the tests conducted in this connection, which are required to assess the safety, quality and usefulness of that sub-
stance, or human blood derivative, taking account of the intended purpose of the device, the results of the design calculations,
checks and technical tests carried out, etc.
The manufacturer shall take all necessary measures to see the manufacturing process ensures the products manufactured conform
to the documentation referred to in 3.1 and in the first paragraph of this section. The manufacturer may authorize the evaluation, by
audit where necessary, of the effectiveness of these measures.

Table 20-3. MDD Conformity Assessment Documentation
Conformity Assessment Documentation

93/42/EEC (MDD)
Annex III Section 7. 7.2. Other notified bodies may obtain a copy of the EC type—examination certificates and/or the supplements
thereto. The annexes to the certificates must be made available to other notified bodies on reasoned application after the manufac-
turer has been informed.
Annex III Section 7.3. The manufacturer or his authorized representative must keep with the technical documentation copies of EC
type—examination certificates and their additions for a period ending at least five years after the last device has been manufactured.
In the case of implantable devices, the period shall be at least 15 years after the last product has been manufactured.
Annex IV Section 7. The manufacturer or his authorized representative must for a period ending at least five years, and in the case of
implantable devices, at least 15 years after the last product has been manufactured, make available to the national authorities:
• Documentation referred to in section 2
• Certificates referred to in sections 5.2 and 6.4
• Where appropriate, the type—examination certificate referred to in Annex III
Annex V Section 5.1. The manufacturer or his authorized representative must for a period ending at least five years, and in the case of
implantable devices, at least 15 years after the last product has been manufactured, make available to the national authorities:
• Documentation referred to in the fourth indent of section 3.1
• Changes referred to in section 3.4
• Documentation referred to in the seventh indent of section 3.1
• Decisions and reports from the notified body as referred to in sections 4.3 and 4.4
• Where appropriate, the type—examination certificate referred to in Annex III
Annex VI Section 5.1 Administrative Provisions. The manufacturer or his authorized representative must for a period ending at least
five years, and in the case of implantable devices, at least 15 years, after the last product has been manufactured, make available to
the national authorities:
• Documentation referred to in the seventh indent of section 3.1
• Changes referred to in section 3.4
• Decisions and reports from the notified body as referred to in the final indent of section 3.4 and in sections 4.3 and 4.4
• Where appropriate, the certificate of conformity referred to in Annex III
Annex VII Section 2. The manufacturer must prepare the technical documentation described in Section 3. The manufacturer or his
authorized representative must make this documentation, including the declaration of conformity, available to the national author-
ities for inspection purposes for a period ending at least five years after the last product has been manufactured. In the case of
implantable devices, the period shall be at least 15 years after the last product has been manufactured
Annex VIII Section 4. The information contained in the declarations concerned by this Annex shall be kept for a period of time of at
least five years. In the case of implantable devices, the period shall be at least 15 years.
Table 20-4. IVDD Conformity Assessment Documentation
98/79/EEC (IVDD)
Article 9 (7). The manufacturer must keep the declaration of conformity, the technical documentation referred to in Annexes III to VIII,
as well as the decisions, reports and certificates, established by notified bodies, and make them available to the national authorities
for inspection purposes for a period ending five years after the last product has been manufactured. Where the manufacturer is not
established in the Community, the obligation to make the aforementioned documentation available on request applies to his autho-
rized representative.

for the last option, manufacturers must substantiate test II and III must be considered in the conformity assessment
specifications adequately, since EU medical devices direc- procedure, including formal Notified Body consultation
tives do not define clearly how to comply with MDD Annex with a Competent Authority or the European Medicines
I’s relevant
Chapter 20 characteristics. In general, the most preferred Agency (EMA).
option is using harmonised standards.
Figure 20-1.
Figure Class
19-1. IIIIIIDevice
Class DeviceConformity AssessmentProcedure
Conformity Assessment Procedure Options
Options
Figure 19-1. Class III Device Conformity Assessment Procedure Options
Class III
MDD 93/42/EEC
Annex III—EC Type Examination

Annex II—Full Quality
Assurance
Annex II.4—Design Dossier Annex IV—EC Verification Annex V – Production Quality

Examination Assurance
CE Mark approval (including CE Mark approval (including CE Mark approval (including

Notified Body identification Notified Body Identification Notified Body identification
number) number) number)

strategy when selecting the appropriate conformity which references a design dossier undergoing a formal
assessment route to prove compliance with essential notified body review. In this case, the notified body would
requirements (Annex I). issue a separate design examination certificate.
Manufacturers may choose between using applica-
For Class III devices incorporating medicinal 11/6/17 1:31 PM
ble EU harmonised standards published in the Official products or human blood derivatives, aspects described
Journal of the EU, international or national standards in Annexes II and III must be considered in the con-
or elect to work independently and use their own test formity assessment procedure, including formal notified
specification(s); for the last option, manufacturers must body consultation with a competent authority or the
substantiate test specifications adequately, since EU European Medicines Agency (EMA).
medical devices directives do not define clearly how to Current conformity assessment procedures for
comply with MDD Annex I’s relevant characteristics. In Class IIb devices (Figure 20-2) allow manufacturers
general, the most preferred option is using harmonised to apply Annex II, full quality assurance, but with-
standards. When this chapter was written, the standards out Section 4, as this section is a design examination
harmonisation process for the EU MDR had just started, required only for Class II devices. Annexes IV, V or
and until it is completed, manufacturers will need to VI shall be combined with Annex III, referring to EC
justify relying on globally well-accepted standards and type-examination. This is the procedure when a notified
standards harmonised previously to MDD/AIMDD. body reviews, and even performs, device testing. The
Elements used in conformity assessment procedure current conformity assessment procedure for Class IIa
are: devices (Figure 20-3) offers multiple choices, allow-
• Quality Management System (QMS) ing manufacturers to select the route they deem most
• postmarket surveillance system appropriate. A manufacturer producing the product
• technical documentation supporting compli- may select Annex II (without Section 4), while a man-
ance with essential requirements ufacturer using contract manufacturing may choose, for
• declaration of conformity example, Annex VII with Annex IV.
Note: Directive 2007/47/EC mentions, even
All these elements are required, regardless of device for devices other than Class III, the notified body is
type, but there is flexibility in their applicability to a expected to review the medical device’s design docu-
particular device, depending on its risk class. mentation. To address this concern, the Commission
Figure 20-1 describes the current options for Class issued a requirement for review of representative design
III device conformity assessment procedures. Annex VI document examples.
cannot be applied in combination with Annex III to these For Class IIa devices, notified bodies should be
devices. Annex II must be applied, including Section 4, expected to assess one representative sample of each

Figure 19-2.
Figure Class
19-2. IIbIIb
Class Conformity Assessment
Conformity Procedures
Class IIb Medical Device Conformity Assessment Procedure
MDD 93/42/EEC
Figure 20-2. Class IIb Conformity Assessment Procedures
Figure 19-2.
Figure Class
19-2. IIbIIb
Class Conformity Assessment
Conformity Procedures
Annex II—Full Quality

Assurance excluding Class IIb Annex III—EC Type
MDD 93/42/EEC Examination
Annex II.4
Annex II—Full Quality Annex IV—EC

Assurance excluding Verification Annex III—EC Type
Annex V—Production
Examination Annex VI—Product
Annex II.4 Quality Assurance Quality Assurance
CE Mark approval Annex IV—EC

CE Mark approval CE Mark approval CE Mark approval
(including Notified Body Verification
(including Notified Body Annex V—Production
(including Notified Body Annex VI—Product
(including Notified Body
identification identification Qualityidentification
Assurance Quality Assurance
identification
number) number) number) number)
Current conformity assessment procedures for Class multiple choices, allowing manufacturers to select the route
IIb devices (Figure
CE Mark approval19-2) allow manufacturers to apply
CE Mark approval theyCE
deem most appropriate. A manufacturer producing the
Mark approval CE Mark approval
Annex II, fullNotified
(including qualityBody
assurance,(including
but without Section
Notified Body 4, product may
(including selectBody
Notified Annex II (without Section
(including 4),Body
Notified while a
identification
as this section is a design examination identification
required only for manufacturer using contract manufacturing
identification may choose,
identification
number) number) number)
Class II devices. Annexes IV, V or VI shall be combined for example, Annex VII with Annex IV.number)
with Annex III, referring to EC type-examination. This Note: Directive 2007/47/EC mentions, even for
Current conformity
is the procedure whenassessment
a Notifiedprocedures
Body reviews,for and
Class
even multiple
deviceschoices, allowing
other than Class manufacturers
III, the NotifiedtoBody
selectisthe route
expected
IIb devices (Figure 19-2) allow manufacturers to
performs, device testing. The current conformity assess- apply theyto review the medical device’s design documentation.the
deem most appropriate. A manufacturer producing To
Annex II, full quality assurance, but without Section
ment procedure for Class IIa devices (Figure 19-3) offers 4, product may select Annex II (without Section 4), while a
as this section is a design examination required only for manufacturer using contract manufacturing may choose,
Figure 20-3. Class IIaClass
Conformity Assessment Procedure
ClassFigure
II devices.Figure 19-3
Annexes IV, VIIaorConformity
VI shall Assessment
be combined
19-3. Class IIa Conformity Assessment Procedure
Procedure
for example, Annex VII with Annex IV.
with Annex III, referring to EC type-examination. This Note: Directive 2007/47/EC mentions, even for
is the procedure when a Notified Body reviews, and even devices other than Class III, the Notified Body is expected
Class IIa
performs, device testing. The current conformityMDD assess-
93/42/EECto review the medical device’s design documentation. To
ment procedure for Class IIa devices (Figure 19-3) offers
Figure 19-3 Class IIa Conformity Assessment Procedure

Figure 19-3. Class IIa Conformity Assessment Procedure
Annex II—Full Quality Annex VII—EC
Assurance Excluding Class IIa Declaration of
Annex II.4 MDD 93/42/EEC Conformity
Annex IV—EC Annex V—Production Annex VI—Product

Annex II—Full Quality Verification Quality
Annex Assurance
VII—EC Quality Assurance
Assurance Excluding Declaration of
Annex II.4 Conformity
CE Mark approval CE Mark approval CE Mark approval CE Mark approval

(Including Notified (Including Notified (Including Notified (Including Notified
Body identification Body IV—EC
Annex identification Body
Annex identification
V—Production BodyVI—Product
Annex identification
number) number)
Verification number)
Quality Assurance Qualitynumber)
Assurance

(Including Notified (Including Notified (Including Notified (Including Notified
Body identification Body identification Body identification Body identification
number) number) number) number)
Regulatory
Regulatory Affairs
Affairs Professionals
Professionals Society
Society 249
213

Figure 19-4. Class I Device, Self-Declaration
Figure 19-4. or Self-Certification
Class I Device, Self-Declaration or Self-Certification
Class I
Chapter 20 MDD 93/42/EEC
Chapter 19
Figure 20-4. Class I Device, Self-Declaration or Self-Certification
Figure 19-4. Class I Device, Self-Declaration
Figure 19-4. or Self-Certification
Class I Device, Self-DeclarationAnnex VII—EC
or Self-Certification
Declaration of
Conformity
Class I
MDD 93/42/EEC
CE Mark (excluding Sterile or Measuring—

Notified Body Annex VII.4—Referring
identification number) to Annex II, IV, V and VI
Annex VII—EC
Declaration of
Conformity
CE Mark Approval
CE Mark (excluding Sterile oridentification
Measuring—number)
Notified Body Annex VII.4—Referring
identification number) to Annex II, IV, V and VI
address this concern, the Commission issued a requirement to previously available Annexes IV, V and VI. However,
for review of representative design document examples. the Notified Body would assess only manufacturing aspects
For Class IIa devices, Notified Bodies should be related to the device’s sterility or conformity with metrology
expected to assess one representative sample of each device requirements
CE MarkforApproval
devices with a measuring function.
subcategory. For Class IIb, the examination would include The Active
(including Implantable
Notified Body Medical Devices Directive
one representative sample for each generic device group. (AIMDD) was thenumber)
identification first EU device directive. Conformity
The current route for a Class I device (Figure 19-4), assessment procedures for these products are limited, and a
self-declaration or self-certification, is Annex
address this concern, the Commission issued a requirement VII, EC Notifiedavailable
to previously Body’s involvement
Annexes IV,is V mandatory. Current confor-
and VI. However,
Declaration of Conformity. Under Directive
for review of representative design document examples. 2007/47/ mity assessment procedures for AIMDs (Figure
the Notified Body would assess only manufacturing aspects 19-5) are
EC, manufacturers now may use Annex
For Class IIa devices, Notified Bodies should be II to obtain CE similar to those for Class III devices.
related to the device’s sterility or conformity with metrology
marking
expected forone
to assess Class I measuring or
representative sterileofdevices,
sample in addition
each device requirements for devices with a measuring function.
subcategory. For Class IIb, the examination would include The Active Implantable Medical Devices Directive
Figure 20-5. AIMDD Conformity Assessment Procedure
one representative
Figure 19-5.sample
AIMDDforConformity
each generic device group.
Assessment Procedure(AIMDD) was the first EU device directive. Conformity
The current Figure 19-5.
route for AIMDD
a Class Conformity
I device (FigureAssessment
19-4), Procedure
assessment procedures for these products are limited, and a
self-declaration or self-certification, is Annex VII,AIMDD EC Notified Body’s involvement is mandatory. Current confor-
Declaration of Conformity. Under Directive 2007/47/ 90/385/EEC mity assessment procedures for AIMDs (Figure 19-5) are
EC, manufacturers now may use Annex II to obtain CE similar to those for Class III devices.
marking for Class I measuring or sterile devices, in addition
Figure 19-5.Annex
AIMDD Conformity Assessment Procedure
II—Complete Annex III—EC Type
Figure 19-5.
Quality AIMDD Conformity Assessment Procedure
Assurance Examination
System AIMDD
90/385/EEC
Annex IV—EC Verification Annex V—Assurance of

Production Quality
Annex II—Complete Annex III—EC Type
Quality Assurance Examination
System
CE Mark approval
CE Mark approval CE Mark approval
(including Notified Body (including Notified Body
identification number)
identification number) identification number)
Annex IV—EC Verification Annex V—Assurance of
Production Quality
CE Mark approval
identification number)
identification number) identification number)
214 250 Regulatory

Regulatory Affairs
Affairs Professionals
Society
device subcategory. For Class IIb, the examination Figure 20-6.
FigureIVD Conformity
19-6. Assessment
IVD Conformity Procedure
Assessment Procedure
Figure 19-6. IVD Conformity Assessment Procedure Figure 19-6. IVD Conformity Assessment Procedure in its
would include
Figure 19-6.oneIVD
representative
Conformitysample for eachProcedure
Assessment in its entirety. Annex III references a design dossier, and
generic device group. Noti
Notified Body involvement is mandatory. Annex IV is
The current route for a Class I device (Figure anoth
another choice,Allapplying for a full
IVDs (except quality
Annex II assurance system,
All IVDs (except Annex II excep
20-4), self-declaration or self-certification, is Annex excepting Sections 4or and 6, which
self-testing) are not applicable for this
or self-testing) risk c
VII, EC declaration of conformity. Under Directive risk category. An alternative option is following Annex V in
2007/47/EC, manufacturers now may use Annex II combination with Annex VI or Annex VII. comb
to obtain CE-marking for Class I measuring or sterile The conformity assessment procedures for IVDD
devices, in addition to previously available Annexes IV, Annex II List B (Figure 19-8) are similar to those for self- Anne
V and VI. However, the notified body would assess only testing devices, except Annex III is not allowed. testin
manufacturing aspects related to the device’s sterility The highest scrutiny is applied to products in Annex
or conformity with Declaration
Annex III—EC metrology requirements for devices Annex
II List A, which are III—EC
consideredDeclaration
high-risk IVDs. The con- II Li
with a ofmeasuring
Conformity function.
(excluding formity assessment procedure (excluding
of Conformity choices for these products are form
The Active Implantable
Annex III.6) Medical Devices Directive very limited. For thisAnnex III.6)all annexes apply (Figure
category, very
(AIMDD) was the first EU device directive. Conformity 19-9). 19-9
assessment procedures for these products are limited, The connection between conformity assessment proce-
and a notified body’s involvement is mandatory. Current dures headlined in all three medical devices directives and dures
conformity assessment procedures for AIMDs (Figure Decision 768/2008/EEC will be discussed, but manufactur- Deci
20-5) areCEsimilar to those
Mark (no for Class III devices.
Notified ers must take each CE directive’s specifics into consideration.
Mark (no Notified ers m
The In Vitro
Body Medical Devices Directive’s (IVDD)
identification The decision highlights eight assessment procedures or
Body identification The
annexes contain requirements similar to those in the
number) modules covering the design number) and production phases: mod
MDD. For example, the conformity assessment proce- • Module A: Internal production control •
dure for all devices not listed in IVDD Annex II and • Module B: EC Type-examination •
not forThe In Vitro Medical
self-testing DevicesinDirective’s
is outlined Annex III (IVDD)
(Figureannexes • ModuleThe In Vitro Medical
C: Conformity Devices
to type basedDirective’s
on internal(IVDD)
pro- annexes •
contain requirements similar to the MDD’s.
20-6). The conformity assessment procedure is similar For example, contain
duction requirements
control similarfor
(not applicable todevice
the MDD’s. For example,
directives)
dossier and notified body involvement is mandatory.
tothe
MDDconformity assessment
Annex VII’s procedure
for Class forbut
I devices, all more
devicesspe-
not the conformity
• Module D: Conformity assessment
to type procedure for all devices not
based on production •
Annex IV is another choice, applying for a full quality
listed in IVDD Annex II and not for self-testing
cific quality system aspects are required. Notified body is outlined listed quality
process in IVDD Annex II and not for self-testing is outlined
assurance
assurance system, excepting Sections 4 and 6, which
in Annex III is
involvement (Figure 19-6). The conformity assessment pro-
not required. in Annex
• Module E: III (Figure 19-6).
Conformity Thebased
to type conformity assessment pro-
on product •
are not applicable for this risk category. An alterna-
cedure is similar to MDD Annex VII’s for Class I devices, quality
cedureassurance
is similar to MDD Annex VII’s for Class I devices,
Self-testing IVDs offer manufacturers a variety tive option is following Annex V in combination with
but more specific quality system aspects are required. • Module
but moreF: Product
specificverification
quality system aspects are required. •
of conformity assessment procedures from which to Annex VI or Annex VII.
Notified Body involvement is not required. • Module
Notified G:BodyUnitinvolvement
verification is(notnot applicable
required. for •
choose (Figure 20-7). Manufacturers may apply IVDD
Self-testing IVDs offer manufacturers a variety of device Self-testing
directives) IVDs offer manufacturers a variety of
Annex III in its entirety. Annex III references a design
conformity assessment procedures from which to choose • Module H: Full
conformity quality assurance
assessment procedures from which to choose •
(Figure 19-7). Manufacturers may apply IVDD Annex III (Figure 19-7). Manufacturers may apply IVDD Annex III
Figure 20-7. Self-Testing IVD Conformity Assessment Procedure
Figure 19-7. Self-Testing IVD Conformity Assessment Procedure Figure 19-7. Self-Testing IVD Conformity Assessment Procedure
Figure 19-9. Self-Testing IVD Conformity Assessment Procedure Figure 19-9. Self-Testing IVD Conformity Assessment P
Self-testing IVDs
Self-testing IVDs Self-testing IVDs
Self-testing IVDs
IVDD98/79/EC
IVDD 98/79/EC IVDD98/79/EC
IVDD 98/79/EC
Annex III—EC Declaration Annex IV (Excluding IV.4 Annex V—EC Type- Annex IV (Excluding IV.4
Annex III—EC Declaration
of Conformity and IV.6)—Full Quality Examination
of Conformity and IV.6)—Full Quality
Assurance System
Assurance System
Annex VI—EC Annex VII (excluding

Annex III.6—Design
Annex III.6—Design Annex VII.5)—Production
Verification
Dossier Examination
Dossier Examination Quality Assurance

(including Notified Body (including Notified Body (including Notified Body
(including Notified Body identification number)
(including Notified Body (in
identification number) identification number) identification number)
identification number) identification number) i

Chapter 20
Chapter 19
Figure 20-8. IVDD Annex II List B Conformity Assessment Procedures

FigureFigure
19-8.19-8.
IVDDIVDD
Annex II List
Annex B Conformity
II List B ConformityAssessment
AssessmentProcedures
Procedures
Annex II List B
IVDD 98/79/EC
Annex IV (Excluding IV.4 Annex V—EC Type-

and IV.6)—Full Quality Examination
Assurance System
Annex VI—EC Verification Annex VII (excluding

Annex VII.5)—Production
Quality Assurance
CE Mark approval CE Mark approval CE Mark approval

(including Notified Body (including Notified Body (including Notified Body
identification number) identification number) identification number)
The new EU MDR and EU IVDR only have two basic types the EU IVDR, and a clinical scrutiny process for selected
of The
conformity assessment.
conformity The most
assessment obviousforone
procedures is the full
IVDD is high-risk devicesassessment
the full quality under both(e.g.,
the EUEUMDR
MDRand EU IVDR.
Annex
Annex II List B (Figure 20-8) are similar to those foralter-
quality assessment (e.g., EU MDR Annex IX); the only IX); the only alternative is a combination of (part of ) a
native is a devices,
self-testing combinationexceptof Annex
(part ofIII
) a type-examination
is not allowed. and Internal Production
type-examination and aControl
product(Module A) assessment
conformity
a product conformity assessment (e.g.,
The highest scrutiny is applied to products EU MDR in Annexes With the EC Declaration of Conformity,
(e.g., EU MDR Annexes X and XI). A much the more
main focus is
Annex II List A, which are considered high-riskvast
X and XI). A much more simplified system the IVDs.major- on the technical documentation (Table 19-5).
simplified system the vast majority will follow is the full
The conformity assessment procedure choices for thesethat
ity will follow is the full quality assurance route. In quality assurance route. In that route, however, there
route, however,
products there now
are very limited. Forare four
this types ofallconsultations
category, annexes now are four types of consultations to agencies under
to agencies under
apply (Figure 20-9). the EU MDR, and requirements include the EU MDR, and requirements include continued
continued batch verification
The connection for selectedassessment
between conformity products under batch verification for selected products under the EU
procedures headlined in all three medical devices direc- IVDR, and a clinical scrutiny process for selected high-
Table
tives and19-5. Internal
Decision Production Control
768/2008/EEC will be discussed, risk devices under both the EU MDR and EU IVDR.
but manufacturers must take each directive’s specifics
intoDecision 768/2008/EC
consideration. AIMDD 90/385/EEC
The decision highlights eight assess- MDD 93/42/EEC
Internal Production ControlIVDD 98/79/EEC
(Module A)
ment procedures
Module A or modules coveringNA the design and WithVIIthe
Annex EC declaration of conformity,
Annex III the focus is on
production phases: the technical documentation (Table 20-5).
• Module
Internal A: Control
Production Internal production control EC Declaration of Conformity EC Declaration of Conformity
• Module B: EC Type-examination EC Type-Examination (Module B)
Table Module
• 19-6. EC C: Conformity to type based on
Type-Examination This is product-related, and the notified body examines
internal production control (not applicable for the product and issues an EC type-examination certifi-
device
Decision directives)
768/2008/EC AIMDD 90/385/EEC MDD 93/42/EEC
cate IVDD 98/79/EEC
(Table 20-6). The notified body may test the device
• Module
Module B D: Conformity to type based
Annex 3 on pro- directly
Annex IIIto confirm the design meets theVapplicable
Annex
duction process quality assurance directive’s requirements and complies with the direc-
EC Type-Examination EC Type-Examination EC Type-Examination EC Type-Examination
• Module E: Conformity to type based on prod- tive’s essential requirements. The EC type-examination
uct quality assurance procedure always will be applied with other procedures.
Table
• 19-7.
ModuleProduction Quality
F: Product Assurance
verification
• Module G: Unit verification (not applicable Production Quality Assurance IVDD
(Module D)
Decision 768/2008/EC AIMDD 90/385/EEC MDD 93/42/EEC 98/79/EEC
for device directives) The production quality assurance procedure’s scope
• Module
Module D H: Full quality assurance
Annex 3 Annex III
(Table Annex are,
20-7) is to ensure the products V in fact, pro-
duced and conform to the type described in the EC
TheConformity
new EU MDR to type
andbased upon only
EU IVDR Production Quality
have two basicAssur- Production Quality Assurance Production Quality
type-examination certificate. Production shall follow
quality assurance of the Produc- ance Assurance
types
tionofProcess
conformity assessment. The most obvious one
252
216 Regulatory Affairs
Regulatory Professionals
Affairs Society

certain requirements that may be fulfilled with the Figure 20-9. High-Risk IVD Conformity Medical Assessment
Device Conformity Assessment Proce
application of the harmonised quality system standard, Procedure
ISO 13485. A notified body is involved.
Figure 19-9. High-Risk IVDFigure
Conformity Assessment
19-9. High-Risk ProcedureAssessment Procedure
IVD Conformity
Annex II List A
Product Quality Assurance (Module E) IVDD 98/79/EC
This procedure’s goal is to ensure, through final inspec-
tion and testing, products actually are in conformity
with the type described in the EC type-examination Annex V—Full Quality Annex V—EC Type-
certificate (Table 20-8). This can be achieved with Assurance System Examination
very limited quality system aspects. The harmonised

standard, ISO 13485, may be used with exemptions
not applicable to this procedure. The product quality Annex IV.4—Design Annex VII—Production
Dossier Quality Assurance
assurance procedure normally is applied with the EC
type-examination. However, the MDD allows the appli-
cation with Annex VII for Class IIa products. In that
case, the procedure shall ensure the devices conform Annex IV.6—Verification Annex VII.5—Verification
of Manufactured of Manufactured
to the technical documentation. A notified body is Products Products
involved. This type of procedure is not applicable for the
AIMDD or the IVDD.
Product Verification (Module F) identification number) identification number)
This procedure’s scope (Table 20-9) is for the notified
body to ensure devices are in conformity with the type
described in the EC examination certificate. The veri- (Module B)
EC Type-Examination certificate. Production shall follow certain requirem
fication may be performed for each individual product
This is product-related, andCurrently,
the NotifiedforBody examines
medical devices,that themayISObe fulfilled
13485 with the application of the harmon
quality
the product
or batch of products. The procedure normally is applied and issues an EC type-examination certifi- quality system
system standard is the most appropriate. Application standard, ISOof13485. A Notified Bod
cate (Table 19-6). The Notified Body may test the device involved.
with the EC type-examination. However, the MDD this standard is voluntary. Manufacturers may use other
directly to confirm the design meets the applicable directive’s
allows the application with Annex VII for Class IIa
requirements and complies quality
with thestandards, but applyingProduct
directive’s Essential harmonised
Qualitystandards
Assurance (Module E)
products. In this case, the procedure shall ensure the conveys the presumption
Requirements. The EC type-examination procedure always of conformity. Independent
This procedure’s goal is to ensure, through final ins
devices conform to the technical documentation.
will be appliedThe of the choice, the quality control
with other procedures. tion level outlined
and testing, in theactually are in conformity
products
notified body must conduct appropriate examinations directives shall be achieved. Using the typea non-harmonised
described in the EC type-examination certifi
and tests. Production Quality Assurance (Module
standard willD) (Table 19-8).
leave it to the notified bodyThis can be achieved
to accept, and with very limited qu
The production quality assurance
the reviewer may find it more difficult to establish com- standard, ISO 13485,
procedure’s scope (Table system aspects. The harmonised
19-7) is to ensure the products are, in fact, produced and be utilised with exemptions not applicable to this pr
Full Quality Assurance System (Module conformH)
pliance with the directives’ requirements.
to the type described in the EC type-examination dure. The product quality assurance procedure norm
This procedure’s main goal is ensuring the manufacturer Basically, following the ISO 13485:2016 standard
applies a full quality assurance system, which includes will lead to fulfilment of the QMS elements from both
Table 19-8. Product Quality Assurance
all aspects of design, manufacture and final product the EU MDR and EU IVDR. That is because the appli-
inspection (Table 20-10). This can be achieved with
Decision 768/2008/ECthe cable regulations are cross-referenced
AIMDD 90/385/EEC MDD 93/42/EEC
in general terms IVDD 98/79/EEC
full application of ISO 13485. For higher-risk classes, in many places of the standard. In reality, the key differ-
Module E NA Annex VI NA
the procedure is extended by the notified body’s design ences when comparing current directives’ expectations
dossier examination. For IVDs, additional notified
Conformity to those from the EU MDR and
bodybased upon
to type EUQuality
Product IVDRAssurance
are:
Product Quality Assurance
product verification is applied within the procedure. • a strategy for regulatory compliance
• identification of applicable safety and perfor-
Table 19-9. Product Verification mance requirements
Quality System Requirements
The directives refer to certain quality assurance aspects
Decision 768/2008/EC
• management’s responsibility
AIMDD 90/385/EEC MDD 93/42/EEC IVDD 98/79/EEC
fulfilled with the application of harmonised standards. • resource management, including supplier and
Module F Annex 4
subcontractor Annexand
selection IV control Annex VI
Specific standards are not mentioned, and standards are
developed independently of the directives. to type based upon • EC Verification
Standards
Conformity risk management EC Verification EC Verification
Product Verification
harmonisation is a faster process than updating an EU • clinical evaluation, including postmarket
directive or regulation. This ensures state-of-the-art clinical
technical aspects and quality system requirements. • product realisation, including planning, design,
Quality system standards are developed over time; ISO development, production and service
9001 was the first standard harmonised and applied. • UDI-code assignments
• a systematic postmarket surveillance system

Chapter 20
Table 20-5. Internal Production Control
Decision 768/2008/EC 90/385/EEC (AIMDD) 93/42/EEC (MDD) 98/79/EEC (IVDD)
Module A NA Annex VII Annex III

Internal Production Control EC Declaration of Conformity EC Declaration of Conformity
Table 20-6. EC Type-Examination
Module B Annex 3 Annex III Annex V

EC Type-Examination EC Type-Examination EC Type-Examination EC Type-Examination
Table 20-7. Production Quality Assurance
Module D Annex 3 Annex III Annex V

Conformity to type based Production Quality Assurance Production Quality Assurance Production Quality Assurance
on Quality Assurance of the
Production Process
Table 20-8. Product Quality Assurance
Module E N/A Annex VI N/A

Conformity to type based on Product Quality Assurance
Product Quality Assurance
Table 20-9. Product Verification

Module F Annex 4 Annex IV Annex VI
Conformity to type based on EC Verification EC Verification EC Verification
Product Verification
Table 20-10. Full Quality Assurance System
Module H Annex 2 Annex II Annex IV
Conformity based on the Complete Quality Assurance Full Quality Assurance System Full Quality Assurance System
Quality Assurance System System

Table 20-11. Authorised Representatives
90/385/EEC (AIMDD) 93/42/EEC (MDD) 98/79/EEC (IVDD)

Annex 2 Annex II Annex IV
Art. 9(3) “Where appropriate, the proce- Art. 11(8) “The manufacturer may instruct Art. 9(6) “The manufacturer may instruct
dures provided for in Annexes 3, 4 and 6 his authorized representative to initiate his authorized representative to initiate
may be discharged by the manufacturer’s the procedures provided for in Annexes the procedures provided for in Annexes III,
authorized representative established III, IV, VII and VIII.” (See also: Annex III, V, VI and VIII”. (See also Annex III, Section
in the Community.” (See also: Annex Section 2, Annex IV, Section 1, Annex VII, 1, Annex V, Section 2, Annex VI, Section 1,
2, Section 2, Annex 3, Section 2, Annex Section 1, Annex VIII, Section 1) Annex VIII, Section 1)
4, Sections 1 and 2, Annex 5, Section 2,
Annex 6, Section 1
• communication with authorities, notified bod- In recent years, notified bodies have been scru-
ies, other economic operators, customers and/ tinised by joint assessment teams composed of members
or other stakeholders from several Member States and EU Commission
• processes for serious incident and field safety inspectors. Many notified bodies meanwhile have
corrective action reporting stopped operating or have asked for their scope of work
• management of CAPA, including verification to be reduced. This scrutiny process is ongoing.
of effectiveness In addition, the new regulations do not permit
• processes for monitoring and measuring out- grandfathering of notified bodies. That means all noti-
put, data analysis and product improvement fied bodies will need to re-apply to be notified bodies
under the new regulations and will need to be inspected
If a company currently complies with current directives from scratch; to date, only a select few have taken this
and ISO 13485, the above items will constitute the key step, and many will be phasing out. This new desig-
elements in the gap assessment for the new regulations. nation process is time-consuming; hence, only a small
The only thing that has been reduced in requirements is number of designations have been completed to date,
the minimum frequency at which unannounced audits with more expected in 2020 and even 2021. This late
need to occur. designation will impede the success of EU MDR and
EU IVDR transition processes.
Notified Bodies
Notified bodies are involved in many conformity Authorised Representatives
assessment stages. The level of involvement increases Manufacturers placing medical devices on the EU
with the product’s associated risk and, most certainly, market without a registered place of business in the ter-
a product shall not be marketed until the conformity ritory shall designate an authorised representative to act
assessment, including notified body issuance of the on their behalves (AIMDD—Article 10a(2); MDD—
appropriate certificates, is completed. Products must Article 14(2); IVDD—Article 10(3)). MEDDEV
fulfil the requirements described in the specific directive 2.5/10 details authorised representatives’ roles across
as well as any additional national requirements. Notified all three devices directives and clearly distinguishes
bodies are approved by their countries’ national com- between the manufacturer’s and authorised representa-
petent authorities. Once approved, they are notified to tive’s responsibilities.
the European Commission and are published with their Under the EU MDR and EU IVDR, these
scope in the Official Journal of the EU. authorised representatives should formally accept the
A notified body may select its specific areas of designation. With that, they take on product liability for
authorisation. Not all notified bodies are notified to defective products, separate from the liability bestowed
the Commission for all directives or for all conformity on the legal manufacturer and on the importer. To bal-
assessment procedures within a directive. A noti- ance this liability, the authorised representative needs
fied body may not be able to review all conformity to review regulatory documents from the manufacturer;
assessment procedures. A manufacturer should review therefore, they must have a person knowledgeable about
notified bodies to identify one to address its particular the regulatory requirements.
needs, but a notified body also should refuse an appli- Authorised representatives are involved in con-
cation from a manufacturer for which it cannot provide formity assessment (Table 20-11) as delegated by
the required service. the manufacturers; those responsibilities should be

Chapter 20
described in the authorised representative’s contract • The medical devices directives allow a choice
with the manufacturer. The manufacturer may instruct of conformity assessment procedures related to
its authorised representative to initiate conformity the product’s risk class.
assessment procedures defined in Annexes III, IV, VII • Conformity assessment procedures may focus
and VIII by: on either product or quality system-related
• lodging conformity assessment applications for aspects.
EC type-examination (Annex III) • Compliance with the essential requirements
• establishing a declaration of conformity to the and principles could be achieved with the
type described in the EC type-examination application of harmonised standards. Under
certificate (Annex IV) the regulations, harmonisation of standards
• establishing the Annex VII EC declaration of might occur only after first compliance reviews.
conformity, including Annex VII, Section 5, in • Notified bodies may be involved during various
case of products placed on the market in sterile conformity assessment procedure stages.
condition and Class I devices with a measuring • Manufacturers may select their notified bodies,
function but fewer notified bodies are expected to be
• establishing statement for custom-made available.
devices (Annex VIII Section 2.1) • Conformity assessment of MDD/AIMDD and
EU MDR will continue in parallel, so double
Under the new regulations, these requirements are main- product certification is an option.
tained and further enhanced by additional regulatory
compliance checks. In addition, the authorised represen- Recommended Reading
1. Decision 768/2008/EC of the European Parliament and
tative should be identified in the new Eudamed database. Council of 9 July 2008 on a common framework for the market-
ing of products and repealing Council Decision 93/465/EEC.
Conclusion EUR-Lex website. http://eur-lex.europa.eu/legal-content/EN/
TXT/?uri=URISERV:l10141. Accessed 16 April 2020.
• Medical devices directives follow the EU new 2. Directive 98/34/EC of the European Parliament and Council
approach; the new medical device regulations of 22 June 1998 laying down a procedure for the provision of
follow the new legal framework but will keep information in the field of technical standards and regulations.
such elements as notified bodies in place. EUR-Lex website. http://eur-lex.europa.eu/legal-content/EN/
ALL/?uri=CELEX:31998L0034. Accessed 16 April 2020.
• Conformity assessment procedures’ scope
are to prove compliance with the essential
requirements.

Chapter 21
Medical Device Compliance:

Postmarket Requirements
Updated by Tran Do and Gert Bos, MSc, PhD, FRAPS
OBJECTIVES □ MEDDEV 2.12/2 (Rev. 2) Medical Devices—

Guidelines on postmarket clinical follow-up,
□ Discuss the mechanisms in place to ensure 2012
postmarket medical device compliance
□ Commission Decision of 19 April 2010 on
□ Review manufacturer postmarket surveillance the European Databank on Medical Devices
procedure requirements (Eudamed) (2010/227/EC)
□ Understand the EU medical device vigilance sys- □ Communication from the Commission of 2
tem and incident reporting requirements July 2003 to the Council and the European
Parliament on Medical Devices
□ Review other measures Member States’ compe-
tent authorities use to ensure medical device □ Regulation (EU) 2017/745 of the European
compliance Parliament and of the Council of 5 April 2017
2001/83/EC, Regulation (EC) No. 178/2002 and
DIRECTIVES, REGULATIONS AND GUIDELINES Regulation (EC) No. 1223/2009 and repealing
COVERED IN THIS CHAPTER Council Directives 90/385/EEC and 93/42/EEC
(EU MDR)
on the approximation of the laws of the Member □ Regulation (EU) 2017/746 of the European
States relating to active implantable medical Parliament and of the Council of 5 April 2017
devices (AIMDD) on in vitro diagnostic medical devices and
repealing Directive 98/79/EC and Commission
□ Council Directive 93/42/EEC of 14 June 1993 Decision 2010/227/EU (EU IVDR)
concerning medical devices (MDD)

and of the Council of 27 October 1998 on in vitro
Introduction
The application and enforcement of the European
diagnostic medical devices
medical devices directives make an effective system for
□ Directive 2001/95/EC of the European collecting, analysing and sharing information about
Parliament and of the Council of 3 December device issues and any adverse effects from their day-to-
2001 on general product safety day use. An effective postmarket surveillance system
allows all interested parties, particularly Member State
□ MEDDEV 2.12/1 (Rev. 8) Medical Devices— competent authorities, to take any action needed to
Guidelines on a medical devices vigilance protect the public.
system (2013)

Chapter 21
Heightened regulatory scrutiny focuses on an competent authority to put into practice any subsequent
effective postmarket surveillance system’s proper protective measures.
implementation and maintenance, as the postmarket
surveillance concept is addressed not only in the medical Relationship Between the General
devices directives and regulations, but also in EN ISO Product Safety Directive, the Medical
13485 and EN ISO 14971. This chapter discusses the
importance of effective postmarket surveillance system Devices Directives and EU Medical Devices
and vigilance system implementation and maintenance. Regulation
This chapter describes the current practice under Other, less-obvious, horizontal directives, such as
the Medical Devices Directive (MDD) and Active Directive 2001/95/EC of the European Parliament
Implantable Medical Devices Directive (AIMDD), as and of the Council of 3 December 2001 concerning
amended. A selection of changes introduced by the new general product safety (General Product Safety Directive
EU Medical Devices Regulation (EU MDR) will be listed (GPSD)), also need to be considered. This directive
at the end of relevant sections. At the time of writing is intended to ensure a high level of consumer prod-
this chapter, detailed interpretation of certain EU MDR uct safety; it completes, complements and reinforces
aspects remains unclear, awaiting updated guidance the medical device vigilance provisions found in the
documents or implementing rules. AIMDD, MDD, EU MDR , In Vitro Diagnostic Medical
The medical devices directives establish two prin- Devices Directive (IVDD) and In Vitro Diagnostic
cipal feedback mechanisms for medical devices. The Medical Devices Regulation (EU IVDR).
first arises from the requirement for manufacturers to Examples of products regulated by the MDD and
implement a systematic postproduction phase device EU MDR and falling under the scope of the GPSD are
experience procedure and appropriate means to apply adhesive bandages, crutches, condoms, glasses, contact
any necessary corrective actions. This mechanism com- lenses, hearing aids and in vitro diagnostics (IVDs) for
monly is referred to as postmarket surveillance. The self-testing. Medical devices supplied to healthcare pro-
MDD and AIMDD indicate postmarket surveillance fessionals and intended to be used by them—even if used
data also may be used to update the clinical evaluation on a consumer—generally do not qualify as consumer
report document. products. Examples include cardiovascular catheters,
The second stems from the requirement to notify laboratory equipment, scalpels and x-ray equipment.
competent authorities when a so-called incident or The GPSD uses the term “producer” for those
recall (Field Safety Corrective Action (FSCA)) occurs. responsible for placing safe products on the market.
An “incident or recall” is defined as: The definition of producer includes: a manufacturer
• any malfunction or deterioration in a device’s of a product when established in the EU, an entity
characteristics and/or performance made avail- presenting as a manufacturer by affixing the name or
able in the market, as well as any inadequacy trademark, a manufacturer’s representative or product
in the labelling or the instructions for use that importer and other professionals in the supply chain
might lead to or might have led to the death whose activities may affect a product’s safety.
of a patient, user or other person or a serious The medical device directives cover most producer
deterioration in his or her state of health obligations specified in the GPSD. However, GPSD
• any technical or medical reason relating to a Articles 5.1 and 5.3 may apply to producers’ general
device’s characteristics or performance for the obligation to track product safety after placing devices
reasons referred to in the bullet point above, on the market, inform competent authorities about dan-
leading to a manufacturer’s systematic recall of gerous products and take actions to prevent risk related
devices of the same type to custom-made devices considered consumer products.
Additionally, the medical device directives have no
The criteria and procedures used by manufacturers, com- provisions related to distributor obligations, though the
petent authorities and all other interested parties to notify “New Approach” directives define economic operators
and handle incidents and FSCAs or recalls are known as manufacturers, authorised representatives, importers
collectively as the Medical Device Vigilance System. and distributors. Therefore, aspects of GPSD Article
Provisions regarding these two mechanisms are 5 are relevant for medical device consumer products’
found in various medical device directives’ sections, distributors.
summarised in Table 21-1. The EU MDR, however, changes these require-
In each case, the objective is to provide feed- ments for economic operators under MDD. As
back and analysis to allow the manufacturer and/or the concepts are derived from a broader European
Legislation from 2008, this new requirement now aligns

Medical Device Compliance: Postmarket Requirements
Table 21-1. Provisions for Providing Feedback about Medical Devices
Mechanism MDD 93/42/EEC AIMDD 90/385/EEC IVDD 98/79/EEC

Manufacturer Annex II.3.1 Annex II.3.1 Annex III.5
Postmarket Annex IV.3 Annex IV.3 Annex IV.3.1
Surveillance Annex V.3.1 Annex V.3.1 Annex VI.3
Annex VI.3.1
Annex VII.4
Medical Device Article 10 Article 8 Article 11
Vigilance System Annex II.3.1 Annex II.3.1 Annex III.5
Annex IV.3 Annex IV.3 Annex IV.3.1
Annex V.3.1 Annex V.3.1 Annex VI.3
Annex VI.3.1
Annex VII.4
MDD = Medical Devices Directive; AIMDD = Active Medical Devices Directive; IVDD = In Vitro Diagnostic Medical Devices Directive
with the obligations stipulated in the GPSD. Under the • product reports and feedback
Article 11, 13 and 14 of the EU MDR, the general obli- • customer complaints
gations of the authorised representative, importer and • customer requirements, contract information
distributor include verification of regulatory compliance and market needs
of the device prior to placing a medical device on the • patient follow-up after clinical trials or
market. This new requirement includes the obligation investigations
for importers and distributors to (1) inform the compe- • services and evaluation reports
tent authority of the Member State if device presents a • scientific papers in peer-reviewed journals
serious risk or is a falsified device; (2) as well as inform- • reports on similar products by competitors
ing manufacturer of complaints or reports received from • compliance-related communications from reg-
healthcare professionals, patients or users about sus- ulatory agencies
pected incidents related to a device. • changes to relevant standards and regulations
Postmarket Surveillance Procedures The important point is that the manufacturer must
As indicated in the corresponding directive articles, implement procedures set up under their quality man-
medical device manufacturers are required to implement agement system and based on a postmarket surveillance
a systematic procedure to review device experience in plan to collect and analyse this information before
the postproduction phase. determining whether any corrective or preventive action
This requirement affects all information concerning is necessary. If incidents or FSCAs are detected through
medical devices that: this procedure, or if the actions to be taken involve
• have been appropriately CE-marked and put change or correction of devices already placed on the
into service or placed on the market market, competent authorities may need to be informed
• are not CE-marked: in accordance with the vigilance system.
o but fall under the directives’ scope (e.g., Procedures for reviewing feedback also are
custom-made devices) mentioned in medical device quality assurance and
o were placed on the market before the management system standards. For example, EN ISO
MDD entered into force 13485 Section 8.2.1 states the manufacturer “shall
o experience incidents leading to corrective establish a documented procedure for a feedback system
actions(s) relevant to the devices men- to provide early warning of quality problems and for
tioned above input to the corrective and preventive action processes,”
and “if national or regional regulations require the
This system should be both proactive (seeking information) organisation to gain experience from the postproduc-
and reactive (collecting and assessing complaints). Possible tion phase, the review of this experience shall form part
sources of information and/or experience include: of the feedback system.”
• customer and user surveys
• adverse incidents (vigilance system)

Chapter 21
Risk Management in the Medical Device complications or problems that might become apparent
Industry only after widespread or long-term use.
Risk assessment, risk analysis and risk management are MDD reference to PMCF is limited to the require-
critical concepts in all phases of the medical device’s ment that where it is deemed unnecessary as part of
lifecycle: during design, production or postmarket the device’s postmarket surveillance plan, the decision
surveillance. must be duly justified and documented (Annex X 1.1c).
Regulatory bodies and standards development However, MEDDEV 2.12-2 (Rev. 2) provides further
committees prefer a descriptive rather than a prescrip- guidance on how to carry out PMCF studies and when
tive approach to the standards development process. they are indicated. It is the manufacturer’s responsibility,
This seems a sensible way to move forward, as the prac- when drawing up a PMS plan, to consider and justify
tice of prescribing numeric values or specific details for whether a PMCF study is required. The guidance con-
compliance with existing standards does not always take tains a non-exhaustive list of circumstances that may
rapidly changing technology into account. Effectively, it warrant a PMCF study. Characteristic examples include:
means the onus is on the manufacturer to define its own • increased risks (e.g., device novelty, vulnerable
risk-acceptance criteria to demonstrate compliance with populations, disease severity)
relevant standards. • limited premarket data generalizability (e.g.,
As part of postmarket surveillance activities, man- device life longer than follow-up, heteroge-
ufacturers need to review developments in regulations neous target populations)
and standards. Currently, manufacturers are reasonably • newly identified risks (e.g., adverse events from
well organised when it comes to generating the initial PMS activities or literature on similar devices)
risk management file. However, they rarely revisit and • CE-marking based on equivalence
update these documents from risk perspectives after
product release. At times, these documents do not Notified body instructions specifically state that when
reflect the current status of known issues with which CE-marking is based solely on clinical data from equiv-
risks may be associated. If a new standard has been alent devices, a PMCF study is mandatory.
implemented, existing products are not necessarily For premarket clinical studies, compliance to EN
considered unsafe. However, it could be questionable ISO 14155:2011 (good clinical practice (GCP)) is
whether a product is still complying with the state-of- expected. For PMCF studies, which investigate, by
the-art principle and notified bodies likely will address definition, on-label use, a less-strict regimen applies.
this question in the context of certificate renewal. When MEDDEV 2.12-2 still requires a study plan describing
new or revised standards are implemented, it is import- objectives, endpoints, a sound study design that com-
ant to maintain a comprehensive risk management file plies with local regulations and standards and a sound
as a living document, reflecting and documenting all analysis plan; however, the manufacturer has more
known product issues from all project phases, including freedom in showing compliance to these requirements,
postmarket surveillance. Data and data trends obtained reducing the administrative burden compared to a full
through postmarket surveillance should be assessed GCP study.
routinely for potential risk management file impact, and With the EU MDR, claiming equivalence for
the assessment should be documented. Manufacturers implantable and Class III devices to devices from
are advised to have a combination of proactive and another manufacturer has become much stricter and
reactive strategies for managing risks throughout the requires a contract to be in place to allow continuing
product lifecycle. full access to the competitor device’s technical doc-
umentation. A thorough PMCF strategy (through a
PMCF plan) allows the manufacturer claiming equiv-
Postmarket Clinical Follow-Up for AIMDs alence under the MDD or AIMDD to obtain sufficient
and MDs clinical evidence with its own device to bypass this EU
Clinical evaluation (AIMDD Annex 7 and MDD Annex MDR requirement (Article 61.6a).
X) and its documentation must be actively updated. As For (premarket/off-label) clinical investigations, the
part of a device’s postmarket surveillance (PMS) plan, EU MDR now incorporates most requirements of EN
residual risks should be investigated and assessed in ISO 14155/GCP, but lighter requirements for on-label
the postmarket phase through systematic postmarket PMCF studies that do not burden the patient are pre-
clinical follow-up (PMCF) studies. In general, PMCF served (Annex XIV part B). However, Article 74 states
is deemed necessary, as premarket data do not nec- that for PMCF studies subjecting the patients to ‘inva-
essarily enable the manufacturer to detect infrequent sive or burdensome’ procedures, a subset of the clinical
investigation requirements apply. The exact interpretation

of the terms ‘invasive or burdensome’ is yet to be defined protecting patients, users and third parties’ health and
by further guidance or implementing rules. safety. On the basis of the information collected and
The EU MDR further underlines the PMCF’s evaluated, competent authorities may decide to dissemi-
importance by requiring the PMCF evaluation report nate information within the market to prevent incidents.
to be part of the clinical evaluation report and technical Extensive guidance on interpreting the direc-
documentation. Main PMCF findings also must be tives’ requirements concerning vigilance is provided in
included in the periodic safety update report (PSUR, MEDDEV 2.12/1 (Rev. 8, January 2013). Revision 8
Article 86), which is mandatory for Class IIa, IIb and was not substantially changed from Revision 7. It now
III devices. explicitly includes in vitro fertilization and assisted
reproductive technology (IVF/ART) devices within the
Medical Device Vigilance System vigilance system’s scope and provides clarity on devices
A medical device vigilance system is intended to not intended to act directly on the individual.
improve the health and safety protection of patients, Although not legally binding, this guidance
healthcare professionals and other users by reducing the represents a general consensus among competent
likelihood incidents related to a medical device’s use authorities, European Commission services and indus-
recur. Competent authorities are responsible for estab- try representatives. Therefore, it is expected that many
lishing and operating a medical device vigilance system Member States will follow the document’s recommen-
within each Member State. Under AIMDD Article dations closely.
8, MDD Article 10 and IVDD Article 11, competent MEDDEV 2.12/1 (Rev. 8) describes the medical
authorities are responsible for taking all necessary steps device vigilance system as a vehicle for adverse inci-
to ensure information concerning incidents is centrally dent notification and evaluation. It covers European
recorded and evaluated. This coordination is facili- Commission, competent authorities, manufacturers,
tated by a central database. However, under EU MDR authorised representatives, users and others’ activi-
(Article 87 and 89), manufacturers are responsible for ties concerned with continued medical device safety.
reporting to the relevant component authorities through Moreover, the vigilance guidelines clarify actions to
the updated Eudamed database. Competent authorities be taken once a manufacturer or competent authority
are responsible for reviewing, evaluating and ensuring receives information concerning an incident. The guide-
information concerning incidents are adequate. line is intended to apply the medical device vigilance
Eudamed is the European databank on medical system uniformly to the AIMDD, MDD and IVDD.
devices. It is a central database, not accessible by the The vigilance system’s procedures are intended to be
public, for information exchange among national com- the same for all three directives and refer to incidents
petent authorities and the European Commission. The occurring within EU Member States, the European
use of Eudamed2 became obligatory in May 2011. An Economic Area (EEA), Switzerland and Turkey regard-
important tool for Eudamed is the Global Medical ing devices bearing the CE Mark. The guidance also
Device Nomenclature (GMDN) code. The GMDN applies to incidents involving devices that do not bear
Maintenance Agency manages web-based nomencla- the CE Mark when they lead to an FSCA relevant to
ture accessible to manufacturers for a fee (https://www. CE-marked devices.
gmdnagency.org/). For IVDs, Eudamed eliminated The vigilance guidance establishes that incident
the regulatory hurdle to file Article 10 notifications in reporting for devices generally not coming into contact
every EU Member State. Table 21-2 gives an overview with patients (i.e., IVDs, IVF/ART devices) may be
of what data are included in Eudamed across the three comparatively difficult to implement because of the
medical device directives and the EU MDR. challenge to demonstrate direct patient harm. Any
Under the EU MDR, Eudamed3 also will include harm is more likely to be indirect—a consequence of
modules for actors (manufacturers, importers and EU a medical decision or action taken or not taken on the
representatives), notified bodies and certificates, vig- basis of information or result(s) provided by the device,
ilance and clinical investigations, with the addition or a consequence of the treatment of cells (e.g., gametes
of modules for UDI, device performance studies and and embryos in the case of IVF/ART devices) or organs
market surveillance. Eudamed3 also will make selected outside the human body that later will be transferred to
information available to the public. patients. Software qualified as medical devices also may
Information and data collected and recorded in lead to indirect harm (incorrect information generated
this manner are intended to be shared among compe- by software).
tent authorities, thereby facilitating corrective action The guidance gives special attention to self-test
earlier than if data were evaluated on a state-by-state devices because these products require the user or
basis. Therefore, the vigilance system is very relevant in patient to make the medical decision. The guidance

Chapter 21
Table 21-2. Eudamed Data Repository
Concern MDD 93/42/EEC AIMDD 90/385/EEC IVDD 98/79/EEC EU MDR

Vigilance Data relating to CE Data relating to CE Data relating to CE certif- Data relating to CE certificates issued,
certificates issued, certificates issued, icates issued, modified, modified, suspended, withdrawn or
modified, suspended, modified, suspended, suspended, withdrawn refused
withdrawn or refused withdrawn or refused or refused
Data relating to registration of
Data relating to Data obtained in Data relating to regis- manufacturers and authorised rep-
registration of accordance with the tration of manufacturers resentatives and devices (excluding
manufacturers and vigilance procedure in and authorised repre- custom-made devices)
authorised represen- the AIMDD sentatives and devices in
tatives and devices accordance with Article Data obtained in accordance with the
(excluding cus- 10 vigilance procedure in the EU MDR,
tom-made devices) enabling manufacturers to:
Data obtained in accor- • submit Periodic Safety
Data obtained in dance with the vigilance • Update Reports (PSURs)
accordance with the procedure in the IVDD • report a Serious Incident (SI)
vigilance procedure in • report a Field Safety Corrective
the MDD Action (FSCA)
• submit/enter a Field Safety
Notice (FSN)
• submit a Periodic Summary
Report (PSR)
• submit a Trend Report (TR)
Clinical Annex VIII: notification Annex 6: notification N/A Article 73: creation of identification
Investigations to the EU country reported in the country numbers for clinical investigations,
where clinical trial is to where clinical investi- and submission of all applications
be conducted gation is conducted or notification to the EU country
where clinical trial is to be conducted
Authority interven- Authority interven- (referred
tions in clinical tions in clinical to in Articles 70, 74, 75 and 78)
investigations investigations
Submission of data, or processing of
Notification of (early) Notification of early data
termination of clin- termination of clin-
ical investigation to ical investigation to Exchange of information relating to
authorities authorities clinical investigations in accordance
with the EU MDR
Manage reporting on serious adverse

events and device deficiencies
Manage information to be provided by

the sponsor (Article 77), including the
clinical investigation
report and its summary as required in
paragraph 5 of that Article
establishes that inadequacies in self-test information 3. events that might have led to death or serious
and Instructions for Use may lead to harm and should deterioration in health but did not, as a result
be reviewed carefully. of fortunate circumstances or the intervention
of healthcare personnel
Types of Incidents to be Reported
Three types of incidents must be reported to the com- The vigilance guidance states specifically, “serious dete-
petent authorities: rioration in the state of health” may include:
1. incidents resulting in a death of a patient, user • a life-threatening illness or injury
or other person • the permanent impairment of or damage to a
2. incidents resulting in a serious deterioration in bodily function
a patient, user or other person’s state of health

• a condition necessitating medical or surgical within a full risk assessment, the risk of death
intervention to prevent a or b above or serious deterioration was quantified and
• any indirect harm as a consequence of using found to be negligible
an ICF/ART device when used according to • expected and foreseeable side effects
manufacturer’s instructions • events described in an advisory notice
• foetal distress, foetal death or any congenital • specific exemptions granted by a competent
abnormality or birth defects authority
Events that might have led to death or serious deterio- Manufacturers should consider all circumstances
ration in health must be reported if the event occurred carefully when deciding whether an event should be
in connection with a medical device’s use and was exempt from reporting duties. All criteria used should
such that it might lead to death or serious deteriora- be documented formally for possible future reference
tion in health if it occurs again. These events also may as evidence the issue was evaluated and to explain the
occur when testing or examining the device, or the decision’s rationale.
Instructions for Use reveal deterioration in characteris-
tics or shortcomings that could lead to death or serious Medical Device Linked to the Incident
deterioration in health. A link must exist between the event and the medical
The term “serious deterioration” can be difficult to device’s use to trigger a reporting duty. The vigilance
define conclusively because each case is subject to eval- guidance recommends manufacturers take certain back-
uative interpretation. When doubt exists as to reporting ground information into account when the link between
requirements, manufacturers should consult a medical the event and the medical device is difficult to establish.
practitioner and, in general, be predisposed to report. Examples of such information are:
• a healthcare professional’s opinion, based on
Criteria for Incident Reporting evidence
When a manufacturer becomes aware of a potential • the manufacturer’s own preliminary assessment
incident, it should use three basic criteria to decide results
whether the relevant national competent authorities • evidence of previous, similar incidents
should be notified: • other evidence held by the manufacturer
• An event has occurred.
• The manufacturer’s device is suspected of being Such a link is assumed in the event of a medical device’s
a contributory cause of the incident. malfunction or deterioration in characteristics or perfor-
• The event led, or might have led, to one of the mance. Malfunction or deterioration is understood to be
following outcomes: the device’s failure to perform its intended purpose when
o death of a patient, user or other person used in accordance with the manufacturer’s instructions
o serious deterioration in the state of health (e.g., a device’s unpredicted biological effect).
of a patient, user or other person Omitted information or labelling or Instructions
for Use errors and inaccuracies also are considered suf-
Some additional considerations must be taken into ficient grounds for establishing a possible link between
account concerning what may be a “serious deteriora- an incident and the medical device.
tion in the state of health,” and certain events may be It may be difficult to ascertain the link between
considered exempt from reporting duties even though the device and the incident when multiple devices and
they meet reporting criteria. Section 5.1.3 of the vigi- drugs are involved. In complex situations, it should be
lance guidance provides criteria for determining such assumed the device may have caused or contributed to
exemptions. Examples include: the incident, and the manufacturer should err on the
• deficiencies in devices found by the user prior side of caution and report.
to use
• events caused by patient conditions Timeline for Initial Incident Reporting
• adverse events related to use of the device after Incidents are to be reported to the competent authority
the stated service life or shelf life has expired immediately, unless there is a justifiable reason for delay.
• events that did not lead to death or serious The vigilance guidance establishes a maximum elapsed
deterioration in the state of health because time from event awareness to competent authority noti-
protection against a fault functioned correctly fication as two calendar days for a serious public health
• events that did not lead to death or serious threat, 10 calendar days for death or unanticipated
deterioration in the state of health and when,

Chapter 21
serious deterioration in state of health and 30 elapsed followed as quickly as possible by written confirma-
calendar days for other incidents. tion. The manufacturer must avoid unduly delaying the
In practice, when a death or serious deterioration is report due to incomplete information and may include
reported, the manufacturer has up to 10 days to deter- a statement to the effect it is making the report without
mine whether the occurrence fulfils event reporting prejudice and does not imply any admission of liability
criteria. If, within that time, the manufacturer is unable for the incident or its consequences.
to rule out a device placed on the market under its
responsibility as the cause, it must inform the compe- Incident Investigations
tent authorities and submit an initial vigilance report. Manufacturers are expected to follow up initial incident
Similarly, when the manufacturer receives a assessments by investigating surrounding circum-
report that a death or serious deterioration could have stances. Competent authorities may initiate their own
occurred, although fortunate circumstances or the investigations and decide to intervene in the manufac-
intervention of healthcare personnel precluded death or turer’s investigation, especially if accessing the device
serious deterioration in the state of health relating to a associated with the incident may alter it in any way
device placed on the market under its responsibility, and that might affect subsequent analysis. If the manufac-
cannot rule out the device as the cause within 30 days, turer cannot perform the investigation, the competent
it must inform the competent authorities and submit an authorities must ensure an investigation is conducted
initial vigilance report. and keep the manufacturer informed.
In the EU MDR, the 30-day reporting timeline Involved competent authorities may monitor
for serious events (not for public health threat, or death the investigation’s progress. Monitoring may include
or serious deterioration) is shortened to 15 days after requesting follow-up reports from the manufacturer on:
the manufacturer becomes aware of the incident. This • how many devices are involved and where they
greatly increases the pressure on manufacturers to inves- have been sold
tigate any incident of which they become aware that is • the current status of devices on the market
potentially device-related. When such an investigation • how long the devices have been on the market
requires an on-site visit from a field service engineer, the • device design change details
timelines will be especially challenging.
The ability to trace medical devices’ distribution,
To whom should the initial report be sent? therefore, is vital to providing reliable information on
In general, the report should be made to the relevant particular devices or batches’ location and state of use in
competent authority in the country in which the inci- the event of an incident.
dent occurred. For incidents involving notification of more than
In addition, national medical device directive one competent authority, a single coordinating com-
transpositions may require manufacturers to inform petent authority may be designated as responsible for
particular Member State competent authorities when most communications.
planning to take action in response to incidents within Following the investigation, the manufacturer
that Member State’s territory. Manufacturers and should take all necessary action, including consulting
individuals responsible for placing medical devices on with the competent authority and performing any
the market must take this into account when applying recalls. The investigation follow-up should conclude
Community-wide corrective or preventive actions. with the manufacturer’s final report to the relevant
If the manufacturer is located outside the EEA, competent authority, illustrating the investigation’s out-
a suitable contact point within the EEA should come. Outcomes may include:
be provided in the initial report (EU authorised • no action
representative). • additional surveillance or follow-up of devices
A suggested format for the initial report is included in use
in MEDDEV 2.12/1 (Rev. 8) Annex 3. This document • disseminating information to users (e.g., by
is available on the European Commission website. advisory notice)
Some Member States have made similar formats avail- • corrective action for future production
able on their websites to facilitate the administrative • corrective action for devices in use
procedure and provide specific incident reporting cri- • device recall or FSCA
teria. Also, some Member States require mandatory • cessation of device commercialisation
electronic reporting.
If the initial report is made by means other than Additionally, the competent authority may take the
mail or fax (e.g., telephone or email), it should be following actions:

• gather more information (e.g., commissioning market for purely commercial reasons are not included
independent reports) and do not require any vigilance reporting. When deter-
• make recommendations to the manufacturer mining whether an FSCA is warranted, a manufacturer
(e.g., to improve information provided with should use the methodology described in EN ISO
the device) 14971 and include incident(s) that occurred outside the
• keep the European Commission and compe- EEA, Switzerland and Turkey affecting devices covered
tent authorities informed (e.g., about recalls by the MDD.
and other actions to be taken) When implementing an FSCA, the manufacturer
• consult with the relevant notified body on must issue an FSN and send FSN copies to the compe-
matters relating to the conformity assessment tent authorities in the countries in which the FSCA is
• consult with the European Commission (e.g., performed as well as to the affected customers. The FSN
if device reclassification may be necessary) also must be translated in the official Union language
• provide additional user education in the countries in which the FSCA is performed. The
• take any other action to supplement manufac- manufacturer or its authorised representative should
turer action notify the responsible competent authority. For devices
with notified body involvement in the conformity
Competent authorities also may decide to dissemi- assessment, the competent authority in the state in
nate information related to reported incidents. Such which the notified body is located also should be noti-
information may be circulated among competent fied. MEDDEV 2.12-1 Rev. 8 Annex 4 and Annex 5
authorities using a competent authority report (CAR). contain recommended formats for an FSCA and an
Such reports are issued by competent authorities and FSN respectively.
intended only for other competent authorities and the
European Commission; the manufacturer should be Trend Reporting
informed when these reports are to be issued. Trend reporting was introduced in MEDDEV 2.12-1
Competent authorities and manufacturers may Rev. 7 and remains unchanged in Rev. 8. Manufacturers
decide to disseminate information to medical device or their authorised representatives are required to report
users. Such information should be directed to specific a significant increase or trend in events or incidents
healthcare practitioners and facilities but, in exceptional usually excluded from individual reporting per Chapter
circumstances, also may be directed to the public. It is 5.1.3 of Rev. 8 to the relevant national competent
important to coordinate competent authority and man- authority. A report (Annex 7) should be filed with the
ufacturer reviews of the information’s possible positive relevant national competent authority. Manufacturers
and/or negative impact, especially when preparing and should have suitable systems in place and proactively
issuing statements to the media. scrutinise trends in complaints and incidents occurring
Manufacturers should submit a final report to the with their devices.
competent authority. The initial and final reports can A trend report (MEDDEV 2.12, Annex 7) should
be one and the same if the investigation is complete be submitted if there is a significant increase in:
at the time the initial report is filed. If not, the final • already reportable incidents
report must be filed with the same competent author- • incidents usually exempt from reporting
ities with whom the initial report was filed. The final • events usually not reportable
report should document the investigation’s outcome and
any actions taken, which may include no action, addi- In the EU MDR, the term “statistically significant
tional surveillance of devices in use, preventive action increase” is introduced. Manufacturer are required
on future production or recall. Following receipt of the to report “any statistically significant increase in the
manufacturer’s final report, the competent authority frequency or severity of incidents that are not serious
may close the incident file and inform the manufac- incidents or that are expected undesirable side effects
turer; however, the competent authority retains these that could have a significant impact on the benefit-risk
reports, and the incident may be re-opened if circum- analysis...and which have led or may lead to risks to the
stances change. health or safety of patients, users or other persons...”
(EU MDR 2017/745, Article 88). Under this require-
FSCAs and Field Safety Notices (FSNs) ment, manufacturers will need to define the approach of
The manufacturer must notify the competent author- determining what is considered a “statistically signifi-
ity of any technical or medical reasons for a device’s cant increase” in the PMS plan.
systematic recall (FSCA). The AIMDD interprets the The trend report is expected regardless of whether
term “withdrawal” in the same way. Removals from the Periodic Summary Reporting has been agreed.

Chapter 21
Relation to Medical Device Global Vigilance by law. Incidents often are detected, for example,
The Global Harmonization Task Force (GHTF) was sup- through such postmarket surveillance procedures as
planted by the International Medical Device Regulators complaint handling.
Forum (IMDRF). IMDRF was conceived in February
2011 as a forum to discuss future directions in medical Other Market Surveillance and Control
device regulatory harmonisation. It is a voluntary group Provisions
of medical device regulators from around the world who The medical devices vigilance system described in
have come together to build on the strong foundational MEDDEV 2.12/1 (Rev. 8) is one mechanism com-
work of GHTF, and to accelerate international medical petent authorities use to control the medical device
device regulatory harmonisation and convergence. market. Various other mechanisms foreseen in the
IMDRF is continuing GHTF’s efforts, working medical device directives specifically are intended to
toward a global medical device vigilance system. The facilitate those provisions’ enforcement. Competent
global vigilance approach has many similarities to the authorities may develop administrative procedures for
European Medical Devices Vigilance System, but also further market control in their corresponding Member
differs in several ways. For instance, the global system States on the basis of the following regulations:
terminology is somewhat different (e.g., it uses the • requirements for technical documentation to
term “adverse event” instead of “incident”). In addition, be made available for competent authority
in contrast to the European manufacturer-oriented inspection
reporting system, the global system is wider in scope, • ability to extend incident reporting obligations
encompassing user reports and user errors. To pro- to include users and persons responsible for
mote systematic notation in global vigilance reporting, medical device calibration and servicing
a technical specification (ISO TS 19218) was pub- • requirements for a registry containing the
lished, which establishes a coding system for adverse names and addresses of all persons responsible
event reporting. The new system facilitates global data for placing medical devices on the market
exchange among regulatory bodies, thereby provid-
ing more accurate reporting and identification of the Therefore, depending on the Member State in question,
involved devices and event types. additional requirements may be in place to enhance
market control:
Vigilance Versus Manufacturers’ Postmarket Duties • license for manufacture, import, assembly and
Although the processes are interrelated, medical device sterilisation activities
vigilance should be distinguished from manufacturers’ • notification of distribution activities, sales
postmarket surveillance duties. activities and sales with individual adaptation
Postmarket surveillance is a process for under- of medical devices (e.g., hearing aids)
standing experience with the device through systematic • regulation of publicity
feedback and review of information from many sources.
It may be understood as a “proactive and reactive” These methods improve competent authorities’ awareness
process involving detecting quality problems through of both the products being placed on the market within
review and analysis of market feedback. The system their territory and the individuals responsible for placing
implemented by the manufacturer to obtain feedback them on the market. Anomalies detected by competent
should fulfil medical device directives’ requirements authorities through market surveillance include:
and EN ISO 13485, clause 8.2.1. Reviewing experience • products bearing a medical device CE Mark
gained with medical devices in the postmarket phase is are not covered by the medical device directives
an important risk management element. Medical device (e.g., borderline products such as cosmetics
risk management should be implemented in accordance and personal protection equipment)
with EN ISO 14971. • devices for which the appropriate Conformity
Vigilance is the “reactive” element of postmar- Assessment Procedure has not been followed
ket surveillance because it involves acting on reports (e.g., Class I sterile devices without notified
a medical device has caused or may cause direct or body intervention)
indirect patient harm or the Instructions for Use are • devices including parts not bearing a CE
inaccurate or open to misinterpretation. It also includes Mark, or devices given a different intended use
communicating with competent authorities regarding by a supplier than that intended by the original
these reports, when required. Vigilance procedures are manufacturer
expected to follow MEDDEV 2.12/1 (Rev. 8) even
though, as guidance, the provisions may not be enforced

Table 21-3. Comparison of Safeguard Clause and Health Monitoring Measures
Concern Safeguard Clause Mechanism Health Monitoring Measure

Initiation of the The Member State must establish (e.g., The Member State must provide sufficient
procedures as a result of vigilance) that a device may evidence to support reasonable doubt that
compromise health or safety when used as the medical device offers an adequate level
intended. of protection of health and safety.
Parties involved The European Commission consults with the The European Commission must consult with
Member State that invoked the Safeguard interested parties and all Member States.
Clause and other interested parties.
Outcome If the European Commission confirms that If the European Commission confirms
the national measure is justified, Member that the national measure is justified, it
States are informed and may adopt appro- develops a measure that must be adopted
priate national measures. (uniformly) throughout the Community after
regulatory committee consultation.
• devices whose labelling is not in the required restricted or subjected to particular requirements.
language The Member State then must inform the European
Commission and all other Member States. These health
The Market Surveillance Operations Group (MSOG) monitoring measures are intended to apply a precau-
was established to improve Member States’ coordi- tionary principle. The Safeguard Clause and health
nation on these and other issues relating to market monitoring measures have fundamental differences,
control. summarised in Table 21-3.
An example of a measure taken in accordance with
Safeguard Clause the Safeguard Clause is Germany’s banning of catgut.
Market control procedures may facilitate information In general, further guidance is considered necessary to
transmittal to competent authorities; this information clarify the conditions under which Member States can
may be used to initiate special measures in accordance use health monitoring measures.
with the Safeguard Clause in the medical devices
directives (AIMDD Article 7, MDD Article 8 and European Databank on Medical Devices—
IVDD Article 8). The Safeguard Clause gives Member Eudamed
States the right to take all appropriate interim mea- Eudamed’s aim is to strengthen medical device market
sures to withdraw a device from the market or prohibit surveillance and transparency by providing Member
or restrict its placement on the market if the device, State competent authorities fast access to information
when correctly installed, maintained and used for its on manufacturers, authorised representatives, devices,
intended purpose, may compromise patients, users certificates, vigilance and clinical investigation data; and
or other persons’ health and/or safety. A Member to contribute to uniform application of the directives,
State taking such measures is obliged to notify the particularly related to registration requirements.
European Commission; it must indicate the reasons
for taking the actions and, if the measures are justified, Eudamed’s Role in Postmarket Requirements
the Commission informs all other Member States.
(Market Surveillance and Vigilance)
However, this process does not mean all other Member
As mentioned earlier, the MDD, AIMDD and IVDD, as
States are obliged to adopt similar measures, even
amended, provide for a central European databank for
though they may be expected to do so.
medical devices, allowing competent authorities to create
transparency and coordinate device directives’ enforce-
Health Monitoring Measures ment, e.g., postmarket requirements. The Commission
The IVDD introduced a new postmarket mechanism for Decision 2010/227/EU annex lists minimal data
competent authorities. Health monitoring may allow a required to be entered in various modules following
Member State to take any necessary and justified tran- medical devices directives’ obligations, including:
sitional measures relative to a given product or group • manufacturer, authorised representative and
of products if, to protect consumer health and safety device registration
or the public health, product availability is prohibited, • devices placed on the Community market

Chapter 21
• certificates issued, modified, supplemented, Conclusion

suspended, withdrawn or refused • Medical device manufacturers are obliged to
• vigilance procedure data implement postmarket surveillance procedures
• clinical investigation data to understand medical devices’ postproduction
experience and provide input to corrective and
Eudamed significantly enhances coordination among preventive processes.
competent authorities regarding medical devices • Information feedback and risk management
directives’ enforcement and is particularly relevant in are important postmarket surveillance aspects;
facilitating communication within the European Medical they may be implemented in accordance
Devices Vigilance System. For this reason, the vigilance with EN ISO 13485 and EN ISO 14971,
module was one of the first features put into operation. respectively.
A 2012 evaluation of Eudamed’s use since its • Manufacturers are obliged to report incidents
conception showed it clearly brings added value for to the relevant competent authorities. In some
participating countries and is able to meet current leg- EU Member States, this reporting obligation
islative requirements; however, increased, more frequent is extended to medical device users.
and timely use is necessary to reap the system’s full ben- • MEDDEV 2.12/1 (Rev. 8) establishes detailed
efits. In the long term, the evaluation showed Eudamed guidance and criteria for both reportable
cannot meet today’s expectations fully in terms of com- incidents and procedures manufacturers and
pleteness, data quality, interlinkage and transparency. competent authorities should follow when
The evaluation confirmed the changes foreseen in the such incidents occur.
proposals for regulations on the revision of the medical • Vigilance reporting is obligatory when manu-
device regulatory framework are adequate to overcome facturers implement medical device recalls for
these shortcomings and transform Eudamed into a technical or medical reasons. Trend reports are
comprehensive and transparent medical device informa- expected regardless of agreements to submit
tion system. periodic safety summaries.
Under the EU MDR, Eudamed’s role will be • Postmarket surveillance and vigilance are
expanded to include more information on device interrelated processes; each uses information
traceability, certificates and clinical studies. Different from the other as input.
users (e.g., competent authorities and notified bodies) • The new EU MDR expands the regulatory due
will have different access levels to stored information. diligence requirements for economic operators
Eudamed also will play a role in informing the general to monitor and verify regulatory compliance of
public, e.g., by making safety and clinical performance the product.
(Article 32) summaries available to the general public. • Member State competent authorities exer-
Eudamed’s functional specifications were published cise market surveillance using mechanisms to
in February 2019. Though the application date of the enforce compliance with medical device direc-
EU MDR is May 2021, the expected application of tives’ provisions.
Eudamed3 is May 2022. The data managed in the • Member State competent authorities may
updated application includes: implement special controls and restrictions
• devices (Unique Device Identifiers (UDI)) under the Safeguard Clause or as health moni-
• certification (e.g., CE marking) toring measures.
• clinical investigations • The Eudamed database facilitates regulatory
• manufacturers and importers — identified by a data exchange and enforcement among com-
Single Registration Number (SRN) petent authorities, particularly concerning
• notified body accreditation and designation vigilance.
• extended vigilance data, including postmarket • Eudamed significantly enhances competent
surveillance authority coordination regarding medical
• applications for conformity assessment by device directives’ enforcement and is partic-
notified bodies ularly relevant in facilitating communication
• summaries of safety and clinical performance within the European Medical Devices
• performance studies for IVDs (like clinical Vigilance System.
investigations) • The EU MDR increases Eudamed’s role, mak-
• market surveillance data ing selected information available to the public.
• Implantable or Class III device manufactur-
ers now claiming equivalence to competitor

devices are advised to use a thorough PMCF

strategy to fulfill the need for clinical data or
access to competitor technical documentation
under the EU MDR.

Chapter 21

Chapter 22
Medical Device National

Particularities
Updated by Robert Falcone, PhD
OBJECTIVES □ Regulation (EU) 2017/746 of the European

Parliament and of the Council of 5 April 2017 on
□ Understand the importance of national transpo- in vitro diagnostic medical devices
sitions for:
o product labelling language requirements

Introduction
o competent authority notification After many years of living with a variety of national
requirements for the regulation of medical devices, the
industry welcomed CE marking for medical devices as
“the passport” to Europe. To bear the CE Mark, and
therefore be allowed movement within the European
single market, a product must be shown to conform
□ Council Directive 93/42/EEC of 14 June 1993 to all applicable requirements. For example, a medi-
concerning medical devices cal device must conform, at minimum, to applicable
requirements of the Medical Devices Directive (MDD)
□ Council Directive of 20 June 1990 on the approx- (Council Directive 93/42/EEC).
imation of the laws of the Member States A directive, such as the MDD, is a European legal
relating to active implantable medical devices instrument; however, it does not, in itself, constitute
European law. The provisions of a directive come into
□ Directive 98/79/EC of the European Parliament effect only when they are transposed into law by a par-
and of the Council of 27 October 1998 on the in ticipating Member State. While, in principle, the model
vitro diagnostic medical devices of the regulatory system should be transposed identi-
cally by each Member State, this is not always the case.
While the European Commission has the duty and
Parliament and of the Council of 5 September
right to review national transpositions and, if necessary,
2007 amending Council Directive 90/385/EEC
act to eliminate inconsistencies, administrative features
of national legislation that do not constitute technical
States regarding active implantable medical
barriers to trade are allowed to remain.
devices, Council Directive 93/42/EEC concern-
This chapter deals with the following aspects of
ing medical devices and Directive 98/8/EC
national transpositions: labelling language requirements
concerning the placing of biocidal products on
and notification/registration requirements under the
the market
current directives. Other aspects of national transpo-
□ Regulation (EU) 2017/745 of the European sitions where variations exist, such as vigilance and
Parliament and of the Council of 5 April 2017 on procedures for initiating clinical investigations, are
medical devices dealt with elsewhere in relevant chapters of this book.
This chapter also touches on the differences between

Chapter 22
Table 22-1. EU Outermost Regionsa
EU Member State Outermost Region(s)

France French Guiana, Guadeloupe, Martinique, Mayotte, Saint-Martin, Réunion
Portugal The Azores, Madeira
Spain The Canary Islands
a. Outermost regions (ORs). European Parliament website. https://www.europarl.europa.eu/factsheets/en/home. Accessed 16 April 2020.
the national implementation requirements between still is subject to the same regulatory framework as the
directives and regulations, and the upcoming transitions other EU Member States.5 However, it is not known if
for medical devices, active implantable medical devices the UK may continue membership in the EU after 31
(AIMDs) and in vitro diagnostics (IVDs). December 2020.
Countries Requiring CE Marking Directives and Regulations

CE marking is required to commercialise products in Until recently, the medical device regulatory framework
the European Economic Area (EEA), comprised of in the EU, including AIMDs and IVDs, has been laid
the 28 EU Member States, including their outermost out in directives. Since EU Member States implement
regions (Table 22-1), and the following three European directives via their own laws, they can vary regionally,
Free Trade Association (EFTA) members: Iceland, such as the requirement to register devices in individual
Liechtenstein and Norway.1,2 Switzerland and Turkey EU countries, regardless of whether the device has been
also may accept and/or require CE marking for specific CE marked to the applicable directive(s). Conversely,
product types.3 regulations are binding legislative acts applicable across
the EU. Recently, the directives that applied to medical
“Brexit” Impact devices in the EU have been replaced by regulations.
The UK is an EU Member State; however, in March The new regulations, the directives that they replace and
2017, the UK notified the European Council of its the transition periods are summarised in Table 22-2.
intention to withdraw from the EU.4 UK withdrawal
from the EU is commonly referred to as “Brexit,” which Language Use for Labelling and
takes effect on 31 December 2020. Negotiations with Instructions for Use
the UK are currently in progress. In the meantime, the The directives and regulations for medical devices,
UK remains a full member of the EU and, therefore, AIMDs and IVDs require labelling content to be
Table 22-2. Current Directives and New Regulations for Medical Devices, AIMDs and IVDsa
Product Directive (Current) Regulation (New) Transition Period

Type
Medical Council Directive 93/42/EEC of 14 June 1993 concerning Regulation (EU) 2017/745 of the Three years after
Devices medical devices (the Medical Devices Directive, (MDD)), European Parliament and of the entry into force
as amended by Directive 2007/47/EC of the European Council of 5 April 2017 on medi- (2020)
Parliament and of the Council of 5 September 2007 cal devices (the Medical Devices
Regulations (EU MDR))
Active Council Directive of 20 June 1990 on the approximation of
Implantable the laws of the Member States relating to active implant-
Medical able medical devices (90/385/EEC) (the Active Implantable
Devices Medical Devices Directive, (AIMDD)), as amended by
(AIMDs) Directive 2007/47/EC of the European Parliament and of
the Council of 5 September 2007
In Vitro Directive 98/79/EC of the European Parliament and of the Regulation (EU) 2017/746 of the Five years after
Diagnostic Council of 27 October 1998 on in vitro diagnostic medical European Parliament and of the entry into force
Devices devices (the In Vitro Diagnostic Devices Directive, (IVDD)) Council of 5 April 2017 on in vitro (2022)
(IVDs) diagnostic medical devices (In Vitro
Diagnostic Regulations, (EU IVDR))
a. https://ec.europa.eu/growth/sectors/medical-devices_en#new_regulations. Accessed 16 April 2020.

Medical Device National Particularities
Table 22-3. Translation Requirements for Medical Devices, AIMDs and IVDs
Product Type Directive Reference Regulation Reference

Medical 93/42/EEC Article 4.4 2017/745 Article 10.11
Devices Member States may require the information, which Manufacturers shall ensure that the device is accompa-
must be made available to the user and the patient in nied by the information set out in Section 23 of Annex I in
accordance with Annex I, point 13, to be in their national an official Union language(s) determined by the Member
language(s) or in another Community language, when a State in which the device is made available to the user
device reaches the final user, regardless of whether it is or patient. The particulars on the label shall be indelible,
for professional or other use.a easily legible and clearly comprehensible to the intended
user or patient.d
AIMDs 90/385/EEC Article 4.4
When a device is put into service, Member States may
require the information described in Sections 13, 14 and
15 of Annex I to be in their national language(s).b
IVDs 98/79/EC Article 4.4 2017/746 Article 10.10
Member States may require the information to be sup- Manufacturers shall ensure that the device is accompa-
plied pursuant to Annex I, Part B, Section 8 to be in their nied by the information set out in Section 20 of Annex I in
official language(s) when a device reaches the final an official Union language(s) determined by the Member
user.c State in which the device is made available to the user
or patient. The particulars on the label shall be indelible,
easily legible and clearly comprehensible to the intended
user or patient.
The information supplied in accordance with Section 20
of Annex I with devices for self-testing or near-patient
testing shall be easily understandable and provided in
the official Union language(s) determined by the Member
State in which the device is made available to the user or
patient.e
a. Council of the European Union. Council Directive 93/42/EEC of 14 June 1993 concerning medical devices. EUR-Lex website. https://eur-lex.
europa.eu/LexUriServ/LexUriServ.do?uri=CONSLEG:1993L0042:20071011:en:PDF. Accessed 16 April 2020.
b. Council of the European Union. Council Directive 90/385/EEC of 20 June 1990 on the approximation of the laws of the Member
States relating to active implantable medical devices. EUR-Lex website. https://eur-lex.europa.eu/legal-content/EN/TXT/
HTML/?uri=CELEX:31990L0385&from=en. Accessed 16 April 2020.
c. European Parliament, Council of the European Union. Directive 98/79/EC of the European Parliament and of the Council of 27 October 1998 on in
vitro diagnostic medical devices. EUR-Lex website. https://eur-lex.europa.eu/legal-content/EN/ALL/?uri=CELEX%3A31998L0079. Accessed 16
April 2020.
d. European Parliament, Council of the European Union. Regulation (EU) 2017/745 of the European Parliament and of the Council of 5
April 2017 on medical devices, amending Directive 2001/83/EC, Regulation (EC) No 178/2002 and Regulation (EC) No 1223/2009
and repealing Council Directives 90/385/EEC and 93/42/EEC. EUR-Lex website. http://eur-lex.europa.eu/legal-content/EN/TXT/
HTML/?uri=CELEX:32017R0745&from=EN. Accessed 16 April 2020.
e. European Parliament, Council of the European Union. Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017
on in vitro diagnostic medical devices and repealing Directive 98/79/EC and Commission Decision 2010/227/EU. EUR-Lex website. http://eur-lex.
europa.eu/legal-content/EN/TXT/HTML/?uri=CELEX:32017R0746&from=EN. Accessed 16 April 2020.
developed with consideration for the intended user, national language(s). The 24 official EU languages, as
taking such factors as technical knowledge, experience, well as the official languages of Iceland, Liechtenstein
education and training into account. Such consider- and Norway, are listed in Table 22-4.
ations may impact factors such as terminology used and Under the new regulations, the phrasing for trans-
translation requirements. lation requirements has been tightened. Where the
Under the current directives (refer to Table 22-3), directives state that Member States “may require” trans-
Member States “may require” labelling information lation, the new regulations state that “manufacturers
to be provided in their national language. Although shall ensure” that specific labelling be translated.
the relevant articles of the directives are written as In some rare cases, a manufacturer may be able to
permissive statements (Member States “may,” rather obtain a translation exemption for a professional-use
than “must” or “should”), almost all EEA countries device from a local competent authority.6 However, it
require labelling information that ensures the safe and should be noted that translation exemptions are rare
proper use of the product. Moreover, manufacturers and may be more costly and time-consuming than the
are required to provide labelling information in their translation process.

Chapter 22
Table 22-4. National Languages of the EU, Iceland, Liechtenstein and Norwaya–d
Language Country/ies
Bulgarian Bulgaria
Croatian Croatia
Czech Czech Republic
Danish Denmark
Dutch Belgium, Netherlands
English Ireland, Malta, UK
Estonian Estonia
Finnish Finland
French Belgium, France, Luxembourg
German Austria, Belgium, Germany, Liechtenstein*, Luxembourg
Greek Cyprus, Greece
Hungarian Hungary
Icelandic Iceland*
Irish Ireland
Italian Italy
Latvian Latvia
Lithuanian Lithuania
Maltese Malta
Norwegian Norway*
Polish Poland
Portuguese Portugal
Romanian Romania
Slovak Slovakia
Slovenian Slovenia
Spanish Spain
Swedish Finland, Sweden
*EFTA country
a. About Medical Devices. Lyfjastofnun Icelandic Medicines Agency website. https://www.ima.is/medical_devices/about_medical_devices/.

Accessed 16 April 2020.
b. Countries. EU website. https://europa.eu/european-union/about-eu/countries_en. Accessed 16 April 2020.
c. Official Languages of the EU. European Commission website. https://europa.eu/european-union/about-eu/eu-languages_en. Accessed 16
April 2020.
d. Official and Spoken Languages of European Countries. The Nations Online Project website. http://www.nationsonline.org/oneworld/euro-
pean_languages.htm Accessed 16 April 2020.
Country Notification Requirements registration requirements include: Spain (which requires

The directives for the regulation of medical devices, the registration of Class IIa, IIb and III medical devices,
AIMDs and IVDs are transposed by the EU Member AIMDs and IVDs)8,9 and the UK (which requires the reg-
States into national law for application.7 Under their istration of Class I devices a company has manufactured,
transposed laws, many EU Member States require refurbished or re-labelled with its own name, any system
notification or registration for products, in addition to or procedure pack containing at least one medical device,
CE marking requirements per the relevant directive(s). custom-made devices and IVDs a company has manufac-
Notification and registration requirements vary on factured or that are undergoing performance evaluation).10
tors including country, product type and classification. In many cases, countries with notification or reg-
Examples of countries that have local notification and istration requirements (above what is required by EU

Medical Device National Particularities
regulation) also have change notification or change 2. European Economic Area. The European Free Trade
approval requirements for currently marketed products. Association (EFTA) website. http://www.efta.int/eea. Accessed
15 April 2020.
3. The Blog: In Which Countries is the CE Marking Required?
Other National Particularities cemarking.net website. Alura Group BV. https://cemarking.net/
In addition to the above, there is much latitude in in-which-countries-is-the-ce-marking-required/. Accessed 15
April 2020.
the different medical device lifecycle stages, from 4. European Council (Art. 50) guidelines for Brexit negotiations.
development to use, that can be regulated by national European Council website. http://www.consilium.europa.eu/
legislation. Reimbursement, purchasing schemes and en/press/press-releases/2017/04/29-euco-brexit-guidelines/.
spare part availability are examples of activities that are Accessed 15 April 2020.
5. United Kingdom. European Union website. https://europa.eu/
excluded from the scope of the current directives and european-union/about-eu/countries/member-countries/united-
new regulations and may be regulated locally. kingdom_en. Accessed 15 April 2020.
6. EU Foreign Language Labelling Requirements. ce-mark.com
website. QNET LLC. http://www.ce-mark.com/index.html.
Conclusion Accessed 15 April 2020.
CE marking to meet European directive specifica- 7. European Union directives. EUR-Lex website. http://eur-lex.
tions has harmonised requirements for medical device, europa.eu/legal-content/EN/TXT/?uri=LEGISSUM:l14527.
AIMD and IVD safety and performance. However, Accessed 15 April 2020.
8. Medical Device Registration in Spain. Thema S.r.l. website.
directives do not come into effect until they are trans- http://www.thema-med.com/en/registrazione-di-un-dispositi-
posed by participating Member States into national vo-medico-in-spagna/. Accessed 15 April 2020.
law; therefore, manufacturers must be familiar not 9. Jausás H and Colomer G, Jausas Law Firm. Medicinal
only with the relevant directive(s), but also with the product regulation and product liability in Spain: over-
view. Westlaw: Thomson Reuters Practical Law website.
relevant national law(s). Conversely, regulations are Accessed 15 April 2020.https://content.next.westlaw.
binding legislative acts applied across the EU without com/Document/Id4af42f21cb511e38578f7ccc38dcbee/
the requirement for national transposition. Current View/FullText.html?contextData=(sc.
directives for medical devices, AIMDs and IVDs have Default)&transitionType=Default&firstPage=true&bhcp=1.
been amended by regulations, with the transition period 10. DORS: Device Online Registration System Terms and
currently in effect. Conditions. MHRA website. https://aic.mhra.gov.uk/era/drsys-
tem.nsf/webvwHelp/Terms_and_conditions?opendocument.
References Accessed 15 April 2020.
1. CE Marking. European Commission website. https://ec.europa.
eu/growth/single-market/ce-marking_en. Accessed 15 April
2020.

Chapter 22

Chapter 23
Overview of Authorisation
Procedures for Medicinal
Products
OBJECTIVES 2003 amending Directive 2001/83/EC of

the European Parliament and of the Council
□ Gain an understanding of the regulatory frame- on the Community code relating to medici-
work necessary to grant a medicinal product nal products for human use
access to the EU market
□ Commission Directive 2004/33/EC of 22 March
□ Learn different procedures for compiling and 2004 implementing Directive 2002/98/EC of
submitting an EU Marketing Authorisation the European Parliament and of the Council
Application (MAA) as regards certain technical requirements for
blood and blood components
□ Learn an EU Marketing Authorisation Holder’s
(MAH) responsibilities and obligations □ Directive 2004/27/EC of the European
Parliament and of the Council of 31 March
2004 amending Directive 2001/83/EC on the
DIRECTIVES, REGULATIONS AND GUIDELINES Community code relating to medicinal products
COVERED IN THIS CHAPTER for human use
□ Council Directive 65/65/EEC of 26 January 1965 □ Directive 2004/24/EC of the European
on the approximation of provisions laid down by Parliament and the Council of 31 March 2004
law, regulation or administrative action relating amending, as regards traditional herbal medic-
to medicinal products inal products, Directive 2001/83/EC on the
□ Directive 2001/83/EC of the European for human use
2001 on the Community code relating to medici- □ Regulation (EC) No. 1901/2006 of the European
nal products for human use, as amended by: Parliament and of the Council of 12 December
2006 on medicinal products for paediatric use
o Directive 2002/98/EC of the European and amending Regulation (EEC) No. 1768/92,
Parliament and of the Council of 27 January Directive 2001/20/EC, Directive 2001/83/EC
2003 setting standards of quality and and Regulation (EC) No. 726/2004
safety for the collection, testing, process-
ing, storage and distribution of human □ Regulation (EC) No. 1394/2007 of the European
blood and blood components and amend- Parliament and of the Council of 13 November
ing Directive 2001/83/EC 2007 on advanced therapy medicinal prod-
ucts and amending Directive 2001/83/EC and
o Directive 2003/63/EC of the European Regulation (EC) No. 726/2004
Parliament and of the Council of 25 June

Chapter 23
□ Directive 2008/29/EC of the European procedures used to authorise medicinal products before
Parliament and of the Council of 11 March their introduction to the EU market.
2008 amending Directive 2001/83/EC on the The EU legal framework utilises several types of
Community code relating to medicinal products legislative instruments to establish laws and policies.
for human use, as regards the implementing Some are binding, such as regulations, directives and
powers conferred on the Commission decisions; others are nonbinding, such as guidelines,
recommendations, opinions, position papers, concept
□ Directive 2009/53/EC of the European papers, notices, communications and ICH Notes for
Parliament and of the Council of 18 June 2009 Guidance. Although the latter are not legally bind-
amending Directive 2001/83/EC and Directive ing, they usually are strongly recommended by either
2001/83/EC, as regards variations to the terms the European Medicines Agency (EMA) or Member
of MAs for medicinal products States’ competent authorities, often having considerable
political force.
□ Commission Regulation (EC) No. 1234/2008 of
• Regulations are directly enforceable, applicable
24 November 2008 concerning the examination
and binding on all Member States.
of variations to the terms of MAs for medicinal
• Directives are binding on all Member States
products for human use and veterinary medici-
but must be transposed and adopted into
nal products
national regulations within a specified time-
□ Commission Regulation (EC) No. 1084/2003 frame. They may be effective in a Member
of 3 June 2003 concerning the examination State even before that state has enacted the
of variations to the terms of MA for Medicinal corresponding national law.
Products for human use and veterinary medici- • Decisions are binding in their entirety upon
nal products granted by a competent authority those to whom they are addressed (Member
of a Member State States or legal entities, e.g., legal persons or
companies).
□ Commission Regulation (EC) No. 1085/2003 • Guidances, recommendations, opinions,
of 3 June 2003 concerning the examination positions and concept papers are issued by
of variations to the terms of MA for Medicinal the Committee for Medicinal Products for
Products for human use and veterinary medici- Human Use (CHMP), scientific advisory
nal products falling within the scope of Council groups and other EMA committees, as well
Regulation (EEC) No. 2309/93 as by the Coordination Group for Mutual
Recognition and Decentralised Procedures—
□ Regulation (EC) No. 726/2004 of the European Human (CMDh).
Parliament and of the Council of 31 March • Communications are issued by the European
2004 laying down Community procedures for Commission to explain Community law or
the authorisation and supervision of medicinal action programmes to governments and eco-
products for human and veterinary use and nomic partners.
establishing a European Medicines Agency • Notices are neither legislation nor enforceable
in law; however, they often take the form of
□ The Rules Governing Medicinal Products in the
guidelines intended to help relevant bodies or
European Union, Volume 2 (Volume 2A, 2B and
applicants meet a specific directive’s terms.
2C), Notice to Applicants (NTA)
□ ICH M4 (CTD) and M8 (eCTD) guidelines The European Commission prepared the Notice to
Applicants (NTA) in consultation with Member States’
competent authorities, EMA and interested parties
Introduction to fulfil the Commission’s obligations with respect to
In the EU, medicinal products are covered by the Regulation (EC) No. 726/2004, Article 6 and Directive
principle of the free movement of goods within the 2001/83/EC, Annex I, as amended.1
internal market. However, before being placed on the The first edition of the NTA (Volume 2 in the Rules
EU market, products must have a valid Marketing governing medicinal products in the European Union)
Authorisation (MA) granted by the appropriate com- was published in 1986. A revised and completed ver-
petent authority(ies). This chapter provides a high-level sion, the second edition, was issued in January 1989.
overview of the EU legal framework for medicinal In 1993, procedures for MAAs were amended, and
products for human use and explains the different the Centralised and Mutual Recognition Procedures

Overview of Authorisation Procedures for Medicinal Products
became applicable from 1995. A decision was made to Note: For the purpose of the chapter, premar-
separate the procedural and presentational parts of this ket authorisation information (e.g., Clinical Trial
guidance into Volumes 2A and 2B, respectively. In 2000, Applications (CTAs) and Paediatric Investigation Plan
additional specific regulatory guidelines were prepared (PIP) submissions) and accelerated regulatory routes
and became Volume 2C. The NTA now includes: intended to bring critical treatments to patients (such as
• Volume 2A—procedures for marketing PRIME, orphan drug, exceptional circumstances, adap-
authorisation tive pathways, accelerated assessment and conditional
• Volume 2B—presentation and content of the marketing authorisation) are not discussed.
dossier
• Volume 2C—regulatory guideline Marketing Authorisation Holder (MAH)
Definition
The latest NTA updates are on the European The MAH is the person who holds the authorisation to
Commission pharmaceutical unit’s website: https:// place a medicinal product on the market and is legally
ec.europa.eu/health/documents/eudralex/vol-2_en. responsible for marketing the medicinal product. The
In 2005, a new pharmaceutical regulation MAH of a centralised marketing authorisation must be
(Directive 2004/27/EC) introduced the Decentralised established within the EEA (Iceland, Liechtenstein and
Procedure, which is another option to gain an MA in the 27 Member States of the European Union). To fulfil
the EU. this requirement, the MAH must have a permanent
legal structure that is formed in accordance with the
European Medicinal Product MA System law of an EEA Member State and allows the concerned
Overview holder to assume the duties and responsibilities as well
MA as to perform the tasks laid down by Union law.3
MA Definition The UK ceased to be a contracting party to the
Before a medicine can be placed on the market, it must EEA Agreement after its withdrawal from the EU
be lawfully given an MA (product licence) by a health on 31 January 2020. This follows from the two-pillar
authority. A marketing authorisation lays down the structure and Article 126 of the EEA Agreement,
terms under which the marketing of a medicinal prod- which states that the EEA Agreement applies to the
uct is authorised in the EU. A marketing authorisation territory of the EU and the three EEA EFTA States.
is composed of: Nevertheless, during the transition period until 31
• a decision granting the marketing authorisa- December 2020, the UK will continue to be treated as
tion issued by the relevant authority an EEA member state.4
• a technical dossier with the data submitted by The MA is granted to a single MAH and includes,
the applicant in accordance with Articles 8(3) when available, the active substance(s) International
to 11 of Directive 2001/83/EC and Annex I Nonproprietary Name (INN) and, when branded, a
thereto, Articles 6(2) and 31(2) of Regulation single invented name (i.e., trade name). Companies
(EC) No. 726/2004, or Article 7 of Regulation wishing to market the same medicinal product with a
(EC) No. 1394/2007 second trade name must submit a separate MAA.
The MA initially is valid for five years and usually sub- Responsibilities and Obligations
ject to one renewal. The MAH is bound by a variety of obligations and
According to Article 24(4) to (6) of Directive responsibilities:
2001/83/EC and Article 14(4) to (6) of Regulation • considering technical and scientific progress to
(EC) No. 726/2004, any authorisation which within update manufacturing and control operations
three years of its granting is not followed by the actual • if the MAH is not the manufacturer, signing
placing on the market of the authorised product in the a written agreement with the manufacturer to
authorising Member State or on the Union market will guarantee manufacturing operations comply
cease to be valid.2 with dossier rules and conditions, informing
health authorities of any information lead-
MA Mechanisms ing to modification of the MA dossier or
This chapter covers the four EU procedures for obtain- Summary of Product Characteristics (SmPC)
ing an MA: National, Centralised, Mutual Recognition or Product Information Leaflet (PIL)
and the Decentralised Procedures. These also can be • submitting the MA renewal application at
linked. least six months before its expiration date; an
MA usually needs to be renewed only once,

Chapter 23
five years after the first MA is granted. (If not and experienced persons (i.e., experts). Experts
renewed on time, the MA will be cancelled.) must sign and add brief information on their
• paying relevant fees (MAs, renewals, variations, educational backgrounds and specific expertise
yearly fees, etc.) in a special Module 1 section.
• having a Qualified Person (QP) in charge of • Module 3 includes chemical, pharmaceutical
pharmacovigilance and a scientific service in and biological documentation.
charge of each medicinal product’s scientific • Module 4 includes the nonclinical study
information reports.
• medicinal product advertising compliance • Module 5 includes the clinical study reports.
• retaining and archiving all medicinal product
documentation; in particular, any documents MA Dossier Quality Section5
related to clinical trials The Active Substance Master File (ASMF),6 con-
• submitting samples of the product, Active taining the information regarding the drug substance
Pharmaceutical Ingredient (API) and reference consists of one applicant’s part (AP) and one restricted
product (for generic applications), upon com- part (RP), containing proprietary information. The
petent authority request ASMF closed part should be supplied directly by the
• submitting samples from each batch of bulk active substance manufacturer and arrive at the same
and/or finished product for examination by a time as the MAA submission. By using this procedure,
state laboratory or a laboratory designated to the MAH takes full responsibility for the drug sub-
review immunological medicinal products and stance’s quality and control and allows protection of the
medicinal products derived from human blood “know-how.”
or human plasma The ASMF holder may have both an ASMF and a
• informing the competent authority granting Certificate of Suitability (CEP) issued by the European
the MA of any new data affecting the medici- Directory for the Quality of Medicines (EDQM) for a
nal product’s benefit-risk balance single active substance.
• informing competent authorities of the date Note: When this chapter was written, the leg-
the product is placed on the market, sales islation did not stipulate the use of open and closed
volume (in each Member State), medicinal parts in the Vaccine Antigen Master File (VAMF) and
product presentations and marketing cessation Plasma Master File (PMF), as well as biological active
substances, creating potential hurdles in terms of shar-
Marketing Authorisation Application (MAA) ing intellectual property between manufacturers and
EU Format and Content MAHs. Different European organisations are working
An MAA comprises administrative information on the adjustment of “raw materials” used in the manu-
and medicinal product quality, safety and efficacy facture of bio-products.
information.
An MAA must be prepared and submitted in Structure7,8
Common Technical Document (CTD) format. • Module 1—Product/Administrative
The CTD was developed by the International Information
Council on Harmonisation (ICH) and introduced in Original signed Letter of Access (LoA) or
July 2003 in all three ICH regions (EU, US and Japan). Letter of Authorisation addressed to the regu-
It is a format for preparing well-structured applications, latory authority must be provided by the active
organised in five modules: Module 1 consists of coun- substance manufacturer to the MA applicant
try- or region-specific administrative data; Modules 2, authorising it to use the ASMF closed part
3, 4 and 5 are common for all regions. information for the MAA. The LoA must be
• Module 1 includes administrative, regional included in Module 1 Annex 5.10.
or national information (e.g., application • Module 2—Quality Overall Summary
form with 22 annexes, proposed summary • Module 3—3.2.S Drug Substance and 3.2.P
of product characteristics, labelling and PIL, Drug Product
pharmacovigilance system description, risk Refer to: Volume 2B - Notice to Applicants -
management plan). Medicinal products for human use (https://
• Module 2 includes high-level summaries and ec.europa.eu/health/sites/health/files/files/
overviews (overall quality summary, nonclinical eudralex/vol-2/b/update_200805/ctd_05-
overview and summary, and clinical overview 2008_en.pdf ), and Volume 6 - Notice to
and summary) prepared by suitably qualified applicants and regulatory guidelines for medicinal

products for veterinary use (https://ec.europa.eu/ submitting applications in eCTD format (e.g., in France,
health/documents/eudralex/vol-6_en) Spain, Germany, the UK and the Netherlands). It is
highly advisable to check national agencies’ guidance
When preparing product information for Centralised, documents and websites before submission. It also is
Decentralised and Mutual Recognition Procedure good practice to check the Member State contact point
applications, Module 1.3.1, using the Quality Review of list for e-submissions published on EMA’s website.
Documents (QRD) convention is mandatory. The QRD The eCTD allows applicants to file submissions
working group’s mission is to ensure clarity, consistency with competent authorities electronically throughout a
and accuracy of medicinal product information and its product’s lifecycle.
translation. The group has developed product informa- Registration documents in an electronic submis-
tion templates to provide practical advice on how to sion are organised according to ICH eCTD version
present product information. 3.2 specifications and the current EU Module 1 spec-
For the National, Decentralised and Mutual ifications. The eCTD is the submission (primarily) of
Recognition Procedures, additional data might be PDFs, stored in the eCTD directory structure, accessed
requested such as: through an internet browser (via index.xml).
• statement of MA transfer signed by both Details on eCTD submission requirements
parties (Bulgaria, Greece, Hungary, Portugal, are in Guidance for Industry on Providing Regulatory
Spain) Information in Electronic Format: eCTD electronic submis-
• statement on having a QP responsible for sions. This document assumes a basic understanding of
pharmacovigilance activities in the national eCTD applications and reflects the current e-submis-
territory where the application is made sion situation. It is updated regularly to reflect changes
(Portugal, Romania, Spain) in national and EU legislation and experience gained
• packaging size and samples declarations in the various EU submission procedures (Centralised,
(Hungary, Poland) Decentralised, Mutual Recognition and National).
• contractual technical agreement between
MAH and manufacturer(s) (Spain) Description of the Different EU MAA Procedures
Centralised Procedure
Additional data may be required by different Member Marketing authorisations granted under the Centralised
States and specified in NTA Volume 2A Chapter 7, but Procedure allow the marketing authorisation holder to
best practice is to check the competent authority web- market the medicine and make it available to patients
site or contact the competent authority via email a few and healthcare professionals throughout the EU on
months or weeks prior to submitting the MAA. the basis of a single marketing authorisation. The
Throughout the CTD, information should be Centralised Procedure was introduced in 1995 and is
unambiguous and transparent to facilitate review of the used for certain medicinal product categories described
basic data and help reviewers become oriented quickly in the annex of Regulation (EC) No. 726/2004. It is
to MAA contents. Text and tables should be prepared compulsory for medicinal products manufactured using
using margins allowing the document to be printed on biotechnological processes, orphan medicinal products,
A4 paper. The left-hand margin should be sufficiently human products containing a new active substance not
wide to avoid information being obscured by binding. authorised in the Community prior to 20 May 2004
Text and table font sizes and styles should be large (date of the regulation’s entry into force) and those
enough to be easily legible, even after photocopying. intended for the treatment of AIDS, cancer, neuro-
Times New Roman 12-point font is recommended for degenerative disorders or diabetes. The Centralised
narrative text. Procedure also is mandatory for veterinary medicinal
products intended primarily for use as performance
Electronic Common Technical Document (eCTD) enhancers to promote animal growth or to increase ani-
Format and Acceptability mal yields.
The eCTD now is the standard for submitting MAAs The Centralised Procedure is optional for other
to EMA and most EU Member States. It is mandatory products containing new active substances not autho-
for centrally authorised products. Since January 2010, rised in the Community before 20 May 2004 or those
all national competent authorities have been obliged constituting a significant therapeutic, scientific or
to accept the eCTD and/or the non-eCTD electronic technical innovation or for which a Community authori-
format (NeeS). However, acceptability of e-submissions sation is in the interest of human or animal health.
in each Member State sometimes is difficult to deter- A “new chemical, biological or radiopharmaceutical
mine. There frequently are some local requirements on active substance” is defined as:

Chapter 23
• a chemical, biological or radiopharmaceuti- members and alternate members of the Committee for
cal substance not previously authorised as a Advanced Therapies (CAT). The rapporteur and co-rap-
medicinal product in the EU porteur are supported by a team of assessors and experts
• an isomer, a mixture of isomers, a complex or (assessment team) during the various application evalu-
a derivative or salt of a chemical substance ation phases. Normally, postauthorisation activities also
previously authorised as a medicinal product are assessed by the same group of people.
in the EU, but differing in safety and efficacy If the applicant is uncertain about some issues
properties from previously authorised chemical regarding the medicinal product or has some concerns
substance about the product’s development, it may seek EMA’s
• a biological substance previously authorised as advice. Such scientific advice and protocol assistance
a medicinal product in the EU, but differing in may be requested either during a medicinal product’s
molecular structure, nature of the source mate- initial development (i.e., before submission of an MAA)
rial or manufacturing process or later, during the postauthorisation phase. Scientific
• a radiopharmaceutical substance that is a advice is subject to a fee, which varies depending on the
radionuclide or ligand not previously autho- scope of the advice; however, some fee reductions and/
rised as a medicinal product in the EU or for or waivers are available (e.g., orphan designation or pae-
which the coupling mechanism to link the diatric use).
molecule and radionuclide has not been previ- Since October 2009, EMA has accepted only
ously authorised in the EU electronic requests for scientific advice and protocol
assistance, including follow-up requests. Applicants
A fixed combination of active substances can be consid- should submit their applications only on a CD or DVD.
ered a new active substance if it has not been authorised For more administrative issues and questions,
previously as a medicinal product in the EU. the applicant may request a presubmission meeting.
The Centralised Procedure also is an option for The presubmission meeting is recommended strongly,
generic medicinal products where the reference product even for companies experienced with the Centralised
is authorised by the Community. Procedure and apparently straightforward applications.
To maintain coherence and preserve the sin- Such a meeting can facilitate MAA submission and
gle Community market, when an MAH wishes to validation significantly. To arrange such a meeting
place another medicinal product on the market with with EMA, the applicant must submit a presubmission
an active substance already subject to a Community meeting request form (available on EMA’s website). The
authorisation, the Centralised Procedure should be form requires administrative details about the applicant,
used, particularly when the new medicinal product’s the contact person and medicinal product information:
therapeutic indication is within the third level of trade name, active substance(s), INN, proposed ATC
the Anatomic, Therapeutic, Chemical Classification code, pharmaceutical form(s), strength(s), packaging
(ATC) code. However, a generic medicinal product and pack sizes, proposed indications and posology.
of a reference medicinal product authorised by the Proposed meeting dates, the proposed application
Community also may be authorised by the Member submission date, a draft summary of product informa-
States’ competent authorities in accordance with tion (SmPC, PIL, labelling) and other relevant draft
Directive 2001/83/EC and its amendments. In this documentation also must be provided. In addition, the
case, applicants have a choice between the Centralised applicant must describe areas it wishes to discuss at the
Procedure and Decentralised Procedure. Applicants are meeting (for example, if the proposed trade name is
strongly advised to notify EMA of their intended MAA acceptable, when the rapporteur(s) will be appointed,
submission date by sending the presubmission request whether the product is eligible for accelerated assess-
form (intent to submit MA) to the email address ment, whether the samples have to be submitted with
specified on EMA’s website. Submission dates must the application, what fees have to be paid, how to han-
be realistic and accurate, so the agency can have suffi- dle multiple applications, whether a risk management
cient time to appoint the rapporteur and co-rapporteur system is required, etc.). Following the meeting, the
and the assessment teams for submission evaluation. applicant must prepare minutes and send them to EMA
The deadline for the letter of intention to submit the for comments within two weeks.
MAA is seven months prior to the intended submission Centralised Procedure applications are made
date. Rapporteurs and, if required, co-rapporteurs, are directly to EMA by a person based in the Community
appointed from among CHMP members and alternate and authorised by the applicant and accompanied by a
members. For Advanced Therapy Medicinal Products fee payable under Regulation (EC) No. 297/95, with
(ATMPs), rapporteurs are appointed from among further amendments. A conventional, approved form of

the dossier (all the documents comprising the MAA) recommending an MA be granted subject to certain
is described in detail in NTA Volume 2B. As noted specific conditions and obligations, which are to be
previously, the mandatory format for the Centralised reviewed annually. The list of these obligations shall be
Procedure is the eCTD. made publicly accessible. Such authorisation shall be
The application must include proof of establish- valid for one year, on a renewable basis.
ment in the EEA as well as: In accordance with Regulation (EC) No. 726/2004
• document identifying the EEA QP respon- Article 14(8), in exceptional circumstances and follow-
sible for batch release and contact person for ing consultation with the applicant, an authorisation
product defects and product recalls may be granted subject to a requirement for the appli-
• document describing, in detail, the pharma- cant to introduce specific procedures, particularly
covigilance system, and where appropriate, concerning the product’s safety. Such authorisation
the risk management system, as required must be based on one of the grounds set out in
in Directive 2001/83/EC Article 8(ia), as Directive 2001/83/EC, Annex I Part II.6 of Annex I.
amended The authorisation’s continuation shall be linked to the
• document describing scientific service in the annual reassessment of these conditions.
EEA in charge of information about the Following positive CHMP scientific evalua-
medicinal product tion, the European Commission drafts a decision
• document identifying the pharmacovigilance on a Community MA. An MA granted under the
QP in the EEA Centralised Procedure is valid for the entire EU market;
the medicinal product may be put on the market in all
Once the application is validated (administratively and Member States. The European Free Trade Association
technically) positively, the applicant is informed in writ- (EFTA) states—Iceland, Liechtenstein and Norway—
ing and given the names of CHMP members to whom through the EEA agreement, have adopted a complete
full or partial copies of the dossier should be sent for Community acquis (EU laws and objectives) on
review. Negative validation outcome notification also medicinal products and consequently are parties to the
is provided in written format to the applicant and may Centralised Procedure, although they still issue national
result from failure to provide the data, information or MAs following the procedure’s successful completion.
clarifications requested or to adhere to the EU CTD With the positive CHMP opinion, and in accor-
format. dance with Regulation (EC) No. 726/2004 Article 13,
Once positively validated and provided, the rappor- EMA shall publish the CHMP assessment report on
teur and co-rapporteur confirm they have received the the medicinal product, which includes the reasons for
dossier. its favourable opinion, after deleting any confidential
For medicinal products of major interest, partic- information. This document is called the European
ularly from a therapeutic innovation viewpoint, the Public Assessment Report (EPAR). If the opinion is
applicant may request an accelerated assessment proce- negative, a summary of the negative opinion is pub-
dure in accordance with Regulation (EC) No. 726/2004 lished at Day 0 (i.e., the day the negative opinion is
Article 14(9). If CHMP accepts the request, the MAA adopted). If a company withdraws its application, this
review timeline is reduced to 150 days. fact also will be published.
The three main possible MAA outcomes are: Once the MA is granted, it can be subject to:
• negative/unfavourable CHMP opinion • Specific obligations (when the conditional
• conditional opinion (conditional MA or MA MA or MA under exceptional circumstances is
under exceptional circumstances) granted)—in this case, the applicant is obliged
• positive opinion to submit additional data (postauthorisation
data) known as “specific obligations” set out in
EMA starts the procedure according to the schedule Annex IIC of the Commission Decision.
published on its website. The standard MAA evaluation • Follow-Up Measures (FUMs)—whether for
timetable is presented in Table 23-1. conditional approval or under exceptional cir-
For centralised applications, CHMP must deliver cumstances—FUMs can be requested by the
its opinion within 210 days. An unfavourable opinion is initial CHMP opinion or in addition to the
given when CHMP does not believe the MAA fulfils CHMP assessment of any submitted addi-
Regulation (EC) No. 726/2004’s authorisation criteria. tional data/applications.
A conditional MA is granted in accordance • Variations (all MAs)—variations may be
with Regulation (EC) No. 726/2004 Article 14(7). required as a result of FUMs or specific obli-
Under this regulation, CHMP may adopt an opinion gations when these data would require changes

Chapter 23
Table 23-1. Standard Timetable for Evaluation of a Centralised Application
Day Action
1 Start of the procedure.
80 Receipt of the Assessment Report(s) or critique from rapporteur and co-rapporteur by CHMP members (including
peer reviewers) and EMA. EMA sends rapporteur and co-rapporteur Assessment Reports/critiques to the applicant,
making it clear this sets out only preliminary conclusions, is sent for information only and does not yet present CHMP’s
position.
100 Rapporteur, co-rapporteur, other CHMP members and EMA receive comments from CHMP members (including peer
reviewers).
115 Receipt of draft list of questions (including the CHMP recommendation and scientific discussion) from rapporteur and
co-rapporteur by CHMP members and EMA.
120 CHMP adopts the list of questions, as well as the overall conclusions and review of the scientific data to be sent to the
applicant by EMA.
Clock stop. By Day 120 at the latest, adoption by CHMP of request by GMP/GCP/GLP inspection, if necessary
(inspection procedure starts).
121* Submission of responses, including revised SmPC, labelling and PIL texts, and clock restart.
Evaluation of Responses
Day Action
150 Joint Assessment Report from rapporteur and co-rapporteur received by CHMP members and EMA. EMA sends report to
the applicant, making it clear it sets out only preliminary, is sent for information only and does not represent CHMP’s
position. Where applicable, inspection is conducted.
EMA/QRD subgroup meeting to review English product information with participation of the applicant (optional)
around Day 165.
170 Deadline for comments from CHMP members to be sent to rapporteur and co-rapporteur, EMA and other CHMP
members.
180 CHMP discussion and decision on the need for adopting a list of “outstanding issues” and/or an oral explanation by
the applicant. If an oral explanation is needed, the clock is stopped to allow the applicant to prepare it. Submission of
final inspection report to EMA, rapporteur and co-rapporteur by the inspections team (at the latest by Day 180).
181 Clock restart and oral explanation (if needed).
181 to 210 Final draft of English SmPC, labelling and package leaflet sent by applicant to the rapporteur and co-rapporteur, EMA
and other CHMP members.
By 210 Adoption of CHMP opinion and CHMP Assessment Report.
Adoption of a timetable for the provision of revised product information translations.
Preparation of Commission Decision Annexes
Day Action
215 at the Applicant provides EMA with SmPC, Annex II, labelling and package leaflet and Annex A in all EU languages. EMA
latest circulates draft translations to Member States for review.
232 at the Applicant provides EMA with final translations of SmPC, Annex II, labelling and package leaflet in all EU languages by
latest Day 229, taking comments received from Member States into account.
By 237 Transmission of opinion and annexes in all EU languages to applicant, European Commission, members of the standing
committee, and Norway, Iceland and Liechtenstein.
By 246 Applicant provides EMA with one final, full-colour “worst-case” mock-up of outer and inner packaging for each
pharmaceutical form.
IMPORTANT NOTE:
Once the medicinal product is authorised, and in all cases before the medicinal product is placed on the market, specimens of
the final outer and immediate packaging and the package leaflet for all product presentations must be submitted to EMA within a
timeframe agreed between the agency and the MAH.
*Target dates for the submission of the responses are published on the EMA website—Presubmission Guidance Source: NTA Volume 2A, Chapter 4.

to the product information or the MA (e.g., • generic products (also generic versions of prod-
changes to quality module). ucts authorised by the Centralised Procedure
before November 2005, with the exception of
The MAH must indicate realistic target dates for those biotechnology-derived)
submitting postauthorisation data in its letter of under- • “abridged” applications, “well-established use”
taking. If no documents are submitted or if obligations or line extensions of old Mutual Recognition
are not fulfilled, in accordance with Regulation (EC) Procedures
No. 726/2004 Article 14(7) and 14(8), CHMP will
formulate an opinion recommending MA “variation/ As mentioned above, the Mutual Recognition
suspension/revocation.” Procedure can be used for standalone and abridged
An MA issued under the Centralised Procedure is applications, provided the application is legally valid
valid throughout the Community under the same trade and meets the requirements of Directive 2001/83/
name in all Member States. Medicinal products autho- EC Article 28(2). Once the procedure has been used,
rised through the Centralised Procedure benefit from the all variations, changes and line extensions (includ-
10-year period of protection in Directive 2001/83/EC ing changes falling under the scope of Commission
Article 10(1), as amended. Protection can be extended Regulation (EC) No. 1234/2008 Annex I and II)
to a maximum of 11 years if, during the first eight years, to these medicinal products must use the Mutual
the MAH obtains an authorisation for one or more new Recognition Procedure. The procedure also is appli-
therapeutic indications that provides a significant clinical cable for line extensions of existing national MAs
benefit in comparison to existing therapies. under certain conditions mentioned in Commission
In accordance with Article (4), the MAH shall Communication 98/C229/03.
inform EMA of the dates of putting the new prod- The Mutual Recognition Procedure, in many
uct (including every presentation) on every Member respects, is similar to the National Procedure, where
State market. Any authorisation not followed by actual a Member State’s competent authority authorises the
marketing in the Community within three years after medicinal product. National procedures differ sig-
authorisation becomes invalid. Similarly, when a prod- nificantly across Member States and depend on the
uct previously marketed in the Community ceases to competent authority’s experience in clinical, regulatory
be present on the market for three consecutive years, and marketing issues. Those factors must be considered
its MA becomes invalid (sunset clause). In certain cir- when selecting the Reference Member State. In theory,
cumstances, however, EMA may grant exemptions from the National Procedure for an MA takes no longer than
these provisions on duly justified public health grounds. 210 days. The reality is a number of factors can lead to
substantial delays.
Mutual Recognition Procedure For a medicinal product with a well-established use
The Mutual Recognition Procedure is to be used in demonstrated in accordance with Directive 2001/83/
order to obtain marketing authorisations in several EC Article 10(a) (bibliographic application), the
Member States where the medicinal product in ques- Mutual Recognition Procedure is applicable. But,
tion has received a marketing authorisation in any when the well-established use is based on data from an
Member State at the time of application. The procedure existing group of products for which no Community
to be followed will depend upon whether the mutual authorisation exists, the applicant has the option to
recognition was triggered by a Member State or initi- follow independent national procedures stated in
ated by the marketing authorisation holder. Commission Communication 98/C229/03.
The legislation allows the Mutual Recognition To fulfil the identical product dossier criteria prior
Procedure to be used only when there is an MA granted to a Mutual Recognition Procedure, the applicant must
already in at least one Member State. If there is no MA harmonise the already approved national SmPCs. This
in any EU Member State, the Decentralised Procedure a priori harmonisation can be achieved through coor-
should be used (or the Centralised Procedure, if its dinated national variation procedures or through the
requirements are met). procedure foreseen in Directive 2001/83/EC Article 30.
The Mutual Recognition Procedure must be used The Mutual Recognition Procedure is regarded as
for the following products: a two-stage process: a national approval process, fol-
• medicinal products containing new active lowed by the mutual recognition process. If the second
substances outside the centralised therapeutic stage fails (due to one or more Member States’ refusal
areas to recognise the first approval), there may be a third
• over-the-counter (OTC) products stage—arbitration (see Community referral below).
• homeopathic medicinal products

Chapter 23
The first Mutual Recognition Procedure phase is use procedure can be applied after completing either
Reference Member State authorisation of the medicinal the Mutual Recognition Procedure or Decentralised
product. Procedure, and is applicable in the following situations:
The second Mutual Recognition Procedure phase • when the application is submitted to a new
follows clear rules and a strict timeline. The procedure Concerned Member State that was not
starts with the assessment report’s preparation or update involved in the first Mutual Recognition or
by the Reference Member State, which takes 90 days. Decentralised Procedure
Once the assessment report is ready and sent to the • when the application is resubmitted to a
Concerned Member State(s) with the SmPC, PIL Concerned Member State where it was
and labelling, the applicant sends the dossier to the withdrawn during the first procedure (“reap-
Concerned Member States, and the validation period plication”) (The repeat-use procedure(s) can be
begins. Usually, the validation period is 14 days, but, in employed until all Member States get involved
reality, it may take 30 days. With positive validation, in the procedure. Before starting the proce-
the procedure starts at Day 0. The first Concerned dure, the applicant should finalise all ongoing
Member State comments are sent on Day 50, and the procedures (variations, renewals, updating
applicant has 10 days to respond (Day 60). Within the SmPCs, etc.) and update the dossier. The next
next eight days, the Reference Member State prepares step is submitting the updated dossier to the
the assessment report on responses and circulates it Reference Member State and formally request-
among interested parties (Day 68). Concerned Member ing an assessment report update. For more
States have until Day 75 to submit their comments details, see procedural advice on repeat use.)9
on the assessment report. If a potential serious risk is
identified, a break-out session may be arranged, usually To coordinate and facilitate Mutual Recognition
around Day 75 (between Day 73 and Day 80). The Procedure operations, a Mutual Recognition
break-out session’s aim is to create a discussion plat- Facilitation Group (MRFG) was established in 1995.
form for the Reference Member State, the Concerned The MRFG meets monthly and comprises senior rep-
Member State(s) and, if necessary, the applicant, to clar- resentatives from each Member State. Under Directive
ify outstanding issues and achieve consensus through 2004/27/EC, the MRFG was renamed the CMDh. It
negotiations. Additional comments (if any) may be sent is chaired by one member for three years, who may be
by Concerned Member States until Day 85. If consen- re-elected once. The vice chair shall be appointed from
sus is reached, the Concerned Member States notify the the coordination group members by the Member State
Reference Member State and applicant of their final holding the EU Council presidency for the duration
positions, and the Reference Member State closes the of the presidency’s term. The secretariat for this group
procedure. If consensus is not reached, the Reference is provided by EMA. CMDh meets monthly at EMA
Member State refers Concerned Member States’ points and can be joined by observers from the European
of disagreement to CMDh within seven days after Day Commission and EMA. When necessary, in connection
90. If consensus is reached at the CMDh level, the with the plenary meeting, breakout sessions related to
Reference Member State closes the procedure at Day ongoing procedures may be held. Additional subgroup
150. If consensus is not reached at the CMDh level, the meetings are organised on specific topics.
Reference Member State refers the matter to CHMP The group provides a forum for discussing pro-
for arbitration. cedural issues arising from Mutual Recognition and
Five days after the procedure is finalised, the Decentralised Procedures and resolving problems. It
applicant must submit high-quality SmPC, PIL and can provide an overview of individual applications;
labelling translations to the Reference Member State however, scientific discussions related to individual
and Concerned Member State(s). In accordance with applications are handled in breakout sessions organised
Directive 2001/83/EC Article 28(5), the Concerned and chaired by the specific Reference Member State.
Member State(s) shall adopt a decision in confor- CMDh considers points of disagreement raised by a
mity with the approved assessment report and grant a Member State related to a medicinal product’s assess-
national MA within 30 days after acknowledgment of ment report, SmPC, labelling and PIL on the grounds
the procedure. In reality, it might take a few months, of “potential serious risk to public health” within
depending on the national competent authority. Mutual Recognition and Decentralised Procedures,
The Mutual Recognition Procedure flowchart and facilitates the dialogue among Member States. On
(Table 23-2) can be used more than once for subse- an annual basis, CMDh prepares a list of products to
quent applications to other Member States for the same be harmonised among all Member States. Further, this
medicinal product (“repeat use procedure”). The repeat group identifies issues to be referred to the European

Table 23-2. Mutual Recognition Procedure Flowchart
Approximately Applicant Requests RMS to Update Assessment Report and Assign Procedure Number
90 Days Before
Submission to
CMS
Day 14 Applicant submits the dossier to Concerned Member States; Reference Member State circulates the assessment
report, including SmPC, PIL and labelling to Concerned Member States. Application validation in the Concerned
Member States.
Day 0 Reference Member State starts the procedure.
Day 50 Concerned Member States send their comments to the Reference Member States and applicant.
Day 60 Applicant sends the response document to Concerned Member States and Reference Member State.
Until Day 68 Reference Member State circulates its assessment of the response document to the Concerned Member States.
Day 75 Concerned Member States send their remaining comments to the Reference Member State and applicant. A break-
out session can be organised between Days 73- 80.
Day 85 Concerned Member States send any remaining comments to the Reference Member State and applicant.
Day 90 Concerned Member States notify the Reference Member State and applicant of their final positions (in case of
negative positions, also EMA’s CMD secretariat); if consensus is reached, the Reference Member State closes
the procedure. If consensus is not reached, points of disagreement submitted by Concerned Member States are
referred to CMDh by the Reference Member State within seven days after Day 90.
Day 150 For procedures referred to CMDh, if consensus is reached at the CMDh level, the Reference Member State closes the
procedure. If consensus is not reached at the CMDh level, the Reference Member State refers the matter to CHMP
for arbitration.
5 Days After Applicant sends high-quality national translations of SmPC, PIL and labelling to Concerned Member States and the
Procedure Reference Member State.
Closes
30 Days After National MAs are granted in the Concerned Member States, subject to submission of acceptable translations.
Procedure
Closes
Source: NTA Volume 2A, Chapter 2, February 2007; CMDh Flowchart on MRP (May 2007).
Commission, Pharmaceutical Committee, Heads of health issues still are raised by one or more of the par-
Medicines Agencies (HMA) or other regulatory bodies; ticipating Member States at the end of the procedure,
works closely with the CHMP’s Pharmacovigilance and despite a withdrawal of the dossier in Concerned
Working Party (PhVWP) to ensure best risk manage- Member States, automatic arbitration by EMA and the
ment practice for medicinal products authorised via European Commission is applicable to both the Mutual
Mutual recognition and Decentralised Procedures; and Recognition and Decentralised Procedures.
creates its own rules of procedure to be endorsed by the The Decentralised Procedure is used for medicinal
HMA and approved by the European Commission. products for which there is no existing MA in any EU
More information on the Mutual Recognition Member State. In accordance with Directive 2001/83/
Procedure can be found in Directive 2001/83/ EC Article 17(2), as amended, the MA for the same
EC, as amended, NTA Volume 2A, Chapter 2 and medicinal product cannot be granted in parallel in two
the HMA/CMDh website (https://ec.europa.eu/ or more Member States by separate national proce-
health/sites/health/files/files/eudralex/vol-2/a/ dures. In such cases, the Decentralised Procedure must
vol2a_chap2_2007-02_en.pdf ). be followed. The Decentralised Procedure covers all
medicinal products not authorised in the EU (for which
Decentralised Procedure the Centralised Procedure is not mandatory). As in the
The Decentralised Procedure was established by Mutual Recognition Procedure, the applicant can select
Directive 2001/83/EC and has been in force since the Reference Member State and list the Concerned
November 2005. Member States. To do so, the applicant has to request
The CMDh group has the same competencies one Member State to act as the Reference Member
for both the Mutual Recognition and Decentralised State for the particular product by filing the common
Procedures. In addition, in cases where serious public request form (the most current version of this document

Chapter 23
can be found on the HMA/CMDh website). Once the steps. Assessment Step I corresponds to the Day 120
Reference Member State agrees, the intended submis- period in which the Draft Assessment Report (DAR) is
sion date is scheduled, and a Decentralised Procedure prepared, followed by draft SmPC, labelling and PIL.
number is assigned. Prior to the submission, the appli- During Assessment Step I, the Reference Member
cant may request a presubmission meeting to familiarise State prepares the Preliminary Assessment Report
the national competent authority with the product and (PrAR) and circulates it to the applicant and Concerned
submission details. Usually, the presubmission meeting Member States. By Day 100, Concerned Member
is held three months before the intended submission States should communicate their comments to the
date. The applicant is encouraged to discuss the neces- Reference Member State, other Concerned Member
sity of conducting a presubmission meeting with the States and the applicant. Between Day 100 and 105, the
Reference Member State. Reference Member State consults with the Concerned
On the agreed date, the applicant submits the Member States on the comments submitted.
dossier simultaneously to the Reference Member State If consensus is reached and the product is approv-
and Concerned Member States (Day 14), and the val- able, but there are relatively easy comments to be
idation period begins. In theory, it is scheduled for 14 resolved, the Reference Member State stops the clock
days, but in practice, can last much longer (sometimes and forwards these comments to the applicant on Day
more than 30 days). The validation period depends on 105. After receiving sufficient responses from the appli-
each Concerned Member States’ national requirements cant, the Reference Member State updates the PrAR,
and the applicant’s ability to meet those requirements creates the Final Assessment Report (FAR) and fina-
on time. As soon as the dossier is submitted, the lises the procedure on Day 120, followed by national
Reference Member State initiates the procedure in the phases in each Member State.
Communication and Tracking System (CTS) data- If consensus is not reached, the Reference Member
base, so the Concerned Member States and Reference State stops the clock at Day 105 and asks the applicant
Member State can communicate about the procedure to answer all remaining issues within a specified time-
through the CTS. Concerned Member States are frame. Usually, the clock stop is scheduled for three
obliged to update the CTS database daily to inform the months, but its duration can be mutually agreed between
Reference Member State of the application’s validation the Reference Member State and the applicant (it can be
status. The most common reasons for nonvalidation are: shortened or lengthened in justified cases). The applicant
• lack of original, signed documents (e.g., LoA may submit draft responses, including updated SmPC,
for a person responsible for communication PIL and labelling proposals, to the Reference Member
during and after the procedure (Annex 5.4), State for pre-assessment. In any case, the applicant
Manufacturer’s Commitment (Annex 5.11)) should reach agreement on the final response submission
• improperly written GMP compliance state- date with the Reference Member State.
ment (Annex 5.22) After the final response is submitted and the list
• lack of some nationally required documents of each Concerned Member State’s dispatch dates
(application form not translated into national are received, the Reference Member State restarts the
language (Spain, Greece), technical agreements procedure at Day 106. Between Day 106 and 120, the
between the applicant and manufacturer(s), Reference Member State updates the PrAR to prepare
declaration on pack sizes and samples, etc.) the DAR and draft product information (SmPC, label-
• application form mistakes ling, PIL). The DAR and draft informative texts are
• wrong dossier format (e.g., the dossier is not in sent to the applicant and Concerned Member States.
the eCTD or NeeS format) On Day 120, Assessment Step II is initiated, and the
• technical issues related to the eCTD (wrong Reference Member State starts the 90-day period, cor-
PDF files, improperly named folders, too many responding to Day 0 of the 90-day period mentioned in
CDs, broken CDs/DVDs, etc.) Directive 2001/83/EC Section 28(4). Each Concerned
• lack of a paper version of administrative doc- Member State should send its final comments on the
uments while submitting an eCTD in some DAR no later than Day 145 of the procedure (i.e.,
Member States Day 25 of the 90-day period). If consensus is reached,
the Reference Member State prepares the FAR and
The applicant must respond to deficiencies daily to have may close the procedure at Day 150 (i.e., Day 30 of
the submission validated positively by the Reference the 90-day period). The procedure continues with the
Member State and Concerned Member States. Once national step if the Member States consider the product
this goal is achieved, the procedure is started, and Day 0 approvable. Between Day 145 and 150, the Reference
is assigned. The Decentralised Procedure consists of two Member State consults with the Concerned Member

States to discuss the comments submitted. If consen- National Authorisations

sus is not reached by Day 150, the Reference Member Each EU Member State’s competent authority is
State informs the applicant of outstanding issues. The responsible for granting MAs for medicinal products
applicant must submit additional clarification by Day placed on its market, except medicinal products autho-
160, including any revised proposal for the SmPC, PIL rised using Community procedures. Since January 1998,
and labelling, and the Reference Member State pre- independent national procedures have been limited
pares a short report and forwards it to the Concerned strictly to the initial phase of mutual recognition and to
Member States no later than Day 180 (i.e., Day 60 of medicinal products not to be authorised in more than
the 90-day period). This is called a Short Report or Day one Member State. Under the legislation, independent
180-Report and includes the Reference Member State’s national procedures are restricted to medicinal products
proposals for an update of the overview portion of the authorised in only one Member State.
DAR to derive the FAR. Independent national procedures can continue to
At the latest, at Day 205 (i.e., Day 85 of the 90-day be followed for medicinal products with a well-estab-
period), a breakout session may be held at EMA with lished use demonstrated in accordance with Directive
the involved Member States to reach consensus on 2001/83/EC Article 10(a), as amended, and based on
major outstanding issues. data referring to an existing group of products with
At Day 210 (i.e., Day 90 of the 90-day period), different SmPCs in the Member States, as long as no
the Reference Member State closes the procedure if Community harmonisation exists on the use of said
consensus was reached with all Member States on product’s constituent(s). They also can be used for line
the outstanding issues. The Reference Member State extensions of authorised medicinal products as long as
includes information in the FAR about how major out- no a priori harmonisation has been achieved.
standing issues were resolved by discussions via written
procedures and by discussion in the CMDh (if applica- Different Types of Applications and Legal
ble). Together with the FAR, which includes the final Basis for the Submission
product release and shelf life specifications, the final
Complete/Full and Independent Applications
informative texts are attached. Any conditions to be
fulfilled or any recommended FUMs are specified in an In accordance with Directive 2001/83/EC Article
End-of-Procedure letter, also attached to the FAR. 8(3), as amended, a full (standalone) MAA must
Once the procedure is finalised, the applicant must include results of:
submit high-quality national translations of the SmPC, • pharmaceutical (physicochemical, biological or
PIL and labelling to the Reference Member State and microbiological) tests
Concerned Member States within five days. For the • preclinical (pharmacological and toxicological)
Decentralised Procedure flowchart, see Table 23-3. tests
Applicants can multiply or duplicate their applica- • clinical trials
tions via either the Mutual Recognition Procedure or
Decentralised Procedure, but there is no definition of a This type of application is compulsory for new chemical
“duplicate” in the pharmaceutical legislation. It can be entities (new active substances).
done at the beginning of the procedure, during the pro-
cedure (i.e., Day 106 in the Decentralised Procedure) Generic Applications for Essentially Similar
or after the procedure is finalised. The possibility of Medicinal Products (Abridged Applications)
duplicating the application should be discussed and Under Directive 2001/83/EC Article 10(1) and Part
agreed with the Reference Member State. In general, a II(2), as amended, the applicant is not required to pro-
duplicate application is defined by the reference to the vide pharmacological and toxicological test or clinical
first MA as follows: trial results when the medicinal product is essentially
• same dossier (copy of Modules 1, 2, 3, 4 and 5) similar to a product authorised in the EU under the
• same legal basis according to Directive previous legislation for not less than six or 10 years
2001/83/EC, as amended (depending on the Member State) and is marketed
• different trade name in that Member State at the time of the application
• same or different applicant/MAH (generic application). The legislation harmonises the
timeframes to an eight-year data protection period
Applications for duplicates result in independent MAs (submission) and a 10-year period of marketing protec-
varied individually. However, MAHs are strongly tion (approval).
encouraged to keep the SmPC, PIL and labelling of the This period can be extended to 11 years if, during
duplicates harmonised whenever possible.10 the first eight years, the MAH obtains an authorisation

Chapter 23
Table 23-3. Decentralised Procedure Flowchart
Pre-Procedural Step
Before Day 14 Applicant discussion with the Reference Member State. Reference Member State allocates procedure
number; creation in CTS
Day 14 Dossier submission to the Reference Member State and Concerned Member States; application validation
Assessment Step I
Day 0 Reference Member State starts the procedure
Day 70 Reference Member State forwards the Preliminary Assessment Report (PrAR), SmPC, PIL and labelling to
Concerned Member States and the applicant
Until Day 100 CMS send their comments to RMS and applicant.
Until Day 105 Consultation between the Reference Member State, Concerned Member States and applicant; if consensus
is not reached, the Reference Member State stops the clock to allow the applicant to supplement the dossier
and respond to questions
Clock-Stop Period Applicant may send draft responses to the Reference Member State and agree to final response
submission date with the Reference Member State; applicant sends the final response document to the
Reference Member State and Concerned Member States within a recommended three-month period,
which could be extended, if justified
Day 106 Valid applicant response submission received; Reference Member State restarts the procedure
Day 106-120 The Reference Member State updates the PrAR to prepare the Draft Assessment Report (DAR), draft SmPC,
draft labelling and draft PIL for Concerned Member States and the applicant
Day 120 The Reference Member State may close the procedure if consensus is reached and proceed to the national
30-day step for granting MA
Assessment Step II
Day 120 (Day 0) If consensus is not reached, the Reference Member State sends the DAR, draft SmPC, draft labelling and
draft PIL to the Concerned Member States and applicant
Day 145 (Day 25) The Concerned Member States send final comments to the Reference Member State and applicant
Day 150 (Day 30) The Reference Member State may close the procedure if consensus is reached and proceed to the
national 30-day step for granting the MA
Until 180 (Day 60) If consensus is not reached by Day 150, the Reference Member State communicates outstanding
issues with applicant, receives any additional clarification and prepares a short report (Day 180
Report) for discussion by the coordination group
Until Day 205 (Day 85) Break-out group of involved Member States reaches consensus on the matter (if applicable)
Day 210 (Day 90) Procedure closure including Concerned Member States’ approval of the Assessment Report, SmPC,
labelling and PIL, or referral to coordination group; proceed to national 30-day step for granting the MA
Day 210 (at the latest) If consensus was not reached at Day 210, points of disagreement will be referred to the coordination
group for resolution
Day 270 (at the latest) Final position adopted by coordination group with referral to CHMP for arbitration in case of unsolved
disagreement
National Step
5 days after close of Applicant sends high-quality national translations of SmPC, labelling and PIL to CMSs and RMS
procedure
30 days after close of National marketing authorisation granted in Reference Member State and Concerned Member States if
the procedure outcome is positive and there is no referral to the Co-ordination group. (National agencies will adopt the
decision and will issue the marketing authorisation subject to submission of acceptable translations.)
30 days after close National marketing authorisation granted in Reference Member State and Concerned Member States if
of CMD referral positive conclusion by the coordination group and no referral to the CHMP/CVMP. (National agencies
procedure will adopt the decision and will issue the marketing authorisation subject to submission of acceptable
translations.)
Source: Decentralised Procedure—Member States’ Standard Operating Procedure (MRFG, October 2005) and Best Practice Guide for Decentralised and
Mutual Recognition (CMDh, Rev. 6 May 2007).

for one or more new therapeutic indications bringing a dossier (abridged applications may not refer to an
significant clinical benefit in comparison with existing abridged dossier). The original product dossier must be
therapies. The new protection periods (8–2–1) do not at the disposal of the regulatory authorities.
apply to reference medicinal products for which the
initial application for authorisation (date of application Hybrid Applications
submission, not validation) was submitted before 20 Hybrid applications under Article 10(3) of Directive
November 2005.11 For those products, the exclusivity 2001/83/EC differ from generic applications in that the
period under the previous legislation applies: results of appropriate preclinical tests and clinical trials
• 10 years for all medicinal products authorised will be necessary in the following three circumstances:
through the Centralised Procedure • where the strict definition of a ‘generic medici-
• 10 years for all other medicinal products original product’ is not met
nally authorised in Belgium, Germany, France, • where the bioavailability studies cannot be
Italy, Netherlands, Sweden, the UK and used to demonstrate bioequivalence
Luxembourg • where there are changes in the active sub-
• 10 years for all medicinal products authorised stance(s), therapeutic indications, strength,
following a CHMP opinion in accordance pharmaceutical form or route of administration
with Article 4 of Directive 87/22/EEC of the generic product compared to the refer-
(ex-concertation procedure) ence medicinal product
• six years in all other Member States, plus
Norway and Iceland In such cases, the results of tests and trials must be
consistent with the data content standards required in
A generic authorisation may be issued for all therapeu- the Annex to the Directive 2001/83/EC as amended
tic indications and all pharmaceutical forms, strengths by Directive 2003/63/EC. These applications will thus
and posology already authorised for the reference drug. rely in part on the results of preclinical tests and clinical
A generic authorisation may be extended to cover more trials for a reference product and in part on new data.
or other indications, strengths and pharmaceutical
forms than the original product if the applicant submits Bibliographic Applications (Well-Established Use)
sufficient bridging data. According to Directive 2001/83/EC Article 10(a),
The European Court of Justice, in its judgment in as amended, and Annex I, Part II(1), it is possible to
Case C-368/96 (Medicinal products—MA—Abridged replace pharmacological and toxicological tests or clin-
procedures—Essentially similar products), confirmed if ical trial results with detailed references to published
the four conditions listed above are fulfilled, a generic scientific literature if a medicinal product’s constituent(s)
authorisation may be issued for all therapeutic indica- has a well-established medicinal use, recognised efficacy
tions, dosage forms, doses and dosage schedules already and an acceptable safety level. The definition of a bib-
authorised for the reference drug, even if some of those liographic application includes specific criteria associated
indications, dosage forms and doses were authorised for with the time period over which the use has been estab-
a period shorter than six or 10 years (old legislation). In lished, quantitative aspects of use and scientific interest
accordance with Directive 2001/83/EC Article 10.2(b), in the substance’s medicinal use. Therefore, different
as amended, different salts, esters, ethers, isomers, mix- time periods may be necessary to verify well-established
tures of isomers, complexes or derivatives of an active use of different substances. In any case, the time period
substance shall be considered to be the same active required to establish a well-established use of a medici-
substance unless they differ significantly in properties nal product constituent must not be less than one decade
with regard to safety and/or efficacy. In such cases, from that substance’s first systematic and documented
additional information providing proof of the safety use as a medicinal product in the EU. This applies to any
and/or efficacy of the various salts, esters or derivatives medicinal product or chemical or biological substance
of an authorised active substance must be supplied by for which there is no original/reference medicinal prod-
the applicant. The various immediate-release oral phar- uct to which essential similarity can be claimed. This is
maceutical forms (i.e., tablets and capsules) shall be the case, for instance, for “old” medicinal products whose
considered to be one and the same pharmaceutical form use is well-established in the medicinal practice, and for
for the concept of essential similarity. known indications, strengths and pharmaceutical forms,
For biotechnology products, the concept of essen- in view of the period of time over which they have been
tial similarity is difficult to apply. Generic and informed used and the information that has been publicly avail-
consent applications (see below) are linked to the orig- able about their safety and efficacy.
inal authorisation granted on the basis of a complete

Chapter 23
“Well-established use” refers to a specific therapeu- and/or 5. All other module(s) are in accordance with
tic use. If well-known substances are used for entirely the structure described in Annex 1 Part I.
new therapeutic indications for which the Directive The competent authority will accept the applicant’s
2003/63/EC Annex I requirements cannot be fulfilled, proposed format on a case-by-case basis.
it is not possible to solely refer to a well-established use.
Additional data on the new therapeutic indication should Herbal Medicinal Products
be provided together with appropriate safety data. Regulation (EC) No. 726/2004 established the
Such assessment reports as the EPAR for Committee on Herbal Medicinal Products (HMPC). In
Community MAs, made publicly available by com- addition, Directive 2004/24/EC was introduced as part
petent authorities for reasons of transparency, do of the legislation amending Directive 2001/83/EC on
not supply sufficient information to meet Directive the Community code relating to medicinal products for
2001/83/EC Annex requirements. human use with regard to traditional herbal medicinal
products. It created a simplified registration procedure
Fixed-Combination Application (“traditional-use registration”) for herbal medicinal
In accordance with Directive 2001/83/EC Article products that fulfil certain criteria.12
10(b), as amended, and Annex I, Part II(5), fixed-com-
bination applications are possible for medicinal Referrals
products containing active substances used in the com- European Community Referrals
position of authorised medicinal products (but not to be EU pharmaceutical legislation has created a binding
used in combination for therapeutic purposes). In that Community arbitration mechanism to achieve coop-
case, the results of new preclinical tests or new clinical eration among Member States as needed. However, EU
trials relating to that combination shall be provided in legislation recognises the need for urgent, unilateral mea-
accordance with Article 8(3)(i), but it is not necessary to sures by Member States when necessary to protect the
provide scientific references relating to each individual public health and until a definitive action is adopted.
active substance. In these specific cases, Member States may take tempo-
Moreover, any fixed combination may be consid- rary national measures suspending a medicinal product’s
ered a complete/full, independent application because marketing and use. They must inform the European
it is a new and unique medicinal product requiring a Commission, EMA and other Member States no later
separate SmPC. than the next working day. The decision following a
referral is applicable only to the specific medicinal
Informed Consent Applications products that have been subject to the referral procedure
Under Directive 2001/83/EC Article 10(c), as and to the Member States involved in the procedure.
amended, these applications are appropriate in cases
when the medicinal product is essentially similar to a Follow-Up Referral
product already authorised in the Member State and This referral may be started by an MAH or Member
the original product’s MAH has given the second appli- State, under Directive 2001/83/EC Articles 35, 26 and
cant rights to refer to its approved dossier. 27, where an MA already has undergone a Community
For regulatory authorities, demonstration of procedure. A follow-up referral is initiated when a
informed consent is a formal prerequisite when the change or variation, suspension or withdrawal of a har-
application is submitted. However, withdrawing the monised MA is necessary to protect the public health, or
informed consent at a later stage has no direct conse- when mutual recognition by one or more national reg-
quences for the MA’s existence or validity. ulatory authorities of the Reference Member State draft
decision on a variation is not possible. This mechanism
Mixed Marketing Applications aims to resolve divergences among Member States after
Directive 2001/83/EC Annex I, Part II(7) specifies harmonisation is achieved.
mixed MAAs must present published scientific liter- CHMP issues a reasoned opinion within 60 days
ature together with original results of tests and trials. of the referral date. This period may be extended by
Such applications must be submitted and processed another 90 days. A binding decision from the European
following the complete, full and independent MA dos- Commission follows.
sier requirements. These requirements apply to the use
of bibliographic references in mixed dossiers both as
supporting data for the applicant’s own tests and trials,
or in order to replace any tests or trials in Module 4

Mutual Recognition and Decentralised Procedure in many cases, are strongly recommended by either
Referral EMA or Member States’ competent authorities.
Under Directive 2001/83/EC Articles 29, 32 and MAAs can be granted following the Centralised,
33, as amended, referral to CMDh may be initiated Decentralised or Mutual Recognition Procedures, or
by the Reference Member State or a Concerned can be a purely national authorisation. Authorisations
Member State in the course of a mutual recognition or not used in the territory for a period of three consecu-
Decentralised Procedure if a medicinal product’s MA tive years become invalid (sunset clause).
presents a potential serious public health risk. The accepted MAA format is the Common Technical
Within the coordination group, all Member States Document, organised into five modules; Module 1 is not
concerned give the applicant an opportunity to present a part of the CTD and consists of administrative applica-
its point of view orally or in writing. If the Member tion data (including specific national requirements for the
States have not reached agreement within 60 days, Concerned Member States).
CHMP undertakes a scientific evaluation of the mat- The eCTD is a standard for submitting MAAs in
ter and issues an opinion, normally within 60 days of the Community and most EU Member States. It is the
receiving the referral. From this opinion, the European mandatory format for centrally authorised products.
Commission drafts a single decision binding the The Centralised Procedure can be utilised for
Member States and applicant. orphan and veterinary products, medicinal products
developed by biotechnological processes and new
Divergent Decision Referral active substances for specified therapeutic indications.
This referral may be started by any Member State, the Once an MA is granted, it can be subject to specific
European Commission or the applicant (or MAH), obligations (conditional MA or MA under Exceptional
according to Directive 2001/83/EC Article 30, when Circumstances), FUMs and variations).
divergent decisions have been made by Member States Applicants/MAHs can submit multiple and/
related to a particular medicinal product (e.g., sus- or duplicate applications via the Mutual Recognition
pension or withdrawal of an MA or divergence of the or Decentralised Procedure; the possibility to duplicate
therapeutic indications of an authorised product). the application should be discussed and agreed with the
CHMP is asked to issue an opinion on the area(s) Reference Member State.
of divergence within 60 days of the procedure’s start Several types of applications (standalone or abridged)
date. This period can be extended by up to 90 days. are specified in Directive 2001/83/EC, with further
The resulting European Commission decision must amendments.
be implemented in all Member States concerned (i.e., For difficult and specific cases, European pharma-
those in which the particular medicinal product’s MA ceutical legislation has created a binding Community
has been granted, refused, suspended or withdrawn). arbitration mechanism to manage cooperation between
Member States and/or the applicant or MAH.
Community Interest Referral References
According to Directive 2001/83/EC Article 31, this 1. Guideline on the Investigation of Bioequivalence, CPMP/
referral may be started by Member States, the European EWP/ QWP/1401/98 Rev. 1/Corr. (1 August 2010). EMA web-
Commission or the applicant (or MAH) when site. http://www.ema.europa.eu/docs/en_GB/document_library/
Scientific_guideline/2010/01/WC500070039.pdf. Accessed 16 April
Community interests are involved. This latter expres-
2020.
sion refers particularly to C ommunity public health 2. Volume 2A Procedures for marketing authorisation Chapter 1
interests related to a marketed medicinal product for Marketing Authorisation. EC website. https://ec.europa.eu/
which new quality, safety and efficacy data or new phar- health/sites/health/files/files/eudralex/vol-2/vol2a_chap1_
en.pdf. Accessed 16 April 2020.
macovigilance information have become available.
3. European Medicines Agency pre-authorisation procedural advice
CHMP issues a reasoned opinion within 60 days for users of the centralised procedure. EMA website. https://www.
of the referral date. This period may be extended by a ema.europa.eu/en/documents/regulatory-procedural-guideline/
further 90 days. A binding decision from the European european-medicines-agency-pre-authorisation-procedural-ad-
vice-users-centralised-procedure_en-0.pdf. Accessed 16 April
Commission follows.
2020.
4. Frequently asked questions on EFTA, the EEA, EFTA
Conclusion membership and Brexit. EFTA website. https://www.efta.
int/About-EFTA/Frequently-asked-questions-EFTA-EEA-
EU laws and policies are established by several types
EFTA-membership-and-Brexit-328676. Accessed 16 April
of legislative instruments. Although not all are legally 2020.
binding, the instruments without binding legal effect, 5. Common Technical Document—Quality M4Q(R1). ICH website.
https://database.ich.org/sites/default/files/M4Q_R1_Guideline.
pdf. Accessed 16 April 2020.

Chapter 23
6. Guideline on Active Substance Master File Procedure. EMA web- 3 ( June 2007). HMA website. h t t p : / / w w w. h m a . e u /
site. http://www.ema.europa.eu/docs/en_GB/document_library/ u p l o a d s / m e d i a / r e c _ m u l t i a p p. p d f. Accessed 16 April
Scientificguideline/2012/07/WC500129994.pdf. Accessed 16 2020.
April 2020. 11. The Rules Governing Medicinal Products in the European
7. Volume 2B - Notice to Applicants—Medicinal products for human Union,Notice to Applicants, Volume 2A, Chapter 1, Section 6.1.
use. Presentation and format of the dossier Common Technical EC website. https://ec.europa.eu/health/documents/eudralex/
Document (CTD). EC website. https://ec.europa.eu/health/ vol-2_en. Accessed 16 April 2020.
sites/health/files/files/eudralex/vol-2/b/update_200805/ctd_05- 12. Communication from the Commission to the Council
2008_en.pdf. Accessed 16 April 2020. and the European Parliament concerning the report on
8. Volume 6 - Notice to applicants and regulatory guidelines for medic- the experience acquired as a result of the application of
inal products for veterinary use. EC website. https://ec.europa.eu/ the provisions of Chapter 2a of Directive 2001/83/EC, as
health/documents/eudralex/vol-6_en. Accessed 16 April 2020. amended by Directive 2004/24/EC, on specific provisions
9. Procedural Advice on Repeat-Use. HMA website. http://www. applicable to traditional herbal medicinal products. EUR-
hma.eu/93.html. Accessed 16 April 2020. Lex website. http://eur-lex.europa.eu/legal-content/EN/
10. Recommendations on Multiple/Duplicate Applications in ALL/?uri=CELEX:52008DC0584. Accessed 16 April 2020.
Mutual Recognition and Decentralised Procedures, Revision

Chapter 24
Adaptive and Alternative

Pathways
OBJECTIVES Directives 93/42/EEC and 90/385/EEC (June

2016)
□ Learn about adaptive licensing pathways for
medicines in the EU
Introduction
In March 2014, the European Medicines Agency
DIRECTIVES, REGULATIONS AND GUIDELINES (EMA) unveiled a pilot program that would seek to
COVERED IN THIS CHAPTER accelerate patient access to drugs intended to treat
serious unmet medical needs via an adaptive licensing
□ Regulation (EC) No. 726/2004 of the European pathway.1 The adaptive pathways program would allow
Parliament and of the Council of 31 March 2004 medicinal products to receive approval for use in a
Laying down Community procedures for the “well-defined patient subgroup” or narrow indication,
authorisation and supervision of medicinal followed by a gradual expansion of the indication using
products for human and veterinary use and postapproval and “real-world data.”
establishing a European Medicines Agency EMA called its adaptive pathways pilot “an oppor-
(March 2004) tunity for early brainstorming discussion among all
relevant stakeholders, including regulators, companies,
□ Commission Regulation (EC) No. 507/2006 of
Health Technology Assessment (HTA) bodies and
29 March 2006 on the conditional marketing
patient representatives, to explore ways to optimise
authorisation for medicinal products for human
development pathways and potentially accelerate
use falling within the scope of Regulation (EC)
patients’ access to medicines.”
No. 726/2004 of the European Parliament and
The pilot was initially called “Adaptive Licensing.”
of the Council (March 2006)
EMA changed the name to Adaptive Pathways “to bet-
□ Guidance for Companies Considering the ter reflect the idea of a life-span approach to bring new
Adaptive Pathways Approach (August 2016) medicines to patients with clinical drug development,
licensing, reimbursement, and utilization in clinical
□ Guideline on the Scientific Application and the practice, and monitoring viewed as a continuum.”
Practical Arrangements Necessary to Implement In December 2016, EMA hosted a workshop to
Commission Regulation (EC) No. 507/2006 further discuss the adaptive pathways concept with
on the Conditional Marketing Authorisation stakeholders and review the experience gained during
for Medicinal Products for Human Use Falling the pilot phase.2
within the Scope of Regulation (EC) No. While similar principles can be applied to the
726/2004 (March 2007) conformity assessment procedure for medical devices
requiring clinical investigations, and have been dis-
□ MEDDEV 2.7/1: Clinical Evaluation: A Guide cussed in the literature,3 no formalised adaptive
for Manufacturers and Notified Bodies Under authorisation pathway allowing early and progressive

Chapter 24
patient access has been implemented so far for medical treatment-eligible population at the time of
devices. marketing authorisation
Medicinal Products In practice, under an adaptive licensing pathway, the

The Adaptive Pathways Approach development program would be structured to allow
EMA launched the adaptive pathways approach to early approval (and coverage) of a new compound for
improve timely access for patients to new medicines a restricted patient population, typically with a highly
addressing unmet medical needs. The concept allows unmet medical need.7 Eligible conditions usually have a
early and progressive patient access to a medicinal prod- major impact on quality of life and/or are life-shorten-
uct by applying gradual data generation.4 ing or severely debilitating.
The approach makes use of the existing regulatory The first approval would be based on smaller initial
framework for medicines in the EU, i.e., no new legis- clinical studies with postapproval commitments to con-
lation was enacted to implement the adaptive pathways duct additional studies and/or collect real-world data;
concept. as the approval based on incomplete data would come
The adaptive pathways approach is based on the with a higher degree of uncertainty, which could be
following principles: reduced through the generation and collection of addi-
• iterative development, which means either: tional postmarketing data.
o approval in stages, with an initial restricted Subsequently, approved indications, target popula-
patient population for a narrow indication tions, coverage and therapeutic value would be revisited
and then gradually expanding to broader at several points along the clinical development pathway
patient populations or once new efficacy and safety data become available from
o conditional approval based on early data the required postapproval studies and real-world data.
using surrogate endpoints, which are con- The initial approval still would be based on a ran-
sidered predictive of the long-term clinical domised clinical trial, the “gold standard” for approval,
outcome; followed by confirmation of a due to its reduction of bias by using blinding and ran-
product’s postapproval benefit-risk balance domisation techniques and its ability to discriminate
• supporting clinical trial data with evidence patient outcomes caused by the test treatment from
through real-life (“real-world”) data outcomes caused by other factors.8
• involvement of patients, health technology However, certain scenarios such as ultra-rare dis-
assessment bodies and payers in discussions on eases or ethical and feasibility issues have challenged
the medicine’s development at an early stage the randomised clinical trial paradigm as the sole basis
of generating clinical evidence: The case has been made
The adaptive pathways concept is intended to be applied that, in a suitable scenario, data generated using a tradi-
primarily in areas of highly unmet medical needs, where:5 tional, randomised clinical trial could be complemented
• it would be difficult to collect data via tradi- by real-world evidence, as envisioned by EMA’s adap-
tional routes, i.e., standard randomised clinical tive pathways scenario.
trials Real-world evidence could contribute to embrac-
• large clinical trials would unnecessarily expose ing the full evidence spectrum and allow efficient
patient populations to the product who are generation of additional knowledge of benefits and
unlikely to benefit from it due to the existence risks. Rather than considering pre- and postapproval
of patient subpopulations characterised by, e.g., evidence generation as “two different lives,” it should
genotypic biomarkers be regarded as “one continuous life” over a medicine’s
entire lifecycle.9
Adaptive pathways change neither the standards
for benefit-risk evaluation nor the requirement to Legal Framework
demonstrate a positive benefit-risk balance to obtain The adaptive pathways approach builds on the existing
marketing authorisation.6 EU legal framework, including:
Through the adaptive pathways program, EMA • The conditional approval provision: EMA
is trying to address the “Access versus Evidence currently allows conditional marketing
Conundrum,” the delicate trade-off between: authorisations to be granted based on early
• enabling rapid patient access to promising clinical trial data. A company receiving con-
therapies ditional marketing authorisation for one of its
• ensuring adequate benefit-risk information products must conduct ongoing or additional
and a positive benefit-risk balance for the studies to demonstrate the product’s benefits

Adaptive and Alternative Pathways
Figure 24-1. Product Eligibility for Adaptive Pathways Approach (Source: EMA, 2016)
Product for adaptive

pathways submission
Yes, but we need to refine

details of the protocol(s)
Is a conventional development
pathway decided?
No, we have
several options
on the table
Are there iterative aspects to the No

development? (conditional marketing Scientific advice request
authorisation or expan-sion)
Yes
Do we need to discuss with health No

technology assessment (HTA) bodies?
Yes
Are we considering the use of real No

EMA-HTA parallel scientific advice
world data for regulatory purposes?
Yes
Adaptive pathways EMA-HTA

parallel scientific advice
and may be given additional requirements to who have a disease with no satisfactory
collect pharmacovigilance data. authorised therapy, and who are not eligible
Conditional marketing authorisations need to to participate in clinical trials. The concerned
be renewed annually and are granted on the products’ safety profiles and dosage guidelines
basis that it is “likely that the applicant will be may not have been established fully.11
able to provide comprehensive data” within a • Multi-stakeholder scientific advice: Using the
reasonable amount of time.10 parallel EMA/Health Technology Assessment
• Compassionate use: Allowing products in (HTA) Body Scientific Advice Procedure.12
development to be made available to patients

Chapter 24
• Patient registries: Pharmacovigilance tools as feasibility studies, compassionate use,

allowing collection of real-life data; postmar- custom-made devices)
keting commitments; risk management plans. o use of Postmarket Clinical Follow-Up
• Adaptive pricing/reimbursement (managed Plans (PMCF) to generate additional
entry agreements): Limiting reimbursement of data for evaluation of clinical efficacy and
medicines to those subpopulations most likely safety
to benefit from treatment and allowing gradual o requirements for annual update and review
expansion of reimbursed indications.13 of the clinical evaluation report by the
notified body based on new data becom-
Procedural Guidance ing available
Over a two-year period, EMA ran a pilot project to • use of surrogate clinically relevant endpoints to
explore the practical implications of the adaptive path- gain market access
ways concept. At the end of the pilot, six applicants had • clinical use limited to a specific target popula-
received parallel advice from EMA and HTA bodies, tion subset
and one benefited from EMA scientific advice.14
Based on the pilot, EMA issued a procedural guid- While no formal adaptive authorisation procedure exists
ance document in August 2016, detailing the requested for medical devices, the current legislative framework
content of the adaptive pathway proposal and the appli- could be used effectively to implement such a gradual
cation process.15 authorisation approach.
The main elements to be outlined in the proposal In the absence of a central medical device regula-
to EMA are: tory authority in the EU, such an initiative likely would
• proposed iterative development approach need to be driven by the Medical Devices Expert Group
• how real-world data will be gathered to sup- (MDEG). It remains to be seen whether the medical
plement clinical trial data device sector follows the example set by EMA and
• proposed approach to involve patients and implements a similar “authorisation in stages” process.
HTA bodies in the discussion of the product
development program Conclusion
As patients are demanding faster access to new med-
A decision tree to determine eligibility of a product for an icines and conventional R&D models may no longer
adaptive pathway approach is presented in Figure 24-1. be financially viable for certain scenarios, more flexible
licensing pathways are being developed for treatments
Medical Devices that address highly unmet medical needs.
While the same adaptive licensing principles discussed The concept of a gradual, adaptive licensing
for medicinal products apply to medical devices, no approach for medicines has been accepted widely and
formalised adaptive authorisation pathways have been also is reflected in legislation outside the EU (e.g., the
implemented for high-risk medical devices, which 21st Century Cures Act in the US). It will continue to
require clinical investigations for their conformity evolve further in coming years.
assessment.
Likewise, the current medical device regulatory References
1. Adaptive pathways. EMA website. http://www.ema.europa.
framework in the EU does not include a conditional eu/ema/index.jsp?curl=pages/regulation/general/general_con-
authorisation provision within the scope of the confor- tent_000601.jsp. Accessed 20 April 2020.
mity assessment. 2. Adaptive pathways workshop. EMA website. http://www.
However, the respective MEDDEV guideline ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/
events/2016/09/event_detail_001324.jsp&mid=WC-
2.7.1 Clinical Evaluation: A Guide for Manufacturers and 0b01ac058004d5c3. Accessed 20 April 2020.
Notified Bodies Under Directives 93/42/EEC and 90/385/ 3. Husereau D, et al. Adaptive approaches to licensing, health
EEC, which details device clinical evaluation require- technology assessment, and introduction of drugs and devices.
ments, does include special conformity assessment International Journal of Technology Assessment in Health Care.
Volume 30(3). July 2014.
provisions,16 which could be applied within the scope of 4. Op cit 1.
an adaptive authorisation pathway: 5. Ibid.
• specific provisions for devices for unmet medi- 6. Eichler H-G, et al. From Adaptive Licensing to Adaptive
cal needs include: Pathways: Delivering a Flexible Life-Span Approach to Bring
New Drugs to Patients. Clinical Pharmacology & Therapeutics.
o market access based on limited clinical Volume 97 (3). March 2015.
evidence, including evidence derived 7. Eichler H-G. Adaptive Pathways: concept and critical issues.
outside randomised clinical trials (such EMA website. http://www.ema.europa.eu/docs/en_GB/

Adaptive and Alternative Pathways
document_library/Presentation/2016/12/WC500218594.pdf. 12. Parallel consultation with regulators and health technology

Accessed 20 April 2020. assessment bodies. EMA website. http://www.ema.europa.
8. Hemmings R. Avenues of knowledge generation throughout eu/ema/index.jsp?curl=pages/regulation/general/general_con-
a medicine’s lifespan: methodological issues. EMA website. tent_001857.jsp&mid=WC0b01ac0580a11c96. Accessed 20
http://www.ema.europa.eu/docs/en_GB/document_library/ April 2020.
Presentation/2016/12/WC500218599.pdf. Accessed 20 April 13. Muscolo L, et al. Managed entry agreements. Orphanet Journal
2020. of Rare Diseases. Volume 9. (November 2014).
9. Ibid. 14. Op cit. 1.
10. Guideline on the Scientific Application and the Practical 15. Guidance for Companies Considering the Adaptive Pathways
Arrangements Necessary to Implement Commission Regulation Approach. (August 2016).
(EC) No 507/2006 on the Conditional Marketing Authorisation 16. MEDDEV 2.7/1 (Revision 4). Clinical Evaluation: A Guide for
for Medicinal Products for Human Use Falling Within the Scope of Manufacturers and Notified Bodies Under Directives 93/42/EEC
Regulation (EC) No 726/2004 (March 2007) and 90/385/EEC ( June 2016).
11. Compassionate use. EMA website. http://www.ema.europa.
eu/ema/index.jsp?curl=pages/regulation/general/general_con-
tent_000293.jsp. Accessed 20 April 2020.

Chapter 24

Chapter 25
Preclinical Testing and

Good Laboratory Practice
Regulations
OBJECTIVES □ Questions and Answers Concerning

Implementation of Directives 2004/9/EC and
□ Understand the preclinical Good Laboratory 2004/10/EC on Good Laboratory Practice
Practice (GLP) study requirements applicable (March 2016)
during drug and biologic development
□ Guidance on Nonclinical Safety Studies for the
□ Review the GLP regulations’ history, purpose Conduct of Human Clinical Trials and Marketing
and requirement Authorization for Pharmaceuticals M3 (R2) (11
June 2009)
□ Understand a quality assurance program’s
significance □ Guidance GLP Compliance Monitoring of
International Multi-Site Studies (adopted by the
□ Examine implications of the GLP regulations’
EU GLP Working Group 5 January 2017)
noncompliance
□ Guidance Document for GLP inspectors and
GLP test facilities: Cross-contamination of
DIRECTIVES, REGULATIONS AND GUIDELINES control samples with test item in animal stud-
COVERED IN THIS CHAPTER ies (adopted by the EU GLP Working Group 27
September 2005)
□ Organization for Economic Cooperation and
Development, Series on Principles of Good □ Guidance for GLP Facilities on the
Laboratory Practice and Compliance Monitoring, Implementation and Maintenance of a Risk-
Number 1 (Revised 1997) based Quality Assurance Programme (adopted
by the EU GLP Working Group 23 February 2017)
and of the Council on the inspection and ver-
ification of good laboratory practice (GLP) (11 Introduction
February 2004) Good Laboratory Practice (GLP) is a quality sys-
tem concerned with the organisational process and
the conditions under which nonclinical health and
Parliament and of the Council on the harmoni-
environmental safety studies are planned, performed,
sation of laws, regulations and administrative
monitored, recorded, archived and reported. Its purpose
provisions relating to the application of the
is to ensure safety data quality and integrity submitted
principles of good laboratory practice and the
to regulatory authorities.
verification of their application for tests on
During drug development, preclinical studies, also
chemical substances (11 February 2014)
called nonclinical studies, are research and experiments
that begin before the first clinical trial and continue

Chapter 25
during clinical development, to collect important feasi- The increasing globalisation of business has affected
bility, mechanism of action, efficacy and safety data. The how companies follow the GLP regulations. To meet
studies could be in vivo or in vitro, but most are in vivo this changing business and regulatory landscape,
studies conducted on animals. the Organisation for Economic Cooperation and
Preclinical drug studies have two general objectives: Development (OECD) member states, including the
1. identify the drug’s pharmacological properties, US, and countries in Europe and Asia, have devel-
which includes pharmacodynamics (PD, mode oped a set of GLP principles similar to the US GLP
of action), pharmacokinetics (PK, metabolism) regulations. These principles cover safety testing of
and comparative physiology pharmaceuticals, animal drugs, food additives, pesticides
2. understand the drug’s toxicological profile, and industrial chemicals. The EU Member States with-
including identifying parameters for monitor- out a specific set of national GLP regulations follow
ing potential adverse effects and special toxicity OECD GLP principles. In 1981, OECD adopted the
Mutual Acceptance of Data (MAD) document that
Each drug product class could undergo different pre- states study data generated in an OECD member state
clinical studies. For instance, a new chemical entity may be accepted by other member states. Today, most
(NCE) has to undergo PD, PK, absorption, distribution, of the major health authorities generally accept GLP
metabolism and excretion (ADME) and toxicology studies performed under the national regulations of
studies. Studies of a drug’s toxicity include identifying the Member State where the study was conducted. The
organs the drug targets as well as any long-term car- additional international efforts have been underway for
cinogenic effects or toxic effects on reproduction. several years, with the goal of harmonising GLPs into
In the mid-1990s, the then International a single set of regulations. The OECD GLP principles
Conference on Harmonisation (ICH) began coordi- are discussed later in this chapter.
nating regulatory agencies in developing harmonised
rules for testing pharmaceutical products, with the GLP Regulations and Guidelines
overall goal of reducing duplicate testing under different A pharmaceutical product’s nonclinical safety assessment
national guidelines. usually includes pharmacology studies, general toxicity
ICH has produced a comprehensive set of safety studies, toxicokinetic, pharmacokinetic, reproduction
guidelines to uncover potential risks like carcinogenic- toxicity studies and genotoxicity studies. Drugs with a
ity, genotoxicity and reproductive toxicity. As noted, special cause for concern or intended for long duration
a recent breakthrough has been a nonclinical testing of use require a carcinogenic potential assessment. Other
strategy for assessing the QT interval prolongation lia- nonclinical studies to assess phototoxicity, immunotoxic-
bility, which is the single most important cause of drug ity, juvenile animal toxicity and abuse liability should be
withdrawals in recent years.1 conducted on a case-by-case basis. The safety assessment
In 2015, ICH changed its name to the International should characterise such toxic effects as target organs,
Council on Harmonisation. ICH has developed several dose dependence, relationship to exposure and, when
guidelines covering pharmaceutical product testing, par- appropriate, potential reversibility. General nonclinical
ticularly in areas related to emerging safety and efficacy study requirements are summarised below:
study technologies. In 2010, EU, Japan and US regula- • Toxicity studies—potentially clinically rele-
tory authorities revised an existing ICH guideline (1997) vant effects can be characterised adequately
on nonclinical safety studies. The current guidance pro- using doses up to the maximum tolerated dose
vides specific recommendations for various toxicology, (MTD), although it is not essential to demon-
pharmacology, carcinogenicity and other nonclinical strate the MTD in every study. Limit doses for
study aspects supporting human clinical studies. acute, sub-chronic and chronic toxicity studies
Additionally, in 1997, the UNICEF/UNDP/World of 1000 milligrams (mg)/kilogram (kg)/day for
Bank/World Health Organization Special Programme rodents and non-rodents or up to 10-fold of
for Research and Training in Tropical Diseases (TDR) the clinical exposure generally are considered
published a handbook on good laboratory practice appropriate in most cases.
(GLP). The handbook was revised in 2009 and is • Pharmacology studies—the core battery of
intended to assist countries in conducting nonclinical safety pharmacology studies includes assessing
research and drug development2. This revised handbook effects on cardiovascular, central nervous and
includes information on: respiratory systems, and generally should be
1. laboratory organisation and administration conducted before human exposure.
2. laboratory documentation • Pharmacokinetic studies—in vitro meta-
3. laboratory techniques and procedures bolic and plasma protein binding should be

Preclinical Testing and Good Laboratory Practice Regulations
evaluated before initiating human clinical tri- whose expected clinical use is continuous for at
als. Further PK information (e.g., ADME) and least six months. Carcinogenicity studies also
potential drug interactions generally should be may need to be considered for certain delivery
available before initiating Phase 3 trials. systems that may result in prolonged exposures
• Acute or repeat-dose toxicity studies—study and, for some other pharmaceuticals, if there is
duration usually is related to the duration, concern about their carcinogenic potential.
therapeutic indication and proposed clinical
trial’s scope. In principle, the studies’ dura- In addition, the full scope of ICH Safety (S) guidelines
tion in two species (one non-rodent) should should be reviewed.3
be equal to or exceed human clinical trials’ GLP regulations require studies to support phar-
duration. maceutical product marketing applications, including
• Local tolerance studies—a single-dose local but not limited to:
tolerance study in a single species is considered • acute, sub-chronic and chronic toxicology
appropriate to support limited human admin- studies, including developmental, reproduc-
istration by non-oral routes. tive, carcinogenic, mutagenic and degenerative
• Genotoxicity studies—an assay for gene toxicology studies based on these effects’
mutation is sufficient to support single-dose appearance in laboratory animals
clinical trials. To support multiple-dose trials, • medical device in vivo or in vitro safety test-
additional assessment to detect chromosomal ing and physical and chemical characteristics’
damage should be completed. A complete testing if a device is a part of a drug-device
genotoxicity test battery should be completed combination product
before initiating the Phase 2 trials. • in vivo and in vitro biochemistry, immunology
• Reproduction studies—women not of child- and microbiology studies
bearing potential can be included in clinical • dermal, eye, venous or muscle irritation studies
trials without reproduction toxicity studies if • pharmacology studies, including PK and PD
the relevant repeated-dose toxicity studies have • test and control article characterisation and
been conducted. A male fertility study should stability
be completed before initiating the Phase 3 tri-
als. For women of childbearing potential, there GLP regulations do not require human clinical tri-
is a high level of concern about unintentionally als, field trials (non-laboratory) in animals, method
exposing an embryo or fetus before informa- development or basic exploratory studies. Exploratory
tion is available concerning potential benefits studies may include research and development testing
versus potential risks. In the US, embryo-fetal to determine a particular drug or substance’s usefulness
development assessment can be deferred until or preliminary laboratory testing to determine a sub-
before the Phase 3 trials, if precautions are stance’s physical or chemical characteristics. Preliminary
taken to prevent pregnancy in clinical trials. in vivo feasibility and drug-dose range or testing are not
Before including pregnant women in clinical required under GLP.
trials, all female reproduction toxicity studies
and the standard battery of genotoxicity tests OECD GLP Principles
should be conducted. With the expanding globalisation of commerce, clini-
• Immunotoxicity—all new pharmaceuticals cal and nonclinical studies increasingly are conducted
should be evaluated for the potential to pro- as multi-site studies in more than one Member State.
duce immunotoxicity using standard toxicity Regulatory and quality assurance professionals must
studies and also may require additional immu- be familiar with the international regulations that
notoxicity studies. impact their organisation’s studies. OECD GLP prin-
• Photo-safety testing—a drug’s phototoxic ciples have been useful particularly for laboratories
potential based on its photochemical proper- conducting multi-site studies. OECD GLP princi-
ties and pharmacological/chemical class should ples set the quality standards for the organisation and
be assessed, which can be undertaken in a non- management of test facilities and for performing and
clinical study. If this study is negative, an early reporting studies related to chemical substances and
assessment of eye/skin distribution studies and preparations’ (including pharmaceutical products) safety.
clinical protective measures are not required. The GLP principles cover all aspects of a laboratory’s
• Carcinogenicity studies—these should be daily activity, such as the layout of testing and storage
performed for any pharmaceutical products areas to prevent contamination, equipment cleaning

Chapter 25
and calibration, handling test animals and recording study (For multisite studies, those conducted at
and archiving test results. The GLP principles help more than one site, the test facility comprises
ensure studies submitted to regulatory authorities are of the site at which the study director is located
sufficient quality and rigor and are verifiable. To date, and all individual test sites, which individually
OECD has issued 17 separate documents on GLP or collectively can be considered to be test
principles. The OECD documents are used by the EU, facilities.)
US, Asia and other countries’ laboratories to supple- o Test site—location(s) at which a study
ment national GLP regulations. The principles can be phase(s) is conducted.
accessed on the OECD website.4 o Raw data—the original test facility
records and documentation or verified
Overview of Directive 2004/10/EC and copies thereof, that are the result of the
OECD GLP Principles original observations and activities in
The GLP principles described in Directive 2004/10/EC a study. Raw data also may include, for
Annex I were developed by OECD. The key principles example, photographs, microfilm or
can be summarised as: microfiche copies, computer readable
• test facility organisation and personnel media, dictated observations, recorded
• quality assurance programme data from automated instruments or any
• facilities other data storage medium that has been
• apparatus, material and reagents recognised as capable of providing secure
• test systems (biological or physical/chemical) storage of information for a time period as
• test and reference items required by the appropriate authorities.
• standard operating procedures (SOPs)
• study performance (planning) Test Facility Organisation and Personnel
• reporting of study results Test Facility Management
• storage and retention of records and materials Test facility management is responsible for ensuring the
personnel working at the site are qualified by training,
The GLP principles’ scope also covers other products education and experience. These qualifications must
besides pharmaceutical products, i.e., veterinary drugs, be documented and available for review in case of an
cosmetic products, etc. Each principle contains subsec- inspection. Test facility management also is responsible
tions providing specific GLP requirements. for designating a study director with the appropriate
qualifications prior to study initiation and for designat-
Definitions ing a PI, if needed, if there is a multi-site study. The test
• Study Director—the individual responsible for facility must be equipped with the appropriate mate-
the overall conduct of the nonclinical health rials and equipment to ensure timely and proper study
and environmental safety study conduct. SOPs must be written and in place with any
• Principal Investigator (PI)—the individual obsolete SOPs archived to ensure retrieval is possible, if
who, for a multi-site study, acts on behalf of necessary. Lastly, test facility management must ensure
the study director and has defined responsi- that the site has a quality assurance programme with
bility for delegated phases of the study (The the appropriate personnel in place, prior to any stud-
study director’s responsibility for the overall ies being performed, and the quality assurance (QA)
study conduct cannot be delegated to the responsibility is being performed according to GLPs.
Principal Investigator(s); this includes study
plan approval and amendments, final report Study Director
approval and ensuring all applicable GLP As mentioned above, the study director is appointed
principles are followed.) by test facility management. The study director must
• Quality Assurance (QA) Programme—a have the appropriate qualifications, i.e., education and
defined system, including personnel, that is experience, to perform the duties assigned for a par-
independent of study conduct and is designed ticular study. The study director is the single point of
to assure test facility management compliance study control and has the responsibility for the study’s
with GLP principles. overall conduct and for the final study report. The study
• Test facility—the persons, premises and oper- director also is responsible for ensuring a study plan is
ational unit(s) necessary for conducting the available for study personnel and providing any amend-
nonclinical health and environmental safety ments to study personnel. To ensure the final report is

acceptable, the study director must: ensure all raw data Archive Facilities
generated are documented and fully recorded, ensure These GLP facilities should provide secure storage and
that all computerised systems are validated and accept retrieval of study plans, raw data, final reports, test item
the responsibility for data validity by signing and dating samples and specimens. All items should be protected
the final report. from untimely deterioration.
Principal Investigator Waste Disposal

The PI ensures any delegated study phases have been Waste handling and disposal should be executed in a
conducted in accordance with the applicable GLP way that does not jeopardise any study’s integrity. There
principles. should be procedures for appropriate waste collection,
storage, disposal, decontamination and transportation.
Quality Assurance (QA) Programme
Quality Assurance (QA) Programme Personnel Apparatus, Materials and Reagents
The test facility should have a documented quality Any apparatus used for data generation, storage or
assurance (QA) programme to ensure studies are con- retrieval and controlling environmental factors, includ-
ducted according to GLP principles. The QA personnel ing computerised systems, should be suitably located,
should be directly responsible to test facility manage- appropriately designed and have adequate capacity.
ment and should be familiar with the test procedures; The apparatus and materials should never interfere
however, they cannot be involved in study conduct. adversely with the test systems. All materials should be
QA personnel maintain copies of all approved labeled appropriately with expiration date and storage
study plans and SOPs and have access to an up-to- requirements.
date master schedule. The most important task for QA
programme personnel is conducting inspections to Test Systems
determine whether studies conducted adhered to GLP Physical or Chemical
principles. QA personnel can conduct three types of Physical or chemical test systems’ integrity should be
inspections: ensured.
1. study-based
2. facility-based Biological
3. process-based inspections Proper biological test systems’ storage, handling and
housing conditions should be established and main-
QA personnel must maintain records of all these tained to ensure data quality. Biological test systems
inspections. should be acclimated to the test environment for an
appropriate period of time prior to the first administra-
Facilities tion or application of the test or reference item. Records
General test systems’ source, date of arrival and condition on
The GLP test facility should be a suitable size, con- arrival should be logged and maintained. The biological
struction and location to meet the requirements for the test systems must be maintained in manner that avoids
type of study to be conducted. The test facility design contamination with other test systems and materials.
should provide an adequate degree of separation of dif-
ferent activities to ensure each study’s proper conduct. Test and Reference Items
Receipt, Handling, Sampling and Storage
Test System Facilities Procedures should be written to cover test and reference
The GLP test facility should have sufficient rooms or items’ handling, sampling and storage to ensure homo-
areas to ensure isolation of test systems and individ- geneity and stability are maintained and contamination
ual projects that may contain biohazardous materials. or mix-up is avoided.
Suitable rooms or areas should be available for disease
diagnosis, treatment and control to ensure there is no Characterisation
unacceptable test system deterioration. Storage rooms Each test and reference item should be appropriately
or areas should be separated adequately from rooms or identified with name, Chemical Abstracts Service
areas housing test systems to protect against infestation, (CAS) number, biological parameters, etc. Test and ref-
contamination or deterioration. erence items’ stability under storage and test conditions
should be available for all studies. For each study con-
ducted at the facility, the test or reference item’s identity,

Chapter 25
purity, composition, concentrations or characteristics Content of the Final Study Report

should be defined for each test batch. At minimum, the final GLP study report should
contain:
Standard Operating Procedures (SOPs) • study, test item and reference item
A test facility should have test facility management identification
approved written SOPs. The SOPs should ensure • test facility and sponsor information
test facility-generated data quality and integrity. Any • start and completion dates
deviation from an SOP related to a study should be doc- • quality assurance programme statement
umented and acknowledged by the study director and • materials and test methods’ description
the PI, if applicable. There should be SOPs covering: • results summary
• test and reference items • study plan, test and reference samples, speci-
• apparatus, materials and reagents mens, raw data storage
• recordkeeping, reporting, storage and retrieval • records and materials’ storage and retention
• test system
• quality assurance procedures Ancillary GLP Quality System Components
Although not mentioned specifically in the GLP
Study Performance regulations, additional ancillary GLP quality sys-
Study Plan tem components are seen throughout the industry
A written plan approved by the study director should and described in guidance(s), including equipment
be in place prior to study initiation. Any amendments qualification and test method validation processes.
should be justified and approved by the study director. The equipment qualification ensures all data collec-
The study director or PI should describe, acknowledge tion equipment has been installed properly, operates
and date deviations in a timely manner and maintain according to manufacturer specifications and performs
them with the raw data. according to the user requirement specifications for its
intended use prior to being used in a nonclinical study.
Content of the GLP Study Plan This equipment qualification process often is
The study plan should contain the following described in three components:
information: 1. installation qualification (IQ)
• study, test and reference item identification 2. operational qualification (OQ)
• information concerning the sponsor and test 3. performance qualification (PQ)
facility
• dates Ultimately, this process ensures data quality and integ-
• test methods rity during the nonclinical GLP laboratory study. Test
• any applicable issues methods also must be validated to ensure their accuracy,
• records reproducibility and suitability for the study type in
which they will be used. Test method validations are
The GLP study plan should contain the information run as separate studies following all applicable GLP
needed to conduct the study successfully. All details requirements.
should be included in the GLP study plan sections, and
the plan must be approved, at a minimum, by the study Guidance for Industry—Purpose and
director. No test or reference system testing or procur- Relevance in GLP
ing should occur without the study director’s approval The EU GLP Working Group, which is chaired by the
and signature. European Commission, has issued guidance to ensure
common understanding among the Member States,
Reporting Study Results competent authorities and the EU GLP Working
The study director must prepare and sign a final report Group on topics related to GLP studies. The first guid-
for each GLP study. The study director’s signature ance on cross-contamination of control samples with
implies acceptance of responsibility for data validity test items in animal studies was approved in 2005.
and compliance with GLPs. Any final study report Subsequent guidance documents have been released
corrections or additions should be in the form of covering international multi-site studies, Q&As on the
amendments. Amendments must specify reasons for implementation of Directives 2004/9/EC and 2004/10/
corrections or additions clearly and must be signed by EC and implementation and maintenance of a risk-
the study director. based QA programme. The guidance on a risk-based

QA programme recognises that the programme has to compliance with GLP principles, which other OECD
cover a broad range of activities. However, in design- countries’ monitoring authors can use, or it can provide
ing and running the programme, the GLP test facility a detailed report to the requesting regulatory authority.
management may not recognise certain activities have For serious deviations, the monitoring authority’s
a higher risk than others. The higher risk activities may action will depend on each case’s circumstances and
need to be inspected or monitored more frequently the legal or administrative provisions under which the
than lower risk activities. An activity’s risk level should monitoring authority was established. The actions may
be considered when deciding on how to focus QA include:
resources. As mentioned previously in this chapter, this • issuing a statement providing details on
guidance also provides an in-depth discussion on the inspection findings that could affect the valid-
three QA inspection types (study-based, process-based ity of studies the test facility conducts.
and facility-based) descriptions. • issuing a recommendation to a regulatory
authority that a study be rejected.
GLP Laboratory Inspections and • suspending test facility inspections or study
Consequences of Noncompliance audits and, when administratively possible,
Directive 2004/9/EC mandates the EU Member States removing the test facility from the national
to verify that any testing laboratory within their terri- GLP compliance programme or any existing
tories is in compliance with GLP. Laboratory sites are list or register of test facilities subject to GLP
divided into two factions: test facility inspections
1. independent sites • requiring a statement detailing the deviations
2. dependent sites be attached to specific study reports.
• acting through the courts.
Independent sites are test sites with test site manage-
ment appointed. Whereas, a dependent site is the one If any problems or differences of opinions cannot be
without its own management. A dependent site relies resolved between inspectors and test facility manage-
on test facility management to take on all responsibili- ment, the test facility management can follow an appeal
ties, including using their own SOPs, since the sites do procedure to obtain a final outcome.
not have their own.
Member States have monitoring authorities to The Future of GLPs
inspect independent sites within their territory for GLP Despite ICH’s efforts to bring pharmaceutical testing
compliance. This is especially important if the sites are under a common implementation umbrella, a stan-
involved in multi-site studies. Joint inspections by the dardised set of GLP regulations has not appeared
monitoring authorities in more than one Member State on the horizon. Sponsors, laboratories and various
may be necessary, if the test site and test facility man- regulatory agencies have realized that a complete har-
agement are located in different countries. monisation of these regulations requires revisions on
Since dependent sites fall directly under the GLP topics specifically including:
responsibility of test facility management, full inspec- • master schedule content requirements
tion is not possible. Depending on national rules and • study protocol, amendment and deviation
practices, some Member States may choose to include approval process
dependent test sites within their territories in their • QA role and assignment
monitoring programmes. The inspection would be • management roles and responsibilities
done in conjunction with the responsible test facility. • test and control article characterisation
Additionally, the Member State’s test site monitor- requirements
ing authority can request a joint inspection with the • final study report management
Member State test facility monitoring authority, if they • closed study amendment methods
are different. • study record archiving parameters and mini-
Once all inspections have been completed, the mum required archiving time
inspector will report any findings. Some findings may • laboratory disqualification and reinstatement
result in a future follow-up inspection to ensure the methods
finding has been remedied. The test facility should
correct minor GLP principle deviations as soon as Overall, the GLP harmonisation remains a long-term
possible after being informed of them. The GLP mon- task, and its role in the future of GLPs remains unclear.
itoring authority may issue a statement regarding sites’ The original idea of harmonisation as a tool to ease the
burden of multinational companies still holds true. The

Chapter 25
actual implementation of a standardised set of regulations, this by primarily emphasising the accountability in each
along with their testing or trouble-shooting, may be one study phase and providing an audit trail of all GLP
of the biggest hurdles in harmonising GLP compliance. study activities to help regulatory agencies ensure the
data is accurate, traceable and complete.
Conclusion Preclinical studies are essential to a comprehen-
Preclinical studies are very important and increase sive drug or biologic product evaluation programme.
overall product development success. Preclinical studies The ultimate goal is to provide safe and effective drug
assist in discovering possible safety hazards to humans, or biologic products for humans, animals and the
and the data obtained help in assessing these findings’ environment.
relevance to potential clinical safety. Animal toxicity
References
study data are required to enable human clinical trials to 1. Safety Guidelines. ICH website. https://www.ich.org/page/
be conducted before a new drug or biologic is approved safety-guidelines” https://www.ich.org/page/safety-guidelines.
for market. Accessed 20 April 2020.
The core GLP regulation principles are universal, 2. Handbook: Good Laboratory Practice (GLP): quality practices
for regulated non-clinical research and development—2nd
regardless of the study type or test site. These principles edition. (2009). WHO website. https://www.who.int/tdr/publi-
are intended to ensure studies are conducted with suffi- cations/documents/glp-handbook.pdf ?ua=1. Accessed 21 April
cient independent oversight and management authority 2020.
to ensure data are accurate, reproducible and stored 3. Op cit 1.
4. OECD Series on Principles of Good Laboratory
securely to enable future documentation and specimen Practice and Compliance Monitoring. OECD iLi-
review. brary website. https://www.oecd-ilibrary.org/
GLPs’ value comes from providing a framework for environment/oecd-series-on-principles-of-good-laborato-
reducing error and strengthening each preclinical study’s ry-practice-and-compliance-monitoring_2077785x. Accessed
21 April 2020.
overall management and oversight. GLPs accomplishes

Chapter 26
Medicinal Product Clinical

Trials
Updated by Ashley Clark, MSc, RAC
OBJECTIVES on medicinal products for human use2 (Clinical

Trials Directive)
□ Understand the regulatory requirements for
conducting clinical trials in the EU under the □ Directive 2001/83/EC of the European
Clinical Trials Directive and the new Regulation Parliament and of the Council of 6 November
on Clinical Trials 2001 on the Community code relating to medic-
inal products for human use3 (Community Code
□ Understand the roles and responsibilities for Medicinal Products)
of Ethics Research Committees and Member
States’ competent authorities □ Commission Directive 2003/94/EC of 8 October
2003 laying down the principles and guidelines
□ Understand how to obtain authorisation for a of good manufacturing practice in respect of
clinical trial and the clinical trial application medicinal products for human use and inves-
submission process and contents tigational medicinal products for human use4
(GMP Directive)
□ Understand trial safety reporting and regulatory
notification requirements □ Commission Directive 2005/28/EC of 8 April
2005 laying down principles and detailed
□ Understand clinical trial data disclosure
guidelines for good clinical practice as regards
requirements
investigational medicinal products for human
use, as well as the requirements for authorisa-
tion of the manufacturing or importation of such
DIRECTIVES, REGULATIONS AND GUIDELINES products5 (GCP Directive)
□ Communication from the Commission (2010/C
□ Regulation No. 536/2014 of the European 82/01), Detailed guidance on the request to the
Parliament and of the Council on clinical trials competent authorities for authorisation of a
on medicinal products for human use, and clinical trial on a medicinal product for human
repealing Directive 2001/20/EC1 use, the notification of substantial amendments
□ Directive 2001/20/EC of the European and the declaration of the end of the trial (CT-1)6
Parliament and of the Council of 4 April 2001 □ Communication from the Commission (2011/C
on the approximation of the laws, regulations 172/01), Detailed guidance on the collection,
and administrative provisions of the Member verification and presentation of adverse event/
States relating to the implementation of good reaction reports arising from clinical trials on
clinical practice in the conduct of clinical trials medicinal products for human use (CT-3)7

Chapter 26
□ Volume 10 Clinical Trials guidelines, EudraLex— Introduction

The rules governing medicinal products in the Clinical trials are investigations in humans intended
European Union8 to discover or verify the effects of one or more inves-
tigational medicinal products (IMPs). Clinical trials
□ EudraLex-Volume 3 Scientific guidelines for generate essential data to evaluate medicinal prod-
medicinal products for human use9 ucts’ safety and efficacy, ability to improve or optimise
□ Inspection procedures and guidance for GCP existing therapies and medical treatments, develop
inspections conducted in the context of the innovative medicines and give patients access to new
Centralised Procedure10 treatments. Regardless of the marketing authorisation
(MA) procedure applied, Member States’ national com-
□ International Conference on Harmonisation petent authorities and the European Medicines Agency
(ICH) guidelines on clinical trials11 (EMA) rely on clinical trial data presented in the mar-
keting authorisation application (MAA) to form their
□ Development Safety Update Report opinions on whether the potential risks are outweighed
E2F (September 2011, EMA/CHMP/ by the therapeutic efficacy of the product.20
ICH/309348/2008)12 Previously, EU clinical trials were conducted
according to each individual Member State’s laws, regu-
□ Good Clinical Practice E6(R2) (CPMP/ lations and administrative provisions. Consequently, for
ICH/135/1995, Adopted 15 December 2016)13 many years, the regulatory landscape was characterised
□ General Considerations for Clinical Trials E8 by a wide array of national application and approval
(CPMP/ICH/291/95)14 processes, combined with a lack of standardisation in
applying Good Clinical Practices (GCPs) and Good
□ Auxiliary Medicinal Products in Clinical Trials, Manufacturing Practices (GMPs). However, after
Recommendations of the expert group on clin- recognising divergent national practices and rules
ical trials for the implementation of Regulation were detrimental to the effective conduct of trials,
(EU) No. 536/2014 on clinical trials on medicinal the European Commission (EC) adopted Directive
products for human use (28 June 2017)15 2001/20/EC on 4 April 2001 (Clinical Trials Directive),
governing clinical trials. The objective was to harmo-
□ Risk proportionate approaches in clinical trials, nise these processes and detail GCP and GMP legal
Recommendations of the expert group on clin- provisions across the EU to increase and standardise
ical trials for the implementation of Regulation protection of clinical trial participants’ rights. EU
(EU) No. 536/2014 on clinical trials on medicinal Member States were required to integrate these provi-
products for human use (25 April 2017)16 sions into their respective national legislation no later
than 1 May 2004. Clinical data submitted with a medic-
□ Summaries of Clinical Trial Results for inal product MAA in the EU had to be generated from
Laypersons, Recommendations of the expert clinical trials conducted in accordance with the Clinical
group on clinical trials for the implementation Trials Directive or, if the clinical trials were conducted
of Regulation (EU) No. 536/2014 on clinical outside the EU, conducted on equivalent principles to
trials on medicinal products for human use (26 those applied in the Clinical Trials Directive.
January 2017)17 Despite this initial harmonisation effort, the direc-
□ Clinical Trial Facilitation Group, Guidance tive’s staggered implementation into national laws and
document for sponsors for a Voluntary differing national competent authorities’ interpretations
Harmonisation Procedure (VHP) for the assess- triggered mounting concerns and criticisms about the
ment of multinational Clinical Trial Applications, regulatory and administrative burden, elevated costs
Version 418 and overall detrimental effect on clinical research in
the EU.21 Overall, stakeholders perceived the direc-
□ Clinical Trial Facilitation Group, Questions and tive as a significant impediment to innovation. The
Answers to the Annual Safety Report Frequently Impact on Clinical Research of European Legislation
asked questions regarding the Development (ICREL) project, financed by the EU 7th Framework
Safety Update Report (DSUR) (22 December Programme, measured and analysed the Clinical Trials
2011)19 Directive and related legislation’s direct and indirect
impact on all categories of EU clinical research and
stakeholders, including regulators, commercial and
noncommercial sponsors, Ethics Committees and

Medicinal Product Clinical Trials
competent authorities. On 17 July 2012, after numer- noninterventional studies or trials. It introduces sig-
ous public stakeholder consultations, including the nificant changes: a new centralised and coordinated
Heads of Medicines Agencies (HMA) and patient clinical trial submission and authorisation process; new
groups, the European Commission adopted Proposal concept of clinical trial risk proportionality; new terms,
for a Regulation of the European Parliament and of the such as low intervention trials, normal clinical practice,
Council on clinical trials on medicinal products for human auxiliary medicinal products; and publication of man-
use, and repealing Directive 2001/20/EC, with an impact datory results’ summaries understandable to laypersons
assessment report providing a detailed rationale for the in addition to the technical summary. One application
proposed changes. dossier will be submitted through a single submission
On 16 April 2014, Regulation (EU) No. 536/2014 portal, grouping all the clinical trial’s information,
of the European Parliament and of the Council on partially accessible to the public. A two-part parallel
clinical trials of medicinal products for human use, and scientific and ethical review will be conducted within
repealing Directive 2001/20/EC (European Clinical specific and shorter timelines: Part I will be an assess-
Trial Regulation (ECTR)) was adopted, repealing the ment coordinated between the relevant Member State
Clinical Trials Directive. This new directive is aimed and a Reporting Member State, leading to a single
at reducing the obstacles and hindrances stemming decision; and Part II will be an assessment performed
from the earlier directive’s implementation. Unlike by each Concerned Member State and national Ethics
the Clinical Trials Directive, the regulation is directly Committees, leading to a national decision. The Part II
applicable and overrules all EU Member States’ rele- assessment, the ethical review, remains under national
vant national laws. The ECTR became effective 16 June competent authorities’ and Ethics Committees’ purview.
2014, with an initial implementation deadline no earlier At the time of publication, the Clinical Trials Directive
than 28 May 2016 or once the new EU clinical trial (directive) still is fully in effect and implemented in all
portal, a single point of entry for clinical trial submis- Member States. Therefore, in the following sections, the
sions and authorisations, and its associated database, ECTR’s requirements are outlined whenever possible, to
become available in October 2018. At the core of the maintain clarity and usefulness, in comparison with the
ECTR’s implementation are the availability, operabil- directive’s requirements.
ity and functionality of the EU portal and database,
and upgrades to the legacy systems EudraVigilance Clinical Trial Legislation and Implementation
Clinical Trial Module, EudraCT and EudraCTR. Clinical trial legislation laid out requirements consis-
After an independent audit, EMA’s management tent with the Declaration of Helsinki’s principles.24 The
board concluded the EU portal and EU database have legislation provides safeguards to protect the rights,
achieved full functionality and the systems meet agreed safety and well-being of subjects participating in any
functional specifications, and six months after the clinical trial conducted in the EU for either authorised
Commission publishes a notice to that effect, ECTR or investigational medicinal products and to ensure
will become applicable. On 16 June 2017, EMA’s the investigation’s data are reliable and credible, for all
management board announced that “due to technical development phases (from first-in-human to interven-
difficulties with the development of IT systems, the tional postauthorisation trials), including bioavailability
application of the clinical trial regulation” had to be and bioequivalence studies. The extensive rules set for
postponed to 2019.22 In December 2019, the manage- subjects’ protection in the directive are upheld in the
ment board provided yet another update that the audit ECTR. The ECTR enforces these principles further by
of the clinical trials information system (CTIS) should adding protection of subjects’ dignity. It reiterates that
commence in December of 2020. In the interim, the the interests of subjects always should take priority over
CTIS has maintained an iterative delivery model to all others.25
maintain the existing systems’ functionality within short Figure 26-1 illustrates the iterative improvement of
development cycles.23 clinical trial legislation.
The ECTR introduces new requirements while Figure 26-2 summarises the ECTR’s goal and
improving or preserving former requirements deemed principles.
essential to ensure human subjects’ safety and rights and As noted in the introduction, the ECTR will take
data reliability and robustness generated in a clinical effect no later than six months after the EU portal is
trial, e.g., GCPs and GMPs. The requirements encom- deemed to meet all necessary functional specifications
pass clinical trial authorisation, conduct, reporting and system requirements and after publication in the
and data transparency and apply to trials conducted Official Journal, which has yet to happen as of early
in at least one site and in at least one EU Member 2020. Due to the delays in designing these systems and
State. Like the directive, the ECTR does not apply to technical difficulties with their development the EMA

Chapter 26
Figure 26-1. Clinical Trial Legislative Improvements
COMING SOON
Regulation (EU) 536/2014
TODAY
Directive 2001/20/EC EU Portal and EU Database
2004-2009 Implementation into ALL EU MS at once
PAST
National Laws
(Before 2004)
National Authorization: Streamlined Authorization:
National/MS Rules
CTA in each MS ONE CTA, ONE decision
Significant Variations in Each
Harmonization of: Largely controlled by MS
MS
Conduct of CT, CTA contents
No Harmonization
Authorization process Parallel Review:
GCP principles 1. Coordinated Scientific Review
EudraCT (RMS; CMS)
2. National, Ethics Review
(Each CMS/EC)
management26 board postposed the portal’s initiation • Risk Proportionate Approaches in Clinical
date and subsequently, ECTR’s application date to 2020. Trials—recommendations of the expert group
The system is anticipated to undergo an independent on clinical trials for the implementation of
audit for functionality in December 2020. Regulation (EU) No. 536/2014 on clinical
The transition period would allow clinical trial trials on medicinal products for human use, 25
applications submitted before the effective date to fall April 2017
under the Clinical Trials Directive’s requirements for • Auxiliary Medicinal Products in Clinical
three years. Upon ECTR implementation, an overlap Trials—recommendations of the expert group
of one year would follow and would allow application on clinical trials for the implementation of
submission under either the ECTR or the Clinical Trials Regulation (EU) No. 536/2014 on clinical
Directive until at least 36 months after the effective date. trials on medicinal products for human use, 28
During this transition period, the EU clinical June 2017
trial requirements will continue to be regulated under • Summaries of Clinical Trial Results for
the Clinical Trials Directive, augmented by the GCP Laypersons—recommendations of the expert
Directive. group on clinical trials for the implementation
These directives are supplemented by several EU of Regulation (EU) No. 536/2014 on clinical
guidance documents (available in a single volume from trials on medicinal products for human use, 26
EudraLex, The Rules Governing Medicinal Products in January 2017
the European Union)27 providing advice on application
format and the content of authorisation requests to As appropriate, these recommendations are briefly sum-
Ethics Committees and national competent authori- marised in the following sections below.
ties. Additionally, Volume 10 of the EudraLex includes The following directives remain effective:
guidance documents covering the existing European • Directive 2001/20/EC of the European
clinical trial database (EudraCT), monitoring and clin- Parliament and of the Council of 4 April 2001
ical safety, IMP quality and inspections. These directives on the approximation of the laws, regulations
and guidance documents provide a general, harmon- and administrative provisions of the Member
ised framework for trials conducted in the EU but States relating to the implementation of good
always should be read in conjunction with the relevant clinical practice in the conduct of clinical trials
Member State’s legislation and guidance documents. on medicinal products for human use
Notably, in anticipation of ECTR implementation, • Commission Directive 2005/28/EC of
multiple recommendation documents were issued for 8 April 2005 laying down principles and
further consultation and should be considered by spon- detailed guidelines for good clinical practice
sors to ensure better operational transition: as regards investigational medicinal products
for human use, as well as the requirements for

authorisation of the manufacturing or impor- Figure 26-2. Regulation (EU) 536/2014

tation of such products (GCP Directive)
• Commission Directive 2003/94/EC of 8
Goal:
October 2003 laying down the principles and
Foster innovation, ensure protection of participant
guidelines of good manufacturing practice in and quality and integrity of trial outcomes.
respect of medicinal products for human use
and investigational medicinal products for
human use (GMP Directive)
Principle:
In March 2010, the European Commission published Protection of Rights, Safety, Dignity, Well-Being of
Communication 2010/C 82/01 (CT-1).28 This docu- Subjects
ment provides detailed guidance on requesting clinical Data Reliability and Robustness
trial authorisation for a medicinal product for human
use from the competent authority, notification of sub- Enabling consistent implementation across all
Concerned Member States and requiring closer col-
stantial amendments and the declaration of the end of
laboration between National Competent Authority
the trial. It replaced the document ENTR/F2/BL D and National Ethic Committee, while supporting risk
(2003), dated October 2005. proportionate approach in clinical trials
In June 2011, the European Commission published
Communication (2011/C 172/01) (CT-3). This docu-
ment provides detailed guidance on collecting, verifying
and presenting adverse event/reaction reports arising “outer packaging” as in points (2), (6), (11), (12), (23)
from clinical trials on medicinal products for human and (24), respectively, of Directive 2001/83/EC Article
use, and enables a single Development Safety Update 1, thus; the same terms defined in the Clinical Trials
Report (DSUR) implementation and acceptance, per Directive may differ in meaning.
International Conference on Harmonisation’s (ICH) For example, the Clinical Trials Directive defines a
guideline, Development Safety Update Report E2F,29 serious adverse reaction (SAR) as “any untoward medical
replacing the Annual Safety Reports (ASR) the Clinical occurrence or effect that at any dose results in death, is
Trials Directive requires. life-threatening, requires hospitalisation or prolongation
In 2004, the EU HMA agreed to establish a of existing hospitalisation, results in persistent or signif-
Clinical Trials Facilitation Group (CTFG) to coordi- icant disability or incapacity, or is a congenital anomaly
nate clinical trials directive implementation. In 2009, or birth defect,” whereas Directive 2001/83/EC defines
CTFG implemented a Voluntary Harmonisation the term as “an adverse reaction which results in death,
Procedure (VHP), which is set up within the direc- is life-threatening, requires inpatient hospitalisation
tive’s legal framework. The latest guidance published or prolongation of existing hospitalisation, results in
by CTFG, for VHP sponsors, states, “With the new persistent or significant disability or incapacity, or is a
Regulation for CT (Regulation 536/2014) the coor- congenital anomaly/birth defect.” The most significant
dinated assessment of multinational trials will be difference between the two definitions is that the for-
addressed and this will limit the need for VHP, which mer does not require a confirmed causality link to the
will then be terminated when the Regulation comes investigated drug, whereas the latter, by using the term
into force for all clinical trials.”30 “adverse reaction,” implies a putative causality link.
Table 26-1 provides an overview of the major Adverse reactions are defined as “all untoward and
ECTR changes that may have the greatest impact on unintended responses to an investigational medicinal
regulatory strategy planning. More details are provided product related to any dose administered” in the Clinical
in the narrative sections of this chapter when relevant. Trials Directive, whereas Directive 2001/83/EC defines
the term as “a response to a medicinal product which
Definitions is noxious and unintended and which occurs at doses
Table 26-2 provides a side-by-side comparison of normally used in man for the prophylaxis, diagnosis or
selected Clinical Trials Directive and ECTR term therapy of disease or for the restoration, correction or
definitions. modification of physiological function.” Albeit minor
Article 2 of both the Clinical Trials Directive and at first glance, these variations may impact existing
the ECTR provide definitions. It is noteworthy the sponsor procedures or clinical trial management during
ECTR will apply the same definitions of “medicinal a clinical development program extending during and
product,” “radiopharmaceutical,” “adverse reaction,” beyond the transition period between the Clinical Trials
“serious adverse reaction,” “immediate packaging” and Directive and the ECTR.

Chapter 26
Table 26-1. Summary of Selected Significant Changes Under Regulation (EU) No. 536/2014 (ECTR)
Elements of ECTR Description/Comparison to Directive 2001/20/EC (Clinical Trials Directive)

Scope All clinical trials conducted in the EU excluding noninterventional studies.
The Clinical Trials Directive excludes noninterventional trials. Considering the nuance between the
definition of trial and study, the scope has been narrowed down implicitly. The ECTR broadly defines
a noninterventional study as “a clinical study other than clinical trial.”
Principle A clinical trial may be conducted only if: subjects’ rights, safety, dignity and well-being are protected
and always prevail over all other interests, and it is designed to generate reliable and robust data.
Albeit already existing in the directive (Paragraph 2) by reference to the 1996 version of the Helsinki
Declaration, the principle of dignity has been emphasised in the regulation by being mentioned up
front, in the first paragraph of the regulation.
Definitions
Clinical Study, Clinical Trial A clinical trial is considered a subset of a clinical study and has a narrower definition.
The ECTR definition of clinical study is similar to the definition of clinical trial in the Clinical Trials
Directive, which may mean some clinical trial types under the Clinical Trials Directive could be
outside the ECTR’s scope.
Non-interventional Trial/Study A study where the medicinal product(s) is (are) prescribed in the usual manner in accordance with
the MA’s terms. The patient’s assignment to a particular therapeutic strategy is not decided in
advance by a trial protocol, but falls within current practice, and the medicine’s prescription is
clearly separated from the decision to include the patient in the study. No additional diagnostic or
monitoring procedures shall be applied to the patients, and epidemiological methods shall be used
for the analysis of collected data.
The ECTR does not define the term “noninterventional.”

Low Intervention Trial This is a new category that introduces the concept of risk proportionate approaches in clinical trials.
If the trial is fulfilling all conditions: authorised Medicinal Product (Aut. MP) to be investigated
within the term of the MA or an IMP for which the use is evidence-based and supported by published
evidence on the safety and efficacy, and no substantial additional risk to normal clinical practice.
Less stringent rules in regard to: insurance requirements, monitoring and reporting obligations and
IMP traceability.
Normal Practice New. Treatment regime typically followed to treat, prevent or diagnose a disease or disorder. The
interpretation of this definition is left to each Concerned Member State.
In the Clinical Trials Directive, the term “current practice” is mentioned in the context of defining the
term “noninterventional trial.”
Auxiliary Medicinal Product New. Products used for clinical trial needs but are not IMPs: rescue medication (excludes placebos
(Aux MP) or reference/comparator). Authorised or unauthorised Aux MPs could be used with conditions for
unauthorised ones. Excludes concomitant medications.
Authorisation Procedure
One Dossier Single online EU Portal for all Member States in which the clinical trial will be conducted. The
EU Portal submission is to be made available to all national competent authorities of the Member State(s) in
which the trial will be conducted.
PART I to national competent authority: IMP Dossier (IMPD), Investigator’s Brochure (IB),
Administrative Documents, Protocol, Benefit-Risk
PART II to national competent authority and national Ethics Committee: Informed Consent, Clinical
Sites, Subjects’ Compensation
Note: some documents submitted to the national competent authority, such as IB and protocol, also
will be made available to the national Ethics Committee.
One Decision: Parallel Assessment Process: Reporting Member State proposed by sponsor
Coordinated Assessment PART I, scientific review: Reporting Member State Assessment/national competent authority. Report
valid for entire EU. Reporting Member State coordinates with national competent authority.
National Assessment
PART II, Ethics/Risk Assessment Review: Each Concerned Member State and its national competent
authority individually, for its own territory. The Ethics Committee organisation and logistics review
is left entirely to each Concerned Member State or national competent authority, and no details are
provided in ECTR.
National Ethics Committee and/or local Ethics Committees may be involved in the ethics/risk
assessment review.
This is similar to the situation prevailing under the Clinical Trials Directive.

Table 26-1. Summary of Selected Significant Changes Under Regulation (EU) No. 536/2014 (ECTR) (cont.)
Elements of ECTR Description/Comparison to Directive 2001/20/EC (Clinical Trials Directive)

Shorter Timeframe Assessment Report Part I and Part II within 45 days of validation date; validation 10 days. Tacit
authorisation if a Concerned Member State does not provide results within timelines. Extension can
be requested, however.
Streamlined Reporting
Serious Unexpected Adverse In newly established electronic database: new module in EudraVigilance database. Instead of
Reactions (SUSARs) reporting SUSARs to each national competent authority separately. DSURs (and/or ASRs) submitted
through the same portal.
Same as Clinical Trials Directive: reporting to Ethics Committee, 7-day and 15-day time limits for
reporting SUSARs to national competent authorities.
Clinical Trial Lifecycle: Clinical trial lifecycle events reported to EU Portal:
Notification of events Start of CT, first-subject-first-visit (start of enrolment), last-subject-last-visit (LSLV) (end of
within 15 days recruitment), LSLV-Last Member State, temporary halt, early termination, end of trial.
Clinical Trials Directive requires submission to each national competent authority and Ethics
Committee, as appropriate.
Public Disclosure of Data
EU Database New database to collect data submitted through the EU Portal.
Within One Year of Trial Technical summary of results (presumably similar to EUDRA CT format) and a summary in
Completion or Termination, understandable language for laypersons in the Member State in which the trial was conducted.
Regardless of the Outcome After trial ends, if clinical trial data submitted in an MAA, regardless of MAA status (approved or
withdrawn) or trial outcome.
Within 30 Days When clinical trial data are submitted in an MAA, the clinical study report is submitted to the EU
Database after obtaining MA or withdrawing application or procedure completed (opinion delivered
to sponsor or applicant).
Under the Clinical Trials Directive, an inves- participating in a trial and used in accordance with the
tigational medicinal product (IMP) is defined as a protocol. For instance, some clinical trial protocols require
pharmaceutical form of an active substance or placebo the use of such medicinal products as concomitant or
being tested or used as a reference in a clinical trial. rescue or escape medication for preventive, diagnostic or
IMPs include products already authorised but used or therapeutic reasons and/or to ensure adequate medical
assembled (formulated or packaged) differently than the care is provided for the subject. Medicinal products also
authorised form or used for an unauthorised indication may be used in accordance with the protocol to induce a
or to gain further information about the authorised physiological response (i.e., as a challenge agent). These
form. On this basis, provided requirement(s) are met, types of medicinal products do not fall within the IMP
reference products used as comparators should be con- definition and may be referred to as “noninvestigational
sidered IMPs. The Clinical Trials Directive applies to all medicinal products” (NIMPs). Member States may have
IMPs, including: their own slightly different interpretations of IMPs and
• chemical entities NIMPs, depending on whether the product in question is
• biotechnology products being used in accordance with its MA terms. If necessary,
• cell therapy products the sponsor should discuss protocol specifics with the
• gene therapy products competent authorities in those Member States in which
• plasma-derived products the study will be conducted prior to submitting a clinical
• other extractive products trial application.
• immunological medicinal products (such as As the UK negotiates the terms of its exit from the
vaccines, allergens and immune sera) EU, the event now referred to as “Brexit,” it is necessary
• herbal medicinal products to understand how and if the implementation of the
• radiopharmaceutical products ECTR in the region will be impacted. As of the official
• homeopathic products Brexit date, 31 January 2020,31,32 the UK Government,
including the MHRA, maintains that CTAs should be
Products not considered IMPs, as defined in Clinical submitted through the Common European Submission
Trials Directive Article 2(d), may be supplied to subjects Portal (CESP), and regulation of clinical trials will

Chapter 26
Table 26-2. Definitions of Selected Clinical Trials Directive and ECTR Terms
Terms Clinical Trials Directive (Article 2) European Clinical Trial Regulation (Article 2)
Clinical Study Any investigation in relation to humans intended:
(a) to discover or verify the clinical, pharmacological
or other pharmacodynamic effects of one or more
medicinal products; (b) to identify any adverse
reactions to one or more medicinal products; or (c)
to study the absorption, distribution, metabolism
and excretion of one or more medicinal products,
with the objective of ascertaining the safety and/or
efficacy of those medicinal products.
Clinical Trial Any investigation in human subjects intended to A clinical study that fulfils any of the following
discover or verify the clinical, pharmacological and/ conditions: (a) the assignment of the subject to
or other pharmacodynamic effects of one or more a particular therapeutic strategy is decided in
investigational medicinal product(s), and/or to identify advance and does not fall within normal clinical
any adverse reactions to one or more investigational practice of the Member State concerned; (b)
medicinal product(s) and/or to study absorption, the decision to prescribe the investigational
distribution, metabolism and excretion of one or more medicinal products is taken together with the
investigational medicinal product(s), with the object of decision to include the subject in the clinical
ascertaining its (their) safety and/or efficacy. study; or (c) diagnostic or monitoring procedures
in addition to normal clinical practice are applied
to the subjects.
Noninterventional A study where the medicinal product(s) is (are) A clinical trial that fulfils all of the following
Trial prescribed in the usual manner in accordance with the conditions: (a) the investigational medicinal
terms of the marketing authorisation. The assignment products, excluding placebos, are authorised; (b)
of the patient to a particular therapeutic strategy is not according to the protocol of the clinical trial, (i)
decided in advance by a trial protocol but falls within the investigational medicinal products are used
current practice, and the prescription of the medicine in accordance with the terms of the marketing
is clearly separated from the decision to include authorisation; or (ii) the use of the investigational
the patient in the study. No additional diagnostic or medicinal products is evidence-based and
monitoring procedures shall be applied to the patients, supported by published scientific evidence on
and epidemiological methods shall be used for the the safety and efficacy of those investigational
analysis of collected data. medicinal products in any of the Member States
concerned; and (c) the additional diagnostic or
monitoring procedures do not pose more than
minimal Additional risk or burden to the safety of
the subjects compared to normal clinical practice in
any Member State concerned.
Noninterventional A clinical study other than a clinical trial.
Study
Normal Clinical A treatment regime typically followed to treat,
Practice prevent or diagnose a disease or a disorder.
Investigational A pharmaceutical form of an active substance or A medicinal product that is being tested or used
Medicinal Product placebo being tested or used as a reference in a clinical as a reference, including as a placebo, in a clinical
trial, including products already with a marketing trial.
authorisation but used or assembled (formulated or
packaged) in a way different from the authorised form,
or when used for an unauthorised indication, or when
used to gain further information about the authorised
form.
Non Investigational A medicinal product that falls within Article 3(3) of Auxiliary MP: a medicinal product used for the
Medicinal Product Directive 2001/83/EC, while not falling within the needs of a clinical trial as described in the protocol,
definition of IMP as defined in Article 2(d) of Directive but not as an investigational medicinal product.
2001/20/EC.*
Authorised Auxiliary MP: a medicinal product
authorised in accordance with Regulation (EC) No
726/2004 or in any Member State concerned in
accordance with Directive 2001/83/EC, irrespective
of changes to the labelling of the medicinal product,
which is used as an investigational medicinal
product.

Table 26-2. Definitions of Selected Clinical Trials Directive and ECTR Terms (cont.)
Terms Clinical Trials Directive (Article 2) European Clinical Trial Regulation (Article 2)
Legal Representative Article 19: Article 74:
of Sponsor The sponsor or a legal representative of the sponsor A contact person in the EU who is the addressee of
must be established in the Community. all communications, might suffice if the concerned
Member State chooses not to apply paragraph 1.
Each Member State concerned has the choice as
to whether or not to require a legal representative,
provided that at least a contact person is
established in the Union.
Sponsor Individual, company, institution or organisation that Individual, company, institution or organisation
takes responsibility for the initiation, management that takes responsibility for the initiation, the
and/or financing of a clinical trial. Note: A sponsor is management and setting up the financing of the
not necessarily the party who funds the trial. clinical trial.
Article 72 covers acceptance and sharing of
responsibilities for co-sponsorship.
*Not defined in the directive; however, it is defined in Eudralex Volume 10—Chapter 3, in Guidance on Investigational Medicinal Products (IMPs) and
Non Investigational Medicinal Products (NIMPs) (Rev.1, March 2011)
** Reference ECTR, Preamble (12): The Recommendation of the Organisation for Economic Cooperation and Development (OECD) Council on the
Governance of Clinical Trials of 10 December 2012 introduced different clinical trial risk categories. Those categories are compatible with the clinical trial
categories defined in this Regulation as the OECD Categories A and B(1) correspond to the definition of a low-intervention clinical trial as set out in this
Regulation, and the OECD Categories B(2) and C correspond to the definition of a clinical trial as set out in this Regulation.
continue to align with EU regulations through the end examples are provided for rescue medications, challenge
of the negotiation period. What remains to be deter- agents (e.g., skin prick test), endpoints assessments (e.g.,
mined is how or if the ECTR will be implemented in PET radiopharmaceutical) and background treatment.
the UK after negotiations, whether the updated regu-
lation will be written into UK law or if equivalent laws Clinical Trial Regulatory Telematic Structure:
will be in place. The MHRA will continue recognising European Clinical Trial Database (EudraCT), EU
current clinical trial applications that have been previ- Clinical Trials Register, EudraVigilance, EU Portal,
ously authorised through 2020. EU Database
The ECTR provides further clarification on IMPs In August 2015, EMA published the “EU Telematics
(including comparator, active control or placebo) and Strategy and Implementation Roadmap 2015–2017,”33
products used in a clinical trial but not investigated, by which delineates, under Programme 2—Clinical Trials,
defining auxiliary medicinal products and authorised the full ECTR implementation strategy. The EU por-
auxiliary medicinal products. The ECTR enables the use tal will be used as a single-entry point for EU trials’
of unauthorised auxiliary medicinal products in justified submission, authorisation and supervision. Data and
cases, i.e., when the procurement of the authorised auxil- information submitted through the EU portal will be
iary medicinal product (AMP) is difficult. However, the stored in the EU database, which will serve as the public
regulation specifies the “price of the authorised auxiliary information source on clinical trial applications assessed
medicinal product should not be considered as having an and all EU clinical trials conducted. In the same year,
effect on the availability of such medicinal products.” EMA’s management board endorsed and published
The expert group on clinical trials published recom- “Functional specifications for the EU portal and EU
mendations for auxiliary medicinal products in clinical database to be audited,”34 which provides an overview of
trials. In the document, the group provides the following clinical trial systems and their specifications. Revision of
examples of AMP: “medicinal products used as rescue Section 6 of the “Functional specifications for the EU
medication, challenge agents, to assess endpoints in the portal and EU database to be audited” set out features
clinical trial, or background treatment.” Further, the to support making information public and added an
medicinal product should be related to and relevant Appendix on disclosure rules.35
for clinical trial design, which excludes ‘concomitant Overall, three distinct workspaces will be designed
medications.’ As outlined in preamble 54, “concomitant to enable each category of stakeholder to collaborate,
medications” are unrelated to the clinical trial and not submit or exchange documents, notifications and dis-
relevant for the design of the clinical trial.” In Annex 1 of close data to the public: sponsor workspace, national
the expert group’s document, detailed clarifications and

Chapter 26
competent authority workspace and a public workspace. EudraCT database information is confidential and, in
It is worth noting: general, accessible only to Member States’ competent
• A specific Ethics Committee access or work- authorities, EMA and the European Commission.
space is not planned. It is presumed at time of However, Regulation (EC) 1901/2006, as amended
publication, the national competent authority (Paediatric Regulation),36 introduced 26 January 2007,
will communicate information to national or established changes in the regulatory environment for
local Ethics Committees, as per their own paediatric medicines designed to better protect EU
national process(es) or system(s). children’s health. Paediatric Regulation Article 41 pro-
• The public workspace will enable the public vides the legal basis for publishing paediatric clinical
to access detailed information on all clinical trial information entered in this database.
trials conducted in the EU, in all official EU A subset of the EudraCT data is made available
languages. through the EU Clinical Trials Register (EUCTR), which
EMA manages on behalf of EU Member States and
In an effort to avoid duplication between the EU forms part of EudraPharm, the EU medicines database.
database, EudraCT and EudraVigilance databases, the In October 2013, EMA upgraded the EudraCT
existing systems will be evaluated: database, enabling sponsors to enter summaries of
• EudraCT and EUCTR: EudraCT will co-ex- clinical trial results. EudraCT Versions V9 and V10
ist with the EU portal and database during the subsequently were launched to make the results publicly
transition period as established by the ECTR. available through the EUCTR.37
Public and nonpublic legacy data will be han- Sponsors’ representatives are advised to register
dled after EudraCT stops accepting new data. with EudraCT to enable them to log into EudraCT
• EudraVigilance: the clinical trial module will and access the data.
be upgraded for electronic reports on sus- As of 21 July 2014, it became mandatory for spon-
pected unexpected serious adverse reactions sors to post clinical trial results in the EudraCT database.
(SUSARs), and an electronic reporting system A European Commission guideline and technical
will be created for Annual Safety Reports guidance describe the content and detail level of these
(ASRs) and Development Safety Update summary results. A typical summary provides informa-
Reports (DSURs) to be stored in a central tion on a given study’s objectives, explains how it was
repository, including related assessment reports designed and provides its main results and conclusions.
and actions. Data warehouse and other report- As of 1 January 2015, clinical reports contained in
ing tools will be developed to support safety all MAAs subsequently submitted are released as soon as
and/or clinical trial information analysis from a decision on the application has been taken (approval,
the EU-CT and EudraVigilance database. withdrawal or decision communicated to the applicant).
Functionality to forward SUSARs and ASRs Of interest to the regulatory professional, annual
to the concerned Member State also will be and monthly clinical trial statistics are available in the
developed. monthly Public Web Report on the EudraCT website.38
It is important to note that a clinical trial will have as
Presently, these systems undergo an iterative delivery many EudraCT numbers as the number of Member
model with continuous updates in functionalities to States in which it will be conducted.
maintain functionality for current users. The first step for any regulatory professional
The following sections present current information intending to obtain authorisation to conduct a clini-
on the EudraCT, EUCTR (accessed via EudraPharm) cal trial in one or multiple Member States is to create
and EudraVigilance. an account (some computer system requirements are
necessary for better functionality), register the trial and
European Clinical Trial Database (EudraCT) obtain a EudraCT number. The EudraCT number is
One of the major provisions of the Clinical Trials specific to the trial protocol and allows preparation of
Directive (Article 11) was the establishment of an electronic clinical trial application form for each
EudraCT, a database of all EU clinical trials from 1 Member State in which the trial will be conducted.
May 2004 onward. The database was set up to provide Thus, a record for each Member State will exist for
information on the status of all EU clinical trials and a specific trial. The EudraCT number is required in
is interfaced with the EudraVigilance Clinical Trial all documentation, i.e., administrative forms and the
Module (EVCTM) for e-submission of adverse event electronic clinical trial application, and is the essen-
reports. EMA supports these databases, which are tial reference for any communications with Ethics
available on the Internet through EMA’s homepage. Committees and national competent authorities.

The EudraCT website includes notices, guidances veterinary use and establishing a European Medicines
and training materials, which are updated periodically. Agency. This online repository for information was
The website’s content39 should be consulted before com- decommissioned in June of 2019.41
mencing the process.
Until the new EU portal is activated, the following EU Clinical Trials Register (EUCTR)
steps continue to apply: The EUCTR provides the description for Phase II to
1. Obtaining an authenticated security code from Phase IV adult clinical trials started after 1 May 2004
the database; the security code is valid for only and recorded in EudraCT, for which sites are located
one EudraCT number and expires after 24 in the EEA, and the description of any clinical trials in
hours. children with EU investigator sites and any trials form-
2. Once a security code has been obtained, a ing part of an agreed Paediatric Investigation Plan (PIP),
EudraCT number should be requested by including those with investigator sites outside the EU.
providing the standard information, e.g., the Most importantly, the website presents summary
sponsor’s name and the unique protocol code, results of clinical trials started after 1 May 2004. The
on the EudraCT request form. website also includes results submitted in an MAA, for
3. The assigned EudraCT number is commu- which a decision has been made (i.e., approval, with-
nicated to the sponsor by email. The sponsor drawal or opinion communicated to the Marketing
should include this information message in the Authorisation Holder (MAH)) and the paediatric trial
clinical trial application.40 The EudraCT num- summary results (with a reduced set of data fields)
ber format is YYYYNNNNNN-CC, where: completed by 26 January 2007, covered by an EU MA,
• YYYY is the year in which the number is including those covered by an agreed PIP.
issued. This information is available in English only.
• NNNNNN is a six-digit sequential However, the EUCTR does not provide information
number. on:
• CC is a check digit. • noninterventional medicinal product clinical
trials (observational studies on authorised
The EudraCT database also is utilised to generate Ethics medicines)
Committee and national competent authority clinical • clinical trials for surgical procedures, medical
trial applications (see Clinical Trial Application sec- devices or psychotherapeutic procedures
tion). The clinical trial application form in both XML • authorisation documents from national medi-
and PDF formats must be saved to a local computer; cines regulators or Ethics Committee opinion
it cannot be saved to the EudraCT database. Only documents
national competent authority personnel are able to save • clinical trials where all investigator sites are
application forms to the EudraCT system when they outside the EU/EEA, except trials forming
are submitted. EudraCT operates a help desk to support part of an agreed PIP
applicants with questions related to EudraCT (eudract@
ema.europa.eu). Submissions to national competent The registry does not enable participation in a clinical
authorities or Ethics Committees may not be accepted trial listed on the website.
as valid (and will be rejected) without a valid EudraCT As of February 2020, the EUCTR (clinicaltri-
number for that trial generated by the system. Detailed alsregister.eu) was displaying information for clinical
guidance on the EudraCT database is available in trials with a EudraCT protocol, including clinical trials
Eudralex Volume 10 Chapter I (revision of April 2004). conducted with subjects less than 18 years of age. The
register also displayed information on older paediatric
EudraPharm trials (within the scope of Paediatric Regulation Article
EudraPharm is intended as a source of information 45). Regulatory professionals may consider consulting
on all medicinal products for human use authorised this database when developing a regulatory strategy plan.
in the EU and European Economic Area (EEA) and
medicinal product clinical trial information, includ- Clinical Trials Directive Clinical Trial
ing products with or without an MA. EudraPharm Authorisation: Process and Clinical Trial Application
was established to meet Articles 57(1)(l) and 57(2) Authorisation Process
of Regulation (EC) No. 726/2004 of the European The sponsor may not start a clinical trial until one or
Parliament and of the Council of 31 March 2004 laying more Ethics Committees have issued a favourable
down Community procedures for the authorisation opinion and the relevant Member State’s national com-
and supervision of medicinal products for human and petent authority has not informed the sponsor of any

Chapter 26
grounds for nonacceptance. The procedures for these • Module 2 is optional and might consist of a
decisions may or may not run in parallel, depending on national or local Ethics Committee application
the sponsor and/or the Member State. As per Clinical form.
Trials Directive Article 7, each relevant Member State
must give an opinion if one or more clinical trial sites is Table 26-3 lists the core information Ethics
in its territory. Committees require. Other documents may be
Authorisation is a two-step process: submission requested, depending on the Member State’s national
of a clinical trial application to the national competent practices and traditions.
authority and required clinical trial information to an An Ethics Committee is required to review the
Ethics Committee, followed by the assessment period application within 60 days of confirming the applica-
to determine if the application is valid (meeting Clinical tion is valid. The application is considered valid if all
Trials Directive and national requirements). During the required documents are complete. Some local Ethics
assessment period, the sponsor may receive requests for Committees set specific dates of the month for appli-
information from national competent authorities and/ cation submission; the sponsor or applicant should
or Ethics Committees with a deadline for the sponsor’s be familiar with local provisions. Within this period,
response. The clock stops while the sponsor addresses the committee may send the applicant one request for
the requests. After the ethical or scientific assessment’s supplementary information, stopping the review clock.
completion, the process ultimately leads to an accep- Longer review periods are permitted for certain specific
tance or nonacceptance decision. Various aspects of product types: gene therapy and somatic cell therapy,
Clinical Trials Directive compliance are checked by the including xenogenic cell therapy and medicinal prod-
national competent authority and/or Ethics Committee, ucts containing genetically modified organisms. For
depending on Member States’ practices. Any delay in these products, except xenogenic cell therapy, the EC
authorising a clinical trial, according to the Clinical may extend the 60-day review period by 30 days. This
Trials Directive, within 60 days, is subject to some 90-day review period may be extended by a further 90
exceptions such as clinical trials involving medicinal days if consultation with an expert group or committee
products for gene therapy, somatic cell therapy includ- is required to meet national requirements. There is no
ing xenogenic cell therapy and products containing review period time limit for xenogenic cell therapy.
genetically modified organisms. Detailed guidance on submitted application format
and documentation for a clinical trial for medicinal
Application for Ethics Committee Opinion products for human use (revision 1 of February 2006) is
The sponsor, its legal EU representative and/or the available in EudraLex Volume 10, Chapter I.
principal/coordinating investigator for a multicentre
trial may file an application for an Ethics Committee Application for National Competent Authorities
opinion. A single Ethics Committee opinion is required Authorisation
for each Member State in a multicentre trial. The appli- As detailed in Clinical Trials Directive Article 9, the
cant must submit a valid application with all required sponsor (if based in the EU) or the sponsor’s legal EU
information; full details about required application representative must submit a clinical trial authorisation
information are provided in the guideline covering EC request to the national competent authority in each
submissions.42 The information required varies depend- Member State in which the clinical trial is planned. If
ing on the Member State to which the application the sponsor is not the applicant, a letter from the spon-
is made. Guideline attachments 1 and 2 include the sor authorising action on its behalf should be enclosed
requirements specific to each Member State.43 with the application. According to Clinical Trials
The Ethics Committee application form may Directive Article 9(2), the applicant must submit a valid
include two modules: application with all required documents.
• Module 1 is compulsory and common to all Table 26-3 presents the core information national
Member States. It includes the EudraCT competent authorities require. Other documents can be
application described in the detailed guidance requested based on national requirements.
on competent authority submission and infor- The Investigator’s Brochure (IB) content, for-
mation on the trial’s administration, trial site(s) mat and update procedures should comply with GCP
with principal investigator(s), trial design and Directive Article 8 and the GCP guideline (CPMP/
the IMP. This module provides the Ethics ICH/135/95). The approved Summary of Product
Committee with an easy trial design over- Characteristics (SmPC) will replace the IB if the IMP
view and an evaluation of the required review is authorised in any Member State, and if it is used
expertise. according to the MA’s terms. The IB, as approved by the

Table 26-3. General Contents of Applications to Ethics Committees and National Competent Authorities
Documents Ethics Committees National Competent

Authorities
Confirmation of receipt of the EudraCT number (copy of the email) X X
Cover letter with the EudraCT number and sponsor protocol X X
number
CTA form composed of Module 1 (and 2, if applicable) X X
Application form as an XML file (on a CD-ROM) and a PDF version (Module 2- national form)
(paper copy); this form is common to both the national competent
authority and Ethics Committee applications (Module 1), but
with different tick boxes (it must be prepared via EudraCT.
Some sections of the clinical trial application form may require
information in the national language (summary of protocol).
In case of fees, proof of payment X
List of competent authorities to which the application has been X X (optional, per Member
submitted and details of decisions, if available State)
Informed Consent Form (if original is in English, must be X
translated into Member State’s official language(s). Certification
may be required.)
Subject information leaflet (if original is in English, must be X
translated into Member State’s official language(s). Certification
may be required.)
Subject recruitment arrangements X
Clinical trial protocol with all current amendments (preferably X X
meeting ICH GCP guidelines)
Protocol summary in the national language(s) (synopsis) X X (optional, per Member State)
Investigator’s Brochure (IB) X X
Trial facilities: quality and certification as applicable X
Curriculum vitae of the coordinating or Principal Investigator X X (optional, per Member State)
• Investigator and sponsor liability insurance or indemnity X X*
• Investigator and subject compensation information X X*
• Agreement between the sponsor and the clinical trial sites X*
• Investigational Medicinal Product Dossier (IMPD) or X**
Simplified IMPD and, if applicable, NIMP dossier
• Content of IMP labelling
• Copy of the opinion of the Concerned Member State’s Ethics X
Committee, as soon as it is available, unless the Ethics
Committee informs the applicant it has copied its opinion to
the national competent authority
• Copy of the summary of scientific advice from any Member X
State or the agency regarding the clinical trial
• If the clinical trial is part of an agreed PIP, a copy of the X
agency’s decision on the PIP agreement, and the Paediatric
Committee’s opinion, unless these documents are fully
accessible via the internet
*This documentation should be submitted to the national competent authority if the concerned Member State has decided, in accordance with Article 6(4) of
Directive 2001/20/EC, that its national competent authority is responsible for considering any of those documents.
**IMPD is discussed in a separate section.

Chapter 26
competent authority (or SmPC for approved products), protocols that combine a number of different study
provides the reference safety information (RSI) for parts (e.g., single ascending dose, multiple ascending
assessing the likelihood and unexpectedness that any dose and food effects). Areas for consideration when
adverse reaction might occur during the clinical trial. As determining IMP risk factors include mode of action,
per the GCP Directive, the sponsor should update the nature of the target, relevance of animal species and
IB at least once a year and should provide an unbiased models and expected exposure.
benefit-risk assessment of the proposed clinical trial’s Sponsors are encouraged to seek scientific advice
appropriateness.44 from either EMA or the competent authority in the
Commission Communication 2010/C 82/0136 Concerned Member State on whether the IMP in
Sections 2.9 and 2.10 provide information on all the question falls within the higher-risk category, and
national requirements in an effort to harmonise the should consider seeking scientific advice from either
procedure across individual Member States. However, throughout clinical development when EMA guidelines
adoption of these recommendations has been staggered, appear to provide no answer or lack appropriate details.
resulting in an equivocal harmonisation among the Additionally, a sponsor wishing to deviate from avail-
Member States. able guidance should obtain advice.
The competent authority is required to review a The Clinical Trials Directive indicates written
valid application within 60 days of its receipt, although authorisation may be required before commencing clin-
individual Member States may apply a shorter period ical trials for the following:
as an internal target. The number of days concerned • medicinal products without an MA and ref-
Member States can take to validate clinical trial appli- erenced in Regulation 2309/93/EEC, Annex,
cations can vary, and these additional days should be Part A (i.e., gene therapy, recombinant DNA
included in the overall clinical study start-up timeline technology)
in a Concerned Member State. If an application is not • medicinal products containing a biological
valid, the national competent authority should inform product of human or animal origin, or biolog-
the applicant within the first 10 calendar days. ical components of human or animal origin as
The national competent authority may notify the an active ingredient
sponsor of grounds for acceptance before the 60-day
review period ends, thus allowing the sponsor to start The sponsor should become familiar with local laws,
the trial. If the national competent authority notifies the regulations and guidance documents for written
sponsor of grounds for nonacceptance, the sponsor may, authorisations, as an explicit approval letter is not
only once, amend the application to take those grounds always issued for these product types. Tacit approval
into account. sometimes may be the standard approach, depending
Sponsors of first-in-human (FIH) trials should on the national competent authority (exercised infre-
take into account the Guideline on strategies to identify quently, e.g., for certain types of trials). Where trial
and mitigate risks for first-in-human and early clinical commencement approval is based on tacit approval, i.e.,
trials with investigational medicinal products, adopted not receiving grounds for nonacceptance within the
20 July 2017. This revised guideline45 became effective specified time limit (60 days), it is advisable to prepare
1 February 2018. The initial version of the guideline a letter for the trial master file, including all pertinent
resulted from experiences in a UK FIH clinical trial in dates and the effective authorisation date.
2006, during which six healthy male volunteers expe- In certain circumstances, written authorisation
rienced severe systemic adverse reactions soon after from the concerned competent authority is mandated
an intravenous injection of the monoclonal antibody before starting clinical trials. This mandate applies to:
TGN1412. All six volunteers developed a cytokine • gene therapy and somatic cell therapy, includ-
release syndrome with multi-organ failure and required ing xenogenic cell therapy
intensive treatment and supportive measures. In January • medicinal products containing genetically
2016, during a clinical trial in France, for a compound modified organisms
named BIA10-2474, six men were hospitalised after
being administered multiple doses as per an approved Detailed guidance for requesting clinical trial authorisa-
protocol. One man was brain-dead shortly after hos- tion from competent authorities for a medicinal product
pitalisation, four others had neurological symptoms of for human use, notification of substantial amendments
varying severity and one man did not develop neurolog- and declaration of the end of the trial is available in
ical symptoms.46 The revised guideline further extends EudraLex Volume 10, Chapter I.47
EU guidance for the increasing practice of performing
FIH and early phase clinical trials with integrated

Amendment Notification For substantial amendments assessed by only the

Clinical Trials Directive Article 10(a) allows a clin- competent authority (e.g., changes to the IMP quality
ical trial to be amended after its commencement. section), the sponsor also should inform the Ethics
Amendments can be classified as nonsubstantial or Committee of the application. Similarly, the sponsor
substantial. Changes to the documentation submit- should inform the competent authority of any substan-
ted to the national competent authority or Ethics tial amendment for which only the Ethics Committee
Committees during a request for the authorisation’s is responsible (e.g., changes to the informed consent
ongoing assessment are not considered amendments. It form). Providing this information by submitting the
is the sponsor’s responsibility to determine whether an Notification of Amendment Form (Annex 2) and indi-
amendment is to be rated as substantial or not. Since cating in Section A4 that it is “for information only” is
2010, an amendment has been considered substantial acceptable. The sponsor may implement a substantial
if changes to the protocol or new information related amendment when the Ethics Committee opinion is
to scientific documents submitted (i.e., new toxicology favourable and the competent authority has raised no
data impacting IMP benefit-risk assessment) are likely grounds for nonacceptance. Clinical Trials Directive
to impact clinical trial participants’ safety or physical Article 10(a) requires an Ethics Committee to give
or mental integrity, or affect the trial’s scientific value. an opinion within 35 days. It does not set a time limit
Commission Communication 2010/C 82/01 Section within which the competent authority must respond to
3.4 provides examples of case-by-case decisions on such a notification. However, as guidance, the amend-
whether amendments to protocols, IMPs and IBs are ment may be implemented 35 days after the competent
substantial or nonsubstantial, as assessed by national authority receives a valid amendment notification if no
competent authorities. For aspects considered sub- grounds for nonacceptance are raised. The response time
stantial amendments by Ethics Committees, sponsors may be extended if the competent authority consults an
should consult Clinical Trials Directive Article 8. expert group or committee.
More information, including trial aspect head- Urgent safety measures should be taken to protect
ings that might involve a substantial amendment, is subjects from any immediate hazard that may affect their
provided in Attachment 5 of the guideline covering safety. Clinical Trials Directive Article 10(b) requires
submissions to competent authorities and in guideline sponsors and investigators to inform the competent
CHMP/QWP/185401/2004/final,48 covering chemistry authority and Ethics Committee of those new events
and pharmaceutical quality data. This latter guideline, and the measures taken as soon as possible, and for a
adopted in October 2006, defines harmonised require- substantial amendment, no more than 15 days later.
ments for the quality documentation to be submitted Such safety measures as temporarily halting enrolment
throughout the EU for multi-centre studies involving in the trial may be taken without prior competent
different Member States. Substantial amendments authority authorisation. However, the trial may not
to the documentation supporting the trial’s initial restart in that Member State until a substantial amend-
authorisation should be reported using the Substantial ment has been submitted. According to Clinical Trials
Amendment Form, which is common to both Ethics Directive Article 12, a competent authority may suspend
Committees and competent authorities. As for the ini- or prohibit a clinical trial if it has objective grounds for
tial clinical trial application, country-specific fees apply considering the authorisation conditions no longer are
to substantial amendment submissions. met, or has information raising doubts about the trial’s
This form is provided in Annex 2 of the competent safety or scientific validity. Before the Member State
authority submission guideline49 and is revised periodi- reaches its decision, except where there is imminent
cally. In addition, the application should contain: risk, it must ask the sponsor and/or investigator for their
• cover letter stating the amendment type and opinions within one week, addressing the issues raised.
reasons, EudraCT number, protocol number When the competent authority suspends a trial,
and amendment number it must inform the other competent authorities, con-
• proposed amendment summary cerned Ethics Committees, EMA and the European
• list of modified documents (identity, version, Commission.
date), pages with previous and new wording, if
applicable, supporting information, including Declaring a Clinical Trial’s End
new versions of modified documents A clinical trial’s end must be defined in the protocol,
• revised initial application XML file and PDF and any change to this definition must be notified
with amended data highlighted as a substantial amendment. Generally, it will be the
• comments on any novel amendment aspect date of the last trial participant’s final follow-up visit.
Any exceptions (e.g., date of database lock) should be

Chapter 26
justified in the protocol and/or application form. The national and local laws, regulations and practices for
sponsor must submit a Declaration of the End of the conducting these studies with human subjects.
Trial Form to the national competent authority and Notably, postauthorisation safety studies (PASS),
Ethics Committee when: as defined in Directive 2001/83/EC Article 1(1), either
• the trial ends in the Concerned Member imposed upon MA or not, often are noninterventional
State’s territory trials. Noninterventional imposed PASS are assessed
• the complete trial has ended in all participat- by the Pharmacovigilance Risk Assessment Committee
ing centres in all countries within and outside (PRAC), except studies to be conducted in only one
the EU Member State that requested the study according to
Directive 2001/83/EC Article 22a. In the latter situa-
This form is in Annex 3 of the competent authority tion, the study authorisation must be from the Member
submissions guideline. In this form, the applicant, on State national competent authority that requested the
the sponsor’s behalf, confirms a summary (or synop- PASS, and as per the Clinical Trial Directive or national
sis) of the clinical trial report will be submitted to the competent authority process (when the directive is no
concerned national competent authority and Ethics longer effective). Both noninterventional PASS types
Committee as soon as possible and within one year after fall outside the scope of the ECTR. Under the directive,
the trial ends in all countries. information about ongoing PASS may be found in the
The sponsor must notify the concerned national EU PAS Register.50 This IT platform enables public
competent authority and Ethics Committee of the trial’s access to postauthorisation study protocols, study results,
end within 90 days. The national competent authority related publications and other relevant information.
is responsible for entering this information into the For interventional postauthorisation efficacy stud-
EudraCT database. In the event the sponsor stops ies, the authorisation and study conduct fall under the
enrolment in the study prematurely, before the declared scope of Directive 2001/20/EC and, thus, are subject to
end-of-study date (or the date that coincides with the the national clinical trial authorisation process until it is
last subject visit) stated in the protocol, it must notify superseded by the ECTR. Under the ECTR, the spon-
the concerned national competent authority and Ethics sor may evaluate whether the PASS could be considered
Committee as soon as possible, but within 15 days from a low-intervention trial (i.e., a trial with an authorised
when the trial is halted, clearly explaining the reasons. medicinal product) based on the risk-proportionate
approach.50
EU Clinical Trial Regulation Clinical Trial
Authorisation: Process and Clinical Trial Clinical Trial Authorisation
Application Before they can begin, all clinical trials falling under the
Under the ECTR, once the EU portal and database ECTR must be authorised by each Concerned Member
are available, there will be a single point of clinical trial State where the trial will be conducted. A clinical trial’s
application submission—the EU portal—no matter start is defined as the first recruitment of a potential
how many Member States are involved. The ECTR subject for a specific clinical trial, unless defined dif-
harmonises the rules for initiating and conducting clini- ferently in the protocol. Thus, limited activities may be
cal trials and the contents of clinical trial applications to undertaken before the trial is authorised. A clinical trial
national competent authorities and Ethics Committees. will be authorised only if subjects’ rights, safety, dignity
The EU portal will provide stakeholders an exclusive and well-being are protected and prevail over all other
platform for interaction in the clinical trial process, interests, and the trial is designed to generate reliable
mainly for clinical trial application submissions and and robust data. Clinical trial information is subject
maintenance and EU authorisations. Excluded from the to separate parallel scientific and ethical reviews. The
ECTR’s scope are all noninterventional studies broadly scientific review is coordinated. The Part I assessment is
defined as “clinical studies other than clinical trials,” conducted by the Reporting Member State, proposed
which means the following study types likely may be by the sponsor in the clinical trial application dossier, in
excluded: observational studies, epidemiological studies coordination with the other Concerned Member States.
or studies meeting all noninterventional trial conditions, During the Part I assessment, the Reporting Member
including studies in which IMP use is evidence-based State’s national competent authority, in conjunction
and supported by published scientific evidence of the with each Concerned Member State’s competent
IMP’s safety and efficacy in any Concerned Member authority, aims to evaluate the proposed trial’s method-
State. The researcher or sponsor of any study(ies) not ological aspects and whether its design is scientifically
falling under the ECTR may be required to follow only sound, will generate robust and reliable data and com-
ply with ECTR principles and requirements. For the

Part II assessment, each Concerned Member State’s 1. Clinical trial application dossier submission
national competent authority, in coordination with local meeting the requirements described in ECTR
or national Ethics Committees, as appropriate, inde- Annex 1:
pendently reviews the proposed trial under its respective a. The sponsor may submit dossier Parts I
national legislation. Each national competent authority and Part II simultaneously.
and Ethics Committee evaluates whether the trial will b. If the sponsor submits only Part I for
be conducted in a manner that ensures requirements review and agreement, Part II may be
and expectations for subjects’ protection are met, includ- submitted up to two years after the Part
ing information and consent enrolment procedures. I assessment is completed. However, Part
The ethical review encompasses, but is not limited to, II cannot be submitted until the Part I
evaluation of the exclusion periods, run-in/wash-out assessment report is completed.
periods (e.g., period when all subjects do not receive an c. Upon submission, the sponsor must
approved treatment), compensation scheme, investiga- propose one of the Concerned Member
tors’ qualifications, overall research site capability and States as the Reporting Member State.
financial provisions. The Reporting Member State is confirmed
Each Concerned Member State is responsible for within six days.
ensuring Ethics Committees’ reviews meet ECTR time- 2. Dossier validation is confirmed by Day 10. If
lines and procedures for the ethical assessment (Part there is a request for information or any inqui-
II assessment). Importantly, a single decision must be ries, the applicant has 10 days to answer (the
rendered or communicated within five days from the clock stops), and the Reporting Member State
reporting date of the Part I assessment, or from the last has five days following receipt of the respon-
day of the clinical trial application’s Part II assessment, se(s) to confirm validation to the applicant.
whichever is later. The clinical trial authorisation deci- Only one clock stop is permitted. The clinical
sion is made after both assessments are completed. The trial application dossier is considered valid
single decision can be authorised, authorised subject if it meets Annex 1 requirements for Part I:
to conditions or authorisation can be refused for all Sections B to J and Q, and Part II: Sections K
Concerned Member States. to R.
A Concerned Member State must refuse to autho- 3. Parts I and II assessments are executed in par-
rise a clinical trial if it disagrees with the Reporting allel within 45 days and up to 76 days (with
Member State’s conclusion about the Part I assessment questions and extension). After the applicable
report, for any of the following reasons: period, a decision must be rendered on the
• clinical trial participation would mean a sub- trial’s acceptability.
ject receives inferior treatment compared to 4. Within five days of the final Part I assess-
normal clinical practice ment report or Part II assessment by each
• subject safety, data reliability and robustness Concerned Member State, whichever is later,
issues are not satisfied according to the Part a decision must be communicated to the
1 assessment; infringement of the Member applicant.
State’s national law (e.g., gene therapy result-
ing in modifications to the subject’s germ line Assuming the validation takes 10–25 days, the overall
genetic identity, or laws restricting the use of process could take 60–106 days.
specific human or animal cells)51 Despite the ECTR’s significant improvements,
• the Member State finds, on duly justi- a clinical trial still could be refused in some Member
fied grounds, noncompliance with aspects States yet accepted in others. This means individual
addressed in the assessment report’s Part II; Member States may decline to participate in a trial even
or an Ethics Committee has issued a nega- when others already have agreed to it.
tive opinion that is, in accordance with the Applications can be withdrawn at any time, up
Concerned Member State’s law, valid for all to the reporting date, but only if withdrawn in all
the Member State’s Ethics Committees Concerned Member States.
Resubmission is possible in a Member State that
When the Reporting Member State concludes, after has refused an application or following a withdrawal,
the Part I assessment’s scientific review, that the clinical but the resubmission will be considered a totally sepa-
trial is not acceptable, that conclusion will be deemed to rate new clinical trial application, with a new EudraCT
be the conclusion of all Concerned Member States. number.
The overall process can be summarised as follows:

Chapter 26
Figure 26-3. Clinical Trial Authorization Procedure
STEP 1: Validation 10-25 days
RMS Validation
Validation
Confirmed questions Decision
CTA by OR
10 days to +5 days
Day 10
6 days respond
STEP 2: Assessments 45-76 days
Step 2A: Part I Assessment by RMS with CMS;

Decision by Day 45 or up to 76 days with questions
and extension Decision
Valid CTA
Step 2B: Part II Assessment by each CMS; 45-76d
Decision by Day 45 or up to 76 days with questions
and extension
Additional countries not included in the original As illustrated in Figure 26-4, the Reporting Member
application may be added subsequently, with the same State’s national competent authority submits an ini-
Reporting Member State as the initial application. tial (Part I) draft assessment report within 26 days
Figure 26-3 illustrates the overall process. to Concerned Member States’ competent authori-
ties. Concerned Member States’ national competent
Clinical Trial Application—Part I Assessment authorities must review and provide comments to
As mentioned previously, Part I is a coordinated scien- the Reporting Member State’s competent authority
tific assessment, and the reporting and other concerned within 12 days, and the Reporting Member State con-
national competent authorities will determine: solidates such input within seven days. To obtain and
• classification of a proposed clinical trial as a review additional sponsor or applicant information, the
low-intervention clinical trial Reporting Member State can request an extension of up
• therapeutic and public health benefit aspects, to 31 days. The sponsor has 12 days after receiving the
including the trial’s relevance, and generated request to respond, during which the clock stops. If the
data’s reliability and robustness sponsor or applicant does not provide additional infor-
• subjects’ risks and inconveniences include the mation within 12 days, the application will be deemed
intervention’s characteristics compared to nor- to have lapsed in all Concerned Member States.
mal practice The Reporting Member State’s national competent
• IMP auxiliary products’ manufacturing or authority issues a final draft assessment report to each
importation compliance with ECTR Chapter 9 Concerned Member State’s competent authority and
• compliance with ECTR Chapter 10 labelling the sponsor and, within five days, a single decision is
requirements rendered for Part I acceptance.
• IB completeness and adequacy
Clinical Trial Application—Part II Assessment
As illustrated in Figure 26-5, each national and/or
local Ethics Committee (coordinated by its relevant
national competent authority) performs an initial Part
II assessment within 19 days. To obtain and review this

Figure 26-4. Clinical Trial Application Scientific Assessment
Step 2A: Part I Scientific Assessment
Reporting
Member State Part I- DAR
(RMS/NCA) to RMS
CMS Review
Concerned Consolidation
Initial Draft Member State/
12 days
Assessment NCA 7 days
Report (DAR) (CMS)
26 days
Part I Clock extension + up to

Final AR To CMS Acceptance 31 days
and Sponsor Questions to Sponsor
Day 45 -76 12 days to reply
additional information from the sponsor or applicant, On 25 July 2017, ANSM published an updated report
the Ethics Committee or national competent authority of this pilot programme.
can request an extension of up to 31 days. All Concerned
Member States, Ethics Committees and national ECTR Clinical Trial Application Dossier
competent authorities have the same deadline but, inde- Dossier contents and requirements are delineated in
pendently and separately, could request an extension. ECTR Annex I. Document language requirements
If the sponsor or applicant does not provide addi- (except labelling, which must be in the Concerned
tional information within 12 days, the application will be Member State’s language) are left to each Member
deemed to have lapsed in all Concerned Member States. State’s discretion.
The Concerned Member States’ national competent Table 26-4 summarises those requirements. The
authorities and Ethics Committees issue a final draft sponsor must submit a signed document specifying:
assessment report to the sponsor within 45 days and, the information provided is complete; the attached
within five days, a national decision is rendered on the documents contain an accurate account of the infor-
acceptance of Part II. mation available; the clinical trial is to be conducted
Of note, the ECTR imposes, although without in accordance with the protocol as well as the ECTR.
clear delineation, a coordination process between For low-intervention trials, the applicant is required to
national competent authorities and Ethics Committees. submit a detailed justification supporting the applicant’s
In most countries, Ethics Committees rarely commu- risk evaluation in the cover letter.
nicate with national competent authorities. In some The Expert Group on Clinical Trials recommends53
Member States, this communication could be more considering the provisions of the Recommendation
cumbersome due to the number of Ethics Committees of the Organisation for Economic Cooperation and
involved in research evaluation. The French agency, Development (OECD), which introduces different risk
Agence Nationale de Sécurité du Médicament et des categories for clinical trials. Low-intervention clinical
Produits de Santé (ANSM), launched a pilot programme trials, as defined in the regulation correspond to the
in June 2015 to “anticipate the next stages in the organ- OECD categories A and B(1). The justification should
isation and coordination of assessments carried out by support Article 2(3)(c): “the additional diagnostic or
ECs and ANSM” to review clinical trial applications.52 monitoring procedures do not pose more than minimal

Chapter 26
Figure 26-5. Clinical Trial Application: Part II Assessment
tep 2B: Part II Ethics Assessment via each Concerned

S
Member State/National Ethics Committee
Each Concerned Final Member State/

Member State – National Ethics
NCA Interaction with Committee Part II DECISION
National Ethics Ethics Assessment Day 45 -76
Committee Report
Initial Assessment to Sponsor
National EC
Review
19 days
Clock extension +
up to 31 days
Questions to Sponsor
12 days to reply
additional risk or burden to the safety of the subjects Detailed guidelines are anticipated, since the ECTR
compared to normal clinical practice in any Member does not provide enough details.
State concerned.” The expert group clarifies further the
concept of acceptable or minimal burden by provid- Clinical Trial Management Considerations and
ing some examples that “may be accepted as minimal Notifications
additional burden, thus rendering the clinical trial a For low-intervention clinical trials using an evi-
low-intervention one: measuring height and/or weight, dence-based IMP supported by published scientific
questionnaires, analysis of saliva, urine, stool samples, evidence of its safety and efficacy, the sponsor must
EEG and ECG measurements, blood withdrawal propose one Concerned Member State where the use
through a pre-existent catheter or with minimal addi- is evidence-based as a Reporting Member State. The
tional venipuncture.”54 Reporting Member State determines whether the pro-
As mentioned previously a Member State national posed clinical trial is a low-intervention trial if claimed
competent authority or Ethics Committee may differ by the sponsor. After any substantial modification to
in opinion from other Concerned Member States or Part I, the clinical trial can be reassessed to confirm it
Ethics Committee about the acceptable minimal risk still meets the definition of a low-intervention trial.
or burden and thus require modification to the pro- The ECTR lessens requirements for low-interven-
tocol design or reject the proposed classification as a tion trials, such as:
low-intervention trial, and require modifications to the • Informed Consent: simplified approach by
submission content. which the potential subject, after receiving
information required by the ECTR, does not
Amendments object to participating in the clinical trial
The ECTR provides a process for substantial amend- • IMP traceability, storage, return and
ments to Part I or II. It would be similar to a Part I or destruction
II assessment as appropriate, with up to 38 days for • clinical trial monitoring
assessment after validation and a 31-day extension if • clinical trial master file
additional information is required; a decision is com- • no additional damage compensation could
municated within five days of the assessment report. be required, with conditions applied, if a

Table 26-4. Contents of Clinical Trial Application Dossier per the ECTR
Part I Part II
(Annex I (Sections B to J, Q)) (Annex I (Sections K to R))
Cover letter Recruitment arrangements (information per Concerned
Member State)
EU application form (EudraCT-CTA form) Subject information, informed consent form and informed
consent procedure (information per Concerned Member
State)
Protocol Investigator suitability (information per Concerned
Member State)
Investigator’s Brochure (IB) with Reference Safety Suitability of the facilities (information per Concerned
Information (RSI) or RSI separately, or SmPC Member State)
Documentation relating to compliance with GMP for the Proof of insurance coverage or indemnification
investigational medicinal product (information per Concerned Member State)
Investigational medicinal product dossier Financial and other arrangements (information per
Concerned Member State)
If applicable, auxiliary medicinal product dossier Proof data will be processed in compliance with EU law on
data protection
If available, scientific advice and Paediatric Investigation
Plan (PIP)
Content of IMP labelling
Proof of fee payment (information per Concerned Member
State)
(Fees will apply per application per Member State; to be
determined)
Note: The ECTR is unclear about how some documents submitted in Part I, i.e., IB, RSI, protocol, will be made available to Ethics Committee. It is pre-
sumed the concerned national competent authority(ies) would provide these documents per their national system and/or process.
compensation system already is in place in the data outside the trial’s protocol in compliance with the
Member State’s territory relevant national law for personal data protection.
• safety reporting Incidentally, in the context of the ECTR, the
Expert Group on Clinical Trials for Implementation
The Expert Group on Clinical Trials for of ECTR published for consultation, “Ethical con-
Implementation of ECTR also provides detailed recom- siderations for clinical trials on medicinal products
mendations for safety reporting, IMP management, trial conducted with minors.”56 The expert group provides
management and monitoring and trial documentation recommendations on balancing risk and benefit while
of low-intervention trials.55 considering the prospect of direct benefit to the minor
ECTR Article 35 provides specific, clear rules to concerned and advice on the informed consent process
apply to clinical trials in emergency situations to obtain for various age or maturity groups.
informed consent. If the trial meets the Article 35 con- The sponsor must notify the start date for recruit-
ditions, the “informed consent to participate in a clinical ing, first-subject-first visit (start of enrolment), end of
trial may be obtained, and information on the clinical recruiting, last-subject-last-visit (LSLV), LSLV-last
trial may be given, after the decision to include the Member State, suspension, temporary halt, early termi-
subject in the clinical trial, provided that this decision is nation and end of trial via the EU portal within 15 days.
taken at the time of the first intervention on the subject.” Each of these events is defined in the ECTR.57
Per ECTR Articles 28(2) and (3), the scientific The sponsor must monitor compliance with the
researcher may use stored data obtained after informed ECTR and GCPs and report serious GCP breaches
consent before the subject’s participation in the trial within seven days via the EU portal. A ‘serious breach’ is
ended. However, the scientific researcher must use the a breach likely to affect subjects’ safety and rights or the

Chapter 26
reliability and robustness of data generated in the trial In parallel with the above-mentioned changes
to a significant degree. and consultation, ICH confirmed in January 2017
On 15 December 2016, EMA’s Committee for its approach60 for “renovation of the ICH Guidelines
Medicinal Products for Human Use (CHMP) adopted related to clinical trial design, planning, management
the revised ICH Guideline for Good Clinical Practice and conduct.”61 The scope of the renovation would
E6(R2), which became effective 14 June 2017.58 The include both the current General Considerations for
GCP guideline is applicable under the directive and Clinical Trials E8 and Guideline for Good Clinical Practice
will be applicable under ECTR. The revised guideline E6. The organisation aims to “address broader concern
expands the previous guideline to account for advances about the principles of study design and planning for an
in electronic data recording and centralised monitoring, appropriate level of data quality” by revising E8 and the
and integrates previous amendments to “encour- necessary “flexibility to anticipate and address a broader
age implementation of improved and more efficient range of study types and data sources” by revising E6.
approaches to clinical trial design, conduct, oversight, Under ECTR, the sponsor must submit all inspec-
recording and reporting while continuing to ensure tion reports from third-country authorities (non-EU
human subject protection and reliability of trial results.” Member States) concerning the clinical trial to each
Notably the revised guideline: Concerned Member State through the EU portal
• defines the terms “certified copy,” “monitoring (when made available). If requested by a Concerned
plan” and “validation of computerized systems” Member State, the sponsor must provide a transla-
• clarifies investigator responsibility in “super- tion of the report or of its summary in the Concerned
vising any individual or party to whom the Member State’s official language.
investigator delegates trial-related duties
and functions conducted at the trial site,” in Investigational Medicinal Product Dossier
addition to ensuring that such “individual or The Investigational Medicinal Product Dossier (IMPD)
party is qualified to perform those trial-related must justify the quality of any IMP to be used in a
duties and functions” clinical trial, including reference products and placebos.
• expands requirements for documentation It also must provide data from IMP nonclinical studies
management such that “source data should be and previous clinical use or justify why information is
attributable, legible, contemporaneous, origi- not provided. An overall benefit-risk assessment must
nal, accurate and complete. Changes to source be included to justify the protocol provisions for which
data should be traceable, should not obscure approval is sought.
the original entry and should be explained if A full IMPD submission is required if the IMP’s
necessary.” information has not been assessed previously as part of
• requires the sponsor to implement a quality an MAA in any Member State or as part of a clinical
management system that encompasses “the trial application to the concerned national compe-
design of efficient clinical trial protocols and tent authorities. The IMPD format should follow
tools and procedures for data collection and the Common Technical Document (CTD) headings.
processing, as well as the collection of informa- However, it is anticipated some CTD headings could
tion that is essential to decision making” be inappropriate or impossible to complete for all IMPs.
• requires the sponsor to identify, evaluate, con- The dossier requirements depend on many factors,
trol, communicate and review potential and including the IMP’s nature, the development stage, the
identified risks to human subject protection population to be treated, the disease’s nature and sever-
and test results’ reliability ity and the nature and duration of IMP exposure. If it is
• instructs on the risk-based approach for trial necessary to omit data for reasons that are not obvious,
monitoring scientific justification should be provided.
The applicant may cross-reference the IB for the
On 22 May 2017, EMA issued for public consultation IMPD’s nonclinical and clinical sections. When con-
a Draft Guideline for the notification of serious breaches sidering this strategy, the sponsor should ensure the IB
of Regulation (EU) No. 536/2014 or the clinical trial contains sufficient information in an appropriate format
protocol.59 The draft guideline includes requirements to to enable national competent authority review. In some
manage serious breaches, clarifies the process on how instances, it also may be necessary to cross-reference the
to report serious breaches and provides general consid- IMPD submitted by another sponsor to a Concerned
erations to help determine when an ECTR, GCP or Member State. This requires a letter of authorisation
protocol breach may be considered reportable. from the sponsor that submitted the IMPD.

Reference Safety Information (RSI) may be person must certify the release of each batch of mate-
included in the IB, and the section should be identi- rial for clinical trials, including imported material. Key
fied conspicuously or it could be a separate document. GCP Directive points include the IMP manufacturing
As noted by the Heads of Medicines Agency’s licence, which differs from a manufacturing licence for
Clinical Trials Facilitation and Coordination Group medicinal products for human use. Annex 13 also covers
(CTFG) in March 2018, the RSI requirements62 are IMP labelling; per Clinical Trials Directive Article 14,
described slightly differently “in various regulatory labelling must be in the official language of the Member
documents like the Clinical Trials Directive 2001/20/ State in which the trial will be conducted. The sponsor
EC, the CT-1 (2010/C 82/01) and CT-3 (2011/C should review the Concerned Member States’ laws,
172/01) guidance of the EU Commission as well as regulations and administrative provisions, since addi-
ICH E2F (Development Safety Update Report) of tional provisions beyond Annex 13 may be applicable.
the International Conference of Harmonization, with The 2010 revision of Annex 13 provided further guid-
regard to type and format as well as update of the docu- ance on reference and retention samples, clarified the
ment.” Importantly, the RSI provides “the safety profile meaning of “reconstitution” as referenced in Directive
of an IMP, the basis for expectedness assessment of 2005/28/EC and provided instructions for batch cer-
an adverse reaction for expedite reporting and annual tificate information. It emphasised the principle of
safety reporting, as well as surveillance of participant’s independence between production and quality control
safety in a clinical trial by regulatory (and ethic) bodies.” functions, especially in cases where a small number of
A simplified IMPD may be submitted if the personnel is involved.
IMP information has been assessed previously as part
of an MAA in any EU Member State or as part of Potential ECTR Impact
a clinical trial application to a Concerned Member Overall, the ECTR does not impact IMPD contents
State’s national competent authority. The European significantly (Annex 165, Section G). However, it does
Commission has provided detailed guidance on simpli- delineate the requirements of the simplified IMPD.
fied IMPD content.63 Annex 1, Section G integrates previous Commission
For marketed products, where the product is to be Communication 2010/C82/) (CT-1). GMP require-
used in accordance with the current SmPC, the sponsor ments are delineated in Chapter IX, largely aligned
may submit the current SmPC version as the IMPD. In with Directive 2001/83/EC, including IMP release by a
that case, the IMP is must be used in the same form, for qualified person. The Commission will issue delegating
the same indications and with a dosing regimen covered acts to supplement requirements for IMP GMPs and
by the SmPC. It also may be used to support studies inspections. The ECTR brings much-needed flexibility
with dosage regimens outside the SmPC’s scope, if jus- and clarification by defining auxiliary medicinal prod-
tification is provided. ucts (Aux MP) and allowing the use of unauthorised
auxiliary medicinal products, albeit with restrictions. A
Good Manufacturing Practices dedicated Annex VI provides additional requirements
IMPs must be manufactured in compliance with the for IMP and Aux MP labelling. Notably, under A1.1,
Good Manufacturing Practices (GMPs), set out in A2.1 and A2.2, the labelling for immediate packaging
Directive 2003/94/EC and the guidance on apply- and outer packaging, even for small containers such
ing those principles set out in Annex 13 (revised July as ampoules, must bear “period of use (expiry date or
2010) to the Community Guide to GMP.64 Annex 13 re-test date as applicable), in month and year format
provides GMPs applicable to IMPs, comparators and and in a manner that avoids any ambiguity.” Annex VI
non-IMPs, such as quality management, personnel, allows the use of a centralised system to provide some
documentation and production, as well as ordering, of the required information but restricts the use of these
shipping and returning clinical supplies. The Annex 13 systems for the period-of-use (typically, sponsors have
provisions are at the interface with, and complementary used interactive response technology to manage changes
to, guidelines on the Good Clinical Practice Directive. to period-of-use dates on IMP packaging). At this time,
Annex 13 includes requirements to comply with the it is uncertain how sponsors will address this change.
Clinical Trials Directive, which requires IMP manu- At the time of publication, the ECTR implementation
facturers to apply GMPs for investigational products phase is ongoing, with revisions for GCP inspection
manufactured within the EU as well as those investi- procedures, preparation of delegated acts on GMP and
gational products imported for trials. Member States necessary updates to GMP guidelines.
must allow each imported IMP production batch to be As of 28 June 2017, the Expert Group on Clinical
manufactured and tested in accordance with standards Trials for the Implementation of ECTR issued recom-
at least equivalent to EU GMPs. Moreover, a qualified mendations,66 “Auxiliary Medicinal Products in clinical

Chapter 26
Figure 26-6. Serious Adverse Event Reporting
Serious Adverse
Events (SAEs)
Authorities do not
need to be informed
Suspected Unexpected
Serious Adverse
Reactions (SUSAR)
Non-life-threatening:
report within 15 days
SUSAR Life-threatening:
report within 7 days
trials,” which replaces Guidance on Investigational Commission Communication 2011/C172/01 (CT-3)

Medicinal Products (IMPs) and “noninvestigational medic- Article 7.39. Only national competent authorities, EMA
inal products” (NIMPs). and the Commission have access (see Figure 26-6).
Per Clinical Trials Directive Article 17(2), the
Safety Reporting sponsor should report annually all suspected serious
According to Clinical Trials Directive Article 16, the adverse reactions that occurred during the past year to
investigator shall report all serious adverse events (SARs), each relevant Member State and Ethics Committee. As
except those the protocol identifies as not requiring described in Communication 2010/82/01, submission
reporting, to the sponsor immediately. This task also of an Annual Safety Report (ASR) is not considered a
involves reporting serious events related to NIMPs. substantial amendment.
Per Article 17, the sponsor should ensure all In the spirit of harmonising safety report format
relevant information about SUSARs for IMPs and and contents throughout the EU, ICH’s guideline, Note
NIMPs is recorded and reported as soon as possible to for guidance on development safety update reports (DSUR)
the relevant national competent authorities and Ethics E2F, was adopted 24 September 2010 and became
Committees and, in any case, no later than seven calen- effective in September 2011, with mandatory adoption
dar days after the sponsor gains knowledge of such an by each EU Member State. The DSUR was developed
occurrence. It also must communicate any relevant fol- as a common standard for periodic reporting on IMPs’
low-up information within an additional eight calendar safety, including marketed drugs under further study.
days (Clinical Trials Directive Article 17). The sponsor The DSUR replaced the ASR in September 2011. A
should report all SUSARS to each relevant national one-year transition period allowed national compe-
competent authority and Ethics Committee as soon tent authorities to develop the systems and processes
as possible, but within a maximum of 15 days of first to receive DSURs. The ASR no longer is accepted in
knowledge. The sponsor is responsible for informing all the EU. Detailed guidance is available in Commission
investigators of the new safety information. Per Article Communication 2011/C172/01. CTFG provides
17(3), each national competent authority is required detailed information and a ‘question and answer’ docu-
to enter any SUSARs brought to its attention in the ment on its website to facilitate DSUR implementation.
EudraVigilance Clinical Trials Module, as defined in Templates and examples also are available.

In summary, a DSUR should be prepared after recommended the sponsor continue submitting DSURs
a clinical trial’s first worldwide authorisation (the to all Concerned Member States, even if no trials are
Development International Birth Date (DIBD) for a ongoing in some of them. The period of time during
given IMP. The DSUR must be submitted within 60 which there is no DSUR data (e.g., the clinical pro-
days of the DIBD anniversary (DIBD + 59 days) to gramme is paused and no clinical development activities
national competent authorities and each relevant Ethics are initiated) should be explained in the DSUR submit-
Committee. The same DSUR should be submitted ted after the programme resumes.
to each relevant EU Member State (and local Ethics The DSUR is an annual review and evaluation of
Committee) where a clinical trial is authorised for the safety information reported during the current period
IMP (still using the DIBD). and an analysis based on previous knowledge of the
The first DSUR can be submitted to a Concerned product’s safety. It describes new issues that may impact
Member State in less than one year, but the covered the overall development program or specific clinical
reporting period should be no longer than one year. The trials, summarises the understanding and management
DIBD also can be a designated date linked to the start of known and potential safety risks to trial subjects,
of the first trial in a country without a formal authori- assesses the impact of new safety information on the
sation process (in the US, it is the investigational new overall IMP safety profile and provides an update on
drug effective date). If an IMP is a marketed, authorised the clinical development program’s status. Only a sin-
drug, its DIBD is the international birth date (IBD)), gle DSUR should exist, unless specific co-sponsorship
which is the date the product first was authorised in any agreements were established to enable mutual sharing
country worldwide. The data lock point for a DSUR of safety information and updating respective DSURs.
reporting period is the last day (or the last day of the The DSUR should include safety data from all clinical
month, see ICH E2F Section 2.2) before the DIBD trials (Phase 1–Phase 4) conducted with the IMP for
anniversary. The first DSUR reporting period should be all indications, all dosage forms—including fixed-dose
no longer than one year. The PSUR IBD and DSUR combination dosage forms—and all intended popu-
DIBD can be synchronised. Once established, the IBD lations. If applicable, it may include significant safety
cannot be changed. findings from noninterventional, observational or epide-
Per Clinical Trials Directive Article 17(2), an ASR miological studies conducted with the product or within
must be submitted while the clinical trial is ongoing the same pharmacological class. Investigator-initiated
in the Member State’s territory. Thus, submission of studies could be cross-referenced, and the DSUR report
DSURs to the Member State should stop at the end should be a concise summary report (30 pages or less,
of the trial. Unfortunately, an ‘ongoing’ trial can have excluding appendices) focusing on patient safety. Only
different definitions: according to ICH E2F, a trial is significant information should be included, and new
considered ongoing until the final clinical study report and significant safety information collected during
is available, whereas Commission Communication the reporting period should be presented. Duplicative,
2011/C172/01 considers a trial to be ongoing until redundant information should be avoided. Table 26-5
the last patient last visit has occurred. To resolve these summarises DSUR content.
discrepancies, CTFG determined a DSUR should
be submitted until the last patient’s last visit in the ECTR’s Potential Impact
Concerned Member State, as specified by the proto- Overall, the ECTR does not significantly impact safety
col. Further, a DSUR should be submitted only to the reporting determination and requirements during clin-
Concerned Member State(s) on whose territory the ical trials. Safety reporting requirements are delineated
clinical trial is still ongoing; no submission is needed to in ECTR Annex III. Annex III further clarifies adverse
the Concerned Member State(s) in which the clinical events to be reported: medication errors, pregnancies and
trial already ended (during the pre-established DSUR uses not anticipated in the protocol, including product
reporting period). misuse and abuse, which are subject to the same report-
If multiple studies for the same IMP are autho- ing obligation as adverse reactions. A sponsor is required
rised by the Concerned Member State within the to report all unexpected events affecting the clinical
reporting period, a DSUR must be submitted until trials benefit-risk balance, but are not SUSARs, via the
the last open trial has ended (last-patient-last-visit) in EU portal within 15 days of being aware. Similar to the
that Concerned Member State. Of note, when clini- Clinical Trials Directive, the IB (or RSI) is referenced to
cal trials continue after the MA is granted, both the establish serious adverse reactions’ unexpectedness.
DSUR and PBER must be maintained and submitted Although the SUSAR reporting criteria and
separately. In the case of a stop/start programme (where timelines have not been revised, the “clock” (Day 0)
a trial is postponed, e.g., due to safety concerns), it is for initial reporting is as soon as the sponsor receives

Chapter 26
Table 26-5. Contents of DSUR
Sections Recommendations
Executive Summary May be used as a separate document submitted to Ethics Committees and other
stakeholders instead of the full DSUR. Introduction; description; estimated clinical
trial exposure (cumulative); MA status worldwide; summary of overall safety
assessment; summary of important risks, focusing on newly identified or potential
risks; confirmation that initial benefit-risk assessment is maintained and/or actions
taken for safety reasons, including associated changes to Investigator’s Brochure (IB)
or Reference Safety Information (RSI); conclusion.
1. Introduction
2. Worldwide Marketing Approval Status
3. Actions Taken in the Reporting Period Description of significant actions related to safety in the reporting period taken
for Safety Reasons by sponsor, regulators, Data Safety Monitoring Board, Ethics Committees. Actions
that could impact clinical trial(s) conduct, including significant actions due to
marketed drug safety and advice from regulatory authorities involving a constraint on
development. Changes to the RSI or IB should be discussed separately.
4. Changes to Reference Safety or to IB
Information
5. Inventory of Clinical Trials Ongoing and Tabulated summary of clinical trials could be used.
Completed
6. Estimated Cumulative Exposure The exposure table should be kept simple. It should include the total number of
patients exposed to the investigational drug, comparator or placebo. There is no need
to provide exposure for each study.
7. Data in Line Listings and Summary
Tabulations
8. Significant Findings from Clinical Trials
9. Safety Findings from Noninterventional
Studies
10. Other Clinical Trial or Study Safety
Information
11. Safety Findings from Marketing
Experience
12. Nonclinical Data Significant findings that impact the IMP’s safety and/or could lead to new potential
risks.
13. Literature Published literature during the covered period containing significant safety or clinical
findings.
14. Other DSURs
15. Lack of Efficacy
16. Region-Specific Information
17. Late-Breaking Information
18. Overall Safety Assessment Evaluation of the risks, including changes to previously identified risks, new safety
issues, new drug-drug interactions, adverse experiences during pregnancy. Review of
the initial benefit-risk assessment.
19. Summary of Important Risks Cumulative summary of important identified and potential risks—those that might
lead to labelling warnings, precautions or contraindications, including: ongoing
or fully mitigated or resolved risks. This section may be the basis of a safety
specification of a risk management plan.
20. Conclusions
Suggested Appendices Reference Safety Information: typically the most current Investigator’s Brochure,
line listings for serious adverse reactions during the covered reporting period,
tabulated summary of cumulative serious adverse events

information containing minimum reporting criteria. The Directive required a database (EudraCT) to be imple-
minimal information, per ECTR Annex III (2.3.10), mented to register clinical trials to be conducted in EU
is a valid EU trial number, a sponsor study number, from 1 May 2004. In 2012, the Commission issued
an identifiable coded subject, an identifiable reporter, Guidance on posting and publication of result-related
a SUSAR, a suspect IMP (including active substance information on clinical trials to implement Article 57(2) of
name-code) and a causality assessment. The majority of Regulation (EC) 726/2004 of the European Parliament
requirements laid out in Annex III enable better align- and of the of the Council of 31 March 2004 laying down
ment with international guidelines. Community procedures for the authorisation and supervi-
The ECTR adds a new streamlined approach sion of medicinal products for human and veterinary use
allowing detailed SUSAR reporting via an upgraded and establishing a European Medicines Agency and Article
EudraVigilance Clinical Trial Module (EVCTM), 41(2) of Regulation (EC) 1901/2006 of the European
which will accept DSUR submissions (if applicable). Parliament and of the Council of 12 December 2006
Instead of submitting a DSUR to each national compe- on medicinal products for paediatric use and amending
tent authority, the sponsor will submit the DSUR once Regulation (EEC) No. 1768/92, Directive 2001/20/
a year. Unfortunately, Ethics Committees and investi- EC, Directive 2001/83/EC and Regulation (EC) No.
gators will not have access to EudraVigilance. Ethics 726/2004. However, for various reasons, EudraCT
committees’ roles and responsibilities in conducting was not functional until June 2014. After announcing
safety analysis will be regulated under national laws. It is that posting clinical trial summary results in EudraCT
expected the sponsor will submit SUSARs and DSURs would become mandatory as of 21 July 2014, opponents
to Ethics Committees, per national requirements. of data disclosure challenged EMA. Shortly after the
The EVCTM’s functionality must be upgraded before ECTR was adopted in June 2014, EMA issued policy
ECTR implementation. In the EU Telematics Strategy 0070 in October 2014, effective 1 January 2015, on
and Implementation Phase (2015–17), Programme publication of data. Under this policy, EMA will pub-
2: Clinical Trials, the following upgrades are being lish the clinical reports it received proactively once the
considered: “for the electronic reporting of suspected medicines are authorised; this also will apply to clinical
unexpected serious adverse reactions (SUSARs) and trials conducted outside the EU but submitted to EMA
an electronic reporting system for annual safety reports for the Centralised Procedure. Clinical reports are
(meaning DSURs) to a central repository at the agency defined as the clinical overviews (generally submitted in
including storage of related assessment reports and MAA Module 2.5), the clinical summaries (generally
actions. Additionally, tools such as the data warehouse submitted in Module 2.7) and the clinical study reports
and other reporting tools will be developed to support (CSR) generally submitted in module 5, together with
the analysis of safety and/or clinical trial information CSR appendices, specifically 16.1.1 (protocol and pro-
from the EU-CT and EV database. It also will deliver tocol amendments), 16.1.2 (sample case report form)
the functionality for forwarding SUSARs and ASRs to and 16.1.9 (documentation of statistical methods).
the MSs concerned.” The ECTR introduces separate additional but
Following an independent audit and a favourable aligned requirements to ensure clinical data transpar-
recommendation from the PRAC, EMA’s manage- ency from trials conducted in the EU or elsewhere.
ment board confirmed in May 2017 that the new Data from a clinical trial can be submitted to sup-
version of EudraVigilance is fully functional. The new port a clinical trial application only if the trial has been
EudraVigilance system was launched in November recorded in a publicly accessible, free database that is
2017, with enhanced functionalities for reporting and a primary or partner registry of, or a data provider to,
analysing suspected adverse reactions and was incorpo- WHO’s International Clinical Trials Registry Platform
rated into EMA’s website.67 (WHO ICTRP). Data included in the IB or IMPD fall
EMA issued an update in December 2019, noti- under this requirement.
fying EudraVigilance users that by June 2022 it will be The EU database will contain all relevant clinical
mandatory to report side effects to the website using a trial information submitted through the EU portal. The
data format based on ISO standards. The required stan- information made available publicly will include but is
dards are referenced in ICH E2B(R3) guideline, as well not be limited to: the trial’s major characteristics, treat-
as EU No. 520. 2012. ment population characteristics and number of subjects,
inclusion and exclusion criteria, main objectives and
Transparency: Clinical Trial Data Disclosure endpoints, recruitment start and end dates, substantial
Before the Clinical Trials Directive’s introduction in protocol modifications made during the trial, the trial
2001, the EU had no legal obligations to make clinical end date and, within one year, the summary of results
trial information publicly available. The Clinical Trials and a lay summary.

Chapter 26
All clinical trials must be registered in the EU assessment outcomes in a timely manner to meet ECTR
database prior to being started in any EU Member requirements. CTFG may facilitate consistent best
State. As a rule, the subject recruitment start and practices and processes across all Member States.
end dates also will be published in the EU database. When the ECTR comes into force for all clinical
However, data will be anonymised. No subject per- trials, the coordinated assessment of multinational trials
sonal data will be entered. The information in the EU will be addressed. Meanwhile, however, the Voluntary
database will be public, unless specific reasons require Harmonisation Procedure (VHP) remains a useful
a piece of information not be published to protect an option to sponsors. All trials in which at least three
individual’s right to privacy and the right to personal EU Member States participate may be assessed in this
data protection. coordinated procedure. Amendments to trials having
The clinical trial results’ summary and a summary undergone a VHP also can be submitted under the
presented in terms understandable to a layperson will coordinated procedure.
be made available in the EU database. Sponsors should VHP is a two-step process. The first step is a
anticipate and plan for the need to translate this infor- consolidated scientific assessment of the core clinical
mation. It is highly likely summaries for laypersons, as trial authorisation package by the applicable Member
defined in Annex V, to be understandable, will require State’s health authorities. On Day 30 of the procedure,
translation into the Member State’s official language. a positive opinion is granted or a request for further
The level of readability is not prescribed in the ECTR information (RFI) is issued if the health authorities
and may be subject to differing Member State expec- have questions relating to the submission.
tations. A reading level of 6th to 8th grades typically is In the latter case, the sponsor has 10 days (by Day
recommended for patient information. 40) to provide a response, with a positive opinion being
Further recommendations on reporting results for received at Day 50 or 60, depending on whether there
lay persons were made available on January 2017, in are outstanding points for discussion. The second step is
“Summaries of Clinical Trial Results for Laypersons.”68 a 10-day review of the national documents done on an
The expert group proposed templates with exam- individual Member State basis.
ples of wording to meet the requirements of ECTR The latest version (V4) of the VHP69 introduces the
Annex V and guidance for neutral language when selection of the Reference Member State, the possibility
describing results, to avoid the use of “unduly positive, of adding new countries in the trial authorised by the
promotional” language or language that would serve a VHP with a second round of assessment and infor-
marketing purpose. mation requests for substantial amendments, and until
For clinical trials included in an EU MAA, clinical ECTR implementation, transfers the responsibilities
study reports also will be published 30 days after the of VHP coordination to the Reference State’s national
procedure for granting the MA has been completed competent authority. To date,70 24 national competent
(opinion delivered to the applicant) or the MA appli- authorities are participating in VHP from Austria,
cant has withdrawn the application. Implementing Belgium, Bulgaria, Czech Republic, Denmark, Estonia,
these requirements may prove to be challenging, as Finland, France, Germany, Greece, Hungary, Iceland,
summaries or results in different registries (e.g., US Ireland, Italy, Latvia, Lithuania, Netherlands, Norway,
clincialtrials.gov) and the EU portal may not be syn- Poland, Portugal, Romania, Spain, Sweden and the UK.
chronised, e.g., the MA is approved in the US but not VHP offers a short- to medium-term alternative to
yet in the EU. the purely national system of clinical trial management
in the EU.
CTFG and the Voluntary Harmonisation Procedure
CTFG coordinates the implementation of the Clinical Conclusion
Trials Directive across the Member States at an opera- Overall, the ECTR represents a significant improve-
tional and national level. Because of its well-established ment in fostering clinical research in Europe and
role in coordinating Clinical Trials Directive implemen- reducing the regulatory hurdles that have plagued effec-
tation, it should be anticipated CTFG would remain tive implementation of the Clinical Trials Directive. It
active to support the operational challenges of ECTR is hoped the ECTR will be a positive change and stim-
implementation. Many clinical trial management char- ulate scientific research and innovation while ensuring
acteristics are not addressed by the ECTR and are left subjects’ rights, safety, dignity and well-being are pro-
to each Member State’s national authority to administer tected. Because ECTR implementation and assessment
and organise. For example, national competent author- outcomes largely are under each individual Member
ities and Ethics Committees will need to develop new State’s laws for the ethical assessment of a clinical trial
procedures to ensure communication and sharing of application (Part II) and because Member States can

opt-out of accepting the assessment of Part I or Part EUR-Lex website. http://eur-lex.europa.eu/legal-content/EN/

II of a clinical trial application, a clinical trial could be TXT/?uri=uriserv:l23111. Accessed 27 April 2020.
5. Commission Directive 2005/28/EC of 8 April 2005, laying
refused in one Member State and accepted in another. down principles and detailed guidelines for good clinical prac-
All stakeholders will face organisational and struc- tice as regards investigational medicinal products for human
tural challenges: use, as well as the requirements for authorisation of the manu-
• Regulators will need to create processes to facturing or importation of such products. EC website. https://
ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/
ensure seamless communication between the dir_2005_28/dir_2005_28_en.pdf. Accessed 27 April 2020.
national competent authority and the Ethics 6. Communication from the Commission 2010/C 82/01—
Committee and to select a single properly Detailed guidance on the request to the competent authorities
trained and qualified Ethics Committee to for authorisation of a clinical trial on a medicinal product
for human use, the notification of substantial amendments
execute the ethical review of a proposed clin- and the declaration of the end of the trial (CT-1). EUR-
ical trial for the entire territory. At the same Lex website. http://eur-lex.europa.eu/legal-content/EN/
time, during the transition period and poten- ALL/?uri=OJ:C:2010:082:TOC. Accessed 27 April 2020.
tially until 2019 or later, regulatory agencies 7. Communication from the Commission (2011/C 172/01)—
Detailed guidance on the collection, verification and
will support Clinical Trials Directive operations. presentation of adverse event/reaction reports arising from
• Because the ECTR still is largely under the clinical trials on medicinal products for human use (CT-3).
influence of each Concerned Member State, EUR-Lex website. http://eur-lex.europa.eu/legal-content/EN/
for the sponsor or applicant, national laws still ALL/?uri=OJ:C:2011:172:TOC. Accessed 27 April 2020.
8. EudraLex—Volume 10 Clinical trials guidelines of The rules
will apply for many documents submitted in governing medicinal products in the European Union contains
Part II of a clinical trial application. guidance documents applying to clinical trials. EC website.
• Many EU or national guidelines will have to https://ec.europa.eu/health/documents/eudralex/vol-10_en.
be revised and implemented, triggering new Accessed 27 April 2020.
9. EudraLex—Volume 3 Scientific guidelines for medicinal products
procedures, processes and systems for national for human use. EC website. http://ec.europa.eu/health/docu-
competent authorities, sponsors or applicants ments/eudralex/vol-3/index_en.htm. Accessed 27April 2020.
and Ethics Committees. 10. EudraLex—Volume 10 Clinical trials guidelines of the rules
governing medicinal products in the European Union contains
guidance documents applying to clinical trials. Chapter IV:
As noted by EMA’s management board, the EU data- Inspections. EC website. https://ec.europa.eu/health/docu-
base and EU portal are prerequisites to successful ments/eudralex/vol-10_en. Accessed 27 April 2020.
ECTR implementation. Although ECTR implemen- 11. International Council on Harmonisation, ICH Efficacy
tation is delayed until late 2020,71 best efforts must be Guidelines. ICH website. http://www.ich.org/products/guide-
lines/efficacy/article/efficacy-guidelines.html. Accessed 27 April
undertaken to offer to all stakeholders robust, intercon- 2020.
nected and user-friendly systems that are secure and can 12. EudraLex—Volume 10 Clinical trials guidelines of the rules gov-
be upgraded easily over time. It means, however, that erning medicinal products in the European Union, Chapter II, ICH
the directive may be applicable until at least 2022. guideline E2F on development safety update report, September
2011, EMA/CHMP/ICH/309348/2008. EMA website. http://
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Chapter 26
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20. Op cit 3, page 3, paragraph 7. 45. Ibid.
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– 2017, EMA/532765/2015 (6 August 2015), EMA website. 2020.
http://www.ema.europa.eu/docs/en_GB/document_library/ 52. EMA Press Release. Over 1,000 studies now recorded
Other/2015/08/WC500191875.pdf. Accessed 27 April 2020. in EU register of post-authorisation studies. EMA web-
32. The UK has left the EU Find out what this means for you. site. http://www.ema.europa.eu/ema/index.jsp?curl=pages/
United Kingdom Government website. https://www.gov.uk/ news_and_events/news/2017/02/news_detail_002692.
transition-check. Accessed 27 April 2020. jsp&mid=WC0b01ac058004d5c1. Accessed 27 April 2020.
33. When did the United Kingdom leave the European Union? 53. Op cit 47.
Government of the Netherlands website. https://www. 54. Clinical Drug Trials submitted within the Pilot Phase to
government.nl/topics/brexit/question-and-answer/when-will- ANSM (French National Agency for Medicines and Health
the-united-kingdom-leave-the-european-union. Accessed 27 Products Safety) and the CPP (French Ethics Committee),
April 2020. Practical Information Guide for Applicants (25 July 2017)
Version 6.0. ANSM website. http://ansm.sante.fr/var/

ansm_site/storage/original/application/09e98ef4c08127fd- 61. Ibid.

f5b849c491944114.pdf. Accessed 27 April 2020. 62. Ibid.
55. Risk proportionate approaches in clinical trials, 63. Question and Answers to the Safety in Clinical Trials:
Recommendations of the expert group on clinical trials for the Frequently asked questions regarding the Reference Safety
implementation of Regulation (EU) No 536/2014 on clinical Information (RSI), Clinical Trial Facilitation Group
trials on medicinal products for human use (25 April 2017). (CTFG). October 2019. HMA website. https://www.hma.
EC website. https://ec.europa.eu/health//sites/health/files/files/ eu/fileadmin/dateien/Human_Medicines/01-About_HMA/
clinicaltrials/2016_06_pc_guidelines/gl_4_consult.pdf. Accessed Working_Groups/CTFG/2017_11_CTFG_Question_and_
27 April 2020. Answer_on_Reference_Safety_Information_2017.pdf. Accessed
56. Ibid. 27 April 2020.
57. Ibid. 64. Op cit 10.
58. Consultation document. Ethical considerations for clin- 65. Op cit 1.
ical trials on medicinal products conducted with minors, 66. Op cit 15.
Recommendations of the expert group on clinical trials for the 67. Op cit 51.
implementation of Regulation (EU) No 536/2014 on clinical 68. Op cit 17.
trials on medicinal products for human use, https://ec.europa. 69. Guidance document for sponsors for a Voluntary
eu/health//sites/health/files/files/clinicaltrials/2016_06_pc_ Harmonisation Procedure (VHP) for the assessment of mul-
guidelines/gl_1_consult.pdf. Accessed 27 April 2020. tinational Clinical Trial Applications, Version 4 (CTFG//
59. Guideline for good clinical practice E6(R2) (15 December 2016, VHP/2016/Rev6, June2016). Lakesmedelsverket website.
EMA/CHMP/ICH/135/1995). EMA website. http://www. https://lakemedelsverket.se/upload/foretag/humanlakemedel/
ema.europa.eu/docs/en_GB/document_library/Scientific_guide- klinisk-provning/VHP%20sponsor%20%20version%20%20
line/2009/09/WC500002874.pdf. Accessed 27 April 2020. 4%20%20final_16.06.2016.pdf. Accessed 27 April 2020.
60. ICH Reflection on “GCP Renovation”: Modernization of 70. VHP metrics on participation of National Competent
ICH E8 and Subsequent Renovation of ICH E6 January Authorities (NCA) (01/2015 until 12/2016).
2017. ICH website. http://www.ich.org/ichnews/newsroom/ 71. Clinical Trials Information System development. EMA website.
read/article/ich-reflection-on-gcp-renovation-moderniza- https://www.ema.europa.eu/en/human-regulatory/research-de-
tion-of-ich-e8-and-subsequent-renovation-of-ich-e6.html. velopment/clinical-trials/clinical-trial-regulation. Accessed 27
Accessed 27 April 2020. April 2020.

Chapter 26

Chapter 27
Registration Procedures for

Medicinal Products
OBJECTIVES EU Bodies Associated with Medicinal

□ Know what criteria must be met before submit-
Products
In 1965, the European Economic Community (EEC)
ting a new marketing authorisation application
enacted the first directive for human medicinal product
□ Learn to select a procedure type and applica- Marketing Authorisations (MAs) (Directive 65/65/
tion type for a new marketing authorisation EEC). In the early 1990s, two pan-EEC procedures, the
application Concertation Procedure and Multistate Procedure, were
established. These were revised in 1995 and became the
□ Understand EU-specific dossier content Centralised Procedure (CP) and Mutual Recognition
requirements Procedure (MRP). This coincided with two important
milestones, namely the pan-EU recognition of pat-
□ Know how to manage eCTD lifecycles and ents and establishment of the European Medicines
exchange valid eCTD submissions within the EU Evaluation Agency (EMEA) to coordinate the CP.
EMEA later was renamed the European Medicines
Agency (EMA). Its Committee for Human Medicinal
DIRECTIVES, REGULATIONS AND GUIDELINES Products (CHMP) oversees medicinal product evalua-
COVERED IN THIS CHAPTER tion for human use and has access to expert groups from
the individual Member States’ competent authorities.
Directive EEC/65/65 was supplanted by Directive
2001/83/EC of the European Parliament and of the
Council of 6 November 2001 on the Community
code relating to medicinal products for human use,
which also replaced various other related directives.1
establishing a European Medicines Agency, as
Directive 2001/20/EC (the Clinical Trials Directive),
amended
also from 2001, lays down requirements for conducting
□ Directive 2001/83/EC of the European clinical trials in the EU.2 EU pharmaceuticals leg-
Parliament and of the Council of 6 November islation, Regulation (EC) No. 726/2004, introduced
2001 on the Community code relating to medici- the centralised authorisation procedure and estab-
nal products for human use lished EMA.3 Major revisions were proposed with the
pharmaceutical package from 2008, which came into
□ EudraLex, Volume 2, “Pharmaceutical Legislation effect with Regulation (EU) No. 1235/2010, Directive
Notice to applicants and regulatory guidelines 2010/84/EU, an implementing regulation and Directive
on medicinal products for human use” 2011/62/EU.
A medicine must be authorised before it can be
□ EU eSubmission guidelines placed on the market. The EU regulatory system offers
several routes for obtaining a marketing authorisation

Chapter 27
(MA): the EU level (CP) or the national level (National implemented within national law before becoming
Procedure (NP), Decentralised Procedure (DCP) and effective; guidelines interpret regulations and laws. An
MRP). Two special authorisation procedures exist outside applicant may deviate from the guidance if it can justify
the conventional routes: Article 58 applications (for med- the alternative interpretation.
icines used extensively outside the EU) and the procedure Over the years, much EU guidance has been
for compassionate use. There are specific regulatory rules released on how to safeguard patients using drugs,
for orphan medicinal products and paediatric, geriatric, and the International Council for Harmonisation
advanced therapy and nonprescription medicines. of Technical Requirements for Pharmaceuticals for
While the CP was intended for innovative products, Human Use (ICH) guidances have been adopted. They
the MRP could be selected for all other products. In do not provide a clear-cut roadmap for any single drug,
2005, another application procedure was added to the but they set a regulatory framework to be considered
MRP to reduce the initial MA assessment period, the when developing and marketing drugs, allowing room
DCP. For either the MRP or DCP, sponsors may choose for interpretation.
a limited number of EU Member States for their initial Further historic regulatory details can be found in
EU MAs. Both procedures are conducted by the selected Chapter 2.
Member States’ competent authorities.4 In both proce-
dures, the sponsor selects a Reference Member State to Marketing Authorisation Holder
conduct the initial product assessment. An MAH can be held liable for a product’s failure after
The MRP is intended to achieve Concerned entering the market. To ensure individuals have overall
Member States’ mutual recognition of the Reference responsibility and accountability, an MAH should be
Member State’s product assessment and provides repeated established in the EU. While the application up to the
assessments by many Concerned Member States. To marketing stage can be controlled by an MAH repre-
facilitate harmonisation of the evaluation outcomes, an sentative (applicant), the actual MA may be granted
informal group, the Mutual Recognition Facilitation only to an applicant established in the Community. The
Group (MRFG), was established in 1995. Currently, the name or corporate name and permanent address of the
individual Member States’ national competent author- applicant and, where applicable, the manufacturer must
ities are organised in the Heads of Medicine Agencies be included in the application.5
(HMA). HMA established the Coordination Group for A sponsor must appoint an EU-based affiliate or
Mutual Recognition and Decentralised Procedures for third-party service provider as its EU legal representa-
human medicinal products (CMDh), an independent tive (EU LR) if the sponsor is based outside the EU.
body within the EU not affiliated with any national com- The EU stimulates innovation and competitiveness.
petent authority or EMA. It is the formal successor to the As a result, it offers benefits for micro-, small- and mid-
MRFG. CMDh was created to examine any questions sized enterprises (SMEs), such as a 90% fee reduction
related to a medicinal product’s marketing authorisation for scientific advice and GxP inspections, deferral of the
application (MAA) in two or more Member States. Its MAA fee and a conditional fee exemption where scien-
goal is to resolve disagreements on potential serious pub- tific advice is followed and an MAA is not successful.6
lic health risks among Member States involved in a MRP
or DCP. CMDh prepares an annual list of medicinal Strategic Decisions Concerning the
products (registered nationally) for which a harmon-
ised summary of product characteristics (SmPC) must Product and Registration
be achieved. In addition, CMDh develops regulatory Orphan Drug Designations
standard operating procedures (SOPs), guidances and In the final decade of the 20th century, pharmaceutical
Q&A documents to streamline processes and reduce the companies intended to develop blockbuster drugs. In
administrative burdens of national competent authorities parallel, when safety issues not apparent during drug
and provide guidance to marketing application holders development occurred during drug marketing, they
(MAHs) and applicants. resulted in further regulatory test requirements during
The EU Directorate on General Health and Food development to prevent their recurrence. This led to
Safety (DG Sanco) develops and releases pan-Euro- significantly higher drug development costs, putting the
pean regulatory guidance. These guidances can have development of potential drugs for small populations
different regulatory powers. Regulations and directives at risk due to the lack of return on investment. This was
are passed by the Council of Europe or the Council recognised by the Community, and regulators developed
and the European Parliament and adopted by the a way to stimulate the development of these “orphan”
European Commission. Regulations immediately come drugs. Orphan medicinal products are covered by
into force within an EU country; directives should be Regulation (EC) No. 141/2000 and its implementing

Registration Procedures for Medicinal Products
regulation.7 This brought such incentives as reduced fees Alternatively, and additionally, the sponsor also
and protection from competition once the medicine may request scientific advice from any or some national
is placed on the market (10-year market exclusivity). competent authorities.
To qualify for these benefits, a company must apply to For the scientific advice application’s content, see
EMA for orphan drug designation.8 the section on Submission Content (Application Type/
The regulation also established a centralised Scientific Advice Application).
procedure for the orphan product designation and a
Committee for Orphan Medicinal Products (COMP) Paediatric Investigations
responsible for orphan medicinal product scientific The EU Paediatric Regulation was introduced in 2007,
assessments. For further details on orphan medicinal with the goal of improving the health of European
products, see Chapter 41. children by facilitating the development and availability
of medicines for children ages 0 to 17 years, ensuring
Scientific Advice medicines are researched ethically and improving usage
Over the last century, a large number of active chemical information.
substances impacting a wide group of patients have been Previously, clinical trials in children were recom-
commercialised. Science progressed, and more-complex mended, but the legal framework to achieve their goals
biotechnological and high-tech products have been were lacking.
developed. Chemical entities’ identity and quality can be The Paediatric Regulation covers obligations,
assessed precisely, allowing safe extrapolation and predic- incentives and penalties to safeguard children, without
tion of the product’s effects on patients based on analyses subjecting them to unnecessary trials or delaying the
of every marketed batch. Compared to chemical entities, authorisation of medicines for use in adults.
biotech product isoforms’ diversity (e.g., recombinant The MAA must include results of studies con-
proteins and monoclonal antibodies) prevents very-spe- ducted in compliance with a Paediatric Investigation
cific determination of drug identity, quality and potency. Plan (PIP) or EMA’s decision granting a PIP waiver
Therefore, more emphasis was on a consistent produc- and/or deferral. This also is required for new indications,
tion process to limit biotech product batch-to-batch pharmaceutical forms and routes of administration if
variability. In parallel, drugs could have beneficial effects the product is protected by a Supplementary Protection
in a subgroup of patients only, and/or adverse events Certificate (SPC) or patent. Paediatric study exceptions
could impact another patient subgroup. This resulted in are generic, hybrid medicinal products, biosimi-
the need to predict responders and non-responders and lars, homeopathic and traditional (herbal) medicinal
explore the concept of personalised medicine. products and products containing one or more active
Biotech product and personalised medicine devel- substances of well-established use.
opment resulted in a wide variety of drug development The PIP includes a research and development
options. To increase the likelihood of future approval, program agreed with EMA’s Paediatric Committee
regulators began offering scientific advice during the (PDCO) prior to completing adult pharmacokinetic
development phase. studies.10 The PIP should consider potential significant
Scientific advice and protocol assistance are use- therapeutic benefits in children. It contains timelines
ful particularly to applicants developing a medicinal for measures for quality, nonclinical and clinical devel-
product when there appears to be no or insufficient EU opment in all paediatric age groups. More information
guidance or if the applicant wants to deviate from avail- on paediatric medicine development and EU regulatory
able guidance. requirements can be found at www.ema.europa.eu/ema/
Within the EU, advice can be requested from index.jsp?curl=pages/regulation/general/general_con-
EMA and national competent authorities. The spon- tent_000023.jsp.
sor can request EMA scientific advice via a scientific Scientific advice for paediatric-related questions is
advice/protocol assistance application.9 Depending free of charge.
on the questions, EMA may respond in writing or Considering the delicacy of paediatric studies and
invite the company to participate in a meeting. It also their impact on development timelines, a PIP presub-
is possible that EMA and the US Food and Drug mission meeting is recommended to discuss the PIP
Administration (FDA) may run scientific advice pro- application’s timing to facilitate smooth validation and
cedures in parallel. The outcome does not necessarily assessment. PIP submission timing varies, although it is
have to be aligned, but EU and US regulators will work best to submit it following adult exploratory trials. PIP
together to increase their knowledge, balance new drug assessment takes quite some time (approximately 12
development costs and ensure an optimal benefit-risk months) and should not interfere with the drug devel-
ratio for single patients and patient groups. opment critical path.

Chapter 27
Under certain circumstances, paediatric trial waiv- the benefit of direct access to the EU market. The CP is
ers can be obtained, e.g., if the drug is ineffective or compulsory for:
unsafe in children, the disease or condition occurs only • human medicines for the treatment of Human
in adults or the new therapy is unlikely to have a ther- Immunodeficiency Virus (HIV) or Acquired
apeutic benefit over existing treatments for children. A Immune Deficiency Syndrome (AIDS), can-
waiver can be issued for one or more specified paediatric cer, diabetes, neurodegenerative diseases, auto
age groups and/or indications. EMA has issued class immune and other immune dysfunctions and
waivers for a wide series of conditions.11 viral diseases
Incentives for paediatric investigations include • medicines derived from biotechnology pro-
six-month extensions of existing SPCs if all measures cesses, such as genetic engineering
agreed in the PIP have been met and the product is • advanced therapy medicines, such as gene ther-
marketed in all EU Member States. This incentive is apy, somatic cell therapy or tissue-engineered
not applicable if the MAH already has received a one- medicines
year extension for the additional paediatric indication. • officially designated orphan medicines
Products no longer protected by a patent or SPC can
be granted 10 years of data exclusivity protection for For medicinal products outside these categories, appli-
the paediatric use data. For orphan drugs, marketing cants may use the CP for medicines with significant
exclusivity for all indications can be extended two therapeutic, scientific or technical innovation or whose
years, provided the MAA includes results of all stud- authorisation would be in the interest of public health.
ies in accordance with the agreed PIP. These benefits CP applications are submitted directly to EMA by
can be awarded following a full compliance check. a person based in the Community and authorised by the
Additionally, Regulation 1901/2009 provides for spe- applicant and are accompanied by a fee payable under
cific authorisation for medicinal products developed Regulation (EC) No. 297/95 with further amendments.
exclusively for use in the paediatric population: The The mandatory format for the CP is the electronic
Paediatric Use Marketing Authorisation (PUMA) as Common Technical Document (eCTD). EMA is
defined in regulation Article 2.4. This authorisation responsible for evaluating MAAs. EMA’s scientific
can be requested for a medicinal product no longer committees have 210 active days plus clock-stops (three-
covered by intellectual property rights and may retain month maximum with a possible six-month extension).
the corresponding adult product’s existing brand At Day 210 of the procedure, the CHMP adopts an
name. Medicinal products with a PUMA benefit from opinion on whether the medicine should be marketed.
the data and marketing protection periods set out in This opinion then is transmitted to the European
Directive 2001/83/EC (Article 38(2) of Regulation Commission, which has the ultimate authority to
(EC) 1901/2006). grant an EU MA. An unfavourable opinion is given
Penalties for nonadherence to the agreed PIP if CHMP does not consider the MAA to fulfil the
include not validating the MAA, variation or extension authorisation criteria set out in Regulation (EC) No.
application after a partial compliance check. Moreover, 726/2004.
the sponsor’s name will be listed on an annual publi- Once an MA has been granted, the MAH legally
cation of companies failing to comply (together with can begin to market the medicine in all EEA countries.
those who did benefit from the incentives).12 For
infringing the Paediatric Regulation, the European Decentralised Procedure
Commission and Member States may apply penalties The DCP, laid down in Directive 2001/83/EC, as
that are effective, proportionate and dissuasive.13 amended, has been in force since November 2005.
Further details on the Paediatric Regulation can be CMDh has the same competencies for both the MRP
found in Chapter 8. and DCP. In general, the DCP is the procedure of
choice if the CP is not applicable and for medicines
Procedure Types that have not been authorised yet in any Member State.
A high-level overview of EU procedure types follows. An applicant interested in marketing the medicinal
For a comprehensive overview, see Chapter 3. product in more than one Member State can submit
identical MAAs simultaneously to those Member
Centralised Procedure States’ competent authorities. It has the shortest time-
The CP, established in 1995, is governed by Regulation line of all procedures, provided Concerned Member
(EC) No. 726/2004. It results in a single MA valid in States reach consensus in the procedure’s first or second
all Member States and thus offers, among other things, round. As in the MRP, the sponsor must select one EU
Member State as the Reference Member State and list

the Concerned Member State (CMS). The Reference one or more Concerned Member States not previously
Member State’s competent authority takes the lead in involved.
dossier evaluation. Other Concerned Member States Like the DCP, the MRP is led by a Reference
can perform an evaluation in parallel or rely on the Member State. This Member State must accept MAH’s
Reference Member State’s judgement. Consensus can invitation to act as a Reference Member State, but, gen-
be obtained at several procedure time points. Consensus erally, is always accepted as long as the product is still
CMDh meetings occur during the third week of the on the market in that country. Even if the product is
month immediately following CHMP meetings. no longer marketed in the country, it still can act as the
Submission and approval deadlines are back-timed from Reference Member State because it is acquainted with
these meeting dates. the product’s full regulatory history, including its bene-
Even if the DCP involves only two countries (the fit-risk evaluation. Alternatively, the Reference Member
Reference Member State and one Concerned Member State or MAH can indicate it would like another
State), CMDh can participate in the consensus meet- Member State to lead the product review.
ings. This allows EU countries not involved in the Prior to starting the MRP, the Reference Member
procedure to vote against a product’s approval if public State should ensure the existing marketed product and
health is at risk (e.g., potential for inferior antibiotic to regulatory dossier still are compliant. The Reference
cause bacterial resistance in surrounding countries). Member State must prepare an assessment report, jus-
The sponsor selects the Concerned Member States tifying the drug’s favourable benefit-risk ratio when
based on where it would like to market the drugs. The used in accordance with its prescribing information
applicant also selects the Reference Member State. and ensuring availability of consistently produced
Selection criteria include the national competent high-quality drugs.
authority’s standing within the EU, its availability for Since 2005, it also has been possible to withdraw
thorough review, its opinion of the applicant’s drug, the application during the MRP in a Member State
availability of registered reference drugs and/or related due to a PSRPH. The Concerned Member State still
drugs, etc. can influence the Reference Member State and other
Prior to procedure Day 120, the application can be Concerned Member States and apply for CMDh
withdrawn in a Member State because of a Potential referral.
Serious Risk for Public Health (PSRPH). A Concerned
Member State can influence the Reference Member National Procedure
State and other Concerned Member States and apply Each EU Member State’s competent authority is
for CMDh referral. responsible for granting MAs for medicinal products
placed on its market; however, this is possible only if the
Mutual Recognition Procedure product is not an innovative medicinal product and is to
The MRP is laid down in Directive 2001/83/EC. It be marketed in a single country.
should be selected to obtain registration in an EU Evaluation and timelines are left to the indi-
Member State based on recognition of an evaluation by vidual Member State’s discretion. Since the national
another EU Member State where the product has been competent authorities participate in CPs and should
registered previously (Reference Member State). contribute to MRPs and DCPs, NPs always are the
The MRP must be used for the following products: lowest priority. Hence, timelines often slip.
• medicinal products containing new active Products registered originally through NP before
substances outside the centralised therapeutic 1995 still can be maintained through that procedure,
areas even if the product is marketed in multiple EU Member
• over-the counter (OTC) products States. However, if the concerned products have signifi-
• homeopathic medicinal products cantly different claims across various Member States,
• generic products (also generic versions agencies can request a referral to harmonise the SmPC
of products authorised by the CP before within the EU. Alternatively, companies can request a
November 2005, with the exception of those referral procedure to harmonise the SmPC. In addition,
biotechnology-derived) the referral procedure can be used to harmonise Module
• “abridged” applications, “well-established use” 3. Once a product has applied for a referral procedure,
and line extensions of “old Mutual Recognition the product must be maintained through the MRP, no
Procedure” longer through the NP.
NP can be submitted in the national language.
A first MRP always involves a previous NP or DCP. Alternatively, submission can be in English, although,
It also is possible to apply a repeat MRP to include aside from the SmPC, the cover letter and application

Chapter 27
form are supposed to be in the national language. Conditional Approval

Dossier contents must be in accordance with the same The conditional MA is provided only for the CP
directive as the MRP, DCP and CP, namely Directive (Regulation (EC) No. 726/2004 Article 14(7)). When
2001/83/EC. Dossier structure should be in accor- a sponsor applies for a full license, EMA may grant
dance with the Common Technical Document (CTD). authorisation subject to certain specific obligations,
Further details on the dossier structure are in the sec- including an annual review. These obligations shall
tion on Submission Format. be made accessible to the public. Such authorisation
If a product is to be registered in multiple EU shall be valid for one year, on a renewable basis. The
Member States, the license must be obtained through a renewal is on a yearly basis until all obligations have
NP, followed by a MRP for any Member State or group been fulfilled and then is converted from a conditional
of additional Member States. Alternatively, if it is known approval into a normal approval. Conditional MAs are
in advance the product is to be registered in multiple EU only for initial MAAs, not for variations (supplements).
Member States, the applicant can use the DCP. Although this can be selected on the application form,
it is up to EMA to decide whether to grant full or con-
Assessment Considerations ditional approval.
Adaptive Pathway
EMA introduced ‘adaptive pathways’ in a pilot from Exceptional Circumstances
March 2014 to August 2016. In March 2014, EMA An MA may be granted subject to certain specific obli-
invited companies to participate. The pilot proposed gations if the applicant can demonstrate it is unable to
either an initial approval in a well-defined patient provide comprehensive data on efficacy and safety under
subgroup with a high medical need and subsequent normal conditions of use. This might be impossible if
widening of the indication to a larger patient popula- the intended indications are encountered so rarely the
tion, or an early regulatory approval (e.g., conditional applicant cannot provide comprehensive evidence, the
approval) that is planned prospectively and where present state of scientific knowledge does not accom-
uncertainty is reduced through collecting postapproval modate the provision of comprehensive information
data on the product’s use in patients.14 or collection of such information would conflict with
This approach is relevant, particularly for medicines medical ethics.
with the potential to treat serious conditions with an These specific obligations may include:
unmet medical need and may reduce a medicinal prod- • Applicant shall complete an identified study
uct’s time to approval or reimbursement for targeted program within a time period specified by
patient groups. It involves balancing timely patient the competent authority, the results of which
access with the need for adequate, evolving information shall form the basis of a benefit-risk profile
on a medicine’s benefits and risks. reassessment.
The adaptive pathways approach builds on regula- • Medicinal product in question may be supplied
tory processes already in place within the existing EU on prescription only and, in certain cases, may
legal framework, including: be administered only under strict medical
• scientific advice supervision, possibly in a hospital and, for a
• compassionate use radio-pharmaceutical, by an authorised person.
• conditional approval mechanism (for medi- • Package leaflet and any medical information
cines addressing life-threatening conditions) shall draw the medical practitioner’s attention
• patient registries and pharmacovigilance tools to the fact the particulars available concerning
allowing collection of real-life data and devel- the medicinal product in question are inade-
opment of each medicine’s risk management quate, as yet, in certain specified respects.
plan (RMP)
The applicant may request EMA advice on justifying
The “standard” MA, conditional MA, MA under an MAA under exceptional circumstances. Usually,
exceptional circumstances and other provisions of the evaluation involves external expert groups (to determine
pharmacovigilance legislation, including RMPs, patient clinical relevance). The inability to provide compre-
registries, etc., can be selected for registration and hensive data should be discussed as early as possible
approval. during drug development. The applicant is encouraged
For further details on the adaptive pathway to seek scientific advice on limitations imposed by dis-
approach, see Chapter 24. ease or the disease’s rarity for collecting comprehensive
safety and efficacy information. scientific advice cannot

be requested on such ethical aspects as information Such meetings typically address product-specific legal,
collection. regulatory and scientific issues.
Any further discussion on appropriateness prefer- MAA presubmission meetings usually take place
ably should occur in the context of the presubmission six to seven months prior to initial MAA submission.
meeting between EMA and the applicant at least four The request should be sent at least six weeks before the
to six months before the MA submission.15 Validity and proposed meeting date.
renewal procedures are the same as those for a “normal” The presubmission meeting request must contain
MA, with annual reassessment of the benefit-risk ratio. an overview of the product and its development pro-
The applicant must indicate the desired approval gram (quality, nonclinical and clinical), a draft table
type in the application form. In certain scenarios, excep- of contents of the eventual CTD listing the studies
tional circumstances may not be granted if conditional performed, draft product information and a draft appli-
approval is more appropriate. cation form.
The form will provide important product and
Accelerated Assessment application type information (e.g., legal basis, refer-
The maximum MAA evaluation timeframe under the ence product details, manufacturing sites, conditional
CP is 210 days, excluding clock-stops when CHMP approval). It also will allow agencies to identify topics
asks the applicant to supply additional written or oral for discussion or clarification other than those requested
information. by the applicant and prevent issues at validation. For
However, the applicant may request an accelerated further details on the type of MAA application, see
assessment procedure for medicinal products of major the section on MAAs. The following items are to be
interest from a public health and therapeutic innovation addressed:17
viewpoint. • quality and Good Manufacturing Practice
Applicants requesting an accelerated assessment (GMP)
procedure should justify why the medicinal product • nonclinical, clinical, Good Laboratory Practice
is expected to be of major public health interest. If (GLP), Good Clinical Practice (GCP), paedi-
CHMP accepts the request, the evaluation timeframe atric and orphan
will be reduced from 210 days to 150 days. • pharmacovigilance
Any request for accelerated assessment should be • regulatory and procedural
made as early as possible before submitting the MAA. • product information
The request, including justification, should be sent elec- • transparency
tronically to EMA’s product team leader and all CHMP • administrative
members at least 10 working days in advance of the • other
CHMP meeting preceding the CP’s intended start date.
In practice, the request’s submission generally should Submission Content (Application Type,
occur at least 10 to 30 days before the procedure’s Regulatory Activity and Submission Units)
intended start.16 EMA strongly recommends applicants EU regulatory bodies’ terminology is not consistent
request a presubmission meeting six to seven months for applications; it would be more useful to distinguish
before submission to prepare for evaluation under accel- clinical trial authorisation applications, MAAs and
erated assessment. The data package and risk assessment active substance master files. Subsequently, each appli-
plan the sponsor intends to include in its application cation could have multiple regulatory activities, such as
can be presented. initial application and maintenance submissions. Each
regulatory activity (submission) can concern one or
Presubmission Meeting Request multiple submission units (e.g., application for a change
The applicant must request a presubmission meeting and subsequent responses to questions). Hopefully, this
with the agency to which the initial MAA will be sub- terminology will become less ambiguous when eCTD
mitted (i.e., EMA for the CP, Reference Member State v4.0 is adopted.18
for the DCP or MRP and national competent authority Following are overviews of relevant application
for a NP). types.
The presubmission meeting is an important point
in product development and the regulatory approval
MAA
process. These meetings enable applicants to submit
The MAA should demonstrate a consistent manufac-
applications in conformity with legal and regulatory
turing process, resulting in a consistent, high-quality
requirements and are able to be evaluated smoothly.
medicinal product with a favourable efficacy and safety

Chapter 27
profile when it is used in clearly defined patient popula- Generic Registration (Article 10(1))
tions according to the product information. The MAH The applicant shall not be required to provide nonclin-
must be established in the European Economic Area ical test or clinical trial results if it can demonstrate the
(EEA), which comprises the 27 EU Member States medicinal product is a generic of a Reference Medicinal
plus Norway, Iceland and Liechtenstein. The MA is Product that is or has been authorised for not fewer
granted to a single MAH and includes, when available, than eight years in a Member State or through EMA.
the active substance’s International Nonproprietary However, the generic medicinal product cannot be
Name (INN) and, when branded, a single invented placed on the market until 10 years have elapsed from
name (the trade name). Companies wishing to mar- the Reference Medicinal Product’s initial authorisation.
ket the same medicinal product with a second trade This 10-year period shall be extended to a maximum of
name must submit a separate MAA in accordance with 11 years if, during the first eight years of those 10 years,
Directive 2001/83/EC. The MAA must be approved the originator obtains an authorisation for one or more
by a competent authority before the product can be new therapeutic indications. Following this, in March
marketed in that authority’s jurisdiction. Moreover, the 2004, the EU introduced the ‘Bolar provision,’ which
MAA must be maintained to reflect medicinal product enabled European manufacturers to develop generic
experience. Product life might be altered by changes medicines within Europe prior to an originator drug’s
in production, product quality or therapeutic use (e.g., patent expiry.20,21
indications, contraindications and warnings and precau- The MAA is submitted in the Common Technical
tions for use). Those maintenance applications are called Document (CTD) format.22 There are four routes of
variations, extensions, etc. (see the section on Marketing approval, and the applicant can submit via any of them
Authorisation Maintenance). Once an MA is granted depending on which market it wants to target. A full
initially, it is good for five years and usually subject to quality section (Modules 2.3 and 3) of the dossier must
one renewal. The MAH should submit the MA renewal be provided. In addition, bioequivalence must be jus-
application at least six months before the expiration tified by either a clinical study or an in vitro study for
date. The consequence of failure to submit the renewal highly soluble, highly permeable, rapidly dissolving,
application is MA cancellation. orally administered drug products.
The MAA is submitted to a competent authority if For further details on generic medicinal product
the applicant is comfortable with the data’s correctness registration, see Chapter 29.
and completeness and documentation justifying the
product information claims. Which competent author- Hybrid Registration (Article 10(3))
ity is selected depends on the procedure type, product Hybrid applications are covered under Directive
characteristics and/or strategy the applicant thinks is 2001/83/EC Article 10(3), as amended, and registra-
best to obtain a marketing license (see the section on tion involves an amalgam of a generic (for the active
Procedure Types). When applying for an MA within substance) and full registration (for a new formulation
the EU, regardless of the type of procedure, the appli- or usage). Appropriate nonclinical or clinical study
cant can apply for various legal product registrations. results shall be provided to support SmPC claims not
MAA content depends on the applicable registration referenced for the medicinal product. This might be
type. These include:19 applicable if bioequivalence cannot be demonstrated
through bioavailability studies or if there are changes in
Full Registration (Article 8(3)) the active substance(s) (not therapeutic moiety), ther-
In accordance with Article 8(3) of Directive 2001/83/ apeutic indications, strength, pharmaceutical form or
EC, as amended, a full (standalone) MAA must include: route of administration. In addition, Modules 2.3 and 3
• physicochemical, biological or microbiological must be dedicated to the medicinal product.
tests
• pharmacological and toxicological tests Similar Biological Registration (Article 10(4))
• clinical trials CHMP/437/04 Rev. 1 (2013) defines a biosimilar as a
“biological medicinal product that contains a version of
This type of application is compulsory for new chemi- active substance of an already authorised original bio-
cal entities (new active substances). Thus, a registration logical medicinal product (reference medicinal product).
must be based on documentation supporting a medic- A biosimilar demonstrates similarity to the reference
inal product’s quality, nonclinical and clinical aspects. medicinal product in terms of quality characteristics,
This concerns a full CTD, including Modules 1, 2, 3, 4 biological activity, safety and efficacy based on a com-
and 5. prehensive comparability exercise.” This registration
applies to a biological medicinal product similar to

a reference biological product, but not meeting the Fixed Combination Registration (Article 10b)
generic medicinal product definition conditions. It In accordance with Directive 2001/83/EC Article
focuses on differences relating to raw materials or the 10(b), as amended, and Annex I, Part II (5), fixed
biologic medicinal product’s manufacturing process. A combination applications are possible for medicinal
full dossier quality section (Modules 2.3 and 3) must products containing active substances used in authorised
be provided. In addition, head-to-head comparison medicinal products’ composition but not in combination
must be provided. The nonclinical and clinical sec- therapeutic products. In that case, the results of new
tions (Modules 4 and 5) are smaller than the reference nonclinical tests or new clinical trials results relating
product’s and must include head-to-head nonclinical to that combination should be provided in accordance
and clinical study results comparing the similar bio- with Article 8(3), but it is not necessary to provide
logical to its reference biological medicinal product. scientific references relating to each individual active
Comparability must be studied in the most sensitive substance.
settings to prove both products are comparable. Similar Moreover, any fixed combination may be consid-
efficacy of the biosimilar and the reference product has ered a complete/full, independent application because it
to be demonstrated in randomised and well-controlled is a new, unique medicinal product requiring a separate
trials, preferably double-blind or at least observer-blind. SmPC. A full dossier quality section (Modules 2.3 and
Pre-licensing safety data and immunogenicity data 3) must be provided.
should be obtained from comparative efficacy trials. For further details on combination products, see
Finally, applicants also need to present an ongoing Chapter 42.
RMP and pharmacovigilance plan, since the data from
the preauthorisation clinical studies usually are too Informed Consent Registration (Article 10c)
limited to identify all potential biosimilar side effects. If Under Directive 2001/83/EC Article 10(c), as
biosimilarity has been demonstrated in one indication, amended, these applications are appropriate in cases
extrapolation to other reference biological medicinal when a medicinal product is essentially similar to a
product indications could be acceptable within the EU, product already authorised in the Member State and
provided it is justified scientifically. the original product’s MAH gave the second appli-
cant rights to refer to its approved dossier. If an MAH
Bibliographic Applications (Well-Established Use would like to have a partner-MAH to co-market its
Registration (Article 10a)) product, it may allow a partner-MAH to reference the
According to Directive 2001/83/EC Article 10(a), as pharmaceutical, preclinical and clinical documentation
amended, and Annex 1, Part II (1), it is possible to contained in the medicinal product’s file. MAHs would
replace pharmacological and toxicological tests or clin- benefit from examining subsequent applications relating
ical trial results with detailed references to published to other medicinal products possessing the same active
scientific literature if a medicinal product’s constitu- substance and pharmaceutical forms’ qualitative and
ent(s) has well-established medicinal use, recognised quantitative composition and SmPC. Such an applica-
efficacy and an applicable safety level. This applies to tion would consist only of Module 1.
any medicinal product or chemical or biological sub- For regulatory authorities, demonstrating informed
stance for which there is no original/reference medicinal consent is a formal prerequisite when the application is
product to which essential similarity can be claimed. submitted. However, withdrawing the informed consent
In theory, it still is possible to register products based at a later stage has no direct consequences for the MA’s
on well-established use. However, in practice, this is existence or validity.
unlikely. Applicants are to demonstrate the medicinal
product to have been in well-established medicinal use Traditional Use Registration for Herbal Medicinal
within the Community for at least 10 years with rec- Products (Article 16a)
ognised efficacy and an acceptable safety level. In that Regulation (EC) No. 726/2004 established the
event, test and trial results can be replaced by appropri- Committee on Herbal Medicinal Products (HMPC).
ate scientific literature. If an herbal medicinal product has been in medici-
A full dossier quality section (Modules 2.3 and 3) nal use for a period of at least 30 years preceding the
must be provided, together with the nonclinical and application’s date, including at least 15 years within the
clinical overview and summaries based on available Community, the applicant can register a traditional use
literature references in Modules 4 and 5. medicinal product according to Article 16a of Directive
2001/83/EC. It created a simplified registration pro-
cedure that fulfils certain criteria.23 At the Member
State’s request in which a traditional use registration

Chapter 27
application has been submitted, HMPC shall develop substances’ quality require not only a combination
an opinion based on adequate evidence of the product’s of physicochemical and biological testing, but also
long-standing use or that of a corresponding product. extensive knowledge of the production process and its
A full dossier quality section (Modules 2.3 and 3) control. Therefore, a biological medicinal product MAH
must be provided, together with nonclinical and clinical or applicant could not comply with the requirement to
overviews based on available literature references in “take responsibility for the medicinal product” without
Modules 4 and 5. having full access to these quality-related data. The use
of an ASMF would prevent such access, and therefore,
Mixed Marketing Applications is not allowed for biological active substances.
Directive 2001/83/EC, Annex I, Part II (7), as In the US, the DMF holder and applicant must
amended, specifies mixed MAAs must present pub- negotiate the information the applicants need to
lished scientific literature together with original test and produce high-quality drugs consistently. In the EU,
trial results. Such applications must be submitted and regulators have defined the information that must be
processed following the complete, full and independent disclosed to the applicant.25 This resulted in two sets
MA dossier requirements. These requirements apply of Module 3.2.S documents the ASMF holder must
to the use of bibliographic references in mixed dossiers maintain, namely the ‘applicant’s part’ and the ‘restricted
both as supporting data for the applicant’s own tests part.’ The restricted part contains the complete Module
and trials or to replace any tests or trials in Module 4 3.2.S, including both the applicant’s part documents
and/or 5. All other module(s) are in accordance with the as well as those belonging in the restricted part. If the
structure described in Part I of the above-mentioned assessor questions the restricted part, it must send those
Annex I. The competent authority will accept the appli- questions to the ASMF holder and inform the appli-
cant’s proposed format on a case-by-case basis. cant answers to those questions have been requested.
The applicant must contact the ASMF holder about
Active Substance Master File (ASMF) progress on answering those questions.
The concept of the ASMF (previously known as
European Drug Master File (EDMF)) is established Scientific Advice Application
in Directive 2001/83/EC, as amended, and described A scientific advice application consists of a letter of
in EMA’s Guideline on Active Substance Master File intent and a briefing document. Templates for the let-
Procedure.24 An active substance manufacturer can ter of intent and briefing package are available from
submit an ASMF to regulators. Subsequently, MA EMA.26
applicants for a product containing the active substances The briefing document comprises:
can reference the manufacturer’s chemical or biotech- 1. summary
nological information. Detailed information regarding 2. questions and applicant’s positions
active substance production need not be disclosed to a. chemical, pharmaceutical and biological
the applicant. An additional benefit is multiple products development questions
and multiple applicants can reference an ASMF. b. multidisciplinary questions on chemical,
A regulator will review the ASMF as soon as it is pharmaceutical, biological and toxi-
referenced by an applicant. Applicants obtaining drug co-pharmacological development
substances from ASMF holders must obtain a letter c. toxico-pharmacological development
of access from the contract manufacturer. The ASMF questions
holder must declare the applicant will be informed d. multidisciplinary questions on tox-
if production process changes are planned and/or ico-pharmacological and clinical
implemented. If applicable, these changes must be doc- development
umented accordingly in the ASMF. Subsequently, the e. clinical development questions
drug product applicant must submit a variation appli- f. questions on significant benefit
cation. Regulatory agencies can review the ASMF in g. background information
context of a marketed product.
The ASMF principle in the EU is similar to the Scientific advice requests must contain not only ques-
Drug Master File (DMF) in the US. However, in the tions, but also the applicant’s positions. Since EMA
US, the DMF also can be used for intermediates and decides whether to agree to the meeting, arguments and
drug products. This is not possible in the EU. MAHs wording need to be selected carefully if the applicant
and applicants are advised the ASMF concept can- wishes the request to be granted.
not be applied to biological medicinal products. The
characterisation and determination of biological active

Specific EU MAA Particulars Table 27-1. EU Module 1 Contents

Module 1
Module 1 is specific for the EU and will deviate from 1.0 Cover Letter (includes tracking table and notes for
any other regional or national Module 1.27 Its contents the reviewer)
are listed in Table 27-1. Module 1 should provide 1.1 Comprehensive eCTD Table of Contents (generated
information (e.g., the application form with 22 annexes, automatically upon opening the eCTD)
proposed summary of product characteristics, labelling 1.2 Application Form (includes supportive and required
(SmPC) and patient information leaflet (PIL), pharma- documents as generated by the application form itself)
1.3 Product Information
covigilance system description and RMP).
1.3.1 SmPC, Labelling and Package Leaflet
Cover letters are not scientific or strategic doc- 1.3.2 Mock-up
uments and contain administrative, descriptive 1.3.3 Specimen
information introducing the submission. Therefore, infor- 1.3.4 Consultation Target Patient Groups
mation about the medicinal product’s characteristics and 1.3.5 PI already approved in the Member States
purpose need not be included. This information should 1.3.6 Braille (statement only)
be at the appropriate locations in the CTD, and any rep- 1.4 Information about Experts
etition might pose a risk because of inconsistencies with 1.4.1 Quality
the actual claims elsewhere in the dossier. EMA’s tem- 1.4.2 Nonclinical
1.4.3 Clinical
plate supports this in a required CP cover letter.28
1.5 Different Application Types
MS Word-based application forms no longer are 1.5.1 Bibliographical Application Information
accepted. Electronic application forms (eAFs) with new 1.5.2 Generic, “Hybrid” or Biosimilar Information
features like electronic data import/export, data pop- 1.5.3 (Extended) Data/Market Exclusivity
ulation within the form, online access to standardised 1.5.4 Exceptional Circumstances
catalogue terms, built-in business rule validation and 1.5.5 Conditional Marketing Authorisation
data validation support are to be used. In accordance 1.6 Environmental Risk Assessment
with the eSubmission roadmap, the eAF29 became man- 1.6.1 Non-Genetically Modified Organism
datory on 1 July 2015 for the CP and mandatory from 1.6.2 Genetically Modified Organism
1.7 Orphan Market Exclusivity Information
1 January 2016 for the MRP and DCP. Various items
1.7.1 Similarity
in the application form must be supported by relevant 1.7.2 Market Exclusivity
documentation, which also can be included in Module 1.8 Pharmacovigilance Information
1.2 (e.g., proof of payment and GMP certificates). 1.8.1 Pharmacovigilance System
Product information (Module 1.3) must be in 1.8.2 Risk-management System
accordance with EMA’s Quality Review of Documents 1.9 Clinical Trial Information
(QRD) group requirements. See the section on Other 1.10 Paediatric Information
Regulatory Documents and Data/QRD Review for 1.10.1 Responses to Questions
further details. 1.10.2 Additional Data
Module 1.8 must contain the RMP and the phar-
macovigilance system master file summary.
• medical device (if applicable)
EU eCTD Envelope • Certificate(s) of Suitability (if applicable)
The eCTD contains descriptive information helping • medicinal products containing or using animal
recipients place this eCTD in the appropriate product, and/or human origin materials in the manu-
applicant and agency perspective. facturing process (if applicable)
The requested envelope information should be the
same as requested in the cover letter and application Further details on the information required for Module
form. If not, it might cause validation issues upon appli- 3.2.R are provided below.
cation submission. The requested envelope information
is listed in Table 27-2. Drug Product Process Validation Scheme
A validated production process must show documented
EU Module 3.2.R evidence the process, operating within established
EU Module 3.2.R (regional information) should con- parameters, can perform effectively and reproducibly to
tain the following information and must be used, if produce a medicinal product meeting its predetermined
applicable: specifications and quality attributes.30 Although this
• drug product process validation scheme section generally was considered a one-off documen-
tation, it has been changed to a dynamic and lifecycle

Chapter 27
Table 27-2. EU eCTD Envelope Information For materials from animals not covered by the
Notice for Guidance on minimising the risk of trans-
mitting animal spongiform encephalopathy agents
• Application Number
• Tracking Number via medicinal products and the Annex I to Directive
• Applicant 2001/83/EC, as amended, applicants are requested to
• Agency complete the template B on ‘Other materials of animal
• Procedure (either Centralised, National, Mutual origin.’ If an application relates to a medicinal prod-
Recognition or Decentralised) uct that contains or uses materials of human origin in
• Invented Name manufacturing, applicants are requested to complete
• INN template C ‘On albumin and other human tissue
• Sequence derived materials’ and include it in Module 3.2 R. More
• Related Sequence
information can be found at http://www.ema.europa.
• Submission Description (<50 characters)
• Submission type, e.g., Initial MAA, Supplemental eu/docs/en_GB/document_library/Regulatory_and_
Information, Type 1A Variation, Type 1B Variation, procedural_guideline/2009/10/WC500004069.pdf.
Type II Variation, Extension, PSUR, Renewal, ASMF,
USR, reformat, withdrawal Other Modules
• Mode (for variations and extensions only), e.g., The EU application does not have to contain all appen-
single, grouping or work-sharing dices belonging to a clinical trial report.31 Appendices
not submitted must be on file and available upon
request. Patient data listings and case report forms
documentation set, allowing the possibility of using (CRFs) (not concerning deaths, serious adverse events
continuous process verification in addition to, or instead and hospitalisation or termination from the study) do
of, traditional process validation. Considering the huge not have to be submitted. In addition, no datasets can
number of submissions required to maintain compli- be submitted for nonclinical and clinical study reports.
ance between approved documentation and applied Study tagging files (associated with nonclinical and
production processes, continuous process verification clinical studies) are not needed in an EU submission
is encouraged. This facilitates the adoption of the ICH and should be omitted because they offer no additional
Q8, Q9 and Q10 approaches. Process validation incor- benefits.
porates a lifecycle approach, linking product and process Further, in comparison to the US dossier, the EU
development, commercial manufacturing process vali- does not require Integrated Analyses on Safety (ISS) or
dation and maintaining the process in a state of control Integrated Analyses on Efficacy (ISE). Nevertheless, if
during routine commercial production. There is no fixed these documents are available, they generally should be
structure for this CTD section. submitted.
Certificate(s) of Suitability Regulatory Dossier Submission

If active substances’ quality (Modules 2.3.S and 3.2.S) Submission Dates
has been reviewed and approved by the European NP dossiers can be submitted at any time. CP, MRP
Directorate of Quality Medicine (EDQM), applicants and DCP dossiers must be submitted on a predefined
can include an EDQM Certificate of Suitability in their schedule to meet CHMP meeting dates for the CP32
submissions. This would allow omitting MAA Modules and CMDh meeting dates for the MRP and DCP.
2.3.S and 3.2.S.
Submission Format
Medicinal Products Containing or Using Materials of Numerous regulatory dossiers have been exchanged
Animal and/or Human Origin between industry and agencies. In 2003, the CTD
This section contains statements and details on the format became mandatory. In the beginning, the CTD
source, supplier and safety of materials of animal and/ was paper, slowly moving to ‘digitalised paper’ dossiers.
or human origin used in manufacturing the medicinal During the last few years, EU regulators have moved
product. For the CP, EMA has developed templates (A, toward electronic regulatory data exchange solutions,
B and C). Template A is specific to ‘Materials of animal as documented in the EMA and HMA eSubmission
origin covered by the notice for guidance on minimising roadmap.33 More information on the eSubmission road-
the risk of transmitting animal spongiform encepha- map can be found at http://esubmission.ema.europa.
lopathy agents via medicinal products’ and should be eu/tiges/docs/eSubmission%20Roadmap%20final%20
completed by the applicant if the medicinal product falls v2.0.pdf.
under the above category and included in Module 3.2 R.

EMA’s mandatory submission format now is the Common European Submission Platform
eCTD. The Common European Submission Platform (CESP)
Even though the eCTD’s name includes the word is a simple and secure mechanism for exchanging
‘electronic,’ it still consists of PDF documents with A4 information (including eCTDs and non-eCTD elec-
or letter-size pages with page numbers and headers tronic submissions (NeeS)) among applicants, national
and footers. Although this is a significant improvement competent authorities, EDQM and DG Sanco.36 It
over the exchange of physical dossiers, the data must be was established to reduce the burden for applicants and
obtained manually from any of those digital documents. national competent authorities handling CD-ROM
Key stakeholders recognise the need for real electronic and DVD submissions. All agencies can download
data allowing automated processing, reporting, searches CESP submissions and upload them to their own sys-
and analyses. This is demonstrated by EMA’s master tems for further processing.
data management (MDM) roadmap,34 initiated by the The applicant receives an acknowledgement of a
European Commission. This MDM roadmap includes successful upload. Similarly, the applicant receives an
data related to substances (S), products (P), organisa- acknowledgement for every successful national compe-
tions (O), such as manufacturers and applicants, and tent authority download.
reference sources (R), such as controlled vocabular- Although CESP is not mandatory, applicants use
ies. This roadmap demonstrated the importance and it frequently. Registration and usage are easy and free of
urgency of the implementation of ISO Identification of charge. Besides applicants, consultancy companies can
Medicinal Products (IDMP). For further information, register and send eCTDs on behalf of the applicant.
see the section on XEVMPD and IDMP.
EudraLink
EMA’s eSubmission Gateway and Web Client EudraLink is the European medicines regulatory net-
EMA’s gateway and web client are electronic channels work’s secure file-transfer system.37 It is independent
allowing applicants to submit applications in eCTD of EudraNet, the EU medicines regulatory network
format securely via the internet.35 One of these routes for regulators only, and can be used by applicants and
must be used for all CP submissions. In addition, MAHs as well as regulatory organisations to transfer
these channels are optional for all referral procedures files. Since this is a dedicated exchange medium, it is
and paediatric submissions, including PIPs. While more secure than regular email. It can be used as an
the web client is an exchange platform, the gateway alternative to emailing highly confidential information.
automatically routes submissions to relevant EMA It can exchange up to 200 MB per message and has an
offices. The gateway is faster for large submissions unlimited number of messages.
and includes customised tools for automated submis- Registration and usage are easy and free of charge.
sion upload. Although EMA does not charge for the Usage can be requested via the EudraLink account
gateway, installation and maintenance of the Axway request form. Once an account is established, it is possi-
Synchrony Gateway Interchange is quite costly. Hence, ble to send EudraLink messages to recipients without a
the web client is the tool of choice for SMEs. From 1 EudraLink account.
September 2015, the eSubmission gateway and/or the Besides applicants, consultancy companies can reg-
web client became mandatory for all Periodic Safety ister and send messages on behalf of their clients.
Update Report (PSUR) submissions to EMA qualify-
ing for single assessments (see the section on PSUR and Regulatory Dossier Validation
Periodic Safety Update Single Assessment (PSUSA)). Technical Validation
The eCTD is validated upon delivery via EMA’s Depending on the type of procedure, validation will be
gateway. Validation results are transmitted to the appli- done by one or multiple agencies.38
cant via the gateway. The web client, upon successful For the CP, technical eCTD validation will be
upload, transmits an acknowledgement to the sender. done upon completion of the EMA gateway upload.
Subsequently, the eCTD will be technically validated Depending on internet bandwidth, the upload can take
and the results transmitted via the web client. For fur- minutes for a small dossier to hours for dossiers of a few
ther validation details, see the section on Regulatory gigabytes in size. Upon upload, the applicant receives a
Dossier Validation. Following technical validation, the receipt message. Subsequently, technical validation will
eCTD is transferred to EMA’s common repository. The take place at EMA. Depending on size and the number
latter is not accessible to applicants. of hyperlinks, particularly those pointing to a specific
Consultancy companies also can register and send page in another document, the eCTD validation report
eCTDs on behalf of their clients. is received within 15 minutes to about an hour. If the

Chapter 27
submission failed validation, the applicant must make Like the CP, validation issues need to be resolved
the applicable correction(s) using the same sequence by submitting a revised sequence with the same
number as the failed one and repeat the upload. If tech- sequence number.
nical validation led to a technically valid dossier, EMA
makes the eCTD available on the common repository. Business Validation
Subsequently, business validation will take place. From 1 Business validation checks whether all data and docu-
July 2015, the common repository has been mandatory ments required for evaluating quality, safety and efficacy
for national competent authorities, and the applicant no are available. For the CP, business validation is con-
longer has to submit the eCTD to CHMP members ducted by EMA’s rapporteur and co-rapporteur. Typical
separately through CESP or CD/DVD. Provided the validation errors involve inconsistencies across cover
applicant uses the same validation tool, EMA should letters, application forms (including annexes), SmPCs
find no validation issues. If the sender and recipients use and Modules 3.2.P.1, 3.2.S.2.1 and 3.2. P.3.1. Other
different versions of the same validation tool, differences validation errors might concern missing documents
may result. generally available for a proper review.
In addition, typical validation errors for an initial For the MRP and DCP, business validation is led
submission involve issues with the size of individual by the Reference Member State, although it can be per-
files or incomplete eCTD contents in the ZIP file. formed by each Concerned Member State individually.
Depending on the recipient’s infrastructure and proces- Besides the issues mentioned for the CP, others might
sors’ performance, errors can occur due to incomplete occur involving country-specific or language-specific
eCTD download or unzipping or runtime errors details in Module 1.
related to large individual files with many external CMDh has provided a list of required conditions
links. Typical errors for follow-up sequences concern an that must be met before the Reference Member State
inability to put the new sequence in the existing life- can start the procedure.40
cycle’s context. This might happen if the applicant has Unlike technical validation, business validation
migrated to another eCTD builder or the agency has must be corrected by submitting a sequence with the
migrated to another review tool. This is confirmed by next available sequence number.
an independent interoperability exercise across various
eCTD-processing tools.39 Regulatory Dossier Assessment Procedure
For the MRP, DCP and NP, the dossier (eCTD Centralised Procedure
or NeeS) has to be uploaded through CESP. Most CP procedural evaluation is coordinated by the EMA
agencies will download the electronic dossiers to their project lead. The scientific evaluation is coordinated
own IT environment. All agencies perform their own by the rapporteur and co-rapporteur. Depending on
technical validation. The Reference Member State’s product characteristics, the production process and ther-
technical validation process usually has tight time lim- apeutic indication, the rapporteur and co-rapporteur
its. Nevertheless, technical issues at other agencies also will select experts associated with any national compe-
need to be addressed, although they cannot be resolved tent authority. The timelines are shown in Figure 27-1.
with submission of a slightly different sequence. Prior to starting the procedure, the applicant
Since not all agencies have the same level of eCTD should meet with EMA or apply for scientific advice
understanding, the applicant must be diplomatic in early in product development. This is not required, but
addressing all individual needs. Typical errors are the it is considered best practice to request a presubmission
same as for the CP, plus some additional issues may meeting two years to six months prior to the intended
occur, such as using a long path before locating the application date. Scientific advice is subject to a fee,
sequence folder. This causes broken hyperlinks to desti- which varies depending on the scope of the advice;
nation documents. however, some fee reductions and/or waivers are avail-
Other technical validation issues might be related able (e.g., orphan designation or paediatric use). EMA
to differences in eCTD standards’ interpretation by only accepts electronic requests for scientific advice and
various validation tool vendors and lack of validation of protocol assistance, including follow-up-requests. Any
validation tools, themselves. eligibility request for nonmandatory products must be
Additional validation issues might concern miss- approved by CHMP in advance, but EMA can help.
ing country-specific modified files if the Concerned About six months prior to the intended application
Member State(s) has not uploaded previous sequences date, the applicant should submit a letter of intent. It
considered inappropriate for them. also is best practice to request a presubmission meet-
ing using EMA’s presubmission request form. If the

Chapter 26
Figure 26-1. Initial Marketing Authorisation Appplication Through the Centralised Procedure
Figure26-1.
Figure 27-1. Initial
InitialMarketing
MarketingAuthorisation
Application Through
Through the Centralised
the Centralised Procedure
Procedure
Day -14: File to EMA, CHMP, Cay 80: Draft Assessment Reports by (Co-)Rapporteur to EMA,
Day 1: Validation
(Co-)Rapporteur CHMP and Applicant
ASAP
Day 150: Joint Assessment Report to EMA, CHMP Day 121: RtQ to EMA, CHMP Day 120: List of Questions to Applicant
and Applicant and (Co-)Rapporteur
Day 157: QRD Comments on English PI Day 180: Oral Explanation at CHMP, if Needed
Day 179: List of Questions
to Applicant
CHMP Meeting
Day 215: Final English PI + Draft PIs QRD- Day 210: CHMP Opinion + Translation Day 181: Final English PI to EMA, CHMP
Form 1 Timetable
+ (Co-)Rapporteur
Day 229: Opinion + all Annexes to all Day 235: Final PIs QRD Form 2 Day 246: Final ‘Worst Case’ Mock-ups to EMA
Parties
Day 277: Final EPAR and Approval by European Commission
Approximately
application qualifies90fordays
thebefore submission
CP, an EMA productto Concerned
team applicant
Member of theirquestions,
States’ final positions. If therethem
consolidate is a negative
and sendposi-
Member
is assembledStates,
to the applicant
coordinate theasks the Reference
application, Member
and CHMP tion,
themConcerned
to the applicant Member States
at Day must
105. inform the the
Subsequently, CMDh
State
membersto update its assessment
can apply report and allocate
to be (co-)rapporteur. a proce-
A provisional secretariat.
clock-stop period begins, and the applicant has three
dure
choicenumber.
is madeFourteen
by EMA, days before the
although CHMP targeted start date,
appoints the monthsIf consensus
to answeristhesereached, the Reference
questions. Member
This period State
can be
the applicant submits the dossier to Concerned Member
(co-)rapporteur. closes the procedure,
extended, if justified.andThethe nationalmay
applicant phase can begin.
submit draft
States. In parallel, the Reference Member State sends the If consensus
responses, is notSmPC,
including reached,PILtheand
points for disagreement
labelling propos-
assessment
Decentralised report, including the SmPC, Patient Leaflet and
Procedure submitted by the Concerned
als to the Reference Member Member
State for States are referred to
pre-assessment.
labelling to Concerned
The DCP consists of two Member
phases:States. Subsequently,
a bilateral each
phase, identi- CMD(h)
In any case, by the
the Reference
applicant Member
should reachState agreement
within sevenondays
Concerned Member State must validate
cal for the Reference Member State and each Concerned the application after Day 90. If date
the submission consensus
of theisfinal
not response
reached at thethe
with CMD(h)
package.
Member All Member
State States mustand
up to consensus, inform one another
a national phase, via level, the Reference
Reference Member State. Member Upon State refers
receipt of the matter to
a valid
the
leading to the registration of the country-specific whether
Communication and Tracking System (CTS) CHMP
response, tothe
arbitrate unsolved
Reference disagreement.
Member State restarts the
all criteriaThe
SmPCs. have been satisfied
timelines are shownfor them to start
in Figure the proce-
27-2. The national
procedure at Day phase
106. Up following
to Day 120,a Mutual Recognition
the Reference
dure During
(Day 0).the Atbilateral
Day 50,phase,
the Concerned Member
the Reference Member States Procedure
Member State is identical
updates to thethe
PrAR Decentralised
to prepare aProcedure,
Draft
send
State takes the lead in reviewing the applicant’s dos-and
their comments to the Reference Member State resulting
Assessment in national
Report MA (DAR) numbers.
and sends it with the draft
applicant. Applicants Member
sier. The Concerned have 10 calendar
States anddaysReference
to prepare their SmPC, draft labelling and draft PIL to the Concerned
responses. This can be a very frenzied
Member State get the dossier at the same time, period for applicants.
so National
Member States.Procedure If consensus is reached, this bilateral
At Day 60, the applicant sends the response
multiple experts might start reviewing the dossier document to National
procedureProcedures
phase canstill can be used
be followed byifparallel
an applicant
30-daywishes
the Concerned
without prejudice Member
based on States
otherand Reference
agencies’ review.Member
The to marketphases
national a medicinal
in eachproduct in a single
Concerned EU Member
Member State.
State and
State. The Reference Member State
Reference Member State will author the preliminary circulates its assess- National
the Reference Procedures
Member are State.
not discussed here was
If consensus because
not they
ment of thereport
assessment response document
(PrAR) and sendto Concerned Member
it with the English are used infrequently,
reached, the Reference andMember
NationalState
Competent
sends theAuthorities
DAR,
States by Day 68. At Day 75, Concerned
product insert (PI) to the Concerned Member States Member States apply different
draft SPC, timelines.
draft labelling and draft PIL to Concerned
send their remaining comments to the
and applicant at Day 70. Subsequently, the applicantReference Member Member States. The Concerned Member States must
State and preparing
can start applicant. forA break-out
potential session
questions,canandbe organised
the Responses
send their final to Questions
comments to the Reference Member
in Days 73–80. At Day 85, Concerned
Concerned Member States can send their actual Member States send
ques- Agencies’
State no later dossier
thanevaluations,
Day 145. The in Reference
general, almost
Memberalways
any remaining comments to the Reference
tions to the Reference Member State before Day 100. Member State result in questions.
State must consolidate Depending
commentsonand themay
dossier’s quality
close the
and
The applicant.
Reference Subsequently,
Member Stateatwill Day 90, the
collect Concerned
Concerned and completeness
bilateral phase at Day and 150,
the drug’s
followedintrinsic characteristics,
by parallel 30-day
Member States notify the Reference Member State and a number of questions will arise. These questions must

Chapter 27
Figure
Figure27-2.
26-2. Initial MarketingAuthorisation
Initial Marketing Authorisation Application
Application Through
Through the Decentralised
the Decentralised Procedure
Procedure
Figure 26-2. Initial Marketing Authorisation Application Through the Decentralised Procedure
Day -14: Application to Reference Member State + All Day 0: Validation Day 70: PrAR + PI to Concerned Member States
Concerned Member States
Day 105: List of Day 106: Responses to Day 120: Consensus Day 150: National Approval by
Questions Reference Member State + Concerned Member States
<3Month
Day 180: National Approval by
Day 121: Draft Assessment Report + English PI to Concerned Day 150: Consensus Concerned Member States
Member States

Day 230: List of Questions Day 180: Consensus Concerned Member States
National Phase
Day 245: Responses to CMDh Day 205: Break out

Day 210: Consensus Concerned Member States
CHMP <270: CMDh

be answered in a Response to Questions (RtQ). The RtQ QRD Review

should consist
national phases inof each
a cover letter, response
Concerned Member document
State and EMA’s
State and QRD group hasMember
Concerned templates andSubsequently,
State. standard termi- the
additional
and new documents
the Reference MemberorState. replacement documents.
If consensus is notThe nologies for each EU
national competent language.
authority willThese templates
confirm and
the correct
responsebydocument
reached Day 150, should contain Member
the Reference questions,State
each on a terminologies
translation and must be applied
grant to the
a national product information,
marketing license, with
different page. Responses
communicates outstanding should be to
issues immediately under each
the applicant, i.e., SmPC; immediate, intermediate
national MA numbers. National competent and outerauthori-
container
obtains any additional clarification and prepares amust
question. However, new or corrective information shortbe labels; and the PIL. These templates must be used
ties also might request a statement from the applicant, regardless
reflected at the appropriate place within the CTD, e.g., of the procedure.
report for discussion prior to Day 180. If consensus stating the national PI is a truthful translation of the
revised specifications are in Module 3.2.S.4.1 or 3.2.P.5.1, For the Centralised Procedure, QRD will review the
is reached at Day 180, the applicant follows up with English PI and, subsequently, some sample checks will
not attached to the response document. This will ensure the English texts for compliance to the template terms and
parallel 30-day national phases in each Concerned suffice. Unfortunately, this national phase sometimes
eCTD’s current view always shows the applicant’s current stylistic matters prior to CHMP’s scientific opinion as part
Member State and the Reference Member State. If takes longer due to priority clashes at national compe-
position on the drug’s quality, safety and efficacy. of the initial MAA review and variations.46 Following the
consensus was not reached at Day 180, a breakout ses- tent authorities.
scientific opinion, but before the Commission’s approval/
sion
Other with Regulatory
involved Member States will be
Documents andheldData
at Day adoption process, QRD and CHMP members check the
205. At Day 210,
Readability Tests closure of the bilateral Decentralised Mutual
same Recognition
criteria Procedure
for translations into other EU languages.
Procedure
The PIL mustphasebeshould
writtenbe obtained,
clearly and beincluding
easily understand- Like the DCP, the MRP consists of two phases: a
Concerned Member States’ approval
able, enabling the user to act appropriately. of theEUassessment
MAA PILs bilateral assessment
Mock-Ups and Specimens phase, identical for the Reference
report, SmPC, labelling and PIL. If no consensus
must have been checked by an appropriate target patient is Member
For State andProcedure,
the Centralised each Concerned Member
the applicant or MAH State up
must
achieved at Day 180, it would be referred to
group. A readability test must have been performed, and CMDh for to consensus,
submit outer and andimmediate
a nationalpackaging
phase, leading
and PILtomock-ups
the reg-
a aresolution at Day 210. If, at this day, no consensus
summary must be included in the application dossier.44 is istration
and of thetocountry-specific
specimens EMA for reviewSmPCs. before The timelines
the medicinal
reached,
The PILthemustReference
have beenMember
checked in State has to consolidate
all applicable languages are shown
product’s in Figure 27-3.47
commercialisation.
the CMDh’s position and initiate
for the Member States in which the medicinala referral to CHMP
product is AApproximately
“mock-up” is a copy 90 days before
of the submission
flat artwork designtoin full
toregistered.
arbitrate The
the readability
unsolved disagreement.
test summary does not have to be Concerned
colour, Member
providing States,
a replica the applicant
of both the outer asks the
and immedi-
The national
submitted with the 30-day
initialphase for granting
application an MA,
submission, but can Reference
ate packaging, Member State to update its
so the three-dimensional assessmentof the
presentation
following consensus in the bilateral phase,
be submitted with the first response document following consists of report and
labelling textallocate a procedure
is clear. A “specimen”number. Fourteen
is a sample days
of the actual
the following. Within
the planned clock-stop. five
45 days after the consensus,
before the
printed targeted
outer start date,
and immediate the applicant
packaging submits
materials and PIL
the applicant must provide truthful translations of the (i.e., sales presentation).
the dossier to Concerned Member States. In parallel,
English product information to the Reference Member the Reference Member State sends the assessment

Chapter 26
Figure 27-3. Initial Marketing Authorisation Application Through National Procedure and Mutual
Figure 26-3. Initial Marketing Authorisation Application Through National Procedure and Mutual Recognition
Recognition
Procedure Procedure
Figure 26-3. Initial Marketing Authorisation Application Through National Procedure and Mutual Recognition Procedure
Day -14: Application to the first Member

State (National Procedure) Day 0: Validation Day <210: Marketing License Reference Member State
Day <+90: Assessment Report, Updated Dossiers and

Day 50: Questions Day 0: Validation
English PI to Concerned Member States
Day 60: Supplement
Day 150 at CMDh: Approval/Referral
Day 75: Oral Explanation if

Day 180 at CHMP: Approval/Refusal Day 90: Approval/Referral Necessary
Day +5 Final Translated PI
National Implementation Step

Day +30: Marketing License
Applicants should provide EMA with mock-ups and/ Even though eCTD specifications require PDF files in
report, including
or specimens the SmPC,
for new Patient
applications in Leaflet
accordanceand with
label-the there
A4 orisletter
a negative position,can
size, mock-ups Concerned Member
be submitted States
as PDF files
ling to Concerned
following requirements: Member States. Subsequently, each must inform the
in any page size. CMDh secretariat.
Concerned Member State must validate the application If consensus is reached, the Reference Member
package.
Mock-Ups All Member States must inform one another State closes the procedure, and the national phase can
Specimens
via the communication
At the time the application andistracking
submitted,system (CTS) full-
one English, begin.
At the latest, 15 working days before marketing, one set of
whether all criteria have been satisfied
size colour mock-up and one multi-lingual, full-size for them to colour If consensus
relevant outer andisimmediate
not reached, the points
packaging for disagree-
and PIL specimens
start the procedure (Day 0). At Day 50, the
mock-up (“worst-case”) of the outer and immediate packag- Concerned ment
for each strength or different total content per States
submitted by the Concerned Member are
total volume
Member
ing for eachStates send their comments
pharmaceutical form in the to the Reference
smallest pack size of referred to CMD(h) by the Reference Member
and each pharmaceutical form in each container type mustState
Member State and applicant. Applicants
each container type must be included in application have 10 Module
cal- within seventodays
be provided EMA.after Day 90. If consensus is not
endar
1.3.2. PIL mock-ups may be included (optional). a very
days to prepare their responses. This can be reached
EMA will perform level,
at the CMD(h) the Reference
a general readabilityMember
check and
frenzied
By Dayperiod
121for applicants.
of the CentralisedAt Procedure,
Day 60, therevised
appli-label- State refers the matter to CHMP
determine whether any previous comments to arbitrate
on unsolved
mock-ups/
cant sends the response document to the
ling and package leaflet mock-ups should be submitted inConcerned disagreement.
specimens have been implemented properly. The agency
Member
Module 1.3.2StatesasandpartReference
of the list Member
of answersState. The
to questions, if will The national
inform phase following
the applicant a Mutual
of the review’s Recognition
outcome within
Reference Member State circulates its assessment
there are comments or the applicant changes the overall of Procedure is
15 working days.identical to the DCP, resulting in national
the response document to Concerned Member States
design. MA Since
numbers.
specimens cannot be submitted as eCTDs, the
by DayBy 68. At Day 75,
Centralised Concerned
Procedure Member
Day 181, States
further send
mock-ups eCTD can provide only a listing of shipped specimens.
their remaining comments to the Reference
may need to be submitted if any outstanding comments are Member National Procedure
State
made and applicant.
at Day 150 andAresolved
break-out session
prior to thecan be organ-
opinion. NP still
ISO’s can be used ifofan
Identification applicantProducts
Medicinal wishes to (IDMP)
market
ised in Days 73–80. At Day 85, Concerned
The applicant will liaise with EMA to resolve any Member aThe
medicinal product in a single EU Member State.
former EudraVigilance Medicinal Product Dictionary
States send any
outstanding remaining
comments oncomments
labelling and to the Reference
package leaflet NP’s are not discussed
(XEVMPD) hereand
was replaced because they in
extended aremid-2016
used by
Member State and applicant.
mock-ups prior to opinion adoption. Subsequently, at Day 90, infrequently,
ISO’s Identification of Medicinal Products (IDMP).apply
and national competent authorities Where
the Concerned
By Day 246Member States notify
of the Centralised the Reference
Procedure, the full-size different
XEVMPD timelines.
data primarily concerned information captured
Member State and applicant of their
colour mock-up (“worst-case”) of the outer and final positions. If
immediate by the SmPC, IDMP data cover additional information
packaging and Patient Leaflet must be submitted. about substances, products, packaging, applicants and
314

Chapter 27
Responses to Questions A “mock-up” is a copy of the flat artwork design

Agencies’ dossier evaluations, in general, almost always in full colour, providing a replica of both the outer and
result in questions. Depending on the dossier’s quality immediate packaging, so the three-dimensional pre-
and completeness and the drug’s intrinsic characteris- sentation of the labelling text is clear. A “specimen” is a
tics, a number of questions will arise. These questions sample of the actual printed outer and immediate pack-
must be answered in a response to questions (RtQ). aging materials and PIL (i.e., sales presentation).
The RtQ should consist of a cover letter, response doc- Applicants should provide EMA with mock-ups
ument and additional new documents or replacement and/or specimens for new applications in accordance
documents. The response document should contain with the following requirements:
questions, each on a different page. Responses should
be immediately under each question. However, new or Mock-Ups
corrective information must be reflected at the appro- At the time the application is submitted, one English,
priate place within the CTD, e.g., revised specifications full-size colour mock-up and one multi-lingual, full-
are in Module 3.2.S.4.1 or 3.2.P.5.1, not attached to the size colour mock-up (“worst-case”) of the outer and
response document. This will ensure the eCTD’s current immediate packaging for each pharmaceutical form in
view always shows the applicant’s current position on the smallest pack size of each container type must be
the drug’s quality, safety and efficacy. included in application Module 1.3.2. PIL mock-ups
may be included (optional).
Other Regulatory Documents and Data By Day 121 of the CP, revised labelling and pack-
age leaflet mock-ups should be submitted in Module
Readability Tests
1.3.2 as part of the list of answers to questions, if there
The PIL must be written clearly and be easily under-
are comments or the applicant changes the overall
standable, enabling the user to act appropriately. EU
design.
MAA PILs must have been checked by an appropriate
By CP Day 181, further mock-ups may need to
target patient group. A readability test must have been
be submitted if any outstanding comments are made at
performed, and a summary must be included in the
Day 150 and resolved prior to the opinion.
application dossier.41 The PIL must have been checked
The applicant will liaise with EMA to resolve any
in all applicable languages for the Member States in
outstanding comments on labelling and package leaflet
which the medicinal product is registered. The readabil-
mock-ups prior to opinion adoption.
ity test summary does not have to be submitted with
By Day 246 of the CP, the full-size colour mock-up
the initial application submission but can be submitted
(“worst-case”) of the outer and immediate packaging
with the first response document following the planned
and patient leaflet must be submitted.
clock-stop.42
Even though eCTD specifications require PDF
files in A4 or letter size, mock-ups can be submitted as
QRD Review
PDF files in any page size.
EMA’s QRD group has templates and standard termi-
nologies for each EU language. These templates and
Specimens
terminologies must be applied to the product informa-
At the latest, 15 working days before marketing, one
tion, i.e., SmPC, immediate, intermediate and outer
set of relevant outer and immediate packaging and PIL
container labels and the PIL. These templates must be
specimens for each strength or different total content
used regardless of the procedure.
per total volume and each pharmaceutical form in each
For the CP, QRD will review the English texts for
container type must be provided to EMA.
compliance to the template terms and stylistic matters
EMA will perform a general readability check and
prior to CHMP’s scientific opinion as part of the initial
determine whether any previous comments on mock-
MAA review and variations.43 Following the scientific
ups/specimens have been implemented properly. The
opinion, but before the Commission’s approval/adop-
agency will inform the applicant of the review’s out-
tion process, QRD and CHMP members check the
come within 15 working days.
same criteria for translations into other EU languages.
Since specimens cannot be submitted as eCTDs,
the eCTD can provide only a listing of shipped
Mock-Ups and Specimens specimens.
For the CP, the applicant or MAH must submit outer
and immediate packaging and PIL mock-ups and
ISO’s Identification of Medicinal Products (IDMP)
specimens to EMA for review before the medicinal
The former EudraVigilance Medicinal Product
product’s commercialisation.44
Dictionary (XEVMPD) was replaced and extended

in mid-2016 by ISO’s Identification of Medicinal before implementing the change (“Tell, Wait
Products (IDMP). Where XEVMPD data primarily and Do” procedure).
concerned information captured by the SmPC, IDMP • Type II variations concern major variations
data cover additional information about substances, requiring a new benefit-risk evaluation and
products, packaging, applicants and manufacturers and regulatory approval before implementation.
authorising agencies. These data are not captured by • Extensions concern additional strengths,
the SmPC, but in documents like cover letters, applica- pharmaceutical forms and presentations for a
tions forms, other agency correspondence and Module product or product range. Such applications
3 documents. IDMP data should be submitted with will be evaluated in accordance with the same
applications and are tagged ‘valid’ at the time of the procedure as for the initial MA to which it
concerned application’s authorisation. EMA is in the relates.
process of implementing the IDMP. This is being done
in a phased programme based on the four master data Various guidances can help sponsors decide what main-
domains in the pharmaceutical regulatory processes and tenance application is to be applied.46–48
include: substance, product, organisation and referential Depending on the maintenance application type,
(SPOR). The transition requires a coordinated pro- various documents need to be provided to support the
gramme involving all key stakeholders, including EMA, changes. If the guidelines are not definitive for a partic-
national competent authorities’ representatives, software ular change, by default, the change will follow the Type
vendors and industry. IB process. However, during the validation period, the
The first SPOR implementation phase focuses on recipient agency might consider it a major change and,
delivering the referentials management service (RMS) accordingly, require a response to questions to be sub-
and organisation management service (OMS), which sup- mitted to adjust the eCTD lifecycle.
port EU-wide regulatory activities.45 This phase-by-phase An applicant may submit the same Type IB and
approach is expected to allow lessons learned during each Type II variations, or the same group of variations
phase to be applied to subsequent phases, processes and can be submitted if they do not contain any extension
systems, to mature over time and to help stakeholders affecting:49
gain an understanding prior to the full roll out. • more than one purely national MA for the
same MAH in more than one Member State
MA Maintenance • more than one mutual recognition MA for the
Regulatory Dossier Changes—Variations same MAH
Regulatory dossier changes can be requested by the • more than one centralised MA for the same
applicant or agency. Eventually, the applicant must sub- MAH
mit a new dossier when changes reflect a new product • one or several purely national MA(s) and one
lifecycle and require new regulatory activity. This also is or several centralised MA(s) for the same
called maintaining regulatory compliance. MAH
• Type IA immediate variations concern minor • one or several purely national MA(s) and one
changes that can be implemented and must be or several mutual recognition MA(s) for the
reflected in the dossier and/or product infor- same MAH
mation immediately. In general, there are no • one or several mutual recognition MA(s) and
additional patient risks. This is considered a one or several centralised MA(s) for the same
“Do and Tell” procedure. MAH
• Type IA variations concern minor changes that • one or several purely national MA(s), one or
can be implemented immediately, although several mutual recognition MA(s) and one or
they must be updated in the dossier no later several centralised MA(s) for the same MAH
than one year after implementation. It is pos-
sible to group multiple Type IA variations in a If EMA and one or more Concerned Member States or
periodic report. Like the other Type IA, this is more than one Reference Member State are involved,
considered a “Do and Tell” procedure. combining variations is called ‘worksharing;’ if only one
• Type IB variations concern minor changes competent authority leads the review of all products
with debatable additional patient risks, not involved, it is called ‘grouping.’
impacting the product information. The MAH Timelines for worksharing and grouping are in
must wait 30 days to ensure the notification is accordance with the timelines for the variation type.
deemed acceptable by the relevant authorities

Chapter 27
PSURs and PSUSAs is a confirmation the submission has lifecycle issues and
PSURs are reports providing an evaluation of a med- there is a need to resubmit, but the submission dead-
icine’s benefit-risk balance. MAHs must submit line has already passed for this procedure, the MAH
PSURs at defined data-lock points published in the should contact EMA to request a late submission ID
EU reference date (EURD) list following a medicine’s for resubmission.
authorisation. The EURD list is legally binding. PSURs
summarise a medicine’s benefit-risk data and include Urgent Safety Restrictions
the study results for the medicine, in both authorised Urgent safety restrictions involve interim product
and unauthorised uses. changes arising from new information on the medicinal
The Pharmacovigilance Risk Assessment product’s safe use, in particular, for changes affecting
Committee (PRAC) and good pharmacovigilance one or more SmPC items (therapeutic indications,
practice (GVP) were established within the EU to posology, contraindications, warnings, target species
improve PSUR review process efficiency.50 PSURs are and withdrawal periods). Interim measures or actions
pharmacovigilance documents submitted by MAHs can include batch recalls, distribution of new packaging
at defined postauthorisation phase points. The PSUR information or dear healthcare provider (DHCP) let-
format follows the structure described in implementing ters. Corresponding timelines must be specified by the
Regulation Article 35, and the Guideline on good phar- MAH’s letter of undertaking.
macovigilance practices Module VII provides guidance on
the preparation, submission and assessment of PSURs. Referral
PSUSAs will be applied to groups of products regis- A referral is used to resolve issues or concerns over a
tered by a single or multiple MAHs for the same active medicinal product or product class safety or benefit-risk
substance. EMA maintains the EURD list and a PSUR balance. The medicinal product or class is ‘referred’ to
submission frequency record for active substances EMA to obtain a recommendation for a harmonised
contained in medicines in the EU.51 The EURD list EU position.
includes active substances and combinations of active The European Commission, CMDh, any Member
substances in medicines subject to different MAs and State or the MAH can initiate a referral. Referrals can
authorised in more than one Member State, as well as be subdivided by type, each with its own procedural
the corresponding EURDs, PSUR submission frequen- and/or dossier content differences. Referral types are
cies and related data-lock points. distinguished by issues: safety, quality, manufacturing
PSUR repository use has been mandatory for all or efficacy, paediatric medicine and NP, MRP or DCP
PSUR submissions since 13 June 2016. MAHs are harmonisation.
required to submit PSURs to EMA via the PSUR For most referrals, the European Commission
repository only, not national competent authoritiess. issues a decision to all Member States, reflecting the
This impacts PSURs for both centrally and nationally measures they should take to implement the agency’s
authorised medicinal products. PSURs can be sub- recommendation.
mitted in eCTD format (mandatory for all centrally
authorised product submissions) or NeeS format. All Conclusion
eCTD format submissions for centrally authorised The EU has harmonised approaches across national
products are run through an automated eCTD techni- competent authorities and among national competent
cal validation. A technical eCTD validation is done for authorities and EMA.
all other eCTD format PSUR submissions; however, MAHs must have permanently established EU
since EMA does not hold the full product lifecycle for addresses.
products authorised via the MRP, DCP or NP, a full Depending on the medicinal product’s character-
lifecycle validation cannot be done at the time of the istics, the applicant can apply one or more registration
submission. The full lifecycle validation may be done routes. EU legislation offers scientific advice opportu-
by the receiving national competent authorities. If the nities to all applicants. Moreover, it offers incentives
national competent authorities detect lifecycle issues in for orphan drugs and for micro-, small- and mid-sized
the submissions in the PSUR repository, they may trig- enterprises. Depending on a product’s characteristics
ger ‘invalidation’ of the submission. The repository will and the desired countries for market approval, the
send an automated email to the relevant MAH, along applicant might select different registration agencies.
with the validation report. The MAH should correct the The CP for a pan-EEA MA, initial MAA and
issue in the submission sequence and contact the rele- maintenance application is relatively straightforward,
vant national competent authority directly if it has any clear and fully eCTD-driven. The DCP seems the
questions or queries regarding the invalidation. If there

second-best choice, because it also is straightforward, 9. Requesting scientific advice or protocol assistance from
clear and open for eCTD bilateral phase submissions. EMA. EMA website. http://www.ema.europa.eu/ema/index.
jsp?curl=pages/regulation/general/general_content_000057.
Subsequent national phases leading to nationally jsp&mid=WC0b01ac05800229bf. Accessed 13 April 2020.
approved SmPCs in a country’s language(s) can be 10. Paediatric investigation plans: questions and answers. EMA
supported outside the eCTD. The MRP should be website. http://www.ema.europa.eu/ema/index.jsp?curl=pages/
used if the medicinal product already is registered in regulation/q_and_a/q_and_a_detail_000015.jsp&mid=WC-
0b01ac0580025b8e. Accessed 13 April 2020.
at least one EU Member State. However, any legacy 11. Class waivers. EMA website. http://www.ema.europa.eu/
products still are supported through NP. If products ema/index.jsp?curl=pages/regulation/general/general_con-
are to be registered in a single EU country, the NP tent_000036.jsp. Accessed 13 April 2020.
is the best choice. An applicant also can choose the 12. Report to the European Commission on companies and prod-
ucts that have benefited from any of the rewards and incentives
DCP (although this procedure is not designed for this in the Paediatric Regulation and on the companies that have
purpose) and select two countries for marketing but failed to comply with any of the obligations in this Regulation—
market the product only in one country. The advantage Year 2012 (EMA/328413/2013 Corr.2). EC website. http://
is shorter timelines. ec.europa.eu/health/files/paediatrics/2012_report_paed_regula-
tion.pdf. Accessed 13 April 2020.
Applicants must be aware of EU agencies’ recom- 13. Regulation (EC) No.726/2004 of the European Parliament
mendations and the increasing acceptance of electronic and of the Council of 31 March 2004 laying down Community
regulatory dossiers and data. The eCTD is mandatory procedures for the authorisation and supervision of medici-
for the CP, DCP and MRP. NPs may be supported nal products for human and veterinary use and establishing
a European Medicines Agency (Article 84). EUR-Lex
by paper or NeeS, depending on national competent website. http://eur-lex.europa.eu/legal-content/EN/TXT/
authority requirements. PDF/?uri=CELEX:32004R0726&from=EN. Accessed 13 April
2020.
References 14. Adaptive pathways. EMA website. http://www.ema.europa.
1. Directive 2001/83/EC of the European Parliament and of the eu/ema/index.jsp?curl=pages/regulation/general/general_con-
Council of 6 November 2001 on the Community code relating tent_000601.jsp. Accessed 13 April 2020.
to medicinal products for human use. EC website. http://ec.eu- 15. Guideline on procedures for the granting of a marketing authorisa-
ropa.eu/health/files/eudralex/vol-1/dir_2001_83_consol_2012/ tion under exceptional circumstances, pursuant to Article 14(8) of
dir_2001_83_cons_2012_en.pdf. Accessed 13 April 2020. regulation (EC) no 726/2004. EMA website. http://www.ema.
2. Directive 2001/20/EC of the European Parliament and of the europa.eu/docs/en_GB/document_library/Regulatory_and_pro-
Council of 4 April 2001 on the approximation of the laws, cedural_guideline/2009/10/WC500004883.pdf. Accessed 13
regulations and administrative provisions of the Member States April 2020.
relating to the implementation of good clinical practice in the 16. Guideline on the procedure for accelerated assessment pursuant to
conduct of clinical trials on medicinal products for human use. article 14 (9) of regulation (EC) no 726/2004. EMA website.
EC website. https://ec.europa.eu/health/sites/health/files/files/ http://www.ema.europa.eu/docs/en_GB/document_library/
eudralex/vol-1/dir_2001_20/dir_2001_20_en.pdf. Accessed 13 Regulatory_and_procedural_guideline/2009/10/WC500004136.
April 2020. pdf. Accessed 13 April 2020.
3. Regulation (EC) No 726/2004 of the European Parliament 17. Pre-authorisation guidance—How is a MAA pre-submission
and of the Council of 31 March 2004 laying down Community meeting conducted at the EMA? Rev. November 2014. EMA
procedures for the authorisation and supervision of medici- website. https://www.ema.europa.eu/en/human-regulatory/
nal products for human and veterinary use and establishing a marketing-authorisation/pre-authorisation-guidance#2.-steps-pri-
European Medicines Agency. EC website. https://ec.europa.eu/ or-to-submitting-the-application-section. Accessed 13 April 2020.
health//sites/health/files/files/eudralex/vol-1/reg_2004_726/ 18. Announcement of the start of the eCTD Version 4 EU M1
reg_2004_726_en.pdf. Accessed 13 April 2020. Implementation Guide Public Consultation. EMA website.
4. Notice to Applicants, Volume 2A, Procedures for marketing authori- http://esubmission.ema.europa.eu/eCTD%20NMV/eCTD.
sation—“Chapter 2 Mutual Recognition.” EC website. http:// html. Accessed 12 April 2020.
ec.europa.eu/health/files/eudralex/vol-2/a/vol2a_chap2_2007- 19. Op cit 1.
02_en.pdf. Accessed 13 April 2020. 20. Sheppard A. Generic Medicines: Essential contributors to the
5 Op cit 1. long term health of society. Medicines for Europe website.
6. User guide for micro, small and medium-sized enterprises. http://www.medicinesforeurope.com/2010/03/21/generic-medi-
EMA website. http://www.ema.europa.eu/docs/en_GB/docu- cines-essential-contributor-to-the-long-term-health-of-society/.
ment_library/Regulatory_and_procedural_guideline/2009/10/ Accessed 13 April 2020.
WC500004134.pdf. Accessed 13 April 2020. 21. Bolar Provision and Regulatory Data Exclusivity in Europe.
7. Commission Regulation (EC) No 847/2000 of 27 April 2000 Yumpu website. https://www.yumpu.com/en/document/
laying down the provisions for implementation of the criteria view/2709592/bolar-provision-and-regulatory-data-exclusivi-
for designation of a medicinal product as an orphan medicinal ty-in-europe. Accessed 13 April 2020.
product and definitions of the concepts ‘similar medicinal prod- 22. Guidance for Industry on Providing Regulatory Information in
uct’ and ‘clinical superiority.’ EC website. https://ec.europa.eu/ Electronic format version 3.0 (August 2013). EMA website.
health//sites/health/files/files/eudralex/vol-1/reg_2000_847/ http://esubmission.ema.europa.eu/tiges/docs/eCTD%20
reg_2000_847_en.pdf. Accessed 13 April 2020. Guidance%20v3.0%20final%20Aug13.pdf. Accessed 13 April
8. Orphans: Regulatory and procedural guidance and forms. EMA 2020.
website. http://www.ema.europa.eu/ema/index.jsp?curl=pages/ 23. “Chapter 2a Specific provisions applicable to traditional herbal
regulation/document_listing/document_listing_000268. medicinal products,” Directive 2001/83/EC of the European
jsp&mid=WC0b01ac058061f01c. Accessed 13 April 2020. Parliament and of the Council of 6 November 2001 on the

Chapter 27
Community code relating to medicinal products for human 40. Member State agreement upon conditions under which the
use, as amended. EUR-Lex website. http://eur-lex.europa.eu/ RMS start the MRP/DCP (Doc. Ref.: CMDh/243/2011/Rev
legal-content/EN/ALL/?uri=CELEX:52008DC0584. Accessed 6 July 2013). HMA website. http://www.hma.eu/fileadmin/
13 April 2020. dateien/Human_Medicines/CMD_h_/procedural_guidance/
24. Guidance CHMP/QWP/227/02 Rev.3 Guideline on Active Application_for_MA/CMDh_243_2011_Rev07_2016_04_
Substance Master File Procedure (October 2012). EMA website. clean.pdf. Accessed 13 April 2020.
www.ema.europa.eu/docs/en_GB/document_library/Scientific_ 41. Guidance concerning consultations with target patient groups for
guideline/2012/07/WC500129994.pdf. Accessed 13 April 2020. the package leaflet. Halmed website. http://www.halmed.hr/
25. Ibid. fdsak3jnFsk1Kfa/ostale_stranice/Link_2_user_consultation_
26. Op cit 9. guideline_en.pdf. Accessed 13 April 2020.
27. Notice to Applicants, Volume 2B—Pharmaceutical Legislation 42. CMDh Questions & Answers—Product Information/Information
Notice to applicants and regulatory guidelines medicinal products for on Medicinal Products. HMA website. http://www.hma.eu/
human use. EC website. http://ec.europa.eu/health/documents/ fileadmin/dateien/Human_Medicines/CMD_h_/Questions_
eudralex/vol-2/index_en.htm. Accessed 13 April 2020. Answers/CMDh-275-2012-Rev0-2012_10.pdf. Accessed 13
28. Active Substance Master File (ASMF) Templates. EMA April 2020.
website. https://www.ema.europa.eu/en/search/search?search_ 43. The linguistic review process of product information in the
api_views_fulltext=active%20substance%20master%20file%20 centralised procedure—human (EMEA/5542/02/Rev 5).
template. Accessed 13 April 2020. EMA website. http://www.ema.europa.eu/docs/en_GB/docu-
29. EU Electronic Application Forms. EMA website. http://esub- ment_library/Regulatory_and_procedural_guideline/2009/10/
mission.ema.europa.eu/eaf/index.html. Accessed 13 April 2020. WC500004182.pdf. Accessed 13 April 2020.
30. Guideline on process validation for finished products—information 44. Pre-authorisation guidance: questions 3.1.6—When
and data to be provided in regulatory submissions. EMA website. shall I submit mock-ups and/or specimens? 06 February
http://www.ema.europa.eu/docs/en_GB/document_library/ 2020). EMA website. https://www.ema.europa.eu/
Scientific_guideline/2014/02/WC500162136.pdf. Accessed 13 en/human-regulatory/marketing-authorisation/
April 2020. pre-authorisation-guidance#2.-steps-prior-to-submit-
31. Note for Guidance on the Inclusion of Appendices to Clinical Study ting-the-application-section Accessed 14 April 2020.
Reports in Marketing Authorisation Applications. EMA website. 45. Presentation: Introduction to SPOR data services. 16 June 2016.
http://www.ema.europa.eu/docs/en_GB/document_library/ EMA website. https://www.ema.europa.eu/en/documents/pre-
Scientific_guideline/2009/09/WC500003638.pdf. Accessed 13 sentation/presentation-introduction-spor-data-services_en.pdf
April 2020. 14 April 2020.
32. Procedural timetables. EMA website. http://www.ema.europa. 46. Guideline on the Categorisation of New Applications (NA) ver-
eu/ema/index.jsp?curl=pages/regulation/document_listing/ sus Variations Applications (V). EC website. http://ec.europa.
document_listing_000330.jsp&mid=WC0b01ac05803d8b9c. eu/health/files/eudralex/vol-2/c/v2c_ea_v__10_2003_en.pdf.
Accessed 13 April 2020. Accessed 13 April 2020.
33. HMA eSubmission Roadmap. EMA website. http://esubmis- 47. Ibid.
sion.ema.europa.eu/tiges/cmbdocumentation.html. Accessed 13 48. Guidelines of 16.05.2013 on the details of the various categories
April 2020. of variations, on the operation of the procedures laid down in
34. European Medicines Agency (EMA) Master Data Management Chapters II, IIa, III and IV of Commission Regulation (EC)
Roadmap—Substance, Product, Organisation and Referential No 1234/2008 of 24 November 2008 concerning the exam-
data. EMA website. http://www.ema.europa.eu/docs/en_GB/ ination of variations to the terms of marketing authorisations
document_library/Other/2015/04/WC500186290.pdf. Accessed for medicinal products for human use and veterinary medicinal
13 April 2020. products and on the documentation to be submitted pursuant
35. eSubmission Gateway and eSubmission Web Client. EMA to those procedures. EC website. https://ec.europa.eu/health/
website. http://esubmission.ema.europa.eu/esubmission.html. documents/eudralex/vol-2_en. Accessed 13 April 2020.
Accessed 13 April 2020. 49. Ibid.
36. Common European Submission Platform. HMA website. 50. Pharmacovigilance legal framework. EMA website. http://www.
http://cesp.hma.eu/Home. Accessed 13 April 2020. ema.europa.eu/ema/index.jsp?curl=pages/special_topics/general/
37. EU Telematics. EMA website. http://www.ema.europa.eu/ema/ general_content_000491.jsp&mid=WC0b01ac058058f32d.
index.jsp?curl=pages/about_us/general/general_content_000116. Accessed 13 April 2020.
jsp&mid=WC0b01ac0580028c2b. Accessed 13 April 2020. 51. Periodic safety update reports (PSURs). EMA website. http://
38. eCTD Validation Criteria v5 0. EMA website. http://esubmis- www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/docu-
sion.ema.europa.eu/ectd/. Accessed 13 April 2020. ment_listing/document_listing_000361.jsp&. Accessed 13 April
39. European Testing and Certification System (ETICS) Phase 2 2020.
Part B and Phase 3. ETICS website. https://etics.org/. Accessed
14 April 2020.

Chapter 28
Quality Systems and

Inspectorate Process—
Pharmaceuticals
Updated by Treena Jackson, MS, MA, CQA, CSSGB, RAC and Siegfried Schmitt, PhD
OBJECTIVES applications for tests on chemical substances

(codified version) (Text with EEA relevance)
□ Learn the inspection process in Europe
□ Guideline on the content, management and
□ Become familiar with the applicable regulations archiving of the clinical trial master file (paper
and/or electronic) of 6 December 2018
□ Gain clarity on which agency (or part of) per-
forms inspections □ Guideline on the responsibilities of the sponsor
with regard to handling and shipping of inves-
□ Understand the benefit and value of inspections
tigational medicinal products for human use in
□ Gain an understanding of quality management accordance with good clinical practice and good
systems manufacturing practice (draft) of 26 April 2018
□ EudraLex Volume 4 good manufacturing prac-

tice (GMP) guidelines
COVERED IN THIS CHAPTER □ EudraLex Volume 10 clinical trials guidelines
Parliament and of the Council of 6 November Introduction
2001 on the Community code relating to medici- This chapter outlines the framework for regulatory
nal products for human use agency inspections in Europe, explains the purpose of
regulatory inspections and describes the actual inspec-
□ Article 288 of the Treaty on the Functioning of
tion process, from general oversight to execution.
the European Union (TFEU)
Pharmaceutical companies develop medicines to
□ Directive 2004/9/EC of the European Parliament cure or treat patients and, thus, the drug lifecycle starts
and of the Council of 11 February 2004 on the with research and development (R&D), followed by
inspection and verification of good laboratory the clinical trial phase before the commercial (postap-
practice (GLP) (Codified version) (Text with EEA proval) phase begins. The lifecycle ends with the drug’s
relevance) withdrawal from the market and the termination or
revocation of the marketing authorisation (licence).
□ Directive 2004/10/EC of the European Figure 28-1 details the applicable good practice
Parliament and of the Council of 11 February regulations that govern the different drug lifecycle
2004 on the harmonisation of laws, regula- stages.
tions and administrative provisions relating The good practice regulations and principles, often
to the application of the principles of good abbreviated as GxPs, encompass the following:
laboratory practice and the verification of their

Chapter 28
Figure 28-1. Drug Lifecycle Regulations
Preclinical Pharmaco- Discontin-

Research Discovery Phase 1 Phase 2 Phase 3 Launch
Development vigilance uation
GLP
GCP
GMP
GPvP
GDP
• Good Laboratory Practice (GLP) is a set of drug’s quality claims. Regulatory agency assessors verify
rules and criteria for a quality system con- the submitted dossiers.
cerned with the organisational process and Inspectors, on the other hand, verify the applica-
the conditions under which nonclinical health tion’s contents as either part of the approval process or
and environmental safety studies are planned, postapproval.
performed, monitored, recorded, archived and Figure 28-2 shows this relationship between asses-
reported. sors and inspectors throughout the drug lifecycle.
• Good Clinical Practice (GCP) is a set of inter- Inspectors also verify the marketing authorisation
nationally recognised ethical and scientific holder or applicant complies with the applicable reg-
quality requirements, which must be observed ulations, i.e., with GXPs. To achieve compliance with
for designing, conducting, recording and report- the regulations, pharmaceutical companies must have
ing clinical trials involving human subjects. an appropriate quality management system (QMS),
• Good Pharmacovigilance Practice (GPvP) is qualified personnel, suitable premises and appropriate
a set of rules and criteria requiring compli- systems in place. The same holds true for any third party
ance with the requirements of legislation and (supplier, contractor, consultant, etc.) to which the com-
guidelines relating to monitoring the safety pany outsources work.
of medicines used in clinical practice and It is notable that much has occurred since the
postmarketing. last publication of this book, making it important to
• Good Manufacturing Practice (GMP) is a set point out that on 29 March 2017, the UK notified the
of rules and criteria formed with the objective European Council of its intention to leave the EU.
to ensure products are produced consistently This exit, commonly referred to as “Brexit,” occurred
and controlled to particular quality standards. on 31 January 2020 in accordance with Article 50 of
• Good Distribution Practice (GDP) is a set the Treaty on European Union. A resource to refer-
of rules and criteria ensuring products are ence the status and implications of this decision is the
consistently stored, transported and handled European Commission’s Task Force for Relations with
under suitable conditions as required by the the United Kingdom (UKTF). The UKTF coordinates
marketing authorisation (MA) or product the work on all strategic, operational, legal and financial
specification. issues related to the UK’s withdrawal and its future
relationship with the EU.1 At least until the end of
Regulatory affairs professionals are tasked with under- 2020, a transition period is in place, during which the
standing the approval processes for bringing a drug rules and regulations of the EU are still followed by the
product to market and, once an MA is granted, how to UK. However, the EU’s regulatory agencies, including
maintain the licence. As part of these processes, com- EMA, have by and large ceased to work with or coop-
panies must submit drug manufacturing and testing erate with the UK’s regulatory agency, the MHRA, or
process descriptions, as well as data that support the to accept regulatory activities, such as inspection out-
comes. The UK appears to have a much more pragmatic

Quality Systems and Inspectorate Process—Pharmaceuticals
Figure 28-2. Assessors and Inspectors
Technical Technology Commercial Product

Development Transfer Manufacturing Discontinuation
Quality Risk Management and Knowledge Management
Assessors
Inspectors
approach. Even though we do not know whether the EU Regulations, Competent Authorities
transition period will be extended or what the agree- and Inspection Processes
ment between the EU and the UK will be, the current
Regulatory Authorities
situation already presents a fait accompli as far as the
Europe is a bit of a paradox—it is one entity but has
EU is concerned.
many parts. There are 45 national competent authorities
and approximately 500 million medicinal product users.
Quality System Requirements in Europe
ICH Q10 Pharmaceutical Quality System Council of Europe
Regulated pharmaceutical companies are required to The Council of Europe was founded in 1949 with the
implement and operate a quality management system aim of developing common and democratic European
(QMS). No two quality systems are the same, as each principles. The Council of Europe has 47 Member States
company’s circumstances are unique. The regulators (28 of which are EU members).3 Its headquarters is in
needed to describe the requirements in a manner that Strasbourg, France. The core values are the protection of
covers all types of enterprises, from the one-person bro- human rights, pluralist democracy and the rule of law.4
ker company that is run out of the home office to the
multi-billion European international pharmaceutical European Commission (EC)
company. A consensus document for the pharmaceu- The EC is the EU governing body. It is the (unelected)
tical industry was created under the umbrella of the law-making group, issuing directives that are imple-
International Council for Harmonisation of Technical mented by each Member State in its national
Requirements for Pharmaceuticals for Human Use legislation. The EC is located in Brussels, Belgium. It
(ICH) and was finalised under Step 4 in June 2008 as created the European Medicines Evaluation Agency
Q10 pharmaceutical quality system.2 Apart from the (EMEA), now the European Medicines Agency
guideline, ICH also published a Q10 concept paper and (EMA), in 19955 to implement and enforce directives.
business plan, as well as a Q10 presentation and ICH
Q8/Q9/Q10 training materials. EMA
During inspections, regulatory authorities assess the EMA moved its headquarters from London, UK to
appropriateness of the QMS for a company’s specific Amsterdam, the Netherlands, in early 2019 following
circumstances, compliance with the applicable regula- the UK departure from the EU. Its main responsibility
tions through the QMS and the company’s adherence to is to protect and promote public and animal health,
the QMS and the licence particulars (e.g., the marketing through the evaluation and supervision of medicines for
authorisation or the wholesale dealer licence). human and veterinary use. It relies on Member States
The responsibility for the QMS lies with senior to provide inspection resources. EMA creates guidance
management, whereas the quality unit (typically referred documents for performing inspections and monitors
to as quality assurance (QA) in Europe) is responsible medicines’ safety through a pharmacovigilance network.
for the creation, implementation and maintenance of the EMA’s remit includes stimulating pharmaceutical inno-
QMS. It is everyone’s responsibility to follow the QMS. vation and research.

Chapter 28
Figure 28-3. EU Legal Instruments
Primary EU Law:
Treaty of the Function of the European Union (TFEU)
Secondary EU Law:
a) Legislative Acts: Regulation, Directive, Decision Medicinal (Drug) Products:
b) Non-Legislative Acts: Recommendation, Opinion
c) New Legal Acts (created by the Treaty of Lisbon): EudraLex Vol 1 (human) & EudraLex Vol 5 (veterinary)
Delegated Act, Implementing Act
European Directorate for the Quality of Medicines Inspection Process

and HealthCare (EDQM) As mentioned previously, inspections are linked to mar-
EDQM6 is a Council of Europe Directorate, based keting authorisations, as depicted in Figure 28-4.
on the Convention on the Elaboration of a European These two directives form the basis for inspections
Pharmacopoeia (1964). Its mission is to contribute to the in the EU:
basic human right of access to good quality medicines • Directive 2003/94/EC provides the basis for
and healthcare. EDQM performs certification of suit- detailed GMP guidelines for human medic-
ability and related inspections for active pharmaceutical inal products and investigational medicinal
ingredients (APIs). EDQM also provides an anti-coun- products. Article 3 covers Member States’
terfeiting traceability service for medicines. authorities’ repeated inspections to ensure
GMP compliance for human medicinal prod-
Regulations and Legal Instruments ucts and investigational medicinal products.
Figure 28-3 provides a summary overview of the EU’s • Directive 91/412/EEC10 for veterinary
legal instruments:7 medicinal products mirrors these requirements.
• regulation—a legal instrument immediately
enforceable It is important to understand EMA and Members
• directives—require Member States to achieve States’ inspectional roles. EMA coordinates inspections
a certain result, but do not dictate the means for human and veterinary medicines authorised under
of achieving the result; a directive’s content the Centralised Procedure or in the context of a referral,
must be transposed into national law in each on request from the Agency’s Committee for Medicinal
Member State and carried out by its national Products for Human Use (CHMP) or Committee for
competent authorities Medicinal Products for Veterinary Use (CVMP).
• delegated act “Commission Delegated EMA does not conduct inspections itself, but
Regulation (EU)” delegates certain powers requests Member States’ national competent authorities
from the European Parliament to the Council to carry out the inspections.10
of Europe EU authorities regularly inspect company sites
within and outside the EU that are involved in develop-
National Competent Authorities ing, manufacturing and distributing medicines intended
These bodies perform inspections. This is part of each for the EU market, to verify their compliance with the
Member State’s remit: relevant standards. For guidance, EMA publishes and
• manufacturer licensing and control updates the Compilation of Community Procedures on
• granting manufacturer authorisations Inspections and Exchange of Information.11
• manufacturing site inspections A government (regulatory authority) inspection’s
objective is to ensure companies manufacture and sup-
Most Members States have separate agencies for ply products that are safe, effective and of the quality
human and veterinary drugs—national competent and purity the companies purport they possess and
authorities (human)8 and national competent authori- that they are supplied in accordance with the licence
ties (veterinary).9 particulars.

Figure 28-4. Inspections as Part of the Drug Approval Process
Marketing Marketing
Preapproval Postapproval
Authorization Authorization
Inspection Inspections
Application Granted
Inspections are the ultimate test of a company’s must ensure submitted documents are in concordance
ability to demonstrate in a short period of time and with the company’s actual situation, and operations are
under stressful conditions how well it is adhering to its informed about any approved authorisation changes
regulatory submissions, quality system and GXPs. (e.g., changes to package leaflets).
Inspection types include: Inspection components include:
• General GMP inspections (also termed reg- • inspection team arrival
ular, periodic, planned or routine) should be • opening presentation
carried out before a manufacturing authori- • site tour
sation is granted. This kind of inspection also • documentation review, documented evidence
may be necessary for a significant manufactur- • answering inspectors’ questions
ing authorisation variation and/or a history of • close-out session
noncompliance. • inspection team departure
• Re-inspections (also called follow-up or reas-
sessment) may be indicated to monitor the Anything related to the marketing authorisation is
corrective actions required from the previous within an inspection’s scope, such as:
inspection. • clinical trial material manufacture, storage and
• Product- or process-related inspections (also distribution logistics
known as special or problem oriented) may • supply chain of any material or service (e.g.,
be indicated to assess the manufacturer’s quality agreements, supplier audits)
adherence to the marketing authorisation • manufacture, storage and packaging
dossier and the way batch documentation is • utilities (e.g., water, HVAC)
maintained. They also can be indicated when • training records
complaints and recalls may concern one • currently valid marketing authorisation
product or group of products or processing • computerised systems (tools)
procedures (e.g., sterilisation, labelling, etc.). • pharmacovigilance systems
• validation and qualification
As the agencies do not have sufficient staff to inspect all
companies regularly, they conduct inspections following Inspectors will compare the dossier and on-site records.
a risk-based inspection program. For example, the dossier section for an aseptic fill
Inspection elements include: operation may be a half-page long, whereas on-site doc-
• planning uments for this step may include 35 pages of instruction
• notification protocol and another 50 pages of attachments for each
• conduct batch manufactured. Plus, supporting engineering,
• definition of deficiencies validation, calibration, maintenance, change control,
• post-inspection letter deviation, etc., documents regularly run into several
• company responses hundred pages.
• inspection report Inspection conduct aspects include:
• Inspectors are accustomed to observing activ-
A company must always be inspection ready. National ities for hours, sometimes days, making sure
authorities do not have to provide prior notification of that whatever the company does is in accor-
an inspection; however, they normally do (from days to dance with the regulations and its written
months). Please note, the regulatory department may instructions.
be inspected. This is because the department’s processes

Chapter 28
• Documented evidence is almost always • On the day of the inspection, the inspectors
required to prove that whatever the company will be met and, at all times, escorted by a
tells the inspectors is true. Using the phrase team, typically headed by the quality unit head.
“believe me” is futile. The inspectors’ credentials should be verified.
• Documentation may have to be retrieved from • Next will be an opening meeting where the
archive. inspectors will lay out the inspection’s pur-
• Anyone involved in any activity related to the pose and clarify the agenda and the expected
manufacturing authorisation may be asked to inspection duration (typically several days, but,
answer questions by the inspectors, including in extreme cases, several months). The com-
the CEO. pany will give a brief presentation on itself, site
layout, the organisation, products, operations
Documents typically reviewed during an inspection are: and its pharmaceutical quality system.
• site master file/trial master file • Normally, this is followed by a site tour, which
• quality manual allows the inspectors to become familiar with
• job descriptions the facility and the operations. The tour may
• standard operating procedures (SOPs) follow the product flow, from raw materials’
• validation reports receipt in the warehouse, to quality control
• manufacturing formulae, records and laboratories’ testing, manufacture, packaging
instructions and labelling, final testing, release and ultimate
• specifications shipment from site. It is possible inspectors
• batch release procedure and the Qualified will split up and go to different areas, depend-
Person’s role ing on their areas of expertise. The inspectors
will speak to many people during the tour and
The close-out meeting involves: take notes. They may even request permission
• Typically, inspectors provide a verbal summary to take pictures or take away samples.
of their findings. • Following the tour, the inspectors will review
• It is possible for the company to provide evi- documents to ensure the processes are
dence that will mitigate a finding. described correctly in instructions and activities
• A written report will follow, which will detail are recorded appropriately. They also will verify
the verbally communicated findings. whether everything is in compliance with the
• Any finding will be classified as critical, major, regulations and in conformance with the mar-
minor or other deficiency. keting authorisation. Normally, inspectors will
find that documents are not entirely self-ex-
Inspection outcome possibilities are: planatory and request subject matter experts
• Depending upon the inspection findings and to provide answers. This is what most inspec-
the company’s response during and following tion participants can find most challenging.
the inspection, the inspector may take one of Although there may be a subject matter expert,
a number of actions, ranging from sending a he or she may not be the best person to explain
GXP certificate or letter confirming essen- the topic to someone outside the company.
tial compliance with GXP to recommending • An inspection’s length, of course, is directly
adverse licensing action against a licence or correlated to the on-site operations’ complexity,
marketing authorisation. e.g., vaccine aseptic processing is eminently
more complex than warehouse operations. This
The following is an example of a typical inspection: also is reflected in the amount of documenta-
• Company A receives written notification (by tion to be reviewed. Inspectors may even take
email addressed to the quality unit head) of documentation to study overnight or to use
an impending inspection. The notification will as evidence. Therefore, the company must be
state preferred inspection dates. The quality prepared to provide copies of documents and
unit head will inform all relevant company records for inspectors’ perusal.
individuals, and preparation activities will • It is normal for inspectors to find issues
commence. Company A will inform the or have concerns, and they normally will
regulatory agency it accepts the inspection. express this during the inspection. This gives
Inspections may be unannounced, but this is the company a chance to provide additional
unusual. information, provide clarifying explanations

or initiate corrective and preventive measures. for the company to keep the submitted information
Regulators expect the company to rectify (dossier) aligned with the actual situation.
noncompliances. The company’s willingness to If a company is found to be out of compliance, reg-
rectify issues will be taken into account when ulators have the following enforcement actions at their
the inspectors make their final inspection deci- disposal (possible triggers for these are examples only):
sion on compliance. • licence suspension—e.g., non-payment of fees
• Almost invariably, a close-out meeting is held • marketing authorisation revocation—e.g.,
at the end of the inspection. The details differ GMP noncompliance
depending on the agency, but the purpose is • CEP revocation—e.g., API not GMP
always for inspectors to inform the company of compliant
their findings (observations) and conclusions. • increased inspection frequency—e.g., critical
They also may tell the company what actions observations in previous inspection
they expect from it before a final decision can • recall—e.g., adulterated product
be made or an inspection report is issued. Once • public alert—e.g., as part of a recall request
the inspectors have left the site, the inspection • importation ban—e.g., foreign inspection
is over. This is when the company should start failure
working to remediate any deficiencies and • seizure—e.g., counterfeit product
prepare follow-up information for the agency. • fines—e.g., continuous noncompliance
Most agencies set very tight timelines by
which the company must submit the additional The above regulatory actions’ impact can be:
information following the inspection. • increased cost
• Assuming all has gone to the agency’s satisfac- • loss of reputation
tion, the company will receive confirmation of • market share loss
its compliance status, e.g., a GMP certificate. • submission approval delays
• increased regulatory scrutiny
EudraGMDP Database • clinical trial abandonment
Information from some inspections will be put into the • drug supply shortages
EudraGMDP database.12 The database is neither com-
plete, nor altogether current, nor necessarily correct and EDQM Inspection Process
the search function is unreliable. EDQM’s role regarding inspections is as follows:13
EudraGMDP contents include: • issuing a CEP for:
• GMP certificates o active pharmaceutical ingredients
• manufacturing and importation authorisations (API), excipients, herbal drugs or herbal
(MIAs) preparations
• GDP certificates and noncompliance reports o chemical or herbal CEP products
for wholesale distributors and API distributors with risk of Transmissible Spongiform
• wholesale distribution authorisations, includ- Encephalopathies (TSE)
ing the suspension and partial suspension
concept based on site management The CEP certifies that a given substance’s quality can
• registration of active substance manufacturers, be suitably controlled by a European Pharmacopoeia (Ph.
importers and distributors (API registration) Eur.) monograph, with additions if necessary (these will
• searches for third-country manufacturers and be stated on the CEP).
registrant sites (accessible for agencies only) Importantly, a CEP:
• does not replace a certificate of analysis
Postapproval (follow-up) inspections typically follow, • is not a GMP certificate
once an initial inspection has been conducted (every two
to three years, on average). The reason for these inspec- As part of its CEP certification program, EDQM per-
tions is that once marketing authorisation is obtained, forms inspections. Directive 2001/83/EC, as amended
the processes and technology, in addition to many other (Article 111) and Directive 2001/82/EC, as amended
things, may change. Regulators are concerned about (Article 80) mandate that EDQM establish an annual
whether the company correctly reports status changes to inspection program including:14
the agencies and whether these changes may have nega- • manufacturing sites and brokers or distributors
tively influenced product quality. Therefore, it is essential holding CEPs
• coordinating with EU inspectorates

Chapter 28
• notifying authorities of issues that may arise forum for harmonisation, and meetings include discus-
sions of common issues, such as updates or amendments
The inspections are carried out by official EU/European to the EU GDP guidelines and the compilation of
Economic Area (EEA) competent authority inspectors Union procedures.18
or in countries that have a GMP Mutual Recognition
Agreement with the EU, as well as EDQM inspectors GCP Inspections
having the same qualifications. For inspections carried The legal basis for GCP inspections is Regulation (EU)
out in non-EU/ EEA/MRA countries, local official No. 536/2014 on clinical trials with medicinal prod-
inspectors are invited as observers. ucts for human use (repealing Directive 2001/20/EC),
In some countries (e.g., China), interpreters accom- which was adopted on 16 of April 2014 and published
pany inspectors to ensure accurate communication with in the Official Journal of the European Union on 27 May
the company’s staff. EDQM does not appoint auditors 2014. It entered into force on 16 June 2014 but will
to carry out inspections. Neither interpreters nor audi- apply no earlier than six months after a new EU portal
tors can claim to be EDQM auditors. and EU database have achieved full functionality. It is
The EDQM inspection program’s goal is to verify expected that the clinical trial regulation will come into
compliance with both GMP and CEP applications (and application during 2021 (at the earliest). Until applica-
any updates) at manufacturing and distribution sites tion of the Clinical Trial Regulation, Directive 2001/20/
covered by CEPs. EC on the conduct of clinical trials will still apply.
The EDQM inspection process includes:15 Directive 2005/28/EC (IDRAC 49720) covers
• one EU/EEA inspector and one EDQM the principles of GCP. Member States had to comply
inspector with this Directive by 29 January 2006, and Directive
• local inspector invited in non-Ph. Eur. 2001/83/EC (IDRAC 37421) (Annex 1) requires
countries all data from clinical trials included in a marketing
• inspection of facilities, production and quality authorisation application must have been conducted in
documents, lasting about three days accordance with GCP.
• reference documentation: ICH Q7 and CEP Inspections may take place before, during or after
application the conduct of a clinical trial, as part of the validation
of a marketing authorisation application and as a fol-
GLP Inspections low-up to the granting of an authorisation. Inspections
Common references and directives concerning GLP may be carried out at the sites of pharmaceutical sponsor
inspections for safety tests on chemicals are as follows:16 companies, contract research organisations, academic
• Directives 2004/9/EC and 2004/10/EC on research organisations, investigational trial sites, clinical
good laboratory practice (GLP)–April 2013 laboratories, GCP archives and other facilities involved
• 2004/9/EC–inspection and verification of in clinical trial research. EMA published guidance for
GLP (recodified) the conduct of good clinical practice inspections.19
• 2004/10/EC–harmonization of laws, regula- The Implementing Regulation (EU) 2017/556 of
tions and administrative provisions relating to 24 March 2017 on the detailed arrangements for the
the application of GLP (re-codified) good clinical practice inspection procedures pursuant
• cross-contamination of control samples with to Regulation (EU) No. 536/2014 was published on
test item in animal studies (November 2004) 25 March 2017 in the Official Journal of the European
Union.20 The Implementing Regulation establishes the
It is notable that as of 31 January 2020, the principle detailed framework for the inspection procedures
outlined in Article 5(1) of Directive 2004/10/EC no with regard to good clinical practice as well as for the
longer applies to the UK17 or other non-member states. requirements on training and qualification and the pow-
Instead, the mutual acceptance of data (MAD) sys- ers of the inspectors responsible for the review of good
tem established under the Organization for Economic clinical practice.
Co-operation and Development (OECD) will apply. The EMA has an EU GCP inspectors working
group that focuses on the harmonisation and co-ordi-
GMP/GDP Inspectors Working Group nation of GCP related activities.21 The group activities
EMA coordinates the GMP/GDP Inspectors Working are outlined in its work plan (none were made public
Group of senior inspectors appointed by all EEA com- since 2018). It is involved in the preparation of new and
petent authorities. Meetings take place at EMA four revised guidance on GCP and procedures relating to
times per year (though this has not happened since inspection in the EU. The GCP working group meets
EMA relocated to Amsterdam). The group provides a with the GMP working group on topics of common

interest. Guidelines are published on a variety of topics to Finland: www.fimea.fi

promote EMA current thinking in areas such as clinical France: www.afssaps.fr
trial master file archiving22 and organisation and investi- Georgia: www.gdna.georgia.gov
gational product shipping and management.23 Following Germany: www.bfarm.de, www.zlg.nrw.de, www.pei.de
these guidelines is advisable to increase preparedness for Greece: www.eof.gr
regulatory inspections and to serve as a standard or base- Hungary: www.ogyi.hu
line for organisational policies and procedures. Iceland: www.imca.is
Ireland: www.imb.ie
GDP Inspections Israel: www.health.gov.il
Good distribution practice (GDP) describes the mini- Italy: www.aifa.gov.it
mum standards that a wholesale distributor must meet Kazakhstan: www.dari.kz
to ensure that the quality and integrity of medicines is Kyrgyzstan: www.pharm.med.kg
maintained throughout the supply chain.24 Guidance on Latvia: www.vza.gov.lv
GDP for drug substance and drug product can be found Lithuania: www.vvkt.lt
in the “Other documents related to GMP” section of Luxembourg: www.ms.public.lu
EudraLex Volume 4.25 Malta: www.medicinesauthority.gov.mt
Partly in response to the restrictions based on Montenegro: sntcg.com/ulms
the inspection process, and partly because of resource Netherlands: www.cbg‐meb.nl
restrictions, the UK’s regulatory agency, the MHRA, Norway: www.legemiddelverket.no
has embarked on a pilot of a new inspection approach Poland: bip.urpl.gov.pl
that will impact holders of a wholesale dealer’s licence Portugal: www.infarmed.pt
(WDA(H)) whose main activities operate from a head Republic of Moldova: www.amed.md
office supplied from a number of ‘satellite’ facilities, Romania: www.anm.ro
named the office based evaluation and risk assessment Russian Federation: www.roszdravnadzor.ru
(OBERA). For the companies selected, their satellite Serbia: www.alims.gov.rs
sites will be assessed remotely using information pro- Slovakia: www.sukl.sk
vided by the company in a standardised format.26 Slovenia: www.jazmp.si
Good distribution practice regulations were only Spain: www.agemed.es
introduced in the past decade in Europe. As a result, Sweden: www.lakemedelsverket.se
GDP inspections are not yet fully implemented in all Switzerland: www.swissmedic.ch
European countries. In general, only the UK’s MHRA Turkey: www.iegm.gov.tr
publishes information, such as inspection experiences, Ukraine: www.dec.gov.ua
for public consumption. UK: www.mhra.gov.uk
Other European Agencies and Their Inspection Mutual Recognition Agreements (MRAs)
Processes MRAs may focus on:
As of April 2020, there are 51 countries in Europe,27 • conduct of inspections
and 27 countries are members of the EU.28 • inspection result acceptance
Most countries have a regulatory agency, and some • recognition of a country’s regulatory system
have more than one (e.g., Germany). • information sharing
The main regulatory agencies in Europe include: • joint inspections
Albania: www.qkkb.gov.al
Andorra: www.salutibenestar.ad Sometimes, only a memorandum of understanding is in
Armenia: www.pharm.am place.
Austria: www.ages.at The status of EU MRAs with other countries:29
Belarus: www.rceth.by • Australia: operational with several exclusions
Belgium: www.fagg‐afmps.be • Canada: operational except for advanced ther-
Bulgaria: www.bda.bg apy medicinal products
Croatia: www.almp.hr • Israel: operational with some exclusions
Cyprus: www.moh.gov.cy • Japan: operational with limited scope
Czech Republic: www.sukl.cz • New Zealand: operational except for advanced
Denmark: www.dkma.dk therapy medicinal products and APIs
EMA: www.ema.europa.eu • Switzerland: fully operational
Estonia: www.sam.ee • US: operational with several exclusions

Chapter 28
Joint Inspection Programs For inspections conducted in third countries, the

These link application assessments and inspections. competent authority may or may not certify, upon
Examples include:30 application by an exporter, importer or the competent
• international API inspection program authority, that the inspected manufacturer complies
• EMA/US FDA inspection program for fin- with recognised GMP requirements.
ished-dosage-form manufacturers The request for information exchange has become
more elaborate. Switzerland can, and is supposed to, use
The following selective information was chosen, as the EudraGMDP. All contractual parties should submit
information is available in the national language and in authorisations, GMP certificates and information on
the English language or because of the importance of GMP noncompliance to this database, which is admin-
the agency in the inspection process in Europe. istered by EMA. Data are to be supplied in a format
compliant with EU-published procedures.
Austria Although Swissmedic is the country’s central
The Bundesamt für Sicherheit im Gesundheitswesen regulatory agency, inspections also are conducted
(BASG) provides information on the inspection process by cantonal or regional authorities (e.g., Regionales
(also in English) on its website.31 Heilmittelinspektorat der Nordwestschweiz). Swissmedic
has issued a mandatory inspection guideline
Germany (Swissmedic-Richtlinie I-SMI.RL.0133), which is used
The Zentralstelle der Länder für Gesundheitsschutz bei by all other Swiss agencies. Additional guidance in the
Arzneimitteln und Medizinprodukten (ZLG) provides local languages can be found online.34
information on the inspection process (also in English)
on its website.32 Turkey
In September 2017, the Turkish Ministry of Health
Russia and the Turkish Medicines and Medical Device
The State Institute of Drugs and Good Practices (SID) Agency published the GMP Guide for Manufacturing
is Russia’s national regulatory authority. The current Plants of Human Medicinal Products in both English
GMP standard was published in 2013 by Russia’s and Turkish.35 This guideline is aligned with PIC/S
Ministry of Industry and Trade (MinPromTorg). It is guidance and, thus, aligned with EU guidance and reg-
divided into two parts, with 18 appendices. ulations. The agency performs inspections to ascertain
Generally, the Russian regulations are aligned with compliance with this guide.
the European ones; therefore, their inspection process is
equally aligned. The state body in control of medicinal UK
product quality and the inspection of medicinal product The UK’s Medicines and Healthcare products
production sites is Roszdravnadzor (RZN). The Decree Regulatory Agency (MHRA) is prolific in issuing
of the Government of the Russian Federation N 1314 guidance and helpful blogs on all regulatory matters,
of 3 December 2015 on “Establishment of Compliance including inspections.36 It is recommended that regula-
of Manufacturers of Medicinal Products with the tory professionals subscribe to MHRA’s news and blogs
Requirements of Good Manufacturing Practice” pro- to stay abreast of developments and to access useful
vides the rules for conducting GMP inspections. RZN guidance. EU regulations are transposed into English
is obliged to use checklists when performing planned law in the form of statutory instruments (SI).
inspections. Inspections may cover any of the areas described in
EU GMP guidelines. They are carried out whenever a
Switzerland company has applied for or has been named on a manu-
Because of its position, i.e., surrounded by EU coun- facturer’s license and periodically during the course of a
tries, Switzerland has always strived to align its licence under the risk-based compliance program.
regulatory system with that of the EU, which also is Companies are required to complete a compliance
reflected in the existing MRA. This MRA was updated report prior to an inspection and submit an interim
in 2017, and covers inspection-related changes, such as compliance report covering any significant changes
recognition of inspections in third countries. occurring between inspections.
Contracting parties now also may recognise man- MHRA also publishes annual reports summarising
ufacturer inspections in third countries. This includes its inspection activities, which make very useful reading.
EDQM inspections.

Pharmacopoeial Compendia ‘scheme.’ From then on, there was no longer a country
These are referenced here because regulatory agencies participation but rather an authority participation.
will accept an application if a company adopts analytical The following is the list of PIC/S participating
methodologies from a pharmacopoeial compendium (if authorities as of April 2020:
one exists). Non-adoption is acceptable; however, the • Argentina
firm has to demonstrate the alternative method is of an • Australia
acceptable quality. • Austria
• Belgium
European Pharmacopoeia (Ph. Eur.) • Canada
The EU and 38 Member States are signatories to • Chinese Taipei
the Convention on the Elaboration of a European • Croatia
Pharmacopoeia.37 There also are some country-specific • Cyprus
pharmacopoeias. Any country that is a signatory to the • Czech Republic
Ph. Eur. must follow its monographs. Compliance with • Denmark
the Ph. Eur. may be investigated during an inspection by • Estonia
EDQM or a national competent authority. • Finland
• France
British Pharmacopoeia (BP) • Germany
The BP 202038 is the latest edition of the British • Greece
Pharmacopoeia. This edition became legally effective • Hong Kong
from 1 January 2020. The two pharmacopoeias that • Hungary
have legal status within the UK are the BP, including • Iceland
the BP (veterinary), and the Ph. Eur. The BP provides • Indonesia
the only comprehensive collection of authoritative offi- • Iran
cial standards for UK pharmaceutical substances and • Ireland
medicinal products and: • Israel
• is published every year in August • Italy
• becomes effective on 1 January of the follow- • Japan
ing year • Korea, Republic of
• incorporates all the monographs and texts of • Latvia
the Ph. Eur. • Liechtenstein
• Lithuania
Swiss Pharmacopoeia (Ph. Helv.) • Malaysia
In Switzerland, the Pharmacopoeia consists of the • Malta
Ph. Eur. and the Swiss Pharmacopoeia (Pharmacopoeia • Mexico
Helvetica, Ph. Helv.). It is published by Swissmedic as • Netherlands
prescribed by the Law on Therapeutic Products and con- • New Zealand
tains risk-oriented prescriptions relating to the quality • Norway
of medicinal products and pharmaceutical excipients • Poland
that are known and in use and certain medical devices.39 • Portugal
• Romania
PIC/S • Singapore
The Pharmaceutical Inspection Convention and • Slovakia
Pharmaceutical Inspection Co-operation Scheme • Slovenia
(PIC/S)40 is an inspectorates’ association or collabo- • South Africa
ration among regulatory authorities. They constitute • Spain
two international instruments between countries and • Sweden
pharmaceutical inspection authorities, which together • Switzerland
provide active and constructive co-operation in the • Thailand
GMP field. • Turkey
When the EU first came together, countries were • Ukraine
prevented from having other bilateral agreements if • UK
the European Community would not sign them. That • US
was the point when the ‘S’ was added to PIC, which is

Chapter 28
PIC/S publishes inspection guides, which are publicly suppliers has also been introduced by another revised
available. Although not legally binding, these are gener- chapter.
ally followed by the inspectorates. PIC/S also provides The revision was completed by the PIC/S Sub-
training to inspectors, which helps harmonise inspec- Committee on the Harmonisation of GM(D)P, led
tion approaches. Some members also conduct overseas by Paul Gustafson (Canada/RORB). PIC/S said the
inspections. revised GMP Guide will enter into force on 1 July 2018
In May 2018, PIC/S issued an interesting state- and will be published on the group’s website before it is
ment on the adoption of a new guidance on GMP published.
inspections, which was summarised in Regulatory “All non-EU/EEA Participating Authorities of
Affairs Professionals Society (RAPS) Regulatory Focus:41 PIC/S (and Applicants) have been invited to transpose
“The Pharmaceutical Inspection Co-operation the revised Chapters of the PIC/S GMP Guide into
Scheme (PIC/S) announced this month that it has their own GMP Guides,” the group said.”
adopted new guidance on good manufacturing practice
(GMP) inspections, outlining a process for “desk-top Industry Associations
assessment” of overseas facilities to identify instances Industry associations also publish inspection and/or
when an acceptable level of GMP compliance can be audit guidelines and checklists that can prove useful,
confirmed and assured without on-site inspections.” including:
Based on a draft from the International Coalition • Association of API Manufacturers— APIC/
of Medicines Regulatory Authorities (ICMRA), PIC/S CEFIC42
said the guidance provides a tool and framework aiming • Association of Pharmaceutical Excipients
to help competent authorities prioritize resources for Manufacturers— IPEC43
GMP inspections for human and veterinary medicines. • International Medical Device Regulators
“The demand for inspecting pharmaceutical man- Forum—IMDRF (formerly GHTF)44
ufacturing facilities far exceeds what any one CA can
accomplish and this framework will assist regulators in Other organizations, including RAPS, the Parenteral
managing product quality risks posed by the increas- Drug Association (PDA), the Drug Information
ingly complex pharmaceuticals global supply chain,” the Association (DIA) and the International Society for
group said. Pharmaceutical Engineering (ISPE), also publish
The main feature of this new guidance, PIC/S inspection-relevant documents.
said, “It is a non-binding (i.e., applicable on a volun-
tary basis) high-level guidance for ICMRA and PIC/S Eurasian Economic Union
participating authorities (PA) alike, whose purpose is to The Eurasian Economic Union Member States com-
facilitate this assessment process. It does not supersede prise the Republic of Armenia, the Republic of Belarus,
country/regional guidance, procedures or legislation the Republic of Kazakhstan, the Kyrgyz Republic and
where they exist.” the Russian Federation. These states have created a
The adoption by PIC/S of this new guidance common pharmaceutical market, and they recognize the
highlights efforts undertaken by the group to improve validity of one another’s inspections. Documentation in
sharing of inspection information between authorities, English is available only from unofficial sources.
which for 2018, PIC/S said contains more than 900
scheduled inspections. International Coalition of Medicines Regulatory
“The procedure should include the information Authorities (ICMRA)
that is needed to make an informed regulatory deci- ICMRA’s goal is to coordinate international coop-
sion about site compliance, triggers and risk factors eration among medicines regulatory authorities to
that would result in an inspection being required, and strengthen dialogue, facilitate the wider exchange of
how the assessment and outcome should be recorded,” reliable and comparable information and encourage
PIC/S said. “The aim in assessing the gathered infor- greater leveraging of the resources and work products
mation is to gain assurance that GMP compliance has of other regulatory agencies. This will avoid duplication
been established by the hosting CA and that there is of efforts and promote informed risk-based allocation
no other new evidence that would warrant an on-site of authorities’ resources. These efforts and others would
inspection by the requesting CA.” strengthen the quality, safety and efficacy of medicinal
The group notes that two chapters in the guide products globally. ICMRA membership is volun-
have been revised to include requirements to prevent tary and is open to all medicinal product regulatory
cross-contamination. A change in the qualification of authorities.

To some extent, this effort also will focus on europa.eu/docs/en_GB/document_library/Regulatory_and_pro-

inspections. cedural_guideline/2009/10/WC500004481.pdf. Accessed 22
April 2020.
5. History of EMA. EMA website. https://www.ema.europa.eu/
The Organisation for Economic Co-operation and en/about-us/history-ema. Accessed 22 April 2020.
Development (OECD) 6. The European Directorate for the Quality of Medicines
OECD publishes key GLP guidelines.45 It is important and HealthCare (EDQM). EDQM website. www.edqm.eu.
to note the fundamental differences between the EU 7. European Union legal acts. EUR-Lex website. http://europa.
and US GLP. The EU, in principle, follows the OECD eu/legislation_summaries/institutional_affairs/treaties/lisbon_
guidelines, as do many other countries or regions. treaty/ai0032_en.htm. Accessed 24 April 2020.
Depending on the applicable GLP regulations, 8. National competent authorities (human). EMA website.
https://www.ema.europa.eu/en/partners-networks/eu-partners/
either national agencies (e.g., FDA) or certification eu-member-states/national-competent-authorities-human.
bodies will perform inspections. Accessed 24 April 2020.
9. National competent authorities (veterinary). EMA website.
https://www.ema.europa.eu/en/partners-networks/eu-partners/
Conclusion eu-member-states/national-competent-authorities-veterinary.
The regulated healthcare industry’s quality systems and Accessed 24 April 2020.
companies’ adherence to their marketing authorisations 10. Compliance in the product lifecycle. EMA website. http://www.
will need scrutinising by the regulators, and inspections ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/
general_content_001258.jsp&mid=WC0b01ac0580b18a40.
are part of this scrutiny process. Inspections always Accessed 24 April 2020.
have been and will be performed using a risk-based 11. Compilation of Community Procedures on Inspections
approach. This is a bare necessity, as no inspectorate has and Exchange of Information. October 2014. EMA
sufficient resources (staff, funding and time) to inspect website. https://www.ema.europa.eu/en/documents/
regulatory-procedural-guideline/compilation-community-pro-
all establishments within their jurisdiction at regular cedures-inspections-exchange-information_en.pdf. Accessed 24
intervals (e.g., at a frequency of at least once every five April 2020.
years). Thus, only some agencies within Europe can 12. Welcome to EudraGMDP. EudraGMDP website. http://
be approached by industry and asked to perform an eudragmdp.ema.europa.eu/inspections/displayWelcome.do.
inspection. In general, drug product manufacturers are 13. Op cit 6.
considered higher risk than drug substance manufac- 14. The Inspection Programme. Council of Europe website. https://
turers or service companies, such as brokers or shipping www.edqm.eu/en/inspection-programme-certification-159.
companies. Manufacturing of sterile and/or biological html. Accessed 24 April 2020.
15. Paraschos S. The EDQM Inspection Programme. EDQM
compounds is perceived as a higher risk than, for exam- website. https://www.edqm.eu/sites/default/files/ws2-s_para-
ple, oral solid dosage form production. schos-inspection_programme.pdf. Accessed 24 April 2020.
This risk-based approach continues to guide 16. The Research Quality Association (RQA). RQA website.
inspection efforts, as agencies are forced to comply https://www.therqa.com/good-practices/good-laboratory-prac-
tice/regulations-guidelines/european-union/. Accessed 24 April
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pandemic. Desktop audits are replacing, at least in the 17. European Commission. Withdrawal of the United Kingdom
interim, on-site inspections.46,47 and EU rules in the field of Good Laboratory Practice
Within Europe, most regulatory agencies try to (GLP). EC website. https://ec.europa.eu/info/sites/info/files/
file_import/good-laboratory-practice_en.pdf. Accessed 24 April
avoid duplication of effort, which means companies 2020.
usually only get inspected by their local agency. This 18. GMP/GDP Inspectors Working Group. EMA website. https://
is unlikely to apply to the UK and the EU relation- www.ema.europa.eu/en/human-regulatory/research-de-
ship when the UK withdrawal transition period ends velopment/compliance/good-manufacturing-practice/
gmpgdp-inspectors-working-group. Accessed 24 April 2020.
(expected to be 31 December 2020). 19. Inspections procedure. EMA website. https://www.ema.europa.
eu/en/human-regulatory/research-development/compliance/
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Chapter 28
scientific-guideline/guideline-content-management-ar- 34. Regionales Heilmittelinspektorat der Nordwestschweiz website.

chiving-clinical-trial-master-file-paper/electronic_en.pdf. http://www.rhinw.ch/inspektorat.html. Accessed 24 April 2020.
Accessed 24 April 2020. 35. Good Manufacturing Practices (GMP) Guide for
23. EMA Guideline on the responsibilities of the sponsor with Manufacturing Plants of Human Medicinal Products. Turkish
regard to handling and shipping of investigational medicinal Medicines and Medical Devices Agency. https://titck.gov.tr/
products for human use in accordance with Good Clinical storage/announcement/GMP%20GUIDE%20V2018-02.pdf.
Practice and Good Manufacturing Practice. EMA website. Accessed 24 April 2020.
https://www.ema.europa.eu/en/documents/scientific-guideline/ 36. Medicines and Healthcare products Regulatory Agency home
draft-guideline-responsibilities-sponsor-regard-handling-ship- page. GOV.UK website. https://www.gov.uk/government/organ-
ping-investigational-medicinal-products_en.pdf. Accessed 24 isations/medicines-and-healthcare-products-regulatory-agency.
24. Good distribution practice. EMA website. https://www.ema. 37. Op cit 6.
europa.eu/en/human-regulatory/post-authorisation/compliance/ 38. British Pharmacopoeia website. https://www.pharmacopoeia.
good-distribution-practice. Accessed 24 April 2020. com/what-is-the-bp. Accessed 24 April 2020.
25. EudraLex Volume 4. EC website. https://ec.europa.eu/health/ 39. Mission of the Swiss Pharmacopoeia. Swissmedic web-
documents/eudralex/vol-4_en. Accessed 24 April 2020. site. https://www.swissmedic.ch/swissmedic/en/home/
26. Introducing the GDP Office Based Evaluation and legal/pharmacopoeia/pharmacopoea-helvetica0/mis-
Risk Assessment programme (OBERA). MHRA web- sion-of-the-swiss-pharmacopoeia.html. Accessed 24 April 2020.
site. https://mhrainspectorate.blog.gov.uk/2019/04/16/ 40. Pharmaceutical Inspection Convention/Scheme home page.
introducing-the-gdp-office-based-evaluation-and-risk-assess- PIC/S website. www.picscheme.org. Accessed 24 April 2020.
ment-programme-obera/. Accessed 24 April 2020. 41. Brennan Z. “PIC/S Adopts New Guidance on GMP
27. List of European countries by population. Wikipedia website. Inspections.” RAPS website. https://www.raps.org/
https://en.wikipedia.org/wiki/List_of_European_countries_by_ news-and-articles/news-articles/2018/5/pics-adopts-new-guid-
population. Accessed 24 April 2020. ance-on-gmp-inspections. Accessed 24 April 2020.
28. The 27 member countries of the EU. Europea.eu website. 42. Active Pharmaceutical Ingredients Committee Publications.
https://europa.eu/european-union/about-eu/countries_en. APIC website. http://apic.cefic.org/publications.html. Accessed
Accessed 24 April 2020. 24 April 2020.
29. Mutual recognition agreements (MRA). EMA website. https:// 43. The International Pharmaceutical Excipients Council Europe
www.ema.europa.eu/en/human-regulatory/research-de- home page. IPEC Europe website. www.ipec-europe.org.
velopment/compliance/good-manufacturing-practice/ Accessed 24 April 2020.
mutual-recognition-agreements-mra. Accessed 24 April 2020. 44. IMDRF documents. IMDRF website. http://www.imdrf.org/
30. Joint Audit Programme. EMA website. http://www.ema.europa. documents/documents.asp. Accessed 24 April 2020.
eu/ema/index.jsp?curl=pages/regulation/document_listing/ 45. Good Laboratory Practice. OECD website. http://www.oecd.
document_listing_000160.jsp&mid=WC0b01ac0580029750. org/chemicalsafety/testing/good-laboratory-practiceglp.htm.
31. Inspections. Austrian Federal Office for Safety in Welfare web- 46. FDA Statement: Coronavirus Disease 2019 (COVID-19)
site. https://www.basg.gv.at/en/inspections. Accessed 24 April Update: Foreign Inspections. FDA website. https://www.
2020. fda.gov/news-events/press-announcements/coronavirus-dis-
32. Zentralstelle der Länder für Gesundheitsschutz bei ease-2019-covid-19-update-foreign-inspections . Accessed 24
Arzneimitteln und Medizinprodukten website. www.zlg.de. April 2020.
Accessed 24 April 2020. 47. Office Based Inspection (OBI). https://mhrainspectorate.blog.
33. Swissmedic home page. Swissmedic website. https://www.swiss- gov.uk/2020/03/10/gcp-inspections-expectations-and-the-dos-
medic.ch/swissmedic/en/home.html. Accessed 24 April 2020. and-donts-for-hosting. Accessed 24 April 2020.

Chapter 29
Generic Medicinal Products

OBJECTIVES • is manufactured without a licence from the

innovator company
□ Understand generic drug products and • is marketed after the expiry date of the patent
biosimilars or other exclusive rights
□ Learn the regulatory requirements and the path-
Generic medicines provide a major benefit to society
way for the marketing authorisation of generic
by ensuring patient access to quality, safe and effective
products
medicines while reducing product cost. The lower cost of
□ Understand the postauthorisation regulatory generic medicines is due primarily to reduced research
obligations for marketing generic products and development investment because manufacturers can
use originators’ preclinical and clinical studies.
From a production point of view, however, the
DIRECTIVES, REGULATIONS AND GUIDELINES manufacturing cost for an originator product or a
COVERED IN THIS CHAPTER generic probably will not differ significantly, as both are
manufactured under the same industry standards and
□ Directive 2001/83/EC of the European conditions. In fact, it is not uncommon for an originator
Parliament and of the Council of 6 November product manufacturer to manufacture a generic version
2001 on the Community code relating to medici- of the drug once the patent has expired and the product
nal products for human use1 is open to generic competition. From an economic per-
spective, this allows the originator company to continue
□ Regulation (EC) No. 726/2004 of the European recouping the cost of its capital and R&D investments.
Parliament and of the Council of 31 March 2004 While the active pharmaceutical ingredient (API)
laying down Union procedures for the authori- does not differ between originator (also called reference
sation and supervision of medicinal products medicine) and generic medicines, other inactive ingredi-
for human and veterinary use and establishing ents (excipients) may differ, and a number of excipients
a European Medicines Agency2 are known to have side effects or contraindications. Due
to differences in excipients between originator medi-
cines and generic products that have been shown to be
Introduction bioequivalent to the originator and, therefore, substitut-
The term “generic drug” or “generic medicine” can have able, community healthcare professionals must be aware
varying definitions in different markets; however, the that a generic product containing an excipient not part
term commonly is understood, as defined by the World of the originator product poses the potential for prob-
Health Organization (WHO), to mean a pharmaceuti- lems in a patient who had no tolerance issues with the
cal product that: originator product.
• usually is intended to be interchangeable with A reference pricing system establishes a reim-
an innovator product bursement level or reference price for a group of

Chapter 29
interchangeable medicines. If a medicine is priced above Bioequivalence has been defined as: two pharma-
the reference price, the patient pays the price differential ceutical products that are pharmaceutically equivalent,
in addition to any other co-payments, e.g., prescription and their bio-availabilities (rate and extent of avail-
fee, percentage co-payment. ability) after administration in the same molar dose are
A reference pricing system generates savings for similar to such a degree that their effects, with respect
third-party payers. Reference pricing can help govern- to both efficacy and safety, can be expected to be essen-
ments contain public pharmaceutical expenditures while tially the same. Pharmaceutical equivalence implies the
controlling medicines’ reimbursement levels. A reference same amount of the same active substance(s), in the
pricing system also may promote generic products’ use same dosage form, for the same route of administration
because originator products priced above the reference and meeting the same or comparable standards.
price likely will lose market share as a result of the addi- Bioequivalence is established to demonstrate equiv-
tional patient co-payment. alence between the generic medicine and the originator
Generic drugs present equally safe and efficacious medicine to allow bridging the preclinical and clinical
alternatives to originator medicinal products, which testing performed on the originator drug.
contain well-known, rigorously tested active ingre- Bioequivalence is demonstrated when the generic
dients. An established originator product undergoes product’s rate and extent of absorption do not show a
expensive and protracted development (up to 15 years), significant difference from the originator drug, or where
with inherently high preclinical and clinical research the extent of absorption does not show a significant
costs before achieving marketing approval. Generic difference, and any difference in rate is intentional or
drug development is relatively quick and inexpensive, not medically significant.
allowing those products to be sold at significantly lower The most important parameters evaluated during a
prices. This is because, in most cases, only bioequiva- bioequivalence study are:
lence studies are required. However, generic products’ • area under the curve (AUC)—the area under
lower prices do not connote ‘cheap quality.’ In fact, the plasma concentration time curve, which
generic medicines undergo the same strict regulatory represents the extent of exposure
scrutiny as reference products. • maximum plasma concentration of the
The pharmaceutical form is the distinct way a prod- active substance (C-max)—C-max provides
uct is administered and, for the generic product, should information on pharmacodynamic and phar-
be the same as the reference product. Surprisingly, var- macokinetic properties and is fundamental in
ious immediate release oral pharmaceutical forms, e.g., evaluating adverse events
tablets and capsules, are considered legally to be the • time to maximum plasma concentration
same pharmaceutical form. Therefore, physicians may (T-max)—T-max allows inferences to be
prescribe either a film-coated tablet or a capsule of the drawn, to a certain degree, on the speed of
same drug. In itself, this does not pose a problem, as the release from the pharmaceutical form and the
generic formulation may be different, but the safety and absorption from the gastrointestinal tract as
efficacy profile impact of the product has been judged to well as a raw estimate of the onset of action
be comparable during the approval procedure.
Composition differences between the generic and The data collected during the bioequivalence study
reference medicinal products are possible, but only undergo exacting statistical analyses, for which a 90%
regarding the excipients, e.g., bulking agents, and colour- confidence interval is used. This interval provides a
ing agents. For active substance differences, the generic range within which it is possible to be 90% confident
drug applicant must demonstrate these differences in the true effect lies. The agreed acceptance limits are
composition do not influence the drug’s therapeutic valid throughout the EU.
efficacy, safety, absorption, distribution, metabolism or Since bioequivalence studies are to detect differ-
elimination by the body, i.e., the drug’s pharmacokinetics ences between formulations or pharmaceutical forms,
also must remain more or less the same. they are used not only as a basis for licensing generic
Innovator medicines (originator products) are new medicinal products. In fact, originators also may use
medicines not commercially used in humans earlier and bioequivalence studies during their own development,
containing new active ingredients.3 since the formulation first used in clinical trials often
Legal requirements vary in different jurisdictions is not the same as that used later in large-scale market
and define the specifics of what is considered a generic production. Bioequivalence studies are used in these
medicine. However, one of the main principles under- cases to allow bridging the results obtained in clini-
pinning generic medicines’ safe and effective use is the cal trials. The same principles for study conduct, data
concept of bioequivalence.

evaluation and assessment of results by the authority are making, using, selling or importing the invention for
applied in such originator studies as in generic drugs. 20 years. SPCs grant up to five years of additional mar-
A generic medicine must: ket protection to pharmaceutical products. Additional
• contain the same active substance(s) as the market protection for the originator product may be
innovator drug generated by data exclusivity, which prevents medicines
• be identical in strength, dosage form and route regulators from accepting an MAA based on bioequiva-
of administration lence during a defined period.
• have the same use indications The “8+2+1” protection period rule is underpinned
• be bioequivalent (as a marker for therapeutic by Regulation (EC) No. 726/2004 Article 14(11) and
inter-changeability) Directive 2001/83/EC Articles 10(5) and 74(a)). This is
• meet the same batch requirements for identity, the period during which a reference medicinal product
strength, purity and quality is shielded from generic competition. Applications for
• be manufactured under the same strict GMP generic or hybrid medicinal products can be submitted
standards required for innovator products after the reference medicinal product’s data exclusiv-
ity period expires (i.e., eight years after the date of
Generic Medicines the reference medicinal product’s MA). However, the
• provide an affordable, gold standard medica- authorised generic or hybrid product can be placed
tion for many major illnesses on the market only 10 or 11 years after the reference
• allow access to medicines for a greater propor- medicinal product’s exclusivity period expires.
tion of the population A generic version of a reference product authorised
• stimulate healthy competition with the under the Centralised Procedure may be authorised by
branded sector Member States’ competent authorities in accordance
• deliver savings to national health bills with the relevant Community code (for human or vet-
• enable future long-term savings in the expand- erinary products) under three conditions:
ing role of medicines vs. hospitalisation • the application is in accordance with the rel-
• are high-quality products evant Community code abridged application
provisions
Medicines for Europe, formerly the European Generics • the summary of product characteristics
Medicines Association (EGA), is the official repre- (SmPC) is “in all relevant respects consistent
sentative body of the European generic and biosimilar with that of the medicinal product authorised
medicines pharmaceutical industry, which is at the fore- by the Community except for those parts of
front of providing high-quality affordable medicines to the summary referring to indications or dosage
millions of Europeans and stimulating competitiveness forms, which were still covered by patent law
and innovation in the pharmaceutical sector. Formed in at the time when the generic medicine was
1993, Medicines for Europe represents generic phar- marketed”
maceutical companies and their subsidiaries throughout • the generic medicinal product is authorised
Europe, either directly or through national associations. under the same name in all Member States
Medicines for Europe plays an important consultative where the application has been made
role in European healthcare policy-making. Medicines
for Europe and its members work with the European Differences in the generic manufacturing process com-
national governments and EU institutions to develop pared to the originator are allowed, but the same strict
affordable solutions for pharmaceutical care and to general quality criteria, e.g., controlled production under
increase Europe’s competitive strength in the global GMPs, apply to the production of both the generic
pharmaceutical medicines market (https://www.medi- medicinal product and the reference product.
cinesforeurope.com/. GMPs are critical to ensure the product’s quality
A generic medicine can be marketed only after the is suited for its purpose. EU companies manufacture
patents and the supplementary protection certificates products worldwide and adhere to international regula-
(SPCs) covering the originator product have expired. tory agencies’ stringent GMP requirements, including
Data exclusivity also limits when a generic manufacturer the European Medicines Agency (EMA), when pro-
can submit a marketing authorisation application (MAA) ducing medicines. The EU also is a key member of
based on bioequivalence to the originator product. the Pharmaceutical Inspection Co-operation Scheme
Patents are used to protect a product, process, (PIC/S), an informal collaboration between members
apparatus or use with a practical purpose. Registration seeking to improve their manufacturing requirement
gives the patentee the right to prevent anyone else from standards. The EU has GMP mutual recognition

Chapter 29
agreements (MRAs) with several countries (Australia, on APIs, while the BP alone publishes monographs
Canada, Israel, Japan, New Zealand, Switzerland and on finished products. APIs that are the subject of a Ph.
the US). Eur. monograph may have been assessed by European
Medicines’ quality depends on the quality of their Directorate for the Quality of Medicines (EDQM) and
ingredients and how these individual components are issued a Certificate of Suitability (CEP). If a CEP is
produced and tested. To maintain the highest quality used in an MAA for a generic product, the competent
levels, excipients also are tested to applicable standards authorities recognise the CEP, and the review of the
(e.g., European Pharmacopoeia) to ensure they are iden- drug substance part of the dossier is less rigorous.
tified properly and guarantee their consistent strength, Pharmacopoeial methods usually are designed to
quality and purity. identify impurities likely to occur during the route of
Pharmacopoeias are official publications contain- synthesis utilised by the originator. Impurities resulting
ing recommended specifications for analysing and from a different route of synthesis or accidental contam-
determining the quality of drug substances, specific ination with other chemicals may not be detected even
dosage forms, excipients and finished drug products. if they pose a danger to health. This is why regulatory
A quality specification is a set of appropriate tests that authorities today never base generic product market-
will confirm the product’s identity and adequate purity, ing authorisations (MAs) solely on pharmacopoeial
ascertain the active substance’s strength and, when pos- monograph quality control testing. Hence, there is more
sible, ascertain its performance characteristics. emphasis on postauthorisation surveillance after the
Two key definitions involve the “reference medic- product is placed on the market.
inal product” and the “generic medicinal product.” The Pharmacopoeial standards should be incorporated
Community code defines the “reference medicinal in the framework of all regulatory measures, such as
product” as a medicinal product authorised under the GMP inspections of active pharmaceutical ingredient
procedures applicable to full applications (including and finished dosage form manufacturing, quality spec-
quality, nonclinical and clinical data), while the “generic ification scientific assessment, data interchangeability
medicinal product” is a medicinal product with the and labelling information provided by the manufacturer.
same qualitative and quantitative composition in active They are most valuable in generic product postmarket-
substance(s) and the same pharmaceutical form as ing quality surveillance.
the reference medicinal product, and whose bioequiv- Biosimilar medicines are medicinal products
alence to the reference medicinal product has been whose active substances are from a biological source,
demonstrated by appropriate bioavailability studies. The such as living cells or organisms (human, animals and
different salts, esters, ethers, isomers, mixtures of isomers, microorganisms such as bacteria or yeast) and are often
complexes or derivatives of an active substance shall be produced by cutting-edge technology. A biosimilar
considered to be the same active substance, unless they product is one that is similar to an already authorised
differ significantly in properties with regard to safety medicine of biological origin (biological reference
and/or efficacy. In such cases, the applicant must pro- product). Biological products are fundamentally differ-
vide additional proof of the safety and/or efficacy of ent from standard chemical products in terms of their
the various salts, esters or derivatives of an authorised complexity; it is unlikely the biosimilar product will
active substance. The various immediate-release oral have a fully identical structure to that of the reference
pharmaceutical forms shall be considered to be one and product, thereby requiring evidence of safety and effi-
the same pharmaceutical form. Bioavailability studies are cacy before approval. As with other generic medicines,
not required if the applicant can demonstrate the generic a biosimilar product undergoes testing to ensure it is as
medicinal product meets the relevant criteria defined in safe and effective as the reference product. For generic
the appropriate detailed guidelines. medicines, bioequivalence studies and/or comparative
In Europe, the national competent authorities dissolution testing normally is required. However, for
within the MAA evaluation framework assess the biosimilars, due to the complex manufacturing process,
excipient quality. the active substance may differ slightly between the two
For generic medicines, formulated after patents and medicines, and additional safety and efficacy studies
other exclusivity rights expire, compendial monographs may be required on a case-by-case basis.
are more important because they allow manufacturers to Since the generic medicinal product contains the
meet compendial standard requirements (for both APIs same active substance as the originator, and comparabil-
and finished dosage forms) rather than elaborate their ity has been demonstrated in a successful bioequivalence
own specifications. study, the generic drug is assumed to behave in the
The European Pharmacopoeia (Ph. Eur.) and the same way as the originator. This equivalence also implies
British Pharmacopoeia (BP) both publish monographs equal efficacy and safety. Follow-up controls include

Table 29-1. Legal Basis of EU Applications from Directive 2001/83/EC
Article 8(3) Full dossier Full Application. Data requirements met by:
• Applicant’s own data, or
• Applicant’s own data and published literature data (mixed marketing authori-
sation application)
Article 10(1) Abbreviated dossier Generics
• Demonstration of bioequivalence
Article 10(3) Abbreviated dossier Hybrid application
• Full or partial reference to nonclinical and clinical data of reference medicinal
product
• Additional data to establish product properties
Article 10(4) Abbreviated dossier Biosimilar application
• Partial reference to nonclinical and clinical data of reference medicinal
product
• Additional data to establish properties of product
Article 10b Full dossier New fixed combination application
• Only data relating to the properties of the new fixed combination required
• Can refer to data of the single components
Article 10c Full dossier Informed consent application
• Duplicate of approved full dossier
Routes for generic and biosimilar medicines are in bold.

Source: Notice to Applicants, Volume 2A
evaluation of recent scientific literature, clinical trials, addition to EMA, which oversees EU-wide medicines’
pharmacovigilance provisions, manufacturing inspec- authorisation.
tions, quality controls and an obligatory marketing No medicinal product may be placed on a Member
authorisation renewal after five years. State’s market unless that country’s competent author-
A referral is a procedure used to resolve issues such ity has granted it an MA in accordance with Directive
as concerns about a medicine’s or class of medicines’ 2001/83/EC.
safety or benefit-risk balance. The medicine, or the class Medicinal products in the EU are authorised via
of medicines, is ‘referred’ to the European Medicines one of four routes: the Centralised Procedure (pan-Eu-
Agency, so it can make a recommendation for a har- ropean license), the Decentralised Procedure or Mutual
monised position across the EU. Recognition Procedure (for more than one Member State)
Referrals can be started by the European and the National Procedure (for an individual Member
Commission, any Member State or the company mar- State). For more details on MAs, see Chapter 23.
keting the medicine. For most referrals, the European To gain product approval in the EU, a generic drug
Commission issues a decision to all Member States manufacturer must submit an abridged product appli-
reflecting the measures they need to take to implement cation that references an existing licensed medicinal
the agency’s recommendation. product (Reference Medicinal Product) whose data
The Coordination group for Mutual Recognition protection period has expired. The reference product
and Decentralised procedures (CMD(h)) is the must be licensed on the basis of a full dossier (complete
European consultative body responsible for ensuring Modules 1–5). The abridged application most likely
the proper functioning of the Mutual Recognition and will be under an Article 10(1) (of the aforementioned
Decentralised Procedures. CMD(h) is composed of the Directive 2001/83/EC) but can come under another
Heads of Medicines Agencies (HMA). It can discuss legal basis depending on the circumstances. For an
any procedural or scientific questions that arise. Each existing active substance developed with a new dosage
Member State has one representative in the group. form or strength, route of administration, a new indi-
Experts may accompany these representatives. cation, or combination of these, an Article 10(3) legal
basis is required (see Table 29-1).
MAs for Generic Medicinal Products If a commercial agreement is made with the MAH
Medicinal product authorisation in the EU is complex, of an existing product, it might be possible to submit
with a competent authority in each Member State in

Chapter 29
under Article 10c an ‘informed consent’ application, trials are not needed. A generics company can use an
whereby a duplicate of an approved full dossier is used. abridged registration procedure and carry out bioequiv-
In most cases, an Article 10(1) application is appro- alence studies to prove its product is therapeutically
priate, and generic companies must prove bioequivalence equivalent to the branded drug.
to the innovator’s reference product and meet such The biologics manufacturing process is different
general requirements as GMPs and labelling and adver- from that for small molecule drugs. Even a small change
tising controls. However, they do not need to conduct to the biotech manufacturing process can have a huge
preclinical and clinical trials to prove product safety and impact on the resulting product’s efficacy and safety.
efficacy because the approved dossier of the reference To obtain authorisation to place a generic medici-
product is considered to demonstrate safety and efficacy. nal product on the market, regardless of the procedure,
The generic company does not have the rights to obtain application shall be made to the Concerned Member
a copy of the reference product’s dossier but is allowed State’s competent authority. Under Directive 2001/83/
to refer the regulatory reviewer to that dossier, so long as EC Article 8, it must be accompanied by the following
the reference product’s patent or regulatory data exclu- particulars and documents:
sivity has expired. As a practical matter, the regulator 1. applicant’s name or corporate name and per-
may not need to refer to the dossier, since the active manent address and, where applicable, that of
substance’s safety and efficacy are treated as having been the manufacturer
established by the innovator’s efforts. 2. medicinal product’s name
Authorisations for generic or biosimilar medici- 3. medicinal product constituents’ qualitative and
nal products are linked to the ‘original’ authorisation. quantitative particulars
However, this does not mean withdrawal of the authori- 4. evaluation of the medicinal product’s potential
sation for the reference product leads to the withdrawal environmental risks
of the generic product’s authorisation. The generic or 5. manufacturing method description
biosimilar medicinal product, once authorised, can only 6. therapeutic indications, contra-indications and
be placed on the market 10 or 11 years after the refer- adverse reactions
ence medicinal product’s authorisation, depending on 7. posology, pharmaceutical form, method and
its exclusivity period. route of administration and expected shelf life
Generic medicine applications typically include 8. reasons for any precautionary and safety mea-
chemical and pharmaceutical data and bioequivalence sures to be taken for the medicinal product’s
study results demonstrating the generic product’s simi- storage, its administration to patients and the
larity to the reference product. Bioequivalence tolerance disposal of waste products, with an indication
levels have been favourably compared to those accept- of the medicinal product’s potential risks for
able for inter-batch variation during the originator’s the environment
production. The authorising regulatory agency(ies) 9. description of the manufacturer’s control
references the data in the originator product’s authorisa- methods
tion application concerning the active substance’s safety 10. written confirmation that the manufacturer of
and efficacy. This is possible only following the origina- the medicinal product has verified compliance
tor product’s data exclusivity period expiry. The majority of the manufacturer of the active substance
of generic product authorisations are granted through with principles and guidelines of GMP by
the Mutual Recognition or Decentralised Procedure, as conducting audits
well as national applications in specific countries. 11. results of pharmaceutical (physicochemical,
EU bioequivalence parameters, as specified in the biological or microbiological) tests, nonclinical
Guideline on the Investigation of Bioequivalence (CPMP/ and clinical trials
EWP/QWP/1401/98 Rev. 1/Corr**),4 require the test 12. detailed description of pharmacovigilance and,
and reference products to fall within an acceptance where appropriate, the risk management sys-
interval of 80.00–125.00% of the AUC, and a Cmax tem, which the applicant will introduce
at a 90% confidence interval. This guidance document 13. a statement to the effect that clinical trials
also provides a tightened acceptance interval of 90.00– conducted outside the EU meet the ethical
111.11% for narrow therapeutic index drugs (NTIDs) requirements of Directive 2001/20/EC
as well as different assessment requirements for highly 14. SmPC, mock-ups of the medicinal product’s
variable drug products (HVDPs). outer packaging, immediate packaging and the
Generally, establishing two batches of APIs as package leaflet
chemically identical, with sufficiently similar impurity
profiles, is fairly uncomplicated. Therefore, full clinical

15. document showing the manufacturer is autho- Drug Substance

rised in its own country to produce medicinal General Information
products This is the structural formula, including relative and
16. copies of any MAs from other Member State absolute stereochemistry, molecular formula and rel-
or third countries and a list of those Member ative molecular mass. Examples of physicochemical
States in which an MAA has been submitted and biological properties that might need to be exam-
17. copies of the SmPC proposed by the applicant ined include solubility, water content, particle size,
or approved by a Member State’s competent crystal properties, biological activity and permeability.
authority Solid-state properties that might affect the in vivo
18. copies of the package leaflet proposed or performance are of particular importance. Additionally,
approved by a Member State’s competent for proteinaceous biological active substances, the sche-
authority matic amino acid sequence indicating glycosylation sites
19. details on any decision to refuse authorisation, or other post-translational modifications and biological
whether in the Community or a third country, activity should be available.
and the reasons for such a decision
20. copy of any orphan designation of the medic- Manufacture
inal product under Regulation (EC) No. The manufacturing process should be well described
141/2000 and a copy of the relevant agency and understood. All critical parameters should be iden-
opinion tified and appropriately controlled. The process should
demonstrate it can reproducibly produce a substance
Notice to Applicants, Volume 2B lays out the information with the desired quality characteristics. In addition, the
and level of detail needed in each CTD section.5 starting materials—all the materials from which the
active substance is manufactured—should be evaluated
Biosimilars and documented. If there is a change in the chemical
A biosimilar is a biologic medical product that is a copy of or biological active substance’s manufacturing process,
an original product manufactured by a different company. it is necessary to ensure the change will not affect the
Biosimilars are officially approved versions of original product. Appropriate definition of starting materials
“innovator” products, and can be manufactured when the is a common deficiency issue, and reference should
original product’s patent expires. Reference to the innova- be made to Guideline on the use of starting materials
tor product is an integral component of the approval. and intermediates collected from different sources in the
In the EU, biosimilar products cannot meet manufacturing of non-recombinant biological medicinal
“generic” criteria, generally because they are large-mol- products (EMA/CHMP/BWP/429241/2013) as well as
ecule proteins that cannot be proven to be sufficiently the Guideline on the Chemistry of New Active Substances
close to innovator products. The term “biogenerics” also (EMA/454576/2016).8,9
is used but is a misnomer because the copy cannot be
identical to the reference product. Characterisation
A number of CHMP guidelines6 on biosimilars Extensive characterisation is performed in the develop-
exist for the various product types (e.g., general bio- ment phase and, where necessary, following significant
technology-derived proteins, specific products such as process changes. Characterisation is necessary to estab-
monoclonal antibodies) that outline the weight of evi- lish relevant specifications.
dence needed to demonstrate comparability. The potential for isomerism, identification of ste-
For more information on biotechnology-derived reochemistry and polymorphism should be evaluated.
medicinal products, see Chapter 30. A substance’s purity often is judged by examining its
impurities. Therefore, special emphasis should be given
Dossier Requirements for Generics to characterising the impurities that arise from both
Notice to Applicants, Volume 2B7outlines the general the method of manufacture and those produced during
information to be included in each section. In the storage, by degradation.
following subsections, some of this information is
discussed as well as any specific European guidance Control of Active Substance
documents that should be consulted. Specifications are critical quality standards based on
thorough characterisation and a mechanistic under-
standing of how formulation and process factors can
impact product performance. Specifications should
reflect the characteristics an active substance should

Chapter 29
have to meet its intended purpose. Conformity with by the CEP. However, additional information might
specifications should provide assurance quality is be necessary depending on how the active substance’s
maintained from the time of release to the end of the attributes affect the finished product performance, for
shelf life/re-test period. Acceptance criteria should example, particle size, sterility, etc. Manufacturers or
be established and justified based on data obtained suppliers of excipients, herbal products used in the pro-
during development, including data from manufactur- duction or preparation of pharmaceutical products, or
ing consistency studies, stability studies and lots used any product with transmissible spongiform encephalop-
in nonclinical and/or clinical studies. The analytical athy (TSE) risk, also may choose to apply for a CEP.
procedures used to test the critical-to-quality attributes
should be validated adequately in accordance with Finished Product
ICH guidelines.10 The applicant should adhere to Ph. Notice to Applicants, Volume 2B also covers the basic
Eur. monographs and tests where possible, and when information needed in the drug product section of the
pharmacopoeial methods are used, analytical method dossier. Key issues applicants should address during the
validation is not required. finished product development are:
Stability Formulation Development

The applicant should study how the active substance’s When developing a formulation, it is important to
quality varies with time under the influence of a variety identify attributes critical to the drug product’s qual-
of environmental factors, such as temperature, humidity, taking into consideration its intended use, route of
ity and light. This allows definition of practical storage administration and the specific needs of the intended
conditions and a ‘window of use’ called the shelf life/ patient population, e.g., paediatrics, geriatrics. If
re-test period (during which the substance may be used the product has a paediatric indication, Guideline on
without further testing). Stability requirements for Pharmaceutical Development of Medicines for Paediatric
existing active substances are outlined in the Guideline Use (EMA/CHMP/QWP/805880/2012 Rev. 2)13 is an
on Stability Testing: Stability Testing of Existing Active essential guideline to consider and reference.
Substances and Related Finished Products (CPMP/ All excipient choices should be justified. Although
QWP/122/02 Rev. 1, Corr).11 excipients usually are inactive substances, their safety
in the target population (e.g., paediatric population or
Active Substance Master File (ASMF) an animal species) should be considered. The poten-
An ASMF contains all the necessary active substance tial effect of the active substance’s physicochemical
information and is composed of two separate sections. properties (e.g., water content, solubility, particle size
The “applicant’s part” contains the majority of the distribution, polymorphic or solid state form) on the
information (non-confidential) and is available to the finished product’s performance should be evaluated.
applicant. However, in the “restricted part,” the active Another key issue to be investigated is the active sub-
substance manufacturer can submit detailed informa- stance’s compatibility with excipients, containers and
tion relating to the manufacturing process, controls and closures. For combination products, the active substances’
validation; this is submitted directly to the competent compatibility with each other also should be evaluated.
authorities to protect the manufacturer’s intellectual For oral generic products, the pharmaceutical
property. The ASMF concept applies only to “well-de- development Section (3.2.P.2) must include a discus-
fined active substances” as described in the Guideline sion on bioequivalence study results and comparative
on active substance master file procedure (CHMP/ dissolution data complementary to bioequivalence
QWP/227/02 Rev. 4).12 Therefore, it cannot be used for studies. The results of in vitro dissolution tests at three
biological active substances, excipients, finished prod- different buffers (normally pH 1.2, 4.5 and 6.8) and the
ucts, container materials, etc. media intended for drug product release (QC media),
obtained with the batches of test and reference products
Certificate of Suitability (CEP) that were used in the bioequivalence study, should be
The active substance manufacturer may submit doc- reported. The criteria for demonstrating comparable dis-
umentation to the Ph. Eur. secretariat requesting solution profiles are laid out in Appendix I of Guideline
evaluation of the suitability of the relevant Ph. Eur. on the investigation of bioequivalence (CPMP/EWP/
monograph to control its active substance’s chemical QWP/1401/98 Rev. 1/Corr**).14
purity and microbiological quality. If a CEP is available In addition, if a biowaiver for other product strengths
from the active substance manufacturer, it can be refer- is sought, dissolution data comparing the biostrength
enced in the application, and no additional information to the other strengths is required. The general biowaiver
will be needed for those parts of the dossier covered criteria specified in the guideline should be met.

For oral dosage forms (excluding sublingual, buccal Usually, process validation involves manufacturing a
and modified release products) containing certain active number of pilot or production scale batches to confirm
substances, it may be possible to avoid carrying out a the process is under control. If process validation has
bioequivalence study against the reference product if the been performed on pilot scale batches, a process valida-
drug substance is either Biopharmaceutics Classification tion protocol for commercial scale batches also should
System (BCS) I or III. be provided. For non-standard processes (e.g., special-
The BCS-based biowaiver approach is meant to ised dosage form manufacture or using new or highly
reduce in vivo bioequivalence studies by acting as a specialised technologies, and non-standard sterilisation
surrogate for in vivo bioequivalence. In vivo bioequiv- methods), commercial scale validation data usually need
alence studies may be exempted if an assumption of to be provided with the submission. Guideline on process
equivalence in in vivo performance can be justified by validation for finished products—information and data to
satisfactory in vitro data. This is detailed in Appendix be provided in regulatory submissions (EMA/CHMP/
III of Guideline on the investigation of bioequivalence CVMP/QWP/BWP/70278/2012-Rev. 1, Corr.1)17 out-
(CPMP/EWP/QWP/1401/98 Rev. 1/Corr**).15 In lines these requirements.
the author’s experience, BCS-based biowaivers are Appropriate excipient specifications should be
underutilised and can reduce generics’ development established, and validated methods should be used to
costs, as well as reduce the exposure of healthy study test them. The Ph. Eur. includes general tests to control
volunteers to medicinal products unnecessarily. the drug product and ensure quality. The BP also con-
tains monographs for drug products of many generic
Process Development medicines. The finished product’s stability throughout
It is important to consider critical formulation attri- its proposed shelf life should be demonstrated under
butes, with manufacturing process options, to address proposed storage conditions. Stability studies should be
the manufacturing process selection and confirm its performed in accordance with ICH recommendations
components’ appropriateness. The manufacturer must (storage conditions, duration, etc.) unless otherwise jus-
have adequate knowledge of the manufacturing process tified. For multiple-dose containers, the proposed in-use
to ensure material and process variability is understood shelf life also should be demonstrated. In all cases, the
and managed adequately. analytical methods used to test the product should be
stability indicating.
Microbiological Attributes and Compatibility Other specific issues include:
All parameters relevant to the dosage form’s micro-
biological attributes should be evaluated. Examples Adventitious Agents
include preservative system selection and effectiveness All materials of human or animal origin used in active
in products containing antimicrobial preservatives substance or finished product manufacturing processes
and, for sterile products, the sterilisation process and or coming into contact with the active substance or fin-
the container/ closure system’s integrity for preventing ished product during the manufacturing process should
microbial contamination. For sterile products, sterili- be identified. The risk of potential contamination with
sation method selection should be justified in line with adventitious agents of human or animal origin should
the guideline on the sterilisation of the medicinal prod- be assessed.
uct, active substance, excipient and primary container
(Guideline on the sterilisation of the medicinal product, TSE Agents
active substance, excipient and primary container (EMA/ The current Note for guidance on minimising the risk of
CPMP/CVMP/QWP/850374/2015).16 transmitting animal spongiform encephalopathy agents via
The drug product’s compatibility with the reconsti- human and veterinary medicinal products (EMA/410/01
tution diluent(s) or dosage devices (e.g., precipitation of Rev. 3)18 should be applied. Suppliers of any substances
drug substance in solution, sorption on injection vessels, with a TSE risk used in medicinal product production
stability) also should be demonstrated. or preparation can apply to Ph. Eur. for a TSE cer-
tificate. Marketing authorisation applicants then can
Other Drug Product Information reference those certificates.
As with active substances, the drug product manufactur-
ing process should be designed carefully to yield product Viral Safety
of the intended quality consistently. All critical steps The risk of introducing viruses into the product and the
should be identified and controlled with appropriate manufacturing process’ capacity to remove or inactivate
in-process controls. Batch-to-batch consistency must be viruses also should be evaluated.
demonstrated via appropriate process validation studies.

Chapter 29
For other adventitious agents, such as bacteria, Group)—This group aims to survey and collate
mycoplasma and fungi, detailed information should be information from each jurisdiction regarding
provided. issues of common interest related to generic
drugs’ bioequivalence assessments. Where
Environmental Risk Assessment (ERA) appropriate, the working group will develop
The purpose of an ERA, which is required for all tools (e.g., assessment templates and guid-
medicinal products, is to investigate the medicinal prod- ance for assessors) to aid in the assessment of
uct’s potential environmental risk. bioequivalence.
• Information and Work Sharing projects—An
Eligibility Request (Centralised Procedure Only) information-sharing pilot was launched in
Regardless of whether the product falls into the man- 2014 using the EU’s Decentralised Procedure
datory or optional scope, an ‘eligibility request’ always as a model for sharing information during the
should be submitted using the presubmission request Decentralised Procedure’s scientific assessment
form template, with relevant additional justification phases with IGDRP non-EU agencies. It sub-
(e.g., draft SmPC and for optional scope, eligibility sequently was expanded in 2015 to also cover
justification) should be provided. the Centralised Procedure. Currently, the pilot
The applicant should submit documents by email to involves the EU and the regulatory agencies of
CPeligibility@ema.europa.eu or vet.applications@ema. Health Canada, Swissmedic, Taiwan FDA and
europa.eu, respectively. EMA recommends submitting Australia’s Therapeutic Goods Administration.
the eligibility request, at the earliest, 18 months before
MAA submission and, at the latest, seven months Pharmacovigilance
before filing the MAA with EMA, at which point it All European pharmaceutical manufacturers have a
may be submitted with the “letter of intent to submit.” legal obligation to monitor a given medication’s use and
effect and to detect, assess, understand and prevent any
International Generic Regulations adverse reactions or other medicine-related problems
The International Generic Drug Regulators Pilot that may arise. This science and its related activities
(IGDRP) was launched in April 2012 in response to comprise pharmacovigilance.
mounting pressures confronting generic drug review Pharmaceutical manufacturers must ensure:
programmes worldwide, and regulatory agencies showed • an appropriate pharmacovigilance system,
a willingness to pursue collaboration and convergence recorded in a pharmacovigilance system master
to help mitigate these pressures. Broadly speaking, this file, is in place to ensure continuous monitor-
would be realised through: ing and supervision of all authorised medicines
• increasing review procedures’ efficiency • the pharmacovigilance system master file
• strengthening the regulatory review process is available for inspection by competent
and human resource capacity authorities
• applying an appropriate level of global regula- • pharmacovigilance measures are planned for
tory oversight through information exchange each individual medicinal product in the con-
and coordination while reducing unnecessary text of a risk management system
regulatory burden • all information impacting a medicine’s bene-
• promoting the adoption of modern science- fit-risk balance is reported to the authorities
and risk-based approaches by both industry • product information is updated
and agencies • a pharmacovigilance responsible person is per-
manently and continuously at their disposal in
It initially operated as a pilot from 2011–2014, and its the EU
work continues in three main areas:
• Quality Working Group (formerly known Member States should take all appropriate measures to
as the ASMF/DMF Working Group)—The encourage doctors and other healthcare professionals
QWG are developing guidance on compiling to report suspected adverse reactions to the competent
the ASMF assessment report as well as look- authorities.
ing at ways to share information on ASMF/ Member States may impose specific requirements
DMF evaluations. on doctors and other healthcare professionals regard-
• Bioequivalence Working Group (for- ing reporting suspected serious or unexpected adverse
merly known as the Biowaivers Working reactions.

To ensure appropriate and harmonised regulatory (PRAC), Committee for Medicinal Products for
decisions concerning medicinal products authorised Human Use (CHMP) or CMDh.
within the Community regarding information obtained PRAC is the EMA committee responsible for
about adverse reactions to medicinal products under assessing and monitoring human medicines’ safety. It
normal conditions of use are adopted, Member States is responsible for assessing all aspects of human medi-
operate a pharmacovigilance system. This system is used cines’ risk management, including detecting, assessing,
to collect useful medicinal product surveillance infor- minimising and communicating the risk of adverse
mation, with particular reference to adverse reactions in reactions, while taking the medicine’s therapeutic effect
humans, and to evaluate such information scientifically. into account. PRAC also evaluates postauthorisation
Member States should ensure suitable informa- safety study design and evaluation and is responsible for
tion collected within this system is communicated to pharmacovigilance audits.
other Member States and EMA. The information must PRAC provides recommendations on pharma-
be recorded in the database and be accessible to all covigilance and risk management system questions,
Member States and the public. including monitoring their effectiveness, to CHMP for
This system also takes into account: centrally authorised medicines and referral procedures,
• any available information on misuse and abuse to CMDh on the use of a medicine in Member States,
of medicinal products that may impact evalua- and to the EMA secretariat, management board and
tion of their benefits and risks European Commission, as applicable.
• preparation of reports for the competent
authorities, in such form as those authorities Pharmacovigilance System Master File (PSMF)
may require MAHs now are required to maintain a PSMF related
• ensuring any competent authority request for to one or more products. The PSMF should be per-
additional information necessary to evaluate manently available for submission or inspection by the
a medicinal product’s benefits and risks is national competent authority within seven days of a
answered fully and promptly request. It should be located at either the EU site where
• providing any other information relevant to the MAH’s main pharmacovigilance activities are per-
the evaluation of a medicinal product’s benefits formed or at the EU site where the qualified person for
and risks to the competent authorities pharmacovigilance (QPPV) operates. This file also may
be stored in electronic form (Guideline on good pharma-
The pharmacovigilance legislation came into effect in covigilance practices (GVP), Module II—Pharmacovigilance
2012 and represented the biggest change to the reg- system master file (EMA/816573/2011 Rev. 2*).22
ulation of human medicines in the EU since 1995.
Directive 2012/26/EU and Regulation (EU) No. Risk Management Plan (RMP)
1027/2012) implemented amendments to the pharma- The RMP is a standalone document summarising what
covigilance legislation.19-21 is known about the product’s safety and discussing how
the applicant or MAH will monitor and investigate the
Handling Pharmacovigilance Information product’s safety profile and manage its associated risks.
The Incident Management Plan, in operation since All applicants submitting an initial MAA are
2009, aims to ensure concerned bodies in the EU take required to submit an RMP in the application dossier.
appropriate action whenever incidents (new events or An RMP (or an update if one exists already) also is
information) arise concerning human medicines. It required if there is an application involving a significant
covers medicines authorised centrally, nationally and change to an existing MA or at the request of EMA or
through the Decentralised and Mutual Recognition a national competent authority. Any product RMP must
Procedures. It is composed of representatives from be updated throughout the product’s lifecycle. RMP
EMA, the European Commission and medicines reg- summaries will be made public by EMA (Guideline on
ulatory authorities in the EU Member States. The plan good pharmacovigilance practices (GVP) Module V—Risk
entails the continuous monitoring of incidents that may management systems (EMA/838713/2011 Rev. 2*).23
have a serious impact on public health. Although inci-
dents may relate to quality, safety or efficacy concerns, Periodic Safety Update Reports (PSURs)
they usually involve issues related to pharmacovigilance, PSURs are reports providing an evaluation of a medi-
such as a new safety hazard. Its actions encompass both cine’s benefit-risk balance. EMA maintains a list of EU
proactive and reactive elements and it works alongside reference dates (EURDs) and frequency of PSUR sub-
the Pharmacovigilance Risk Assessment Committee missions for active substances contained in medicines in

Chapter 29
the EU. The EURD list includes the active substances • specify the medicinal products and pharma-
and combinations of active substances contained in med- ceutical forms to be manufactured or imported
icines subject to different marketing authorisations and and the place where they are to be manufac-
authorised in more than one Member State, together tured and/or controlled
with the corresponding EU reference dates, frequencies • have at its disposal, for the manufacture or
for PSUR submissions and related data lock points. import of the above, suitable and sufficient
The EU reference date refers to the date (or alter- premises, technical equipment and control
natively the earliest of the known dates) of the first facilities complying with the legal require-
marketing authorisation of a medicine containing that ments the concerned Member State lays down
active substance or that combination of active sub- regarding manufacture and control and medic-
stances in the EU. inal product storage
The PSUR frequency and related data lock points • have at its disposal the services of at least one
for a given active substance or combination of active qualified person
substances in the EURD came into effect in 2013 and
supersede the submission schedule described in Article The Member States must take all appropriate measures
107c (2) of Directive 2010/84/EU and any conditions to ensure the time taken to assess the manufacturing
related to the frequency of PSUR submission included authorisation procedure does not exceed 90 days from
in the marketing authorisation.24 the day on which the competent authority receives the
The EURD enables the harmonisation of data application.
lock points and frequency of PSUR submissions for
medicines containing the same active substances or Labelling and Package Leaflet
combinations of active substances and thus facilitates The SmPC and the package leaflet (PL) form an
the single assessment of related PSURs to take place. intrinsic part of the authorisation process for medicinal
MAHs are required to submit PSURs according products in the EU. The general principles to follow
to the dates published in the EURD list. A single for the preparation of the SmPC for a generic, hybrid
PSUR assessment procedure, with a recommendation or biosimilar medicinal product to be authorised via
from EMA’s PRAC, has been introduced for medicinal the Centralised Procedure using a reference medicinal
products authorised in more than one Member State product authorised either at national level or centrally
(i.e., products authorised through Centralised, Mutual are outlined in the guideline, QRD general principles
Recognition or Decentralised Procedures) and for regarding the SmPC information for a generic/hybrid/
products subject to various national MAs and contain- biosimilar product (EMA/627621/2011 Rev. 1).25 The
ing the same active substance or combination of active SmPC content has to be consistent with the reference
substances for which EU PSUR submission dates and medicinal product for the common information appli-
frequency have been harmonised. This approach is pro- cable to the generic or biosimilar product.
portionate to medicinal products’ risks. Thus, routine The current QRD template and the SmPC
PSUR reporting no longer is necessary for low-risk guideline should be applied to the generic, hybrid or
products or established products (such as generics) biosimilar SmPC, labelling and package leaflet as far as
unless it is a condition in the MA or requested by the possible, if the relevant information is available.
Competent Authority. The following information must appear on the
medicinal product’s outer packaging or, where there is
Manufacture and Importation no outer packaging, on the immediate packaging:
Member States should take all appropriate measures to • the medicinal product’s name followed by
ensure medicinal products manufactured within their its strength and pharmaceutical form, and
territory are subject to an authorisation. This manu- whether it is intended for babies, children or
facturing authorisation shall be required even if the adults; where the product contains up to three
medicinal products are intended for export. active substances, the international non-pro-
However, such authorisation is not required for prietary name (INN) must be included or, if
preparation, dividing up, changes in packaging or pre- one does not exist, the common name
sentation where these processes are carried out, solely • a statement of the active substances expressed
for retail supply, by pharmacists in dispensing phar- qualitatively and quantitatively per dosage unit
macies or by persons legally authorised in the Member or according to the form of administration for
States to carry out such processes. a given volume or weight, using their common
To obtain manufacturing authorisation, the appli- names
cant must meet at least the following requirements:

• the pharmaceutical form and the contents by • suitable and adequate premises, installations
weight, by volume or by number of product and equipment, to ensure proper medicinal
doses product conservation and distribution
• a list of those excipients known to have a • staff, in particular, a responsible qualified per-
recognised action or effect (If the product is son meeting the conditions set by the Member
injectable, or a topical or eye preparation, all State’s legislation
excipients must be stated.)
• method of administration and, if necessary, the Advertising
route of administration ‘Advertising of medicinal products’ includes any form
• a special warning the medicinal product must of door-to-door information, canvassing activity or
be stored out of the reach and sight of children inducement to promote the prescription, supply, sale or
• a special warning, if necessary, for the medici- consumption of medicinal products.
nal product • Member States must prohibit advertising to
• the expiry date in clear terms (month/year) the general public of medicinal products that:
• special storage precautions, if any o are available by medical prescription only
• specific precautions relating to the disposal of o contain substances defined as psychotropic
unused medicinal products or waste derived or narcotic
from medicinal products • Medicinal products that, by virtue of their
• the MAH name and address and, where appli- composition and purpose, are intended and
cable, the name of the MAH representative designed for use without a medical practi-
• the authorisation number allowing the medici- tioner’s intervention for diagnostic purposes, a
nal product to be placed on the market prescription or treatment monitoring, with the
• the manufacturer’s batch number advice of the pharmacist, if necessary, may be
• for non-prescription medicinal products, advertised.
instructions for use • Member States may ban, on their territory,
advertising to the general public of medic-
Wholesale Distribution of Medicinal inal products for which the cost may be
Products reimbursed.
Good distribution practice (GDP) describes the mini- • An advertising prohibition cannot apply to
mum standards that a wholesale distributor must meet vaccination campaigns carried out by the
to ensure that the quality and integrity of medicines is industry and approved by Member State’s
maintained throughout the supply chain.26 competent authorities.
1. Member States must take all appropriate • Member States must prohibit the direct indus-
action to ensure only medicinal products with try distribution of medicinal products to the
a Community MA are distributed on their public for promotional purposes.
territory.
2. For wholesale distribution and storage, medic- Good Pharmaceutical Practices
inal products must be covered by an MA Good Manufacturing Practice (GMP)
granted pursuant to Regulation (EC) No. GMP is defined as the part of quality assurance that
726/2004 or by a Member State’s competent ensures products are produced and controlled consistently
authority in accordance with this directive. to the quality standards appropriate to their intended
3. Any distributor not the MAH, that imports use. GMP principles and guidelines are laid out in
a product from another Member State, must Commission Directive 2003/94/EC of 8 October 2003
notify the MAH and competent authority in laying down the principles and guidelines of good man-
the Member State into which the product will ufacturing practice in respect of medicinal products for
be imported of its intention to import it. human use and investigational medicinal products for
human use.27 Compliance with these principles and guide-
Member States must ensure the time taken to assess the lines is mandatory within the European Economic Area.
distribution authorisation application does not exceed Following a site inspection demonstrating the
90 days from the day on which the Member State com- manufacturer complies with the GMP principles
petent authority concerned receives the application. identified in Community legislation, a certificate of
To obtain distribution authorisation, applicants good manufacturing practice is issued. The Member
must fulfil, at minimum, the following: State national competent authority that performs the

Chapter 29
inspection enters the GMP certificate information into Electronic Submission of Medicinal Product
EudraGMDP. If the inspection finds the manufacturer Information
does not comply with the GMP principles, that infor- MAHs are required to submit information on all med-
mation also is entered into EudraGMDP. icines authorised or registered in the EU pursuant to
MAHs are obliged to comply with GMP require- Regulation (EC) 726/2004 to EMA electronically.
ments for medicinal products and to use only active Required data are:
substances manufactured in accordance with GMP • medicinal product’s (invented) name
guidelines. • MAH details—name and address
• MA details and status
Good Distribution Practice (GDP) • pharmacodynamic properties—medicinal
Wholesale distribution of medicinal products is an product’s ATC code(s)
important activity in integrated supply chain manage- • therapeutic indication(s) description—medical
ment. GDP should be implemented through a quality concepts coded in MedDRA
system operated by the distributor or wholesaler. • qualitative and quantitative composition
GDP’s aim is to ensure authorised medicines’ quality • pharmaceutical form(s)
level, determined by GMP, is maintained throughout • excipient(s) description
distribution to retail pharmacists and others selling • medical device(s) description for combined
medicines to the general public. The quality system also advanced therapy medicinal product
should ensure the right products are delivered to the • posology and method or route(s) of
right addressee within a satisfactory time period. administration
• whether the medicinal product is authorised
Good Clinical Practice (GCP) for the treatment of children
GCP for human medicinal products is an international • electronic copy of the latest approved SmPC
ethical and scientific quality standard for designing, • QPPV name, address and contact details
recording and reporting trials involving human subjects. • contact email and phone number for pharma-
Compliance with this standard provides public assurance covigilance enquiries (Only pharmacovigilance
trial subjects’ rights, safety and well-being are pro- enquiry contact information (email and phone)
tected, consistent with the principles originating in the will be made public by EMA.)
Declaration of Helsinki, and clinical trial data are credible.
Clinical trials included in any EU MAA legally are Supervision and Sanctions
required to be conducted in accordance with GCP. The relevant Member State’s competent authority must
ensure—via repeated inspections and (if necessary)
Good Laboratory Practice (GLP) unannounced inspections and, where appropriate, by
GLP defines a set of rules and criteria for a quality requesting an Official Medicines Control Laboratory or
system concerned with the nonclinical organisational laboratory designated for that purpose to carry out tests
process and conditions under which nonclinical studies on samples—compliance with legal requirements gov-
are planned, performed, monitored, recorded, reported erning medicinal products.
and archived. Detailed GLP information can be found The competent authority also may conduct unan-
on the Organisation for Economic Co-operation and nounced inspections of the premises of manufacturers
Development (OECD) and European Commission of active substances used as starting materials or MAHs
websites. For human products, Directive 2001/83/EC if there are grounds for suspecting noncompliance with
indicates safety tests reported in MAAs should be per- GMP principles and guidelines. These inspections also
formed in compliance with GLP principles. may be conducted at the request of a Member State, the
Commission or EMA.
Good Pharmacovigilance Practices (GVPs) • Member States must take all appropriate steps
GVPs apply to MAHs, EMA and EU Member States’ to ensure product manufacturing processes are
competent authorities. They cover centrally authorised validated properly and attain batch-to-batch
medicines and those authorised at national level. consistency.
• After every inspection, competent authority
officials must report on the manufactur-
er’s compliance with GMP principles and
guidelines.

• Without prejudice to any arrangements • The MAH must ensure a risk management
among the Community and third countries, a plan is in place to investigate drug product
Member State, the Commission or EMA may safety issues and manage associated risks.
require a third-country manufacturer to submit • The MAH must follow GMP principles and
to an inspection. guidelines to ensure products are produced and
• Within 90 days of an inspection, a GMP controlled consistently to meet quality stan-
certificate must be issued if the inspection dards appropriate to their intended use.
demonstrated manufacturer compliance with • The relevant Member State competent
GMP principles and guidelines in Community authority must ensure, by means of repeated
legislation. inspections and, if necessary, unannounced
• Member States must enter issued GMP cer- inspections, compliance with legal require-
tificates into a Community database managed ments governing medicinal products.
by EMA.
References
1. Directive 2001/83/EC of the European Parliament and of the
Conclusions Council of 6 November 2001 on the Community code relat-
• Generic medicines usually are intended to be ing to medicinal products for human use. EC website. https://
interchangeable with an innovator reference ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/
dir_2001_83_consol_2012/dir_2001_83_cons_2012_en.pdf.
medicinal product, manufactured without a Accessed 21 April 2020.
license from the innovator company and mar- 2. Regulation (EC) No. 726/2004 of the European Parliament and
keted after the expiry of the patent or other of the Council of 31 March 2004 laying down Union procedures
exclusive rights. for the authorisation and supervision of medicinal products
for human and veterinary use and establishing a European
• The main principle underpinning generic Medicines Agency. EUR-Lex website. https://eur-lex.europa.eu/
medicines’ safe and effective use is the con- legal-content/EN/TXT/?uri=CELEX:02004R0726-20190128.
cept of bioequivalence. Bioequivalence studies Accessed 21 April 2020.
establish equivalence between the generic and 3. Questions and Answers on Generic Medicines
(EMA/393905/2006 Rev. 2). EMA website. http://www.
originator medicinal products to allow bridg- ema.europa.eu/docs/en_GB/document_library/Medicine_
ing the originator product’s preclinical and QA/2009/11/WC500012382.pdf. Accessed 24 April 2020.
clinical testing. 4. Guideline on the investigation on bioequivalence (CPMP/EWP/
• A generics company can use an abridged regis- QWP/1401/98 Rev. 1/Corr**). EMA website. https://www.ema.
europa.eu/en/documents/scientific-guideline/guideline-investi-
tration procedure and conduct bioequivalence gation-bioequivalence-rev1_en.pdf. Accessed 21 April 2020.
studies to prove its product is therapeutically 5. Notice to Applicants, Volume 2B—Medicinal products for human use.
equivalent to the branded drug. EC website. https://ec.europa.eu/health//sites/health/files/files/
• A pharmaceutical product’s EU MA is eudralex/vol-2/b/update_200805/ctd_05-2008_en.pdf. Accessed
21 April 2020.
complex, since each Member State has its 6. Biosimilar Medicines: Overview. EMA website. https://www.
own competent authority in addition to ema.europa.eu/en/human-regulatory/overview/biosimilar-medi-
EMA, which oversees EU-wide medicines’ cines-overview. Accessed 24 April 2020.
authorisations. 7. Op cit 5.
8. Guideline on the use of starting materials and intermediates collected
• Four generic MA routes result in the issue of from different sources in the manufacturing of non-recombinant bio-
three authorisation types: a National Procedure logical medicinal products (EMA/CHMP/BWP/429241/2013).
(for a single Member State); the Mutual EMA website. https://www.ema.europa.eu/en/documents/
Recognised or Decentralised Procedure (for scientific-guideline/guideline-use-starting-materials-interme-
diates-collected-different-sources-manufacturing-non_en.pdf.
multiple Member States); and the Centralised Accessed 21 April 2020.
Procedure for a pan-EU authorisation. 9. Guideline on the Chemistry of New Active Substances
• Generic or similar biological medicinal prod- (EMA/454576/2016). EMA website. http://www.ema.
ucts, once authorised, can be placed on the europa.eu/docs/en_GB/document_library/Scientific_guide-
line/2009/09/WC500002815.pdf. Accessed 21 April 2020.
market only 10 to 11 years after the reference 10. ICH Guideline Q8 (R2) on pharmaceutical development
medicinal product’s authorisation, depending (EMA/CHMP/ICH/167068/2004). EMA website. https://
on the reference medicinal product’s applicable www.ema.europa.eu/en/documents/scientific-guideline/
exclusivity period. international-conference-harmonisation-technical-require-
ments-registration-pharmaceuticals-human-use_en-19.pdf.
• The MAH must ensure an appropriate Accessed 21 April 2020.
pharmacovigilance system is in place and is 11. Guideline on Stability Testing: Stability Testing of Existing
recorded in a pharmacovigilance system master Active Substances and Related Finished Products (CPMP/
file to ensure authorised medicines’ continuous QWP/122/02 Rev. 1 corr. EMA website. https://www.
ema.europa.eu/en/documents/scientific-guideline/
monitoring and supervision.

Chapter 29
guideline-stability-testing-stability-testing-existing-active-sub- legal-content/EN/TXT/?uri=CELEX:32012R1027. Accessed

stances-related-finished-products_en.pdf. Accessed 21 April 21 April 2020.
2020. 21. Guidelines on good pharmacovigilance practices (GVP)
12. Guideline on Active Substance Master File Procedure (CPMP/ (EMA/757334/2013). EMA website. https://www.ema.
QWP/227/02 Rev. 4). EMA website. https://www.ema.europa. europa.eu/en/documents/regulatory-procedural-guideline/
eu/en/documents/report/final-guideline-active-substance-mas- guidelines-good-pharmacovigilance-practices-gvp-introducto-
ter-file-procedure-revision-4_en.pdf. Accessed 21 April 2020. ry-cover-note-last-updated-chapter-piii_en.pdf. Accessed 21
13. Guideline on Pharmaceutical Development of Medicines for April 2020.
Paediatric Use (EMA/CHMP/QWP/805880/2012 Rev. 2). 22. Guideline on good pharmacovigilance practices (GVP)
EMA website. https://www.ema.europa.eu/en/documents/ Module II—Pharmacovigilance system master file
scientific-guideline/guideline-pharmaceutical-develop- (EMA/816573/2011 Rev 2*). EMA website. https://
ment-medicines-paediatric-use_en.pdf. Accessed 24 April 2020. www.ema.europa.eu/en/documents/scientific-guideline/
14. Guideline on the investigation of bioequivalence —- Appendix I guideline-good-pharmacovigilance-practices-module-ii-phar-
(CPMP/EWP/QWP/1401/98 Rev. 1/ Corr **). EMA website macovigilance-system-master-file-rev-2_en.pdf. Accessed 21
https://www.ema.europa.eu/en/documents/scientific-guideline/ April 2020.
guideline-investigation-bioequivalence-rev1_en.pdf. Accessed 23. Guideline on good pharmacovigilance practices (GVP) Module
24 April 2020. V—Risk management systems (EMA/838713/2011 Rev. 2*).
15. Ibid. EMA website. https://www.ema.europa.eu/en/documents/
16. Guideline on the sterilisation of the medicinal product, active scientific-guideline/guideline-good-pharmacovigilance-practic-
substance, excipient and primary container (EMA/CPMP/ es-module-v-risk-management-systems-rev-2_en.pdf. Accessed
CVMP/QWP/850374/2015). EMA website. https:// 21 April 2020.
www.ema.europa.eu/en/documents/scientific-guideline/ 24. Directive 2010/84/EU of the European Parliament and of
guideline-sterilisation-medicinal-product-active-substance-ex- the Council of 15 December 2010 amending, as regards phar-
cipient-primary-container_en.pdf. Accessed 21 April 2020. macovigilance, Directive 2001/83/EC on the Community
17. Guideline on process validation for finished prod- code relating to medicinal products for human use Text with
ucts—information and data to be provided in EEA relevance. EUR-Lex website. https://eur-lex.europa.eu/
regulatory submissions (EMA/CHMP/CVMP/QWP/ legal-content/EN/TXT/?uri=CELEX:32010L0084. Accessed
BWP/70278/2012-Rev. 1, Corr.1). EMA website. https:// 21 April 2020.
www.ema.europa.eu/en/documents/scientific-guideline/ 25. QRD general principles regarding the SmPC information
guideline-process-validation-finished-products-information-da- for a generic/hybrid/biosimilar product (EMA/627621/2011
ta-be-provided-regulatory-submissions_en.pdf. Accessed 21 Rev. 1). EMA website. https://www.ema.europa.
April 2020. eu/en/documents/regulatory-procedural-guideline/
18. Note for guidance on minimising the risk of transmitting animal quality-review-documents-general-principles-regarding-sum-
spongiform encephalopathy agents via human and veterinary medic- mary-product-characteristics-information/hybrid/
inal products (EMA/410/01 Rev. 3). EMA website. https:// biosimilar-product_en.pdf. Accessed 21 April 2020.
www.ema.europa.eu/en/documents/scientific-guideline/ 26. Guidelines of 19 March 2015 on principles of Good
minimising-risk-transmitting-animal-spongiform-encephalop- Distribution Practice of active substance for medicinal
athy-agents-human-veterinary-medicinal_en.pdf. Accessed 21 products for human use. (2015/C 95/01). EUR-Lex web-
April 2020. site. https://eur-lex.europa.eu/legal-content/EN/TXT/
19. Directive 2012/26/EU of the European Parliament and of the PDF/?uri=CELEX:52015XC0321(01)&from=EN. Accessed 21
Council of 25 October 2012 amending Directive 2001/83/ April 2020.
EC as regards pharmacovigilance Text with EEA relevance. 27. Commission Directive 2003/94/EC of 8 October 2003 laying
EUR-Lex website. https://eur-lex.europa.eu/legal-content/EN/ down the principles and guidelines of good manufacturing
TXT/?uri=CELEX:32012L0026. Accessed 21 April 2020. practice in respect of medicinal products for human use and
20. Regulation (EU) No. 1027/2012 of the European Parliament investigational medicinal products for human use. EC website.
and of the Council of 25 October 2012 amending Regulation http://ec.europa.eu/health/files/eudralex/vol-1/dir_2003_94/
(EC) No. 726/2004 as regards pharmacovigilance Text with dir_2003_94_en.pdf. Accessed 21 April 2020.
EEA relevance. EUR-Lex website. https://eur-lex.europa.eu/

Chapter 30
Biosimilar Medicinal
Products
OBJECTIVES 2001 on the Community code relating to medici-

nal products for human use, as amended
□ Define biologicals, biosimilar and reference
medicinal products □ Directive 2004/27/EC of the European
Parliament and of the Council of 31 March
□ Understand the development complexities for 2004 amending Directive 2001/83/EC on the
biosimilar medicinal products Community code relating to medicinal products
for human use
□ Understand the comparability exercise for bio-
similar medicinal products □ Guideline on similar biological medicinal prod-
ucts (CHMP/437/04 Rev. 1), 23 October 2014
□ Understand the EU regulatory process for regis-
tering biosimilar products □ Guideline on similar biological medicinal prod-
ucts containing biotechnology-derived proteins
□ Understand the EU regulatory processes for
as active substance: quality issues (Revision 1)
postapproval lifecycle management of biotech-
(CHMP/BWP/247713/2012), 22 May 2014
nology-derived products
□ Guideline on similar biological medicinal prod-
ucts containing biotechnology-derived proteins
DIRECTIVES, REGULATIONS AND GUIDELINES as active substance: nonclinical and clinical
COVERED IN THIS CHAPTER issues (Revision 1) (CHMP/BMWP/42832/2005,
18 December 2014)
laying down Community procedures for the Introduction
authorisation and supervision of medicinal According to Part I of Annex I of Directive 2001/83/
products for human and veterinary use and EC, a biological medicinal product is a product that
establishing a European Medicines Agency, as contains a biological substance. A biological substance
amended is a substance that is produced by or extracted from a
biological source and that needs for its characterisation
and the determination of its quality a combination of
physio-chemical-biological testing together with the
2007 on advanced therapy medicinal prod-
production process and its control. Recombinant pro-
ucts and amending Directive 2001/83/EC and
teins, monoclonal antibodies, medicinal products derived
Regulation (EC) No. 726/2004, as amended
from human blood and plasma, immunological medic-
□ Directive 2001/83/EC of the European inal products and advanced therapy medicinal products
Parliament and of the Council of 6 November are all considered biological medicinal products.

Chapter 30
Biotechnology-derived medicinal products are the concerned products. This includes comprehensive
biological products developed via one of the following physicochemical and biological characterisation and
biotechnological processes: comparison and requires an understanding of how to
• recombinant DNA technology interpret any differences between a biosimilar and its
• controlled expression of gene coding for bio- reference medicinal product.
logically active proteins in prokaryotes and Biosimilarity cannot be shown using the generic
eukaryotes, including transformed mammalian medicinal product approach, which is a demonstration
cells of bioequivalence with a reference medicinal product
• hybridoma and monoclonal antibody methods1 using bioavailability studies. This type of testing is only
applicable to chemically derived medicinal products.
A similar biological medicinal product or biosimilar is a The basic principle underlying the development of
biological medicinal product that contains a version of a biosimilar product is comparability with the reference
active substance of an already authorised (in the EEA) medicinal product. The biosimilar approach is one based
original biological medicinal product (reference medic- on a comprehensive comparability exercise. That compa-
inal product). A biosimilar demonstrates similarity to rability exercise applies scientific principles to examine
the reference medicinal product in terms of quality the quality, safety and efficacy of the biosimilar medic-
characteristics, biological activity, safety and efficacy, inal product against the reference medicinal product
based on a comprehensive comparability exercise.2 using a stepwise approach.
The reference medicinal product must be a medic- A biosimilar should be highly similar in phys-
inal product authorised in the EEA, on the basis of a iochemical and biological terms to the reference
complete dossier in accordance with the provisions of medicinal product. Therefore, development should start
Article 8 of Directive 2001/83/EC, as amended. with a thorough physiochemical and biological char-
The EU was the first region in the world to have a acterisation comparison between the biosimilar and
defined policy and legal framework for the approval of the reference medicinal product. If there are relevant
biosimilar products. The concept was first introduced differences between the biosimilar medicinal product
into EU legislation in 2003, and further developed with and the reference medicinal product, it is unlikely that
the adoption of the revised EU pharmaceutical legisla- biosimilarity can be established. The ultimate goal of the
tion in 2006.3 comprehensive comparability exercise is to show no or
The first biosimilar was approved and marketed in slight differences in the biosimilar and reference medic-
the EU in 2006. A large number of diverse biosimilars inal product.
are approved for use in the EU subsequent to relevant The scientific principles used in the comparability
patent expiration of the reference medicinal products, exercise are rooted in analysing the impact of changes in
thereby providing cost-effective treatment options to the biological medicinal product’s manufacturing pro-
physicians and patients in comparison to higher-priced cess. Biosimilar medicinal product quality is defined by
innovator biologic medicines. High-quality biosimilar the production and manufacturing process, which must
medicines approved under the EU’s extensive regulatory conform fully to good manufacturing practice (GMP)
assessment process provide a major opportunity to help requirements; therefore, even minor process changes
governments control biopharmaceutical medicines’ cost could affect product quality. Collecting and evaluating rel-
and availability. For example, if biosimilar medicines evant data can determine whether manufacturing process
are used as an alternative to the top seven conventional changes result in an adverse impact to the biosimilar..
biopharmaceuticals within the EU, they could provide A demonstration of comparability does not mean
a 20% price reduction compared to the innovator ref- the quality attributes of the pre-change and post-
erence medicinal products, resulting in savings of more change are identical, but that they are highly similar
than €1.6 billion per year.4 and that existing knowledge is sufficiently predictive
to ensure differences have no impact on the biosimilar
Development of Biosimilar Medicinal medicinal product’s safety or efficacy. The determina-
Products tion of comparability can be based on a combination of
The concept of biosimilarity is applicable to any bio- analytical testing, biological assays, and in some cases,
logical medicinal product. However, in practice, the nonclinical and clinical data. If comparability can be
success of developing a biosimilar will depend on the demonstrated with analytical studies alone, post-change
manufacturer’s ability to produce a medicinal prod- nonclinical and clinical studies are not needed. If there
uct that is similar to the reference medicinal product, is a relationship between specific quality attributes for
and to convincingly demonstrate the similar nature of which safety and efficacy have not been established,
and differences are observed between pre-change and

Biosimilar Medicinal Products
post-change product, it may be appropriate to include a from a number of comparative in vitro studies, some
combination of quality, nonclinical and/or clinical stud- of which may be available already from quality-related
ies in the comparability exercise.5 assays, normally should be provided. These studies should
Additionally, to identify the impact of a manufac- include relevant assays of receptor-binding studies, signal
turing process changes, all foreseeable consequences transduction and functional activity/viability of relevant
should be evaluated against appropriate defined criteria. cells for the reference product’s pharmaco-toxicological
Quality data are generated on the pre-and post-change effects. These studies should be comparative in nature
products, and a comparison is performed that integrates and scientifically valid, sensitive, specific and sufficiently
all collected data (e.g., routine batch analyses, in-process discriminatory, providing evidence that observed dif-
control, process validation/evaluation data, character- ferences in quality attributes are not clinically relevant.
istics and stability), if appropriate. A comparison of These studies should compare the concentration-activity/
results allows for an objective assessment of whether the binding relationship of the biosimilar and the reference
pre- and post-change product are comparable. These medicinal product at the pharmacological target(s), cov-
manufacturing (quality) comparison exercises can be ering a concentration range where potential differences
adopted for use with the biosimilar medicinal product are most sensitively detected.6
and the reference medicinal product. Due to the potential likelihood of mediating in vivo
Similar to quality programme comparability effects that may not be assessed fully through the in vitro
exercises, preclinical (or nonclinical) and clinical pro- comparability exercise, a proposed biosimilar product’s
grammes for biosimilar medicinal product development preclinical development programme usually requires an
should be designed to assess the safety, tolerance, abbreviated comparability assessment of in vivo animal
immunogenicity potential, clinical efficacy and lack of studies, as required by EU guidelines, such as repeat-
any clinically meaningful differences, compared to the dose toxicity studies and pharmacokinetic (PK) and
reference medicinal product. The biosimilar development pharmacodynamic (PD) studies in an appropriate ani-
scheme can be seen in Figure 30-1 and Figure 30-2. mal model, together with local tolerance testing. PK/PD
An appropriate preclinical study programme design parameters for these studies, as well as the predefined
for a proposed biosimilar requires a clear understanding similarity level of these parameters, need to be justified
of the reference product’s characteristics. Results from scientifically to support comparability with the reference
the physicochemical and biological characterisation product. Safety concerns may arise from the product
studies (i.e., the proposed biosimilar’s comparability to itself and/or from impurity or contaminant presence.
the reference product) should be reviewed for potential Cellular host contaminants may result in allergic reac-
impact on efficacy and safety and a stepwise approach tions and other immuno-pathological effects. The aim of
determined for initial in vitro assessment followed by these studies should be to further support comparability
in vivo assessment in animals. To assess any potential or detect potential differences between the biosimilar
difference in biological activity between the proposed and the reference medicinal product in suitable animal
biosimilar and the reference medicinal product, data models. If no relevant animal model is available in which
Figure 30-1. Biosimilar Development
Comparative clinical studies

Step 3
• Pharmacokinetic/pharmacodynamic
• Efficacy + safety + immunogenicity
Comparative non-clinical studies

Step 2
• Pharmacodynamic
• Toxicology
Comparative quality studies

Step 1
• Analytical: physical + chemical properties

• Functional: biological/pharmacological activity
Reference medicine Biosimilar medicine

Chapter 30
Figure 30-2. Stages of Development of a Biosimilar Medicine
Confirm comparability
Complete product and between biosimilar
Define and characterize
process development of medicine and the
the reference product
the biosimilar medicine reference product
QUALITY NONCLINICAL CLINICAL

Physiochemical Mulitiple in vitro Comparative pharmacokinetic/
characterization studies, in vivo studies pharmacodynamic, efficacy
Biological characterization in exceptional cases and safety studies as required
the test material is pharmacologically active due to only in small quantities and may be expensive in early
receptor or epitope expression, use of transgenic animals development phases.
expressing the human receptor, gene knockout animal Clinical testing for a proposed biosimilar is not
models or homologous proteins should be considered. required to the same extent as for a new active sub-
When these models or proteins are not available, it still stance, due to clinical experience acquired from the
may be prudent to assess some potential toxicity aspects reference product’s use over many years. Clinical devel-
in limited toxicity evaluations, e.g., performing a repeat- opment programme design should be based on the
dose toxicity study of a few weeks’ duration, including biosimilar medicinal product profile and characteristics
an evaluation of important functional endpoints (e.g., and its intended use and also on how comparable the
cardiovascular and respiratory). proposed biosimilar’s profile is to that of the reference
As is the case for conventional products, biosimilar product. The closer the profile of the biosimilar is to
medicinal products used in pivotal preclinical pharma- that of the reference product, the greater the possibility
cology and toxicology studies should be comparable to of demonstrating similarity through appropriate studies,
products proposed for clinical studies. Toxicity studies e.g., comparative quality, biological and receptor-bind-
are expected to be performed in compliance with good ing assays, and testing in animals, and the more likely
laboratory practices (GLPs). the regulatory agency will accept an abbreviated clinical
Many biosimilar medicinal products that are trial programme. Therefore, if in-depth comparability
biotechnology-derived for human use are immuno- between the biosimilar and the reference product has
genic in animals, whether through binding antibodies, been demonstrated, the clinical experience gained with
neutralising antibodies and/or allergic reactions to the the reference product and its established efficacy and
intended medicinal product or one of its impurities safety profile can be considered. Abbreviated clinical
(cell substrates, media components, fragments, cell trials can eliminate unnecessary human testing and
aggregates). Antibody responses should be character- reduce the high development costs associated with clin-
ised (titre, number of responding animals, neutralising ical trials.
or non-neutralising), and their appearance should be The clinical comparability exercise, conducted in
correlated with any pharmacological or toxicological accordance with good clinical practices (GCPs), usually
changes. Antibody detection should not be the sole begins with PK and/or PD studies followed by compar-
criterion for early termination of a preclinical safety ative assessment of efficacy and safety in representative
study unless immune response neutralises the product’s patient populations for one or more indications. Besides
pharmacological and/or toxicological effects in a large comparative efficacy, an assessment of the comparable
proportion of animals. Immunogenicity and toxicoki- safety profile must be shown in terms of seriousness
netic data should be obtained after the first and last and frequency of different side-effects. Assessing com-
dose in repeat-dose studies. Local tolerance also must parable immunogenicity profiles for the biosimilar and
be determined, if applicable. A factor to consider when reference product also is very important and should be
designing a biosimilar medicinal product’s preclinical conducted within the biosimilar comparability exercise
development programme is the availability of test mate- using the same assay format and sampling schedule to
rial, since products of adequate quality may be available meet all current standards.6 Analytical assays should

be performed with both the reference and biosimilar therefore, immunogenicity from the studied indication/
molecules in parallel (in a blinded fashion) to mea- route of administration to other uses of the reference
sure immune response against the product received product should be justified.8 Figure 30-3 provides
by each patient. Preferably, analytical assays should a look at the development timeline for a biosimilar
be capable of detecting antibodies against both the medicine.
biosimilar and reference molecules but should be able
to detect all antibodies developed against the biosim- Registration of Biosimilar Medicinal
ilar molecule at minimum. The incidence and nature Products
(e.g., cross-reactivity, target epitopes and neutralising In the EU, marketing authorisation (MA) proce-
activity) of antibodies and antibody titres are usually dures, such as the Centralised Procedure (CP), Mutual
measured, presented, assessed and interpreted in relation Recognition Procedure (MRP) and Decentralised
to their potential effect on clinical efficacy and safety Procedure (DCP), are available to register a medici-
parameters.7 nal product (see Chapter 27). In February 1995, the
While the proposed biosimilar’s posology and route European Medicines Agency (EMA) made the CP
of administration must be the same as those of the compulsory for medicinal products manufactured using
reference medicinal product, any deviations from the biotechnological processes, for orphan medicinal products
reference medicinal product in drug strength, pharma- and for human products containing a new drug substance
ceutical form, formulation, excipients or presentation not authorised in the Community before 20 May 2004
require justification. If needed, additional data should (introduction date of Regulation (EC) No. 726/2004)
be provided. Any difference in these aspects should not and intended for treatment of AIDS, cancer, neurodegen-
compromise the proposed biosimilar product’s safety. erative disorder or diabetes. The CP allows for a single
In a well-developed comparable clinical assessment, if application, a single evaluation and a single authorisation,
biosimilarity of the proposed biosimilar and the refer- allowing direct access to the single EU market.
ence medicinal product has been demonstrated in one Regulation (EC) No. 726/2004, as amended,9-12
indication, extrapolation to other approved reference provides the legal basis for the CP and describes the
medicinal product indications could be acceptable marketing application and review processes specifically
with appropriate scientific justification. If it is unclear for medicinal products developed using biotechnologi-
whether the safety and efficacy confirmed in one indica- cal processes.
tion would be relevant for another indication, additional As mentioned above, biosimilar medicinal prod-
data would be required. Extrapolation is considered ucts developed via biotechnological processes must be
when evaluating the totality of data, i.e., quality, nonauthorised via the CP. The reference medicinal product
clinical and clinical data. could have been authorised via a National Procedure
Immunogenicity relates to a number of factors, (NP), MRP, DCP or CP. The CP has an optional scope
including the route of administration, dosing regi- per Regulation (EC) No. 726/2004, as amended, which
men, patient-related factors and disease-related factors is applicable to biosimilars when they do not fall into
(e.g., co-medication, type of disease, immune status). the mandatory scope of the regulation. In this case, the
Immunogenicity could differ among indications; applicant has two options for their biosimilar product:
Figure 30-3. Timeline for Development of a Biosimilar Medicine
1–1.5 years
Step 1: Developing equivalent host-cell clone
Step 2: Preparing cell banks clone

1–1.5 years
Step 3: Process Development
Fermentation Purification
Step 4: Manufacturing scale-up
3.5–4.5 years
Step 5: Comparability Testing, Analytical Characterisation,
Non-Clinical studies, Clinical studies
Years
0 1 2 3 4 5 6 7 8

Chapter 30
• If the reference medicinal product was autho- product. In addition, all general requirements—such
rised via the CP, the biosimilar has automatic as GLP, GCP, GMP and the need to have a manufac-
access to the CP. turing licence—apply equally to biosimilar medicinal
• If the reference medicinal product was autho- products. GMP inspections for all biopharmaceuticals
rised via the NP, MRP or DCP, the applicant (both reference and biosimilar medicines) are coordi-
can request consideration to be accepted under nated by EMA and performed by national competent
the CP if the applicant can show that the ref- authorities to determine whether the required man-
erence medicinal product constitutes: ufacturing conditions are in place. The data package
o a significant therapeutic, scientific or tech- requirements can be found in Table 30-1.
nical innovation or A fair number of guidelines describe specific
o the granting of a Union authorisation for production and testing requirements for various bio-
the reference medicinal product is in the similar medicinal products, especially those derived
interest of patients at the Union level from biotechnological processes. Many of these guide-
lines were developed by The International Council
EMA will consider whether a reference medicinal prod- for Harmonisation of Technical Requirements for
uct constitutes a significant therapeutic, scientific or Pharmaceuticals for Human Use (ICH) and are appli-
technical innovation if: cable in the EU, US and Japan, and in other countries
• the medicinal product provides a new alter- that recognise ICH. The biosimilar must meet the same
native to patients in treating, preventing or requirements and quality standards as the reference
diagnosing a disease or product. As mentioned above, slight differences must be
• the medicinal product development is based on scientifically justified.
significant new scientific knowledge or on the The preclinical and clinical sections should be in
application of a new scientific knowledge or accordance with ICH and EU-specific product guide-
• a new technology or a new application of lines and should include the comparative nonclinical
technology is used for the development or the data along with a summary of results from compara-
manufacture of the medicinal product tive clinical trials in healthy volunteers and patients.
Submission of immunogenicity data also is required.
An ‘eligibility request’ should always be submitted using In addition, a description of the pharmacovigilance
the correct form and accompanied by a justification of (PV) system and risk management plan (RMP), in
eligibility for evaluation under the CP. The eligibility accordance with current EU legislation and PV guide-
request is a presubmission request form, available on lines, must be included in registration dossier Module
the EMA website. A draft summary of product charac- 1. The RMP should consider identified and potential
teristics (SmPC) must be submitted with the eligibility risks associated with the use of the reference product
request form and the justification for eligibility.13 and should detail how these issues will be addressed
Before submitting an MAA, the applicant must in postmarketing follow-up. Immunogenicity should
ensure the protection period of the reference medicinal specifically be addressed in this context. Any specific
product has expired. This allows the applicant of the safety monitoring imposed on the reference medicinal
biosimilar to rely on the dossier of the reference medic- product or product class should be adequately addressed
inal product. The calculation to assess the protection in the biosimilar’s PV plan. Applicants are encouraged to
period expiration date can be found on the EMA web- participate in already existing pharmacoepidemiological
site’s biosimilar page. studies in place for the reference product. However, new
Six to 18 months prior to submission of the MAA, studies might have to be initiated. Risk minimisation
the applicant of a proposed biosimilar product should activities in place for the reference medicinal product
notify EMA with a ‘letter of intent to submit,’ and should, in principle, also be included in the biosimilar’s
request an appointment of a rapporteur and co-rap- risk management programme. Any deviations (e.g., when
porteur if preferred, based on the known reference the risk minimisation is linked to the device used with
product’s authorisation information. The eligibility the reference product) should be justified.30 The RMP
request can be submitted as part of the “letter of intent is published in the European Public Assessment Report
to submit.’ (EPAR) after the biosimilar’s authorisation and must
The MAA for a proposed biosimilar should contain be updated throughout the biosimilar’s lifecycle. Figure
a data package based on the requirements laid down 30-4 provides a schematic of the pillars of the compara-
in the appropriate scientific guidelines.14-29 Biosimilar tive exercise and requirements for marketing approval.
medicinal products must fulfil the same basic quality, Upon satisfactory acceptance of all MAA prod-
safety and efficacy criteria as any other pharmaceutical uct-related data, the biosimilar product will receive an

Figure 30-4. Biosimilar Product Development and Marketing Approval
REFERENCE PRODUCT
Quality Module
Target Physio-chemical Comparative
(own Product Comparative Risk Management
Definition and and Biological Nonclinical
and Process Clinical Studies Plan
Characterisation Comparability Studies
Development)
BIOSIMILAR DEVELOPMENT IS FUNDAMENTALLY COMPARATIVE
MA from the European Commission, allowing the conducted by CHMP and all submitted data in order to
sponsor to market the medicinal product in the EU; the substantiate their decisions. Of course, these practices
regulatory scientific data are published by EMA in the will vary from country to country and may take both
EPAR. Then, the approved product can be marketed scientific and reimbursement factors into account.31
in the 27 EU Member States. Additional information
on registration procedures and marketing authorisation Variations
can be found in Chapter 27 Registration Procedures A safety variation refers to safety issues, including those
for Medicinal Products and Chapter 32, Marketing related to quality issues, a change to the SmPC, package
Authorisations for Biotechnology-Derived Products. leaflet (PL) and/or labelling, that does not need to be
implemented via an urgent safety restriction (USR) but
Postapproval Lifecycle Management of should be implemented as soon as possible. A USR is
Biosimilars an urgent regulatory action instigated by the MAH of
Interchangeability a CP biosimilar or the European Commission in the
Interchangeability refers to the medical practice of event of, or to prevent, risk to public health.
changing one medicine for an equivalent medicine, If a centrally authorised biosimilar refers to a
in a given clinical setting on the initiative or with the centrally authorised reference medicinal product,
agreement of the prescriber. A medicinal product is EMA will provide the MAH of the biosimilar with
considered to be interchangeable if it can be admin- the exact wording to be implemented at the time of
istered or dispensed instead of another clinically the CHMP opinion on a safety variation for the ref-
equivalent product. The regulatory scientific data pub- erence medicinal product. The MAH of the biosimilar
lished via the EPAR, should guide prescribers’ decisions will need to submit a type IB variation as soon as pos-
on interchangeability. sible or at the latest within two months to implement
In the context of interchangeability, it should be the product information (PI) changes as adopted for the
noted that if a reference medicinal product’s company reference medicinal product.
changes the manufacturing process of an existing If the implementation of the change requires
product, interchangeability between the pre- and post- additional data to be submitted by the MAH of the
change products is accepted as long as the change is biosimilar (e.g., comparability exercise), a type II
supported by a package of comparability data that variation will be requested.
reviews the pre- and post-change product. The same For centrally authorised biosimilar products of
approach needs to be taken for biosimilar medicines nationally authorised reference medicinal products, EMA
based on comparability data with a reference product. will provide the MAH of the biosimilar with the exact
The decisions on interchangeability and/or substi- wording to be implemented after notification has been
tution is governed by national competent authorities made to the respective competent authority. The MAH
and are outside the remit of the EMA/CHMP. will need to submit a variation as soon as possible or at
Member States have access to the scientific evaluation

Chapter 30
Table 30-1. Data Package Required for a Marketing Authorisation Application to EMA
Quality Data The quality of the biosimilar medicinal product must meet the same requirements and stan-
dards as that of the reference product. The registration dossier includes all the necessary data
to establish the quality of the product, including:
• definitions and descriptions of the manufacturing process, and associated control tests
and standards
• data on the consistency of manufacturing (quality control of the process)
• data on analytical tests (molecular structure, potency and purity/impurity profile)
• data on stability of the product
In addition, the results of the comprehensive comparability exercise with the reference prod-
uct will be presented.
Nonclinical Data The registration dossier for a biosimilar medicinal product will usually include comparative
nonclinical data. The amount of nonclinical data required is specific to the product, and will be
determined on a case-by-case basis. The following nonclinical tests usually are included:
• a variety of in vitro studies
• in exceptional cases, pharmacokinetic/pharmacodynamic studies, including local toler-
ance testing in appropriate models
Clinical Data The registration dossier for a biosimilar medicinal product will usually
include clinical data, summarising the results of comparative clinical trials
conducted in healthy volunteers and in patients with the biosimilar product. For most bio-
similar medicines, extensive comparative trials have been conducted, often including several
hundreds of patients. Companies applying for a marketing authorisation must submit all trial
results, both positive and negative. Immunogenicity data are required.
Pharmacovigilance A Risk Management Plan (RMP), which is a detailed description of
the company’s risk management system, must be submitted with the
registration dossier. The RMP describes what is known about the safety of the medicine and
outlines how the manufacturer will further monitor and fill any potential or known gaps in
knowledge as well as any measures needed to prevent or minimise any potential risk of the
medicinal product. The RMP also includes the description of the routine pharmacovigilance
system, which requires the submission of Periodic Safety Update Reports (PSURs).
the latest within two months to implement the changes There are rare circumstances where changes related to
in the PI as adopted for the reference medicinal product. quality issues will require a change to the PI.
The EMA Secretariat shall handle and finalise Any change to a MA due to a USR requires that
‘administrative’ harmonisation between the reference healthcare professionals are informed as quickly as
and the biosimilar medicinal product.32 possible regarding the safety concern and the revised
Fees may be applicable and are listed in the pre-au- SmPC. The MAH will be required to prepare and
thorisation guidance on the EMA website.33 send a direct healthcare professional communication
(DHPC) (“Dear Doctor Letter”).34
Urgent Safety Restriction (USR)
As mentioned in the section above, a USR is imple- Pharmacovigilance (PV) and Safety Reporting
mented to protect public health. The outcome of a USR Pharmacovigilance is the science and activities relating
is an interim change to the PI based on new nonclinical to the detection, assessment, understanding and preven-
or clinical information related to the safe use of the tion of any adverse effects of medicinal products placed
biosimilar, concerning one or more of the following in on the market. All European pharmaceutical companies
the SmPC: are legally required to monitor the use and effects of
• indications all their medicines continuously. They must have sys-
• posology tems in place to collect, detect, assess, understand and
• contraindications and warnings communicate any adverse reactions or any other medi-
cine-related problem.

Once the medicines are marketed, companies must biotechnology-derived products are available for use by
prepare regular reports to review all available safety applicants developing biosimilar products. Additionally,
data. These are known as periodic safety update reports required information on the reference medicinal prod-
(PSUR). The purpose of these reports is to detect uct posted on the EMA website can be used by the
any change in the risk-benefit balance of a medicine. applicant to develop comparability exercises and sub-
Sometimes, additional postauthorisation safety studies stantiate biosimilarity.
(PASS) are also required. For adverse reaction (ADR) Biosimilar medicinal products must adhere to the
reports relating to all biopharmaceuticals, the definite same regulations and guidelines as other pharmaceutical
identification of the medicine with regard to its manu- products, including requirements for quality testing,
facturing is of particular importance. Therefore, for every nonclinical and clinical studies, and the development of
adverse reaction report of a biological medicine, EU leg- a pharmacovigilance system and risk management plan.
islation requires the name of the medicine and the batch All processes and data required for a marketing authori-
number to be included in the ADR report, so a suspected sation apply equally to biosimilar products.
adverse reaction can be linked to the correct medicine. The majority of biosimilar products will qualify
The EU pharmacovigilance legislation also has for the Centralised Procedure automatically, due to
foreseen that for all medicines with a new active the authorisation procedure of the reference medicinal
substance and all new biological medicinal products, product. The Centralised Procedure allows for a single
including new biosimilar medicines, a black symbol and marketing authorisation application, approval by EMA
a sentence inviting all adverse reactions to be reported and a single EU marketing license in all 27 Member
are to be added to the SmPC and the PL. EMA also States. Authorisation of biosimilar products allows for
is responsible for the development and maintenance of great cost savings to Member States and provides alter-
EudraVigilance,35 which is a data processing network natives for patients.
and management system for reporting and evaluating
suspected adverse reactions during the development References
1. Regulation (EC) No. 726/2004, as amended, of the European
stage and after marketing authorisation of medicinal Parliament and of the Council of 31 March 2004 laying down
products in the European Economic Area (EEA). Community procedures for the authorisation and supervision
Within EudraVigilance, adverse reactions that are of medicinal products for human and veterinary use and estab-
reported to EMA or the national competent authorities lishing a European Medicines Agency (Consolidated version 28
January 2019). EC website. https://ec.europa.eu/health/docu-
either by pharmaceutical companies, healthcare prac- ments/eudralex/vol-1_en. Accessed 22 April 2020.
titioners such as physicians, pharmacists or nurses, or 2. Guideline on similar biological medicinal products (CHMP/437/04
patients, or that are retrieved from worldwide scientific Rev. 1). 23 October 2014. EMA website. http://www.ema.
literature through active continuous screening, are col- europa.eu/docs/en_GB/document_library/Scientific_guide-
lated.36 Additional information on pharmacovigilance, 3. Directive 2001/83/EC of the European Parliament and of the
including the EudraVigilance system, can be found in Council of 6 November 2001 on the Community code relating
Chapter 34 Pharmacovigilance. to medicinal products for human use, as amended 21 July 2011.
EC website. https://ec.europa.eu/health/sites/health/files/
files/eudralex/vol-1/dir_2001_83_consol_2012/dir_2001_83_
Conclusion cons_2012_en.pdf. Accessed 22 April 2020.
The EU was the first region to provide a legal and 4. Biosimilar Medicines Handbook. Medicines for Europe website.
regulatory framework for similar biological medicinal http://www.medicinesforeurope.com/2016/04/25/biosimi-
lar-medicines-handbook-new-edition/. Accessed 22 April 2020.
products (biosimilars). Thus, the EU has a considerable 5. Comparability of biotechnological/Biological Products Subject
wealth of knowledge regarding biosimilar medicinal to Changes in Their Manufacturing Process Q5E, November
products, has developed a rigorous development and 2004. ICH website. https://database.ich.org/sites/default/files/
regulatory evaluation process and has authorised more Q5E_Guideline.pdf Accessed 22 April 2020.
6. Guideline on similar biological medicinal products containing bio-
than 55 biosimilar products according to the EPAR on technology-derived proteins as active substance: non-clinical and
the EMA website. clinical issues (Revision 1) (CHMP/BMWP/42832/2005). 18
Biosimilar medicinal products are biological prod- December 2014. EMA website. http://www.ema.europa.eu/
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WC500180219.pdf. Accessed 22 April 2020.
biological activity, safety and efficacy to the reference 7. Op cit 4.
biological products, as demonstrated through a detailed 8. Op cit 6.
stepwise comparability exercise of the biosimilar’s qual- 9. Op cit 1.
ity characterisation, preclinical testing, clinical safety 10. Regulation (EC) No. 1394/2007 of the European Parliament
and of the Council of 13 November 2007 on advanced therapy
and efficacy. Therefore, an approved biosimilar can be medicinal products and amending Directive 2001/83/EC and
very cost-effective, compared to the reference medicinal Regulation (EC) No. 726/2004. EC website. http://ec.europa.
product. A number of product-specific guidelines for

Chapter 30
eu/health/files/eudralex/vol-1/reg_2007_1394/reg_2007_1394_ Substance: Nonclinical and Clinical Issues; Guidance on Similar

en.pdf. Accessed 22 April 2020. Medicinal Products Containing Somatropin (EMEA/CHMP/
11. Op cit 3. BMWP/94528/2005). 22 February 2006. EMA website. http://
12. Directive No. 2004/27/EC of the European Parliament and www.ema.europa.eu/docs/en_GB/document_library/Scientific_
of the Council of 31 March 2004 amending Directive No. guideline/2009/09/WC500003956.pdf. Accessed 22 April 2020.
2001/83/EC on the Community code relating to medicinal 23. Guideline on nonclinical and clinical development of similar biolog-
products for human use. EC website. http://ec.europa.eu/health/ ical medicinal products containing recombinant human insulin and
files/eudralex/vol-1/dir_2004_27/dir_2004_27_en.pdf. Accessed insulin analogues (EMEA/CHMP/BMWP/32775/2005_Rev.
22 April 2020. 1). 26 February 2015. EMA website. http://www.ema.europa.eu/
13. Biosimilar medicines: marketing authorisation. EMA web- docs/en_GB/document_library/Scientific_guideline/2015/03/
site. https://www.ema.europa.eu/en/human-regulatory/ WC500184161.pdf. Accessed 22 April 2020.
marketing-authorisation/biosimilar-medicines-marketing-au- 24. Annex to Guideline on Similar Biological Medicinal Products
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14. Guideline on similar biological medicinal products containing Non-clinical and Clinical Issues; Guidance on Similar Medicinal
biotechnology-derived proteins as active substance: quality issues Products Containing Recombinant Human Soluble Insulin
(Revision 1) (CHMP/BWP/247713/2012), 22 May 2014. (EMEA/CHMP/BMWP/32775/2005). 22 February 2006.
EMA website. http://www.ema.europa.eu/docs/en_GB/docu- EMA website. http://www.ema.europa.eu/docs/en_GB/docu-
ment_library/Scientific_guideline/2014/06/WC500167838.pdf. ment_library/Scientific_guideline/2009/09/WC500003957.pdf.
15. Guideline on non-clinical and clinical development of similar 25. Guideline on immunogenicity assessment of monoclonal anti-
biological medicinal products containing recombinant human bodies intended for in vivo clinical use (EMA/CHMP/
follicle stimulating hormone (r-hFSH) (EMA/CHMP/ BMWP/86289/2010). 24 May 2012. EMA website. http://
BMWP/671292/2010). 21 February 2013. EMA website. www.ema.europa.eu/docs/en_GB/document_library/Scientific_
http://www.ema.europa.eu/docs/en_GB/document_library/ guideline/2012/06/WC500128688.pdf. Accessed 22 April 2020.
Scientific_guideline/2013/03/WC500139624.pdf. Accessed 22 26. Guideline on Comparability of Biotechnology-Derived Medicinal
April 2020. Products After a Change in the Manufacturing Process Nonclinical
16. Guideline on similar biological medicinal products containing and Clinical Issues (EMEA/CHMP/BMWP/101695/2006).
interferon beta (EMA/CHMP/BMWP/652000/2010). 21 19 July 2007. EMA website. http://www.ema.europa.eu/docs/
February 2013. EMA website. http://www.ema.europa.eu/ en_GB/document_library/Scientific_guideline/2009/09/
docs/en_GB/document_library/Scientific_guideline/2013/03/ WC500003935.pdf. Accessed 22 April 2020.
WC500139622.pdf. Accessed 22 April 2020. 27. Concept paper on the revision of the guideline on immunogenicity
17. Guideline on similar biological medicinal products containing mono- assessment of biotechnology-derived therapeutic proteins (CHMP/
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BMWP/403543/2010). 30 May 2012. EMA website. http:// www.ema.europa.eu/docs/en_GB/document_library/Scientific_
www.ema.europa.eu/docs/en_GB/document_library/Scientific_ guideline/2014/03/WC500163623.pdf. Accessed 22 April 2020.
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18. Guideline on non-clinical and clinical development of similar bio- Therapeutic Proteins (EMEA/CHMP/BMWP/14327/2006).
logical medicinal products containing recombinant erythropoietins 13 December 2007. EMA website. http://www.ema.europa.eu/
(Revision) (EMEA/CHMP/BMWP/301636/2008 Corr.). docs/en_GB/document_library/Scientific_guideline/2009/09/
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WC500089474.pdf Accessed 22 April 2020. Changes in Their Manufacturing Process (CPMP/ICH/5721/03).
19. Guideline on non-clinical and clinical development of similar June 2005. EMA website. http://www.ema.europa.eu/docs/
biological medicinal products containing low-molecular-weight-hep- en_GB/document_library/Scientific_guideline/2009/09/
arins—Draft (EMEA/CHMP/BMWP/118264/2007 Rev. 1). WC500002805.pdf. Accessed 22 April 2020.
17 January 2013. EMA website. http://www.ema.europa.eu/ 30. Op cit 6.
docs/en_GB/document_library/Scientific_guideline/2013/01/ 31. Op cit 13.
WC500138309.pdf. Accessed 22 April 2020. 32. Ibid.
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Medicinal Products Containing Recombinant Interferon Alpha europa.eu/en/human-regulatory/marketing-authorisation/
(EMEA/CHMP/BMWP/102046/2006). 23 April 2009. pre-authorisation-guidance. Accessed 22 April 2020.
EMA website. http://www.ema.europa.eu/docs/en_GB/docu- 34. Guideline on good pharmacovigilance practices (GVP) 3 Module XV
ment_library/Scientific_guideline/2009/09/WC500003930.pdf. – Safety communication. EMA website. https://www.ema.europa.
Accessed 22 April 2020. eu/en/human-regulatory/post-authorisation/pharmacovigilance/
21. Annex to Guideline on Similar Biological Medicinal Products good-pharmacovigilance-practices#final-gvp-annex-iii---oth-
Containing Biotechnology-Derived Proteins as Active Substance: er-pharmacovigilance-guidance-section. Accessed 22 April
Nonclinical and Clinical Issues Guidance on Similar Medicinal 2020.
Products Containing Recombinant Granulocyte-Colony Stimulating 35. EudraVigilance. EMA website. https://www.ema.europa.eu/en/
Factor (EMEA/CHMP/BMWP/31329/2005). 22 February human-regulatory/research-development/pharmacovigilance/
2006. EMA website. http://www.ema.europa.eu/docs/ eudravigilance. Accessed 22 April 2020.
en_GB/document_library/Scientific_guideline/2009/09/ 36. Op cit 4.
WC500003955.pdf. Accessed 22 April 2020.
22. Annex to Guideline on Similar Biological Medicinal Products
Containing Biotechnology-Derived Proteins as Active

Chapter 31
Nonprescription Medicinal
Products
OBJECTIVES European Parliament and of the Council Text

with EEA relevance3
□ Define and understand the role of nonprescrip-
tion medicinal products in self-care □ European Commission, the Rules Governing
Medicinal Products in the European Union,
□ Review the EU pharmaceutical legislation deal- Notice to Applicants: Volume 2C, “Guideline on
ing with nonprescription medicinal products changing the classification for the supply of a
medicinal product for human use” Revision 1
□ Provide an overview of EU policies and proce-
(January 2006)4
dures for reclassifying medicinal products from
prescription to nonprescription status □ Directive 2004/24/EC of the European
□ Understand the regulatory framework for tradi-
amending, as regards traditional herbal medic-
tional herbal medicinal products in the EU
inal products, Directive 2001/83/EC on the
for human use5
DIRECTIVES, REGULATIONS AND GUILDELINES
COVERED IN THIS CHAPTER □ European Commission, the Rules Governing
Medicinal Products in the European Union,
□ Directive 2001/83/EC of the European Notice to Applicants: Volume 2C, “Guideline on
Parliament and the Council of 6 November 2001 the Readability of Labelling and Package Leaflet
on the community code relating to medicinal of Medicinal Products for Human Use” Revision
products for human use1 1 (12 January 2009)6
□ Regulation (EC) 726/2004 of the European □ European Commission, the Rules Governing
Parliament and of the Council of 31 March 2004 Medicinal Products in the European Union,
laying down Community procedures for the Notice to Applicants: Volume 2C; Regulatory
authorisation and supervision of medicinal Guideline, “Guidelines on Excipients in the
products for human and veterinary use and Label and Package Leaflet of Medicinal Products
establishing a European Medicines Agency2 for Human Use” (March 2018)7
□ Regulation (EU) No. 520/2012 of 19 June 2012
on the performance of pharmacovigilance
activities provided for in Regulation (EC) No.
Introduction
Medicines available without a prescription commonly
726/2004 of the European Parliament and of
are called nonprescription or over-the-counter (OTC)
the Council and Directive 2001/83/EC of the
medicines. Nonprescription medicinal products, includ-
ing some homeopathic and herbal medicines, comprise

Chapter 31
a large part of the pharmaceutical market. Many differ- Where appropriate, nonprescription medicines also
ent nonprescription medicines have been available for can help individuals self-treat “embarrassing” conditions
a long time and have lengthy safety and efficacy track they do not wish to discuss with their doctors. Some
records. Examples are nonprescription medicines used common conditions treated by nonprescription medic-
to treat mild-to-moderate pain, cough and cold, minor inal products are provided in Table 31-1. However, the
skin problems and heartburn. Nonprescription medi- legal classification of a medicinal product may vary from
cines have expanded to include additional indications one Member State to another.
as a result of prescription medicines being “switched” As people take on greater responsibility for their
to nonprescription status. Examples are the triptans for healthcare, it is important for them to have access to
migraine, proton pump inhibitors for preventing acid high-quality information from multiple sources in a
indigestion, antivirals for cold sores and antihistamines variety of formats to meet the needs of different patient
for hay fever. groups.10 Individuals with a poor understanding of the
nature and use of nonprescription medicines are at risk
Definition of Nonprescription Medicinal for incorrect use, misuse or over consumption.
Product
Nonprescription medicines are defined in Article 72 Legislation of Nonprescription Medicinal
of Directive 2001/83/EC (as amended) as medicinal Products
products that do not meet the following criteria listed Article 70 of Directive 2001/83/EC, as amended by
in Article 71: Directive 2004/27/EC states, “When a marketing
• likely to present a danger either directly or authorisation is granted, the competent authorities shall
indirectly, even when used correctly, if used specify the classification of the medicinal product into:
without medical supervision a medicinal product subject to medical prescription, a
• frequently and to a very wide extent used medicinal product not subject to medical prescription.”
incorrectly, and as a result are likely to present As previously mentioned, nonprescription medicines are
a direct or indirect danger to human health defined in Article 72, which implies all medicinal prod-
• contain substances or preparations thereof, ucts should be nonprescription, unless they meet the
the activity and/or adverse reactions of which criteria listed in Article 71.
require further investigation
• normally prescribed by a doctor to be adminis- EU Marketing Authorisation Application
tered parenterally Procedures
Several different pathways11 for nonprescription medi-
The Role of Nonprescription Medicinal cines’ marketing authorisation (MA) are available in the
Products in Self-Care EU; the pathways are the same as those for prescription
The healthcare environment is changing across the EU.8 medicines. Understanding the nonprescription med-
An ageing population and economic constraints on icine’s intended use and whether it is licensed already
healthcare systems have prompted an increased focus on in a particular EU market helps determine the most
how to make the best use of healthcare resources. Self- appropriate authorisation pathway.
care has an important role to play in all of the following: Each pathway has advantages and risks. Strategic
• encouraging people to take more responsibility consideration should be given to the following:
for their own health and well-being • What health condition or symptoms will the
• making healthy life choices nonprescription medicine help to relieve?
• doctor and/or pharmacist consultations where • Is this a significant therapeutic, scientific or
appropriate technical innovation medicine?
• knowing if and when medical treatment • What is the product’s licensed and legal status
should be sought in the EU?
• What countries are being considered for prod-
Self-medication is an important part of self-care and uct launch?
enables people to treat or prevent short-term or chronic • What are the requirements for each market
illnesses without consulting a doctor, or after receiving being considered?
an initial medical diagnosis.9 Access to nonprescription
medicines allows people to take a more active role in the The types of procedures available are presented in
management of their own health and to treat common Regulation (EC) No. 726/2004 and summarised briefly
illnesses. in Table 31-2.

Nonprescription Medicinal Products
Table 31-1. Some Common Health Conditions Treated Using Nonprescription Medication
Health Nonprescription
Example What they do?
Condition Medication
Allergy Antihistamine Cetirizine, Loratidine Alleviates sneezing, runny or itchy nose
Nasal Decongestant Oxymetazoline, Makes breathing easier, relieves nasal congestion
congestion Pseudoephedrine
Constipation Stimulant Laxative Bisacodyl Stimulates the intestines to promote bowel movement
Osmotic Laxative Macrogol (Polyethylene Increases the amount of water in the small intestine to
Glycol 3350) promote bowel movement
Cough Cough Suppressant Dextromethorphan Eases dry, hacking coughs
Expectorant Guaifenesin Thins and helps clear mucus
Diarrhoea Intestinal Motility Loperamide Works by acting on opioid receptors that are found in
Modifiers the muscle lining the walls of the intestines. By acting
on these receptors, loperamide reduces the muscular
contractions of the intestine (called peristalsis) that move
food and faecal matter through the gut
Heartburn Antacid Calcium Carbonate Neutralizes acid in the stomach
Reduces production of stomach acid
Acid Reducer Ranitidine
Itching skin Corticosteroid Hydrocortisone Cream Soothes itching from bug bites, mild-to-moderate eczema
Cream
Mouth sores Local Anaesthetic Benzocaine Numbs pain
Pain, fever Non Steroidal Anti- Acetylsalicylic Acid, Relieves pain symptoms and fever
Inflammatory Drugs Ibuprofen, Naproxen
Sodium and Paracetamol
Source: Association of the European Self-Medication Industry. OTC ingredients. AESGP website. https://aesgp.eu/databases. Accessed 20 February 2020.
The Centralised Procedure is available for nonpre- Legal Basis of Marketing Authorisation Application
scription medicines of significant therapeutic value or (MAA)
benefit to society and/or patients. The first nonprescrip- The MAA’s legal basis is the same whether the medici-
tion medicinal product approved via the Centralised nal product is intended to be classified as prescription or
Procedure was ALLI (orlistat) 60 mg capsules, indi- nonprescription. Therefore, the MAA must comply with
cated for weight loss in overweight adults aged 18 and one of the following articles of Directive 2001/83/EC:
over. • Article 8(3)—full application (including
The Mutual Recognition Procedure can be used the so-called “full-mixed application” where
when a nonprescription license already exists in one Module 4 and/or 5 is a combination of reports
Member State, in which case the Member States of limited nonclinical and/or clinical studies
included in the procedure will recognise the license ini- carried out by the applicant and bibliographi-
tially granted. The Decentralised Procedure can be used cal references)
when the nonprescription medicine is not authorised • Article 10—generic, hybrid or similar biologi-
in any country. However, other pathways may be con- cal application
sidered. Many nonprescription medicines have received • Article 10a—well-established use application
MAs through these procedures. • Article 10b—fixed combination application
Note that when using the National Procedure • Article 10c—informed consent application
pathway, many markets generally follow the EU guide-
lines; however, it is best to confer with that Member Product Information Including Labelling
State’s health authority to better understand its Title V of Directive 2001/83/EC, as amended, states
requirements. medicinal products (including those not subject to
medical prescription) must be accompanied by clear

Chapter 31
Table 31-2. Comparison of EU MAA Procedure Advantages and Risks for Nonprescription Medicines
Requirements/ Length of
Procedure Advantage Risks
Conditions Procedure
New nonprescription Apply to all EEA countries— If consensus is not
medicine application single marketing achieved, and the marketing
based on significant authorisation. authorisation is rejected, it
therapeutic, scientific or Legal status is is not possible to submit an
Centralised technical innovation, or nonprescription medicine application for a national
210 days
Procedure legal status switch from in all Member States once marketing authorisation for an
prescription. approval is granted. identical product even when
all national requirements for
the marketing authorisation
are met.a
New nonprescription Simultaneous Discussion between Reference
medicine application or authorisation in more than Member State, Concerned
legal status switch from one EU country. Specific Member States and applicant
prescription. markets identified. to resolve issues. A negative
Medicine not authorised Reference Member decision on an application
in any EU Member State. State leads procedure, will affect approval in other
210 daysb
Does not fall within authorisation recognised Member States.
Decentralised plus national
Centralised Procedure. in Concerned Member Legal status still is determined
Procedureb phase (market-
Request for one Member States. nationally, which can result in
dependent)
State to act as Reference Harmonised product a mixed status for a product
Member State. information, even if across the EU.
national licences are
granted.
Different brand names
possible.
New nonprescription Obtain marketing Application is submitted to
medicine application or authorisation in several only one EU Member State. If
legal status switch from Member States. Based an application is rejected in
prescription. on the principle that that Member State, approval in
Existing marketing the desired countries other EU Member States may
authorisation in one of recognise the national be preempted.
the Member States. licence already granted. Legal status still is determined 90 daysb
Mutual
Recommend to discuss Harmonised product nationally, which can result in plus national
Recognition
a timetable for the information even if a mixed status for a product phase (market-
Procedureb
procedure with the national licences are across the EU. dependent)
Reference Member granted.
State before the dossier Different brand names
is submitted to the possible.
Concerned Member
States and the Reference
Member Stateb
New nonprescription Products intended for only Each Member State has
medicine application or one market. its own procedures and
legal status switch from If the application is governmental regulatory
National prescription. rejected in the Member bodies to grant a marketing Market-
Procedure State, the applicant still authorisation for a new drug. dependent
Country-specific can access other EU Product information not
Member States. harmonised among Member
States.
a. European Medicines Agency. Generics/Non prescription medicines - Nonprescription switching. EMA website. http://www.ema.europa.eu/docs/
en_GB/document_library/Presentation/2011/06/WC500107874.pdf. Accessed 22 April 2020.
b. CMDh Best practice guide for decentralised and mutual recognition procedures. CMDh website. https://www.hma.eu/fileadmin/dateien/
Human_Medicines/CMD_h_/procedural_guidance/Application_for_MA/CMDh_068_1996_Rev.12_2020_02_clean_-_CMDh_BPG_
for_DCP_and_MRP_1.pdf. Accessed 22 April 2020.

instructions for use. A comprehensive list of mandatory authorities are obliged to consider the classification
product information is provided. status of medicinal products regularly.
Product information is of particular importance for However, because the responsibility for legal status
nonprescription products because diagnosis of the con- remains the remit of each competent authority, clas-
dition and product selection and administration are the sification differences among Member States persist
responsibility of the consumer, not the medical prac- (unless the medicine is registered under the Centralised
titioner. Instructions for use contained on the package Procedure).
and package leaflet (if required) must be legible, clear Some Member States even have subcategories
and easy to understand. of nonprescription medicinal products. For example,
For consumer protection, suitable warning state- in France, not all nonprescription medicines can be
ments regarding excipients should be included in the advertised to the public, and in the UK, nonprescription
product labelling and package leaflet as detailed in the medicines can be purchased only in a pharmacy or as
Guideline on Excipients in the Label and Package Leaflet of general sales.
Medicinal Products for Human Use .12 The following text also is in Article 74: “Where a
The Guideline on the Readability of the Label and change of classification of a medicinal product has been
Package Leaflet of Medicinal products for Human use13 authorised on the basis of significant preclinical tests
provides detailed recommendations for preparing a or clinical trials, the competent authority shall not refer
package leaflet, e.g., font type and size, design and lay- to the results of those tests or trials when examining an
out of information, writing style and consideration for application by another Applicant for or holder of mar-
blind and partially sighted patients. Quality review of keting authorisation for a change in the classification of
documents (QRD) templates for labelling can be found the same substance for one year after the initial change
on the European Medicines Agency’s (EMA) website. was authorised…”
One way to ensure key product information is With the exception of the Centralised Procedure,
consumer-friendly is through consumer testing of reclassifying a medicinal product from prescription to
the package leaflet. The Guideline on the Readability of nonprescription legal status, generally called a “switch,”
the Label and Package Leaflet of Medicinal Products for is managed at the national level in the EU. Indeed, the
Human Use defines user testing as: “…readability of a availability of nonprescription medicines varies consid-
specimen with a group of selected test subjects. It is a erably across Member States. These disparities are due
development tool which is flexible and aims to identify largely to previous national evaluations, Member States’
whether or not the information as presented, conveys reimbursement policies and cultural differences.
the correct messages to those who read it…” A point for consideration is whether the change
Since nonprescription medicines primarily are sold in legal status refers to a product or an active sub-
directly to the consumer (user), package artwork designs stance. In Germany, a switch normally refers to an
tend to be more colourful and consumer-focused than active substance and not to a specific medicinal prod-
for prescription medicines. The regulatory professional uct. Therefore, it is bound for approval by a German
should work closely with marketing and/or commercial Switch Committee (external from the Bundesinstitut
colleagues to ensure artwork and text meet all applicable für Arzneimittel und Medizinprodukte (BfArM)),
regulatory requirements, e.g., the mandatory statements which then will be transposed into law, before a license
discussed above, Braille and compliance with summary for a specific medicinal product can be granted with a
of product characteristics (SmPC) text. The actual prod- nonprescription status. In other Member States, such as
uct information content is submitted in the MAA and Italy, the switch process is based on individual products.
approved by the agency based on supportive data, from The switch process in Member States also can differ
either clinical trials or published literature, especially in active substance doses, therapeutic indications and
regarding efficacy and safety. pharmaceutical forms.
In an attempt to harmonise basic medicinal prod-
Reclassification of Medicinal Products uct assessment and classification principles in the EU,
From Prescription to Nonprescription the European Commission issued the Guideline on
Directive 2001/83/EC Article 74 states, “When new Changing the Classification for the Supply of a Medicinal
facts are brought to their attention, the competent Product for Human Use14 for use by applicants and com-
authorities shall examine and, as appropriate, amend petent authorities.
the classification of a medicinal product by applying The guideline has five parts:
the criteria listed in Article 71…” Therefore, competent • Part 1 defines classification criteria

Chapter 31
• Part 2 describes the data required to support 3. responding to citizens’ and health professionals’
a switch (including safety/efficacy data and needs and demands, particularly in terms of
product information) patient empowerment, timely access, access to
• Part 3 discusses the potential for data improved treatments and improved quality of
exclusivity life
• Part 4 outlines principles and procedure to 4. fulfilling unmet needs and addressing condi-
claim one year of data exclusivity tions that would otherwise remain untreated
• Part 5 provides options for naming the medic- 5. embraced by healthcare professionals
inal product
EMA encourages the use of benefit-risk assessment mod-
Although the guideline is not binding, it has furthered els as effective tools for communicating benefit-risk views
the harmonisation process. with the agency and as a basis for discussions on a med-
Most Member States have similar application dos- icine’s legal status. A benefit-risk assessment is used to
sier formats for product switching. The package includes evaluate a medicinal product’s positive therapeutic effects
safety evidence based on prescription use, switch experi- in relation to its risks to patients’ or public health.16,17
ence gained from other nations and efficacy data (if the
proposed indication differs from that for prescription use). Nonprescription Medicinal Product
In recent years, seven prescription medicines (orl- Advertising and Promotion
istat, pantoprazole, esomeprazole, ulipristal, sildenafil, The regulation of nonprescription medicinal product
ibuprofen-diphenhydramine, sumatriptan) have gone advertising and promotion is different from that for
through the Centralised Procedure for the switch to prescription medicines, as nonprescription medicines
nonprescription status. However, only the first four can be purchased without a health provider’s input.
listed have received marketing authorisation. Member Information provided to the consumer comes in vari-
State self-care policies bear a clear impact on centralised ous formats (printed material, electronic media, audio
switches at the national level. and audiovisual advertising, etc.). Advertising plays an
One year of protection may be granted to appli- important role in raising public awareness of health
cants providing safety (preclinical) and/or efficacy issues, which provides a health benefit.
(clinical) data to support changing the legal classi- As stated in Directive 2001/83/EC, as amended,
fication of a medicine (usually from prescription to Title VIII, Article 88, in the EU, it is permissible to
nonprescription) (Article 74a of Directive 2001/83/ advertise nonprescription medicines to the general pub-
EC). However, the one-year protection is more theoret- lic. It is not permissible to advertise prescription-only
ical than practical. It has been suggested this is a barrier medicines to the general public.
to manufacturer investment due to the poor return on Article 89 of the same directive lists conditions to
the investment required for switch submissions. be fulfilled when advertising a nonprescription medic-
Self-diagnosis and symptom recognition are inal product to the general public. An advertisement
essential components in switching a product from pre- must:
scription to nonprescription. Therefore, the following • be set out in a way that makes it clear the mes-
factors must be considered carefully for legal switches: sage is an advertisement, and the product is
indications (including patient age), dosage and risks of identified clearly as a medicinal product
misdiagnosis, misuse or overdose. Risk management • include, at minimum, the following
and mitigation plans are important when such risks are information:
identified and should be discussed in the MAA. o medicinal product name and its common
In February 2011, CMDh established a task force name if the medicinal product contains
on self-medication to explore making the Mutual only one active substance
Recognition and Decentralised Procedures more practi- o the information necessary for the medici-
cal for nonprescription medicines. nal product’s correct use
o an express, legible invitation to read the
Elements of a Successful Switch Strategy package leaflet or outer packaging instruc-
Many factors affect access to nonprescription medicines; tions carefully, whichever is appropriate
therefore, Member States evaluating a reclassification
should consider the five elements of a successful switch:15 Article 90 details what should not appear in a med-
1. switched products’ safety, ease of use and icine’s advertisement. The advertisement must not
appropriate monitoring contain information that:
2. a clear beneficial impact on public health

• gives the impression a medicinal consultation Control of Advertising to the General Public
or surgical operation is unnecessary, partic- Different advertising control systems (e.g., preap-
ularly by offering a diagnosis or suggesting proval at the Member State level, voluntary control
treatment by mail by self-regulatory bodies, post-publication survey)
• suggests the effects of taking the medicine are were established in the EU to fulfill the requirements
guaranteed, have no adverse reactions or are documented in Article 97 of Directive 2001/83/
better than, or equivalent to, those of another EC, as amended, which states: “Member States shall
treatment or medicinal product ensure that there are adequate and effective methods
• suggests the subject’s health can be enhanced to monitor the advertising of medicinal products. Such
by taking the medicine methods, which may be based on a system of prior vet-
• suggests the subject’s health could be affected ting, shall in any event include legal provisions under
by not taking the medicine; this prohibition which persons or organizations regarded under national
shall not apply to the vaccination campaigns law as having a legitimate interest in prohibiting any
referred to in Article 88(4) advertisement inconsistent with this Title, may take
• is directed exclusively or principally at children legal action against such advertisement, or bring such
• refers to a recommendation by scientists, advertisement before an administrative authority com-
healthcare professionals or persons who are petent either to decide on complaints or to initiate
none of the foregoing but who, because of their appropriate legal proceedings.”
celebrity, could encourage the medicinal prod- Methods available to Member States include stop-
uct’s consumption ping (by legal means, if necessary) existing or planned
• suggests the medicinal product is a foodstuff, advertising deemed to be misleading and publishing
cosmetic or other consumer product corrective statements if necessary.
• suggests the medicinal product’s safety or effi-
cacy is due to the fact it is natural Postmarket Reporting of Adverse Events/
• could, by a description or detailed represen-
tation of a case history, lead to erroneous
Pharmacovigilance
Postmarket adverse event reporting, also known as
self-diagnosis
pharmacovigilance, is the process and science of mon-
• refers, in improper, alarming or misleading
itoring medicines’ safety and taking action to reduce
terms, to claims of recovery
a product’s risks and increase its benefits and is a key
• uses, in improper, alarming or misleading
public health function. All nonprescription medicinal
terms, pictorial representations of changes in
products marketed within the EU are subject to post-
the human body caused by disease or injury,
market reporting of adverse events.
or of the action of a medicinal product on the
The legal pharmacovigilance framework for med-
body or parts thereof
icines marketed within the EU is provided for in
Regulation (EC) No. 726/2004 with respect to cen-
Article 88 of Directive 2001/83/EC, as amended, has a
trally authorised medicinal products, and in Directive
provision addressing the potential burden on national
2001/83/EC with respect to nationally authorised
reimbursement systems: “Member States shall be enti-
medicinal products (including those authorised through
tled to ban on their territory, advertising to the general
the Mutual Recognition and Decentralised Procedures).
public of medicinal products, the cost of which may be
In addition, Commission Implementing
reimbursed.”
Regulation (EU) No. 520/2012 on the performance of
Historically, brands began as a form of consumer
pharmacovigilance activities18 stipulates certain phar-
protection, as a statement by the applicant of its offering
macovigilance operational details to be respected by
and its guarantee, to customers. Use of the same brand
marketing authorisation holders, national competent
name for both prescription and nonprescription versions
authorities and EMA. Also, EMA has released good
of a medicinal product is not allowed in some Member
pharmacovigilance practice (GVP) guidelines to facili-
States (e.g., Italy, Portugal and Spain). In addition, these
tate pharmacovigilance activities.
Member States do not allow immediate public advertis-
ing of switched medicinal products. In France, Ireland,
Italy, Norway and Spain, nonprescription medicines Traditional Herbal Medicinal Products
automatically lose reimbursement status if the manufac- The Traditional Herbal Medicinal Products Directive
turer advertises them in the general media. (THMPD),19 Directive 2004/24/EC (an amendment
to Directive 2001/83/EC), and Regulation (EC) No.

Chapter 31
726/2004, established the Committee on Herbal The simplified registration procedure for traditional
Medicinal Products (HMPC) as part of EMA. herbal medicinal products is based on evidence not
In accordance with THMPD Article 16h, HMPC’s supported by safety and efficacy tests and trials. Instead,
primary task is to establish a Community list of herbal the applicant is asked to present bibliographic or
substances, preparations and combinations thereof for expert evidence on the product’s traditional use, as
use in traditional herbal medicinal products and to well as a bibliographic safety data review and an expert
establish Community monographs for herbal medici- report. Also, a traditional herbal medicinal product
nal products containing the substances in this list. The complying with a Community monograph or contain-
Community list is defined in Article 16f of the same ing substances, preparations or combinations on the
directive and can be found on EMA’s website. Community list in one of the Member States should be
The THMPD defines herbal medicinal products, recognised by other Member States. However, products
substances and preparations. Herbal medicinal products under consideration for the simplified registration pro-
exclusively contain as active ingredients one or more cedure or complying with a Community monograph are
herbal substances (whole, fragmented or cut plants, subject to the same pharmaceutical quality (chemistry,
plant parts, algae, fungi and lichen) or one or more manufacturing and controls) requirements as other
herbal preparations (refined herbal substances) or one or medicinal products.
more such herbal substances in combination with one Further, the THMPD mandates product labelling
or more such herbal preparations. for traditional herbal medicinal products contain a
EU legislation on pharmaceutical products for statement to the effect that: “…the product is a tra-
human use, in general, also applies to traditional herbal ditional herbal medicinal product for use in specified
medicines. However, to overcome difficulties encoun- indication (s) exclusively based upon long-standing
tered by EU Member States in uniformly applying use… the user should consult a doctor or a qualified
pharmaceutical legislation to herbal medicinal products, healthcare practitioner if the symptoms persist during
a simplified “traditional use” registration procedure was the use of the medicinal product or if adverse effects not
introduced in 2004 thanks to the THMPD. mentioned in the package leaflet occur…” (THMPD,
Under the THMPD, all herbal medicinal products Article 16g).
are required to obtain an MA within the EU. Any advertising information also should state: “…
The only herbal medicines exempted from the Traditional herbal medicinal product for use in specified
THMPD’s provisions are those unlicensed remedies indication(s) exclusively based upon long-standing use.”
prepared for a patient following consultation with an
herbalist. Conclusion
Herbal medicinal products now must be manufac- This chapter provides an overview of EU legislation for
tured under Good Manufacturing Practices to ensure medicinal products not subject to medical prescription,
finished product quality and to demonstrate safety. including the legal basis for the MAA and reclassifica-
Under the THMPD, a company must demonstrate tion of legal status from prescription to nonprescription.
a product has been in medicinal use for at least 30 years, The regulatory framework for traditional herbal medici-
including at least 15 years within the EU. nal products also is discussed.
Key eligibility criteria for an herbal medicinal
product to qualify under this legislation are: References
• indications intended and designed for non- 1. Directive 2001/83/EC of the European Parliament and of the
Council of 6 November 2001 on the Community code relat-
prescription use exclusively for administration ing to medicinal products for human use. EC website. https://
in accordance with a specified strength and ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/
posology, oral, external and/or inhalation dir_2001_83_consol_2012/dir_2001_83_cons_2012_en.pdf.
preparation Accessed 22 April 2020.
2. Regulation (EC) 726/2004 of the European Parliament
• sufficient data on the medicinal product’s tra- and of the Council of 31 March 2004 laying down
ditional use; in particular, the product is proven Community procedures for the authorisation and supervi-
not to be harmful in the specified conditions of sion of medicinal products for human and veterinary use
use, and its pharmacological effects or efficacy and establishing a European Medicines Agency. EC web-
site. https://eur-lex.europa.eu/legal-content/EN/TXT/
are plausible on the basis of long-standing use PDF/?uri=CELEX:02004R0726-20190128&from=EN.
and experience Accessed 22 April 2020.
• vitamins and minerals may be added to the 3. Regulation (EU) No. 520/2012 of 19 June 2012 on the per-
herbal medicinal product, provided their use is formance of pharmacovigilance activities provided for in
Regulation (EC) No. 726/2004 of the European Parliament
ancillary to the herbal ingredient(s) and of the Council and Directive 2001/83/EC of the European
Parliament and of the Council Text with EEA relevance. EC

website. https://eur-lex.europa.eu/legal-content/EN/TXT/ Products for Human Use (EMA/CHMP/302620/2017 Rev. 1).

PDF/ ?uri=CELEX:32012R0520&qid=1583098655334&- EMA website. http://www.ema.europa.eu/docs/en_GB/docu-
from=EN. Accessed 22 April 2020. ment_library/Scientific_guideline/2009/09/WC500003412.pdf.
4. European Commission, the Rules Governing Medicinal Accessed 22 April 2020.
Products in the European Union, Notice to Applicants: Volume 13. Guideline on the Readability of the Labelling and Package Leaflet
2C, Guideline on changing the classification for the supply of a of Medicinal Products for Human Use (Rev. 1.) 12 January 2009.
medicinal product for human use. Revision 1. January 2006. EC EC website.http://ec.europa.eu/health/files/eudralex/vol-
website. https://ec.europa.eu/health/sites/health/files/files/ 2/c/2009_01_12_readability_guideline_final_en.pdf. Accessed
eudralex/vol-2/c/switchguide_160106_en.pdf. Accessed 22 22 April 2020.
April 2020. 14. European Commission, the Rules Governing Medicinal
5. Directive 2004/24/EC of the European Parliament and of the Products in the European Union, Notice to Applicants: Volume
Council of 31 March 2004 amending, as regards traditional 2C, Guideline on Changing the Classification for the Supply of a
herbal medicinal products, Directive 2001/83/EC on the Medicinal Product for Human Use. Revision 1. January 2006). EC
Community code relating to medicinal products for human use. website.http://ec.europa.eu/health/files/eudralex/vol-2/c/switch-
EC website. https://eur-lex.europa.eu/legal-content/EN/TXT/ guide_160106_en.pdf. Accessed 22 April 2020.
PDF/?uri=CELEX:32004L0024&from=EN. Accessed 22 April 15. Ibid.
2020. 16. Committee for Medicinal Products for Human Use.
6. European Commission, the Rules Governing Medicinal Reflection Paper on Benefit-Risk Assessment Methods in
Products in the European Union, Notice to Applicants: Volume the Context of the Evaluation of Marketing Authorization
2C, Guideline on the Readability of Labelling and Package Leaflet Applications of Medicinal Products for Human use (EMEA/
of Medicinal Products for Human Use. Revision 1. 12 January CHMP/15404/2007, 19 March 2008). EMA website.
2009. EC website. https://ec.europa.eu/health/sites/health/files/ http://www.ema.europa.eu/docs/en_GB/document_library/
files/eudralex/vol-2/c/2009_01_12_readability_guideline_final_ Regulatory_and_procedural_guideline/2010/01/WC500069634.
en.pdf. Accessed 22 April 2020. pdf. Accessed 22 April 2020.
7. European Commission, the Rules Governing Medicinal 17. Brass E P. “A Decision-Analysis Tool for Benefit-Risk
Products in the European Union, Notice to Applicants: Volume Assessment of Nonprescription Drugs.” Journal of Clinical
2C, Guidelines on Excipients in the Label and Package Leaflet of Pharmacology. 53(5) 475–482, 2013.
Medicinal Products for Human Use. March 2018. EC website. 18. Commission Implementing Regulation (EU) No. 520/2012
https://ec.europa.eu/health/sites/health/files/files/eudralex/ of 19 June 2012 on the performance of pharmacovigilance
vol-2/c/guidelines_excipients_march2018_en.pdf. Accessed 22 activities provided for in Regulation (EC) No. 726/2004 of
April 2020. the European Parliament and of the Council and Directive
8. Report of the Working Group on Promoting Good Governance 2001/83/EC of the European Parliament and of the Council.
of Non-Prescription Drugs in Europe. June 2013. EUR-Lex website. http://eur-lex.europa.eu/LexUriServ/
9. Yiangou G. “Valuing Self Care.” Self Care. 2011, 2(2): 41–54. LexUriServ.do?uri=OJ:L:2012:159:0005:0025:EN:PDF.
https://selfcarejournal.com/article/valuing-self-care/. Accessed Accessed 22 April 2020.
on 22 April 2020. 19. Directive 2004/24/EC of the European Parliament and of the
10. Bodenheimer. Patient Self-Management of Chronic Disease Council of 31 March 2004 amending as regards traditional
in Primary Care. 2002. https://www.ncbi.nlm.nih.gov/ herbal medicinal products, Directive 2001/83/EC on the
pubmed/12435261. Accessed on 22 April 2020. Community code relating to medicinal products for human use
11. Op cit 1. (Traditional Herbal Medicinal Products Directive (THMPD)).
12. European Commission, the Rules Governing Medicinal EUR-Lex website. https://ec.europa.eu/health//sites/health/
Products in the European Union, Notice to Applicants: files/files/eudralex/vol-1/dir_2004_24/dir_2004_24_en.pdf.
Volume 2C, Annex to the European Commission, Guideline Accessed 22 April 2020.
on Excipients in the Labelling and Package Leaflet of Medicinal

Chapter 31

Chapter 32
Marketing Authorisations
for Products Derived From
Biotechnology
OBJECTIVES □ Directive 2001/83/EC of the European

□ Understand the special considerations involved 2001 on the Community code relating to medici-
in developing a biotechnology-derived product nal products for human use, as amended
for the EU market
□ Understand the registration principles for a bio- Parliament and of the Council of 31 March
technology-derived product for the EU market 2004 amending Directive 2001/83/EC on the
□ Recognise the advantages and disadvantages
for human use
of obtaining an EU marketing authorisation
through the Centralised Procedure
□ Understand the EU regulatory processes for Introduction

postapproval lifecycle management of biotech- In Europe, several marketing authorisation (MA) pro-
nology-derived products cedures are available to register a medicinal product. The
distinction depends on the type of drug: new chemical
□ Become familiar with sources of information entities, products derived from biotechnology or other
about EU regulatory procedures innovative products.
European legislation prescribes certain proce-
dures for specific product types. In February 1995, the
DIRECTIVES, REGULATIONS AND GUIDELINES European Medicines Agency (EMA) implemented the
COVERED IN THIS CHAPTER Centralised Procedure (CP). This procedure is manda-
tory for biotechnologyderived products, orphan drugs
□ Regulation (EC) No. 726/2004 of the European and drugs designed for certain disease groups. Other
Parliament and of the Council of 31 March 2004 products can be registered via the national route or
laying down Community procedures for the using one of the other European procedures, namely
authorisation and supervision of medicinal the Mutual Recognition Procedure (MRP) or the
products for human and veterinary use and Decentralised Procedure (DCP).
establishing a European Medicines Agency, as Regulation (EC) No. 726/2004, as amended,1
amended provides the legal basis for the CP and describes the
marketing application and review processes specifically
□ Regulation (EC) No. 1394/2007 of the European for biotechnology-derived products. The CP involves
Parliament and of the Council of 13 November a single application; a single evaluation of the highest
2007 on advanced therapy medicinal prod- possible standard for these products’ quality, safety
ucts and amending Directive 2001/83/EC and and efficacy; and a single authorisation allowing direct
Regulation (EC) No. 726/2004, as amended access to the entire Community market. This regulation

Chapter 32
also established the Committee for Medicinal Products o autoimmune diseases and other immune
for Human Use (CHMP), previously the Committee dysfunctions
for Proprietary Medicinal Products (CPMP), as part o viral diseases
of EMA. Following a positive CHMP opinion, the • medicinal products designed as orphan medic-
European Commission makes the final decision about inal products pursuant to Regulation (EC) No.
granting a MA. This regulation reinforced the need for 141/20002
a centralised approval process for products derived from
biotechnology and for new active substances for certain Community authorisation via the CP is optional for
therapeutic areas. certain product types detailed in Article 3 of Regulation
An MA granted through the CP is valid for the (EC) No. 726/2004:
entire Community market. The marketing authorisation • medicinal products containing new active sub-
holder (MAH) has one European licence to market the stances not authorised in the Community at
product, rather than individual national licenses in EU the date of entry into force of the regulation
Member States. Consequently, a medicinal product may • medicinal products for which a significant
be marketed in all EU Member States; however, it is therapeutic, scientific or technical innovation
still necessary to arrange price and reimbursement on a can be demonstrated in the interest of patients’
country-by-country basis. This is unlikely to change in health
the near future because financial aspects of the medici-
nal product supply are still regulated by national laws. Similar biological (biosimilar) medicinal products
that are developed by means of biotechnological pro-
Registration Procedures of Biotechnology cesses must be authorised via the CP (see Chapter 30
Products Biosimilar Medicinal Products for more details on
similar biological products).
Products Eligible for the Centralised Procedure
Community authorisation via the CP is compulsory for
products appearing in the annex to Regulation (EC) Centralised Procedure (CP)
No. 726/2004, as amended. These include: The CP is described in detail in the Rules Governing
• medicinal products developed via one of the Medicinal Products in the European Union, Notice
following biotechnological processes: to Applicants, Volume 2A Procedures for Marketing
o recombinant DNA technology Authorisation, Chapter 1.3 A summary of the CP is
o controlled expression of gene coding for provided in Chapter 23 Overview of Authorisation
biologically active proteins in prokaryotes Procedures for Medicinal Products and Chapter 27
and eukaryotes, including transformed Registration Procedures for Medicinal Products of
mammalian cells this book.
o hybridoma and monoclonal antibody EMA issues specific presubmission guidance for
methods applications under the CP. An eligibility request must
• advanced therapy medicinal products: be submitted within 18 months prior to the intended
o gene therapy medicinal products submission date. An eligibility request form, and dates
o somatic cell therapy medicinal products for submission of requests, linked to CHMP meeting
o tissue-engineered products dates, are available in the presubmission guidance.
o combination (with medical device) EMA encourages applicants to request a pre-
advanced medicinal products submission meeting with the agency to discuss the
• medicinal products for human use containing a authorisation process. This meeting should take place
new active substance that, on the date of entry approximately seven months prior to submission.4
into force of this regulation, was not authorised Whether a meeting is scheduled or not, the applicant
in the Community and for which the thera- must notify EMA of its intention to submit an applica-
peutic indication is the treatment of any of the tion seven months prior to submission.
following diseases: A rapporteur and co-rapporteur, who are CHMP
o acquired immune deficiency syndrome members, are assigned to a particular application
o cancer to assess the product’s quality, safety and efficacy.
o neurodegenerative disorder Applicants may indicate in a letter of intent (to sub-
o diabetes and, with effect from 20 May mit an application) their request for appointment of a
2008: rapporteur and co-rapporteur. These requests should
be received approximately seven months prior to the
intended submission date and at least two weeks prior

Marketing Authorisations for Products Derived From Biotechnology
to a CHMP meeting, so the appointment can take formally request an accelerated evaluation. This pro-
place six months prior to submission. The names of the cedure applies to products that represent a therapeutic
rapporteur and co-rapporteur are communicated to the innovation and are of major interest to public health.
applicant before the start of the evaluation process. The 210-day assessment period is reduced to 150
CP authorised medicinal products have eight years days.9 (For more details about the CP, see Chapter 23
of data protection and a 10-year market exclusivity Overview of Authorisation Procedures for Medicinal
period in all EU Member States, Liechtenstein, Norway Produces and Chapter 27 Registration Procedures for
and Iceland. Products for which the initial submission Medicinal Products.)
was made prior to this time continue to benefit from
the previous period of protection, which is 10 years for Advantages and Disadvantages of the
CP approved products. Centralised Procedure
While the CP has proven to be efficient, it is, in any
Procedure Applications in Exceptional case, mandatory for biotechnology products.
Circumstances Important features introduced in 2005 included
Article 14(8) of Regulation (EC) No. 726/2004 permits an expanded scope of the procedure, establishment of
authorisations to be issued in exceptional circumstances, a procedure for conditional MAs, formalisation of an
including a situation where the applicant is unable to accelerated procedure and available assistance for small-
provide the normal efficacy and safety data because the and medium-sized enterprises (SMEs).10
indication is rarely encountered. In such cases, it rarely It also has some disadvantages. One of the main
will be possible to generate the full data; hence, the drawbacks is the requirement that the product be made
authorisation will not be converted into a “normal” MA. available in all 27 EU countries plus Norway, Iceland
The grounds for claiming exceptional circumstances and Liechtenstein; selective filing or withdrawals are
are detailed in Annex I of Directive 2001/83/EC, as not possible, whether the MAH has a commercial
amended.5 Conditions relating to the product’s safety, interest in a particular country or not.
notification of adverse events and actions taken are Among other things, this requirement involves pre-
described in detail in the Guideline on Procedures for the paring the summary of product characteristics (SmPC),
Granting of a Marketing Authorisation Under Exceptional patient leaflet and labelling and, subsequently, the
Circumstances (EMEA/357981/2005).6 mock-ups-in all 24 EU languages, in accordance with
The authorisation’s continuation is linked to an the quality review of documents (QRD) templates.
annual assessment of these conditions. Another potential CP disadvantage is the require-
ment to limit the product to only one EU trade name.
Conditional Authorisation Normally, only one invented name can be used for a
Regulation (EC) No. 507/2006 permits the granting of product registered via the Centralised Procedure. A
a conditional licence, valid for one year, where there is guideline (CPM P/328/98)11 is available on features of
specific patient need.7 Possible examples include prod- proposed invented names that tend to give rise to public
ucts for life-threatening diseases, designated orphan health concerns. The guideline describes the EMA cri-
medicinal products and medicinal products for use in teria for identifying difficulties with such names:
emergency situations. • misleading therapeutic or pharmaceutical
Applications should contain—unless otherwise connotations
justified—the same quality and nonclinical data as for • misleading with respect to product
a normal authorisation.8 The applicant will be required composition
to finalise ongoing clinical trials or conduct new studies • likely to cause confusion in print, handwriting
to verify a presumed positive benefit-risk balance. The or speech with the trade name of an existing
authorisation is subject to specific obligations that are medicinal product
reviewed annually. The authorisation will not remain
conditional. Once the missing data are provided, the The applicant should use the request form to submit
conditional MA becomes a “normal” MA. If appropri- the proposed name at most 12 months, and at least four
ate, sponsors applying for conditional authorisations to six months, prior to the planned submission date. A
also may apply for accelerated assessment. satellite group of CHMP, the (invented) name review
group (NRG), considers proposals, which are then pre-
Accelerated Assessment Procedure sented at a subsequent CHMP meeting. Submission
A legal provision was introduced in Regulation (EC) dates with respect to NRG/CHMP meetings are pro-
No. 726/2004, Article 14(9) for the applicant to vided in the presubmission guidance. An additional

Chapter 32
form is available for justifying a previously unacceptable The frequency of periodic safety update report
invented name. (PSUR) submissions has been increased to compensate
In general, a minimum of three letters distinguishing for the reduced requirements related to renewals.
the proposed trade name from an existing trade name are
required. In practice, the requirement for one legally and Development Aspects Particular to Biotechnology
linguistically acceptable trade name in all EU Member Products
States has proven to be a challenge for the industry. An MA for a biotechnology-derived product for human
Another potential CP disadvantage is that, fol- use will be granted following assessment of its quality,
lowing the issuance of the MA, the European public safety and efficacy. Although details of the assessment
assessment report (EPAR) is made available via the differ among the various authorities, the approval criteria
EMA website. The sponsor has the opportunity to are generally similar in the EU and US. Biotechnology
delete commercially sensitive, confidential information products must fulfil the same basic quality, safety and
before it is published, but the EPAR still gives the com- efficacy criteria as any other pharmaceutical product. In
petition a good idea of the basis for product approval. addition, all general requirements, such as good labora-
tory practice (GLP), good clinical practice (GCP), good
Maintenance of the Marketing manufacturing practice (GMP) and the need to have a
Authorisation manufacturing licence, apply equally to biotechnology
Once a product has been granted a Community MA, and conventional products. Along with the standard
any postauthorisation regulatory activities, e.g., varia- regulatory requirements, however, a number of issues are
tions or renewals, must be done via the CP. specific to biotechnology products.
Variations Quality: Chemical, Pharmaceutical and

The MAH has an obligation to update the MA by Biological Information
variation applications as new data emerge. This is par- Development Pharmaceutics
ticularly important for new information that affects the A fair number of guidelines describe specific
benefit-risk balance. production and testing requirements for various bio-
A large proportion of variations relate to changes in technology-derived product types. Many guidelines
the dossier’s chemical-pharmaceutical section, i.e., Module have been developed by the International Council
3 in the common technical document (CTD). In January for Harmonisation of Technical Requirements for
2010, previous legislation was replaced by Regulation Pharmaceuticals for Human Use (ICH) and are
(EC) No. 1234/200812 to provide a simpler and more flex- applicable in the EU, US and Japan, as well as other
ible legal framework for the handling of variations. countries that recognise ICH.
The primary change allows annual reporting of all The section on development pharmaceutics (CTD
Type IA variations within the 12-month period follow- Module 3.2.P.2, detailed in ICH Q8(R2)13) is an
ing the implementation of the variations. However, for important part of any EU dossier. It requires special
some of these minor changes, notification submitted attention for biotechnology products (ICH Q5D.)14
immediately after the implementation of the variation is Underlying physicochemical differences between
required (Type IAIN). biological/biotechnological products and chemically
Detailed dossier requirements, per variation type, synthesised products may necessitate special pharma-
are described in the regulation and guidance documents. ceutical and biopharmaceutical considerations during
(For more details about variations, see Chapter 33 the research and development programme. For instance,
Pharmaceutical Postmarketing Requirements and to maintain biological activity, the active moiety’s
Compliance.) integrity must be preserved biologically and chemically
during the manufacturing process and throughout the
Renewals defined shelf life, requiring design of appropriate stabil-
An MA is valid for five years and will then be renewed ity-indicating assays.
based on a re-evaluation of the benefit-risk balance. Rationale and experimental processes that lead to a
Once renewed, the MA is valid for an unlimited period finalised manufacturing process and established product
unless there are justified grounds related to pharma- specifications usually require a more elaborate descrip-
covigilance. In such a case, one additional five-year tion than is required for a conventional product. This
authorisation would be necessary. description includes nonactive constituent selection and
role, process development and optimisation, reason for
cell line choice, etc. While conventional products often

reference standard pharmaceutical techniques or excipi- as autoclaving at 121°C for 15 minutes and dry heat
ents, this is not an option for biotechnology products. processes such as 160°C for one hour or irradiation at
25 kGy, do not inactivate the agents. Because TSE-
Manufacturing Information associated diseases, particularly CJD, are incurable and
Production of biotechnological drug substances requires fatal, the policy has aimed to eliminate the use of tissues
high-quality processes and testing, including a detailed at particular risk for carrying BSE.
description of source material and production strain or Unfortunately, the pharmaceutical industry uses
cell line preparation, genetic stability testing, cell bank many materials from bovine, ovine or caprine sources
system details, fermentation and harvesting informa- and their derivatives. Many organs, tissues and sera,
tion, purification details, a full product characterisation, such as heparin, glucagons, lactose, foetal calf serum
analytical development of the special techniques and bovine serum albumin, are used as raw material
involved, process validation and a detailed explanation sources. Materials are extracted from hair and wool, and
of potential impurities, including batch results. derivatives of materials of animal origin (in particular
Biotechnology product quality is defined by the gelatine and tallow derivatives) are used in many phar-
production and manufacturing process. Minor process maceutical products. In addition, animal tissues are used
changes can affect the drug product’s quality. Detailed to manufacture incubation media for the production of
establishment of the manufacturing process is, there- biotechnology products. Banning the use of bovine-de-
fore, of paramount importance. It must be known rived materials in producing pharmaceuticals would have
which manufacturing parameters (e.g., pH, heat, shear) resulted in removal of a vast range of products from the
can affect the drug substance’s quality and stability EU market. Instead, EU legislation has been amended
in a formulated product to ensure consistency. This to require the applicant to demonstrate that the medic-
is particularly important in relation to scaling up the inal product is manufactured in accordance with a Note
manufacturing process. In contrast to traditional drugs, for Guidance on Minimising the Risk of TSE.15-17
biotechnology-derived products typically are complex The goal still is to replace all ingredients of animal
and labile proteins. For authentic in vivo activity, the origin in human medicinal products with vegetable-de-
primary amino acid sequence is essential, as are the sec- rived or synthetic materials, using the appropriate
ondary linkages and tertiary folding of the molecule to variation procedures. Animal-derived materials may still
reveal the appropriate functional sites. Small changes in be used, at least temporarily, provided compliance with
structure can radically alter the in vivo immunogenicity the requirements are demonstrated by:
and pharmacokinetics of proteins. • submitting detailed information on animal
Because of biotechnology products’ physicochem- materials used, including manufacturing proce-
ical properties, it is usually not possible to terminally dure details, to the competent authorities
sterilise them in the final container by autoclaving. In • submitting a European Pharmacopoeia (Ph.
most instances, they are sterilised by membrane filtra- Eur.) certificate of TSE compliance (certificate
tion before filling. Aseptic techniques are an absolute of suitability)18
requirement.
Compatibility with excipients and primary pack- The information required in both cases is the same. The
aging components requires special attention. When difference in the second case is that the information
infusion sets are used to administer the product in the must be assessed only once, as the certificate of suit-
clinic, compatibility studies with the infusion lines, fil- ability is recognised by both the 27 signatory states of
ters and fluids are necessary. the European Pharmacopoeia Convention and the EU.
The manufacturers or suppliers of any drug substance
Transmissible Spongiform Encephalopathy (TSE) or excipient with TSE risk that is used in producing
After many years of heated discussions and near bans or preparing pharmaceutical products can apply to the
on the use of ingredients of animal origin in medici- European Directorate for the Quality of Medicines
nal products, the EU situation has stabilised. Concern (EDQM) for a certificate evaluating TSE risk reduction
about the use of animal ingredients is related to the according to a specific TSE monograph. A full dossier
potential for causing TSE. Scrapie in sheep and goats, on the substance’s manufacturing method and associ-
bovine spongiform encephalopathy (BSE) in cattle and ated impurities must be sent to EDQM. The dossier
Creutzfeldt-Jakob disease (CJD) in humans all belong is reviewed by independent experts. Once a certificate
to the TSE family. is issued, the applicant can include it in the dossier as
TSE is believed to be caused by prion proteins and proof the substance concerned will not pose a TSE risk.
not associated genetic material. TSE agents are diffi- The certificate of suitability can be used every time
cult to destroy; such conventional sterilisation methods the particular substance is used in the production of

Chapter 32
any medicinal product. In contrast, when the first route Therefore, a company should carefully consider which
is followed, each competent authority must make the tests to list under release specifications and which could
assessment separately for every final product appli- be considered in-process or bulk final product tests. The
cation. The competent authorities strongly encourage repeat testing requirement applies to all tests presented
the use of the certification scheme. The information as final product release tests. Although this requirement
required is as follows: is not specific to biotechnology products, the complexity
• geographic source of the animals from which of some release tests, the often-small batch sizes and
materials are derived (some countries are con- significant product cost may necessitate special atten-
sidered higher risk than others) tion to this issue.
• nature of the animal tissue used in manufac-
ture (certain tissues carry a higher risk) Preclinical Information
• production and inactivation processes Regulatory standards for biotechnology-derived prod-
ucts generally are comparable across the EU, Japan
No single approach necessarily establishes a product’s and the US. All regions have adopted a flexible, case-
safety. Therefore, these three approaches should be used by-case, science-based approach to preclinical safety
in combination in assessing an ingredient’s risk in bio- evaluations.20,21
technology-derived medicinal production. Safety concerns may arise from the product itself
Information regarding the raw material source and and/or from the presence of impurities or contaminants.
manufacturing processes must be supplemented with Cellular host contaminants may result in allergic reac-
information regarding the material’s traceability and tions and other immunopathological effects. As is the
a summary of the auditing procedures employed to case for conventional products, the product used in the
demonstrate control over the material’s source. pivotal pharmacology and toxicology studies should be
comparable to the product proposed for clinical studies.
Viral Clearance Toxicity studies are expected to be performed in
When ingredients of animal or human origin are used compliance with GLP. Conventional pharmaceutical
in producing a medicinal product, the capacity of the toxicity testing may not be appropriate for biopharma-
manufacturing process to remove all viral contamination ceuticals due to their unique and diverse structural and
is vitally important. Testing and evaluating biotechnol- biological properties, which may include species specific-
ogy products’ viral safety are standard requirements.19 ity, immunogenicity and unpredicted pleiotropic activities.
The three complementary approaches for addressing In vitro studies usually play an important role in
viral safety are: pharmacological testing of these substances to deter-
1. selecting and testing cell lines and other raw mine product properties. They also help select an
materials, including media components, for appropriate animal species for further in vivo pharma-
the absence of undesirable viruses that may be cology and toxicology studies.
infectious or pathogenic to humans The in vivo safety evaluation should involve
2. assessing the capacity of the production relevant animal species (i.e., species in which the
process to clear infectious viruses by virus inac- test material is pharmacologically active due to the
tivation and virus removal expression of the receptor or an epitope). The species
3. testing the product at appropriate production commonly used for conventional products are not nec-
steps for the absence of contaminating infec- essarily relevant for biotech products. Normally, safety
tious viruses evaluations should include two species; in justified cases,
one relevant species may suffice (when only one relevant
All three approaches are necessary to establish product species can be determined or when the biopharmaceu-
safety, and it is crucial to demonstrate that the purifi- tical’s biological activity is well understood). Toxicity
cation regimen can remove and inactivate the viruses. studies in nonrelevant species are discouraged. If there
Viral clearance requirements continue to become more is no relevant species, the use of transgenic animals
stringent, and although there may be differences in expressing the human receptor, gene knockout animal
implementing certain requirements, global regulatory models or homologous proteins should be considered.
requirements are comparable. When these models or proteins are not available, it still
may be prudent to assess some aspects of potential tox-
Release Testing in Europe icity in limited toxicity evaluations, e.g., conducting a
When a medicinal product is manufactured outside the repeat-dose toxicity study of a few weeks’ duration that
EU/EEA and imported into the market, release testing includes an evaluation of important functional end-
must be performed on every batch in the EU/EEA. points (e.g., cardiovascular and respiratory).

Many biotechnology-derived products for human product’s physicochemical and biological characteristics.
use are immunogenic in animals, whether through A change in these characteristics may lead to a different
binding antibodies, neutralising antibodies and/or aller- safety or efficacy profile.
gic reactions to the intended medicinal product or one The means of demonstrating comparability in
of its impurities (cell substrates, media components, either case that is, one (or a related) manufacturer
fragments, aggregates). Antibody responses should be amending its own process or a product claiming sim-
characterised (titre, number of responding animals, ilarity to a product already on the market (generic/
neutralising or non-neutralising), and their appearance biosimilar) should be identical.
should be correlated with any pharmacological or toxi- Comparability must be shown for product quality,
cological changes. safety and efficacy in a sequential process.22,23 Even
Antibody detection should not be the sole criterion changes classified as minor may result in relevant qual-
for the early termination of a preclinical safety study ity profile modifications for a biotechnology product.
unless the immune response neutralises the product’s As an initial approach when introducing a process
pharmacological and/or toxicological effects in a large change, the following parameters, on which specifica-
proportion of animals. Nevertheless, the usefulness of tions have been based, should be considered key:
preclinical animal studies may be limited to repeat- • characterisation studies
dose studies or intermittent dosing studies of limited • validated manufacturing process
duration in a model as closely related to humans as • release data
possible. Immunogenicity and toxicokinetic data should • stability data
be obtained after the first and nth dose in repeat-dose • in wider perspectives, preclinical and clinical
studies. Local tolerance also must be determined, if experiences
applicable. A factor to consider when designing a bio-
technology product’s preclinical development program Parameters should be evaluated in a step-by-step
is the available quantity of test material. Especially in manner when discussing comparability. Of primary
the early development phases, products of adequate importance is the ability of analytical techniques to
quality may be available only in small quantities and at detect slight or discrete modifications to the char-
high costs. acteristics of biotechnology derived products. The
manufacturer must provide evidence that the analytical
Clinical Information method has the sensitivity and selectivity to discern
Clinical studies must be tailor-made for each medicinal such changes.
product and should consider the route of adminis-
tration, indication, intended treatment population, Pharmacovigilance
treatment duration, etc. Several guidelines have been Depending on sponsor commitments, postapproval
published by CHMP on each therapeutic area and are pharmacovigilance monitoring is crucial in EU bio-
available on EMA’s website. technology-derived products’ lifecycle management.
Due to the nature of biotechnology products, Postapproval safety updates and annual reports must be
immunogenic reactions are not unexpected and must be provided to the agency.
considered when determining the optimal posology.
In addition, the EPARs published on other Other Postapproval Changes
biotechnology products can be useful sources of infor- In addition, as mentioned above in the Variations
mation. These EPARs also are available on EMA’s section, as new data emerge that require subsequent
website. changes to manufacturing sites and presentation or
other postapproval changes to the product profile, spon-
Postapproval Lifecycle Management of sors should file variation applications (Type IA, Type
Biotechnology-Derived Products IAIN, Type B, Type II variations or extension applica-
Comparability Guideline tions) with EMA for review, approval or notification, as
Medicinal products of biotechnological origin are often deemed necessary based on regulations.
subject to manufacturing process changes (drug sub-
stance, drug product or both) during the development Conclusion
phase or after the MA has been granted. In either case, In the EU, biotechnology-derived products can only be
it is necessary to compare the product derived from the registered using the Centralised Procedure and upon
modified process with the one derived from the current approval by EMA, will receive a single EU licence that
process to confirm that the change did not alter the is valid for marketing in all 27 EU Member States.

Chapter 32
Biotechnology-derived products’ special and the conditional marketing authorisation for medicinal products for
sensitive nature requires a chemical-biological-phar- human use falling within the scope of Regulation (EC) 726/2004.
25 February 2016. (EMA/CHMP/509951/2006, Rev.1).
maceutical and preclinical development program that is EMA website. https://www.ema.europa.eu/en/documents/
specific to the concerned product. These requirements scientific-guideline/guideline-scientific-application-practi-
are described in ICH and EMA guidelines. cal-arrangements-necessary-implement-commission-regula-
The manufacturer also should demonstrate com- tion-ec/2006-conditional-marketing-authorisation-medici-
nal-products-human-use-falling_en.pdf. Accessed 12 April
pliance with the Note for Guidance on Minimising the 2020.
Risk of Transmitting Animal Spongiform Encephalopathy 9. Guideline on the scientific application and the practical arrangements
Agents via Human and Veterinary Medicinal Products and necessary to implement the procedure for accelerated assessment pursu-
ensure it demonstrates the required viral inactivation or ant to Article 14(9) of Regulation (EC) No. 726/2004. 6 February
2016. (EMA/CHMP/671361/2015 Rev. 1). EMA website.
viral clearances. https://www.ema.europa.eu/en/documents/scientific-guideline/
Biotechnology-derived products that have imple- guideline-scientific-application-practical-arrangements-neces-
mented manufacturing process changes must ensure sary-implement-procedure-accelerated/2004_en.pdf. Accessed
comparability showing that product quality, safety and 12 April 2020.
10. Commission Regulation (EC) No. 2049/2005 of 15 December
efficacy are intact with any analytical methods showing laying down, pursuant to regulation (EC) No. 726/2004 of the
sensitivity and selectivity to discern the changes. European Parliament and of the Council, rules regarding the
payment of fees to, and the receipt of administrative assistance
References from, the European Medicine Agency by micro, small and medi-
1. Regulation (EC) No. 726/2004, as amended, of the European um-sized enterprises. EC website. https://ec.europa.eu/health/
Parliament and of the Council of 31 March 2004 laying down documents/eudralex/vol-1_en. Accessed 12 April 2020.
Community procedures for the authorisation and supervision 11. Guideline on the acceptability of names for human medicinal products
of medicinal products for human and veterinary use and estab- processed through the centralised procedure. 22 May 2014. (EMA/
lishing a European Medicines Agency. (Consolidated Version). CHMP/287710/2014–Rev. 6). EMA website. https://www.
28 January 2019. EC website. https://ec.europa.eu/health/docu- ema.europa.eu/en/documents/regulatory-procedural-guideline/
ments/eudralex/vol-1_en. Accessed 12 April 2020. guideline-acceptability-names-human-medicinal-products-pro-
2. Regulation (EC) No. 141/2000 of the European Parliament cessed-through-centralised-procedure_en.pdf. Accessed 12
and of the Council of 16 December 1999 on orphan medicinal April 2020.
products. EC website. https://ec.europa.eu/health/documents/ 12. Commission Regulation (EC) No. 1234/2008 of 24 November
eudralex/vol-1_en. Accessed 12 April 2020. 2008 concerning the examination of variations to the
3. European Commission, the Rules Governing Medicinal Products terms of marketing authorisations for medicinal products
in the European Union Notice to Applicants: Volume 2A, Chapter for human use and Veterinary medicinal products. EUR-
1: Marketing Authorisation. July 2019. EC website. https:// Lex website. https://eur-lex.europa.eu/legal-content/EN/
ec.europa.eu/health/documents/eudralex/vol-2_en. Accessed 12 TXT/?uri=CELEX:02008R1234-20130804. Accessed 12 April
April 2020. 2020.
4. European Medicines Agency. European Medicines 13. ICH Q8(R2) Pharmaceutical Development. August 2009.
Agency pre-authorisation procedural advice for users ICH website. https://database.ich.org/sites/default/files/
of the centralised procedure, (EMA/821278/2015), 6 Q8%28R2%29%20Guideline.pdf. Accessed 12 April 2020.
February 2020. EMA website. https://www.ema.europa. 14. ICH Q5D Quality of biotechnological products: derivation
eu/en/documents/regulatory-procedural-guideline/ and characterisation of cell substrates used for production of
european-medicines-agency-pre-authorisation-procedural-ad- biotechnological/biological products. 16 July 1997. ICH website.
vice-users-centralised-procedure_en-0.pdf. Accessed 12 April https://database.ich.org/sites/default/files/Q5D%20Guideline.
2020. pdf. Accessed 12 April 2020.
5. Directive 2001/83/EC, as amended, of the European 15. Note for guidance on minimising the risk of transmit-
Parliament and of the Council of 6 November 2001 on the ting animal spongiform encephalopathy agents via
Community code relating to medicinal products for human use human and veterinary medicinal products. 1 July 2011.
(Consolidated Version.) 2009. EC website https://ec.europa.eu/ (EMA/410/01, Revision 3). EMA website. https://
health/documents/eudralex/vol-1_en. Accessed 12 April 2020. www.ema.europa.eu/en/documents/scientific-guideline/
6. Guideline on procedures for the granting of a marketing authori- minimising-risk-transmitting-animal-spongiform-encephalop-
sation under exceptional circumstances, pursuant to Article athy-agents-human-veterinary-medicinal_en.pdf. Accessed 12
14 (8) of Regulation (EC) 726/2004. 15 December 2005. April 2020.
(EMEA/357981/2005). EMA website. https://www.ema. 16. Joint CPMPICVMP Note for guidance on minimising the risk
europa.eu/en/documents/regulatory-procedural-guideline/ of transmitting animal spongiform encephalopathy agents via
guideline-procedures-granting-marketing-authorisation-un- human and veterinary medicinal products, explanatory note for
der-exceptional-circumstances-pursuant/2004_en.pdf. Accessed medicinal products for human use on the scope of the guideline.
12 April 2020. 28 February 2001. (EMEA/CPMP/BWP/498/01). EMA
7. Commission Regulation (EC) No. 507/2006 of 29 March website. https://www.ema.europa.eu/en/documents/scientif-
2006 on the conditional marketing authorisation for medicinal ic-guideline/joint-committee-proprietary-medicinal-products/
products for human use falling within the scope of Regulation cvmp-note-guidance-minimising-risk-transmitting-ani-
(EC) 726/2004 of the European Parliament and of the Council. mal-spongiform-encephalopathy-agents-human_en.pdf.
EC website. https://eur-lex.europa.eu/legal-content/EN/ Accessed 12 April 2020.
TXT/?uri=CELEX:32006R0507. Accessed 12 April 2020. 17. Questions and Answers on Bovine Spongiform
8. Guideline on the scientific application and the practical arrangements Encephalopathies (BSE) and Vaccines. 18 October
necessary to implement Commission Regulation (EC) 507/2006 on 2018. (EMA/CHMP/BWP/192228/2017). EMA

website. https://www.ema.europa.eu/en/documents/ 21. ICH S8 Immunotoxicity studies for human pharmaceuticals. 15

scientific-guideline/questions-answers-bovine-spongiform-en- September 2005. ICH website. https://database.ich.org/sites/
cephalopathies-bse-vaccines-revision-1_en.pdf. Accessed 12 default/files/S8_Guideline_0.pdf. Accessed 12 April 2020.
April 2020. 22. ICH Q5E Note for guidance on biotechnological/biological prod-
18. Resolution AP-CSP (07)1 of the Council of Europe, Public ucts subject to changes in their manufacturing process. (CPMP/
Health Committee, certificate of suitability to the monographs ICH/5721/03). June 2005. EMA website. https://www.ema.
of the European pharmacopoeia (Revised Version). 21 February europa.eu/en/documents/scientific-guideline/ich-q-5-e-com-
2007. EDQM website. https://www.edqm.eu/medias/fichiers/ parability-biotechnological/biological-products-step-5_en.pdf.
cep_procedure_revised_version.pdf. Accessed 12 April 2020. Accessed 12 April 2020.
19. ICH Q5A Viral safety evaluation of biotechnology products 23. Guideline on comparability of biotechnology-derived medicinal
derived from cell lines of human or animal origin. ICH website. products after a change in the manufacturing process-non-clin-
https://database.ich.org/sites/default/files/Q5A%28R1%29%20 ical and clinical issues. 1 November 2007. (EMEA/
Guideline_0.pdf. Accessed 22 April 2020. CHMP/BMWP/101695/2006). EMA website. https://
20. ICH S6 (Rl) Preclinical safety evaluation of biotechnology-de- www.ema.europa.eu/en/documents/scientific-guideline/
rived pharmaceuticals. June 2011. ICH website. https://database. guideline-comparability-biotechnology-derived-medici-
ich.org/sites/default/files/S6_R1_Guideline_0.pdf. Accessed 12 nal-products-after-change-manufacturing-process_en.pdf.

Chapter 32

Chapter 33
Pharmaceutical Postauthorisation
Requirements and Compliance
With the Marketing Authorisation
OBJECTIVES human use and veterinary medicinal products

(Consolidated Version 4 August 2013)
□ Understand marketing authorisation holders’
postauthorisation requirements in the EU □ Commission Guidelines on the details of the
various categories of variations, on the opera-
□ Understand regulations regarding postauthori- tion of the procedures laid down in Chapters II,
sation commitments IIa, III and IV of Commission Regulation (EC) No.
1234/2008 of 24 November 2008 concerning
□ Understand variations to marketing authorisa-
the examination of variations to the terms of
tion applications
marketing authorisations for medicinal prod-
□ Understand renewal requirements ucts for human use and veterinary medicinal
products and on the documentation to be sub-
□ Understand compliance requirements mitted pursuant to those procedures (2013/C
223/01) (Version 2 August 2013)

COVERED IN THIS CHAPTER Introduction
In accordance with Directive 2001/83/EC of the
□ Regulation (EC) No. 726/2004 of the European European Parliament and of the Council of 6 November
Parliament and of the Council of 31 March 2004 2001 on the Community code relating to medicinal
laying down Community procedures for the products for human use, as amended,1 a medicinal prod-
authorisation and supervision of medicinal uct for human use requires a marketing authorisation
products for human and veterinary use and (MA), which when granted, is valid for five years from
establishing a European Medicines Agency, as date of notification. It is renewable upon application
amended (Consolidated Version 5 June 2013) nine months before expiration, and once renewed, will
be valid for an unlimited period. One exception to this
□ Directive 2001/83/EC of the European unlimited period is when the competent authority agrees
Parliament and of the Council of 6 November to allow one additional five-year renewal period based
2001 on the Community code relating to on justification related to pharmacovigilance.
medicinal products for human use, as amended Regardless, the marketing authorisation holder
(Consolidated Version 16 November 2012) (MAH) shall provide the competent authority with a
consolidated version of the file including an evaluation
□ Commission Regulation (EC) No. 1234/2008
of suspected adverse reaction reports, periodic safety
of 24 November 2008 concerning the exam-
update reports (PSURs) (if applicable) and any relevant
ination of variations to the terms of marketing
new information affecting the benefit-risk of the prod-
authorisations for medicinal products for
uct in addition to a list of all variations introduced since

Chapter 33
the MA was granted but at least nine months before The MAH and Reference Member State (RMS)
the MA expires. should agree on a common renewal date at the com-
Throughout the postauthorisation phase, the pletion of the initial Mutual Recognition Procedure.
medicinal product must be manufactured in accordance In practice, this agreement should take place within
with the submitted marketing authorisation application 30 days of Day 90 of the procedure. Establishing this
(MAA). This medicinal product lifecycle phase also sets date should aid the MAH in renewing different prod-
out specific MAH responsibilities in different areas: uct presentations, the dates based on the international
• compliance with good manufacturing practice birth date (date of the first MA in any country in the
(GMP), good distribution practice (GDP) and world), the European birth date (date of the first MA
good pharmacovigilance practices (GVP) in the EU) or both. For products authorised through
• submission of data and updates on autho- the Decentralised Procedure, the common renewal date
rised medicines, including medicine shortage should be proposed by the RMS and agreed to when
notification, the procedure is completed (in practice, within 30 days
• renewals, variations, annual conditional MA of the procedure’s end).
renewals and annual re-assessments The MAH may apply for a renewal in less than
• carrying out postauthorisation studies, risk five years to synchronise renewal dates between the
management plans (RMP), MA transfer, mar- RMS and the Concerned Member States (CMS). This
keting and cessation notification and sunset is an optional procedure to be followed on a voluntary
clause monitoring, etc. basis by the MAH and Member States. At the end of
the 90-day European phase, the mutually recognised
The medicinal product’s quality, safety and efficacy product will have been approved by the CMS, and a
information must be updated continuously, considering five-year MA will have the same renewal date. The
scientific and technical progress, as well as the product’s product may be renewed immediately in the RMS,
safety data. In such cases, the MAH is required to make before the usual five-year renewal date on the basis
changes and variations to enable the medicinal product of the agreed SmPC and any minor changes arising
to be manufactured and checked by generally accepted from discussions. This renewal date change would be a
scientific methods. voluntary MAH request to the RMS. In the event the
The MAH is responsible for ensuring the medic- Mutual Recognition Procedure is repeated for subse-
inal product’s use is as safe and effective as possible. quent applications to other Member States, known as
If, during the postauthorisation phase, new safety data the repeat use procedure (RUP), the MAH could apply
regarding the medicinal product become available, for a renewal earlier than five years to synchronise the
they must be evaluated carefully and submitted to the renewal dates with the RMS. In case of an MRP or
authorities as an MAA variation. Sometimes, such RUP, where unlimited validity already has been agreed
variations result in changes to the product information in the RMS or in the “old” CMS, any MA granted as a
(summary of product characteristics (SmPC), labelling result of the new MRP will be subject to a renewal pro-
and package leaflet). It is essential to conduct pharma- cedure. However, some Member States may not require
covigilance activities throughout each drug product’s a renewal or may agree with an administrative renewal
lifecycle. Pharmacovigilance should include collecting with reduced documentation.3
and evaluating safety data from all available interna- A common EU renewal application form should
tional sources. be used for medicinal products authorised through
the Centralised, Mutual Recognition or Decentralised
Postauthorisation Requirements Procedures. The MAH should complete the EU
Mutual Recognition Procedure and Decentralised renewal application form and submit one form for each
Procedure Renewal MA. If an expert raises any significant issues, requiring
In accordance with Directive 2001/83/EC, Article 24, a revised SmPC, labelling and/or package leaflet to be
as amended, an MA is valid for five years and may be attached to the renewal application, the application
renewed on the basis of the authorising competent form should contain the exact current and proposed
authority’s re-evaluation of the benefit-risk balance. wording. Alternatively, such a listing may be provided as
Once renewed, the MA shall be valid for an unlimited a separate attachment using a tabular format, indicating
period unless the competent authority decides, as noted the current and proposed texts. Any proposed amend-
above, to proceed with one additional five-year renewal. ments to the SmPC should be discussed and agreed
If an MAH does not submit a renewal application, the with the RMS before submission.
MA will lapse.2 Since 1 January 2015, the Co-ordination
Group for Mutual Recognition and Decentralised

Pharmaceutical Postauthorisation Requirements and Compliance With the Marketing Authorisation
Procedures-Human (CMDh) has been piloting a new which obliges the MAH to take account of
streamlined renewal application procedure. Certain technical and scientific progress and intro-
clinical overview addendum elements can be omit- duce any changes to the medicinal product
ted for products authorised under Human Medicinal to ensure it is manufactured and checked
Products Directive Articles 10(1) and 10a, unless there is using generally accepted scientific methods
an obligation to submit periodic safety update reports o confirmation that all changes relating
(PSURs) for the product as an MA condition, or the list to the product’s quality have been made
of European Union Reference Dates (EURD) indicates following variation applications, and
PSURs are required for products authorised or regis- the product conforms to the European
tered under these articles and contain the substance or Medicines Agency’s (EMA) Committee
combination of substances concerned. for Medicinal Products for Human Use
(CHMP) current quality guidelines
Dossier Requirements o confirmation of currently authorised drug
When applying for renewal, the application must con- substance and drug product specifications
tain a consolidated version of the file, containing the (with latest approval date and procedure
documents listed below at minimum,4 presented as number)
follows (preferably in electronic Common Technical o active substance(s) and excipient(s)
Document (eCTD) format): qualitative and quantitative composition
(with latest approval date and procedure
Module 1: number)
1.0 Cover Letter
1.1 Comprehensive Table of Contents 2.4 Addendum to the Nonclinical Overview
1.2 Renewal Application form with Annexes An addendum to the nonclinical overview
1.3 Product Information: is not required automatically as part of the
o revised SmPC, labelling and/or pack- renewal application. When new data are sub-
age leaflet (exact current and proposed mitted in the nonclinical addendum, a critical
wording should be specified), taking into discussion must be submitted as part of the
account issues raised by the expert(s)(clin- renewal application, supporting the product’s
ical, nonclinical and quality) benefit-risk re-evaluation and taking into
account any new nonclinical data accumulated
1.4 Information About Expert(s) (Quality, since the initial MAA or last renewal or any
Nonclinical and Clinical, if applicable, includ- relevant new information in the public domain.
ing signature and CV)
2.5 Addendum to the Clinical Overview
1.8.2 Risk Management Plan (RMP) o the clinical expert statement should
o the RMP format and content should address the product’s current benefit-risk
follow the requirements set out in balance based on PSUR and safety/effi-
Commission Implementing Regulation cacy data accumulated since the MA was
on the performance of pharmacovigilance granted or its last renewal, referencing rele-
activities provided for in regulation (EC) vant new information in the public domain
No. 726/2004 and Directive 2001/83/ o the clinical expert statement also should
EC of the European Parliament and of confirm no new (preclinical or clinical)
the Council and for which guidance is data are available that change or result
provided in Module V of the Guidelines on in a new benefit-risk evaluation (where
Good pharmacovigilance practices there are new preclinical data, the MAH
o if the product does not have an RMP, this may submit a nonclinical expert report as
should be indicated in this module appropriate), confirm the product can be
renewed safely for an unlimited period
Module 2: after five years or specify and justify any
2.3 Addendum to the Quality Overall Summary action recommended or initiated and
The quality expert statement should include: confirm the authorities have been kept
o declaration of compliance with the Human informed of any additional data significant
Medicinal Products Directive, as amended, in assessing the concerned product’s bene-
fit-risk ratio

Chapter 33
Assessment Procedure Article 14(2) of Regulation 726/2004. The renewal

An automatic validation process begins the renewal date takes into account the international birth date and
procedure. The RMS starts the procedure based on maintenance of PSUR synchronisation and should be
MAH assurance the renewal applications have been agreed upon in advance with EMA, EMA’s CHMP
submitted to all CMS, and the relevant national fees, and Pharmacovigilance Risk Assessment Committee’s
where appropriate, have been paid (i.e., there is no (PRAC) rapporteurs. To facilitate the renewal applica-
requirement for CMS to acknowledge receipt). tion’s preparation and submission, the MAH is advised
A 90-day procedure is followed, and no more than to refer to EMA’s postauthorisation procedural advice
30 additional days are allowed. In exceptional circum- for Centralised Procedure users, contact the EMA
stances, and only with RMS agreement, the amount procedure manager responsible for its product and, if
of time the clock is stopped may be extended. If the considered necessary, organise a prerenewal submission
renewal takes longer to resolve, the product may remain meeting well in advance at a compatible date.
on the market while the renewal application is pending. The MAH should complete one renewal appli-
The Member States’ assessment approach focuses cation form per core EU number for the centrally
on a safety evaluation using PSUR data and any authorised medicinal product, appending a list of all the
relevant new information affecting the product’s bene- concerned authorised product’s strengths, pharmaceuti-
fit-risk ratio. A full dossier re-evaluation normally does cal forms and presentations. If the MAH does not wish
not occur. Module 3 quality data are not updated at to renew certain product presentations (e.g., a certain
renewal. The MAH is obligated to update quality data pharmaceutical form, strength or pack-size), this should
on an ongoing basis throughout the product’s lifecycle be indicated clearly in the cover letter, and that product
using the variation procedure. should not be included in the appended list.
If there is agreement the product’s benefit-risk
balance remains favourable at the end of the procedure, Dossier Requirements
and there are no pharmacovigilance issues, the MA may Renewal applications assist in re-evaluating the medici-
be granted unlimited validity. As mentioned previously, nal product’s benefit-risk balance. Renewal applications
in some circumstances, an additional five-year renewal should be submitted in eCTD format and must contain:
may be required. If serious public health issues remain
at the time of renewal, the MA will not be renewed. The Module 1:
non-renewal criteria are specified in Human Medicinal 1.0 Cover Letter
Products Directive Article 116, as amended. Additionally,
this non-renewal may apply when the MAH fails to 1.2 Renewal Application Form with the following
respond within the given timeframe to issues raised Annexes:
during the assessment and does not provide adequate o list of all authorised product presentations
justification or explanation.5 (follow the template for CHMP Opinion
Annex A)
Renewal of Centrally Authorised Products o details of contact persons: qualified person
In accordance with Regulation (EC) 726/2004 Article in the EEA for pharmacovigilance, person
14(1-3), an MA is valid for five years. Once renewed, in the EEA with overall responsibility for
the MA shall be valid for an unlimited period, unless, product defects and recalls and person for
as noted previously, the competent authority decides, on scientific service in the EEA in charge of
justified pharmacovigilance grounds, to proceed with one information about the medicinal product
additional five-year renewal. If an MAH does not submit o list of EU Member States, Norway and
a renewal application, the MA will expire. In accordance Iceland in which the product is marketed,
with regulation Article 12(1), the authorisation will be with each presentation and launch date
refused if the labelling and patient leaflet do not com- o chronological list of all postauthorisation
ply with Directive 2001/83/EC Title V’s requirements. submissions since the MA was granted or
Certain changes to the MA can be made at renewal, last renewed: list of all approved or pend-
which shall not trigger a variation procedure. Further ing Type IA/IB and Type II variations,
details of permitted changes are given in the Guideline on extensions, Article 61(3) Notifications,
the processing of renewals in the centralised procedure.6 USR and PSURs, giving the procedure
The MAH should submit the renewal applica- number (where applicable), submission
tion by the recommended submission dates published date, approval date (if approved) and brief
on the EMA website and, in any case, no later than description of the change
nine months before the MA ceases to be valid as per

o chronological list of conditions and spe- marketed product presentations after five years,
cific obligations submitted since the MA in one submission.
was granted or last renewed, indicating In case the MAH plans to change the
scope, status, date of submission and date overall design and readability of the labelling
the condition or obligation was fulfilled and/or package leaflet at renewal, it will not
(where applicable) be necessary to submit specimens of the “old”
o revised list of all remaining conditions and product design. If the MAH would like EMA
specific obligations (where applicable) feedback on its proposed new packaging prior
o statement, or when available, certificate to specimen submission and review, this should
of GMP compliance issued by an EEA be discussed with the EMA product lead
competent authority or MRA partner (EPL) or procedure manager (PM) prior to
authority, not more than three years old, renewal submission.
for the medicinal product manufacturer(s)
listed in the application. A reference to 1.4 Information About the Expert (If MAHs
the Community EudraGMP database, if wish to distinguish these declarations from any
available, is acceptable. previous declarations, the EMA renewal pro-
o for medicinal product manufacturing sites cedure number may be included on top.)
not located in the EEA or in an MRA’s 1.4.1 Information about the Expert: quality (includ-
territory, a list of the most recent GMP ing signature and CV)
inspections, indicating the date, inspection 1.4.2 Information about the Expert: nonclinical
team and outcome (including signature and CV), if applicable
o a declaration by the Qualified Person 1.4.3 Information about the Expert: clinical (includ-
(QP) for each MAH (i.e., located in ing signature and CV)
the EEA) listed in the application form,
stating the active substance is used as a 1.8.2 Risk Management Plan:
starting material and has been manu- o when no new data justify changes to the
factured in accordance with the detailed latest approved RMP, the MAH should
GMP guidelines (refer to Directive provide this information in the clinical
2001/83/EC Article 46(f )) overview declaration and confirm the cur-
o a declaration by the MAH QP listed in rent approved RMP remains unchanged
the application as responsible for batch and applicable
release o when the medicinal product has no RMP,
the cover letter should state this
1.3.1 Summary of Product Characteristics, Labelling
and Package Leaflet: Module 2:
A clean version of the SmPC, Annex II, outer 2.3 Addendum to Quality Overall Summary
and inner labelling and package leaflet in The addendum should include a declaration
English must be provided. In addition, the of compliance with Regulation (EC) No.
application should include a Word version 726/2004 Article 16(1), which obliges the
highlighting the MAH’s proposed changes. MAH “…to take account of technical and sci-
entific progress and introduce any changes that
1.3.3 Specimens: may be required to enable the medicinal prod-
At renewal, EMA will perform a new check of uct to be manufactured and checked by means
specimens across all marketed product presen- of generally accepted scientific methods.”
tations. Relevant example specimens should be The addendum to the quality overall sum-
provided to EMA as part of the renewal appli- mary also should include:
cation for each strength, pharmaceutical form o confirmation that all changes relating to
and container type in the smallest marketed product quality have been made following
pack-size. Ideally, multi-lingual specimens applications for variations and that the
should be provided but, if not available, a sin- product conforms to current CHMP qual-
gle-language specimen may be submitted. ity guidelines
EMA will receive and check at least o currently authorised specifications for the
one example specimen of the whole range of active substance and the finished product

Chapter 33
(with most recent approval date and pro- influencing the approved medicinal
cedure number) product’s benefit-risk balance (e.g., sus-
o qualitative and quantitative composition pension, withdrawal, temporary halt or
for the active substance(s) and the excipi- premature clinical trial ending for safety
ent(s) (with most recent approval date and reasons or issues requiring communication
procedure number) to healthcare professionals, etc.) All these
actions taken since the last PSUR’s DLP
2.4 Addendum to Nonclinical Overview up to the current renewal’s DLP should be
An addendum to the nonclinical overview highlighted clearly.
is not required automatically as part of the o significant changes to the reference
renewal application. information (RI) during the period from
When new data are submitted in the non- the initial marketing authorisation or
clinical addendum, a critical discussion must last renewal, a track changes version of
be submitted as part of the renewal application the document identifying changes made
supporting the product’s benefit-risk balance during the period from the initial market-
re-evaluation, taking into account any new ing authorisation or the last renewal also
nonclinical data accumulated since the initial should be provided up to the 90 days prior
MAA or the last renewal or any relevant new to renewal submission
information in the public domain. o estimated exposure and use patterns: data
If no new nonclinical data have been gath- on clinical trial subjects’ cumulative expo-
ered since the granting of the MA or the last sure as well as patients’ postmarketing
renewal, this may be stated in the addendum. exposure; if the MAH becomes aware of
a pattern of the medicinal product’s use,
2.5 Addendum to Clinical Overview considered relevant for interpreting and
The clinical overview addendum should implementing safety data, a brief descrip-
include a critical discussion addressing the tion should be provided, such patterns
product’s current benefit-risk balance on the may include, in particular, off-label use
basis of PSUR data and safety and efficacy o data in summary tabulations: summary
data accumulated since the MAA was granted tabulations of serious adverse events from
or the last renewal, referencing relevant new clinical trials and adverse reactions from
information in the public domain. The discus- postmarketing data sources reported
sion should clearly reflect the data previously during the period from the initial mar-
included in the PSUR and new data that have keting authorisation or the last renewal’s
been collected from the last PSUR’s data lock DLP up to the current renewal’s DLP
point (DLP) to the renewal’s DLP, which o summaries of significant safety and effi-
should not exceed 90 days prior to the renewal cacy findings from clinical trials and
submission. noninterventional studies: description of
The addendum should contain: any significant safety findings impact-
o pharmacovigilance system inspection ing clinical trial or noninterventional
history (date, inspecting authority, site studies, whether milestones from post-
inspected, inspection type and, if the authorisation safety studies (PASS),
inspection is product-specific, the list of postauthorisation efficacy studies (PAES),
products concerned) and an analysis of studies included in pharmacovigilance
overall findings’ impact on the medicinal plan and studies conducted as MA condi-
product’s benefit-risk balance tions or specific obligations (SOBs) have
o worldwide marketing authorisation status: been reached in accordance with agreed
overview of number of countries where timeframes; all changes should be clearly
the product has been approved and mar- highlighted
keted worldwide o tabulated overview of signals: high-level
o actions taken for safety reasons during the overview of signals evaluated during the
period from the initial marketing authori- period covered by the renewal and any
sation or last renewal up to the current action taken or planned and high-level
renewal’s DLP: description of signifi- overview of ongoing signals (i.e., those
cant actions related to safety, potentially

undergoing evaluation at the renewal • confirm the product information is up to date

application’s DLP) should be provided with current scientific knowledge, including
o signal and risk evaluation: the MAH the assessments’ conclusions and recommen-
should summarise signals evaluated during dations made publicly available on the EU
the renewal reporting period, signals that medicines website
became important in characterising the
risk should be provided, new signals eval- The above data are to be submitted in EU eCTD for-
uated should be clearly highlighted, the mat. More details can be found in the Guideline on the
MAH should discuss whether any changes processing of renewals in the centralised procedure.
are considered necessary to existing safety
concerns and whether any additional Assessment Procedure
product risk minimisation activities are EMA validates the application. Once validated, the
warranted, taking into consideration the MAH, CHMP and PRAC rapporteurs and other
data collected during the period covered CHMP members are informed, the timetable is
by the renewal adopted and the clock starts accordingly. Renewal
o literature: review of important literature application assessment consists of a benefit-risk bal-
references published during the period ance re-evaluation based on a consolidated version of
since the initial marketing authorisation the submitted file regarding quality, safety and effi-
or the last renewal’s DLP with a potential cacy, including evaluation of data in suspected adverse
impact on the medicinal product’s bene- reaction reports, PSUR data and any relevant new
fit-risk balance information on the product’s benefit-risk balance. A full
o benefit evaluation: the MAH should sum- re-evaluation of the whole dossier normally does not
marise important efficacy and effectiveness take place.
information (including information on lack The final CHMP opinion on the renewal applica-
of efficacy) for the period from the initial tion may be:
marketing authorisation or last renewal’s • favourable (recommending MA renewal with
DLP up to the current renewal’s DLP unlimited validity or requiring one additional
o benefit-risk balance: a discussion on the five-year renewal) or
approved indication’s benefit-risk balance • unfavourable (nonrenewal) if serious pub-
should be presented, based on the above lic health issues remain at the end of the
information procedure
o late-breaking information: the MAH
should summarise potentially important None of the changes introduced at renewal can substi-
safety, efficacy and effectiveness findings tute for the marketing authorisation holder’s obligation
arising after the DLP but during the to update the marketing authorisation throughout
clinical overview’s addendum preparation the life of the product by variation application as data
period emerge, provided that the implemented changes fall
within the scope of application of Regulation (EC) No.
Note: MAHs are advised to consider the Good 1234/2008 concerning the examination of variations
Vigilance Practice Module on PSURs as guidance for to the terms of marketing authorisations for medici-
preparing the clinical overview sections. nal products for human use and veterinary medicinal
The clinical expert statement should: products. Major changes to the product, such as the
• confirm no new clinical data are available that introduction of new indications and quality changes,
change or result in a new benefit-risk balance such as an extension of shelf life, shall not be mod-
evaluation ified through the renewal procedure and must be
• confirm the product can be renewed safely at assessed through the appropriate variation procedure.
the end of a five-year period for an unlimited Accordingly, no new studies should be submitted within
period or any action recommended or initiated the renewal unless they impact the benefit-risk balance
should be specified and justified of the medicinal product. However, any new data should
• confirm the authorities have been kept be discussed in the Addendum to the relevant overview
informed of any additional data significant for For medicinal products authorised under excep-
the assessment of the concerned product’s ben- tional circumstances, in accordance with Regulation
efit-risk balance (EC) No. 726/2004 Article 14(8) and Directive
2001/83/EC Annex Part II.6, as amended, the CHMP

Chapter 33
will have to consider whether any SOBs have been granting the MA. Flexibility in submitting data to
fulfilled. If any amendments were made to product synchronise with the SOBs’ submission is permissible.
information, the MAH must submit the relevant MAHs are advised to discuss this request with the
amended SmPC, labelling and package leaflet transla- agency and rapporteur well in advance of the submis-
tions within five days following the CHMP opinion. sion. Each MA is considered a standalone dossier and,
therefore, requires a separate annual re-assessment appli-
Re-examination cation, even if identical to another MA. For this reason,
The marketing authorisation holder may notify EMA/ no cross-references will be accepted, and complete appli-
CHMP in writing of its intention to request a reexam- cations must be submitted for each MA.
ination of the opinion within 15 days after receipt of
the opinion; if such a request is not made within the 15 Dossier Requirements
days, the opinion becomes final. The detailed grounds Annual re-assessment applications should follow the
for the request must be forwarded to EMA within appropriate headings and numbering in accordance
60 days after receipt of the opinion. If the marketing with the EU-eCTD format.
authorisation holder wishes to appear at the CHMP
for an oral explanation, such request also should be sent Module 1:
at this stage. A new CHMP Rapporteur, new CAT 1.0 Cover Letter with the following documents:
Rapporteur as applicable and a new PRAC Rapporteur, o a chronological tabulated summary table
different from those for the initial opinion, will be of SOBs stating the following for each:
appointed to coordinate the re-examination procedure, description, model system for comput-
accompanied, if necessary, by additional experts. er-assisted drug registration (SIAMED)
Within 60 days after the receipt of the detailed reference number, agreed due date indi-
grounds for re-examination, the CHMP will re-ex- cated in Product Information Annex II,
amine its opinion. If considered necessary, an oral SOB submission date and procedure (if
explanation can be held within this 60-day procedure. appropriate) and status. The cover letter
Once the CHMP issues a final opinion, it is for- also should contain the template table to
warded (with the required annexes and appendixes) to facilitate submission and registration.
the European Commission, the Member States, Norway o revised list of pending SOBs (where
and Iceland and the marketing authorisation holder. applicable)
At the end of the re-examination procedure, EMA
will publish a ‘summary of opinion’ of the CHMP final 1.3 Product Information: texts for SmPC, Annex
opinion. EMA will prepare an update of the EPAR, II, labelling and package leaflet, if changes are
reflecting the renewal assessment and CHMP opinion. proposed
After the Commission decision on the renewal, the 1.4 Information about the Expert—Clinical
updated EPAR shall be published.7 (including signature and CV)
1.8.2 Risk Management Plan
Annual Re-Assessment
In exceptional circumstances and following consulta- Module 2:
tion with the applicant, the MA may be granted subject 2.5 Addendum to Clinical Overview: expert report
to certain conditions or SOBs, particularly relating to addressing the data and the SOBs’ fulfilment
the medicinal product’s safety, notification to national status and impact on the medicinal product’s
competent authorities of any incident relating to its use overall benefit-risk profile on which the clin-
and action to be taken. Refer to Regulation (EC) No. ical overview update or addendum will be
726/2004, Article 14(8).8 When an MA is granted under based:
such conditions, the MAH must submit postauthorisa- o information already submitted to fulfil
tion data on a defined schedule. These additional data, or ongoing SOBs
SOBs, are described in Annex II.E of the Commission o information submitted at the anniversary
decision forming the basis of the annual re-assessment date to address outstanding SOBs
or the annual renewal. The SOBs are to be reviewed at o critical evaluation of fulfilment status
the intervals indicated and at least annually. The annual
review includes a benefit-risk profile re-assessment. The 2.7 Clinical summaries generally will need to be
annual re-assessment application should be submitted updated, as appropriate, when new clinical
on the anniversary date of the Commission decision study reports are submitted

Module 5: in the CHMP assessment report. These data should be

5.3.5 Reports of Efficacy and Safety Studies (as reviewed in accordance with the agreed deadlines.
appropriate)
PAMs Enforcement
Assessment Procedure In case of an MAH’s noncompliance in satisfying
Depending on the CHMP assessment, one of the fol- PAMs, the responsible committee(s) will consider the
lowing outcomes can be predicted: need for appropriate actions to be taken focusing pri-
1. Maintenance of the MA regarding SOBs marily on assessing these data’s impact on the affected
remains in place unchanged and SOBs’ data product’s benefit-risk balance. A letter may be sent to
do not necessitate MA changes (e.g., changes the MAH, an oral explanation requested or a referral
to the medicinal product’s benefit-risk balance procedure undertaken on whether to vary, suspend or
and product information). All SOBs will be revoke the MA or request an inspection.
reviewed again at the next annual re-assess-
ment, as will their impact on the medicinal Variations
product’s benefit-risk profile. MAHs are responsible for marketed medicinal products
2. Variation of the MA considering SOBs needs throughout their lifecycles. MAHs also are required to
to be modified and/or SOBs’ data necessi- track technical and scientific developments and make
tate changes to the MA (e.g., changes to the any necessary amendments to enable their products to
medicinal product’s benefit-risk profile and/ be manufactured and verified by generally accepted sci-
or product information). All SOBs will be entific methods. In addition, MAHs may wish to alter or
reviewed again at the next annual re-assess- improve the medicinal product or introduce additional
ment, as will their impact on the medicinal safeguards. Such variations to the MA may require not
product’s benefit-risk profile. only administrative data but also more substantial infor-
3. MA suspension or revocation due to SOBs’ mation. The following section describes Centralised,
data affects the medicinal product’s bene- Mutual Recognition and Decentralised Procedure varia-
fit-risk profile to the extent it necessitates MA tions. Regardless of the procedure used, Regulation (EC)
suspension or revocation or the SOBs’ compli- No. 1234/2008 (Variations Regulation) applies.
ance status is unsatisfactory; therefore, CHMP Variations to medicinal products can be classified in
considers the SOBs, as conditions to the MA, different categories, depending on the public health risk
have not been fulfilled. level and the impact on the concerned medicinal prod-
4. CHMP may consider all SOBs have been uct’s quality, safety and efficacy. It should be clarified
fulfilled and, therefore, will recommend lifting that certain changes with the highest potential impact
the exceptional circumstances. on medicinal products’ quality, safety or efficacy require
the same complete scientific assessment as a new MAA
The agency subsequently will forward the opinion to the evaluation.9
European Commission, the Member States, Norway, The different MA variation types (e.g., administra-
Iceland and the MAH with the CHMP assessment tive, quality, safety, efficacy and pharmacovigilance) have
report. The European Commission’s decision-making been categorised:
process starts when the opinion and annexes in all • A Type IA Variation is any well-defined, minor
official EU languages have been received. If the MA change with minimal or no impact on the
annexes have not been affected by the annual re-assess- concerned product’s quality, safety or efficacy.
ment, no Commission decision will be issued. The Type IA variation classification is listed in
Annex II(1) of the Variations Regulation. These
Other Postauthorisation Measures (PAMs) variations do not require prior approval before
Other PAMs are conditions imposed on the MA, implementation (“Do and Tell” procedure) and
whether the MA is granted under exceptional circum- are classified in two subcategories: Type IAIN
stances, that might arise from the renewal procedure. (requiring immediate notification) and Type
Other PAMs are classified as conditions reflected in IA (requiring notification within 12 months
Annex II of the Commission decision (ANX), addi- following its implementation). The review time
tional pharmacovigilance activities in the RMP (MEA), is 30 calendar days following the competent
legally binding measures (LEG) already defined as stat- authority’s receipt of the documentation.
utory obligations or recommendations (REC) included • A Type II Variation is a major change to
the MAH’s proposed documentation with
a potentially significant impact on product

Chapter 33
quality, safety or efficacy. The Type II variation application to the same authority. Variation
classification is listed in Annex II(2) of the groupings may be used for:
Variations Regulation. Type II variations require o several Type IA or IAIN variations affect-
prior approval before implementation (“prior ing one medicinal product
authorisation” procedure). The standard assess- o one Type IA or IAIN variation affecting
ment time is 60 days for adopting the opinion; several medicinal products from the same
however, the regulation allows the possibility MAH
of reducing or extending the review time (30 o several Type IA and/or IAIN variations
or 90 days, respectively). Following application affecting several medicinal products from
review, an assessment report is written. the same MAH, provided those variations
• Minor Type IB Variations, which are classified apply to all medicinal products and are
as neither Type IA variations nor major Type submitted to the same authority
II variations or extensions, also are considered o Type IA or IAIN variations grouped
notifications. Such minor variations (notifi- with other variation types (Type IB or
cations) must be notified to the competent II extensions)—such grouped variations
authority but do not require formal approval. will follow the highest level variation
However, the MAH must wait 30 days to review procedure in the group. (It should
ensure the competent authority deems the be noted when submitting Type IA/IAIN
notification acceptable (“Tell, Wait and Do” variations as a part of a group, the legal
procedure).10 A Type IB by default is a change deadlines for submission of each variation
not mentioned in Annex II of the Variations should be respected.)
Regulation (or the classification guideline) or • Work-sharing variations allows the MAH to
is used if the conditions for a minor variation submit the same Type IB or Type II variation
of Type IA are not met, and the change is not or the same group of variations affecting more
specifically classified as a major Type II varia- than one marketing authorisation from the
tion. If the competent authority considers that same MAH in one application.
a variation submitted as a Type IB by default • A line extension application is for a major
may impact the medicinal product’s quality, change requiring a full assessment in accor-
safety or efficacy significantly, it may request dance with Article 17 of the Human Medicinal
that the application be upgraded and processed Products Directive (i.e., 210 days). The catego-
as a Type II variation.11 ries are listed in Variations Regulation Annex I.
• An unforeseen variation is one where the
proposed variation is considered to be neither An urgent safety restriction (USR) is an interim prod-
a minor variation of Type IB following the uct information change resulting from new information
Commission classification guideline nor has with a bearing on the product’s safe use, particularly
been classified as a Type IB variation in an concerning one or more of the following items in the
Article 5 recommendation. When one or more SmPC: indication(s), posology, contraindications,
of the conditions established in the guideline warnings, target species and withdrawal periods. This
for a Type IA variation is not met, the con- variation is used in the event of a risk to public health.
cerned change may be submitted as a Type IB A USR must be implemented within a timeframe
variation unless the change is classified spe- agreed upon with the competent authority. The MAH
cifically as a major Type II variation. Prior to must submit the corresponding variation application
submitting an unclassified variation, the MAH reflecting the USR within 15 days of initiating the USR
may request the competent authority, CMDh in accordance with Variations Regulation Article 22(3).12
or, in the case of a centralised MA, EMA, to
provide a recommendation on the variation’s Dossier Requirements for Variations
classification. This shall be delivered within 45 A common application form for National,
days from receipt of the request. Centralised, Decentralised and Mutual Recognition
• Variation grouping was introduced in the Procedures, “Application for Variation to a Marketing
Variations Regulation to facilitate the variation Authorisation,” always should be used. It must contain:
reviews and reduce the administrative burden. • procedure type (Mutual Recognition,
Multiple variations of the same type to one or Decentralised, Centralised or National)
several MAs owned by the same MAH can be • variation type (Type IA, Type IAIN, Type IB
notified simultaneously in a single variation Unforeseen, Type IB foreseen, Type II, Type

II Article 29 (of Regulation (EC) 1901/2006) MAH sends notification simultaneously to the RMS
and, additionally, whether it is a single varia- and CMS within 12 months (annual report) for Type
tion, grouping or work-sharing IA, or immediately after implementation of a minor
• for Type IB and Type II variations only, reason variation for Type IAIN. A Type IA/IAIN variation
for change (indication, safety, safety follow- notification should contain the elements listed in Annex
ing USR, quality, annual variation for human IV of the Variations Regulation and should be pre-
influenza vaccines) sented in accordance with the appropriate headings and
• administrative data numbering of the EU-CTD format. The Commission
• products, including their invented names, Variations Guidelines further specifies which elements
active substance(s), pharmaceutical forms, should be included in a Type IA/IAIN variation notifi-
strengths, MAH name, MA number and vari- cation. To help MAHs ensure that their Type IA/IAIN
ation number variations are complete and correct before submitting
• change type (relevant classification guideline them to the agency, it is strongly recommended to use
section) the prenotification checklist before
• change scope, background and justification for submission of any Type IA or Type IAIN varia-
grouping, work-sharing and classification tion. Deficient and missing documentation can lead to
• other related application(s), if any rejection of the variation. However, in exceptional cases
• present and proposed situation and wording the agency may issue a single request for supplementary
• applicant declarations information, for which a response should be provided
• proposed implementation date within four working days in the mandatory eCTD for-
• applicant signature(s) mat for electronic submissions.13
The procedure starts at Day 0, provided the required
In addition to the application form, the following documentation has been submitted and the relevant fees
should be submitted to the competent authority(ies): paid. If all the documentation has not been provided, the
• cover letter (for groupings, include a short notification will be deemed unacceptable and the MAH
overview of the nature of changes) should cease applying the concerned variation(s) imme-
• copy of the relevant Commission guideline diately. Alternatively, the MAH may decide to submit
page(s), indicating all conditions and require- a new variation, which will require a new variation pro-
ments are met cedure number. The RMS checks only the notification’s
• for variations affecting the SmPC, label- validity with respect to the supporting documentation.
ling and/or package leaflet, revised product Neither the RMS nor CMS will perform a full assess-
information and, if appropriate, mock-ups or ment of the supporting data in detail. The CMS should
specimens not comment to the RMS or MAH about the content’s
• relevant data to support the proposed variation acceptability; however, the CMS may comment if docu-
• for an unclassified variation, a detailed jus- mentation is not received or fees are not paid. For Type
tification for its submission as a Type IB IA variations, the RMS requests no clarification, infor-
notification mation or documentation from the MAH, and there is
• for variations requested by the authority fol- no clock stop or suspension of the process.14
lowing PAMs, SOBs or PSURs’ assessment, or The RMS will make the decision as to whether the
following class labelling, annex a copy of the notification is accepted or rejected within 30 days. If
request to the cover letter the notification is acceptable, the RMS will inform the
• for Type II variations, an addendum or MAH on behalf of the CMS and issue an “acknowledge-
updated Module 2 overview and/or summary ment of an acceptable notification.” If the notification is
• proof of payment or declaration that fees have unacceptable, the MAH also is informed in writing with
been paid (if applicable) a specified reason for nonacceptance. If any amendment
• if the variation is submitted via the Mutual to the decision granting the authorisation is required, all
Recognition or Decentralised Procedure, the Member States concerned will update the MA within
RMS should receive the list of dispatch dates two months following receipt of the variation’s positive
from the applicant to the CMS outcome or within six months for minor Type IA varia-
tions requiring immediate notification (Type IAIN).
Assessment and Notification for Variations For Type IA variation applications submitted
Notification for Minor Variations of Type IA/IAIN through the Centralised Procedure, the MAH sends
For variation applications submitted through the notification to EMA, without involving the rapporteur.
Mutual Recognition or Decentralised Procedures, the However, the agency will submit a copy of the Type IA

Chapter 33
notification to the rapporteur for information purposes. 30, the RMS and CMS accept the variation, the RMS
EMA checks the notification’s validity with respect to circulates an acceptance notification to the MAH,
the supporting documentation. By Day 30 after receiv- informs the CMS by updating CTS and the procedure
ing the notification, EMA advises the MAH of its ends. If the RMS does not accept the variation, taking
validity or invalidity. Where the assessment’s outcome into account CMS comments, the RMS circulates a
is favourable, and the Commission decision granting rejection notification to the CMS and MAH (“refusal”)
the MA requires any amendment, EMA will inform the and the procedure ends.16
Commission and transmit the revised documentation. Where necessary, the competent authorities will
In this case, the Commission will update the decision update the MA nationally within six months following
granting the MA within 12 months at the latest.15 the procedure being closed by the RMS. However, the
MAH may implement accepted Type IB minor varia-
Notification for Minor Variations of Type IB tions without awaiting the MA update.
For Type IB variation applications submitted through For Type IB variation applications submitted
the Mutual Recognition or Decentralised Procedure, through the Centralised Procedure, the MAH sends the
the MAH sends the notification simultaneously to the notification to EMA and the rapporteur. The co-rap-
RMS and CMS and sends the list of dispatch dates porteur is not involved in Type IB variations; however,
to the RMS. After receiving the application, the RMS a copy of the complete Type IB notification also must
and CMS will check its validity. The RMS also will be submitted to the co-rapporteur. EMA checks the
check within seven calendar days whether the proposed application’s validity within seven calendar days, and all
change can be considered a Type IB minor variation issues identified during validation are emailed to the
and whether the notification is correct. When the MAH. The MAH will be asked to provide responses to
proposed variation is not considered a Type IB minor the issues raised within five working days. If the valida-
variation and, in the RMS’ opinion, impacts the medic- tion phase is finalised positively, the agency confirms the
inal product’s quality, safety or efficacy significantly, positive outcome to the MAH and the procedure starts.
the CMS and MAH are informed immediately. If the Within 30 calendar days following acknowledgement of
CMS do not disagree within a further seven days, the a valid notification’s receipt, EMA will notify the MAH
MAH will be asked to reclassify the variation to Type via Eudralink of the procedure’s outcome. If, within 30
II and supplement its application to meet the Type II days, EMA has not informed the MAH the notifica-
major variation requirements. Following receipt of the tion cannot be approved, the variation shall be deemed
valid revised variation application, a Type II assessment to have been accepted. If there are any deficiencies (an
procedure will be initiated. If the CMS disagree with unfavourable outcome), the MAH has 30 days to submit
the RMS, the RMS will make the final decision on the an amendment. If the MAH does not amend the notifi-
proposed variation’s classification, taking into account cation within 30 days, as requested, the notification will
comments received. be rejected. Within 30 days of receiving the amended
Once the Type IB notification classification is notification, the agency will inform the MAH of the
accepted and validated, the RMS starts the procedure, final outcome—acceptance or rejection—and whether
informing the MAH of the start date (Day 0). The the Commission decision requires any amendments. If
RMS should notify the CMS within 20 days from the it has to be amended, the Commission will update the
procedure’s start on its position regarding the change. MA within one year following receipt of EMA’s noti-
The CMS should send their comments, if any, on the fication. However, MAH may implement the accepted
RMS position and update the communication and minor variation without awaiting the MA update.17
tracking system (CTS) accordingly between Day 20
and Day 27 of the procedure. If the RMS accepts the Notification for Major Type II Variations
variation, taking into account any CMS comments, For Type II variation applications submitted through
the RMS sends the MAH an acceptance notification, the Mutual Recognition or Decentralised Procedure
informs the CMS by updating the CTS and the pro- (standard 60-day timetable), the MAH sends the
cedure ends (Day 30). If the rms does not accept the application simultaneously to the RMS and CMS.
variation, taking into account the CMS comments, the Additionally, the RMS should receive the list of dis-
RMS circulates the “notification with grounds” to the patch dates indicating the Type II variation procedure
CMS and MAH, and the clock stops. Within 30 days number, the dates on which the applications have been
of receiving this notification, the MAH submits an sent to each CMS and confirmation that relevant fees
amended notification to the RMS and CMS and a list have been paid as required by national authorities. The
of dispatch dates to the RMS only. The RMS restarts RMS and CMS check the application’s validity, and the
the clock, and a new Day 0 is set. If, after the new Day RMS informs the MAH of the start date (Day 0). As a

general rule, a 60-day standard evaluation timetable will Day 50. By Day 60, CHMP formulates its opinion
apply. It can be reduced to 30 days for safety issues or based on the rapporteur’s assessment report or requests
extended to 90 days for variations concerning therapeu- supplementary information. If supplementary infor-
tic indication changes or additions. mation is requested, the procedure will be suspended
By Day 40, the RMS prepares the preliminary until this information is provided. As a general rule, a
variation assessment report (PVAR) and circulates it standard one-month clock will apply. In justified cir-
to the MAH and CMS. The RMS should indicate cumstances, it can be suspended for up to two months.
clearly in the PVAR whether it endorses the variation Upon adoption of the CHMP opinion, EMA will
in its proposed form or thinks it should be rejected or inform the MAH within 15 days whether the CHMP
amended. By Day 55, the CMS send the RMS their opinion is favourable or unfavourable (including
comments on the PVAR. If there are no objections to grounds for an unfavourable outcome) and whether the
the variation, the procedure may be finalised on Day 60. Commission decision granting the MA requires any
If any amendments are required, the RMS sends the amendments. Any necessary MA updates must be made
MAH and CMS a request for supplementary infor- within two months. The standard 60-day timetable may
mation (RSI) on Day 59. The procedure is suspended be reduced to 30 days (particularly for safety issues) or
until the supplementary information is provided. The extended to 90 days (for variations concerning thera-
recommended clock-stop period is one month; however, peutic indication changes or additions).19
a longer suspension is possible, provided the MAH The approved Type II major variations may be
sends the RMS a justified request. The RMS’ evalua- implemented only after the Commission amends the
tion of responses may take up to 60 days, depending decision and notifies the MAH. If there are no amend-
on the data complexity and amount submitted with ments to the Commission decision granting the MA,
the response. On Day 60, the RMS circulates the final the MAH may implement the approved variation only
variation assessment report (FVAR) to the CMS for after it is informed by the Commission.
comments and to the MAH for information purposes.
If the RMS and CMS disagree, a breakout session can Major Changes Necessitating an Extension
be arranged (Day 75). By Day 85, the CMS send the Application
RMS their final comments on the FVAR. If the vari- Certain MA changes are considered to alter the
ation is accepted, the RMS will inform the MAH and authorisation’s terms fundamentally; therefore, they
CMS that it is considered acceptable, together with the cannot be considered as variations. To make these
acceptance date. The MAH can implement the varia- changes, an extension application is necessary. Variations
tion 30 days after being informed of its acceptance by Regulation Annex I includes three main change catego-
the RMS. Competent authorities should implement ries requiring an extension application:
the decision nationally within two months of the pro- 1. drug substance(s) changes
cedure’s end. If the RMS and CMS reject the variation, 2. strength, pharmaceutical form or route of
the RMS will inform the MAH and CMS it is rejected administration changes
and provide a reason(s) for the rejection. If mutual rec- 3. other changes specific to veterinary medicinal
ognition by one or more CMS is not possible due to products to be administered to food-producing
a potential serious risk to public health (PSRPH), the animals, change or addition of target species
matter is referred to CMDh. To avoid arbitration, the
MAH may withdraw the variation application from all These applications require a complete scientific evalua-
CMS and the RMS.18 tion to support the change.20
For Type II variations to applications submitted
through the Centralised Procedure, the MAH sends
the application to EMA and the rapporteur. The Conclusion
co-rapporteur normally is not involved in assessing a • Once a medicinal product is authorised, the
Type II variation application unless it concerns a new MAH must ensure the MA remains in com-
indication. In this case, MAHs should contact EMA pliance with the actual manufacturing process
at least two months prior to the intended submission and product information.
date. EMA acknowledges receipt of a valid application • MAs are subject to:
and informs the MAH of the start date (Day 1) in o specific obligations
accordance with the official start dates published on the o variations
agency’s website. Under the standard 60-day timetable, o renewals
the rapporteur prepares an assessment report (Day 30). o postmarketing pharmacovigilance
Other CHMP members can send their comments until activities

Chapter 33
• Postmarketing activities are the most Community procedures for the authorisation and supervi-
resource-intensive phase for a regulatory sion of medicinal products for human and veterinary use
and establishing a European Medicines Agency, as amended
department and extend throughout the entire (Consolidated version: 5 June 2013). EUR-Lex website.
product lifecycle. http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=O-
• Variations can be classified in different cate- J:L:2004:136:0001:0033:en:PDF. Accessed 24 April 2020.
gories (Type IA, IAIN, IB, II, Line extension, 9. Commission Regulation (EC) No. 1234/2008 of 24 November
2008 concerning the examination of variations to the terms
USR), depending on the level of the risk to of marketing authorisations for medicinal products for
public health and the impact on the concerned human use and veterinary medicinal products, as amended.
medical product’s quality, safety and efficacy. (Consolidated Version). 2 November 2012). EUR-Lex website.
• The Variations Regulation does not apply to http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=O-
J:L:2008:334:0007:0024:en:PDF. Accessed 24 April 2020.
transfers of an MA from one MAH to another. 10. European Medicines Agency post-authorisation procedural
• Regulation (EC) No. 1234/2008 on varia- advice for users of the centralised procedure, EMA-H-19984/03
tions allows MAHs variation grouping and Rev. 84 (Dec 2019). EMA website. https://www.ema.
work-sharing to avoid duplication of work for europa.eu/en/documents/regulatory-procedural-guideline/
european-medicines-agency-post-authorisation-procedural-ad-
both competent authorities and MAHs. vice-users-centralised-procedure_en.pdf. Accessed 24 April
• The initial MA is valid for a period of five 2020.
years. At the end of this period, an application 11. Commission Guidelines on the details of the various categories of
for renewal must be submitted. variations, on the operation of the procedures laid down in Chapters
II, IIa, III and IV of Commission Regulation (EC) No. 1234/2008
• In most cases, MAs are renewed only once. of 24 November 2008 concerning the examination of variations
Therefore, special provisions regarding phar- to the terms of marketing authorisations for medicinal products for
macovigilance activities and frequency of human use and veterinary medicinal products and on the documenta-
PSUR submission have been reinforced. The tion to be submitted pursuant to those procedures (2013/C 223/01).
GMP Compliance website. http://www.gmp-compliance.org/
new pharmacovigilance legislation will have a guidelines/gmp-guideline/id-2013-c-223-01-guidelines-on-
major impact on renewal procedures. the-details-of-the-various-categories-of-variations-on-the-op-
• None of the changes introduced at renewal can eration-of-the-procedures-laid-down. Accessed 24 April 2020.
substitute for the MAH’s obligation to update 12. Ibid.
13. Ibid.
the MA throughout the product’s lifecycle by 14. Best Practice Guides (BPGs) for the submission and processing of
variation procedure as data emerge, provided variations in the Mutual Recognition Procedure, Chapter 3: CMDh
the implemented changes fall within the BPG for the processing of Type IA Minor Variations (Notifications)
scope of application of Regulation (EC) No. in the Mutual Recognition Procedure, CMDh/293/2013/Rev
22 (September 2016). CMDh website. http://www.hma.eu/
1234/2008. fileadmin/dateien/Human_Medicines/CMD_h_/procedural_
guidance/Variations/CMDh_293_2013_Rev22_2016_09_clean.
References pdf. Accessed 24 April 2020.
1. Directive 2001/83/EC of the European Parliament and of 15. Op cit 11.
the Council of 6 November 2001 on the Community code 16. Best Practice Guides (BPGs) for the submission and processing of
relating to medicinal products for human use, as amended variations in the Mutual Recognition Procedure, Chapter 4: CMDh
(Consolidated Version. 16 November 2012. EUR-Lex website. BPG for the processing of Type IB Minor Variations (Notifications)
http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=O- in the Mutual Recognition Procedure, CMDh/294/2013/Rev. 23
J:L:2001:311:0067:0128:en:PDF. Accessed 24 April 2020. ( July 2016). CMDh website. http://www.hma.eu/fileadmin/
2. Best Practice Guide on the processing of renewals in the Mutual dateien/Human_Medicines/CMD_h_/procedural_guidance/
Recognition and Decentralised Procedures, CMDh/004/2005/ Variations/CMDh_294_2013_Rev23_2016_07_-_Chapter_4_
Rev 16 (February 2018). CMDh website. https://www.hma.eu/ clean.pdf. Accessed 24 April 2020.
fileadmin/dateien/Human_Medicines/CMD_h_/procedural_ 17. Op cit 10.
guidance/Renewal/CMDh_004_2005_Rev16_02_2018_clean. 18. Best Practice Guides (BPGs) for the submission and processing
pdf. Accessed 24 April 2020. of variations in the Mutual Recognition Procedure, Chapter 5:
3. Ibid. CMDh BPG for the handling of Type II Variations in the Mutual
4. Ibid. Recognition Procedure, CMDh/295/2013/Rev 22 ( July 2016).
5. Ibid. CMDh website. http://www.hma.eu/fileadmin/dateien/
6. Guideline on the processing of renewals in the Centralised Procedure, Human_Medicines/CMD_h_/procedural_guidance/Variations/
EMEA/CHMP/2990/00 Rev. 5 (14 July 2016). EMA website. CMDh_295_2013_Rev22_2016_07_-_Chapter_5_clean.pdf.
http://www.ema.europa.eu/docs/en_GB/document_library/ Accessed 24 April 2020.
Regulatory_and_procedural_guideline/2016/08/WC500211495. 19. Op cit 10.
pdf. Accessed 24 April 2020. 20. Ibid.
7. Ibid.
8. Regulation (EC) No. 726/2004 of the European Parliament
and of the Council of 31 March 2004 laying down

Chapter 34
Pharmacovigilance
OBJECTIVES European Medicines Agency, and Regulation

(EC) No. 1394/2007 on advanced therapy medic-
□ Provide a brief background on pharmacovigi- inal products
lance (PV)
□ Regulation (EU) No. 1027/2012 of the European
□ Orient readers on the regulations and directives Parliament and of the Council of 25 October
that define EU PV requirements 2012 amending Regulation (EC) No. 726/2004
as regards pharmacovigilance
□ Describe the Good Pharmacovigilance (GVP)
guideline □ Regulation (EU) No. 658/2014 of the European
Parliament and of the Council of 15 May 2014 on
□ Discuss the GPV’s relevance to the regulatory
fees payable to the European Medicines Agency
professional
for the conduct of pharmacovigilance activities
□ Discuss how key guideline elements are inter- in respect of medicinal products for human use
preted by regulatory agencies and companies
□ Directive 2010/84/EU of the European
□ Review recent updates to the guideline and Parliament and of the Council of 15 December
anticipated future changes 2010 amending, as regards pharmacovigilance
Directive 2001/83/EC on the Community code
relating to medicinal products for human use
DIRECTIVES, REGULATIONS AND GUIDELINES □ Directive 2012/26/EU of the European
COVERED IN THIS CHAPTER Parliament and of the Council of 25 October
□ European Medicines Agency (EMA) Good phar- 2012 amending Directive 2001/83/EC as
macovigilance practices regards pharmacovigilance
□ ICH Periodic Benefit-Risk Evaluation Report □ Commission Implementing Regulation (EU) No.
(PBRER) E2C(R2) 520/2012 of 19 June 2012 on the performance
of pharmacovigilance activities provided for in
□ Regulation (EU) No. 1235/2010 of the European Regulation (EC) No. 726/2004 of the European
Parliament and of the Council of 15 December Parliament and of the Council and Directive
2010 amending, as regards pharmacovigi- 2001/83/EC of the European Parliament and of
lance of medicinal products for human use, the Council
Regulation (EC) No. 726/2004 laying down
Community procedures for the authorisation □ Directive 2001/20/EC of the European
and supervision of medicinal products for Parliament and of the Council of 4 April 2001
human and veterinary use and establishing a on the approximation of the laws, regulations

Chapter 34
and administrative provisions of the Member event reports, e.g., the use of social media, which has
States relating to the implementation of good increased the amount of patient information avail-
clinical practice in the conduct of clinical trials able, and patient participation at regulatory agency
on medicinal products for human use committee meetings on drug safety. In addition, more
sophisticated methods to detect safety signals within
large safety datasets have been implemented, regulatory
Introduction agencies now have wider powers to require postapproval
Recognised as a key public health function, phar- safety studies and summary of product characteristics
macovigilance (PV) is defined by the European (SmPC) updates and pharmaceutical industry and reg-
Commission as the process and science of monitoring ulatory agency efforts to harmonise global requirements
the safety of medicines and taking action to reduce their continue to reduce burden and facilitate a common
risks and increase their benefits. understanding and faster communication of a product’s
PV’s origin generally is considered to have been benefit-risk profile.
the thalidomide disaster in the early 1960s. This led
to the implementation of systematic procedures to Regulations
detect adverse reactions that occurred for the first time Regulation (EU) No. 1235/2010 and Directive
after the product was placed on the market. Although 2010/84/EU were approved in December 2010 by the
medicines undergo preclinical testing and clinical European Parliament and Council, with an imple-
evaluation of safety and benefit-risk before marketing mentation deadline of July 2012. They were supported
approval, often in thousands of patients, the number by Commission Implementing Regulation (EU) No.
of patients receiving the product postapproval usually 520/2012, published in June 2012, which provides addi-
increases several-fold, including patient groups not tional information and includes transitional timeframes
evaluated extensively preapproval. Patients who would for several of the new legislation’s elements through
have been excluded by clinical trial protocols, e.g., 2016. The full texts of regulations and directives are on
women of childbearing potential, pregnant women, the the Commission’s website http://ec.europa.eu/health/
elderly and children, may receive the treatment. Further, documents/eudralex/.
postapproval patient treatment rarely is monitored as While the regulation, directive and GVP refer to
rigorously for adverse events as during a clinical trial. the EU, GVP also has been adopted by three mem-
These factors increase the risk of previously unidentified bers of the European Free Trade Association (EFTA):
adverse reactions. Norway, Liechtenstein and Iceland. Collectively, the EU
Through the end of the 20th century, regulations Member States, combined with Norway, Liechtenstein
were enacted worldwide, requiring companies and reg- and Iceland, are known as the European Economic
ulatory agencies to implement systematic procedures to Area (EEA). References to the EU in this chapter,
detect unexpected adverse reactions, as were oversight unless otherwise noted, also mean EEA.
committees such as the UK’s Committee on Safety of Implemented in July 2012, the GVP guideline
Medicines. The procedures were known collectively as provides definitive instructions to companies operating
postmarketing surveillance, at the centre of which was in the EU on interpreting and implementing the PV
spontaneous reporting of suspected adverse reactions Regulation and PV Directive. It is the primary refer-
(ADRs) by healthcare professionals, usually on a volun- ence on how pharmaceutical companies are expected
tary basis. This fundamental methodology has strengths, to comply with PV obligations and, therefore, sets the
including its simplicity and the ability to detect rare standard against which internal company auditors and
ADRs, and remains pivotal to PV; however, for most EU regulatory agency inspectors scrutinise companies’
products, these procedures were limited due to ADR PV systems. GVP is a comprehensive, detailed guideline
underreporting and an absence of accurate patient reflecting PV principles and practices adopted world-
exposure, leading to unreliable risk estimates. Over just wide, not only in the EU. This chapter focuses on the 12
a few decades, regulatory agencies added several related GVP modules released from 2012 to 2017 (Table 34-1).
requirements and standards, extending the scope to GVP’s scope is medicinal products with a pending
additional data collection methods, analysis guidance or approved marketing authorisation (MA), whether
and control and safety information reporting, and intro- authorised centrally or nationally. A PV system compli-
duced measures to minimise medicines’ risks. ant with GVP needs to be in place and fully operational
The discipline became known more commonly from the day the company’s first marketing authorisation
as pharmacovigilance. PV continues to change, as the application (MAA) is submitted. Companies must sum-
practice of medicine and access to medicinal products marise their PV systems in common technical document
evolve, calling for new approaches for collecting adverse (CTD) Module 1.8.1 in their first MAA submission,

Pharmacovigilance
Table 34-1. Overview of Good Pharmacovigilance Practices
Module Module Title Status at Time of Publication

Number
I Pharmacovigilance Systems and Their Quality Systems Published (June 2012)
II Pharmacovigilance System Master File Published (June 2012)
Revision 2 published (March 2017)
III Pharmacovigilance Inspections Published (December 2012)
Revision 1 published (September 2014)
IV Pharmacovigilance Audits Published (December 2012)
Revision 1 published (August 2015)
V Risk Management Systems Published (June 2012)
Revision 2 published (March 2017)
VI Management and Reporting of Adverse Reactions to Medicinal Published (June 2012)
Products Revision 1 published (September 2014)
VII Periodic Safety Update Reports Published (June 2012)
Revision 1 published (December 2013)
VIII Post-Authorisation Safety Studies Published (June 2012)
Revision 2 published (August 2016)
IX Signal Management Published (June 2012)
X Additional Monitoring Published (April 2013)
XV Safety Communication Published (January 2013)
XVI Risk Minimisation Measures: Selection of Tools and Published (February 2014)
Effectiveness Indicators Revision 1 published (March 2017)
and ensure a qualified person for pharmacovigilance to be considered not just during its use in accordance
(QPPV) is available who meets the responsibilities with the terms of the marketing authorisation, but also
described in GVP Module I. A PV system description during its off-label use and through occupational expo-
(pharmacovigilance system master file (PSMF); see sure. Finally, GVP emphasises efficacy, or a lack thereof,
GVP Module II) should be kept up to date at all times, is a safety concern to be monitored by PV systems.
as a regulatory authority may request it at any time with
no notice. Companies with no authorised products are Good PV Practices
not required to implement a postmarketing PV sys- GVP Module I: Pharmacovigilance Systems and
tem, although it is common practice to have several PV Their Quality Systems
system elements in place, such as a safety database, to This module focuses on applying International
facilitate management of serious adverse events, reac- Organisation for Standardization (ISO) 9000 standards
tions and serious unexpected suspected adverse reactions on good quality management systems to pharmacovig-
(SUSARs) reported in clinical trials. ilance. It introduces the quality cycle concept, with the
The GVP modules have continued to expand the following steps:
scope of safety information subject to GVP processes. • quality planning: developing standard oper-
In addition to including adverse events that may or may ating procedures (SOPs) to ensure consistent
not be related to the company’s products and those sus- quality of processes, personnel training and
pected of being related, these processes must be applied appropriate facilities and equipment
to a wider range of individual patient experiences that • quality adherence: conducting processes in
may or may not have been associated with adverse accordance with SOPs, including quality con-
patient consequences. These include overdoses, abuse, trol steps to ensure compliance with required
misuse, medication errors, use of counterfeit product, lack standards and document activities
of effect, exposure during pregnancy, exposure during • quality control and assurance: monitoring
breastfeeding, transmission of infectious agents and departmental compliance metrics, conducting
off-label use. Importantly, product safety concerns need

Chapter 34
a robust internal audit program, implementing Changes to QPPV information must be com-
an internal compliance monitoring program municated to the EudraVigilance registration team
• quality improvements: a corrective and preven- immediately or no later than 30 calendar days from the
tive action (CAPA) program date the change applies.
The pharmaceutical industry and contract service GVP Module II: Pharmacovigilance System Master
organisations (CSOs) increasingly are centralising File
and offshoring global PV activities. Consequently, PV The new PSMF concept as an EU legal requirement was
activities subject to these requirements may be con- introduced in 2012 in accordance with the provisions of
ducted not in the EU, but in a global PV unit in North Regulation (EU) 1235/2010. The PSMF describes the
America or offshored to countries with lower expenses, PV system’s organisation and administration and must be
e.g., India or China. However, any PV activity related updated continually to document the PV system’s current
to a product with a pending or approved EU MA still status and its compliance with legislative requirements
is required to adhere to GVP quality standards and (Figure 34-1).
processes. Consequently, centralised and/or offshored The PSMF contains not only EU-specific informa-
activities must be scrutinised to ensure they meet EU tion, but also global information derived from activities
and local jurisdiction requirements. outside the EU affecting MAH EU obligations. For
GVP quality standards apply to any pharmaceutical example, the PSMF may describe a central individ-
company functional area playing a role in PV activities. ual case study report (ICSR) study centre’s activities
This includes regulatory departments whose responsi- outside the EU, explain how adverse events from a
bilities may include managing variations to approved non-EU country are available for submission in the
product information for safety reasons, maintaining core EU or declare studies occurring in a non-EU country
data sheets and extended EudraVigilance medicinal involving a product authorised or pending authorisation
product dictionary (xEVMPD) entries for company in the EU. All MAHs will need to assess their global
products, submitting periodic safety update reports processes and data to determine which data need to be
(PSURs) and risk management plans (RMPs), etc. maintained in the PSMF.
Management and upper management personnel’s Regulatory departments play a key role in main-
responsibilities related to the PV system are described, taining the PSMF. Module 1.8.1 of all MA dossiers
including providing sufficient personnel, facilities and must contain a summary of the applicant’s pharma-
equipment, motivating personnel and monitoring PV covigilance system (SPS), providing QPPV contact
system compliance. PV system accountability is shared information, confirming a compliant PV system is in
between the marketing authorisation holder (MAH) place and confirming the PSMF’s nominated location.
and the QPPV; each MAH is required to appoint a Regulatory departments also provide a number of
QPPV. A QPPV should be appointed before the com- key PSMF contributions, including current MA status
pany’s first MAA is submitted and must be identified lists, descriptions of how safety variations are managed
in MAA Module 1.8.1. GVP Module I expands the and compliance metrics on regulatory submissions for
QPPV’s role. safety variations, PSURs and RMPs.
Corporate mergers or acquisitions complicate PV
and necessitate close attention to the requirements GVP Module III: Pharmacovigilance Inspections
and careful planning to ensure the PV quality man- European regulatory agencies have active PV system
agement system and QPPV responsibilities remain inspection programmes. Regulatory professionals can be
unambiguous throughout the process. Merger and involved in any aspect of an inspection: initial inspector
acquisition activity may trigger a PV inspection (see point of contact, host the inspection or answer specific
Module III). It is relatively simple for a company to questions on their relevant PV responsibilities, e.g.,
change the QPPV, by submitting the necessary type updating reference safety information, managing PSUR
IAIN variation, noting the PSMF (see Module II) has preparation or submitting safety information to regu-
been updated and notifying the European Medicines latory agencies. Therefore, it is important for regulatory
Agency’s (EMA) EudraVigilance team. A type IAIN professionals to be familiar with relevant procedures,
variation is required within two weeks of implementing timelines and standards. For example, a company may
the change. The procedure for registering a new QPPV have a standard timeline for submitting an important
with EudraVigilance is described at: http://www.ema. SmPC safety change; although PV regulations and the
europa.eu/ema/index.jsp?curl=pages/regulation/general/ GVP Modules mandate no timeline, inspectors expect
general_content_000679.jsp. to see an SOP with appropriate timelines, employees

Pharmacovigilance
Figure 34-1. Pharmacovigilance System Master File
Describe the Pharmacovigilance System Document Status and Compliance
EU Qualified Person for Pharmacovigilance Qualifications and Responsibilities
Organisational Structure MAH and PV Sites
Data Safety Sources List of Ongoing Studies
Computerised Systems and Databases Validation and Electronic Respository
Pharmacovigilance Processes List of SOPs, Policies, etc. Monitor Benefit-Risk
Pharmacovigilance System Performance Compliance Metrics
Quality System List of Audits
familiar with the procedure, a record of SOP training received by the MAH or EU QPPV several weeks prior
completion and evidence of adherence to the timelines. to the inspection date. The documentation requested
Routine inspections occur every few years depend- can be extensive, e.g., line-listings from the company’s
ing on the risk level assigned by a regulatory agency adverse event report safety database for a pre-selected
based on information provided by the MAH and date range, usually requested to be provided electron-
gathered from other available sources. These are sup- ically, e.g., on a CD-ROM or flash-drive and in a
plemented by ad hoc inspections conducted on a “for specific format according to a template provided. The
cause” basis. For centralised products, the inspection inspectors use the requested material, information
is conducted by the competent authority in the EU received on request during the inspection and answers
Member State the company has nominated as the to their questions from individuals involved in the PV
location of the PSMF, although other Member State system, to assess the system’s quality, compliance and
competent authorities may perform separate PV activity robustness. Global activities and processes involving
inspections in their own jurisdictions, particularly for products with a pending or approved EU MA are
nationally approved products, or may conduct a joint within the inspection’s scope, including the global
inspection with the applicable competent authority. ICSR processing centre’s performance, regardless of its
“For cause” inspections may be triggered for a num- location, and contractual relationships with partners
ber of reasons, including lack of communication with in non-European countries. Interviewees can include
agencies when there is a change in the product’s bene- colleagues from any company department involved in
fit-risk balance, compliance issues with expedited and receiving and communicating adverse events internally,
periodic reporting obligations, information from other including commercial sales, legal and medical affairs.
agencies or issues with fulfilling obligations related At the end of the inspection, verbal feedback gen-
to safety. Inspections generally are announced several erally is provided to the company’s representatives at
weeks in advance, although GVP Module III allows a close-out meeting. A written report issued within
unannounced inspections. approximately one month lists any findings, with the
Inspections usually follow a standard format and evidence for the finding, and references to the regula-
can last several days. A request to send the inspectors tion or GVP module observed to have been violated.
a list of documents, including the PSMF, normally is Findings are categorised into “critical,” “major” and

Chapter 34
“minor,” as defined in GVP Module III. Comments, auditing or interviewing the auditor, since the MAH is
which are observations to be considered for future legally responsible for the PV system.
processes, may be provided in addition to any findings. All PV system activities should be subject to a risk
The written report requests a response within a month, assessment that examines the impact of not perform-
detailing any CAPA. Inspectors also may request a root ing an activity and the likelihood the activity will not
cause analysis and impact analysis. Some inspection be performed appropriately, including local country
findings (e.g., critical and major) are available to all EU office or affiliate personnel, the IT department validat-
competent authorities via a database held by EMA and, ing, maintaining and updating the safety database and
additionally, may be shared on a more proactive basis vendors performing any part of case processing (e.g.,
with agencies inside or outside the EU. patient support programmes, marketing surveys, prod-
Some regulatory agencies provide further informa- uct distribution, etc.). A numerical scoring system may
tion and guidance on their websites. For example, the be helpful to calculate a risk score for each PV system
UK’s Medicines and Healthcare products Regulatory area to support the long-term audit schedule (typically
Agency (MHRA) publishes extensive guidance on for the next two to five years), the short-term schedule
providing pre-inspection information, completing the (typically, for the current year) and to plan individual
standard template it provides for companies to use audits. The EU QPPV should be involved in setting the
when responding to findings, etc. Regulatory agen- schedule for internal audits and can request an audit be
cies also may publish their (anonymised) findings in performed of any PV system part. The audit schedule
aggregate. For example, MHRA has indicated common and a list of completed audits should be included in a
critical and major inspection findings in the last few PSMF annex.
years include discrepancies in reference safety infor- The auditor may ask a regulatory professional to
mation or the time taken to introduce a safety update describe PV processes in which he or she is involved
to the SmPC, failure of patient support programme and should prepare for an audit in much the same way
oversight, failure to comply with timelines for submit- as for a competent authority inspection (GVP Module
ting case reports to the health authority and inadequate III). This includes such processes as SmPC manage-
follow-up of suspected adverse event case reports. ment, ensuring physician education material is kept up
While UK is no longer part of the EU (Brexit) there is to date whenever a safety update is necessary, preparing
a transition period until the end of 2020 therefore all or submitting the PSUR and overseeing controlled
current regulations still apply until after the transition product distribution.
period ends. All departments should retain sufficient records of
Regulatory agencies may impose sanctions if there their PV activities and contributions to the PV system
are significant concerns about the PV system’s status. to demonstrate they are fulfilling their responsibilities
These sanctions can range from repeat inspection, MA and following standard PV processes. Auditors may
suspension or withdrawal, clinical trial suspension, consider the absence of records to be a system defi-
financial penalties and criminal prosecution. Although ciency. If an SOP was not followed, an explanation
regulatory agencies use many of these infrequently, the should be recorded in a written deviation.
potential impact on a pharmaceutical company’s finan- At each audit’s conclusion, a written report should
cial performance could be significant. Additionally, the describe any deficiency in sufficient detail to allow the
EU QPPV is personally liable for effective oversight of relevant department to understand the finding, conduct
the PV system. More commonly, the company provides a root cause analysis, consider any broader impact and
a written commitment in the form of a CAPA plan to develop and execute a CAPA. The audit report should
address each finding, and the inspectors confirm the describe a deficiency not only by explaining that a
action was taken, normally at the next inspection. process was not followed, but also should discuss how
a PV-related regulation, directive or guideline was not
GVP Module IV: Pharmacovigilance Audits satisfied. Even if the auditor observes MAH processes
Companies are expected to ensure their PV system’s have been followed diligently, the processes may be
quality and identify any deficiencies by risk-based audit- inadequate to ensure PV obligations are met. Auditors
ing. Therefore, PV system quality assurance is expected should refrain from finding a sub-optimal process is
to include an internal auditing system, conducted by deficient if no deficiency in meeting PV obligations has
either an internal quality assurance department that is been identified.
independent of the PV department or external audi- Any audit finding should be categorised as crit-
tors. Before engaging an external auditor, the company ical, major or minor, according to the definitions in
should ensure the auditor is qualified and able to GVP Module IV. Critical and major findings must be
provide the service the company needs, e.g., through listed in the PSMF, with the CAPA, until the CAPA

Pharmacovigilance
is complete. During an inspection, the inspectors may A modular format enables uniform data presentation
make an observation if CAPAs remain open longer across multiple regulatory documents, with interchange-
than they consider appropriate or have not been closed able modules across the RMP, the periodic benefit risk
according to the standard procedure and timeline. evaluation report (PBRER) and the development safety
update report (DSUR) (Table 34-2).
GVP Module V: Risk Management Systems
Since any medicinal product’s use is associated with a GVP Module VI: Management and Reporting of
degree of risk, MAHs are expected to implement and Adverse Reactions to Medicinal Products
maintain a risk management system (RMS) to ensure Module VI is the most detailed GVP module, describ-
safe product use, reduce the occurrence of adverse reac- ing a wide range of requirements to be considered when
tions and ensure the treatment’s benefits outweigh its processing adverse event ICSRs. These will be familiar
risks to the greatest extent possible. The RMS comprises from the evolution of Volumes 9 and 9A of the Rules
PV activities that identify and investigate risks and the Governing Medicinal Products in the European Union.
implementation of interventions to prevent or minimise These requirements should be applied to any ICSRs
those risks. In addition, the RMS includes assessment received for a product with a pending or approved EU
of the interventions’ effectiveness. MA, regardless of where the ICSR originated (i.e.,
Regulatory professionals often are involved in including non-EU countries). This includes unsolicited
arranging or monitoring specific measures to reduce risk, ICSRs (spontaneous reports from healthcare profes-
such as managing SmPC and patient leaflet content, sionals, consumers, literature, media, lawyers, etc.) and
preparing physician educational material, organising solicited sources (organised data collection schemes
controlled distribution or engaging with regulatory including noninterventional studies, registries, postap-
agencies to reach agreement on risk minimisation activ- proval named patient use/compassionate use, patient
ities; this may include coordinating measures of the support programmes, patient reimbursement pro-
intervention’s effectiveness, e.g., by organising periodic grammes, marketing surveys, compliance surveys, etc.).
healthcare professional or patient knowledge surveys. Some key changes need to be considered by any
Every product should have an RMP appropriate group responsible for expedited ICSR submission to EU
to its risks, and the RMP should be updated whenever regulatory agencies. All serious related adverse events
there is a significant change to the MA, such as a new need to be submitted to regulatory agencies within
dosage form, new route of administration, new manu- 15 days, regardless of the country of occurrence and
facturing process, a paediatric or significantly different including events that are both expected and unexpected.
new indication or new safety issue or achieving a mile- However, having a greater impact is the requirement to
stone in RMP-associated activities. As risks must be submit non-serious ICSRs to regulatory agencies on an
considered in the context of product benefit, the RMP expedited basis. This does not affect non-serious adverse
contains efficacy information. Postapproval efficacy events occurring outside the EU, but non-serious adverse
studies should be described where efficacy questions events occurring within the EU require expedited sub-
remain unanswered by the preapproval clinical develop- mission within 90 days. EMA’s EudraVigilance website
ment program, or if understanding of the target disease publishes regular updates on current non-serious ICSR
changes. reporting requirements. Finally, ICSRs received from
GVP Module V introduced a new, required consumers and other non-healthcare professionals now
European RMP format in 2013. EMA provides a tem- are eligible for expedited submission; previously, EU
plate with guidance on its content. The RMP has seven competent authorities required healthcare professional
sections: confirmation (Figure 34-2).
I. Product(s) overview
II. Safety specification describing existing safety GVP Module VII: Periodic Safety Update Reports
information MAHs are required to submit periodic safety update
III. PV plan, including postauthorisation safety reports (PSURs) containing safety information and
studies benefit-risk evaluations for every authorised product
IV. Plans for postauthorisation efficacy studies to competent authorities. The regulatory professional
V. Risk minimisation measures, including eval- contributes to PSUR content, including worldwide
uating the effectiveness of risk minimising MA status and changes made for safety reasons to
activities prescribing information inside or outside the EU. The
VI. Summary of the RMP regulatory professional may be responsible for initiating,
VII. Annexes co-ordinating, tracking or submitting the PSUR.

Chapter 34
Table 34-2. Periodic Benefit-Risk Evaluation Report (PBRER), Development Safety Update Report (DSUR) and
Risk Management Plan (RMP) Interchangeable Modules
PBRER DSUR RMP

Section 2 Section 2
Worldwide Marketing Authorisation Worldwide Marketing Approval Status
Status
Section 3 Section 3 Part II Module SV
Actions Taken in the Reporting Actions Taken in the Reporting Regulatory and Marketing
Interval for Safety Reasons Interval for Safety Reasons Authorisation Holder Action for Safety
Reasons
Section 5.1 Section 6.1
Cumulative Subject Exposure in Cumulative Subject Exposure in the
Clinical Trials Development Program
Section 5.2 Section 6.2 Part II Module SV
Cumulative and Interval Patient Patient Exposure from Marketing Post-Authorisation Experience
Exposure from Marketing Experience Experience
Cumulative Summary Tabulations of Cumulative Summary Tabulations of
Serious Adverse Events from Clinical Serious Adverse Events
Trials
Section 7 Section 8
Summaries of Significant Findings Significant Findings from Clinical
from Clinical Trials During the Trials During the Reporting Period
Reporting Interval
Section 8 Section 9 Part II Module SIV Populations not
Findings from Noninterventional Safety Findings from Studied in Clinical Trials
Studies Noninterventional Studies
Section 9 Section 10
Information from Other Clinical Trials Other Clinical Trial/Study Safety
and Sources Information
Section 10 Section 12 Part II Module SII Nonclinical Part of
Nonclinical Data Nonclinical Data the Safety Specification
Literature Literature
Lack of Efficacy in Controlled Clinical Lack of Efficacy
Trials
Section 16.1 Part II Module SVIII
Summary of Safety Concerns Summary of Safety Concerns
Evaluation of Risks and New Evaluation of the Risks
Information
Section 16.4 Part II Module SVII
Characterisation of Risks Identified and Potential Risks
Section 16.5 Part V
Effectiveness of Risk Minimisation Risk Minimisation Measures

Pharmacovigilance
The PSUR format has undergone considerable Figure 34-2. ICSR Expedited Submissions
change following the revision to the International Requirements
Council for Harmonisation’s (ICH) guideline
E2C(R2), which EMA’s Committee for Medicinal
Related
Products for Human Use (CHMP) adopted in 2013.
Adverse
This introduced evaluation of safety information in the Reaction
context of efficacy, and the new PSUR format came to
be known as the PBRER. However, the report contin-
ues to be referred to as the PSUR in EU regulations,
directives and GVP Modules.
Previously, the PSUR focused on presenting safety
information received during the interval since the Serious Non-Serious
preceding report. Several other changes also were intro-
duced, further emphasising the shift from the PSUR
as a vehicle for transferring information to regulatory
agencies to an evaluation of all new safety information
and its impact on the product’s benefit-risk assess-
ment: ICSR line-listings no longer were required, since
Within Occurred Occurred
ICSRs already would have been submitted to European 15 Days in EU Outside EU
competent authorities through the revised expedited
reporting requirements in GVP Module VI, while post-
authorisation efficacy studies must be described with
any new information impacting the previously estab-
lished benefit.
EU PSUR scheduling changed radically with Within No Reporting
the introduction of the list of EU reference dates and 90 Days Required
frequency of PSUR submissions (EURD list). Each
PSUR’s submission is based on the active substance’s
EU reference date, as defined by EMA and usually
based on the innovator product’s international birth
date (IBD) (the date of first MA in any country format and, therefore, companies should be prepared to
worldwide). Consequently, all MAHs with a product submit periodic reports in both the old and new formats
containing the same active substance will be required to to meet international requirements. Harmonisation
submit their PSURs at the same time. The EURD list enables regulatory agencies internationally to review
is updated monthly and is available on EMA’s website. the same information, potentially fostering a future
However, when preparing the company’s PSUR sched- standard global approach to regulatory review and deci-
ule, the EURD list is not the only source to consider. A sion making. For products with more than one MAH,
product may have a mandated PSUR schedule intro- harmonisation enables the assessment by regulatory
duced as a condition of approval, which will override authorities of a cumulative data set for the active sub-
any schedule described in the EURD list. Additionally, stance across all MAHs, a single opinion applicable to
some products may not be listed in the EURD list, par- all MAHs and common product information in the
ticularly if they are authorised in only one EU country. SmPCs for all products containing the active substance.
In this situation, GVP provides a routine PSUR sched-
ule to follow based on the product’s maturity, namely GVP Module VIII: Postauthorisation Safety Studies
every six months for the first two postmarketing years, GVP Module VIII’s content is aligned primarily with
annually for the next two years and, thereafter, every the requirements of the European Network of Centres
three years. for Pharmacoepidemiology and Pharmacovigilance
Many other countries accept the EU format, (ENCePP) and the International Society of
including Australia and Canada. Agencies elsewhere Pharmacoepidemiology (ISPE). It is not mandatory
are indicating their acceptance of the PBRER format, for an organisation to be registered with ENCePP to
which is welcomed by the industry, as it should reduce comply with GVP, although use of ENCePP-registered
the resources required to produce them. However, a organisations provides a level of reassurance to regula-
steadily decreasing minority of countries still require tory agencies.
periodic reporting in the previous ICH E2C (R1)

Chapter 34
A postauthorisation safety study (PASS) is defined hepatotoxicity of the product of interest. The exception
in Directive 2010/84/EU as: to this is fatal outcomes, which GVP Module VI always
“any study relating to an authorised medicinal requires to be collected as adverse events. However, an
product conducted with the aim of identifying, opportunity to exclude their collection is provided with
characterising or quantifying a safety hazard, con- appropriate justification, e.g., fatality is a study end-
firming the safety profile of the medicinal product, point, or fatality has no relation to the study’s objective.
or of measuring the effectiveness of risk manage- All serious related adverse events (i.e., reactions)
ment measures.” from noninterventional studies must be submitted to
competent authorities within 15 days, including events
This differs from previous definitions by adding mea- that are both expected and unexpected. Of more impact,
surement of risk management measures’ effectiveness. however, is the requirement to submit non-serious
The revised pharmacovigilance legislation reinforces adverse events to competent authorities on an expedited
an expectation that risk minimisation activities’ effec- basis. This does not affect non-serious adverse events
tiveness will be monitored and that the PASS will be a occurring at a site outside the EU, but nonserious
common tool used in this activity. adverse events occurring at an EU site require expedited
A PASS may be interventional or noninterven- submission within 90 days. Industry needs to review its
tional (observational). Interventional studies must procedures for managing non-serious adverse events in
follow the requirements outlined in the Clinical Trial PASS to ensure information about appropriate non-
Directive (2001/20/EC). GVP requirements apply serious adverse events is available to PV personnel who
largely to noninterventional studies only. are responsible for expedited adverse event submissions
It is recommended information regarding both from these studies. This may require investigators to
interventional and, particularly, noninterventional send non-serious adverse event data directly to PV
studies be included in the electronic EU PASS register. personnel within fixed timeframes; alternatively, and
This is an evolution of the previous ENCePP regis- more commonly, PV personnel liaise directly with
ter, currently hosted by ENCePP. GVP Module VIII data management groups to obtain these data without
provides guidance on conducting PASS, including having to involve the investigator.
investigator research contracts, protocol development, Regulatory professionals may be involved exten-
managing substantial protocol amendments, progress sively in the regulatory management of PASS studies,
report requirements and preparing the final study including submissions of protocols, protocol amend-
report. Recommended document formats and contents ments, progress reports, final study reports, publication
are described, and the use of ENCePP checklists and manuscripts, updates to the EU postauthorisation
guidance documents is recommended. study (PAS) register and, finally, submitting any SmPC
A key revised PV legislation impact is adverse amendments the study outcome may require.
event management in PASS. Although adverse events
occurring in interventional clinical studies continue to GVP Module IX: Signal Management
follow traditional processes, adverse event management For several years, companies have been expected not
in observational studies has become increasingly com- only to collect and submit reports of possible adverse
plex. GVP Module VIII requires adverse events from events, but also to analyse accumulated safety informa-
observational studies to be managed in accordance with tion to identify and evaluate safety signals, and to take
GVP Module VI’s requirements (see above). Adverse action to minimise risk if a signal indicates a new prod-
events observed in studies based on retrospective record uct use hazard. GVP Module IX describes a structured
review do not require submission to regulatory agencies, signal management lifecycle, providing detailed guid-
with the exception of the final study report. However, ance for each step (see Figure 34-3). Signal detection
requirements for collecting adverse events in studies data sources should include ICSRs from spontaneous
based on primary data collection have been subject to and study sources, worldwide medical and scientific
extensive debate, clarified only with the publication of literature, clinical studies, PASS and any other sources
GVP Module VI’s Revision 1 in September 2014. available to the MAH. Data reviewed should include
GVP Module VI now states all adverse events product quality, nonclinical information, clinical infor-
should be collected unless the protocol provides dif- mation, PV data and pharmacoepidemiological data.
ferently, with justification for not collecting certain Signal detection methodology traditionally includes
adverse events. This allows adverse event collection to individual case review by an experienced person who
be tailored to the noninterventional study’s objectives, is, or has access to, a medically qualified person. This
e.g., collecting adverse events associated with hepatic review is to identify a previously unidentified adverse
disorders only, if the study objective is to observe the reaction or risk factor for a known reaction and monitor

Pharmacovigilance
Figure 34-3. Signal Management Lifecycle
Detection
Recommendation for Action

Assessment Validation
Exchange Information
Prioritisation
adverse event reporting from month-to-month to detect EMA provides a dedicated email address for this pur-
any increase in an adverse event’s frequency. A number pose (P-PV-emerging-safety-issue@ema.europa.eu).
of statistical methods are available, each of which seeks Validated signals that are undergoing evaluation or
to detect a signal of disproportionate reporting (SDR). have been completed are provided to competent author-
An SDR indicates a drug/adverse effect pairing has ities in the PSUR (GVP Module VII) and RMP (GVP
been observed more frequently than expected from Module V), including a description of the evaluation’s
overall product or product basket safety reporting. For outcome.
example, all adverse reactions reported for all a com- Finally, GVP Module IX introduced a new
pany’s marketed products can provide a background MAH requirement to conduct signal detection in
dataset against which to compare a single drug and EudraVigilance (EMA’s repository of ICSRs), to the
adverse event pairing of interest. Therefore, SDR detec- extent of their accessibility. EMA is working to increase
tion requires a sufficiently large safety database and, if accessibility to EudraVigilance data over the next few
an appropriate background data set is not available, is of years via the EudraVigilance data warehouse and anal-
limited value. Individual case review is appropriate for ysis system (EVDAS). All competent authorities and
products used in small patient populations. all MAHs with a medicinal product authorised in the
A validated signal is one for which available evi- EEA have access to EVDAS.
dence verifies a new potential causal association or a
new aspect of a known association, justifying further GVP Module X: Additional Monitoring
assessment. Further assessment considers the public GVP Module X calls for additional monitoring to col-
health impact or the impact on the product’s bene- lect information as early as possible during the product’s
fit-risk profile to prioritise signals for urgent attention postauthorisation clinical use and to increase awareness
and action. Finally, a recommendation for action or about certain medicinal products’ safe and effective use.
no further action is required. Although there is no EMA will include products containing new active
mandated timeline for conducting signal detection substances not included in any authorised product prior
and managing emerging signals, competent authorities to 1 January 2011 (including biological products) and
expect the company to be able to track each identified biological products authorised after 1 January 2011 in
signal from detection to consequent risk reduction a list of products subject to additional monitoring, as
activity implementation, including SmPC updates, well as certain products authorised with obligations
and are likely to scrutinize the signal management to conduct various pharmacovigilance and/or risk
process during an inspection. Emerging safety issues minimisation activities. These products will have an
with implications for public health and/or the product’s inverted black triangle on the approved product infor-
benefit-risk profile should be reported immediately to mation, a statement confirming the product is subject
competent authorities, as described in GVP Module VI. to additional monitoring and an explanatory paragraph

Chapter 34
encouraging healthcare professionals and patients to and MAHs to ensure information is understood in the
report suspected adverse reactions. In general, new manner intended.
active substances will remain on the list for five years, The pharmaceutical industry should review its
although this period may be extended at the request of communication processes to ensure they are aligned
the Pharmacovigilance Risk Assessment Committee with GVP requirements. In particular, safety com-
(PRAC). This committee also will determine how long munication effectiveness is not monitored frequently,
a product with pharmacovigilance and/or risk minimis- and industry may be required to explore monitoring
ation activities is listed. processes.
The SmPC and package insert quality review of
documents (QRD) templates were updated in 2013 GVP Module XVI: Risk Minimisation Measures:
to include language for products subject to additional Selection of Tools and Effectiveness Indicators
monitoring. MAH responsibilities will be limited to GVP Module XVI came into effect in April 2014 and
submitting appropriate variations or removing the black was revised in March 2017. It reviews considerations
symbol, statement and explanatory paragraph. Of note, for selecting risk minimisation activities appropriate
the paragraph encouraging adverse event reporting is to the product’s risks and measuring the activities’
required for all products, whether or not they are on the effectiveness. This module provides considerations on
additional monitoring list. preparing the RMP (GVP Module V). It also describes
In March 2013, EMA issued an implementation risk minimisation measures, such as educational mate-
plan for the centrally approved product revised QRD rials for healthcare professionals, patients or caregivers,
templates. For existing products placed on the addi- controlled access (including actions taken at the patient,
tional monitoring list, a variation was required by the dispenser and prescriber levels) and other measures,
end of 2013. For existing products not on the additional such as controlled distribution, pregnancy prevention
monitoring list, MAHs were encouraged to use the first and DHPC. The design and objectives differ depending
upcoming regulatory procedure to include the standard on the nature of the risk.
paragraph regarding adverse reaction reporting. Risk minimisation effectiveness is measured
GVP Modules XI, XII, XIII and XIV will stay by applying two indicators. Process indicators show
void. The planned topics for these GVP Modules have whether risk minimisation was implemented success-
been addressed by other guidance documents on EMA’s fully, e.g., whether the intervention reached the target
website. audience, the audience gained the appropriate clinical
knowledge and the audience took the appropriate clini-
GVP Module XV: Safety Communication cal actions. Outcome indicators are focused on the safety
Module XV provides guidance on communicating outcomes, e.g., demonstrating a reduction in reporting
safety information to patients and healthcare profes- of an adverse reaction in a PASS. Changes in an adverse
sionals, describing the content of safety announcements reaction’s spontaneous reporting rates over time may be
and the communication methods that may be used. suitable to monitor changes in certain risks in some cir-
Particular focus is given to the direct healthcare pro- cumstances but must be used with caution, since they do
fessional communication (DHCP), and a template is not provide a direct measure of a risk’s size.
provided. The module recommends measuring safety For a new, centrally authorised product, the
communication effectiveness using research methods to CHMP opinion includes any postapproval commit-
ensure DHCPs have been disseminated to the appro- ments or conditions for the product’s safe and effective
priate audience and that the message is understood as use. For nationally approved products, equivalent condi-
intended. The module describes processes for agreeing tions are agreed with the relevant competent authority.
on safety announcement content with regulatory agen- These will be recorded and managed in the RMP.
cies and coordinating safety announcements across the The RMP and tools used for generic products
EU regulatory network. Regulatory professionals likely should be aligned with the activities and tools used for
will be involved in the mandatory notification to EU the reference medicinal product, and risk minimisation
competent authorities of announcements intended for effectiveness should be assessed by the MAHs in close
release outside the EU if they involve a product with a cooperation with the competent authorities. Formal
pending or approved EU authorisation. studies should be planned and executed jointly for all
The communication method and the public per- involved generic medicinal products.
ception of the communicating organisation will have The RMP should be updated when new knowledge
a significant influence on public opinion. The media’s is gained from conducting and assessing risk minimis-
role is critical. GVP Module XV makes it clear commu- ation, and the evaluation results should be included in
nication needs to come from both regulatory agencies the PSUR.

Pharmacovigilance
Module VXI Addendum I, which was finalized • Procedure-based fees—these cover the submis-
December 2015, provides guidance on preparing the sion of PSURs, PASS protocols, PASS study
content and submission of educational materials to reg- reports and safety referral procedures.
ulatory agencies. It references the role of the PRAC and • Annual fees—these are charged on 1 July every
CHMP in approving material, in some circumstances year for nationally authorised medicines only.
before submission. • Fee calculation can be complex, with proce-
dure-based fees being shared between MAHs
Other Pharmacovigilance Regulatory with the same active substance and involved in
Requirements the same procedure. Current algorithms and
It is important to be aware EU requirements are not rates can be found on EMA’s website.
limited to the GVP modules. PV and regulatory depart-
ments will require robust regulatory intelligence to keep Conclusion
up with continually changing requirements. The changes affecting EU pharmacovigilance legislation
reach far beyond the Community’s borders, affecting
Notification of Withdrawn Products global PV processes for the pharmaceutical industry,
Directive 2012/26/EU and Regulation (EU) No. CSOs and regulatory agencies.
1027/2012 amended the PV legislation described There are numerous challenges in aligning require-
above to include mandatory requirements for notify- ments across international territories. These include
ing competent authorities of product withdrawal. This significantly different expedited reporting requirements
amendment was introduced to ensure EU agencies are for ICSRs received spontaneously, or in the context of
aware when a product is withdrawn anywhere in the a PASS study, including global processes and data in an
world due to potential safety and/or efficacy concerns, EU PSMF, formally reporting signals to EU regulatory
so they can consider whether similar action is required agencies and others.
in their jurisdictions. Further, new requirements are being introduced
For products with an EU MA, MAHs are required that will affect global PV processes. All 12 GVP mod-
to notify EU competent authorities of the following: ules are being updated continually. Expedited reporting
• temporary or permanent cessation of a medici- requirements will continue to change, with the intro-
nal product’s marketing duction of expedited submission of non-serious adverse
• suspension of a medicinal product’s marketing reactions for all EU countries and centralised reporting
• a medicinal product’s withdrawal from the to EMA. ICH E2B (R2) was implemented in the EU
market in 2016, affecting electronic ICSR submission among
• request for withdrawal of an MA all stakeholders.
• non-application for an MA renewal All organisations conducting PV activities should
consider this impact when planning resources and pro-
This notification is required regardless of the reason for cess development for their global PV departments. The
the product’s withdrawal, although the notification pro- skill set required by both PV and regulatory departments
cedure depends on whether the reason for withdrawal is will need to be expanded significantly to manage these
related to public health concerns. It also applies regard- GVP modules’ diverse requirements. Departments
less of whether the country where the action is taken is need sophisticated logistics management to juggle the
in the EU or elsewhere, i.e., notification also is required increasing complexity and interdependencies of these
for product withdrawals outside the EU. EMA has regulatory requirements across multiple functional
provided a questions and answers webpage with current areas. The many pharmaceutical company departments
guidance on which notification procedure to use. involved in the PV system (PV, medical affairs, regula-
tory, clinical development and operations, epidemiology,
Pharmacovigilance Fees data management, library services, legal, vendor man-
In 2014, Regulation (EU) No. 658/2014 was adopted, agement) all are affected by the legislation, and most, if
allowing EMA to collect fees to cover the cost of not all, could require additional resourcing as the GVP
PV activities allocated to the agency following GVP modules are updated. This will impact regulatory depart-
implementation. In particular, these fees will be used to ments and professionals in particular, as PV legislation
remunerate national competent authorities carrying out requires increasing collaboration between PV and regu-
activities on behalf of the PRAC. The fees fall into two latory groups, and regulatory professionals will need to
main categories: take an active role in complying with PV requirements.

Chapter 34
Recommended Reading • Commission Implementing Regulation (EU) No. 520/2012

• European Medicines Agency. Good pharmacovigilance prac- of 19 June 2012 on the performance of pharmacovigilance
tices. EMA website. http://www.ema.europa.eu/ema/index. activities provided for in Regulation (EC) No. 726/2004 of
jsp?curl=pages/regulation/document_listing/document_list- the European Parliament and of the Council and Directive
ing_000345.jsp&mid=WC0b01ac058058f32c. Accessed 26 2001/83/EC of the European Parliament and of the Council.
April 2020. EUR-Lex website. https://ec.europa.eu/health/documents/
• Regulation (EU) No. 1235/2010 of the European Parliament eudralex/vol-1_en. Accessed 26 April 2020.
and of the Council of 15 December 2010 amending, as • Volume 9 of the Rules Governing Medicinal products in the
regards pharmacovigilance of medicinal products for human European Union—Guidelines on Pharmacovigilance for Medicinal
use, Regulation (EC) No. 726/2004 laying down Community Products for Human Use. EC website. http://ec.europa.eu/health/
procedures for the authorisation and supervision of medici- documents/eudralex/vol-9/index_en.htm. Accessed 26 April
nal products for human and veterinary use and establishing 2020.
a European Medicines Agency, and Regulation (EC) No. • Volume 9A of the Rules Governing Medicinal products in the
1394/2007 on advanced therapy medicinal products. EUR-Lex European Union—Guidelines on Pharmacovigilance for Medicinal
website. https://ec.europa.eu/health/documents/eudralex/ Products for Human Use. EC website. http://ec.europa.eu/health/
vol-1_en. Accessed 26 April 2020. files/eudralex/vol-9/pdf/vol9a_09-2008_en.pdf. Accessed 26
• Regulation (EU) No. 1027/2012 of the European Parliament April 2020.
and of the Council of 25 October 2012 amending Regulation • ICH. Periodic Benefit-Risk Evaluation Report (PBRER)
(EC) No. 726/2004 as regards pharmacovigilance. EUR- E2C(R2). ICH website.https://database.ich.org/sites/default/
Lex website. http://eur-lex.europa.eu/legal-content/EN/ files/E2C_R2_Guideline.pdf. Accessed 26 April 2020
TXT/?uri=CELEX:32012R1027. Accessed 26 April 2020. • Health Canada. Notice: Adoption of the International Conference
• Regulation (EU) No. 658/2014 of the European Parliament and on Harmonisation (ICH) Guidance on Periodic Benefit Risk
of the Council of 15 May 2014 on fees payable to the European Evaluation Report - ICH Topic E2C(R2), as of March 1,
Medicines Agency for the conduct of pharmacovigilance activ- 2013. Health Canada website. https://www.canada.ca/en/
ities in respect of medicinal products for human use. European health-canada/services/drugs-health-products/drug-prod-
Commission website. http://ec.europa.eu/health/files/eudralex/ ucts/applications-submissions/guidance-documents/
vol-1/reg_2014_658/reg_2014_658_en.pdf. Accessed 26 April international-conference-harmonisation/efficacy/notice-adop-
2020. tion-international-conference-harmonisation-guidance-peri-
• Directive 2010/84/EU of the European Parliament and of the odic-benefit-risk-evaluation-report-topic-march-1-2013.html.
Council of 15 December 2010 amending, as regards pharma- Accessed 26 April 2020.
covigilance, Directive 2001/83/EC on the Community code • Directive 2001/20/EC of the European Parliament and of the
relating to medicinal products for human use. EC website. Council of 4 April 2001 on the approximation of the laws,
http://ec.europa.eu/health/files/eudralex/vol-1/dir_2010_84/ regulations and administrative provisions of the Member States
dir_2010_84_en.pdf. Accessed 26 April 2020. relating to the implementation of good clinical practice in the
• Directive 2012/26/EU of the European Parliament and of the conduct of clinical trials on medicinal products for human use.
Council of 25 October 2012 amending Directive 2001/83/EC EC website. http://ec.europa.eu/health/files/eudralex/vol-1/
as regards pharmacovigilance. EC website. http://ec.europa.eu/ dir_2001_20/dir_2001_20_en.pdf. Accessed 26 April 2020.
health/documents/eudralex/vol-1/index_en.htm. Accessed 27
April 2020.

Chapter 35
Regulatory Framework for

Advanced Therapy Medicinal
Products
By Daniela Drago, PhD, RAC, Florence Houn, MD, MPH and James McBlane, PhD
OBJECTIVES □ Commission Directive 2006/86/EC of 24

October 2006 implementing Directive 2004/23/
□ Outline the regulatory framework for advanced EC of the European Parliament and of the
therapy medicinal products (ATMPs) in the Council as regards traceability requirements,
European Union (EU) notification of serious adverse reactions and
events and certain technical requirements for
□ Identify the legal definitions of ATMPs, somatic
the coding, processing preservation, storage
cell therapy medicinal products (CTMP), tis-
and distribution of human tissues and cells
sue-engineered products (TEP), gene therapy
medicinal products (GTMP) and combined ATMPs □ Commission Directive 2006/17/EC of 8 February
2006 implementing Directive 2004/23/EC of
□ Describe the implications of Article 28 of
the European Parliament and of the Council as
Regulation 1394/2007/EC and supply outside
regards certain technical requirements for the
grant of a marketing authorization
donation, procurement and testing of human
□ Discuss somatic cell-based, gene therapy and tissues and cells
tissue-engineered medicinal product develop-
□ Commission Directive 2003/63/EC amending
ment EU guidelines
Directive 2001/83/EC of the European Parliament
and of the Council on the Community code relat-
ing to medicinal products for human use
COVERED IN THIS CHAPTER □ Directive 2004/23/EC of the European
□ Commission Directive (EU) 2015/566 of 8 April on setting standards of quality and safety for
2015 implementing Directive 2004/23/EC as the donation, procurement, testing, processing,
regards the procedures for verifying the equiva- preservation, storage and distribution of human
lent standards of quality and safety of imported tissues and cells
tissues and cells
□ Directive 2002/98/EC setting standards of
□ Commission Directive 2009/120/EC of 14 quality and safety for the collection, testing,
September 2009 amending Directive 2001/83/ processing, storage and distribution of human
EC of the European Parliament and of the blood and blood components and amending
Council on the Community code relating to Directive 2001/83/EC
medicinal products for human use as regards
advanced therapy medicinal products □ Directive 2001/83/EC of the European

Chapter 35
2001 on the Community code relating to medici- of these therapies may offer durable and curative,
nal products for human use or near-curative, benefits to patients suffering from
devastating conditions. Therapies based on cells manu-
□ Regulation (EC) No. 1394/2007 of the European factured to target specific biological processes or based
Parliament and of the Council of 13 November on gene modification, offer new treatment modalities.
2007 on advanced therapy medicinal prod- Transferring genetic material to cure a genetic disease
ucts and amending Directive 2001/83/EC and started to be explored in the ‘90s.3 Tissue-engineered
Regulation (EC) No. 726/2004 product development has taken off in the last 20 years.4
These products are intended to regenerate, repair or
replace human tissue. Thus, developers of ATMPs have
been trying to overcome hurdles in translating ATMP
therapies from the laboratory bench to the patient
bedside for decades.5-6 Despite high expectations in
the field, there also are concerns and debates. Many
focus on how to best accommodate these new inno-
□ Guideline on the risk-based approach accord- vative products in the existing regulatory frameworks
ing to Annex I, Part IV of Directive 2001/83/EC and healthcare delivery systems so that it facilitates
applied to advanced therapy medicinal prod- innovation, ensures patient safety and promotes public
ucts (EMA/CAT/CPWP/686637/2011) health.7-8 Table 35-1 and Figure 35-1 provide infor-
mation on pathways and expedited evaluation programs
□ Guideline on safety and efficacy follow-up—risk that might apply to ATMPs. Notably, advanced thera-
management of advanced therapy medicinal pies represent over 40% of products receiving PRIority
products (EMEA/149995/2008 Rev. 1) MEdicines (PRIME) eligibility—far more than any
other type of product (e.g., chemical, biological or
□ Guidelines on good manufacturing practice spe- immunological).9
cific to advanced therapy medicinal products Many ATMPs were initially developed by aca-
demic clinical centers, but most products brought to the
□ Guideline on non-clinical studies required
market have been done so by commercial organisations.
before first clinical use of gene therapy medici-
At the time this book was written, 14 ATMP prod-
nal products (EMA/125459/2006)
ucts have been licensed in the EU since the regulatory
□ Guideline on human cell-based medicinal prod- framework for ATMPs was established (see Table
ucts (EMEA/CHMP/410869/2006) 35-2). Five of these products have been withdrawn,
suspended or not renewed (Provenge, Zalmoxis, MACI,
□ Guideline on non-clinical testing for inadvertent ChondroCelect and Glybera), all for reasons of limited
germline transmission of gene transfer vectors use. The first ATMP product approved in the EU was
(EMEA/273974/2005) ChondroCelect, a tissue-engineered product indicated
for the treatment of cartilage defects, which received
□ Guideline on quality, non-clinical and clinical approval in 2009.10 In 2012, the European Commission
requirements for investigational advanced ther- granted approval to Glybera as the first gene therapy.11
apy medicinal products in clinical trials (EMA/ The approval of Holoclar, the first stem cell-containing
CAT/852602/2018) (Draft) therapy, occurred in February 2015.12 In June 2019, the
European Commission granted a conditional marketing
authorisation to Zynteglo, which treats a rare blood
Introduction disorder. The gene therapy product was reviewed under
Advanced therapy medicinal products (ATMPs) are a accelerated assessment in just 150 days, two months
class of complex, innovative therapies.1 They include faster than a typical centralised procedure applica-
somatic cell therapy medicinal products (sCTMPs), tion.13 The pipeline of new ATMPs is growing rapidly,
gene therapy medicinal products (GTMPs), tissue-en- as noticeable from the number of products discussed
gineered products (TEPs) and combined ATMPs by the Committee for Advanced Therapies (CAT) in
(cATMPs), consisting of one of the first three catego- scientific advice and classification procedures.14 In late
ries combined with one or more medical devices as an 2017, the European Commission and the European
integral part (e.g., cells embedded in a biodegradable Medicines Agency (EMA) released a joint action plan
matrix).2 These therapies have the potential to improve for ATMPs. The main objective is to “streamline pro-
healthcare in a way that is transformational. Some cedures and better address the specific requirements of

Regulatory Framework for Advanced Therapy Medicinal Products
Table 35-1. EU Pathways and Expedited Evaluation Programs That Might Apply to ATMPs
Description/Eligibility Criteria
Accelerated Offers reduced evaluation time by the CHMP/CAT for innovative medicinal products expected to be
assessment of major public health interest. The evaluation time is reduced from 210 days to 150 days.
PRIME Medicines entitled to treat conditions that have no available treatment options, or medicines
showing therapeutic superiority over the current treatments for a specific indication are designated
as PRIority MEdicines (PRIME) and benefit from early scientific advice and eligibility for accelerated
assessment, aiming to reach patients earlier.
Compassionate Member States can allow the use of unauthorised medicines to treat patients with life-
use threatening, long-lasting, or seriously debilitating illnesses for which no currently authorised
medicine is available for treatment. It is not a centralised endorsement, but EMA also may provide
recommendations for the national authorities about the compassionate use of certain therapies
when requested.
Orphan A denomination granted to medicines intended to be used as a treatment for rare conditions
designation where the EU prevalence is not more than 5 in 10,000, or it is unlikely that marketing of the product
would generate sufficient returns to justify the investment needed for is development. An orphan-
designated product benefits from scientific advice, procedural assistance, 10-year market exclusivity
for each particular indication, which can be extended by two additional years upon obtaining a
pediatric investigation plan (PIP), and offers a potential administrative fee reduction.
Hospital Use of an unauthorised ATMP in a hospital or clinical setting within the same Member State and
exemption under the exclusive responsibility of the treating physician.
Conditional Marketing authorisation of medicine that fulfils unmet medical needs based on less comprehensive
approval safety and efficacy data than normally required, where the expectation is that further clinical data
will be provided. The authorisation is valid for one year and can be renewed based on submission
of new clinical data.
Exceptional Marketing authorisation of medicine in absence of comprehensive safety and efficacy data, where
circumstances such data are never likely to be generated, e.g., rarity of patients. This authorisation is annually
reviewed for risk-benefit balance.
Source: Elsanhoury, Ahmed, et al. “Accelerating patients’ access to advanced therapies in the EU.” Molecular Therapy—Methods & Clinical
Development. 7 (2017): 15–19.
ATMP developers.” The plan was updated in February came into force.17 This regulation, also known as the
2020 and is available on the EMA website.15 ATMP Regulation, brought all three product classes
This chapter discusses the legal framework for how under the same legislation. The ATMP Regulation:
ATMPs are regulated, how they are classified within • outlines the principles for the authorisation,
the framework and selected guidelines and topics. supervision and pharmacovigilance of ATMPs
Developers are encouraged to review relevant guidelines • established the CAT
and seek EMA scientific advice about their specific • provides financial and procedural incentives to
circumstances. assist in the development of ATMPs
Legal and Regulatory Framework for ATMPs ATMPs must comply with the same scientific and
The European Commission established the European regulatory requirements as other conventional medic-
legal and regulatory framework for ATMPs in 2007. inal products. However, the unique nature of ATMPs
Gene and cell therapy products have been regulated in called for a tailored regulatory approach. A risk-based
the EU as medicinal products since 2003, when they approach allowing flexibility for the regulatory require-
were introduced into legislation through Directive ments has been introduced in the legislation. The EU
2003/63/EC.16 However, tissue-engineered products, risk-based approach enables developers to have flexi-
although already used in hospitals, remained outside bility on the quality, safety and efficacy data necessary
of the legal framework and were not subject to medic- to support a favorable benefit-risk profile. Guidance
inal product regulatory oversight in most EU Member on the implementation of the risk-based approach
States. In December 2008, Regulation 1394/2007/EC started to be established in 2012.18 The methodology

Chapter 35
Figure 35-1. Decision Tree for Potential Pathways and Expedited Evaluation Programs in the EU
1. Is the product an ATMP? 2. Is the product for a rare disease?
No Other biolgoical medicinal

ATMP Classification Procedure product or governance under Orphan Orphan
medical procedural use Designation incentives not
Procedure available
Yes Hospital Exemption
Q. Is the ATMP custom-made on a non-routine basis?
for non-routine use
Paediatric Orphan
Yes
Q. Could the product be used in children? Investigation Plan: incentives are
Waiver? Deferral? available
Q. Will clinical trials provide

comprehensive data?
Yes In time Never

Conditional Exceptional
Standard MA
MA Circumstances MA
3. Is a non-standard
development plan with adaptive
Eligibility licensing envisaged?
4. Is the product a Priority Medicine confirmed Accelerated
or for an urgent unmet need? Assessment
Source: Detela, Giulia, and Anthony Lodge. “EU regulatory pathways for ATMPs: standard, accelerated and adaptive pathways to marketing authorisa-
tion.” Molecular Therapy—Methods & Clinical Development. 13 (2019): 205.
is described in Risk-based approach according to Annex I, scientific committees, which consist of representatives
part IV of Directive 2001/83/EC applied to advanced ther- from Member States, as well as representatives of patient
apy medicinal products19 and involves four steps aimed at and healthcare professional organisations. EMA’s scien-
systematically integrating information: tific committees have various tasks, including guideline
1. identify the risks associated with the ATMP’s development and scientific advice. Specifically, the
clinical use CAT plays an essential role in the regulatory oversight
2. identify product-specific risk factors contribut- of ATMPs. Among other responsibilities, the CAT is
ing to each identified risk the main scientific committee in charge of evaluating
3. map the relevant data for each identified risk marketing authorisation applications for ATMPs. The
factor against each of the identified risks CHMP is the body that makes the final scientific deci-
4. conclude on the risk factor-risk relationships sion on licensing, but CHMP must consider the opinion
from CAT to make its decisions on ATMPs. CAT also
In 2017, EMA also published additional guidance in provides scientific recommendations for the classifica-
the form of a question and answers document on how tion of these products (see ATMP Classification and
to apply the risk-based approach in the context of Classification Procedure). Five of the CAT members are
non-substantially manipulated cell-based ATMPs.20 also CHMP members to ensure proper collaboration
Furthermore, the 2018 GMP for ATMP guideline cov- and flow of information between the two committees.
ers applications of the risk-based approach by ATMP Physicians and patient organisations also are represented
manufacturers.21 Principles and requirements for long- in the CAT. The CAT is responsible for evaluation and
term safety and efficacy follow-up also were included in draft opinion of ATMP marketing authorisation appli-
the ATMP legislation22 and in a specific guideline.23 cations, which are further discussed by the CHMP to
The ATMP Regulation also specifies that the cen- generate the final opinion. The final scientific opinion is
tralised procedure is mandatory for sponsors of ATMPs then transmitted to the European Commission, which
seeking a marketing authorisation in the EU. Most of has the responsibility to issue the marketing authori-
EMA’s scientific evaluation work is conducted by its sation. Once granted by the European Commission, a

Table 35-2. ATMPs That Have Been Granted a Marketing Authorisation in the EU
Product ATMP Class Disease Area Year Company

Zynteglo GTMP Transfusion-dependent β-thalassemia 2019 Bluebird bio
(TDT)
Luxtuma GTMP Retinal disease 2018 Spark Therapeutics
Yescarta GTMP Relapsed or refractory DLBCL and 2018 Kite, a Gilead Company
PMBCL
Kymriah GTMP B-cell acute lymphoblastic leukaemia 2018 Novartis Europharm
(ALL) and diffuse large B-cell lymphoma
(DLBCL)
Alofisel sCTMP Rectal fistula 2018 TiGenix NV/Takeda
Pharmaceutical Company
Spherox TEP Cartilage diseases 2017 CO.DON
Zalmoxis sCTMP HSCT adjunctive treatment 2016 MolMed
Strimvelis GTMP SCID 2016 Orchard Therapeuticsa
Imlygic GTMP Melanoma 2015 Amgen
Holoclar TEP Corneal diseases 2015 Chiesi Farmaceutici
Provenge b
sCTMP Prostatic neoplasms 2013 Dendreon Pharmaceuticals
Macib
combined ATMP Fractures, cartilage 2013 Vericel
Glybera b
GTMP Hyperlipoproteinemia type I 2012 uniQure
Chondrocelectb TEP Cartilage diseases 2009 TiGenix
The MA was transferred from GlaxoSmithKline to Orchard Therapeutics on 23 August 2018.

a
These products are no longer authorised or are suspended.

b
GTMP=gene therapy medicinal product sCTMP=somatic cell therapy medicinal product TEP=tissue-engineered products combined=either
GTMP, sCTMP, or TEP combined with one or more medical devices as an integral part of the product
centralised marketing authorisation is valid throughout covers different aspects, such as storage, processing and
the EU. transport. Each competent authority can still require
Since its inception a decade ago, the CAT has additional testing beyond what is covered in the direc-
further discussed and revisited the regulatory require- tive via implementation into national law. National
ments and guidance for ATMPs. For example, an requirements also apply to the collection and storage
updated version of the procedural advice on the eval- of cells used in the manufacture of cellular therapies:
uation of ATMPs was published in January 2018.24 ATMPs are not exempt from these regulations.
This document aims to establish timely and effective Other key legislation that developers of ATMP
interactions between EMA and the different commit- products also will need to consider include:
tees (CAT, CHMP and the pharmacovigilance risk • legislation on traceability and pharmacovigi-
assessment committee (PRAC)) during the evaluation lance follow-up26
of an ATMP’s marketing authorisation application. The • legislation on genetically modified organisms
document confirms the CAT responsibilities for the (GMOs), which is relevant to developers of
assessment of the ATMP applications. It also empha- gene therapy products27
sises the importance of a proper flow of information and • Directive 2002/98/ EC28 and its implementing
interactions between CAT, CHMP and PRAC. In addi- directives29-30
tion, adapted timetables for a standard and accelerated
centralised procedure are provided in the document. Supply Without Grant of a Marketing
Per the Tissues and Cells Directive,25 the collection Authorisation
of cell and tissue is regulated at the donation site by The ATMP Regulation includes Article 28, which
the national competent authority. Minimum testing foresees a possibility for ATMPs that are not man-
requirements are covered in the directive. The directive ufactured routinely to be exempt from the need to

Chapter 35
have a marketing authorisation. However, it is still classification that determines the regulatory framework.
a requirement that the site of production does have ATMP products are a subset of biologics. Biological
manufacturer’s licenses. The term ‘hospital exemption’ is products comprise several product types, including
sometimes used, as the licensed facility will likely be a immunological products (e.g., vaccines), products
hospital or clinic. Of note is that the product is not to derived from human blood or plasma (e.g., immuno-
be supplied across an international border, even within globulins), antibodies and ATMPs.37 In many instances,
the EU and must be used within the same Member it will be clear that the product does meet the require-
State. Exempt products must fulfill the requirements ments of being classified as an ATMP. However, in a
defined in the regulation: minority of cases, it may not be obvious what regulatory
“Advanced therapy medicinal products which are regime applies to the product. For instance, whether an
prepared on a non-routine basis according to spe- intended use of a cell therapy is considered homologous,
cific quality standards, and used within the same or not, influences product classification as an ATMP or
Member State in a hospital under the exclusive not; use agreed as homologous supports classification
professional responsibility of a medical practitioner, not as an ATMP, and for such products, there is no
to comply with an individual medical prescrip- requirement to obtain a marketing authorisation.
tion for a custom-made product for an individual As mentioned earlier, according to the ATMP
patient, should be excluded from the scope of this Regulation, advanced therapy medicinal products can be
Regulation whilst at the same time ensuring that divided into four subcategories:
relevant Community rules related to quality and 1. somatic cell therapy medicinal products
safety are not undermined.” (sCTMPs)
2. gene therapy medicinal products (GTMPs)
This part of the ATMP Regulation targets rare, cus- 3. tissue-engineered products (TEPs)
tom-made treatments, which can be manufactured, 4. combined ATMPs (cATMPs)
administered to individual patients and used under
the responsibility of a medical professional only on a The definitions and requirements for advanced therapies
national level. The Member States must ensure compli- are given in Directive 2009/120/EC, which amended
ance with traceability, pharmacovigilance and quality Directive 2001/83/EC. It is worth noting the European
standards, but not with all EU approval requirements. framework differentiates between ATMP cell-based
The Guideline on Good Manufacturing Practice specific therapies, which are medicinal products, and cell-based
to Advanced Therapy Medicinal Products31 also mentions products, which are not medicinal products but which
products manufactured under the hospital exemption. are covered by other legal frameworks (i.e., the European
The expectation is that these products are manufactured Tissues and Cells Directive; i.e., Directive 2004/23/EC
under equivalent quality standards as other medicinal and its two technical directives, Directive 2006/17/
products. In the field, while some pointed out that EC and Directive 2006/86/EC). The important point
ATMP Article 28 may facilitate innovation and patient is whether a product is classified as an ATMP or not;
access,32 others criticised the hospital exemption. The each of the categories of ATMP require an applicant
main reasons for criticism discussed in the literature to follow the same regulatory pathway to market by
appear to be requiring a marketing authorisation granted by the
1. differences in the interpretation and imple- European Commission, after scientific review by CAT
mentation at the national level and CHMP; the subcategories of ATMP are important
2. a lack of clarity about requirements to the extent that they describe the product accurately.
3. potential misuse as an instrument that could Using the ATMP classification procedure, sponsors
disincentivise companies to invest in the devel- can submit a request to the CAT to opine whether their
opment of ATMPs product fulfills the definition of an ATMP or not (see
4. difficulty for a licensed ATMP to compete in Table 35-3 for some recent examples of CAT ATMP
a market where one product has the burden of classifications). While the CAT classification provides
proving its safety and efficacy and another does information on the applicable legal framework and
not33-36 scientific guidance, it is nonbinding, which means that
a national authority can have a different view, is not
ATMP Classification and Classification bound by the opinion from CAT and can apply that
Procedure different view in considering, for instance, the need
The correct classification of a regulated product at or otherwise, for regulatory approval of a clinical trial
an early stage of development is critical. It is the application for a particular product. The application of
the correct legal framework is the responsibility of the

Table 35-3. Recent Examples of CAT ATMP Classifications
Product Description Therapeutic Area Classification Date of Adoption of

Recommendation
Allogeneic Epstein-Barr virus specific Treatment of refractory/ Somatic cell therapy 18 October 2018
cytotoxic T lymphocytes relapsed EBV-associated medicinal product
post-transplant
lymphoproliferative disease
In vitro cultured autologous Treatment of ischemic stroke Tissue engineered 18 October 2018
mesenchymal stem cells isolated medicinal product
from bone marrow
Codon-optimized mRNA that will be Treatment of cystic fibrosis Gene therapy medicinal 18 October 2018
translated to functional human cystic product
fibrosis transmembrane conductance
regulator protein after cellular uptake
Recombinant adeno-associated Treatment of CLN2 disease Gene therapy medicinal 18 October 2018
virus serotype 9 vector encoding the product
soluble lysosomal enzyme TPP1
Organ donor derived CD34+ Prevention of graft rejection Not an advanced 20 September 2018
haematopoietic stem cells and a in recipients of HLA- therapy medicinal
defined dose of donor-derived CD3+ matched living donor kidney product
T-cells transplant recipients
Autologous suspension of Treatment of No-Option Tissue engineered 20 July 2018
blood-derived endothelial and Patients with Peripheral product
hematopoietic stem/progenitor cells Arterial Disease (PAD) and
Critical Limb Ischemia (CLI)
Allogeneic pancreatic islets Treatment of severe forms of Not an advanced 28 March 2018
encapsulated by elastin-like type 1 diabetes therapy medicinal
recombinamers product
Autologous dendritic cells, pulsed Treatment of malignant Somatic cell therapy 29 January 2018
with allogeneic tumour cell lysate mesothelioma medicinal product
Autologous adipose-derived stem Treatment of cancer-related Tissue engineered 20 December 2017
cells seeded on a collagen matrix lymphedema in breast cancer product (combined)
scaffold patients
Cultured human retinal pigment Treatment of Hemophilia B Gene therapy medicinal 9 November 2017
epithelial cells genetically modified to product (combined)
express human factor IX protein
Source: EMA website. Summaries of scientific recommendations on classification of advanced therapy medicinal products. The products listed in the table were
selected as examples of different classifications.
product’s developer. Figures 35-2 and 35-3 provide • If a product could be defined both as a GTMP
decision trees for the classification of ATMPs. The and a TEP, it will be classified as a GTMP.
classification procedure is a 60-day procedure, and there • If a product could be defined both as a TEP
is no fee associated with it. Since the procedure’s incep- and a sCTMP, it will be classified as a TEP.
tion, the CAT has classified more than 300 products
based on cells, genes and tissues. A list of the CAT’s Criteria Precluding ATMP Classification and
decisions is available on the EMA website.38 Borderline Products
If a product meets the criteria for more than one In Europe, there is a differentiation between cell- or tis-
ATMP subcategory, it will be classified according to sue-containing products considered advanced therapies
the following hierarchy: GTMP > TEP > sCTMP. and human tissue and cells for use in clinical practice
Therefore, for example: covered by other legal frameworks.39-41 The following
criteria are used for the differentiation:

Chapter 35
Chapter 33
Figure 35-2.
Figure 33-2.Decision Treefor
Decision Tree forClassification
Classification of TEPs
of TEPs and CTMPs
and CTMPs
Product containing
cells
or tissues (human,
animal or both)?
No Yes
Not a CTMP
or a TEP Does the prouct
contain exclusively
nonviable cells or No
tissue(s)?
Cells or
Yes
tissue(s)
substantially Yes
Nonviable manipulated?
cells or tissues
act principally by Cells
pharmacological, Yes genetically Yes
immunological or modified?
No
metabolic action?
Not a sCTMP No
nor a TEP
Product intended
Product
for treatment, Go to gene Gene
intended for
prevention therapy therapy
No regeneration,
or diagnosis of a flowchart medicinal
repair,
disease through product
replacement
pharmacological, Not a
Different of
immunological or gene therapy
essential human tissue
metabolic action medicinal
function? of its product
cells/tissues
Yes
No
sCTMP TEP
Product intended Product intended
for for
Not an sCTMP treatment, regeneration,
or a TEP prevention or repair,
diagnosis of a replacement of Does the product
disease human tissue contain one of
Yes
more medical devices/
sCTMP active
TEP Combined
ATMP
No
Not a
combined
ATMP
*According to the reflection paper, a viable cell is one that is able to produce energy and synthesise new molecules from raw materials.
Source: EMA Reflection paper on classification of advanced therapy medicinal products.
Source: EMA Reflection Paper on classification of advanced therapy medicinal products. According to this reflection paper, a viable cell is one that is able to produce energy and
synthesise new molecules from raw materials.

Chapter 33
Figure 35-3.
Figure Decision
33-3. Tree
Decision forforthe
Tree Classification
GTMP of GTMPs
Classification
Biological
active substance contains or
consists of a recombinant
nucleic
acid sequence.
Vaccine against
No Yes infectious
disease?
Yes
Not a GTMP Recombinant
nucleic acid sequence
used in or administered to human
being Not a GTMP
with a view to regulating, repairing No
or
deleting a genetic sequence.
No Yes
Not a GTMP Its primary therapeutic,

prophylactic or diagnostic
effect relates directly to the
product of the expression
of the recombinant nucleic
acid sequence.
No Yes
Its primary therapeutic, GTMP

prophylactic or diagnostic effect
relates directly to the product
of the
expression of the recombinant
nucleic acid sequence. Does the product
contain one or more
Yes
medical devices as an
integral part?
No Yes Does the product

contain
(genetically
modified) cells?
Not a GTMP GTMP
No Yes
Not a Combined
combined ATMP
ATMP
Source: Reflection Paper on classification of advanced therapy medicinal products. The product can contain genetically modified cells for which specific requirements should be
followed
Source: EMA(see Guidelinepaper
Reflection on human cell-based medicinal
on classification products therapy
of advanced (EMEA/CHMP/410869/2006).
medicinal products.

Chapter 35
1. the extent of manipulation (i.e., substantial or borderline between ATMPs and transplant or transfu-
minimal) sion also are discussed in the 2015 Reflection paper on
2. the intended use (i.e., homologous or classification of advanced therapy medicinal products.43
non-homologous)
ATMP Certification
In the EU, a manipulation would be considered sub- Micro-, small- and medium-sized enterprises (SMEs)
stantial if it implies a modification of the physiological developing ATMPs can take advantage of the ATMP
functions, biological characteristics or structural certification procedure. The procedure is defined in
properties that would be relevant for the intended use Article 18 of the ATMP Regulation. It is restricted to
in the clinic. For example, cell-culturing leading to SMEs and can provide them with an indication if their
expansion or cell activation with growth factors rep- ATMP development program is on track to meet the
resent a substantial manipulation. On the other hand, standards of a future marketing authorisation application.
cell separation, concentration or purification would not During the certification procedure, the CAT will per-
be considered a substantial manipulation if the cells form a scientific evaluation of quality/manufacturing and,
performed the same biological activity as in the human if available, preclinical data that are generated with the
body. Annex I of the ATMP Regulation provides a list product. However, the evaluation of clinical data is not
with examples of manipulations that are not considered included in this procedure, but the review of quality and
substantial for ATMP purposes. The list includes cell preclinical data takes place in the context of the intended
separation, centrifugation, concentration, cutting, filtra- clinical use. After an assessment, the CAT may recom-
tion, irradiation, lyophilisation, purification, soaking in mend the granting of a certificate, which is then issued
antibiotic or antimicrobial solutions and sterilisation. by EMA. The certification serves as a confirmation of the
Homologous use relates to where the action of the extent to which the available data comply with the stan-
cells that is relevant to its medical benefit is the same dards of evaluating a marketing authorisation application.
in the recipient patient as in the donor. Where use of It takes 90 days to complete the certification procedure.
cells is in the same patient but for a different effect of Details on the certification process and how to apply are
the cells from their normal function, this is not con- provided on the EMA website.44
sidered homologous use, as the intended function has
changed. These criteria are elaborated further in the Somatic Cell Therapy Medicinal Products
2015 Reflection paper on classification of advanced therapy The European framework defines sCTMPs as products
medicinal products.42 It is significant whether a cell or tis- administered to treat, prevent or diagnose a disease
sue product meets the criteria discussed above because through the pharmacological, immunological or met-
it determines whether a marketing authorisation appli- abolic actions of its cells or tissues. For a product to be
cation is required. considered a sCTMP, it must fulfill at least one of the
In some cases, it might be challenging to assess a following principles:45
product’s classification as an ATMP. So-called border- 1. have been subject to substantial manipulation
line products are addressed in the ATMP Regulation as 2. intended not to be used for the same essential
follows: function(s) in the donor and the recipient
“ The Agency [EMA] should be empowered to give (non-homologous use)
scientific recommendations on whether a given
product based on genes, cells or tissues meets the The cells may be viable (i.e., have a functional cytoplas-
scientific criteria which define advanced therapy mic membrane) or non-viable. Cells may be xenogeneic,
medicinal products, to address, as early as possible, defined as animal somatic cell preparations adapted for
questions of borderline with other areas such as implantation/infusion into humans or extracorporeal
cosmetics or medical devices, which may arise as treatments that bring animal cells into contact with
science develops. The Committee for Advanced human body fluids, tissues or organs.46 Alternatively,
Therapies, with its unique expertise, should have a cells can be human cell-based medicinal products,
prominent role in the provision of such advice.” which are heterogeneous in origin, type of cell and may
be autologous or allogeneic.47 If used with a product
The classification procedure described above outlines that is, in its own right, registered as a medical device,
how the CAT is tasked with providing a nonbinding the cell therapy would likely be classified as a combined
scientific recommendation on whether a product is ATMP. However, if used with a component that is
an ATMP. If the product is an ATMP, the CAT also not registered in its own right as a medical device, the
will opine on which subcategory it belongs. Cases in
which products comprising cells or tissues may be at the

product is considered a somatic cell therapy and is not a a patient received the corrective gene for ornithine
combined ATMP. transcarbamylase deficiency delivered via recombi-
Common scientific requirements apply to all nant adenoviral vector, and died of a systemic immune
cell-based medicinal products. These products are all response to the vector.52 Use of immunosuppression
complex, difficult to characterise and their manufac- should be considered especially to enhance safety in
turing process needs to be clearly defined. For example, early clinical testing, but this should be evaluated sys-
it is known that certain characteristics might be lost tematically in clinical trials as, ideally, this should not
during long-term culture. A list of scientific guidelines be recommended for routine clinical use unless there
on cell therapy that aim to help developers prepare is evidence supporting its use. Product standardisation,
marketing authorisation applications for human medi- toxicity and immune response studies, shedding studies
cines is available on the EMA website.48 An important and study of genomic integration sites are all factors
overarching, multidisciplinary guideline on ATMPs that are thoroughly evaluated during the development
containing human cells is the Guideline on Human Cell- of a gene therapy product. To address concerns specific
Based Medicinal Products.49 This guideline addresses to gene therapy products and ensure product safety,
preclinical, clinical, manufacturing and quality control homogeneity and compliance, multiple resources for
aspects in the development of cell-based medicinal developers are available on the EMA website.53
products. Although the guideline is intended for late- In 2019, a study was published that identified
stage products, its principles should also be considered major objections, issues and concerns raised between
by developers that are commencing clinical trials. 2008 and 2017 during the marketing authorisation
application process of gene therapies.54 The authors
Gene Therapy Medicinal Products report that quality issues were often identified as major
The European legislation defines a GTMP as deficiencies, whereas preclinical issues appeared less
“a biological medicinal product (excluding vaccines) frequently. Unsuccessful outcomes for GTMP mar-
that: keting applications analysed in the study were due to
(a) Contains an active substance which contains clinical efficacy and safety issues. An analysis published
or consists of a recombinant nucleic acid used in in Nature Review Drug Discovery also highlighted major
or administered to human beings with a view to objections for ATMPs overall from December 2007 to
regulating, repairing, replacing, adding or deleting a June 2018, showing the clinical data package had the
genetic sequence and highest percentage overall, followed by comparability
(b) Its therapeutic, prophylactic or diagnostic effect and consistency issues.55
relates directly to the recombinant nucleic acid
sequence it contains, or to the product of genetic Tissue-Engineered Products
expression of this sequence. TEPs are administered to regenerate, repair or replace
Gene therapy medicinal products shall not include human tissue. This intended function is largely what
vaccines against infectious diseases.”50 separates TEPs from sCTMPs. EU Regulation No.
1394/2007 defines TEP:
Gene therapies are often divided into in vivo and ex “contains or consists of engineered cells or tissues,
vivo. An in vivo gene therapy consists of the direct and is presented as having properties for, or is used
modification or insertion of genetic information to cells in or administered to human beings with a view
within a tissue body. Ex vivo gene therapies rely on the to regenerating, repairing or replacing a human
genetic manipulation of cells outside the patient, which tissue.”
are then administered to the patient. As ex vivo gene
therapy necessitates the introduction of significantly A TEP may contain cells or tissues of human or animal
manipulated cellular products into the patient, these origin or both, and the cells can be viable or non-via-
products need to comply with regulations for both cell- ble. It also may contain additional substances, such as
based and gene therapy products. There is also a specific cellular products, biomolecules, biomaterials, chemical
guidance for genetically-modified cell-based products, substances, scaffolds or matrices. Of note, products
which is currently under revision with a final version containing or consisting exclusively of nonviable human
expected to be published in Q2 2020.51 or animal cells and/or tissues, which do not contain
A GTMP can be based either on viral or non-viral any viable cells or tissues and do not act principally by
vectors and contain transgene(s) responsible for the pharmacological, immunological or metabolic action
therapeutic effect. Gene-editing technologies are con- are excluded from this definition. As mentioned above,
sidered as GTMPs. Immune responses are a significant to be considered engineered, there must be substantial
concern with some types of GTMPs. Notably, in 1999, manipulation and/or non-homologous use.

Chapter 35
Aspects of Product Characterisation, Also, in the cases of ATMPs, the data generated in
Manufacturing and Quality Control clinical trials are the basis for the product’s commercial
As of May 2018, Annex 2 of Volume 4 EU guidelines use. Therefore, it is essential to adequately define the
for Good Manufacturing Practice for Medicinal Products quality of the cell therapy used in the trials and its com-
for Human and Veterinary use is no longer applica- parability to the one for commercial use. Failing to do
ble to ATMPs. The Commission guideline on Good so would jeopardise the marketing authorisation appli-
Manufacturing Practice for Advanced Therapy Medicinal cation. In December 2019, the agency released a Q&A
Products, published in Part IV of Eudralex Volume 4 document on Comparability Considerations for Advanced
replaced Annex 2 for ATMPs. Unique challenges may Therapy Medicinal Products.56 This document addresses
be faced during the manufacturing of ATMPs, e.g., lim- questions on how to demonstrate comparability for
ited availability and intrinsic variability of the starting ATMPs following a change to the manufacturing pro-
materials, very small batch sizes and short shelf lives. cess or the manufacturing site.
The new document adapts the GMP requirements to A robust process development informs an adequate
the specifics of ATMPs and addresses scenarios unique program for the characterisation of the product and is
to these types of products, such as decentralised man- needed to support the release testing strategy. A poten-
ufacturing and automated production. The risk-based tial issue with cell-based products that are based on
approach outlined in the guideline enables manufactur- mixed populations is how the specifications relate to the
ers to have enhanced flexibility in their processes and cell population responsible for the biological function.
control systems if the level of risk permits it. Developers should consider if the activity of the target
Article 15 of the ATMP Regulation requires population receives positive, negative or no contributions
ATMP manufacturers to keep traceability data. It is from additional cell populations present in the prod-
recognised a system that allows complete traceability uct. The product characterisation should cover relevant
of the patient and the product and its starting mate- assays for identity, purity, safety, potency, viability and
rials is essential to monitor the ATMP’s safety and suitability for the intended use.57 To ensure consistency
efficacy. Article 15 defines a two-tiered system, which of the manufacturing process, valuable information is
is intended to ensure the anonymity of the donor drawn from data, such as comparability, potency assays
while maintaining traceability from the procurement and stability. For combined products, data on the char-
of the donor cell or tissue to the administration to the acterisation are required for all components, as well
recipient. The ATMP manufacturer is required to keep as for the final product. The integration of different
traceability data on sourcing, manufacturing, packaging, components may alter product characteristics. The com-
storage, transport and delivery to the place where the plete characterisation for the cellular component can be
product is used for 30 years after the product’s expiry particularly challenging. When considering the extent
date. The guideline on Good Manufacturing Practice for of product characterisation, developers should consider
Advanced Therapy Medicinal Products describes in detail several factors, including the intended use, if the cells
the type and amount of data that needs to be generated are autologous vs. allogeneic, the extent of manipulation
and kept. in vitro, the presence of immunological activity and
the cells’ proliferative capacity. Developers also need to
physically and chemically characterise the noncellular
Somatic Cell Therapy Medicinal Products
components in the final product in a way that is satis-
The manufacturing processes of ATMPs based on
factory. Adequate release testing relies on the parameters
human cells are different from those of other medicinal
defined during the characterization studies. However,
products. Cell-based products are complex in terms
for some therapies, such as autologous products, this
of composition and, as live materials, are dynamic in
may be particularly challenging. In such cases, product
nature. Their manufacturing process often combines
release may be justified by data collected via the process
several biologically active reagents and relies on condi-
validation. Finally, stability testing is an integral part
tions requiring specific considerations to ensure product
of development, and a shelf life is set not only for the
consistency. Nevertheless, changes impacting the man-
active substance and the finished product but also for all
ufacturing process are often necessary (e.g., renewal of
applicable intermediates subject to storage as well as the
cell lots for production, process optimisation, scale-up,
components of a combined cell-based medicinal product.
change of a raw material supplier, etc.). In all such cases,
manufacturers need to conduct a comparability exercise.
Comparability is the tool used to demonstrate that Gene Therapy Medicinal Products
safety and efficacy data collected with a given batch is It is advisable that developers focus on a robust CMC
also applicable after the proposed change is introduced. development before commencing preclinical and clin-
ical studies. Reportedly, developers of gene therapy

products experience difficulties in potency testing.58 vivo studies are necessary for almost all ATMPs under
The potency assay(s) for the product should be specific, development. In some cases, where specific risks and
follow the mechanism of action and correlate with effi- risk factors have been clearly identified, developers
cacy. Developers may be able to prevent failure during may adequately justify that some animal studies are not
late stage of development by investing early in adequate necessary. For some products, in vivo testing in animals
evaluation of potency testing and validating the method may not be relevant or predictive. In such cases, devel-
before commencing pivotal trials. For potency testing, opers should not conduct irrelevant testing; agreement
functionality of the GTMP or expression level and with regulators can be sought in scientific advice pro-
functionality of the produced therapeutic protein may cedures, if this situation seems to apply. Developers of
be required. Also, European regulators require an envi- genetically modified cells targeting a human-specific
ronmental risk assessment (ERA)59 based on preclinical antigen may be able to rely on in vitro testing because
and/or clinical data addressing possible shedding and the administration of the cells to animals would not
transmission to the environment for GTMPs, as they be expected to result in target engagement.64 However,
may contain genetically modified organisms (GMO). there may well be proof of principal studies with ver-
Different Member States of the EU have different ERA sions of the product that are active in animals, even
requirements, resulting in wide variability in how the though these are not the same as products intended for
risk is assessed. This is the case in the context of clinical use in human patients.
trials for GMO-containing products—although efforts
by the European Commission and Member States Somatic Cell Therapy Medicinal Products
have sought to bring a level of harmonisation to ERA European regulators encourage developers of cell-based
requirements through guidance and common applica- products to use a risk-based approach when designing
tion forms for different product types.60 their preclinical plans.65 The risk factors will depend
Of note, in the EU, evaluation of risk posed by on the therapy’s quality, biological activity and clinical
GMOs is typically not by regulators evaluating the application. The identified risk informs the extent of
quality, safety and efficacy of the product and its use in the preclinical package. The factors associated with a
patients, but rather by regulators responsible for envi- given risk are often multifactorial and product-specific,
ronmental safety. so they need to be assessed on a case-by-case basis.66 A
successful approach to support the progression of a cell-
Tissue-Engineered Products based product to entry into humans is the use of animal
EMA’s guideline on human cell-based medicinal models of the targeted disease or injury. The models can
products61 also covers TEPs. Quality control over the include induced or spontaneous models of the disease,
procurement and traceability of tissue is expected as with or alternatively, genetically modified animals. Animal
all cell-based products. EMA advises the entire process, models must be thoroughly evaluated for any poten-
starting from tissue procurement, isolation of tissue, crit- tial limitation. It should be born in mind that animal
ical processing steps, intermediate products, operating testing is conducted to determine whether later clinical
parameters, in-process controls and acceptance criteria, testing of the intended clinical product can be done
be in a flow diagram. Characterisation of the finished safely and also whether there is sufficient evidence to
TEP should include identity, purity, potency, viability support a rationale for expecting therapeutic actions in
and suitability for intended use. Noncellular components patients. Both genders should be studied, unless the dis-
should be characterised in the context of their required ease is only present in either male or female patients. In
function in the finished product. vivo studies of a cell-based product are often conducted
only in small animals, unless the nature of testing
Aspects of Preclinical Development requires the use of a large animal species. The most rel-
Preclinical studies serve to demonstrate proof of evant species should be used. If it is possible to conduct
principal and to define the pharmacological and toxi- testing only in a single rodent species, whether, mouse,
cological effects that could occur on administration of rat or another species, this is preferred. The use of larger
the product to humans. Such studies also support the animals may be necessary, for instance, for combination
determination of safe doses for subsequent clinical trials products, where there is a need to use the cell therapy
and could help to identify target organs for toxicity.62 with a medical device in the animal study, and it would
As with other medicinal products, preclinical studies not be possible to do so with mice or rats.
aim to support later clinical testing. However, conven- Developers of cell-based products need to con-
tional requirements applied to small chemical entities sider that biodistribution and persistence of cells can
are not always appropriate for ATMPs, and alternative have a significant impact on the overall development
approaches may be used.63 In general, preclinical in plan. For example, biodistribution studies are needed

Chapter 35
to understand the fate of the product after its adminis- location or quantity. Toxicology studies performed
tration. In some products, the cells may be distributed with the finished ATMP help identify any of these
within the body by the blood, or cells may migrate to potential hazards. As mentioned for the biodistribution,
unwanted sites. However, even where a product is given depending on the intended clinical use of the product,
at a particular anatomical site, its local distribution and developers might need to conduct single- and repeat-
whether it distributes into the rest of the body should be ed-dose toxicity studies. The route of administration
studied. Relevant animal models can help predict unin- and the dosing regimen in the studies should reflect the
tended physiological effects for patients and to study the intended use in the clinic. At times, the duration of the
potential biodistribution. At times, developers might be observation may need to be longer than the standard in
able to consider studying a systemic application reflect- conventional toxicity studies.
ing a worst-case scenario by injecting the product into
the bloodstream of an animal to follow their distribution Gene Therapy Medicinal Products
and the possible resulting adverse effects on unintended There are many factors affecting the nature and extent
target organs.67 Biodistribution studies also may need to of a preclinical development package for GTMPs.
look at the product’s potential to accumulate in a partic- Examples are the nature of the GTMP, the availability
ular organ or tissue, which would show a negative impact of relevant models, the intended route of administra-
on long-term safety. Biodistribution studies should be tion, the targeted patient population and the treatment
done before entering the clinical trial phase. If a repeated regimen. Nonclinical development of GTMPs, to some
dose option is included in the clinical protocol, develop- extent, follows the same principles as those for human
ers may need to conduct a repeated dose biodistribution cell-based medicinal products. The most appropriate
study in animals to support the trial. Data generated pharmacologically relevant in vitro and in vivo mod-
from studying biodistribution in animals are relevant els available should be used for the preclinical studies.
to better interpreting safety studies in the same species Developers are asked to discuss and justify the ratio-
exposed by the same route. This is a different perspective nale for the preclinical development and the criteria
from using the data to suggest what distribution profile used to choose the selected models. As mentioned
is expected in humans. earlier, a risk-based approach might be used to justify
One particular focus in biodistribution studies is the omission of studies and to mitigate specific risks
whether there is any spread to the gonads; if there is, there with appropriate measures.68 Some detailed guidance
may be a need for dedicated studies to evaluate potential is available for GTMPs in Guideline on Non-clinical
toxic effects on reproduction function; alternatively, such Studies Required Before First Clinical use of Gene Therapy
studies can be excluded based on evidence that the prod- Medicinal Products,69 Guideline on Non-clinical Testing
uct cannot be detected in reproductive tissues. for Inadvertent Germline Transmission of Gene Transfer
Persistence also should be characterised, as it is Vectors,70 and the draft Guideline on Strategies to Identify
of interest to understand the duration over which the and Mitigate Risks for First-in-Human Clinical Trials
administered product, or if relevant, also its transgene Within Investigational Medicinal Products Revision
product, can be detected after a single administration. 1.71 Developers of GTMPs face similar issues when
This may be long-lasting but if not, this may suggest selecting appropriate animal models as those for other
that toxicity needs to be assessed after repeated dosing. ATMPs discussed earlier in this chapter. It will be
The immunological status of the animal chosen necessary to assess the utility of animal models for
needs to be considered for these studies too. If an ani- preclinical proof of concept studies and to justify the
mal with an intact immune system is given a human relevance of selected models. In case no appropriate
cell product, it may be expected to mount an immune animal models are available to address all aspects of
response to clear that product. Therefore, immunodefi- preclinical testing, models might be developed or in
cient animals may be preferred, as these will not mount vitro evaluations performed using systems appropriately
such a response. Developers should consider whether reflecting the disease state.
that immunodeficiency should be induced genetically or Transduction and subsequent expression of
by use of immunosuppressive drugs. transgene product is an important factor for proof of
Toxicity of cell-based products may arise from principle studies. Developers of GTMPs should look at
different types of hazards and is not limited to effects differences in tropism of a gene therapy vector between
at the intended biological target. Examples are the the animal species and human when extrapolating the
allogeneic use of the product, interaction with com- results from animals to humans. Regulators would
ponents used during manufacturing, unknown cellular expect a description of the duration of the transgene
alterations that may occur during manufacturing or expression and the therapeutic effect associated with
proliferation of the administered cell in an undesired

the nucleic acid sequence and support for the proposed tissue components should be performed to define deg-
dosing regimen in the clinical studies. radation rates and expected lifetime of the product and
The distribution profile of the gene therapy vector its components.73
influences the interpretation of the therapeutic effects in
the proof of principle studies and is considered necessary Aspects of Clinical Development
prior to first exposure to humans. Analysis of the biodis- EMA has provided general guidelines and reflection
tribution throughout the body to better predict the safety papers on clinical aspects of sCTMPs, GTMPs and
and tolerability of the product is deemed appropriate. TEPs.74-76 Developers of ATMPs target different thera-
Biodistribution studies should include investigations on peutic areas. For example, many sCTMPs are developed
persistence, clearance and mobilisation of the GTMP. as cancer immunotherapies or to treat graft-versus-host
Excretion of a novel GTMP is also an important issue disease, while some key therapeutic areas for gene thera-
together with shedding, as GMOs may cause environ- pies are genetically based diseases and conditions. TEPs
mental risks. Details on expectations for biodistribution are studied for muscular-skeletal diseases, eye and skin
analysis of GTMPs and considerations for the design of diseases, cardiac diseases and renal diseases. Sponsors
biodistribution studies, assay methods and special con- that design the development plan should consider the
sideration for modified vectors can be found in the IPRP existing general guidelines for their specific therapeutic
Reflection Paper on Expectations for biodistribution (BD) areas, which are available on the EMA website.77
assessments for gene therapy (GT) products.72 Exploratory ATMP studies help developers assess
In addition to more traditional toxicology the safety of the product, estimate the optimal dose for
studies, such as single- and/or repeated-dose toxicity, subsequent studies, collect information on pharmaco-
tumorigenicity, immunotoxicity and reproductive and dynamics and set a foundation for confirmatory studies.
developmental toxicity other toxicity issues unique to As mentioned earlier, the translation of ATMP safety
genetic modification, i.e., genotoxicity, shedding, may data from preclinical studies may have limitations in
need to be investigated. To adequately assess poten- predicting safety issues and target organs of toxicity in
tial undesired consequences of the distribution and humans. The product’s mode of action and the lack of
persistence of the vector as well as immunogenicity or relevant animal models may present challenges. EMA
other unwanted pharmacological effects, toxicity should has a guideline on strategies to identify and mitigate
be assessed for the entire GTMP (i.e., virus, vector risks for first-in-human clinical trials that, although it
particle, delivery system; nucleic acid sequences, etc.) formally applies to new chemical and biological prod-
and for the transgene product. In general, these studies ucts except gene and cell therapy products, contains
use the same evaluations as are applied to other types principles that might apply and help early-stage spon-
of product. However, different methods may be applied sors of ATMPs.78 However, as ATMPs are not tested in
to assess genotoxicity. Where gene editing is the aim of healthy volunteers, this poses additional challenges e.g.,
the therapy, specialist methodologies may be applied to the initial dose should offer the potential for therapeutic
try to evaluate risks associated with unintended effects benefit in the patient to be dosed, which is not the case
of the ATMP on the genome. with first-in-human trials in healthy volunteers.
Tissue-Engineered Products Early Clinical Considerations

In vitro assay(s) can be based on the expression of Somatic Cell Therapy Medicinal Products
markers that have been demonstrated to be directly Developers aiming to conduct early exploratory stud-
or indirectly correlated to the intended biological ies derive the number of cells to be administered from
activity. In vivo animal model(s) can be used to study the outcome of preclinical studies with the product or
the intended clinical tissue repair/regeneration. The from the relevant literature. However, if the product has
potency should be defined as the required time to been extensively manipulated or contains a potentially
obtain a predefined effect (e.g., recovery of function harmful noncellular component, the use of data from
or repair of anatomical structure) or the amount of relevant literature might not be considered appropriate.
effect in a defined period of time. Other pharmacology Administration of cell-based products is highly variable,
studies may be done, depending on the relevancy of and the route of administration needs to be considered
animal models. Because the local microenvironment in safety monitoring.
is influenced by cell-signalling, growth factors and Data from relevant literature could support the
inflammatory responses, studies should characterise definition of the dose if there is a solid comparability
biocompatibility and mechanical strength of TEPs to exercise of the cellular and structural components and
permit proper growth and function of target repair the formulation between the new product and the one
organ. Stability studies of both cellular and non-cellular from the literature. In general, the optimal dosage of the

Chapter 35
cell-based product is identified in dose-finding studies. efficacy in a more typical patient population, more
At times, due to manufacturing parameters, dose-ranges representative of that to be treated with the product
with a target delivery of a precise “dose” may not be once on the market. Key points to address in confirma-
possible. Moreover, dose-finding studies with cell-based tory study design are similar to those for other types
products may be difficult to perform, not meaningful or of medicinal products, such as the target population,
not always feasible. In these cases, the developers should control group, bias minimisation strategies, choice of
justify a potential omission of dose-finding studies.79 In primary and secondary endpoints, sample size, statisti-
addition, where the target number of cells has not been cal methods, etc. The design of confirmatory studies is
achieved in manufacture, a decision may be needed as dependent on the product, the administration procedure
to whether the patient should be treated, albeit with and the indication explored. Additional endpoints that
product that does not meet its release criteria, or not are ATMP product-specific may be required and used
treated at all. This should be considered in advance and as co-primary or secondary variables. Endpoints that
the judgements detailed in the protocol. However, the focus on the duration of the response also are often
presumption is that if the patient can be treated safely, included in cases where there is an expectation of long-
it is worth evaluating the effect of the product at a cell term efficacy. Before using any non-validated endpoint
dose lower than that considered optimal, if the alterna- or novel biomarkers as a surrogate endpoint in confir-
tive may be no treatment. matory clinical trials, the sponsor would have to validate
such endpoint in a prospective study.
Gene Therapy Medicinal Products ATMPs are often developed for rare diseases,
Studies into the time course of expression of transgene which can pose problems in establishing the optimal
product (e.g., expressed proteins or genomic signatures) trial design of a prospective, randomised, blinded clin-
and pharmacodynamic studies (e.g., the function and ical trial. Put simply, there may not be enough patients
expression of the therapeutic nucleic acid sequence) eligible to enter the trial to randomise between two
might be needed for GTMPs, while classical absorption, different treatment arms, and the product benefit might
distribution, metabolism and excretion (ADME) studies have to be demonstrated by other means. This can
are not required. EU regulators also expect shedding include comparison with historical controls. Where this
studies and identifying the risk of third-party trans- is intended, scientific advice from regulatory authorities
mission, as well as studies of persistence, clearance and should be sought to ensure regulators agree in principle
mobilisation, along with the risk of germline transmis- before embarking on studies.
sion of the gene therapy vector. Pre-existing immunity to The administration of many TEPs is often per-
the vector itself should be determined prior to initiation formed within surgical procedures, which influences
of the therapy if a vector is chosen for which pre-exist- the design of their confirmatory studies. The blinding/
ing immunity can be assumed. These data might also masking of the physician or patient may not be pos-
determine the need for immune suppression. sible. Furthermore, from a methodological point of
view, it may be challenging to randomise patients with
Tissue-Engineered Products advanced tissue defects to control or experimental sur-
The tissue functionality and structural aspects of the gical therapy because it may be difficult to identify a
regenerated, repaired and/or replaced tissue as well as standard surgical control arm.
its persistence in the human body are specific attributes Finally, developers must provide to regulators suf-
of TEPs that must be assessed in early clinical studies. ficient human safety data, in terms of exposure as well
Pharmacodynamic studies should address structural and/ as duration of follow-up, about the product so that the
or functional integrity and interactions with surround- risks of the product can be identified with adequate
ing tissues, while pharmacokinetic studies examine the certainty to allow a benefit-risk determination.80 RMPs
biodistribution, longevity and possible degradation. must be formulated for the product and risk minimis-
Local tolerance safety studies may be needed, depend- ation measure proposed. While RMPs are not unique
ing on the application of the TEP. Dose as defined to ATMPs and are required for all new medicinal
by characteristics of the tissue such as cell density or products, unique aspects of risk for ATMPs should
concentration of main constituents should be based on be considered based on the guidelines. For example,
quality and preclinical data. Dose-finding studies should additional educational programs for healthcare per-
be conducted and dose variability justified, if needed. sonnel who administer product and manage serious
adverse events may be needed. Moreover, there may be
Phase 3 Studies and Risk Management for ATMPs requirements for controlled distribution, such as use
As with other medicinal products, ATMP pivotal Phase restricted to physicians experienced in treatment of the
3 efficacy studies are usually required to demonstrate disease. These additional risk minimisation activities are

required for approved chimeric antigen receptor T-cell minimal) and the intended use (i.e., homolo-
therapies.81 Also, postauthorisation studies and pharma- gous or non-homologous).
covigilance activities may be required to study potential • Micro-, small- and medium-sized enterprises
long-term effects such as risk of oncogenesis with (SMEs) developing ATMPs can take advan-
insertional mutagenesis.82,83 Requirements for long- tage of the ATMP certification procedure. The
term follow up and duration, particularly in the case of procedure is defined in Article 18 of the ATMP
GTMPs, are provided in the guideline on follow-up of Regulation and can provide SMEs with an indi-
patients administered a gene therapy medicinal product cation if their ATMP development program
(EMEA/CHMP/GTWP/60436/2007) covering pre- is on track to meet the standards of a future
and postauthorisation use. marketing authorisation application. Note that
only quality and preclinical data are evaluated
Conclusion in a certification procedure (clinical data are
• Cell and gene therapies and tissue-engineered excluded), but the review is conducted with an
products are generally regulated as ATMPs understanding of the intended clinical use.
under the ATMP Regulation; however, some • A list of specific scientific guidelines on cell
cell-based products are regulated only under therapy is available on the EMA website. An
the Tissues and Cells Directive. important overarching one is the Guideline on
• ATMPs include somatic cell therapy medicinal Human Cell-Based Medicinal Products, which
products (sCTMPs), gene therapy medic- addresses preclinical, clinical, manufacturing
inal products (GTMPs), tissue-engineered and quality control aspects in the development
products (TEPs) and combined ATMPs of cell-based medicinal products.
(cATMPs), consisting of one of the first three • Gene therapies are often divided into in vivo
categories combined with one or more medical and ex vivo. An in vivo gene therapy con-
devices as an integral part. sists of the direct modification or insertion
• Sponsors can use the ATMP classification of genetic information to cells within a tis-
procedure and request the CAT to opine on sue body. Ex vivo gene therapies rely on the
the product classification. genetic manipulation of cells in vitro, which
• All cell and tissue collection is regulated under are then administered to the patient.
the Tissues and Cells Directive for donation, • To address developers’ concerns specific to
procurement and testing. Member States can GTMPs and ensure product safety, homo-
impose further testing beyond the minimum geneity and compliance, multiple resources
requirements in the Tissues and Cells Directive. are available on the EMA website: https://
• When a marketing authorisation application is www.ema.europa.eu/en/human-regulatory/
required, the centralised procedure is manda- overview/advanced-therapy-medicinal-prod-
tory for ATMPs. ucts-overview.
• The EU risk-based approach enables develop- • The Commission Guideline on Good
ers to have flexibility on the quality, safety and Manufacturing Practice for Advanced Therapy
efficacy data necessary to support a favorable Medicinal Products adapts the GMP require-
benefit-risk profile. ments to the specifics of ATMPs and addresses
• Article 28 of the ATMP Regulation (i.e., sup- scenarios that are unique to these types of
ply outside a marketing authorisation) allows products.
individual patients to be treated with prod- • The EMA Q&A document on Comparability
uct exempted from marketing authorisation Considerations for Advanced Therapy Medicinal
provisions. Products addresses questions on how to
• If a product meets the criteria for more than demonstrate comparability following a change
one ATMP subcategory, it will be classified to the manufacturing process or the manufac-
according to the following hierarchy: GTMP > turing site.
TEP > sCTMP. • European regulators require an ERA based
• European regulators differentiate between on preclinical and/or clinical data addressing
cell- or tissue-containing products considered possible shedding and transmission to the
advanced therapies and those for use in clinical environment for GTMPs, as they may contain
practice covered by other legal frameworks. GMOs.
The criteria used for the differentiation are • Animal models for ATMP’s preclinical studies
the extent of manipulation (i.e., substantial or must be thoroughly evaluated for any potential

Chapter 35
limitation, such as the absence of historical 2. European Commission. Commission Directive 2009/120/EC
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European Parliament and of the Council on the Community
• Developers aiming to conduct early explor- code relating to medicinal products for human use as regards
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15. Commission Directive 2003/63/EC amending Directive
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The content outlined herein represents the individual opinions of the Community code relating to medicinal products for human
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21(9): 1644–1648. aspects of investigational ATMPs covers clinical consider-
65. Sharpe M, Leoni G, Barry J, Schutte R and Mount N. Non- ations for exploratory and early trials. EMA website. https://
clinical studies for cell-based medicines. Guide to cell therapy www.ema.europa.eu/en/documents/scientific-guideline/
GxP: quality standards in the development of cell-based medi- draft-guideline-quality-non-clinical-clinical-requirements-in-
cines in non-pharmaceutical environments. Cambridge: Academic vestigational-advanced-therapy_en.pdf. Accessed 26 April
Press. 2015. p. 49–106. 2020).
66. Bailey A M. Balancing tissue and tumor formation in regenera- 79. Op cit 51. Dose selection for genetically modified cell-based
tive medicine. Sci Transl Med. 2012; 4(147): 147fs28. products is discussed in section 6.2 of the draft revised guideline
67. Reinhardt J, Flory E, Büttel I, Schröder C, Fricke S, Vucinic V 80. Op cit 47.
and Niederwieser D. MSCs: clinical applications and European 81. Summary of the risk management plan for Kymriah (tis-
regulatory aspects. In Mesenchymal Stromal Cells. 2013, pp. 355- agenlecleucel). EMA website. http://www.ema.europa.eu/
364. Humana Press, New York, NY. en/documents/rmp-summary/kymriah-epar-risk-manage-
68. Guideline on the risk-based approach according to annex I, part IV ment-plan-summary_en.pdf. Accessed 26 April 2020.
of Directive 2001/83/EC applied to advanced therapy medicinal 82. Op cit 23.
products (EMA/CAT/CPWP/686637/2011). EMA website. 83. Summary of risk management plan for YESCARTA (axi-
http://www.ema.europa.eu/docs/en_GB/document_library/ cabtagene ciloleucel). EMA website. https://www.ema.europa.
Scientific_guideline/2013/03/WC500139748.pdf. Accessed 26 eu/en/documents/rmp-summary/yescarta-epar-risk-manage-
April 2020. ment-plan-summary_en.pdf. Accessed 26 April 2020.
69. Guideline on non-clinical studies required before first clinical
use of gene therapy medicinal products (EMA/125459/2006).

Chapter 36
Human Tissue Regulation

OBJECTIVES donation, procurement and testing of human

tissues and cells2
□ Outline the evolving EU Tissue and Cell
Directives (EUTCD) regulatory framework and □ Commission Directive 2006/86/EC of 24
their contiguous legislation October 2006 implementing Directive 2004/23/
EC of the European Parliament and of the
□ Detail key aspects of the EUTCD from donation Council as regards traceability requirements,
to final distribution, including tissue estab- notification of serious adverse reactions and
lishment requirements and the associated events and certain technical requirements for
responsible person’s responsibilities the coding, processing, preservation, storage
and distribution of human tissues and cells3
□ Discuss existing national market access regula-
tions applicable in various countries □ Commission Directive 2015/565 of 8 April 2015
amending Directive 2006/86/EC as regards
□ Present a brief overview of tissue regulation
certain technical requirements for the coding of
in the Advanced Therapy Medicinal Product
human tissues and cells4
(ATMP) Regulation
□ Commission Directive 2015/566 of 8 April 2015
□ Detail the key aspects of the new EU Medical
implementing Directive 2004/23/EC as regards
Devices Regulation (EU MDR) as it affects
the procedures for verifying the equivalent stan-
human tissue
dards of quality and safety of imported tissues
and cells5
DIRECTIVES, REGULATIONS AND GUIDELINES □ Regulation (EC) No. 1394/2007 of the European
COVERED IN THIS CHAPTER Parliament and of the Council of 13 November
2007 on Advanced Therapy Medicinal Products
□ Directive 2004/23/EC of the European and amending Directive 2001/83/EC and
Parliament and of the Council of 31 March 2004 Regulation (EC) No. 726/20046
on setting standards of quality and safety for
the donation, procurement, testing, processing, □ Guidelines on good manufacturing practice
preservation, storage and distribution of human specific to advanced therapy medicinal prod-
tissues and cells1 ucts. Eudralex Volume 4: Good Manufacturing
Practices7
□ Commission Directive 2006/17/EC of 8 February
2006 implementing Directive 2004/23/EC of □ Guideline on safety and efficacy fol-
the European Parliament and of the Council as low up and risk management of ATMPs
regards certain technical requirements for the (EMEA/149995/2008)8

Chapter 36
□ Directive 2010/45/EU of the European of related technology and products. Examples include
Parliament and of the Council of 7 July 2010 assisted reproductive technology, adipose-derived tissues
on standards of quality and safety of human and cells for reconstructive surgery, amniotic membranes
organs intended for transplantation9 to repair damaged eye surfaces, pericardial grafts for
guided tissue regeneration and hematopoietic stem cell
□ Procedural advice on the evaluation of transplantations and umbilical cord blood for treating
advanced therapy medicinal product in accor- hematologic cancer and adoptive immune therapy.20-23
dance with Article 8 of Regulation (EC) No. As human tissue- and cell-based technologies
1394/2007 (EMA/630043/2008)10 have become more innovative and complex, so too
has the EU regulatory environment for these prod-
□ Regulation (EC) 726/2004 of the European
ucts. The regulatory framework now consists of the
EUTCD, including the national transposing legisla-
tion of the Member States, the ATMP Regulation EC
No. 1394/2007 and the recently adopted EU MDR
Regulation (EU) 2017/745. Nevertheless, safety and
establishing a European Medicines Agency11
performance requirements for human tissue- and cell-
□ Guideline on the Procedure for Accelerated based products remain the same.
Assessment Pursuant to Article 14 While addressing unmet therapeutic needs,
(9) of Regulation (EC) No. 726/2004 allograft-derived human tissue and cell-based prod-
(EMEA/419127/05)12 ucts inherently carry risk for disease transmission. The
EUTCD were established to provide a harmonised
□ Directive 2001/83/EC of the European framework for regulation of human tissues’ and cells’
Parliament and of the Council of 6 November quality and safety across the EU. It is intended to
2001 on the Community code relating to medici- safeguard public health, prevent transmission of infec-
nal products for human use13 tious diseases and facilitate human tissue exchange
by ensuring uniform high quality and safety. The
□ Commission Directive 2009/120/EC of 14 EUTCD is comprised of one main directive (Directive
September 2009 amending Directive 2001/83/ 2004/23/EC) and four implementing technical direc-
EC of the European Parliament and of the tives (Directive 2006/17/EC, Directive 2006/86/EC,
Council on the Community code relating to Directive 2015/565 and 2015/566/EC). Specifically,
medicinal products for human use as regards these directives set quality and safety standards for tis-
advanced therapy medicinal products14 sue and cell donation, procurement, testing, processing,
preservation, storage, technical requirements for the
□ Regulation (EU) No. 2017/745 of the European
coding of human tissues and cells and distribution. In
addition, they provide a system of tissue traceability
on medical devices and amending Directive
from donor to recipient and vice versa, and require-
2001/83/EC and Regulation (EC) No 178/2002
ments for tissue establishment accreditation.
and Regulation (EC) No. 1223/2009 and repealing
Aimed at safeguarding public health, the EUTCD
Council Directives 90/385/EEC and 93/42/EEC15
did not intend to harmonise tissue product authorisa-
tion for human application. As a result, in addition to
differences in local transposition of the EUTCD, mar-
Introduction
ket access nonuniformity exists for those products not
Human tissue- and cell-based products encompass a
covered by the scopes of the ATMP Regulation or the
large diversity in type and nature of originating tissues,
EU MDR. Conformance to the EUTCD, for example,
their processing methods and related quality standards.
may allow distribution of a particular tissue product
They have been applied in multiple surgical disciplines,
within a certain Member State, while in others, the
such as burn care, orthopaedics, neurology, ophthalmol-
identical product is regulated as a medicinal product
ogy, oncology and cardiovascular. Allograft skin, cornea
requiring marketing authorisation prior to distribution.
and bone grafts, including femoral heads and demin-
This chapter outlines the evolving regulatory
eralised bone, were the first tissue products successfully
framework for human tissues and cells intended for
applied for therapeutic purposes.16-19
therapeutic purposes. EUTCD requirements are
Emerging developments in transplantation therapy,
detailed, with emphasis on tissue establishments,
cell biology and regenerative medicines have led to a
serological testing and vigilance aspects. Differences
significant increase in the variety and clinical availability
in EUTCD transposition among Member States and

nonuniformity in obtaining market access for tis- transplantation.32-34 It was the first legislation aimed
sue-based products are discussed. Aspects of the ATMP at achieving uniformity among Member States on the
Regulation and the newly adopted EU MDR, as they quality of human tissue transplantations, donor and
relate to human tissues and cells, are explained. Lastly, recipient protection and enhancing medical science
guidance is given as to when a human tissue falls under and therapeutics’ progress. Following transplantation
the EUTCD, ATMP Regulation and/or EU MDR. therapy and regenerative medicine advancements and
to facilitate further access to safe and ethical organ
Historical Perspective on Tissue transplantations, the Council of Europe established a
Legislation committee of transplantation experts in 1987.35 This
As a result of their long-term experience and expertise committee has been instrumental in developing recom-
in human tissue and transplantation practices, tissue mendations, policies and technical standards related to
banks have played a pivotal role in establishing guid- ethical issues and transplantation practices. The recom-
ance and standards for tissue quality and safety.24,25 mendation on human tissue banks adopted in 1994 is
Significant progress in tissue banking—bone and skin noteworthy, as it indicates some key aspects covering
banking in particular—originated in the mid-20th human tissue safety and quality, such as considerations
century as a result of both military need to treat war for organisation, processing, internal quality control and
injuries and the development of new tissue processing testing for transmittable diseases and tissue traceabil-
methods, such as cryopreservation, freeze drying and ity.36 However, recommendations are nonbinding acts
irradiation. The first tissue bank (Navy Tissue Bank) for Member States and, therefore, without legal force.
was established in the US in 1949.26,27 Its purpose was In 1999, the Council of Europe’s European Health
to store frozen bone for clinical and research purposes. Committee (CDSP) established a working group tasked
This was followed by a rapidly expanding international with preparing guidance on required human organ,
network of tissue banks to meet growing demands with tissue and cell transplantation standards and quality
a focus on civilian medical needs. Many techniques and assurance measures in Member States. It resulted in
standards used today, including identifying appropriate publication of the Guide to Safety and Quality Assurance
donor screening criteria, developing procurement and for Organs, Tissues and Cells in 2002, which subsequently
processing methods and establishing a graft registry, are was broken into two guides: the Guide to the Quality
based on principles and practices established in that first and Safety of Organs for Transplantation, 6th Edition, and
tissue bank’s development programmes.28 the Guide to the Quality and Safety of Tissues and Cells
Although national tissue transplantation legal for Human Application, 3rd Edition.37-39 This compre-
frameworks were in place prior to EUTCD imple- hensive guidance document covers requirements for
mentation, tissue and cell banks essentially were ensuring human tissue and cell safety and quality and
autonomous. They self-regulated tissue and transplanta- provides standards for human cell and tissue procure-
tion practice quality and safety aspects.29 Tissue banks’ ment, preservation, processing, storage and distribution.
own protocols and procedures were established based on It addresses donor selection, serological testing
national legislation and available national and regional requirements and the importance of encompassing
guidance documents. In addition, different developing tissue- or transplant-related activities under a quality
standards from a plethora of technical-scientific inter- management system. This guidance document became
national associations were taken into consideration, a main reference for the EUTCD, as prepared by the
each covering specific tissue or cell types. These associ- Directorate General for Health and Consumer Affairs
ations include, for example, the European Association (also known as DG Sanco).
of Tissue Banks (EATB), European Blood and Marrow On 7 April 2004, the main EUTCD directive
Transplantation Group (EBMT), European Eye (Directive 2004/23/EC) was adopted and transposed
Banking Association (EEBA), European Transplant into national law by all Member States by 7 April 2006.
Coordinators Organisation, European Society of Shortly thereafter, two implementing technical direc-
Human Reproduction and Embryology (ESHRE) and tives, Directive 2006/17/EC and Directive 2006/86/
American Association of Tissue Banks (AATB).30,31 EC, were adopted and transposed into national laws
Differences in national legislation and the absence during 2006–2008. There have been two amending
of adequate common documents and guidelines empha- directives and one implementing directive added to the
sised the need for tissue legislation harmonisation. EUTCD family of legislation since its introduction,
European initiatives to this end started as early as which are discussed further in sections below.
1978 with the adoption of Resolution (78)29, related With newer technology to manipulate or “engineer”
to human organ and tissue removal, grafting and human tissues came new legislation to ensure safety
and performance; the ATMP Regulation addresses

Chapter 36
requirements for engineered tissue that is used for a including donor identification details and describing
“medicinal” function or tissue not used for its original and identifying procured tissues and cells, that is passed
function. Most recently, the EU MDR was adopted in on to the tissue establishment.
April 2017 with a transposition period of three years,
which includes regulation of certain nonviable human Donor Selection and Testing
tissues and cells and their derivatives, a subset of human To select appropriate consenting human tissue donors,
tissue products not addressed completely by either the donor selection procedures should comply with the
ATMP Regulation or EUTCD. requirements established in Directive 2006/17/EC
Annexes I and III. These annexes define the require-
EUTCD Requirements ments for deceased donors and autologous or allogeneic
If tissues and cells are being used as starting materials living donors. Procedures and standards employed
in a medicinal product, applicants should consult the for appropriate donor(s) selection and exclusion of
EUTCD directives, including its technical implement- high-risk or otherwise unsuitable candidates should be
ing directives, in terms of donation, procurement, donor clearly delineated and justified. A donor’s medical and
selection and testing, processing and storage, distribu- behavioural history is reviewed to highlight potential
tion, import and traceability of human tissues and cells. risk factors, such as a previous xenograft transplantation,
cancer presence or previous cancer history, rendering
Donation the donor unsuitable.
EU legislation on tissues and cells covers donation of In addition to assessing medical and behavioural
such material from both living and deceased donors history, all donors must be tested for transmissible
and specifies requirements for autologous or alloge- diseases using a range of biological tests. The required
neic tissue donation. Directive 2004/23/EC Article 13 biological tests are specified in Directive 2006/17/EC
requires all donors to give informed consent; in this Annexes II and III, as amended by Directive 2012/39/
regard, information to be provided to donors at the time EU, and are summarised in Table 36-1. These include,
of consent is specified in the directive’s annex. Further at minimum, tests for the following diseases: human
details of the actual procedure for obtaining consent and immunodeficiency virus (HIV)-1 and -2, Hepatitis
donor identification are set out in Annex IV of imple- B, Hepatitis C and Syphilis. Human T-lymphotropic
menting Directive 2006/17/EC. This directive states virus (HTLV) type I antibody testing also must be
consent should be obtained by persons appropriately performed for donors living in or originating from
qualified, provided with timely and relevant training high-prevalence areas or with sexual partners origi-
and, where appropriate, registered in accordance with nating from those areas or where the donor’s parents
appropriate professional and/or statutory bodies. This originate from those areas. In certain circumstances,
information should be documented in regularly updated additional testing may be required, depending on the
training records. In addition to outlining donor iden- donor’s history and the donated tissue or cell charac-
tification and consent procedures, Directive 2004/23/ teristics (e.g., RhD, HLA, malaria, CMV, toxoplasma,
EC specifies whether financial incentives may be pro- EBV, Trypanosoma cruzi).
vided to donors. Since the directive’s aim is to promote Biological tests must be performed by a qualified
altruistic tissue and cell donation to help ensure such laboratory, authorised as a testing centre, including
material’s safety, donors may receive compensation only Tissue Establishment Licensing by the Member State’s
covering expenses and inconveniences related to the competent authority, using CE-marked testing kits,
donation, not the donation itself. The directive allows where appropriate. Blood samples must be collected
each individual Member State to define conditions within the timeframes specified in the directive. The
under which compensation may be granted. amount of blood required will depend on the testing
laboratory and the test kits used, and these require-
Procurement ments should be communicated before collection. In
In addition to specifying donor identification require- the case of a neonatal donor, the tests may be carried
ments to ensure tissue quality and safety, Directive out on samples from the donor’s mother to avoid med-
2006/17/EC Annex IV also sets out procurement ically unnecessary interventions for the infant. When a
procedure requirements. The intent is to ensure donor potential donor has lost blood, and recently has received
safety during procurement and to minimise microbial blood, blood components, colloids or crystalloids, the
contamination risks during material collection under degree of haemodilution must be assessed to confirm
aseptic conditions. In this regard, Annex IV requires the sample’s validity for testing. In addition to the ini-
the procurement establishment to produce a report, tial test requirements, living allogeneic donors must
undergo repeat sampling and testing after 180 days

Table 36-1. Serological Donor Testing Requirements
Disease Required Test per 2006/17/EC Additional Legally Binding National

Requirements*
HIV–1 and 2 Anti-HIV-1,2 HIV-1 p24 antigen:
Czech Republic, France, Lithuania, Slovakia
HIV-1 NAT:
Austria, Belgium, Cyprus, Estonia, Finland,
France, Croatia, Hungary, Italy, Poland,
Portugal, Slovenia
Hepatitis B HBsAg Anti-HBs:
Anti-HBc Greece, France, Hungary, Lithuania,
Romania
HBV NAT:
Austria, Belgium, Cyprus, Estonia, Finland,
France, Hungary, Italy, Lithuania, Portugal,
Slovenia
Hepatitis C Anti-HCV-Ab HCV NAT:
Austria, Belgium, Cyprus, Estonia, Spain,
Finland, France, Hungary, Italy, Lithuania,
Portugal, Slovenia, Slovakia
Syphilis Non-Trepanemal Rapid Plasma Reagin test and T. Pallidum NAT:
if positive, a confirmatory Trepanemal antibody Lithuania
test (validated test algorithm)
T-Lymphotropic virus Anti-HTLV-I: Anti-HTLV-2:
(donor living in or HTLV-I antibody testing must be performed Cyprus, Estonia, Greece, Spain, France, Italy,
originating from a for donors living in, or originating from, Lithuania, Luxembourg, Norway, Portugal,
high incidence area) high-incidence areas or with sexual partners Sweden
originating from those areas or where the
donor’s parents originate from those areas.
*Refer to the 2015 Mapping Exercise on the Commission’s website for the full list of testing requirements.
unless the initial samples also are tested by nucleic acid entitled “Mapping of More Stringent Blood Donor
amplification technique (NAT) for HIV, HBV and Testing Requirements—Mapping Exercise 2015.”40
HCV. Repeat testing also is not required if the process- Table 36-1 provides several examples from this report
ing includes an inactivation step that has been validated of additional tests required in various Member States.
for the viruses concerned. A survey focused on the more stringent requirements
As the EUTCD sets only the minimum standards related to donor selection has been discussed, but it is not
for donor selection and testing, each Member State may yet known when it will be undertaken and published.
introduce more stringent requirements. Many Member
States have adopted additional donor screening and Processing and Storage
testing measures, resulting in a challenging verification Tissue establishments require standard operating pro-
process of each Member States’ requirements prior to cedure implementation for all processes and activities
undertaking intra-EU tissue and cell distribution. These affecting tissue and cell product quality and safety
additional tests often originate from national legislation (Directive 2004/23/EC Article 20). Processes, equip-
in place prior to EUTCD transposition or best practices ment and controlled environments must be validated.
in certain tissue professional societies. To provide trans- Compliance with good manufacturing practice (GMP)
parency on this topic, the European Commission and the is mandatory for all medicinal products that have been
Member State competent authorities initiated a project granted a marketing authorisation. Likewise, advanced
in 2015 to map the more stringent quality and safety therapy medicinal products administered to patients
requirements across the EU. In July 2016, the reports must be manufactured under equivalent quality stan-
from this project were made available on the European dards as described in Eudralex Volume 4 EU Guidelines
Commission’s website for blood, tissues and organs, to Good Manufacturing Practice specific to Advanced

Chapter 36
Table 36-2. Structure of the Single European Code
Donation Identification Sequence Product Identification Sequence

EU Tissue Establishment Unique PRODUCT CODE SPLIT NUMBER EXPIRY DATE
CODE Donation (YYYYMMDD)
ISO Country Tissue Number Product Product
Code Establishment Coding System Number
Number Identifier
2 Alphabetic 6 Alpha- 13 Alpha- 1 Alphabetic 7 Alpha- 3 Alpha- 8 Numeric
Characters Numeric Numeric Character Numeric Numeric Characters
Characters Characters Characters Characters
Therapy Medicinal Products, in effect since 22 May 2018. end user being required to obtain a tissue establishment
These guidelines detail the GMP requirements that license when receiving tissues or cells from another EU
should be applied in the manufacturing of ATMPs Member State.
granted a marketing authorisation and used in a clinical
trial setting. These guidelines do not apply to medicinal Traceability
products other than ATMPs. Tissue and cell traceability is an important means of
monitoring and quickly communicating disease trans-
Distribution and Import mission risks and other adverse events in recipients.
Distribution must be validated to ensure the primary The EUTCD requires traceability of tissues and cells,
package and shipping container maintain the specified from the donor to the recipient and vice versa, be
conditions for the tissues and cells. As a result of the maintained. Tissue and cell traceability also includes
increasing global exchange of tissues and cells, an addi- the materials and equipment that come into contact
tional Directive 2015/566/EU on import requirements with them. Directive 2006/86/EC, as amended by
for human tissues and cells from third-country suppliers Directive 2015/565/EU, sets out the detailed traceabil-
was adopted on 8 April 2015 and took effect 29 April ity requirements.
2017. The aim of this directive is to ensure an equiv- Unique identification of each tissue or cell is the
alent level of quality and safety from tissues and cells foundation of an effective traceability system. While
imported into the EU. Importing can be undertaken national, regional or local coding systems existed in
only by tissue establishments that are accredited, des- each Member State, it was the adoption of Directive
ignated, authorised or licensed by the Member States 2015/565/EU in April 2015 that introduced the require-
for this activity. To obtain a license as an importing ments for the creation and application of a Single
tissue establishment under the new directive, establish- European Code (SEC). As shown in Table 36-2, the
ments must provide their competent authorities with SEC is an alphanumeric code comprised of a donation
the information and documentation outlined in the identification sequence and a product identification
directive’s Annex I. Included are general information sequence. The donation identification includes the EU
on the applicant and third-country supplier, details on tissue establishment code and the unique donation num-
tissues or cells to be imported, a copy of the written ber. The product identification sequence includes the
agreement between the importing tissue establishment product code identifier (“E” for EUTC, “A” for ISBT128,
and third-country supplier, a detailed flow chart from “B” for Eurocode), the corresponding tissue or cell prod-
procurement to reception at the importing tissue estab- uct number, the split number and the expiry date. As of
lishment and an export authorisation certificate from 29 April 2017, the SEC must be included on the tissue
the third-country supplier. The minimum requirements or cell product label and relevant accompanying docu-
for written agreements between the importing tissue mentation prior to its distribution for human application.
establishment and third-country supplier are specified For the transfer of human tissues and cells to
in Annex IV of Directive 2015/566/EU. another processing tissue establishment, the label
Currently, various definitions of “import” still exist. must include, at minimum, the donation identification
In some Member States, import is defined as “outside sequence. Human tissues and cells used for ATMP
the European Economic Area (EEA),” while in others, products have to be traceable using the SEC at least
import is defined as “outside of the Member State.” until transfer to the ATMP manufacturer. Existing
These definition differences can lead to the hospital or labelling and coding systems can continue to be used

by tissue establishments, but the SEC will need to be of the request. The agency publishes the outcomes
added to the final product label. In addition, tissue of these assessments in the format of summary
establishments will need to ensure a clear mapping reports. These summary reports are available for
between their local coding system and the SEC. SEC classification recommendations from July 2011
traceability exemptions remain for emergencies autho- (ordered by date of adoption of recommendation)
rised by the competent authority, tissues and cells under the following link: https://www.ema.europa.
distributed directly for immediate transplantation to the eu/en/human-regulatory/marketing-authorisation/
recipient, and tissues and cells imported by a licensed advanced-therapies/advanced-therapy-classification/
tissue establishment when they remain within the same summaries-scientific-recommendations-classifica-
centre from importing to application. tion-advanced-therapy-medicinal-products.
As part of the implementation of Directive
2015/565/EU, the EU Coding Platform was launched Pharmacovigilance
on the European Commission’s website and contains All relevant legislation and guidelines regarding phar-
the EU Tissue Establishment Compendium and macovigilance in the EU are applicable to ATMPs.
the EU Tissue and Cell Compendium. The Tissue In February 2018, EMA released a draft revised
Establishment Compendium is the listing of all Guideline on safety and efficacy follow up and risk man-
licensed EU tissue establishments. The EU Tissue and agement of ATMPs (EMEA/149995/2008) for a
Cell Product Compendium is the listing of all tissue three-month public consultation. This revision takes into
and cell types distributed in the EU along with their consideration the experience gained with the authori-
respective product numbers under the EUTC, ISBT128 sation of these medicines and with scientific advice and
and Eurocode systems. protocol assistance. It also provides advice on:
In addition to the unique tissue and cell coding, • early detection of risks during development
the EUTCD requires documentation on the donor, and provides a framework for the effective
the products and the end user to be maintained by the mitigation of their consequences for patients
tissue establishment for a minimum of 30 years after • the design of appropriate postauthorisation
the tissue’s clinical use or expiry date. Organisations studies to follow up on the safety and efficacy
responsible for human application also are required to of these medicines.
maintain traceability and must keep records on the tis-
sue establishment supplier, the recipient and the surgery It encourages developers of ATMPs to plan timely
for 30 years in accordance with Directive 2006/86/EC interactions with EMA to ensure an efficient develop-
Annex VI. ment process. The revision of this guideline is part of
the joint action plan of the European Commission and
Classification of ATMPs EMA to streamline procedures and better address the
Companies can consult the EMA to determine whether specific requirements of ATMP developers.
a medicine they are developing is an ATMP. The The EUTCD also comprises vigilance reporting and
procedure allows them to receive confirmation that a recall system as well as follow-up requirements for tis-
medicine, which is based on genes, cells or tissues, meets sue-related incidents in both living donors and patients.
the scientific criteria for an ATMP. The criteria for Directive 2004/23/EC Article 3 contains two incident
ATMPs are set out in Article 17 of Regulation (EC) definitions, which differ from those in the medicinal prod-
No. 1394/2007. uct and medical devices directives and the new EU MDR
The classification procedure is optional. EMA due to the risk of communicable disease transmission:
established the procedure to address questions on bor- • Serious Adverse Event (SAE) means any
derline classification with other areas, such as medical untoward occurrence associated with the
devices, as early as possible (https://www.ema.europa. procurement, testing, processing, storage and
eu/en/human-regulatory/marketing-authorisation/ distribution of tissues and cells that might lead
advanced-therapies/advanced-therapy-classification). to the transmission of a communicable dis-
To submit an application for ATMP classification, a ease, to death or life-threatening, disabling or
pre-submission request form should be completed and incapacitating conditions for patients or which
returned with briefing information to advancedthera- might result in, or prolong, hospitalisation or
pies@ema.europa.eu. morbidity.
EMA’s Committee for Advanced Therapies • Serious Adverse Reaction (SAR) means an
(CAT) delivers scientific recommendations on unintended response, including a communi-
ATMP classification after consultation with the cable disease, in the donor or in the recipient
European Commission within 60 days after receipt associated with the procurement or human

Chapter 36
application of tissues and cells that is fatal, Frequently, tissue banks dedicated to certain tissues
life-threatening, disabling, incapacitating or share knowledge and best practices in professional net-
which results in, or prolongs, hospitalisation or work organisations. Under the EUTCD, in addition to
morbidity. non-profit tissue banks, for-profit organisations came
into being, such as distributors that store and distribute
These definitions differentiate incidents that occur after human tissues and cells, and these organisations are
application on the patient or procurement from the eligible for tissue establishment licensing. Hospitals also
donor from those occurring before the tissue and cells can be certified as tissue establishments. After EUTCD
are used for human application. Each Member State implementation, hospitals had to organise all tissue-re-
has developed its own vigilance and recall reporting lated activities in different departments, a tedious and
system, and tissue establishments should report SARs, complex task. In addition, organising registration and
SAEs and recalls. Many Member States use online communicating biovigilance reports within a hospital
reporting systems for this purpose, where tissue estab- often is a cross-departmental task and requires novel
lishments can enter details securely and follow-up on communication routes.
incidents, including recalls. A second tier of tissue establishments is donor
Vigilance procedures for donated tissues and cells test laboratories. These test laboratories often were
must be complementary to the vigilance system for certified already by additional (national) certification
organs, as described in Directive 2010/45/EC. This is and licensing equivalent to the US Clinical Laboratories
important in cases where organs, tissues and cells from Improvements Amendments (CLIA) licensing system.
one donor are used for transplantation and might have Donor testing on either the living or deceased must be
resulted in an SAE or SAR. performed by laboratories with a tissue establishment
SAE/SAR follow-up and investigation can be license for those specific tests. The specific tests for
challenging when evaluating whether the tissue or cell which a laboratory is certified are mentioned on the
was the root cause, e.g., a transmittable disease. A very laboratory’s tissue establishment license.
useful information resource for tissue- and cell-related
incidents is the “global vigilance and surveillance data- Tissue Establishment Licensing and Competent
base for medical products of human origin,” also known Authority Inspections
as the NOTIFY Library. The Commission is required to provide the European
If an incident or recall has an international impact, Parliament and the Council with an overview report
Member States can use the electronic rapid alert system on implementing the directives, particularly regarding
for tissues and cells (RATC) to notify all concerned inspections and monitoring. The most recent report,
Member State competent authorities in due course. COM (2016) 223 Final, was published in April 2016
However, the RATC system is intended for communi- (report with corrigendum) and can be found on the EU
cation among Member State competent authorities and Commission website.41 It is important to note that even
is not accessible by the public. the tissue establishment definition differs from country
Importantly, in the new EU MDR, Article 89 to country; for example, one country may require facil-
point (6) states “In the case of devices covered by this ities storing cells/tissues for a period of greater than 24
regulation and where the serious incident or field safety hours to be registered as a tissue establishment, while
corrective action may be related to the derivatives of another country might allow up to 48 hours.
tissues or cells of human origin utilised for the man- The competent authority is responsible for biannual
ufacture of the device, the competent authority or the tissue establishment inspections, including provision
coordinating competent authority shall inform the of licenses. An operations manual for tissue and cell
competent authority for human tissues and cells.” procurement and tissue establishment inspections was
developed to guide and harmonise the inspection and
Diversity of Tissue Establishments and Tissue licensing process among Member States based on
Banks Commission Decision 2010/453/EU.42,43
Before the EUTCD was implemented, most Member
States had their own regulated tissue bank networks. Tissue Establishment Quality System and
These tissue banks often were part of hospitals or Responsible Person
government institutions focused on centralised pro- Tissue establishments must implement processes and
curement, storage and distribution of different tissue procedures to ensure human tissue products’ pres-
and cell types. Examples of these nonprofit organi- ervation, safety, quality and integrity. Implementing
sations are bone banks, cornea banks and skin banks. Directive 2006/86/EC describes the quality
They often follow the same principles as organ banks.

Table 36-3. Qualifications and Responsibilities of the Responsible Person Under the EUTCD, Qualified
Person for Human Medicinal Products and Responsible Person for Regulatory Compliance Under the EU MDR
Aspect Responsible Person, Qualified Person, Person Responsible for

EUTCD Human Medicinal Products Regulatory Compliance, EU MDR
Legislative Article 17, 2004/23/EC Annex 16, Eudra-Lex, Volume 4, Article 15, 2017/745/EU
Reference Good Manufacturing Practice
(GMP) Guidelines
Qualifications • University degree • University degree in • University degree or course
or course of study pharmacy, medicine, of study recognised by
recognised by the veterinary, chemistry, the Member State in law,
Member State in medical biology or pharmaceutical medicine, pharmacy,
or biological sciences chemistry engineering or another
and • Two years’ relevant relevant scientific
• two years’ relevant experience discipline and at least
experience • Additional training one year of experience in
requirements regulatory affairs or quality
management systems of
medical devices, or
• four years’ experience
in medical devices’
regulatory affairs or quality
management systems
Responsibilities • Ensures products • Ensures drug preparation • the conformity of the
are procured, tested, is according to GMP devices is checked
processed, stored and guidelines appropriately, before they
distributed in accordance • Ensures batch preparation are released
with EUTCD and the laws is according to dossier • technical documentation
in force in the Member requirements and the EU declaration of
State conformity are drawn up
• Ensures the competent and updated
authority is notified of • compliance with
any serious adverse postmarket surveillance
events and reactions obligations
• Provides the ministry • reporting obligations are
with appropriate fulfilled
information as required
in Article 6
management system, which is based on ISO 9001 and as well as disposition of tissues and cells after new
includes specifics on activities associated with tissue donor requirement introduction. This also includes an
and cells for human application. General requirements, established inventory and tissue (donor) review system,
such as those for organisation, training, job descrip- separating eligible from non-eligible donors.
tions, responsibilities and quality review, including SAE Each tissue establishment should appoint a quali-
and SAR reporting and recall processes, are described, fied RP as defined in Directive 2004/23/EC Article 17.
including annual reporting on tissue establishment Although the RP is responsible for the final release of
activities to the competent authority. The activities are human tissue and cells for human application, the RP’s
summarised and reported by the competent authorities qualifications and responsibilities differ from those of
to the European Commission, which retains oversight of the qualified person for medicinal products, and in the
EU tissue- and cell-related activities, SAEs and SARs. cases where the human tissue is required to follow the
The quality system also covers more specific pro- EU MDR, there is an additional requirement to have a
cess descriptions for handling tissues and cells within RP for regulatory compliance (Table 36-3).
the tissue establishment, including a risk assessment Competent authorities must accept the proposed
under the supervision of the responsible person (RP), RP, and Member States have interpretative differences

Chapter 36
on the RP’s qualifications, especially those with tissue ATMP Regulation

establishments accredited only for tissue and cell storage The regulatory framework for ATMPs is designed to
and distribution. The RP ensures compliance with the ensure the free movement of these medicines within the
EUTCD and national transposing laws and is the tissue EU, to facilitate their access to the EU market and to
establishment’s point of contact with the competent foster the competitiveness of European pharmaceutical
authority. Further, the RP supervises the establishment’s companies in the field, while guaranteeing the highest
quality system, including verifying tissues and cells level of health protection for patients. Regulation (EC)
meet all appropriate specifications prior to release and No. 1394/2007 provides the overall framework on
eventual distribution. The RP also must ensure third- ATMPs.
party agreements are in place with all critical suppliers Viable and nonviable human tissues and cells that
and eventual parties for tissue distribution (depending are substantially manipulated (“engineered tissue”) or do
on Member State requirements). If applicable, the RP not perform the same function in the recipient as they
ensures all human tissue imports from non-EU coun- do in the donor, and act principally by pharmacological,
tries meet EUTCD quality and safety standards, as immunological or metabolic action are regulated under
required by Directive 2015/566/EU. Regulation (EC) No. 1394/2007, the ATMP Regulation.
The ATMP Regulation amended Directive 2001/83/
Marketing Authorisation Procedure for EC on medicinal products for human use and estab-
ATMPs lished requirements for ATMP market authorisation,
As provided for in the ATMP Regulation (EC) No. supervision and pharmacovigilance. As a regulation,
1394/2007, the scientific evaluation of marketing the ATMP Regulation is directly applicable without
authorisation applications (MAAs) for ATMPs is the need for transposition into national legislation.
primarily performed by the CAT. The CAT prepares Directive 2003/63/EC, amending Directive 2001/83/
a draft opinion on the quality, safety and efficacy of EC, revised marketing authorisation application dossier
each ATMP subject to MAA, which is sent for final requirements (Part IV of Annex I to 2001/83/EC) to
approval to the Committee for Medicinal Products for include ATMPs. Directive 2009/120/EC (Part IV of
Human Use (CHMP). The CHMP recommendation is Annex I to Directive 2001/83/EC Annex I, Part IV)
then sent to the European Commission, which adopts a further amends ATMP definitions and authorisation
decision binding in all Member States. requirements to include tissue-engineered products and
Procedural advice on the evaluation of advanced combined ATMPs.
therapy medicinal product in accordance with Article 8 of Table 36-5 illustrates the current generally applica-
Regulation (EC) No. 1394/2007 (EMA/630043/2008), ble regulatory regime for medicinal products comprising
released in January 2018, describes the procedure for human tissues and/or cells for human application and
the evaluation of MAA for ATMPs. This procedure is pertinent tissue activities requiring conformance with
put in place to establish timely and effective interactions the EUTCD. When human tissues and cells are used
between EMA and the different committees (CAT, to manufacture ATMPs, the EUTCD is applicable as
CHMP and the Pharmacovigilance Risk Assessment far as donation, procurement and testing are concerned.
Committee (PRAC)) in conjunction with the applicant Cultured autologous chondrocytes intended for the
during the centralised evaluation of an ATMP. repair of cartilage lesions, for example, contain viable
The standard timetable for the evaluation of an cells and are regulated as ATMPs under Regulation
ATMP for initial MAA under the centralised proce- (EC) No. 1394/2007. These tissue-engineered products
dure is presented in Table 36-4. need to comply with the EUTCD with respect to carti-
The principles for the accelerated assessment pro- lage cell donation, procurement and testing.
cedure in accordance with Article 14(9) of Regulation
(EC) 726/2004 also apply for ATMPs as per the EU MDR
Guideline on the Procedure for Accelerated Assessment Regulation (EU) 2017/745 of the European Parliament
Pursuant to Article 14 (9) of Regulation (EC) No. and of the Council on medical devices, commonly
726/2004. In case of ATMPs, the CAT decides on the termed the EU Medical Devices Regulation (EU MDR),
accelerated assessment request. The timetable will be was adopted 5 April 2017 was recently amended with
arranged to include the review by the CAT. The initial Regulation 2020/56144 to postpone its implementation
assessment phase will last 120 days, similar to the stan- until May 2021, due to coronavirus crisis. Its aim is
dard marketing authorisation procedure; the second to increase regulatory consistency across the EU and
phase of assessment will last 30 days; therefore, the provide a more transparent and sustainable regula-
timetable 120 + 30 days. tory framework for devices that supports innovation
while ensuring patient safety. It addresses, for example,

Table 36-4. Standard Timetable for Initial ATMP Marketing Authorisation Application Evaluation Under the
Day/ Milestones Action Responsibilities

Day 1 The procedure starts after validation of the application. EMA
In the case of an ATMP containing or consisting of GMOs, EMA will inform
Start Date the GMO competent authorities of the start of the procedure and manage the
coordination with the GMO competent authorities.
In the case of ATMPs that incorporate medical devices or active implantable
medical devices (“combined ATMPs”), EMA manages the coordination of the
consultation with the notified body at the relevant time points of the procedure.
Day 80 CAT Rapporteur and Co-Rapporteur each send their Assessment Report(s) to the CAT (Co-)
CAT (Co-) CAT, CHMP Coordinators, CHMP members and EMA. Rapporteurs
Rapporteur ARs EMA sends the Day 80 Assessment Reports (AR) to the applicant, making it
clear that it only sets out their preliminary conclusions, is sent for information
purposes only and does not yet represent the position of the CAT.
Day 94 PRAC Rapporteur circulates the RMP AR, focusing on the prospective planning PRAC Rapporteur
aspects: pharmacovigilance plan and risk minimisation measures, and
PRAC proposed RMP LoQ to CAT (Co-) Rapporteurs, CHMP Coordinators, other CAT,
Rapporteur AR PRAC and CHMP Committee members and EMA.
Sent to the applicant for information.
Day 100 CAT (Co-)Rapporteurs, CHMP Coordinators, other CAT, PRAC and CHMP CAT (Co-) Rapporteurs, CHMP
CAT, CHMP Committee members (including peer reviewers) and EMA send comments. Coordinators, CHMP, PRAC
and PRAC and CAT
comments members
Day 101- PRAC adopts PRAC RMP Assessment Overview and Advice for D120 List of PRAC
104 questions (LoQ).
Day 106 PRAC PRAC Rapporteur circulates the updated RMP AR and LoQ (PhV and RMin PRAC
Rap AR activities only) based on the Committee members’ comments for D120 LoQ.
Day 114 CAT adopts the Day 120 LoQ as well as the overall conclusions and review of the CAT
scientific data to be sent to the applicant by EMA.
CAT List of By Day 114 at the latest, CAT adopts a request for GMP/GLP/GCP inspection, if
Questions necessary (inspection procedure starts).
(Called “Day 120
LoQ”) The major objections and key scientific issues (from the LoQ) are presented to CHMP Coordinators and CAT
the CHMP. (Co-) Rapporteurs
In the exceptional case that the CHMP identifies major issues with the Day
120 LoQ (e.g., identification of de novo important scientific questions), these
will be added to the LoQ in collaboration with the CAT Chair and the CAT (Co-) CHMP
Rapporteurs. The updated LoQ will be circulated to the CAT for information and
sent to the applicant.
Clock Stop On justified grounds, the CAT may agree to a longer clock-stop. The CHMP is Applicant
informed about the clock stop.
Day 115 Responses submitted, including revised summary of product characteristics Applicant
Restart (SmPC) labelling and package leaflet texts in
English, and clock restarts.
Day 150 CAT (Co-)Rapporteurs send the Joint Response Assessment Report to CHMP CAT (Co-) Rapporteurs
CAT Coordinators, PRAC, CAT and CHMP members and EMA.
Rapporteurs There is no standalone PRAC Rapporteur AR on the RMP circulated at this stage.
Joint AR (JAR) EMA sends this joint Assessment Report to the applicant, making clear that it is
sent for information purposes only and does not yet represent the position of the
CAT.
Where applicable, inspection is carried out. EMA/QRD sub-group meeting for
the review of English product Information with participation of the applicant
(optional) around day 165.

Chapter 36
Centralised Procedure (cont.)
Day 160 Comments from PRAC on Joint CAT AR PRAC members

PRAC
comments
Day 164 Comments from CAT and CHMP on Joint CAT AR CAT and CHMP members
CAT and CHMP
comments
Day 166 PRAC Rapporteur presents the assessment on the prospective planning aspects PRAC Rapporteur
Updated PRAC of the RMP, and members’ comments received at the PRAC plenary.
Rap AR PRAC Rapporteur will then liaise with the CAT (Co-) Rapporteurs to reflect the
members’ comments and the PRAC plenary discussion in the joint AR. PRAC
adopts PRAC RMP Assessment Overview and Advice for D180 LoOI.
Day 170 Updated CAT Joint AR CAT (Co-)
Rapporteurs
Updated CAT JAR
Day 174 CAT discussion and decision on the need for an adoption of a LoOI and/or an CAT
oral explanation by the applicant or CAT draft opinion.
CAT List of CAT adopts the LoOI as well as the overall conclusions and review of the
outstanding scientific data to be sent to the Applicant by the EMA.
issues/draft Clock stop.
opinion
(Called “Day 180 The major objections and key scientific issues from the LoOI are presented to CHMP Coordinators and CAT
LoOI”) the CHMP. (Co-) Rapporteurs
In the exceptional case that the CHMP identifies major issues with the Day 180
LoOI (e.g., identification of de novo important scientific questions), these will be
added to the LoOI in collaboration with the CAT Chair and the CAT Rapporteurs.
The updated LoOI will be circulated to the CAT for information and sent to the CHMP
applicant.
Submission of final inspection report to EMA, CAT (Co-) Rapporteurs, CHMP
Coordinators by the inspections team (at the latest by Day 174).
If there is no LoOI or oral explanation, CAT can adopt the draft opinion and
transmit it to the CHMP.
Clock Stop On justified grounds, CAT may agree to grant a longer Applicant
clock-stop. The CHMP is informed about the clock stop.
Day 175 Restart of the clock with submission of responses or oral explanation (if Applicant
Restart needed).
Day 189 The CAT(Co-) Rapporteurs draft a joint AR (including the RMP aspects), taking CAT (Co-)
into account the input from CHMP Coordinators/PRAC Rapporteurs and the Rapporteurs
CAT JAR applicant’s responses.
A PRAC discussion is not foreseen at this stage.
Day 195 CAT, CHMP and PRAC Committee members and EMA send comments on the AR. CAT, CHMP, PRAC
CAT, CHMP, and EMA
PRAC and EMA
comments
Day 200 The updated AR is circulated to the PRAC and CHMP Committee members and CAT (Co-)
Updated CAT JAR EMA. Rapporteurs
Day 204 CAT adopts the draft opinion and draft AR and transmits it to the CHMP. CAT
CAT opinion
By Day 210 Adoption of CHMP Opinion and CHMP AR (and timetable for the provision of CHMP
CHMP product information translations).
opinion

Centralised Procedure (cont.)
After adoption of a CHMP opinion, the preparation of the annexes to the Commission Decision is carried out in
accordance with the following timetable:
Day Action Responsibilities

Day 215 at the Applicant provides the product information and Annex A in the 25 languages (EU Applicant
latest official languages and Icelandic and Norwegian) and the “QRD Form 1” to EMA by
Eudralink*
Day 229 Member States will send linguistic comments on the product information by Member States
e-mail to the applicant, with a copy to the EMA product shared mailbox together
with QRD Form 1.
Day 235 Applicant provides EMA with final translations of summary of product Applicant
at the latest characteristics, Annex II, labeling and package leaflet in the 25 languages (+
“QRD Form 2” and “PDF checklist”) by Eudralink.
Day 237 Transmission of Opinion and Annexes in all EU languages to applicant, EMA
Commission and Norway and Iceland.
Days 239-261 The Commission adopts a draft decision and consults the Standing Committee. European Commission
By Day 277 Finalisation of EPAR in consultation with Rapporteur, Co-Rapporteur, CAT, CHMP EMA
and Applicant (the latter for confidentiality reasons).
Day 277 Commission adopts a decision. European Commission
*By e-mail: qrd@ema.europa.eu
increased conformity assessment procedure scrutiny and derivatives of tissues or cells of human origin
requirements for high-risk medical devices. which are nonviable or are rendered nonviable.”
Nonviable human tissue and cell products that • (10) “Any device which, when placed on the
are not classified as ATMPs currently are regulated market or put into service, incorporates, as
only by the EUTCD, as Article 1(5) point (f ) of the an integral part, nonviable tissues or cells of
Medical Devices Directive explicitly excludes from its human origin or their derivatives that have an
scope human tissues or cells and products incorporating action ancillary to that of the device shall be
or derived from them. With the EU MDR’s adoption, assessed and authorised in accordance with
products utilising nonviable tissues or cells or their this regulation. In that case, the provisions for
derivatives may be classified as medical devices. donation, procurement and testing laid down
To determine whether the human tissue or cell in Directive 2004/23/EC shall apply.
product is or is not a medical device, it is necessary to However, if the action of those tissues
look at the following EU MDR sections: or cells or their derivatives is principal and
• The EU MDR states in Recital (11) “Union not ancillary to that of the device and the
legislation, in particular Regulation (EC) No. product is not governed by Regulation (EC)
1394/2007 of the European Parliament and of No. 1394/2007, the product shall be gov-
the Council (1) and Directive 2004/23/EC of erned by Directive 2004/23/EC. In that case,
the European Parliament and of the Council the relevant general safety and performance
(2), is incomplete in respect of certain products requirements set out in Annex I to this reg-
manufactured utilising derivatives of tissues or ulation shall apply as far as the safety and
cells of human origin that are non-viable or are performance of the device part are concerned.”
rendered non-viable.”
• Article 1 (6) point (g) states this regulation It also is important to look at the EU MDR derivative
does not apply to “transplants, tissues or cells of definition: “‘derivative’ means a ‘non-cellular substance’
human origin, or their derivatives, covered by extracted from human or animal tissue or cells through
Directive 2004/23/EC, or products containing a manufacturing process. The final substance used for
or consisting of them; however, this regulation manufacturing of the device in this case does not con-
does apply to devices manufactured utilising tain any cells or tissues.”

Chapter 36
Table 36-5. General Applicable Regulatory Framework for Medical Products Containing Human Tissue
Intended for Human Clinical use and its Interconnection with Directive 2004/23/EC (Tissues and Cells
Directive)
Preservation
Procurement
Distribution
Processing
Donation
Storage
Product and Intended Use
Testing
Human tissues and cells, not substantially manipulated (as defined in
Annex I, ATMP Regulation), and intended for the same essential func-
tions in the recipient as in the donor.
TISSUE
2004/23/EC
(e.g., (concentrated) bone marrow aspirate intended for repair avascular
necrosis of the femur head; cornea transplant; skin grafts intended for
treatment of burn wounds; artificial reproductive technologies (IVF))
VIABLE
Medicinal product containing human tissues or cells that are substan-

tially manipulated or are not being used for the same essential func-
tion(s) in the recipient as in the donor.
ATMP
2004/23/EC 1394/2007/EC
(e.g., cultured autologous chondrocytes intended for the repair and
regeneration of cartilage lesions; autologous peripheral blood mononu-
clear cells intended for the treatment of prostate cancer)
Human tissues or cells not covered by the ATMP Regulation or EU MDR. 2004/23/EC
(e.g., mineralised and/or demineralised bone graft, acellular dermis)

Human tissues or cells or their derivatives incorporated as an integral 2004/23/EC
TISSUE
part of a medical device with action principle to the device and not regu- and
lated as ATMP. 2017/745/EU Annex 1 (for the
device part only - conformance
to the general safety and
NON-VIABLE
(e.g., bone pre-filled in delivery syringe)

performance requirements)
Nonviable tissues or cells that act principally by pharmacological, im- 2004/23/EC 1394/2007/EC
ATMP
munological or metabolic action and are substantially manipulated or

perform a different essential function.
Nonviable derivatives (extracted) from human tissues or cells; or human 2004/23/EC 2017/745/EU
tissues or cells or their derivatives incorporated as an integral part of a
DEVICE
medical device with action ancillary to the device.
(e.g., collagen fillers, orthopaedic plate impregnated with demineral-

ized bone fibres)
In the EU MDR, human tissues or cells or their the device part must comply with EU MDR Annex I
derivatives that do not qualify as ATMPs and are incor- General Safety and Performance Requirements.
porated as an integral part of a device are classified The new EU MDR’s scope is limited to devices
according to their mode of action, principal or ancillary. manufactured utilising tissue or cell derivatives of
All devices manufactured utilising tissues or cells of human origin that are nonviable or rendered nonviable.
human origin, or their derivatives, which are nonviable By contrast, nonviable tissues and cells themselves do
or rendered nonviable, and whose mode of action is not fall within the scope of this regulation.
ancillary to the devices are classified as Class III med-
ical devices; if its mode of action is principal to that of Other Contiguous Legislation
the device, the product is regulated by the EUTCD plus Directive 2004/23/EC excludes blood and blood
products (other than haematopoietic progenitor cells)

and human organs, as well as organs, tissues or cells ensured. This can be particularly challenging for larger
of animal origin. The quality and safety standards for hospitals, as it requires organising all tissue-related
human organ transplantation are defined in Directive activities in different departments while maintaining
2010/45/EC. Specifically, it addresses the donation, full tissue traceability and ensuring proper communica-
testing, characterisation, procurement, preservation tion of biovigilance reports.
and transport of organs intended for transplantation in EUTCD legislation’s evolving nature is illustrated
humans. Its goal is to minimise risks for disease trans- by the 2015 directives on tissue coding and importing
mission to the recipient. The directive was established requirements. The Coding Directive introduced the
as a result of the steady increase of transplantations to Single European Code (SEC) as a unique identifier
ensure uniform procurement and transportation qual- to facilitate traceability and ensure tissues and cells
ity and safety practices and use of human organs for distributed within the EU are traceable from pro-
transplantation among Member States. Competent curement to human application and vice versa. The
authorities’ authorisation of transplantation centres and Importing Directive, established as a result of increasing
use of traceability systems further improve quality and global exchange of human tissue and cells, outlines
safety and indirectly reduce risks for organ trafficking. importing requirements from third-country suppliers.
The Human Organ Transplantation Directive is inter- Its goal is to verify imported tissue and cells’ quality
connected with the EUTCD regarding SAE and SAR and safety standards are at least equivalent to those
reporting and management. An organ donor frequently laid down in Directive 2004/23/EC. These directives’
also is a tissue donor. An unexpected adverse reaction in implications will be significant for the majority of tissue
an organ donor or recipient, therefore, must be traced by establishments. A new labelling system may need to
the competent authority and reported through Directive be introduced, and the generation of new labels using
2004/23/EC’s adverse event notification system. the selected EU code must be integrated with existing
coding formats, replacing or co-existing with them. In
Conclusion addition, donor release practices must be standardised,
This chapter outlines the main characteristics of human more detailed quality agreements will need to be estab-
tissue legislation in Europe as well as its non-uniform lished with third-country suppliers by importing tissue
and evolving nature. The EUTCD provide a harmonised establishments and these suppliers must be audited
framework for regulating human tissue and cell quality regularly to ensure compliance with applied EUTCD
and safety. They comprise main Directive 2004/23/EC quality and safety practices.
and four implementing technical directives, aimed at The new EU MDR now provides some clarity on
safeguarding public health, preventing the transmis- requirements for market access of nonviable human
sion of infectious diseases and facilitating exchange tissue products that do not qualify as ATMPs. It is
of human tissues and cells across the Community. clear for traditional medical devices that incorporate
Specifically, they lay down quality and safety standards nonviable human cells and/or tissues whose function is
for human tissue and cell donation, procurement, test- ancillary to the device, yet the process for market access
ing, processing, preservation, storage and distribution via CE marking is brand new to tissue establishments
for human application. In addition, the directives pro- and requires substantial resources and time to achieve.
vide system requirements to ensure tissue traceability Defining what constitutes a nonviable tissue or cell
from donor to recipient and vice versa. Although fully product whose action is principal to that of the device
transposed by Member States, the EUTCD allowed likely will need continuous updating in the delegating
the introduction of additional local requirements, mak- acts defined by the MDCG, the notified body, compe-
ing the intra-EU exchange of tissues and cells more tent authorities and the Member States.
challenging. Examples include differences in donor
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Manufacturing Practices. EUR-Lex website. https://ec.europa.eu/ 19. Hermans MHE. Preservation Methods of Allografts and Their
health/sites/health/files/files/eudralex/vol-4/2017_11_22_guide- (Lack of ) Influence on Clinical Results in Partial Thickness
lines_gmp_for_atmps.pdf. Accessed 27 April 2020. Burns. Burns. 2011;37:871–881.
8. Guideline on safety and efficacy follow up and risk management 20. Hsu VM, Stransky CA, Bucky LP, Percec I. Fat Grafting’s Past,
of ATMPs (EMEA/149995/2008). EMA website. https:// Present, and Future: Why Adipose Tissue is Emerging as a
www.ema.europa.eu/en/documents/scientific-guideline/ Critical Link to the Advancement of Regenerative Medicine.
guideline-safety-efficacy-follow-risk-management-ad- Aesthet Surg J. 2012;32(7):892–9.
vanced-therapy-medicinal-products_en.pdf. Accessed 27 April 21. Barriga F, Ramírez P, Wietstruck A, Rojas N. Hematopoietic
2020. Stem Cell Transplantation: Clinical Use and Perspectives. Biol
9. Directive 2010/45/EU of the European Parliament and of Res. 2012;45(3):307–16.
the Council of 7 July 2010 on standards of quality and safety 22. Navarrete C, Contreras M. Cord Blood Banking: A Historical
of human organs intended for transplantation. EUR-Lex Perspective. Br J Haematol. 2009 Oct;147(2):236–45.
website. https://eur-lex.europa.eu/legal-content/EN/TXT/ 23. Op cit 16.
PDF/?uri=CELEX:32010L0053&from=EN. Accessed 27 April 24. Strong DM. The US Navy Tissue Bank: 50 Years on the Cutting
2020. Edge. Cell Tissue Bank. 2000;1(1):9–16.
10. Procedural advice on the evaluation of advanced therapy medici- 25. Hyatt GW. The Founding of the US Navy Tissue Bank.
nal product in accordance with Article 8 of Regulation (EC) No. Transplant Proc. 1976;8(2 Suppl 1):17–20.
1394/2007 (EMA/630043/2008). EMA website. https://www. 26. Op cit 24.
ema.europa.eu/en/documents/regulatory-procedural-guideline/ 27. Op cit 25.
procedural-advice-evaluation-advanced-therapy-medici- 28. Op cit 25.
nal-product-accordance-article-8-regulation-ec/2007_en.pdf. 29. Kalter ESJ, de By TMMH. Tissue Banking Programmes in
Accessed 27 April 2020. Europe. British Medical Bulletin. 1997;4:798–816.
11. Regulation (EC) 726/2004 of the European Parliament 30. Tatarenko A. European Regulations and Their Impact on Tissue
and of the Council of 31 March 2004 laying down Banking. Cell Tissue Banking. 2006;7:231–235.
Community procedures for the authorisation and supervi- 31. López-Fraga1 M, Domínguez-Gil B, Fehily D, Chatzixiro E,
sion of medicinal products for human and veterinary use Fischer-Fröhlich CL, Arredondo E, Manyalich M, Trias E,
and establishing a European Medicines Agency. EUR-Lex Matesanz R,Nanni Costa A. Concerted Efforts to Promote
website. https://eur-lex.europa.eu/legal-content/EN/TXT/ Donation and Transplantation in Europe: the Leading Role of
PDF/?uri=CELEX:02004R0726-20190128&from=EN. the Council of Europe and the CD-P-TO. Organs, Tissues and
Accessed 27 April 2020. Cells. 2014;(17), 39–48.
12. Guideline on the Procedure for Accelerated Assessment 32. Op cit 30.
Pursuant to Article 14 (9) of Regulation (EC) No. 726/2004 33. Op cit 31.
(EMEA/419127/05). EMA website. https://www.ema. 34. Resolution CM/Res(78) 29 on Harmonisation of Legislations
europa.eu/en/documents/regulatory-procedural-guideline/ of Member States Relating to Removal, Grafting and
guideline-procedure-accelerated-assessment-pursuant-arti- Transplantation of Human Substances. Council of Europe, 11
May 1978.

35. Op cit 31. 43. Commission Decision of 3 August 2010 establishing guidelines
36. Recommendation No. R (94) 1, of the Committee of Ministers concerning the conditions of inspections and control measures,
to Member States on Human Tissue Banks. 14 March 1994. and on the training and qualification of officials, in the field of
37. Guide to Safety and Quality Assurance for Organs, Tissues and Cells, human tissues and cells provided for in Directive 2004/23/EC
4th Edition. Council of Europe, 2010. of the European Parliament and of the Council (notified under
38. Guide to the quality and safety of organs for transplantation. 7th document C(2010) 5278) (2010/453/EU). EUR-Lex website.
Edition. Council of Europe, 2018 https://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=O-
39. Guide to the quality and safety of tissues and cells for human applica- J:L:2010:213:0048:0050:EN:PDF. Accessed 27 April 2020.
tion, 4th Edition, 2019 44. Regulation (EU) 2020/561 of the European Parliament
40. Mapping of More Stringent Blood Donor Testing and of the Council of 23 April 2020 amending Regulation
Requirements—Mapping Exercise, 2015. EC website. https:// (EU) 2017/745 on medical devices, as regards the dates
ec.europa.eu/health/blood_tissues_organs/key_documents/test- of application of certain of its provisions. EUR-Lex web-
ing_blooddonors_mapping_en. Accessed 26 April 2020. site. https://eur-lex.europa.eu/legal-content/EN/TXT/
41. COM (2016) 223 final: Report from the Commission to the PDF/?uri=CELEX:32020R0561&from=EN. Accessed 29 April
European Parliament, the Council, the European Economic and 2020.
Social Committee and the Committee of the Regions on the
implementation of Directives 2004/23/EC, 2006/17/EC and Recommended Reading
2006/86/EC setting standards of quality and safety for human • Economic landscape of human tissues and cells for clinical application
tissues and cells. EUR-Lex website. http://eur-lex.europa.eu/ in the EU. European Commission, 2015.
legal-content/EN/TXT/?uri=CELEX%3A52016DC0223.
42. Inspection of Tissue and Cell Procurement and Tissue
Establishments. Operational Manual for Competent
Authorities, Version 1.1, April 2015.

Chapter 36

Chapter 37
Vaccines
Updated by Frédéric Béard
OBJECTIVES and administrative provisions of the Member

States relating to the implementation of good
□ Understand EU vaccine pre- and post-licensure clinical practice in the conduct of clinical trials
development on medicinal products for human use
□ Understand EU regulation of vaccines □ Directive 2001/18/EC of the European
□ Understand EU lot release requirements for
on the deliberate release into the environment
vaccines
of genetically modified organisms and repeal-
□ Understand special topics in vaccines, such as ing Council Directive 90/220/EEC
adjuvants, influenza vaccines, etc.
amending Directive 2001/18/EC on the deliber-
DIRECTIVES, REGULATIONS AND GUIDELINES ate release into the environment of genetically
COVERED IN THIS CHAPTER modified organisms, as regards the implement-
□ Commission Directive 2003/94/EC of 8 October ing powers conferred on the Commission
2003 laying down the principles and guidelines
of good manufacturing practice in respect of
medicinal products for human use and investi-
Introduction
Unlike most medicinal products designed to treat dis-
gational medicinal products for human use
eases, vaccines are designed to prevent disease. Vaccines
□ Commission Directive 2005/28/EC of 8 April 2005 are developed, in general, with healthy patients in mind.
laying down principles and detailed guidelines Vaccines’ purpose is to protect the population and
for good clinical practice as regards investiga- prevent illness and death. A number of safe and effec-
tional medicinal products for human use, as well tive approved vaccines protect the EU public against
as the requirements for authorisation of the man- approximately 20 serious diseases.1
ufacturing or importation of such products In the EU, vaccines are considered medicinal
products. Thus, their development pathway is similar to
□ Directive 2001/83/EC of the European other medicinal products such as small molecule drugs.
Parliament and of the Council of 6 November However, vaccines do differ, because they are, in most
2001 on the Community code relating to medici- cases, produced from live organisms, which qualifies
nal products for human use them as biological products. In vaccine manufacture,
biological materials, such as bacteria, are used to produce
□ Directive 2001/20/EC of the European a quantity of antigen. An antigen is a toxin or other for-
Parliament and of the Council of 4 April 2001 eign substance that induces an immune response in the
on the approximation of the laws, regulations

Chapter 37
body, especially the production of antibodies. In com- Another relevant guideline is Requirements for
parison to small molecule drugs, antigens are the vaccine quality documentation concerning biological investigational
equivalent of active pharmaceutical ingredients. Due to medicinal products in clinical trials.3 This guidance was
the nature of the vaccine manufacturing process, quality revised in 2012 and aims to harmonise quality infor-
control can be very complex. Additionally, the regulatory mation requirements and assessment for biological and
professional should understand vaccines are unique, biotechnological investigational medicinal products
considering their short-term exposure and long-term throughout the EU. Additionally, it provides a descrip-
response. In general, as noted above, vaccines are pro- tion of the data to include in the common technical
vided as a preventive (prophylactic) measure to healthy document (CTD) Module 3 pertaining to biological
individuals. In most cases, children at vulnerable ages products. Similar guidance covering all investigational
receive vaccinations. Therefore, safety is a major vaccine medicinal products (IMPs) in clinical trials already
development concern. exists.4 In terms of clinical trial quality documentation,
There is no immediate health benefit for an indi- manufacturers need to submit an investigational medic-
vidual who is vaccinated, limiting the acceptance of inal product dossier (IMPD).
risks. The European Medicines Agency (EMA) assesses Vaccines, like other medicinal products, must be
vaccines through a different benefit-risk profile than manufactured in compliance with good manufacturing
that of therapeutic drugs and biologics. practice (GMP)5 for both clinical trial materials and
approved products. In the EU, all manufacturers of
Vaccine Development medicinal products, even investigational products, are
Vaccines are intended to induce an individual’s immune required to obtain manufacturing authorisation from
system to help protect against infection and disease. the respective Member State’s national or regional
Vaccine development follows a similar path as other authority. The EU requires drug and biological man-
medicinal products. During development, there are ufacturers to have a qualified person (QP) certifying
short- and long-term goals, from obtaining first-in- every lot or batch is in compliance with the approved
human data to conducting a pivotal study and fulfilling product specification for use in clinical trials or on the
product licensure requirements. Given vaccines’ biological market. For a number of years, QP release was required
nature and ability to stimulate an individual’s immune only for products with marketing authorisation (MA).
system, specific guidance for vaccines is essential. However, since 2004, QP release also is required for
IMPs. Details of the QP’s role can be found in GMP
Manufacturing guidelines and are applicable to all medicinal products,
Vaccines are biological products, typically derived after including vaccines. Lots manufactured outside the EU
identifying an antigen to induce an immune response. also are subject to QP certification and release.
Compared to a small molecule (drug) or a medical EMA’s Committee for Medicinal Products for
device, a vaccine’s production is difficult because live Human Use (CHMP) has published a specific position
organisms are involved, which means every vaccine lot paper6 on the quality of water used for parenteral vac-
is slightly different. Ensuring the quality and consis- cine formulation; lesser quality water may be used for
tency of biotechnological or biological products can be other manufacturing steps. Local clinical trial require-
complex. Ensuring quality also impacts trial subjects’ ments vary to some extent among the EU Member
risks and benefits and those of vaccines when they are States. For example, for vaccine or biologic IMP lot
licensed. Regulatory professionals should remember or batch release, some competent authorities do not
vaccine trial subjects are drawn from a healthy popula- require an official release for clinical trial products as
tion; thus, the acceptable risk level is significantly lower long as the clinical trial application (CTA) is in place
than for therapeutic products, e.g., cancer treatments. and the company’s QP has certified the lot. However,
EU directives and EMA medicinal product other Members States require lot release before the
guidelines provide the basic principles of vaccine devel- IMP can be used in humans; usually, this is a “paper
opment, production and control. An International release,” i.e., only lot-relevant documents like certifi-
Council on Harmonisation (ICH) guideline on cate of analysis documentation must be submitted and
Development and manufacture of drug substances (ICH approved, while other Member States specify certain
Q11)2 discusses both synthetic entities and biotechno- official medicines control laboratory (OMCL) tests,
logical products, such as vaccines. Certain principles including vaccine potency. Some Member States require
should be considered during the vaccine development specific lot release, while others do not. The regulatory
stage because the manufacturing process defines the professional should contact the appropriate clinical
product, like the master cell bank used to produce the trial authority for vaccine IMP lot release require-
antigen for any given vaccine. ments. Additionally, the regulatory professional should

Vaccines
Vaccines
Figure 37-1. General Principles of VAMF Certification
VAMF Application
Antigen X
1 VAMF per vaccine
antigen First Step
VAMF
certification
(EMA,
Certificate of
centralised)
Compliance
(Valid throughout the
EU)
Second Step
Impact on the
Vaccine A Vaccine B Vaccine C medicinal
Antigen X Antigen X Antigen X products
Antigen Y Antigen Z Antigen Y (Competent
Centralised Mutual Antigen T Authority)
MA Recognition MA National MA
Source: EMEA/CPMP/4548/03/Final/Rev
Source: EMEA/CPMP/4548/03/Final/Rev. 1. 1.
Source: EMEA/CPMP/4548/03/Final/Rev 1.
remember all marketed Vaccinesvaccine lots are

often contain subject
certain additives lotaddition to provide
to in protection
protection againstagainst
multiplemultiple
diseases. diseases. If anisanti-
If an antigen
release, as is discussed laterresulting
the impurities in thisfrom the manufacturing process, genused
chapter. is used in more
in more than
than one one combination
combination vaccine, it vaccine,
could be it
Vaccines often such as contain certainand
host cell proteins additives
preservatives. The antimicro- could
in addition be subject
subject to Vaccineto vaccine antigen
Antigen Master Filemaster
(VAMF) filecertifi-
(VAMF)
to the impurities bial resulting
organic mercury
fromcompound,
the manufacturing cation through
thiomersal, historically certification a two-step
through assessment.
a two-step
9
First, the 9VAMF
assessment. First, the
has been used in vaccine manufacture as a preservative. In application dossier is assessed, in a manner similar to the
process, such as host
2004, EMAcellissued
proteins and
a public preservatives.
statement Theof vac- VAMF
on the safety application
Centralised dossier
Procedure, is assessed,
resulting in an EMA in acertificate
manner
antimicrobial cines organic mercury compound, thiomersal,
containing thiomersal. In this statement, the agency
7 similar
of compliance. This certificate is valid throughoutinthe
to the centralised procedure, resulting an
historically hasnoted been theused
latestin vaccine
CHMP manufacture
studies had found no asassociation
a EMA certificate
Community. In of
thecompliance.
second step, This certificate
the local Competent is valid
preservative. In 2004,vaccination
between EMA issued a public statement vaccines throughout
with thiomersal-containing Authority takesthe Community.
VAMF certificationIn the second step,for
or re-certification the
and specific neurodevelopmental disorders. However,
on the safety of vaccines containing thiomersal.7 In this locala concerned
competent medicinal product into account. Figure 35-1
authority takes VAMF certification or
the statement also encouraged vaccine manufacturers provides a visual of this process.
statement, thetoagency producenoted thewith
vaccines latest
veryCHMP
low to nostudies
thiomersal. If re-certification
Proceduralfor a concerned
guidance medicinal
in Guideline product
on requirements for into
had found no using association between vaccination with
thiomersal in vaccine manufacture, the regulatory account. Figure 37-1 provides a visual of
Vaccine Antigen Master File (VAMF) certification outlines this
10 process.
thiomersal-containing professionalvaccines and specific
should consult guidanceneurode-
on how to include Procedural
steps guidance
for the regulatory in Guideline
professional to take on requirements
in determining
velopmental disorders. the sensitisation
However,warningthestatement
statement in the
also Summary of for Vaccine
an initialAntigen
VAMF orMastervariation, as(VAMF)
File well as application and 10
certification
Product Characteristics (SmPC).8 EMA review timing.
encouraged vaccine manufacturers to produce vaccines outlines steps for the regulatory professional to take in
Some vaccine additives are adjuvants and stabilisers. A VAMF application is identical to CTD Section
with very low Additionalto no thiomersal.
information on adjuvants is provided later in determining
If using thiomersal in 3.2.S, includingan initial VAMF
the relevant CTDor variation,
3.2.A sections onasequip-
well as
vaccine manufacture, the regulatory professional should
this chapter. Stabilisers generally are covered in the vaccine application and EMA review timing.
ment and facilities and adventitious safety evaluation.
consult guidance on how to include the sensitisation
guidelines. A VAMF application is identical to CTD Section
warning statement in the summary of product charac- Nonclinical
3.2.S, including the relevant CTD 3.2.A sections on
Vaccine Antigen Master File Note for guidance on preclinical pharmacological and toxi-
teristics (SmPC). 8
equipment and facilities and adventitious safety evaluation.
Vaccines frequently are developed for inclusion in a com- cological testing of vaccines (CPMP/SWP/465/95) outlines
Some vaccine additives are adjuvants and stabi-
bination vaccine product. Combination vaccines can be nonclinical studies expected to be included in a Marketing
lisers. Additional information
advantageous onthey
because adjuvants is provided
are convenient and provide Nonclinical
Authorisation Application (MAA), such as a single- or
later in this chapter. Stabilisers generally are covered in Note for guidance on preclinical pharmacological and
the vaccine guidelines.Regulatory Affairs Professionals Society toxicological testing of vaccines (CPMP/SWP/465/95) 433
outlines nonclinical studies expected to be included in
Vaccine Antigen Master File a marketing authorisation application (MAA), such as
Vaccines frequently are developed for inclusion in a a single- or repeat-dose study in a single species (typ-
combination vaccine product. Combination vaccines
ically rabbits). This guideline notes other toxicology 11/6/17 1:51 PM
can be advantageous because they are convenient and studies, such as reproductive toxicology, genotoxicity

Chapter 37
and carcinogenicity, are not necessary but should be vaccine development, such as cross-reactivity and lot-
justified. In addition to the toxicology work, the guide- to-lot consistency. The guideline also provides examples
line notes primary pharmacodynamic studies should be of when vaccine efficacy studies may or may not be
conducted to evaluate the “antigen-protective response” appropriate. All vaccine developers are encouraged to
in a relevant species, as well as secondary pharmacology establish immunological protection correlates during
studies on circulatory and respiratory systems. Although the development process. The annex15 to this guidance
the guideline suggests pharmacokinetic studies need provides detail on new vaccines’ SmPC requirements.
to be evaluated, if necessary, on a case-by-case basis,
local tolerance studies should be conducted, considering Vaccine Licensure
whether a vaccine’s administration is intramuscular, sub- A vaccine MA follows the same route as other bio-
cutaneous or intracutaneous. technological products. The Centralised Procedure now
However, in July 2016, CHMP released a Q&A is mandatory for certain product types, such as those
document11 on the withdrawal of the CPMP note for using biotechnological processes, and can be used for
guidance on preclinical pharmacological and toxicolog- products presenting an EU-wide public health inter-
ical testing of vaccines. Following discussion within the est, such as pandemic vaccines. This process offers the
CHMP Safety Working Party and Vaccine Working advantage of having a single MAA for all EU countries.
Party, it was agreed to remove the CPMP guideline on A vaccine MAA’s evaluation, like all MAAs, is based
preclinical pharmacological and toxicological testing on the product’s benefit-risk ratio. The electronic CTD
of vaccines and refer to the WHO guideline on non- (eCTD) format is required for submitting EU MAAs,
clinical evaluation of vaccines.12 The aim of this Q&A and there are no special requirements for vaccines. If the
document is to provide clarification on the grounds for MAA contains a VAMF, the appropriate documents
this decision and its consequences. must be included in the application (eCTD Section
3.2 S). A summary of the VAMF also is included in
Clinical Section 2.3.S, Quality Overall Summary (QOS). For
EU clinical trials are required to be conducted in more information on the EU licensure procedure, refer
accordance with the EU Clinical Trials Directive13 and to Chapter 27.
must comply with good clinical practices (GCPs). EMA is responsible for scientific evaluation of
Additionally, when conducting a study in any given applications (including license applications) through
Member State, the regulatory professional should the Centralised Procedure. CHMP is responsible for
confirm any additional local requirements. Similar to human medicines. CHMP consists of several groups,
those for drugs, vaccine clinical trials are regulated at called working parties. The working party for vaccines
the national level. Therefore, in addition to following is the Vaccine Working Party (VWP), which provides
the EU directives, trial sponsors should expect minor recommendations to CHMP on all issues directly and
local differences among Member States and be pre- indirectly related to vaccines. The VWP is tasked with
pared to allow for such differences during the clinical some of the following with regard to vaccines in the
trial application process. This especially can be true for EU: preparing, reviewing and updating guidelines, sup-
such complex products as vaccines and biotechnological porting dossier evaluation for new MAAs providing
products. More specifics on the conduct of clinical trials scientific advice at CHMP’s request, monitoring new
in the EU can be found in Chapter 26. vaccine technology and new adjuvant development and
As mentioned earlier in this chapter, vaccines are additional tasks related to vaccines. CHMP’s detailed
administered to healthy individuals; therefore, a vac- tasks and mandate are described on EMA’s website.16
cine’s safety review is particularly critical. The regulatory On the other side, the European Commission is an
professional should consider recommending countries EU subsidiary that handles enforcement of EU treaties
with experienced competent authorities in a specific and proposed legislation. The Commission is the only EU
disease or product area when preparing regulatory branch that can formally propose legislation and, there-
strategy for conducting EU trials. Typically, healthcare fore, the body that issues licenses for medicinal products
locations used for clinical trials with specific patient such as vaccines following a positive EMA opinion.
populations and clinical research organisations are clus-
tered in the same regions. Postmarketing
More specific requirements for vaccine clinical Lot Release
development are described in Guideline on clinical Vaccines, like all biological products, are subject to spe-
evaluation of new vaccines.14 This guideline outlines cial lot release requirements in almost all EU Member
requirements for pharmacokinetic/pharmacodynamics States. In addition to a company’s QP release, vaccines
studies, pivotal studies and special considerations for

Vaccines
also are tested by laboratories (OMCLs) assigned by It is recommended that several lots of the candidate
the competent authorities. These laboratories are nom- vaccine with a formulation similar to that of the final
inated by the Member State and are responsible for product intended for marketing be tested during the
vaccine quality control in their countries. clinical development programme. If this is not possible
OMCLs may test vaccine lots, but, at minimum, due to late stage manufacturing changes, the sponsor
will check release documentation before vaccine lots should justify the relevance of the clinical trial data
can be released onto the market. A vaccine certified by to the lots intended for marketing based on quality
one OMCL is recognised by all other laboratories in attributes and/or should conduct a clinical comparison
the network. Within this OMCL organisation, the offi- between lots.
cial control authority batch release (OCABR) network
is responsible for human biologicals (vaccine) testing. Pharmacovigilance
EMA recommends contacting potential OMCLs to Serious, clinically relevant adverse events usually are rare.
exchange information approximately one year prior to Therefore, they are unlikely to be seen during vaccine
submitting an MAA. This is key because not all agencies development because exposure to vaccines is limited.
have the resources and/or technical capabilities for all Postlicensure vaccine monitoring through risk manage-
vaccine types. Because the OMCL decides which tests ment plans (RMPs) and pharmacovigilance (PV) are
are required for lot release, the manufacturer may need to very important. Although these monitoring activities are
transfer methods or technology to the OMCL. As with required for all medicinal products, vaccine PV plans and
method transfer from a sponsor to a contract manufac- RMPs are unique in some ways, including:
turer, this can take time and should be considered when • vaccines are given to healthy people, including
the regulatory professional is considering timing. The children and elderly, resulting in a low toler-
regulatory professional should keep in mind an OMCL, ance for risks
such as the National Institute of Biological Standards • a vaccine’s benefit is not immediate and is
and Control, is different than a competent authority. dependent upon population vaccination, and
Because the OMCL information is discussed some vaccines protect against very rare and
during the presubmission meeting with the competent even virtually non-existent diseases (e.g., polio
authority, it is advantageous if the OMCL and rappor- in Europe)
teur are from the same country and/or institution. The • vaccines are provided to large populations
regulatory professional should be aware the marketing
authorisation holder (MAH) is expected to send the Vaccine dossiers, like those for other medicinal prod-
OMCL samples of each batch to be released onto ucts, need to contain RMPs according to the Guideline
the market along with the required documentation. on Good Pharmacovigilance Practices (GVP)—Module
Once the samples have been tested and documenta- V—Risk Management Systems.18 EMA also provides an
tion reviewed, the OMCL issues an Official Control RMP template.
Authority Batch Release Certificate, which confirms The EU has no equivalent to the US vaccine
the batch has been tested and found to be compliant adverse event reporting system (VAERS). Like other
with OCABR-defined guidelines, MA specifications medicinal products, vaccines are subject to various
and relevant European Pharmacopoeia (Ph. Eur.) mono- postmarketing reporting requirements and studies. All
graphs. This certificate is recognised by all OMCL postauthorisation adverse events and individual case
network countries. safety reports (ICSRs) are required by Regulation (EC)
More detailed information and product-specific No. 726/2004,19 Directive 2001/83/EC as amended20
lot release guidelines can be found on the European and Directive 2001/20/EC21 to be reported via the
Directorate for the Quality of Medicines’ (EDQM) EudraVigilance Postauthorisation Module (EVPM).22
website.17 The regulatory professional should note vaccine failures
A lot-to-lot consistency trial is not routinely are considered adverse reactions.
required but may be considered useful under certain cir- The Pharmacovigilance Regulation23 is applicable to
cumstances that should be considered on a case by case all medicinal products, including vaccines. There are no
basis. If such a trial is conducted, it is important to con- additional special requirements for vaccines. However,
sider and justify the number of lots to be compared and EMA does provide guidance on what a sponsor should
the method of lot selection (e.g., consecutively produced consider when drafting an RMP.
or chosen at random). Careful consideration needs to For more information on risk management and
be given to the primary immune response endpoint and pharmacovigilance in the EU, refer to Chapter 34.
the predefined acceptance criteria.

Chapter 37
Special Populations the immune response to a specific type of vaccine, trials

Pregnant Women that assess safety, immunogenicity or efficacy in a broad
Not all vaccines are suitable for administration to immunodeficient population are not recommended.
pregnant subjects. Candidate vaccines proposed for Trials intended to support dose recommendations
administration during pregnancy should have been for immunodeficient subjects should plan to enrol
assessed in appropriate nonclinical studies and will be well-defined sub-populations of subjects with immune
comprised of antigen(s) ± adjuvant not known to pose a deficiencies that have been selected based on those
risk to the pregnant subject or fetus. most likely to affect the immune response to a specific
Vaccination during pregnancy may have one or vaccine. Unless there is a well-established immune
more of the following aims: correlate of protection (ICP) that can be applied to the
• to protect the pregnant subject data, the usual aim of such trials will be to identify a
• to protect the fetus from intra-uterine posology that achieves comparable immune responses
infection to those observed in immunocompetent subjects.
• to protect the infant for as long as protective It is not expected to be feasible to study all immu-
levels of maternal antibody persist in the post- nodeficient subpopulations. The extent to which any
natal period one posology may be recommended beyond the exact
population in which it was studied must be decided
It is important that vaccines proposed for use during based on what is known about the relative importance
pregnancy have very benign safety profiles, including of different immunological parameters for protection.
low systemic reactogenicity. If the safety profile in non-
pregnant subjects raises any safety concerns, it may be Influenza Vaccines
necessary to conduct larger studies in this population to Influenza vaccines can be classified as seasonal, prepan-
quantify the risk before deciding whether to proceed to demic and pandemic.24 Seasonal vaccines are produced
pregnant subjects. every year for the strains most predominant on an
annual basis. Prepandemic vaccines are intended for
Elderly Subjects immunisation in the context of outbreaks of zoonotic
For most vaccines, elderly subjects have lower responses influenza viruses with pandemic potential, including
to vaccination compared to younger subjects, which use when a possible pandemic is anticipated due to the
may reflect immunosenescence and/or the prevalence same or a similar strain. Pandemic influenza vaccines,
of specific underlying diseases or medications that have on the other hand, are produced only when there is an
a negative impact on the immune system. On occasion, influenza pandemic, such as the H1N1 influenza pan-
immune responses may be higher in the elderly if they demic in 2009.
are more likely than younger adults to have been primed
by natural exposure or prior vaccination. Therefore, it Seasonal Influenza Vaccines
is important that adequate dose-finding studies are The manufacturing and approval process for seasonal
conducted for vaccines proposed for use in the elderly influenza vaccines is standardised as shown in Figure
and that all age subgroups are investigated (e.g., 65–74 37-2. Twice a year, the process begins with a WHO
years, 75–84 years and 85 years or more) to determine epidemiology data review in February for the north-
whether different doses and/or regimens are needed ern hemisphere (and in September for the southern
as age increases. If efficacy trials are to be conducted hemisphere). In March, EMA’s Influenza Working
in elderly subjects, stratification by age sub-groups is Party meets and recommends the use of reassortants
recommended. Furthermore, the impact of any under- for seasonal influenza vaccine manufacture. Once the
lying conditions or medications known or likely to recommendation is announced, manufacturers begin
affect immune responses should be investigated during vaccine production.
the clinical trials. The safety of vaccines in the elderly The submission is a two-step Type II Variation to
should be documented in subsets with certain underly- EMA (Centralised Procedure), in which the manufac-
ing conditions and levels of frailty to determine whether turer submits quality information (Module 3), followed
the safety profile is broadly acceptable. by clinical trial data, resulting in vaccine approval in late
August or early September.
Immunodeficient Subjects The first step begins within 45 days from the vali-
Due to the wide range of types of immunodeficiency dation, when CHMP adopts an opinion to approve or
resulting from congenital or acquired conditions or from refuse the variation application or suspends the procedure
iatrogenic intervention, only some of which may impact (clock-stop) by adopting a request for additional data.

Vaccines
Vaccines
Figure 37-2. Procedure for Seasonal Influenza Vaccines in the EU (EMA/56793/2014)a

Figure 35-2. Procedure for Seasonal Influenza Vaccines in the European Union (EMA/56792/2013)a
Fast track procedure for human influenza vaccines annual strain(s) update
Submission Variation application (the

Agency to publish yearly submission 1 to 5 days validation
deadlines)
Start variation procedure Day 1*
Rap AR Day 15
Max 45 days for CHMP
Circulation to BWP around Day 20 assessment of data
submitted in the first phase
CHMP members comments Day 21
CHMP opinion or RSI or request

Day 30 July CHMP**
for additional data
MAH responses Day 33
RAP AR Day 40
Members comments
Day 42
CHMP opinion or RSI or request for additional
data (written procedure) Day 45
If request for additional data,
clock-stop until the
submission of the data.
Applicant is recommended to
Day 46
submit them within 12 days
Submission of additional data
RAP AR Day 51 Max 10 days for

assessment of the
Comments Day 52 additional data
CHMP opinion (written procedure) Day 55

3 days
Agency sends to EC and applicant
*Calendar Days
**If possible
a. Guideline on Influenza
a. Guideline vaccines—submission
on influenza and
vaccines—submission andprocedural
procedural requirements (EMA/56793/2014;
requirements (EMA/56793/2014 Rev.March 2017).
1; March 2017).
by the Member State and are responsible for vaccine resources and/or technical capabilities for all vaccine types.
quality control in their countries. Because the OMCL decides which tests are required for lot
OMCLs may test vaccine lots, but, at minimum, release, the manufacturer may need to transfer methods or
will check release documentation before vaccine lots technology to the OMCL. As with method transfer from a
can be released onto the market. A vaccine certified by sponsor to a contract manufacturer, this can take time and
one OMCL is recognised by all other laboratories in the should be taken into account when the regulatory profes-
network. Within this OMCL organisation, the Official sional is considering timing. The regulatory professional
Control Authority Batch Release (OCABR)
Regulatory Affairs Professionals Society network is should keep in mind an OMCL, such as the 495National
responsible for human biologicals (vaccine) testing. EMA Institute of Biological Standards and Control, is different
recommends contacting potential OMCLs to exchange than a Competent Authority.
Chapter 37
A request for supplementary information (RSI) without clinical. The core dossier’s safety and immunogenicity
suspending the procedure may be issued at Day 30. data, therefore, are based on the premise subjects will
The second step is triggered only if a request for respond similarly to the actual pandemic strain. Once a
additional data has been adopted. Where a request for pandemic starts, the strain is replaced. Then, the sponsor
additional data has been adopted, the MAH is recom- performs specific predefined development steps, which
mended to submit the additional data within 12 days provide data to be submitted and reviewed as a varia-
from the adoption of the additional data request. Upon tion to the MAA. Preparing for pandemics in this way
receipt of this data, the procedure is re-started, and significantly accelerates a vaccine’s licensure and avail-
CHMP adopts an opinion within 10 days. ability while reducing pandemic response time.
Within three days from the opinion’s adop- ‘Pandemic preparedness vaccines’ are indicated for
tion, EMA sends the opinion to the MAH and the immunization against potential pandemic strain(s),
European Commission. This will be followed by a once an official pandemic declaration in the EU has
Commission decision to amend the MA’s terms. been recognised and after the variation to include the
declared pandemic strain has been authorised.
Prepandemic Influenza Vaccines As noted above, several guidelines are in place for
An MAA for a zoonotic influenza vaccine can be influenza vaccines. From lessons learned during pandemic
submitted to EMA upon confirmation of eligibility outbreaks, CHMP has developed a single comprehensive
for the Centralised Procedure. Submission of a new influenza vaccine guideline dealing with nonclinical and
prepandemic vaccine is expected to be based on a com- clinical requirements for all kinds of influenza vaccines.
prehensive CTD dossier. The guideline, Influenza vaccines—Non-clinical and clinical
A standard evaluation process is applied, unless module,26 in force since 1 February 2017, replaces the fol-
a request for accelerated assessment is justified by the lowing guidances and core SmPC:
applicant and accepted by CHMP. Once adopted by • Guideline on dossier structure and content
CHMP, the opinion is forwarded to the Commission for pandemic influenza vaccine marketing
for the decision-making process. authorisation application (EMEA/CPMP/
Applicants are advised to consult the relevant VEG/4717/03 Rev. 1)
aspects of the pre-authorisation procedural advice on • Guideline on influenza vaccines prepared from
the submission of centralised MAAs published on viruses with the potential to cause a pandemic and
EMA’s website, with regard to such practical aspects as intended to be used outside of the core dossier con-
the number of applications or fees. text (CHMP/VWP/263499/2006)
Replacement of the vaccine virus in a zoonotic • Explanatory note on the withdrawal of the note
influenza vaccine should be processed via a Type II for guidance on harmonisation of requirements for
Variation application. influenza Vaccines (CPMP/BWP/214/96) and of
the core SmPC/PL for inactivated seasonal influ-
Pandemic Influenza Vaccines enza vaccines (CMDh/128/2003/Rev. 5 and
Once WHO officially announces a pandemic on the CMDh/129/2008/Rev. 3)
basis of global flu virus activity information, EMA • Points to Consider on the development of live
implements a pandemic influenza crisis manage- attenuated influenza vaccines (EMEA/CPMP/
ment plan,25 which provides fast-track data review for BWP/2289/01)
authorising pandemic influenza vaccines and liaising • Core SmPC for pandemic influenza vaccines
with the European Commission and regulatory author- (EMEA/CHMP/VEG/193031/2004)
ities in EU Member States.
For pandemic influenza vaccine manufacturers, Other Vaccine Aspects
EMA and the European Commission have developed Many vaccines have improved delivery and immune
an innovative core pandemic dossier approach for pan- response if adjuvants are included in the final product.
demic influenza outbreaks. This approach is explained in This section is an overview of some unique aspects of
Dossier structure and content for pandemic-influenza mar- vaccines like adjuvants, immunomodulators, DNA vac-
keting authorisation application. In this dossier, a sponsor cines and therapeutic vaccines.
submits a license application with a mock strain of
influenza with pandemic potential (so-called ‘pandemic Adjuvants
preparedness vaccine’). The mock strain is an available Adjuvants are vaccine components that help enhance or
strain to which the population is naïve and could cause modulate the immune response. Adjuvants can either
a pandemic. This allows a sponsor to mimic a future aid in enhancing higher titres, long-lived titres or both.
pandemic vaccine in all aspects: quality, nonclinical and Additionally, adjuvants influence the immune response

Vaccines
via either humoral or cellular immune response. A include treatments for cancer and other life-threatening
number of adjuvants affect vaccines through different illnesses. In most cases, these products contain geneti-
mechanisms. Some function as delivery systems, while cally modified cells or genetically modified organisms
some others enhance adaptive immune response.27 (GMOs) and generally can be used to target a cancer
Alum (either aluminium hydroxide or aluminium type or specific mutations in a particular cancer type.
phosphate) is the most commonly used adjuvant in Not only are these vaccines, they also are considered
vaccines licensed for human use in the EU and US. advanced therapy medicinal products (ATMPs) in the
Adjuvant requirements are defined in Guideline on adju- EU. In that case, applicable gene therapy and cellular
vants in vaccines for human use.28 This guidance outlines therapy guidelines will apply, depending on the ther-
the expectations for adjuvant manufacturing, nonclinical apeutic vaccine type. However, as stated in Directive
and clinical studies in vaccines, supported by WHO 2009/120/EC: “gene therapy medicinal products shall
guidelines.29 Adjuvants are not licensed independently. not include vaccines against infectious diseases.”31 These
They are licensed as a part of a vaccine product. All guidelines are discussed in Chapter 35. Like other
EU MAAs are expected to provide full information biotechnology products, these therapeutic vaccines
on an adjuvant, even if the adjuvant has been approved must be submitted for marketing approval through the
previously in another vaccine and the proprietary infor- Centralised Procedure. In lieu of specific therapeutic
mation is held by another manufacturer. vaccine guidance, especially for those treating can-
Guideline on adjuvants in vaccines for human use cer indications, the regulatory professional is advised
asserts novel adjuvants need to be characterised thor- to adhere to the US Guidance for Industry: Clinical
oughly through physicochemical-biological methods. Considerations for Therapeutic Cancer Vaccines.32
This characterisation includes obtaining microbiolog- Special regulations and guidelines are in place for
ical and chemical purity, as well as conducting studies medicinal products using GMOs, e.g., Directive 2001/18/
demonstrating the adjuvant-antigen’s mechanism of EC33 and Guideline on Environmental Risk Assessments for
action and stability. Additional routine studies for adju- Medicinal Products Consisting of, or Containing, Genetically
vants also are recommended. Preclinical studies are Modified Organisms.34 The regulatory professional also
determined in conjunction with this guideline. The reg- should refer to the Guideline on quality, nonclinical and
ulatory professional should review this guideline closely clinical aspects of live recombinant viral vectored vaccines.35
because the strategy for adjuvant alone and adjuvant-an- Usually, a GMO vaccine product requires more time for
tigen combination is decided on a case-by-case basis. clinical trial assessment and includes additional reviews
Clinical studies should be designed to demonstrate an during license approval. Generally, a 90-day clinical trial
adjuvant’s benefit and safety. If an adjuvant is intended application assessment is needed for a product containing
to replace a licensed adjuvant-antigen (vaccine), the a GMO versus 30 days for other medicinal products like
regulatory professional should ensure immune response simple vaccines. As every country has different regula-
non-inferiority studies are included in the MAA. tions and pathways, regulatory professionals are advised to
check with the respective Competent Authority for more
Immunomodulators details on GMOs.
In the last decade, the field of adjuvants has expanded, Additionally, GMO-based vaccines typically
with the introduction of immunomodulators included contain a vector that could be an attenuated virus or
in the production of certain vaccines and other medic- bacteria containing a heterologous antigen or gene.
inal products affecting an individual’s immune system. These vaccine candidates require environmental risk
EMA has clarified the difference between an adjuvant assessments in addition to quality, safety and efficacy
and an immunomodulator in the Explanatory note on assessments for both clinical trials and marketing
immunomodulators for the guideline on adjuvants in vac- approval. Live attenuated vaccines, including GMOs,
cines for human use: if a compound is given separately sometimes but not always, are subject to critical envi-
from a vaccine antigen, it is an immunomodulator, ronmental assessment, as they may find their way
not an adjuvant. Immunomodulators differ from adju- into the environment (Environmental risk assessment
vants because they precondition the immune system of medicinal products for human use, currently under
more systemically.30 All differences aside, guidelines revision).36,37 Assessing environmental risks posed by
on adjuvants for human use also are applicable to a GMO product due to its release and/or excretion is
immunomodulators. an important aspect of the application. A number of
sponsors and academic institutions are exploring DNA
DNA and Therapeutic Vaccines vaccine possibilities. However, no specific guidelines
Currently, a number of sponsors are researching thera- exist with regard to these products. To date, only a con-
peutic vaccines. Indications of interest for these vaccines cept paper has been published in March 2012.38 A draft

Chapter 37
guideline has not yet been made available. Until such more relevant than some medicinal product
time, the Guideline on quality, non-clinical and clinical guidelines. Guidelines also are available for dif-
aspects of medicinal products containing genetically modified ferent disciplines such as vaccine development
cells,39 currently under revision, should be followed. quality, nonclinical and clinical aspects.
• Since vaccines are produced from biotechno-
EU Pricing, Reimbursement and Policy logical processes, many licensure considerations
Making must be implemented during the development
In the EU, most medicines are under price controls, process.
and nearly all vaccines are reimbursed. Vaccine pric- • Unique EU manufacturing requirements
ing and reimbursement are important elements of include site manufacturing authorisations
EU regulatory activities. Reimbursement and pricing (even for IMPs) and QP certification.
are determined at a national level, regardless of the • Vaccines are subject to lot release by OMCLs
authorisation pathway used. Often, Member States use involved in vaccine lot testing and certification.
different schemes and policies due to their own medical • EU adjuvant requirements are defined clearly,
and economic pricing and reimbursement needs. Each and a number of adjuvants are licensed in con-
Member State has its own reimbursement assessment junction with vaccines.
authority based on health technology assessment • With justification, vaccine nonclinical activities
(HTA). Almost all childhood vaccines are provided free may be limited.
of charge in the EU, and costs are borne by the national • Vaccines containing live virus vectors also
health service. are regulated as GMOs. Both licensure and
Pricing and reimbursement were discussed in a clinical assessments of these products add
revised Transparency Directive in 2011. The directive complexity due to environmental assessments.
covered the speed of pricing, transparency and reim- • Seasonal influenza vaccines follow a well-de-
bursement decisions. Under this directive, Member fined path; pandemic influenza vaccines follow
States would have had to make a reimbursement deci- a core pandemic dossier approach.
sion within 120 days of an innovative drug’s approval • Pharmacovigilance activities are centrally
and within 30 days for a generic product. This was organised through EudraVigilance.
a significant reduction from the previously required • Every EU Member State makes policies on
180 days. A public consultation on the Transparency vaccinations and reimbursement.
Directive (Directive 89/105/EEC) was completed in References
2011. In March 2013, the proposal was amended to 1. Vaccine-preventable diseases. Vaccines and Immunization.
require Member States to make reimbursement deci- WHO website. http://www.euro.who.int/en/health-topics/
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ventable-diseases. Accessed 27 April 2020.
the Commission withdrew this proposal. 2. ICH Guideline Q11 on Development and Manufacture of Drug
A full list of national price sources can be found at: Substances (chemical entities and biotechnological/biological enti-
http://www.who.int/medicines/areas/access/sources_ ties). (EMA/CHMP/ICH/425213/2011; November 2012).
prices/national_medicine_price_sources.pdf. EMA website. http://www.ema.europa.eu/docs/en_GB/docu-
ment_library/Scientific_guideline/2012/05/WC500127803.pdf.
Conclusion 3. Guideline on the Requirements for Quality Documentation
• Vaccines are regulated at the Community Concerning Biological Investigational Medicinal Products in
Clinical Trials (EMA/CHMP/BWP/534898/2008; 10 February
level through several EU directives and reg- 2010). EC website. https://ec.europa.eu/health/sites/health/
ulations and at the national level by laws and files/files/eudralex/vol-10/2012-05_quality_for_biological.pdf.
legislation. Accessed 27 April 2020.
• Guidelines are issued centrally by EMA and 4. Guideline on the Requirements to the Chemical and Pharmaceutical
Quality Documentation Concerning Investigational Medicinal
by national competent authorities, making Products in Clinical Trials (CHMP/QWP/185401/2004; 31
marketing in the EU complex due to the num- March 2006). EC website. https://ec.europa.eu/health/sites/
ber of organisations involved in the regulation health/files/files/eudralex/vol-10/18540104en_en.pdf. Accessed
of medicinal products and the drafting of 27 April 2020.
5. Eudralex—Volume 4—Good Manufacturing Practice (GMP)
guidelines. Guidelines. EC website. https://ec.europa.eu/health/documents/
• General guidelines applicable to medicinal eudralex/vol-4_en. Accessed 27 April 2020.
products also apply to vaccines. 6. Quality of Water Used in the Production of Vaccines for
• Biological and biotechnological product guide- Parenteral Use (EMEA/CPMP/BWP/1571/02; 20 October
2003). EMA website. http://www.ema.europa.eu/ema/index.
lines and those specifically for vaccines are

Vaccines
jsp?curl=pages/regulation/general/general_content_000908. European Medicines Agency. Regulation (EC) No. 726/2004.

jsp&mid=WC0b01ac058002956b. Accessed 27 April 2020. EC website. https://ec.europa.eu/health/sites/health/files/files/
7. EMEA Public Statement on Thiomersal in Vaccines for eudralex/vol-1/reg_2004_726/reg_2004_726_en.pdf. Accessed
Human use—Recent Evidence Supports Safety of Thiomersal- 27 April 2020.
Containing Vaccines (EMEA/CPMP/VEG/1194/04; 24 20. Directive 2001/83/EC of the European parliament and of the
March 2004). EMA website. http://www.ema.europa.eu/ council of 6 November 2001 on the community code relating
docs/en_GB/document_library/Scientific_guideline/2009/09/ to medicinal products for human use. Directive 2001/83/EC.
WC500003904.pdf. Accessed 27 April 2020. EC website. https://ec.europa.eu/health/sites/health/files/
8. CHMP Position Paper on Thiomersal: Implementation of the files/eudralex/vol-1/dir_2001_83_consol_2012/dir_2001_83_
Warning Statement Relating to Sensitisation (EMEA/CHMP/ cons_2012_en.pdf. Accessed 27 April 2020.
VWP/19541/2007; 11 January 2007). EMA website. http:// 21. Directive 2001/20/EC of the European parliament and of
www.ema.europa.eu/docs/en_GB/document_library/Scientific_ the council of 4 April 2001 on the approximation of the laws,
guideline/2009/09/WC500003905.pdf. Accessed 27 April 2020. regulations and administrative provisions of the member states
9. Guideline on the Scientific Data Requirements for a Vaccine Antigen relating to the implementation of good clinical practice in the
Master File (VAMF) (EMEA/CPMP/BWP/3734/03; 15 conduct of clinical trials on medicinal products for human use.
December 2003). EMA website. http://www.ema.europa.eu/ Directive 2001/20/EC. EUR-Lex website. http://eur-lex.europa.
docs/en_GB/document_library/Scientific_guideline/2009/09/ eu/legal-content/EN/TXT/PDF/?uri=CELEX:02001L0020-
WC500003861.pdf. Accessed 27 April 2020. 20090807&from=EN. Accessed 27 April 2020.
10. Guideline on Requirements for Vaccine Antigen Master File 22. EudraVigilance. EMA website. http://www.ema.europa.eu/
(VAMF) Certification (EMEA/CPMP/4548/03/Final/Rev. 1. ema/index.jsp?curl=pages/regulation/general/general_con-
17 March 2015). EMA website. http://www.ema.europa.eu/ tent_000679.jsp&mid=WC0b01ac05800250b5. Accessed 27
docs/en_GB/document_library/Scientific_guideline/2009/09/ April 2020.
WC500003828.pdf. Accessed 27 April 2020. 23. Regulation (EU) No. 1235/2010 of the European parlia-
11. Questions and Answers on the Withdrawal of the CPMP Note ment and of the council of 15 December 2010 amending, as
for Guidance on Preclinical Pharmacological and Toxicological regards pharmacovigilance of medicinal products for human
Testing of Vaccines (EMA/CHMP/SWP/242917/2016; 21 use, Regulation (EC) No. 726/2004 laying down community
July 2016). EMA website. http://www.ema.europa.eu/docs/ procedures for the authorisation and supervision of medici-
en_GB/document_library/Other/2016/07/WC500210581.pdf. nal products for human and veterinary use and establishing
Accessed 27 April 2020. a European Medicines Agency, and Regulation (EC) No.
12. WHO Expert Committee on Biological Sterilisation, including 1394/2007 on advanced therapy medicinal products phar-
Guidelines on Nonclinical Evaluation of Vaccines. Annex I of macovigilance regulation (Regulation (EU) No. 1235/2010).
WHO Technical Reports Series, No. 927, 2005. WHO website. EUR-Lex website. http://eur-lex.europa.eu/LexUriServ/
http://apps.who.int/medicinedocs/documents/s16102e/s16102e. LexUriServ.do?uri=OJ:L:2010:348:0001:0016:EN:PDF.
pdf. Accessed 27 April 2020 Accessed 27 April 2020.
13. Directive 2001/20/EC of the European parliament and of 24. Guideline on Influenza Vaccines—Submission and Procedural
the council of 4 April 2001 on the approximation of the laws, Requirements (EMA/56793/2014; March 2017). EMA website.
regulations and administrative provisions of the member states http://www.ema.europa.eu/docs/en_GB/document_library/
relating to the implementation of good clinical practice in the Scientific_guideline/2017/03/WC500223481.pdf. Accessed 27
conduct of clinical trials on medicinal products for human use. April 2020.
EUR-Lex website. http://eur-lex.europa.eu/legal-content/EN/ 25. EMEA Pandemic Influenza Crisis Management Plan for the
TXT/PDF/?uri=CELEX:02001L0020-20090807&from=EN. Evaluation and Maintenance of Pandemic Influenza Vaccines
Accessed 27 April 2020. and Antivirals. (EMEA/214301/2006 (21 August 2006). EMA
14. Guideline on Clinical Evaluation of New Vaccines (EMEA/ website. http://www.ema.europa.eu/docs/en_GB/document_
CHMP/VWP/164653/2005; 18 October 2006). EMA website. library/Other/2009/11/WC500015526.pdf. Accessed 27 April
http://www.ema.europa.eu/docs/en_GB/document_library/ 2020.
Scientific_guideline/2009/09/WC500003870.pdf. Accessed 27 26. Guideline on Influenza Vaccines—Non-Clinical and Clinical
April 2020. Module (EMA/CHMP/VWP/457259/2014; 21 July 2016).
15. Guideline on Clinical Evaluation of new Vaccines—Annex: EMA website. http://www.ema.europa.eu/docs/en_GB/docu-
SPC requirements (EMEA/CHMP/VWP/382702/2006; 18 ment_library/Scientific_guideline/2016/07/WC500211324.pdf.
October 2006). EMA website. http://www.ema.europa.eu/ Accessed 27 April 2020.
docs/en_GB/document_library/Scientific_guideline/2009/09/ 27. Vaccine Adjuvants Review. http://www.invivogen.com/
WC500003871.pdf. Accessed 27 April 2020. review-vaccine-adjuvants. Invivogen website. Accessed 20
16. Vaccines Working Party. EMA website. http://www.ema.europa. February 2020.
eu/ema/index.jsp?curl=pages/contacts/CHMP/people_list- 28. Guideline on Adjuvants in Vaccines for Human use (EMEA/
ing_000023.jsp. Accessed 27 April 2020. CHMP/VEG/134716/2004; 20 January 2005). EMA website.
17. Human OCABR Guidelines. EDQM website. https://www. http://www.ema.europa.eu/docs/en_GB/document_library/
edqm.eu/en/Human-OCABR-Guidelines-1530.html. Accessed Scientific_guideline/2009/09/WC500003809.pdf. Accessed 27
27 April 2020. April 2020.
18. Guideline on Good Pharmacovigilance Practices (GVP)—Module 29. Guidelines on the Nonclinical Evaluation of Vaccine Adjuvants
V—Risk Management Systems (Rev. 2) (EMA/838713/2011 Rev and Adjuvanted Vaccines—WHO 2013. WHO web-
2. 28 March 2017). EMA website. http://www.ema.europa.eu/ site. http://www.who.int/biologicals/areas/vaccines/
docs/en_GB/document_library/Scientific_guideline/2012/06/ ADJUVANTS_Post_ECBS_edited_clean_Guidelines_NCE_
WC500129134.pdf. Accessed 20 February 2020. Adjuvant_Final_17122013_WEB.pdf. Accessed 27 April 2020.
19. Regulation (EC) No. 726/2004 of the European parliament 30. Explanatory Note on Immunomodulators for the Guideline
and of the council of 31 March 2004 laying down community on Adjuvants in Vaccines for Human use (EMEA/CHMP/
procedures for the authorisation and supervision of medici- VWP/244894/2006; 27 July 2006). EMA website. http://
nal products for human and veterinary use and establishing a www.ema.europa.eu/docs/en_GB/document_library/

Chapter 37
Scientific_guideline/2009/09/WC500003810.pdf. Accessed 27 35. Guideline on Quality, Non-Clinical and Clinical Aspects of

April 2020. Live Recombinant Viral Vectored Vaccines (EMA/CHMP/
31. Commission Directive 2009/120/EC of 14 September 2009 VWP/141697/2009; 24 June 2010). EMA website. http://www.
amending Directive 2001/83/EC of the European parliament ema.europa.eu/docs/en_GB/document_library/Scientific_guide-
and of the council on the community code relating to medicinal line/2010/08/WC500095721.pdf. Accessed 27 April 2020.
products for human use as regards advanced therapy medic- 36. Guideline on Environmental Risk Assessment of Medicinal
inal products. Directive 2009/120/EC. EC website. https:// Products for Human use (EMEA/CHMP/SWP/4447/00 Corr
ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/ 2; 01 June 2006). EMA website. http://www.ema.europa.eu/
dir_2009_120/dir_2009_120_en.pdf. Accessed 27 April 2020. docs/en_GB/document_library/Scientific_guideline/2009/10/
32. Guidance for Industry: Clinical Considerations for Therapeutic WC500003978.pdf. Accessed 27 April 2020.
Cancer Vaccines (October 2011). FDA website. https://www. 37. Questions and Answers on Guideline on the Environmental
fda.gov/downloads/biologicsbloodvaccines/guidancecompli- Risk Assessment of Medicinal Products for Human use (EMA/
anceregulatoryinformation/guidances/vaccines/ucm278673.pdf. CHMP/SWP/44609/2010 Rev. 1; 26 May 2016). EMA web-
Accessed 27 April 2020. site. http://www.ema.europa.eu/docs/en_GB/document_library/
33. Directive 2001/18/EC of the European parliament and of the Scientific_guideline/2016/06/WC500207858.pdf. Accessed 27
council of 12 March 2001 on the deliberate release into the April 2020.
environment of genetically modified organisms and repealing 38. Concept Paper on Guidance for DNA Vaccines (EMEA/
council directive 90/220/EEC. EC website. https://ec.europa. CHMP/308136/2007; 15 March 2012). EMA website. http://
eu/health/sites/health/files/files/eudralex/vol-1/dir_2001_18/ www.ema.europa.eu/docs/en_GB/document_library/Scientific_
dir_2001_18_en.pdf. Accessed 27 April 2020. guideline/2012/03/WC500124898.pdf. Accessed 27 April 2020.
34. Guideline on Environmental Risk Assessments for Medicinal 39. Guideline on Quality, Nonclinical and Clinical Aspects of Medicinal
Products Consisting of, or Containing, Genetically Modified Products Containing Genetically Modified Cells (EMA/CAT/
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Corr; 11 December 2006). EMA website. http://www.ema. www.ema.europa.eu/docs/en_GB/document_library/Scientific_
europa.eu/docs/en_GB/document_library/Scientific_guide- guideline/2012/05/WC500126836.pdf. Accessed 27 April 2020.

Chapter 38
Food Supplements
OBJECTIVES 2011 on the provision of food information to

consumers3
□ Understand EU and related national legislation
on food supplements □ Directive 2001/83/EC of the European
□ Understand the requirements for informing 2001 on the Community code relating to medic-
consumers about specific health properties inal products for human use, as amended by
(labelling, nutrition and health claims) Directive 2004/24/EC and Directive 2004/27/
EC, incorporating Directive 2004/24/EC of the
□ Learn what general safety and notification
European Parliament and of the Council of 31
requirements apply
March 2004 amending, as regards traditional
□ Understand the food-drug continuum, including herbal medicinal products, Directive 2001/83/
personalized nutrition and how the borderline EC on the Community code relating to medicinal
between food supplements and medicinal prod- products for human use4
ucts is interpreted
□ Understand recent developments and topics Parliament and of the Council of 20 December
(botanicals, microbiome/probiotics, FSMP, etc.) 2006 on nutrition and health claims made on
foods5

DIRECTIVES, REGULATIONS AND GUIDELINES Parliament and of the Council of 20 December
COVERED IN THIS CHAPTER 2006 on the addition of vitamins and minerals
□ Directive 2002/46/EC of the European and of certain other substances to foods6
Parliament and of the Council of 10 June 2002 □ Regulation (EC) No. 2015/2283 of the European
on the approximation of the laws of the Member Parliament and of the Council of 25 November
States relating to food supplements1 2015 on novel foods, amending Regulation (EU)
□ Regulation (EC) No. 178/2002 of the European No. 1169/2011 of the European Parliament and
Parliament and of the Council of 28 January of the Council and repealing Regulation (EC) No.
2002 laying down the general principles and 258/97 of the European Parliament and of the
requirements of food law, establishing the Council and Commission Regulation (EC) No.
European Food Safety Authority and laying 1852/20017
down procedures in matters of food safety2 □ Regulation (EC) No. 764/2008 of the European
□ Regulation (EC) No. 1169/2011 of the European Parliament and of the Council of 9 July 2008 lay-
Parliament and of the Council of 25 October ing down procedures relating to the application

Chapter 38
of certain national technical rules to products the European Commission in 2010 to stop the claims
lawfully marketed in another Member State and assessments of botanicals and in 2015 to carry out an
repealing Decision No. 3052/95/EC8 impact assessment under the Commission’s REgulatory
FITness and performance programme (REFIT)10
EU-wide harmonised approach for botanical foods
Introduction supplements is expected following the constitution in
The Food Supplements Directive (FSD) (Directive 2019 of the new EU Parliament and Commission, in
2002/46/EC, Recital 3) recognises “an adequate and consideration of scientific, legal and political aspects. In
varied diet could, under normal circumstances, provide the meantime, some limited harmonisation efforts by
all necessary nutrients for normal development and Member States have continued, e.g., the BELFRIT list
maintenance of a healthy life in quantities which meet by Belgium, France and Italy.
those established and recommended by generally accept-
able scientific data. However, surveys show that this ideal Food Supplements Directive (FSD)
situation is not being achieved for all nutrients and by all
(Directive 2002/46/EC)
groups of the population across the Community.”
Principles
The increased marketing of food supplements in
The FSD establishes the legal category of food supple-
the EU led Member States to develop national rules
ments under EU food law. The relevant legal framework
interfering with the free movement of goods, creating
for individual products or ingredients is the General
unequal competition and barriers to trade. As a result,
Food Law Regulation (Regulation 178/2002), which
the European Commission undertook a harmonisation
specifies specific obligations for food manufacturers to
exercise, resulting in the FSD in 2002.
ensure the safety of the products. This also means the
This legislation harmonised the status of food sup-
horizontal legislation applicable to foodstuffs applies to
plements under food law for all Member States, making
food supplements as well. This includes:
the general food law requirements applicable also to
• the provision of food information to consum-
food supplements and distinguishing these products
ers (Regulation 1169/2011)
clearly from medicinal products.
• food additives (Regulation 1333/2008)11 and
However, harmonising rules for all possible sub-
their purity criteria12
stances used in food supplements, including essential
• setting maximum levels for certain contami-
nutrients such as vitamins, minerals, amino acids and
nants in foodstuffs (Regulation 1881/2006)13
essential fatty acids, fibres, other substances with a
and maximum residue levels of pesticides
nutritional or physiological effect (e.g., glucosamine,
(Regulation 396/2005)14 and extraction sol-
coenzyme Q10, various carotenoids, etc.) and various
vents (Regulation 2009/32)15
plant and herbal extracts, is a huge endeavour. For
• hygiene of foodstuffs rules (Regulations
practical reasons, it was decided the first step would
852/2004 and 853/2004)16,17
be to harmonise vitamins and minerals and conduct a
study on the need or usefulness of harmonising other
The FSD covers food supplements and their ingredi-
substances at a later time. This study concluded in 2008
ents. It allows food supplements to contain vitamins,
that further harmonisation was not feasible and also
minerals and “other substances with a nutritional or
not necessary.9 It was considered not feasible because
physiological effect,” such as bioactive compounds and
of the limited scientific information available and not
botanicals or botanical extracts. The directive lays down
necessary because of a number of recently adopted
specific rules only for vitamins and minerals used as
legal instruments already cover various aspects of
food supplement ingredients.
these products (e.g., the Nutrition and Health Claims
Rules and provisions on ‘other substances’ remain
Regulation (NHCR) (Regulation 1924/2006), the
subject to national legislation. The directive aims to
Addition of Vitamins, Minerals and Other Substances to
harmonise Member States’ national legislation based on
Foods Regulation (Regulation 1925/2006), the Mutual
the following elements:
Recognition Regulation (Regulation 764/2008) and the
• establish the food supplement category (pre-
Novel Foods Regulation (Regulation 2015/2283).
viously also called diet integrators, dietary
Unfortunately, these new legal instruments have
supplements, etc.) and give a precise definition,
not been able to solve the barriers to trade between
regulating food supplements under food law
the Member States that continue to exist. In fact, the
• establish positive lists of vitamins and miner-
application of the NHCR resulted in a fundamental
als and their chemical forms allowed in food
inconsistency in the way botanicals are treated under
supplements
food and medicinal law. This sparked a decision by

Food Supplements
• determine derogation and amendment proce- plants and plant preparations in medicinal products,
dures for those lists confirms that botanicals can be used in both legal frame-
• agree on appropriate labelling and presentation works. However, because of interpretation differences
standards among the Member States, it has created a grey zone as
• introduce safeguards in the event of a public to the status of certain botanicals. Given the divergent,
health risk case-by-case Member State legislation, further harmoni-
sation is again on the Commission’s agenda.
Scope and Definition
The FSD defines “food supplements” as “foodstuffs, Quality Requirements
the purpose of which is to supplement the normal The FSD has not established substance purity crite-
diet and which are concentrated sources of nutrients ria for nutritional substances yet. In general, however,
or other substances with a nutritional or physiological purity criteria specified by European Commission
effect, alone or in combination, marketed in dose form” legislation for nutritional substances used in foodstuffs
(Article 2a). apply. If purity criteria are not specified by European
“Dose form” means “forms such as capsules, pas- Commission legislation, generally acceptable interna-
tilles, tablets, pills and other similar forms, sachets tional purity criteria shall be applicable, and national
of powder, ampoules of liquids, drop dispensing bot- rules setting stricter purity criteria may be maintained.
tles, and other similar forms of liquids and powders Given that food supplements in the EU are clas-
designed to be taken in measured small unit quantities.” sified legally as foodstuffs, all applicable general food
“Nutrients” (as a first stage) means only vitamins and safety requirements apply. This also includes hygiene
minerals (Article 2b). Only the vitamins and minerals legislation (Regulations 852/2004 and 853/2004) to
listed are allowed in food supplements and also their ensure food supplements’ safe production.
chemical forms are included in a positive list.
The FSD does not contain specific provisions relat- Information to Consumers (Labelling)
ing to substances other than vitamins and minerals that Information relating to food supplements’ nutrient con-
have a nutritional or physiological effect when used as tent is essential to allow consumers to make informed
food supplement ingredients (e.g., amino acids, essential choices and use supplements properly and safely. As
fatty acids, fibre and various plants and herbal extracts food supplements legally are considered foodstuffs, the
such as ginseng). Until the FSD is amended further, Food Information to Consumers Regulation (Regulation
national rules remain applicable subject to European 1169/2011) requirements relating to labelling, presenta-
Treaty Articles 34 and 36 on the free movement of tion and advertising are applicable. However, given the
goods and mutual recognition.18 specific nature of food supplements, certain foodstuff
Basically, this means food supplements lawfully requirements do not apply. Indeed, food supplements’
manufactured or marketed in one Member State also energy, protein, fat, carbohydrate and fibre content usu-
should be allowed to be marketed in all other Member ally is negligible, and products are consumed in relation
States. In practice, this often is difficult to achieve, and to the daily amount specified on the label. Therefore, the
the Court of Justice of the European Union (CJEU) FSD contains a number of specific provisions that take
has condemned various Member States for not applying precedence over the general ones:
mutual recognition. • Sales denomination is “food supplement”
Since 2008, the principle of mutual recognition (Article 6 paragraph 1).
has been subject to specific legislation, the Mutual • Specific labelling requirements (Article 6 para-
Recognition Regulation (Regulation 764/2008) laying graph 3) include:
down a procedure to be followed in case Member States a. nutrient or substance category character-
intend to refuse access to their market of such products. ising the product or an indication of those
Safety considerations and borderline issues are among nutrients’ or substances’ nature
the most frequent reasons for not accepting certain food b. product portion recommended for daily
supplements on national markets. Still, some Member consumption
States have worked together to align their legislations, c. warning not to exceed the stated recom-
such as the establishment of a common positive list of mended daily dose
botanicals by Belgium, France and Italy. d. statement food supplements should not be
The fact the FSD allows plants and plant extracts used as a substitute for a varied diet
to be marketed as food supplements in parallel to e. statement the products should be stored
the Traditional Herbal Medicinal Product Directive out of the reach of young children
(THMPD) (Directive 2004/24) governing the use of

Chapter 38
• Food supplement labelling, presentation and notification differ. In some cases, competent authorities
advertising must not include any statement request additional information, in particular for food sup-
or implication that a balanced and varied diet plements containing botanicals or botanical preparations.
cannot provide appropriate quantities of nutri- The notification requirement is mandatory but is not a
ents in general (Article 7). registration or premarket approval process, although it is
• Nutrient or substance amount with a nutri- used as such in practice by some Member States.
tional or physiological effect present in the
product must be declared per product por- Safety Assessment of Food Supplement
tion as recommended for daily consumption Ingredients
(Article 8). Safety obligations of food supplement manufacturers,
• Vitamin and mineral information must be importers and sellers are included in the General Food
expressed as a percentage of the reference Law Regulation (Regulation 178/2002) in the same way
values mentioned in Food Information to this applies to other foodstuffs. Also, as for regular food-
Consumers Regulation Annex XIII per daily stuffs, there is no general premarket approval applicable
recommended amount. to ingredients used in such products, except in two cases:
• Additives, which are substances used for
Minimum and Maximum Amounts of Vitamins technological purposes, must be approved for
and Minerals Based on Safety use in the specific products, with conditions
The FSD does not specify minimum and maximum of use that need to be respected (Regulation
food supplement vitamin and mineral content yet. The 1333/2008).
European Commission is long overdue with proposing • Food or food ingredients that had not been
such maximum levels given the difficulties of getting used in food in the EU to a significant extent
Member States agree on common levels. before 15 May 1997 are considered novel foods
However, the FSD does specify the principles to and require a premarket authorisation.
be observed for setting maximum levels: the maximum
vitamin and mineral amounts present in food supple- For such ingredients, the new Novel Foods Regulation
ments per daily consumption portion, as recommended (Regulation (EU) 2015/2283) expects companies to
by the manufacturer, shall be set based on the following: submit an application for authorisation, containing
• upper vitamin and mineral safe levels estab- appropriate safety data and information on the nature
lished by scientific risk assessment based on and exposure of the food or ingredient. The scope and
generally accepted scientific data, taking into principles of its 1997 predecessor are largely main-
account, as appropriate, the varying degrees of tained. The main change pertains to risk assessments
sensitivity of different consumer groups now systematically being carried out by EFSA at the
• vitamin and mineral intake from other dietary EU level and no longer at the national level.
sources Foods and food ingredients already marketed
also can be submitted for a safety assessment under
In addition, when the maximum levels are set, “due the Addition of Vitamins and Minerals and of Other
account” also should be taken of vitamin and mineral Substances to Food Regulation (EC No. 1925/2006),
reference intakes for the population. In the absence of which came into force on 1 July 2007. This legalisation
EU harmonised maximum levels, national levels apply, enables the Commission to request a risk assessment
subject to the mutual recognition principle. In the from EFSA for substances other than vitamins or min-
absence of maximum levels, some Member States have erals added to foods or used in their manufacture, in
taken initiative to establish maximum levels for prod- cases where their use would result in these substances’
ucts marketed in their territory. In doing so, they are ingestion in amounts far greater than reasonably
bound by the above principles, as has been confirmed by expected under normal consumption of a balanced and
the CJEU in a number of court cases.19,20 varied diet and/or would otherwise represent a potential
risk to consumers. This also covers ingredients used in
Notification food supplements.
To facilitate efficient food supplement monitoring, the Based on the EFSA opinion’s conclusions, the sub-
FSD allows Member States to require manufacturers or stance is included in one of three lists:
distributors to notify competent authorities when food • List A—addition to foods or use in the manu-
supplements are placed on the market by submitting a facture of foods is prohibited
copy of the product label (Article 10). Most Member
States have exercised this option, but the modalities for

Food Supplements
• List B—addition to foods or use in the man- • Health Claims (HCs)—These claims state,
ufacture of foods is allowed only under the suggest or imply a relationship exists between
conditions specified health and a food category, a food or one of its
• List C—if the possibility of harmful health constituents. HCs based on generally accepted
effects is identified, but scientific uncertainty scientific evidence and well understood by
persists, it is the interested parties’ respon- average consumers are allowed only when they
sibility to submit a file to EFSA containing are included in a positive list (Article 13). This
scientific data demonstrating safety for eval- list has been established in 2011.21 Most of
uation (Within four years, a decision will be these relate to the well-recognised functions of
made via comitology, taking EFSA’s opinion vitamins and minerals in the body.
into account, to allow the substance’s general • HCs based on newly developed scientific
use or include it on list A or B.) evidence and/or including a request for pro-
prietary data protection are allowed only after
This risk assessment procedure under Regulation (EC) a European Commission decision following
No. 1925/2006 has been applied in few cases to food dossier submission and an EFSA opinion
supplement ingredients, such as the botanicals yohimbe, (Articles 13.5 and 18).
Ephedra, green tea, hydroxyanthracene derivatives • Reduction of Disease Risk Claims —These
containing foods and monacolin K, leading to a ban or health claims state, suggest or imply the con-
restrictive conditions of use. sumption of a food category, food or a food’s
constituents significantly reduces a human
Health Claims disease development risk factor. These claims
The FSD contains no specific rules for food supplement require being allowed specifically by the
health claims. It only specifies that food supplement European Commission after dossier submis-
labelling, presentation and advertising must not attri- sion and an EFSA opinion (Articles 14, 15, 16,
bute any property of preventing, treating or curing a 17 and 19).
human disease to the product or refer to such properties • Claims referring to Children’s Development
(Article 6, Paragraph 2; Article 2). and Health—These claims have to follow the
As of 1 July 2007, nutrition and health claims for same procedure as Reduction of Disease Risk
foods have been covered by the Nutrition and Health Claims.
Claims Regulation (NHCR) (Regulation (EC) No.
1924/2006). This regulation’s primary goal is ensur- Statements referring to general, non-specific benefits
ing adequate and appropriate labelling to protect and for overall good health or health-related well-being
inform consumers. It harmonises many differences may be made only if they are accompanied by a specific,
between national legislative provisions relating to claims approved health claim. Despite the thousands of HC
and their conditions of use impeding free movement submissions, less than 300 have been approved after
of goods. By involving EFSA, uniform review and receiving positive EFSA opinions. A majority of claims
approval procedures are included for different claim received negative reviews (mostly for ingredients such as
types, based on adequate scientific substantiation. probiotics, other substances and botanicals), for a variety
The NHCR covers all foods, including food sup- of reasons, yet in particular for insufficient characterisa-
plements, with no specific provisions relating to claims tion of the substance, failure to demonstrate a beneficial
described in the relevant regulatory texts. It foresees a health effect in a given target population or failure to
premarket approval system for all nutrition and health demonstrate a cause-and-effect relationship through
claims, which covers not only claims used in product randomised controlled trials (RCTs). In a few cases,
labelling but also in commercial communications, includ- even when EFSA provided a positive scientific assess-
ing advertising, publicity and website product claims. ment, such as for glucose, the EU Commission—the
Specific procedures are in place for four main types competent risk manager—decided not to grant a health
of claims: claim for public safety reasons. NCs not included in the
• Nutrition Claims (NCs)—These claims state, annex and HCs not listed in the EU permitted list are
suggest or imply a food has particular beneficial prohibited. An overview of the submitted claims and
nutritional properties due to its energy content, their legal status (allowed or prohibited) can be found
level of nutrients or other substances it does in the EU Commission register.22
or does not contain or contains in reduced or This register does not list claims for botanicals or
increased proportions. The only permissible botanical preparations used in food supplements, as the
NCs are those listed in the NHCR annex. EU Commission has decided not to proceed with the

Chapter 38
assessments for now. The reason is that under THMPD 2. by virtue of its function—any substance or
medicinal effects are accepted with no need for scien- combination of substances that may be used in
tific proof of efficacy if the activity is plausible on the or administered to human beings either with
basis of the botanical’s traditional use. However, to have a view to restoring, correcting or modifying
a health claim approved for food supplements, RCTs physiological functions by exerting a pharma-
would be required, which is not consistent. The EU cological, immunological or metabolic action
Commission currently is assessing how this discrepancy or to making a medical diagnosis
can be resolved and, under its REFIT programme,
carrying out a detailed impact assessment. Until a final According to this definition, a product can be classified
decision is taken, the submitted “on-hold’ claims can as a medicinal product either because it is presented for
continue to be used on food supplements. the prevention or therapy of a disease or has inherent
therapeutic or diagnostic functions. However, this is not
Food-Drug Continuum: Borderline Issues, absolute because—if taken literally—many components
Personalised Nutrition contained in foods could be considered medicinal based
The definitions of “food,” “food supplement,” “food on this definition, especially since foods are allowed to
for special medical purposes,” “medicinal product” and contain substances with a physiological effect by virtue
“health claim” are complex and legally difficult, creating of the definitions of “food supplement” in the FSD and
some areas of overlap, leading to grey zones. Defining a “health claims” in the NHCR. A broad interpretation of
product’s intended use and other characteristics is para- the definition of “medicinal product” would make these
mount in assessing applicable legislative requirements.23 other definitions ineffective and meaningless. A number
It is a company’s obligation to identify the right of legal arguments support this:
legal framework to apply to its product and this obvi- • MPD Article 2.2 gives conditions for the
ously will be guided by the opportunities the company superiority of medicinal law to be applied (only
sees. However, because of interpretation differences, to individual products, in cases of doubt, while
such decisions for certain products and, in particular, taking into consideration all the product’s
food supplements containing certain botanicals can be characteristics).
challenged by individual Member States, which creates • Amending MPD, “whereas” 7 in Directive
barriers to trade. It is little wonder the dispute con- 2004/27/EC states, “Where a product comes
cerning so-called “borderline products,” in particular clearly under the definition of other product
the dividing line between medicinal products and food categories, in particular food, food supple-
supplements, has been the subject of CJEU proceedings ments, medical devices, biocides or cosmetics,”
over the years. the MPD should not apply.
Medicinal products, in accordance with the • “Whereas” 12 of the THMPD states it “allows
Medicinal Product Directive (MPD) (Directive 2001/83/ non-medicinal herbal products, fulfilling the
EC), are excluded from the field of food law. Although criteria of food legislation, to be regulated
the recitals make it clear the MPD and THMPD should under food legislation in the Community.”
not apply to other product categories, including food • The FSD defines food supplements as concen-
and food supplements, no explicit exclusion of food is trated sources of nutrients or other substances
specified. with a nutritional or physiological effect, and
Therefore, the MPD provisions overrule those of acknowledges, in “whereas” 6, “There is a wide
the General Food Law Regulation in case of challenge. range of nutrients and other ingredients that
But this is not absolute. MPD Article 2.2 specifies that might be present in food supplements includ-
the directive’s provisions shall apply to specific products, ing, but not limited to, vitamins, minerals,
only in cases of doubt and taking into account all the amino acids, essential fatty acids, fibre, and
product’s characteristics. A case of doubt means the various plants and herbal extracts.”
product falls equally well within both the definition of a • The NHCR explicitly covers “other substances,”
medicinal product and other Community legislation. which are defined as substances other than
Article 1.2.1 defines “medicinal product” in two nutrients having nutritional or physiological
ways: effects.
1. by virtue of its presentation—any substance or
combination of substances presented as having These principles and the fact there is a limit to the
properties for treating or preventing disease in superiority of medicinal law when applied to individ-
human beings ual products have been confirmed explicitly by various
CJEU judgments. For example, in the judgment on

Food Supplements
“the garlic case” (Case 319/05), where the European increasingly possible, including health apps, wearables and
Commission brought charges against the Federal other devices with the potential to address any nutritional
Republic of Germany for classifying a garlic prepara- gaps and/or sports-related needs linked to gene, gender,
tion in capsule form as a medicinal product, although and age. This opens a multitude of opportunities for per-
it did not satisfy the statutory definition, the CJEU sonalised nutrition; however, these technologies are not
spelled out once again the basic rules for distinguishing currently addressed by regulation. It is worth noting the
between a product’s medicinal and food status:24 novel approaches being studied to address possible influ-
• Case-by-case approach—The CJEU con- ences on the gut microbiome and host health via dietary
sistently has held it is up to the national means, including food supplementation.25
authorities to determine on a case-by-case
basis whether a product falls within the defi- Conclusion
nition of a medicinal product, taking into • Food supplements are harmonised as a
account all the product’s characteristics, par- category of products under food law by the
ticularly its composition; its pharmacological FSD. Food supplements are concentrated
properties, to the extent to which they can be sources of food compounds intended to
established in the present state of scientific supplement the diet. Specific harmonised
knowledge; the manner in which it is used; the rules exist only for vitamins and minerals. The
extent of its distribution; its familiarity to con- composition of food supplements, regarding
sumers; and the risks its use may entail. maximum levels and other substances,
• Therapeutic effect—The CJEU holds the defi- including botanicals, still is subject to largely
nition of “by virtue of its function” is broad divergent country-by-country legislation.
enough to include products that, although Such legislation may be very detailed, based
capable of having an effect on bodily func- on positive and/or negative lists of ingredients
tions, in fact have another purpose. However, that are allowed or not.
that criterion must not lead to classification as • Communication about foods’ health benefits,
medicinal products by function of substances including food supplements, is regulated by
that, while having an effect on the human the NHCR, which provides for premarketing
body, do not affect metabolism significantly approval of all claims. Because of botani-
and, thus, do not strictly modify the way in cals’ inconsistent treatment between food
which it functions. The definition of medicinal and medicinal law, botanical health claim
product by function is designed to cover prod- assessments currently are on hold. The claims
ucts whose pharmacological properties have submitted may continue to be used until a final
been observed scientifically and genuinely are decision is made.
designed to make a medical diagnosis or to • As they are regulated under food law, food
restore, correct or modify physiological func- supplements need to conform with the General
tions. A physiological effect is not specific to Food Law and Novel Foods Regulations’ general
medicinal products but also is among the crite- food safety requirements. Also, other horizon-
ria used for the definition of food supplements. tal food law provisions, such as labelling, the
Therefore, for a product to fall within use of additives and restrictions for contami-
medicinal law, it is not sufficient it possesses nants and residues apply.
properties beneficial to health in general; • In principle, food supplements legally mar-
strictly speaking, it must have the function of keted in one Member State can be sold in all
treating or preventing disease. The fact many Member States by virtue of the principle of
products generally recognised as foodstuffs also mutual recognition. Still, significant barriers
may serve therapeutic purposes is not suffi- to trade exist among certain Member States,
cient to confer on them the status of medicinal keeping the food supplements market frag-
product. mented. The Mutual Recognition Regulation
specifies the principles and procedures for
This illustrates clearly the EU legal framework intends those situations where Member States intend
for food supplements and medicinal products to to refuse market access to such products. Safety
co-exist, each category in conformity with its legal and borderline issues are among the most fre-
framework’s rules. quent reasons.
The arrival of new diagnostic technologies (e.g., • Food supplements making health claims can
“omics”) makes advances in precision medicine be close to medicinal products because of

Chapter 38
their format and health benefit. The MPD EN/TXT/PDF/?uri=CELEX:02006R1925-20150401&rid=1.

may overrule a given product’s food status Accessed 27 April 2020.
7. Regulation (EU) 2015/2283 of the European Parliament
but only in cases where there is doubt about and of the Council of 25 November 2015 on novel foods,
the applicable framework and when all the amending regulation (EU) No. 1169/2011 of the European
product’s characteristics are considered. CJEU Parliament and of the Council and Repealing Regulation (EC)
rulings essentially confirm this should be a No. 258/97 of the European Parliament and of the Council
and Commission Regulation (EC) No. 1852/2001. EUR-Lex
product-by-product assessment. The fact the website. http://eur-lex.europa.eu/legal-content/EN/TXT/
product may exhibit beneficial health effects is PDF/?uri=CELEX:32015R2283&rid=1. Accessed 27 April
not, in itself, sufficient to classify the product 2020.
as medicinal. 8. Regulation (EC) No. 764/2008 of the European Parliament
and of the Council of 9 July 2008 laying down procedures
• Food supplements can be useful in filling relating to the application of certain national technical
specific nutrition gaps. In addition, the role rules to products lawfully marketed in another Member
of novel diagnostics (e.g., “omics,” wearables, State and repealing Decision No. 3052/95/EC. EUR-Lex
health and sports apps) in personalised nutri- website. http://eur-lex.europa.eu/legal-content/EN/TXT/
PDF/?uri=CELEX:32008R0764&rid=1. Accessed 27 April
tion—in addition to population-based dietary 2020.
approaches—may hold great promise, although 9. Commission of the European Communities. Report from the
they have not yet been specifically addressed by Commission to the Council and the European Parliament
regulations. on the use of substances other than vitamins and minerals
in food supplements (12 May 2008). COM(2008) 824 final.
EUR-Lex website. http://eur-lex.europa.eu/legal-content/EN/
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relating to medicinal products for human use. EUR-Lex 15. Directive 2009/32/EC of the European Parliament and of
website. http://eur-lex.europa.eu/legal-content/EN/TXT/ the Council of 23 April 2009 on the approximation of the
PDF/?uri=CELEX:02001L0083-20121116&rid=1. Accepted laws of the Member States on extraction solvents used in
27 April 2020. the production of foodstuffs and food ingredients. EUR-Lex
5. Regulation (EC) No. 1924/2006 of the European website. http://eur-lex.europa.eu/legal-content/EN/TXT/
Parliament and of the Council of 20 December 2006 on PDF/?uri=CELEX:02009L0032-20161109&rid=1 Accessed 27
nutrition and health claims made on foods. EUR-Lex April 2020.
website. http://eur-lex.europa.eu/legal-content/EN/TXT/ 16. Regulation (EC) No. 852/2004 of the European Parliament
PDF/?uri=CELEX:02006R1924-20141213&rid=1. Accessed and of the Council on the hygiene of foodstuffs. EUR-Lex
27 April 2020. website. http://eur-lex.europa.eu/legal-content/EN/TXT/
6. Regulation (EC) No. 1925/2006 of the European Parliament PDF/?uri=CELEX:02004R0852-20090420&rid=1. Accessed
and of the Council of 20 December 2006 on the addition of 27 April 2020.
vitamins and minerals and of certain other substances to foods. 17. Regulation (EC) No. 853/2004 of the European Parliament
EUR-Lex website. http://eur-lex.europa.eu/legal-content/ and of the Council of 29 April 2004 laying down specific

Food Supplements
hygiene rules for food of animal origin. EUR-Lex web- 22. EU Register of nutrition and health claims made on foods. EC
site. http://eur-lex.europa.eu/legal-content/EN/TXT/ website. http://ec.europa.eu/food/safety/labelling_nutrition/
PDF/?uri=CELEX:02004R0853-20160401&rid=1. Accessed claims/register/public/?event=register.home. Accessed 27 April
27 April 2020. 2020.
18. Consolidated version of the Treaty on the Functioning of the 23. Coppens P, Delmulle L, Gulati O, Richardson D, Ruthsatz M,
European Union. EUR-Lex website. http://eur-lex.europa. Sievers S and Sidani S. Use of Botanicals in Food Supplements.
eu/legal-content/EN/TXT/PDF/?uri=CELEX:12012E/ Regulatory Scope, Scientific Risk Assessment and Claim
TXT&from=EN. Accessed 27April 2020. Substantiation. Ann Nutr Metab. 2006; 50:538–554.
19. Judgment of the Court: Case C-446/08 (29 April 2010). 24. Judgment of the Court: Case 319/05 (15 November 2007).
InfoCuria website. http://curia.europa.eu/juris/document/ InfoCuria website. http://curia.europa.eu/juris/showPdf.
document.jsf ?text=&docid=84475&pageIndex=0&do- jsf ?text=&docid=69867&pageIndex=0&doclang=EN&mode=l-
clang=EN&mode=lst&dir=&occ=first&part=1&cid=788072. st&dir=&occ=first&part=1&cid=826769. Accessed 27 April
20. Judgment of the Court: Case C-672/15 (27 April 2017). 25. D’Hondt K, Kaput J and Ruthsatz M. “Personalized Nutrition
InfoCuria website. http://curia.europa.eu/juris/document/ for Better Health: Targeting the Human Microbiome.”
document.jsf ?text=&docid=190163&pageIndex=0&do- Regulatory Focus. July 2019. Regulatory Affairs Professionals
clang=EN&mode=lst&dir=&occ=first&part=1&cid=788072. Society.
21. Commission Regulation (EU) No. 432/2012 of 16 May 2012 DISCLAIMER: This chapter reflects the personal opinion and expe-
establishing a list of permitted health claims made on foods, rience of the author. By no means can it be construed as an official
other than those referring to the reduction of disease risk position by any organisation with which the author is affiliated.
and to children’s development and health. EUR-Lex website.
http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=O-
J:L:2012:136:0001:0040:en:PDF. Accessed 27 April 2020.

Chapter 38

Chapter 39
Food for Special Medical

Purposes
OBJECTIVES □ Commission Notice on the Classification of Food

for Special Medical Purposes (2017/C 401/01)
□ Introduce the food for special medical purposes
(FSMP) category □ Directive (EU) 2019/904 of the European
Parliament and of the Council of 5 June 2019 on
□ Understand the regulatory framework for FSMPs the reduction of the impact of certain plastic
in the EU products on the environment
□ Understand the notification requirements
related to placing FSMPs on the market in the EU
Introduction
□ Understand FSMP usage and unique practical FSMPs have a longstanding history of practical usage
implications related to revised regulation in the EU over the last decades, laying a foundation for
nutritional patient care.1 Subject to framework legislation
in the EU since 1979,2 subsequent specific harmonised
legislation for FSMPs generally reflect the principles
laid down in the relevant CODEX standards on food
for special dietary use3 and food for special medical
□ Commission Delegated Regulation (EU) purposes.4,5 FSMPs are a food category specially formu-
2016/128 of 25 September 2015 supplementing lated or processed to meet a disease, disorder or medical
Regulation (EU) No. 609/2013 of the European condition’s medically determined nutrient requirements
Parliament and of the Council as regards the for patients under the supervision of a healthcare pro-
specific compositional and information require- fessional. These foods are important resources healthcare
ments for food for special medical purposes professionals (HCPs) use to feed patients with specific
diagnosed diseases, disorders or medical conditions that
□ Regulation (EU) No. 609/2013 of the European make it impossible or very difficult for patients to satisfy
Parliament and of the Council of 12 June 2013 on their nutritional needs through the consumption of other
food intended for infants and young children, foods. FSMPs can be either the only source of nourish-
food for special medical purposes, and total ment or part of the diet for acute or chronic conditions,
diet replacement for weight control and repeal- from short-term to sometimes longer-term use or for the
ing Council Directive 92/52/EEC, Commission remainder of a patient’s life.
Directives 96/8/EC, 1999/21/EC, 2006/125/ FSMPs are used under medical supervision and
EC and 2006/141/EC, Directive 2009/39/EC of in quantities recommended by healthcare profession-
the European Parliament and of the Council and als, forming an integral part of patient management.
Commission Regulations (EC) No. 41/2009 and Their recognition as a specific food category reflects
(EC) No. 953/2009 the importance of nutritional interventions to improve
patient outcomes. Relevant FSMP uses include those

Chapter 39
associated with disease-related malnutrition (e.g., Directive 2009/39/EC (PARNUTs)12 and abolishing
stroke, cancer), infants suffering from severe cow’s milk the concept of “dietetic foods.”
allergy and patients with Crohn’s disease or rare inborn The FSG Regulation is intended to strengthen
metabolic disorders (e.g., Phenylketonuria (PKU), provisions on foods for vulnerable population groups
Maple Syrup Urine Disease (MSUD)).6 needing particular protection, e.g., infants and children
FSMPs are used across all healthcare settings, up to the age of three, overweight or obese people and
including the community, care homes and hospitals, people with specific medical conditions. Article 1 lays
demonstrating that enteral nutrition, by maintaining down the categories of food included within the scope:
adequate nutritional intake and status, can provide • infant and follow-on formulae
clinical benefits and lower healthcare costs by reducing • processed cereal-based foods and other baby
hospital stays and maintaining patients’ independence foods
longer.7,8 Similar results were shown for oral nutrition • food for special medical purposes
supplements (ONS) in various settings.9-11 • total diet replacement for weight control
FSMPs are for enteral usage (including oral nutri-
tional supplementation) and regulated as foods. This A number of FSG Regulation articles are specifically
should not be confused with “parenteral nutrition” (i.e., relevant to FSMPs:
infusion of nutrients directly into the blood circulation), • Article 2(2)(g) contains the legal FSMP
which is regulated under medicinal law. definition.
• Article 3 permits the Commission to make
EU FSMP Regulatory Framework interpretation decisions as to whether a prod-
General Principles uct falls within the FSG Regulation’s scope and,
FSMPs are regulated as a specific food category in the if so, in which category it belongs.
EU. As such, they are subject to all relevant EU food • Article 9 sets down general compositional and
law, including food safety rules such as good manufac- information requirements applicable to all
turing practice (GMP) and hygiene, contaminants in FSG categories. It also clarifies the labelling,
foods, use of food ingredients, additives, novel foods presentation and advertising rules, particularly
and packaging materials. They also are governed by with reference to properties of preventing,
general rules on labelling and communication. They treating or curing a human disease and shall
must be safe and effective for their intended use, as not prevent dissemination of useful informa-
demonstrated by generally accepted scientific data, and tion and recommendations intended for HCPs
communication must be truthful and not misleading. (persons with qualifications in medicine, phar-
The specific framework and delegated regulations macy, nutrition or other HCPs responsible for
that govern FSMPs contain mandatory provisions for maternal care and childcare).
the category on composition, labelling, communication • Article 11 sets down the areas in which the
and notification that apply in addition to general food Commission should adopt specific rules for
law. There also are provisions that make derogations to food category composition and labelling
the general food law, but where there is no specific der- within the regulation’s scope.
ogation, general food law prevails. • Articles 15 and 16 include the requirements
for a Union list of substances that may be
Framework Regulation on Food for Specific Groups added to foods for specific groups. The annex
contains the Union list of permitted sub-
(FSG)
stances, which includes sources of vitamins,
Some individuals or population groups require specific
minerals, amino acids, carnitine and taurine,
nutritional support due to their physiological condi-
nucleotides, choline and inositol.
tions or the specific diseases from which they suffer.
For such individuals, the EU established a harmonised
legal dietetic foods framework in the 1980s, cover- Specific FSMP Regulation
ing the so-called foods for particular nutritional uses FSMPs are foodstuffs specifically developed for the
(PARNUTs). Regulation (EU) No. 609/2013 on food dietary management of patients who have specific
intended for infants and young children, food for special nutritional needs. They are intended to be used under
medical purposes and total diet replacement for weight medical supervision for the exclusive or partial feeding
control, known as the Foods for Specific Groups (FSG) of people whose nutritional requirements cannot be met
Regulation, revised this framework in 2013, repealing by normal foods.
In 2016, the European Commission adopted a leg-
islative text via a delegated act (i.e., legislative process

Food for Special Medical Purposes
not involving comitology), covering the specific com- disease management. However, it has been recognized
positional and information requirements for FSMP. that, although harmonized, this definition may be inter-
This Regulation (EU) No. 2016/128, closely reflects the preted differently across the EU Member States, and
rules previously included in FSMP Directive 1999/21/ interpretative differences would impact the EU internal
EC,13 with some additional provisions and adaptations market’s functioning.
to reflect the change in the FSG framework legislation
and the abolition of the concept of “dietetic food.” Commission Notice on the Classification of Food for
The EU FSMP Regulation—a result of expert Special Medical Purposes
input from 28 Member States—provides a well-de- The European Commission issued a guidance docu-
fined framework, including compositional criteria, ment aimed at food business operators (FBOs) and
specific and relevant provisions on labelling, infor- Member State national authorities, with the objective of
mation and monitoring products on the market. This striking a balance between ensuring the boundaries of
framework allows the development and assessment the FSMP category are interpreted narrowly within the
of products positioned as FSMPs, recognizing the context of the total food and food supplement market
flexibility required to accommodate the diversity of while recognizing that nutritional science will continue
medical conditions for which FSMPs are and should to develop for use in the management of other disease
be used. FSMPs are not subject to premarket approval. areas.15 During development of the guidance and con-
The legislation allows flexibility in formulating such sultation with stakeholders, a number of key principles
products based on sound medical and nutritional were established, critical to the concept of FSMP:
principles, supported by generally accepted scientific • All elements of the FSMP definition must be
data (e.g., European Society for Clinical Nutrition taken into consideration, and no one element
and Metabolism (ESPEN) guidelines),14 to meet their should be considered in isolation to include or
intended use for the dietary management of diseases, exclude a product from the categories of spe-
disorders or medical conditions. cial processing and/or formulation.
Additional elements within the FSMP Regulation • Use in partial or exclusive feeding of patients
include rules for pesticides and communication on and under medical supervision (i.e., recom-
FSMPs intended for infants and young children, com- mendation of a qualified HCP) for the dietary
parable to those already in place for infant formula and management of patients, who as a result of
follow-on formula; a prohibition on the use of nutrition their disease, disorder or medical condition,
and health claims for FSMPs, given such products are have medically-determined nutrient require-
not intended for the ‘normal’ healthy population; and ments, and those medically determined
some specific rules and derogations applicable to nutri- nutrient requirements cannot be met by modi-
tion information provided for FSMP. fication of the normal diet alone.
• The measure of whether it is possible to achieve
Definition the required nutritional intake by modification
FSMPs are defined in the framework Regulation (EU) of the normal diet must be considered in the
No. 609/2013: context of the patient and the challenges of
“FSMP means food specially processed or formu- their disease, disorder or medical condition.
lated and intended for the dietary management of • FSMP also can offer nutritional and clinical
patients, including infants, to be used under med- advantages to patients over and above mod-
ical supervision; it is intended for the exclusive or ification of normal diet and this too must be
partial feeding of patients with a limited, impaired taken into account. It can be impossible for
or disturbed capacity to take, digest, absorb, metab- some patients to meet their requirements
olize or excrete ordinary food or certain nutrients via normal foods, but it also can be unsafe,
contained therein, or metabolites, or with other impractical or disadvantageous to modify
medically-determined nutrient requirements, patients’ diets to meet the nutritional demands
whose dietary management cannot be achieved by of their disease or medical condition, and
modification of the normal diet alone.” FSMP provide a pragmatic solution.
This definition is broad to encompass the wide variety “Article 3” Interpretation Decisions and EFSA
of FSMP products necessary to meet the needs of the Scientific and Technical Guidance
many diseases, disorders and medical conditions in A provision in the FSG Regulation (Article 3) permits
which their use can benefit patients and to allow inno- the Commission to make a determination on whether
vation in areas where nutrition will play a future role in

Chapter 39
a food falls within the scope of FSG or one of its cat- to the disease, disorder or condition, which
egories. Article 3 is intended for exceptional use and cannot be reasonably or realistically satisfied by
is not intended to replace the general rules at national modifying the normal diet
level, which permit FBOs to market foods on the basis • the product’s specific role in the dietary man-
of their own determination as to compliance with the agement of the disease, disorder or intended
FSMP definition and leaves national authorities with condition, particularly the extent to which
the general responsibility for enforcing food law. the specific product is different from or more
When there is uncertainty whether a product is suitable than non-FSMP foods (i.e., including
considered an FSMP, a national competent authority food supplements and fortified foods), tak-
may ask the European Commission to interpret and ing into account the product’s composition,
decide, by means of implementing acts as defined in manufacturing process, physical form, mode
Regulation (EU) 609/2013 Article 3, to which specific of administration, pattern of consumption,
category a given product belongs to ensure uniform intended use and the proposed instructions of
implementation across the EU. In this context, follow- use
ing a request from the European Commission, in 2015, • the extent to which the use of the specific food
the European Food Safety Authority (EFSA) Panel product is necessary or more practical or safer
on Dietetic products, Nutrition and Allergies (NDA) than the exclusive use of foodstuffs that are
provided scientific and technical guidance on FSMPs.16 not FSMPs, and/or has a nutritional or clini-
It presents a common format and outlines the data that cal advantage for the patient, and the reasons
could be included in the dossier as well as the key issues why it needs to be administered under medical
the dossier should address to assess the extent to which supervision
a food product notified as an FSMP falls under the • any potential restrictions of use
regulation’s scope, based on its proposed use.
The EU Commission may ask EFSA to address Categories and Flexibility in Compositional
whether a specific food product and disease, disorder Requirements
or medical condition are characterized sufficiently for An FSMP’s composition may differ substantially
classification as an FSMP. It considers the impos- depending on its intended use, among other things,
sibility or difficulty of taking, digesting, absorbing, the specific disease, disorder or medical condition it is
metabolizing or excreting ordinary foodstuffs or certain intended to manage, patient age and where patients
nutrients, and specific medically determined nutrient receive healthcare support. Because of FSMPs’ wide
requirements that cannot be satisfied reasonably or diversity, the rapidly evolving scientific knowledge on
realistically by modifying the normal diet, i.e., if it is which they are based, and the need to ensure adequate
impossible, impractical or unsafe for patients to con- flexibility to develop innovative products, it is not
sume exclusively foodstuffs (including fortified foods appropriate to lay down detailed compositional rules for
and food supplements) that are not FSMPs, or whether such products. However, it is important to set principles
this would result in patients suffering a nutritional or and requirements specific to them to ensure they are
clinical disadvantage. The guidance will be updated, as safe, beneficial and effective for the patients for whom
appropriate, as additional experience is gained. they are intended, on the basis of generally accepted
EFSA’s scientific and technical guidance aims to scientific data. To this end, minimum and maximum
address key questions, which the Commission may need values are set for micronutrients (vitamins and miner-
to take into consideration in order to take decisions als), but there is provision for deviations based on the
under Article 3: product’s intended use.
• whether the specific food product is sufficiently Article 2(2) states that FSMPs’ formulation shall
characterized be based on sound medical and nutritional principles
• the extent to which the disease/disorder/med- and shall be safe, beneficial and effective in meeting
ical condition for which the specific product is the specific nutritional requirements of the persons for
intended is sufficiently characterized whom they are intended, as demonstrated by generally
• extent to which patients suffering from the accepted scientific data. This means an FSMP’s com-
specific disease, disorder or condition are position/formulation should be supported by a strong
unable to or have difficulty taking, digesting, nutritional and medical rationale, but specific clinical
absorbing, metabolising or excreting ordinary trials may not always be required for FSMPs if there are
foodstuffs, or certain nutrients contained adequate data already available in the public domain to
therein or metabolites, or have specific medi- support their composition and use.
cally determined nutrient requirements, typical

FSMPs can be classified in different categories intended use. FSMPs in this category include
depending on whether their composition is standard or products for rare inborn errors of metabolism
adapted specifically for a disease, disorder or medical (e.g., amino acid supplements for PKU) and
condition and whether they constitute the patient’s thickeners for patients with certain neuro-
sole nourishment source. Regulation (EU) 2016/128 logical disorders (e.g., stroke) suffering from
differentiates FSMPs into three categories, depending dysphagia.
on their intended use. For both categories (b) and (c),
there is flexibility to deviate from the compositional FSMPs developed to satisfy the nutritional require-
criteria laid down in Annex I, based on the product’s ments of infants (0–12 months) shall comply with the
specific intended use—which may be either the disease, provisions relating to levels of other nutrients, i.e., mac-
disorder or medical condition for which the product is ronutrients, applicable to infant formula and follow-on
formulated, or the way in which it will be used within formula (Regulation (EU) 2016/127),17 provided they
the patient’s diet. are in line with the intended use. For other FSMPs
The categories are described below. The corre- intended for patients more than one year of age, there
sponding compositional criteria are contained in Annex are no compositional criteria for macronutrients due to
I of Regulation (EU) No. 2016/128 Annex Part A these products’ diverse nature and use.
includes compositional criteria for FSMPs intended
for infants up to 12 months of age, and Part B for 1–10 Food Information (Labelling), Nutrition
years of age and adults. Information
a. Nutritionally complete food with a standard Unless otherwise specified by a specific derogation within
nutrient formulation that, used in accordance Regulation (EU) 2016/128, an FSMP shall comply with
with the manufacturer’s instructions, may con- all mandatory aspects of Regulation (EU) 1169/2011
stitute the sole source of nourishment for the on food information to consumers.18 Given the specific
persons for whom it is intended. These “stan- intended use, there also are some very distinct additional
dard” FSMP products are designed for use by a mandatory particulars that labels shall include:
wide variety of patients who are malnourished a. a statement that the product must be used
or at risk while unable to consume adequate under medical supervision
conventional foods to meet their nutrient b. a statement whether the product is suitable for
requirements due to their disease or medical use as the sole source of nourishment
condition. Products in this category should c. a statement that the product is intended for a
comply with the minimum and maximum lev- specific age group, as appropriate
els for vitamins and minerals given in Annex I d. where appropriate, a statement that the prod-
of the regulation. uct poses a health hazard when consumed by
b. Nutritionally complete food with a nutri- persons who do not have the disease, disorder
ent-adapted formulation specific for a disease, or medical condition for which the product is
disorder or medical condition that, used in intended
accordance with the manufacturer’s instruc- e. the statement ‘For the dietary management
tions, may constitute the sole source of of ...’ where the blank shall be filled in with
nourishment for the persons for whom it is the disease, disorder or medical condition for
intended. These FSMP products are suitable which the product is intended
for use by patients with specific disease-re- f. where appropriate, a statement concerning
lated nutritional needs; hence, there may be adequate precautions and contraindications
minimum and maximum compositional level g. a description of the properties and/or charac-
deviations from (Annex I) with scientific teristics making the product useful in relation
justification. to the disease, disorder or medical condition,
c. Nutritionally incomplete food with a standard for the ‘dietary management’ of which the
or nutrient-adapted formulation specific for product is intended, particularly, as the case
a disease, disorder or medical condition that may be, relating to the special processing and
is not suitable to be used as the sole source of formulation, the nutrients that have been
nourishment. FSMP products in this cate- increased, reduced, eliminated or otherwise
gory are diverse and should comply with the modified and the rationale for the product’s
maximum compositional levels (Annex I) use
unless modifications for one or more of these
nutrients are necessitated by the product’s

Chapter 39
h. where appropriate, a warning that the product on formula. Since FSMPs are intended to be used under
is not for parenteral use medical supervision, the necessity to communicate to
i. instructions for appropriate product prepa- healthcare professionals is recognized, allowing them to
ration, use and storage after opening the assess different products’ suitability for their intended
container, as appropriate use as well as provide appropriate information about the
critical use and compositional information to patients
Whereas (3) of Regulation (EU) No. 2016/128 clar- and care providers. This is clarified in Article 8(4) on
ifies “medical supervision” may be with the assistance advertising, where it states that restrictions shall not
of other competent health professionals (e.g., with prevent the dissemination of information exclusively
qualifications in medicine, dietetics, nutrition, nursing, intended for healthcare professionals.
pharmacy).
Nutrition information is mandatory for FSMPs Notification
and should follow the general rules laid down in A premarket authorization is not required before plac-
Regulation (EU) No. 1169/2011 for all foods, but ing an FSMP on the market. The FBO must notify the
there are some additional provisions within Article 6 of competent authority of each Member State where the
Regulation (EU) No. 2016/128 that take into account product is being marketed, by sending a model of the
the need for relevant information for the healthcare label used and any other information they may reason-
professional or patient using the product. ably request to establish compliance with the regulation,
• It is mandatory to declare the amount of each unless a Member State exempts the FBO from that
vitamin and mineral listed in Annex I where it obligation under a national system that guarantees an
is present in the product. efficient official monitoring of the product concerned
• Additional components of protein, carbohy- (Regulation (EU) No. 2016/128, Article 9).
drate, fat and other nutrients may be added to
the list of nutrients declared where they are Single-Use Plastics Directive
necessary for the appropriate intended use. The recent EU directive on the reduction of the impact
• The amount of nutrients does not need to of certain plastic products on the environment attempts
be expressed as a percentage of the reference to prevent and reduce their impact on the environment.
intakes. It should be noted that single-use plastic beverage con-
tainers for the administration of FSMP in liquid form
Communication, Claims are exempted from product recycling and collection
Nutrition and health claims will no longer be per- requirements.20
mitted on FSMPs (Article 7 of Regulation (EU) No.
2016/128). However, Whereas (14) clarifies that all Market Access—Health Economics—
information on the product’s properties and charac-
teristics (e.g., any special processing and formulation, Reimbursement
nutritional composition and rationale of the product’s FSMPs are consumed across all healthcare settings,
use that make it useful for its intended purpose) are such as hospitals, clinics and nursing homes and at
mandatory particulars (Article 5(g)) and, therefore, is home. They have been shown to result in lower health-
not considered as nutrition and health claims within the care costs by reducing hospital stays and maintaining a
meaning of Regulation (EC) 1924/2006.19 patient’s independence longer.21,22 While EU legislation
The FSG Regulation introduces a provision to lay on FSMP composition and labelling is harmonised
down rules for labelling, presentation, advertising and across the Member States, there is no harmonisation
promotional and commercial practices for FSMPs of healthcare systems. Hence, reimbursement is based
intended for infants (0–12 months), similar to those on national, regional or local health organisations and
applicable to infant formula and follow-on formula. budgets. Even within countries, rules could be applied
Article 8 of Regulation (EU) No. 2016/128 includes differently by regions or provinces. The criteria for
these specific provisions on labelling, presentation and FSMP reimbursement approval vary according to local
advertising of FSMPs intended for infants. It states that rules and may be based on composition or provision of
any mandatory information intended for the consumer scientific rationale and/or health economic evidence.
must appear in a language that is easily understood, and In most EU Member States, many products
that labelling, presentation and advertising of FSMPs notified as FSMPs are reimbursable as part of local
intended for infants shall not include pictures of infants healthcare systems (public or private payers). This
and shall be designed to enable consumers to make a typically includes nutritionally complete FSMPs that
clear distinction between FSMPs and infant and follow may serve as sole nutrition sources. Reimbursement

levels also may be based on specific compositional 11. Elia M, Normand C, Norman K and Laviano A. A Systematic
criteria (e.g., protein, energy level, i.e., Kcal/KJ, fibre) Review of the Cost and Cost Effectiveness of Using Standard
Oral Nutritional Supplements in the Hospital Setting. Clinical
per specific categories (e.g., infants/adults, hydrolysed/ Nutrition. 35 (2016) 370–380.
non-hydrolysed proteins) or according to national 12. Directive 2009/39/EC of the European parliament and of
guidances.23,24 Apart from products designed for dis- the Council of 6 May 2009 on foodstuffs intended for partic-
ease-related malnutrition, reimbursement also may be ular nutritional uses (recast). Official Journal of the European
Union 20.5.2009 L124 pp 21– 28. EUR-Lex website. http://
possible for specific FSMPs that manage diseases or eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=O-
medical disorders such as: J:L:2009:124:0021:0029:en:PDF. Accessed 27 April 2020.
• infant allergy to cow’s milk proteins or multi- 13. Commission Directive 1999/21/EC of 25 March 1999 on
ple food allergies dietary foods for special medical purposes. EUR-Lex website.
http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=CON-
• malabsorption syndromes (e.g., short bowel SLEG:1999L0021:20070119:EN:PDF. 27 April 2020.
syndrome) 14. European Society for Clinical Nutrition and Metabolism
• hereditary inborn errors of metabolism of car- (ESPEN). Guidelines and Position Papers. ESPEN website.
bohydrate, fat or protein (e.g., PKU) https://www.espen.org/guidelines-home/espen-guidelines.
• epilepsy (ketogenic diet formulas) 15. Commission Notice on the Classification of Food for Special
Medical Purposes (2017/C 401/01), Official Journal of
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aged foods for special dietary uses. CODEX STAN 146-1985 specific compositional and information requirements for infant
(updated 2009). FAO website. http://www.fao.org/docrep/005/ formula and follow-on formula as regards requirements on
Y2770E/y2770e04.htm. Accessed 27 April 2020. information relating to infant and young child feeding. EUR-
4. CODEX Standard for the labelling of and claims for pre- Lex website. http://eur-lex.europa.eu/legal-content/EN/TXT/
packaged foods for special medical purposes. CODEX STAN PDF/?uri=CELEX:32016R0127. Accessed 27 April 2020.
180-1991. Global FoodMate website. http://files.foodmate. 18. Regulation (EU) No. 1169/2011 of the European
com/2013/files_1081.html. Accessed 27 April 2020. Parliament and of the Council of 25 October 2011 on the
5. Ruthsatz M and Morck T. “Medical Food/Food for Special provision of food information to consumers. EUR-Lex
Medical Purposes: Global Regulatory Challenges and website. http://eur-lex.europa.eu/legal-content/EN/TXT/
Opportunities.” Regulatory Focus. August 2016. Regulatory PDF/?uri=CELEX:32011R1169. Accessed 27 April 2020.
Affairs Professionals Society. 19. Regulation (EC) No. 1924/2006 of the European Parliament
6. Patient Perspectives on Nutrition. By EPF, EGAN and and of the Council on nutrition and health claims made on
ENHA (May 2013). European Patients’ Forum website. foods. EUR-Lex websitehttps://eur-lex.europa.eu/legal-content/
http://www.eu-patient.eu/contentassets/3998bf037bca4ddc- en/ALL/?uri=CELEX%3A32006R1924. Accessed 27 April
890b934a3d1b460d/patient_perspectives_on_nutrition_-1.pdf. 2020.
Accessed 27 April 2020. 20. Directive (EU) 2019/904 of The European Parliament and
7. National Alliance for Infusion Therapy and the American of the Council of 5 June 2019 on the reduction of the impact
Society for Parenteral and Enteral Nutrition Public Policy of certain plastic products on the environment. EUR-Lex
Committee and Board of Directors. “Advocacy and Public website. https://eur-lex.europa.eu/legal-content/EN/TXT/
Policy Special Report: Disease-Related Malnutrition and PDF/?uri=CELEX:32019L0904. Accessed 27 April 2020.
Enteral Nutrition Therapy: A Significant Problem with a Cost- 21. Clinical and Cost-Effective Prescribing of Oral Nutritional
Effective Solution.” Nutr Clin Pract. NCP website. http://ncp. Supplements for Adults in the Community (2011).
sagepub.com/content/25/5/548.full.pdf. Accessed 27 April 2020. NICE website. https://www.nice.org.uk/sharedlearning/
8. Cangelosi MJ, Auerbach HR and Cohen JT. Brief Review: clinical-and-cost-effective-prescribing-of-oral-nutritional-sup-
A Clinical and Economical Evaluation of Enteral Nutrition plements-for-adults-in-the-community. Accessed 27 April
(2011). Current Medical Research and Opinion. Vol 27, 2, 2020.
413-422. 22. Op cit 10.
9. Medical Nutrition International Industry (MNI). Oral 23. Op cit 11.
Nutritional Supplements to Tackle Malnutrition. A Summary 24. Nutrition support in adults overview (Updated 28 January
of the Evidence Base. 3rd version, 2012. MNI website. https:// 2016). NICE website. http://pathways.nice.org.uk/pathways/
medicalnutritionindustry.com/files/user_upload/documents/ nutrition-support-in-adults. Accessed 27 April 2020.
ONS_2012/Dossier2012FINAL2012-09-04.pdf. Accessed 27
April 2020. Disclaimer: This chapter reflects the personal opinion and experience of the
10. Elia M, Normand C, Laviano A and Norman K. A Systematic author. By no means can it be construed as an official position by any orga-
Review of the Cost and Cost Effectiveness of Using Standard nization with which the author is affiliated.
Oral Nutritional Supplements in Community and Care Home
Settings. Clinical Nutrition. 35 (2016) 125-137.

Chapter 39

Chapter 40
Products Manufactured From

Human Blood or Plasma
OBJECTIVES as regards certain technical requirements for

blood and blood plasma, amended by Directive
□ Learn why blood and plasma products are nec- 2014/110/EU3
essary for therapeutic treatments
□ Commission Directive 2005/61/EC of 30
□ Understand the requirements for human September 2005 implementing Directive
medicinal products derived from human blood 2002/98/EC of the European Parliament and of
or plasma the Council as regards traceability requirements
and notification of serious adverse reactions
□ Understand how human blood and plasma
and events4
products are classified and regulated
□ Commission Directive 2005/62/EC of 30
□ Get an overview of which accessory products
September 2005 implementing Directive
are on the market
2002/98/EC of the European Parliament and of
the Council as regards Community standards
and specifications relating to a quality system
DIRECTIVES, REGULATIONS AND GUIDELINES for blood establishments, amended by Directive
COVERED IN THIS CHAPTER 2016/12145
□ Commission Directive 2001/83/EC of the □ Regulation (EEC) No. 726/2004 of the European
European Parliament and of the Council of 6 Parliament and of the Council of 31 March 2004
November 2001 on the Community code relating laying down Union procedures for the authori-
to medicinal products for human use, amended sation and supervision of medicinal products
by Directives 2002/98/EC, 2003/63/EC, for human and veterinary use and establishing
2004/24/EC and 2004/27/EC1 a European Medicines Agency6
□ Commission Directive 2002/98/EC of the □ Regulation (EC) No. 141/2000 of the European
European Parliament and of the Council of 27 Parliament and of the Council of 16 December
January 2003 setting standards of quality and 1999 on orphan medicinal products7
safety for the collection, testing, processing,
storage and distribution of human blood and □ Guideline on plasma-derived medicinal prod-
blood components and amending Directive ucts (EMA/CHMP/BWP/706271/2010)8
2001/83/EC2
□ Guideline on investigation of manufacturing
□ Commission Directive 2004/33/EC of 22 March processes for plasma-derived medicinal prod-
2004 implementing Directive 2002/98/EC of ucts with regard to variant Creutzfeldt-Jakob
the European Parliament and of the Council disease risk (CPMP/BWP/CPMP/5136/03)9

Chapter 40
□ Guideline on the replacement of rabbit pyro- Plasma-Derived Medicinal Products and

gen testing by an alternative test for plasma Their Indications
derived medicinal products (EMEA/CHMP/ Human plasma contains many proteins that, following
BWP/452081/2007)10 extraction, purification and formulation into medicinal
products, are of great medical importance. Plasma-
□ Guideline on requirements for plasma master
derived products provide life-saving therapies, but the
file certification (CPMP/BWP/4663/03)11
quantity of plasma for fractionation is limited by the
□ Note for Guidance on virus validation studies number of donors. Therefore, the exchange of interme-
by CHMP’s predecessor, the Committee for diates between manufacturers or the use of a variant
Proprietary Medicinal Products (CPMP) (CPMP/ manufacturing process may be possible to assure the
BWP/268/95)12 best use of blood/plasma donations.
Although the therapeutic use of blood transfu-
□ CHMP position statement on CJD and plasma- sion goes back to the beginning of the 20th century, it
and urine-derived medicinal products (EMA/ was not until the 1940s that the technique of plasma
CHMP/BWP/303353/2010 Rev. 3)13 fractionation enabled the widespread use of medicinal
products extracted from human plasma.
□ Note for guidance on minimising the risk of Improvements in protein purification and molec-
transmitting animal spongiform encephalopa- ular separation technology have made available a
thy agents via human and veterinary medicinal wide variety of products of unquestioned therapeutic
products (EMA/410/01 Rev. 3)14 value, covering a broad range of medical applications.
However, the potential for viral transmission is well rec-
□ Guideline on Epidemiological Data on Blood
ognised, and because of the large number of donations
Transmissible Infections (EMA/CHMP/BWP/
that are pooled, a single contaminated batch of a plas-
548524/2008 Rev. 1)15
ma-derived product, with the contamination possibly
□ Guideline on the scientific data requirements originating from a single donation, can transmit viral
for a plasma master file (EMEA/CHMP/BWP/ disease to a large number of recipients.
3794/03 Rev.1)16 The quality and safety of plasma-derived products
are based on qualified measures in two major areas:
□ Regulation (EU) No. 2017/745 of the European • starting materials’ control: includes donor
Parliament and of the Council of 5 April 2017 selection, individual plasma unit testing,
on medical devices and amending Directive plasma quarantine periods and plasma pool
2001/83/EC and Regulation (EC) No. 178/2002 testing for viral markers
and Regulation (EC) No. 1223/2009 and repeal- • manufacturing control: emphasises validated
ing Council Directives 90/385/EEC and 93/42/ and controlled protein purification, including
EEC17 the manufacturing process step choice to inac-
tivate or remove microbial contaminants
What Is Plasma? Both measures ensure the safety of therapies derived

Plasma is the fluid portion of blood that functions as a from human plasma.
carrier for red and white blood cells, proteins and met- Plasma-derived medicinal products can be divided
abolic products. Blood is 55% plasma. Plasma remains into seven therapeutic groups:
after separation of all cells from blood when clotting is 1. coagulation factors
prevented by an anticoagulant. Plasma contains 7–8% 2. immunoglobulins
proteins, primarily albumin, immunoglobulins and 3. albumin
fibrinogen. 4. inhibitors (antiproteases)
Plasma used to manufacture plasma-derived medic- 5. fibrin sealants
inal products is obtained from healthy donors—mainly 6. fibrinogen
by plasmapheresis (source plasma)—in specialised plas- 7. thrombin
mapheresis centres. In addition, plasma derived from
whole blood donations (recovered plasma) is available as Life-saving treatments for conditions such as Factor
a remnant of transfusion product production. VIII deficiency and immunoglobulin deficiency are
among the best-known uses of plasma-derived products.
Table 40-1 summarises the seven different groups and
their fields of indications.

Products Manufactured From Human Blood or Plasma
Table 40-1. Medicinal Products Derived From Human Plasma and Their Indications
Medicinal Products Derived From Indications (Examples)

Human Plasma
Coagulation Prothrombin complex concentrate Prophylaxis and therapy of haemorrhages caused by a congenital or
Factors (Coagulation Factors II, VII, IX, X) acquired deficiency
Coagulation Factor VII Prophylaxis and treatment of bleeding in patients with antibodies against
Factor XIII and Factor IX
Coagulation Factor VIII • Prophylaxis and treatment of bleeding in haemophilia A (congenital
Factor VIII deficiency)
• Acquired Factor VIII deficiency
von Willebrand Factor Prophylaxis and treatment of bleeding in von Willebrand disease
Coagulation Factor IX • Prophylaxis and treatment of bleeding in haemophilia B (congenital
Factor IX deficiency)
• Acquired Factor IX deficiency
Coagulation Factor XI Treatment of bleeding in congenital deficiency
Coagulation Factor XIII • Congenital deficiency
• Haemorrhagic diatheses caused by acquired Factor XIII deficiency
Immunoglobulins Nonspecific normal • Substitution in primary and secondary antibody deficiency
immunoglobulins (i.m./s.c.) • Prophylaxis (passive immunisation) of hepatitis A and measles
• Therapy of radiogenic mucositis
Nonspecific normal • Substitution and replacement therapy in primary and secondary
immunoglobulins (i.v.) antibody deficient disorders such as agammaglobulinaemia and
hypogammaglobulinaemia
• Secondary immunodeficiency syndrome due to underlying diseases
(e.g., chronic lymphocytic leukaemia)
• Idiopathic thrombocytopenic purpura (ITP)
Anti-D immunoglobulin Treatment and prevention of haemolytic disease of foetus and newborn
due to Rh-incompatible blood transfusions
Cytomegalovirus immunoglobulin Passive immunisation
Hepatitis A immunoglobulin Passive immunisation
Hepatitis B immunoglobulin Passive immunisation
Measles immunoglobulin Passive immunisation
Rabies immunoglobulin Passive immunisation
Rubella immunoglobulin Passive immunisation
Tetanus immunoglobulin Passive immunisation
Tick-borne encephalitis Passive immunisation
immunoglobulin
Varicella-zoster immunoglobulin Passive immunisation
Critical Care Albumin solutions 5%, 20%, 25% Restoration and maintenance of blood volume in volume deficiency where
Products use of a colloid is inappropriate
Fibrin Sealants Fibrinogen concentrates with • Tissue adhesion
various combinations of thrombin, • Suture support
Factor XIII and inhibitors • Homeostasis
• Wound care
• Sealing of body cavities and subarachnoid space
Inhibitors Antithrombin III Congenital (prophylaxis and prevention of progression of deep vein
thrombosis) and acquired deficiency of Antithrombin III
C1-Inactivator (C1 esterase Congenital angio-edema (HAE) caused by deficiency, absence or defective
inhibitor) synthesis of C1 esterase inhibitor
Alpha-1-Antitrypsin Treatment of emphysema caused by genetic deficiency
Others Fibrinogen Treatment of bleeding:
• Replacement therapy
• Complementary therapy in cases of acquired hypofibrinogenaemia
Thrombin Wound care, sealing of body vessels and cavities

Chapter 40
Regulatory Environment Virus and Chikungunya. This decision was based on the
Political Institutions adequacy of virus inactivation and removal steps in the
The European Commission ratifies Committee for manufacture of plasma-derived medicinal products.
Medicinal Products for Human Use (CHMP) opin-
ions on all pharmaceutical products. The Commission European Directorate for the Quality of Medicines
publishes the legal framework for licensing pharma- and Healthcare
ceuticals—the Rules Governing Medicinal Products in the European Pharmacopoeia
European Union.18 The publishing organ is the Official The European Pharmacopoeia (Ph. Eur.) publishes
Journal of the European Union. pharmacopoeial monographs, which are quality spec-
As of 1 January 2015, the Directorate-General for ifications for pharmaceutical preparations and their
Health and Food Safety (DG SANTE) is responsible ingredients. Monograph 0853 on human plasma for
for public health, food safety and consumer protection, fractionation is particularly important to manufacturers;
including the control and framework for blood and it describes general collection and storage conditions
plasma collection. Prior to 2015, the control of blood and serves as the basis for all other related monographs
products was the responsibility of the Directorate- on plasma-derived medicinal products.
General for Health and Consumers (DG SANCO). Ph. Eur. provides reference standards for tests
described in the monographs. Coagulation factor stan-
CHMP dards and nucleic acid amplification technology (NAT)
CHMP is responsible for scientific guidelines for mar- virus testing standards are important in plasma product
keting applications for all pharmaceuticals, including testing.
plasma-derived medicinal products. Draft and final
guidelines released by European Medicines Agency Official Control Authority Batch Release
(EMA) committees for consultation are available on The European Directorate for the Quality of Medicines
EMA’s website. and Healthcare (EDQM) publishes regulatory pro-
CHMP has established numerous working par- cedures for official control authority batch release
ties comprised of experts to provide recommendations (OCABR) for medicinal products derived from human
relating to specific areas. Those with crucial impact blood or plasma. The European Commission and the
on plasma-derived medicinal products are the Blood Council of Europe decided on 26 May 1994 to create
Products Working Party (BPWP) and the Biologics a network of official medicines control laboratories
Working Party (BWP). (OMCLs).21 Independent from manufacturers, such
OMCLs support regulatory authorities in controlling
BPWP available medicinal products’ quality for human and
BPWP has been involved in the production of guide- veterinary use. Within the EU, OMCLs such as the
lines and reflection papers, including adopting several National Institute for Biological Standards and Control
Notes for Guidance (NfGs) on clinical investigations in the UK are nominated by responsible national
of blood products. In addition, BPWP issues a core authorities for evaluating medicines’ quality control in
summary of product characteristics (SmPC), providing their countries. Each OMCL’s expertise may differ, and
common ground for several product characteristics in a manufacturer may use the OMCL of its choice.
the EU, e.g., Factor VII, Fibrinogen, Prothrombin com- Such laboratories are responsible for batch release
plex and von Willebrand Factor products. testing of plasma-derived medicinal products. If a
Member State’s competent authority informs the market-
BWP ing authorisation holder (MAH) its authorised human
BWP covers plasma-derived medicinal products, vac- biological medicinal product is subject to OCABR, sam-
cines and all biotechnology-derived medicinal products, ples of the batch to be released are sent to an OMCL
including gene therapy. A key manufacturing and within the EU/European Economic Area (EEA), which
quality control document for the plasma industry is issues an OCABR certificate to the MAH.22
Guideline on plasma-derived medicinal products EMA/
CHMP/BWP/706271/2010.19 Legal Basis
Recent BWP documents include a report on viral The legal basis for EU minimum standards for the
safety of plasma-derived and urine-derived medicinal prod- quality and safety of the starting material for plas-
ucts with respect to Zika virus,20 which concluded specific ma-derived medicinal products has been established
testing for the Zika virus in plasma donors for fraction- along with the pharmaceutical legislation, and specific
ation was not necessary, in line with current strategies provisions have been laid down in the pharmaceutical
for other viruses, such as West Nile Virus, Dengue

Directive 2001/83/EC. In this legislation, the option Medicinal products manufactured from human blood
of a centralised certification of Plasma Master File or plasma normally do not fall within the scope of the
(CPMP/BWP/4663/03) was established. annex to Council Regulation (EEC) No. 726/2004;
In 2003, the European Parliament and the Council thus, the use of the Centralised Procedure is not
adopted the overarching Directive 2002/98/EC Setting mandatory for such products, which more often are
standards of quality and safety for the collection, testing, regulated under Directive 2001/83/EC (as amended)
processing, storage and distribution of human blood and alone or by National Procedures.
blood components and amending Directive 2001/83/ If a medical condition does not affect more than
EC, also known as the Blood Directive. Thereby, from five in 10,000 people in the Community, it is possible
8 February 2005, the Blood Directive establishes the to apply for orphan medicinal product designation.
requirements for the collection and testing of human Plasma-derived products are eligible for designation as
blood and blood components whatever the intended orphan medicinal products under Regulation (EC) No.
purpose. In line with this Directive, technical Directives 141/2000 and Regulation (EC) No. 847/2000.
2004/33/EC, 2005/61/EC and 2005/62/EC have been
issued by the Commission. The Guide to the Preparation, Council of Europe Publications
Use and Quality Assurance of Blood Components from the Prior to Directive 2002/98/EC, standards for the
Council of Europe contains a compendium of measures collection and use of blood and its components were
designed to ensure the safety, efficacy and quality of described in publications from the Council of Europe.
blood components. Directive 2002/98/EC and its annexes establish the
Furthermore, it is a legal requirement that before minimum requirements at a legislative level, but two
an authorisation to market a plasma-derived medicinal publications provide additional detail.
product is granted, the manufacturer must demonstrate • Council Recommendation R (95) 15—Guide
batch-to batch consistency. In addition, the absence of to the preparation, use and quality assurance of
specific viral contaminants must be demonstrated to the blood components (19th edition, published June
extent the state of technology permits. 2017)
Ph. Eur. standards for plasma-derived medicinal • Council Recommendation 98/463/EC—Guide
products are provided in the monograph “Human on the Suitability of Blood and Plasma Donors
plasma for fractionation” and specific monographs for and the Screening of Donated Blood in the
plasma-derived medicinal products. European Community
Whereas the free movement of goods is applied
for medicinal products in general, Member States General Documents and Guidelines
are allowed to apply more stringent requirements for Guidelines issued by Ph. Eur. and the International
plasma-derived medicinal products. The Treaty on Council on Harmonisation (ICH) are not legally bind-
the Functioning of the EU (Title XIV, Art. 168 (4a)) ing. However, if an applicant chooses not to apply a
states that Member States cannot be prevented from guideline, that decision must be explained and appro-
maintaining or introducing more stringent protective priately justified. If the justification is not deemed
measures as regards standards of quality and safety of acceptable, the regulator may recommend the applicant
blood and blood derivatives. apply the guideline or a specific portion of it. Important
The competent authority may request that the examples of guidelines for plasma-derived medicinal
MAH submit samples from each bulk or batch of products include:
medicinal product for testing by a State laboratory • CHMP and its working groups
before being released to the market (Directive 2001/83/ o Plasma-derived medicinal products EMA/
EC Article 114; EC/EEA Official Control Authority CHMP/BWP/706271/201023 covers source
Batch Release). material, manufacture, quality control and
process validation studies, including virus
Registration Procedures inactivation/removal validation; refers to
There are four main EU authorisation routes for medic- Ph. Eur. monographs; and lists more guid-
inal products, including plasma-derived products: ance documents in the annex. It includes
1. National Procedure an explanatory note on albumin’s use as a
2. Mutual Recognition Procedure stabiliser (i.e., the shelf life of the albumin
3. Decentralised Procedure shall not expire earlier than the shelf life
4. Centralised Procedure of the stabilised medicinal product).

Chapter 40
o Investigation of manufacturing processes (renamed 3ab13a). Since July 1999, NAT for detecting
for plasma-derived medicinal products with HCV in plasma pools has been mandatory in the EU
regard to variant Creutzfeldt-Jakob disease (CHMP/BWP/390/97).24 Validation requirements for
risk CPMP/BWP/CPMP/5136/03 viral marker assays have been revised and are set out in
o Replacement of rabbit pyrogen testing CHMP/BWP/298388/05 (human immunodeficiency
by an alternative test for plasma derived virus) and 298390/2005 (hepatitis B surface antigen).
medicinal products EMEA/CHMP/ Some Member States conduct plasma pool testing
BWP/452081/2007 during batch release procedures. Appropriate samples of
o Requirements for plasma master file certi- starting material pools and intermediate plasma pools
fication CPMP/BWP/4663/03 must be provided to the OMCLs.
o core SmPCs released by BPWP
• EDQM Virus Safety Evaluation
o Monographs are issued by Ph. Eur. for Note for Guidance on virus validation studies by CHMP’s
plasma for fractionation and most plasma predecessor, the Committee for Proprietary Medicinal
products. Products (CPMP), CPMP/BWP/268/95, describes
o Control authority batch release procedures the design, contribution and interpretation of studies
necessitated by Directive 2001/83/EC validating virus inactivation and removal. For plas-
are described in a group of documents ma-derived products, the manufacturing process should
published by EDQM, including the include independent and validated inactivation and
EU Administrative Procedure for Official removal steps with a significant reduction factor.
Control Authority Batch Release (PA/PH/
OMCL (01/01/2020)) and the Procedure TSE Safety Evaluation
for Official Control Authority Batch Release A CHMP expert group has worked to assess the impact
of Centrally Authorised Immunological of transmissible spongiform encephalopathies (TSE),
Medicinal Products for Human Use and variant Creutzfeldt-Jakob Disease (CJD), on the safety
Medicinal Products Derived From Human evaluation for medicinal products derived from human
Blood and Plasma (PA/PH/OMCL plasma or human urine. Although cumulative epide-
(01/07/2010)). miological evidence and other considerations do not
o Several product-specific guidelines have support transmission of sporadic, familial or iatrogenic
recently been published, e.g., clotting fac- CJD by plasma-derived products, donor residence in a
tor concentrates, human albumin, human high-risk country such as the UK is recognised as a risk
immunoglobulin, protocol for approval factor to be taken into account with regard to donor
of plasma pools, Anthrax vaccine, BCG exclusion criteria. The following guidance documents
vaccine, etc. are available:
• CHMP position statement on CJD and
Sourcing and Manufacture Control plasma- and urine-derived medicinal products,
In general, sourcing and manufacturing control require- EMA/CHMP/BWP/303353/2010 Rev. 3
ments for medicinal products derived from human • Note for guidance on minimising the risk of trans-
blood or plasma are the same as those for other biolog- mitting animal spongiform encephalopathy agents
ical and biotechnology products, with some key focus via human and veterinary medicinal products,
areas. EMA/410/01 Rev. 3
Testing of Donations Marketing Authorisation Dossier

Directive 2002/98/EC and Ph. Eur. monograph 0853 In general, the marketing authorisation process for plas-
prescribe basic testing requirements for each blood and ma-derived medicinal products is the same as for other
plasma donations. For starting materials for medicinal pharmaceutical products. The current legally binding
products—namely plasma for fractionation—testing requirements for the EU MAA dossier content are
for hepatitis B (HBs-Ag), hepatitis C (anti-HCV) described in the Rules Governing Medicinal Products in the
and HIV 1 and 2 (anti-HIV 1.2) are the minimum European Union, Notice to Applicants, Volume 2B. Effective
requirements. 1 July 2003, all dossiers, whether for new submissions or
Plasma pool testing for HIV 1 and 2, hepatitis variations, are required to conform to the five-module
C virus (HCV) and hepatitis B virus (HBV) viral CTD structure released by ICH. The EU CTD format is
markers was introduced for medicinal product starting published in the Notice to Applicants, Volume 2B.
materials 1 November 1994 by Guidance III/5193/94

Dossier Contents extended by several EDQM documents. These are avail-

The MAA dossier table of contents originally was able for download on the EDQM website.25.
designed for pharmaceuticals in general and did not Labelled samples of each batch shall be delivered
take the specific needs for plasma product documenta- for testing to the OMCLs. Thereafter, OMCLs issue
tion into account. The table of contents was integrated an EU batch-release certificate valid in all EU Member
into the new ICH CTD dossier, but still does not States.
match the needs of plasma products fully. Module
3.2.S.2.3 requires extended information on blood or Postmarket Requirements: Renewal and
plasma sourcing. Pharmacovigilance
Licenses for all medicinal products, including plas-
The Plasma Master File ma-derived products, approved through the Centralised
Information on plasma starting material collection Procedure, Mutual Recognition Procedure or
and control must be documented as either part of the Decentralised Procedure must be renewed after the first
dossier or, preferably, as a plasma master file (PMF). five years. Thereafter, the marketing authorisation usu-
The data requirements are outlined in the Guideline ally is unlimited.
on the Scientific Data Requirements for a Plasma Master Licensed medicinal products’ drug safety sur-
File (CHMP/BWP/3794/03 Rev.1), which takes the veillance (pharmacovigilance) is regulated by Council
new CTD structure into account and provides further Regulation (EEC) No. 2309/93 and Directive 2001/83/
PMF concept detail. A PMF contains information on EC. Commission Regulation (EC) No. 540/95 sets
plasma that one company uses for manufacturing all forth specific requirements for reporting non-serious,
intermediates and plasma products as active substance unexpected adverse reactions. Two major legislative acts
or excipient. If another manufacturer uses human were released in December 2010: Directive 2010/84/
albumin as a stabiliser for an active ingredient, the EU26 and Regulation (EU) No. 1235/2010,27 accom-
excipient manufacturer’s PMF may be referenced. PMF panied by Commission Implementing Regulation No.
structure and content are set out in the Guideline on 520/201228 of June 2012.
Epidemiological Data on Blood Transmissible Infections Since December 2001, all guidance documents
(EMA/CHMP/BWP/548524/2008 Rev. 1, which came have been summarised in Volume 9 of the Rules
into effect in August 2016. Governing Medicinal Products in the European Union;29
Currently, the PMF can be introduced either however, as of July 2012 Volume 9—Pharmacovigilance
directly as part of the dossier of each single medic- guidance for human medicinal products was replaced by
inal product license or cross-referenced as a PMF, Guidelines on Good Pharmacovigilance Practices (GVP).
authorised centrally. The standalone PMF allows man- These cover pharmacovigilance inspections, risk man-
agement and approval through EMA. agement systems and safety communication. Volume
9B—Pharmacovigilance for Medicinal Products for
Batch Release (OCABR) Veterinary Use remains.
Plasma-derived product batch-release requirements are Companies provide individual adverse reaction
incorporated into the codified Directive 2001/83/EC. Its case reports, periodic safety update reports (biannually
Article 114 allows, but does not require, a Member State and annually during the first five years of a marketing
laboratory to test a batch of a medicinal product derived authorisation) and, depending on licencing conditions,
from human blood or plasma before it can be marketed. postauthorisation safety studies.
The procedure is described in detail in EDQM docu-
ments, namely EU Administrative Procedure for Official Outlook
Control Authority Batch Release (PA/PH/OMCL (2020)) • Directive 2002/98/EC: This directive covers
and Procedure for Official Control Authority Batch Release all blood components for transfusion (e.g., red
of Centrally Authorised Immunological Medicinal Products blood cells, platelets) and plasma for fraction-
for Human Use and Medicinal Products Derived From ation. It sets high quality and safety standards
Human Blood and Plasma (PA/PH/OMCL (2010)), in for blood and blood derivatives across the EU.
the case of blood products. The directive was adopted 27 January 2003 and
Guidance originally available on control authority was required to be transposed into national law
batch release of blood products (III/3008/93 for coag- by 8 February 2005. A number of Commission
ulation factors, III/3010/93 for immunoglobulins and directives implement the technical annexes of
III/3009/93 for albumin) was overhauled during a 2002 Directive 2002/98/EC.
review of OCABR procedures and was replaced and

Chapter 40
• Dossier structure: With the eCTD format’s europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX-

introduction for all dossiers from 1 July 2003, :32004L0033&qid=1583086017554&from=EN. Accessed 27
April 2020.
information on starting materials, such as 4. Commission Directive 2005/61/EC of 30 September 2005 im-
those for human blood and plasma, was placed plementing Directive 2002/98/EC of the European Parliament
in Module 3.2.S.2.3. To facilitate submission, and of the Council as regards traceability requirements and
applicants may reference the PMF, which is notification of serious adverse reactions and events. EUR-Lex
website. https://eur-lex.europa.eu/legal-content/EN/TXT/PD-
intended to be distinct from the submission F/?uri=CELEX:32005L0061&qid=1583086079822&from=EN.
dossier. Accessed 27 April 2020.
• Medical devices incorporating blood products: 5. Commission Directive 2005/62/EC of 30 September 2005 im-
Regulation (EU) 2017/745 of the European plementing Directive 2002/98/EC of the European Parliament
and of the Council as regards Community standards and spec-
Parliament and of the Council on medical ifications relating to a quality system for blood establishments,
devices, commonly termed the EU Medical amended by Directive 2016/1214. EUR-Lex website. https://
Devices Regulation (EU MDR) was adopted eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX-
5 April 2017 and amended by Regulation :32005L0062&qid=1583086137630&from=EN. Accessed 27
April 2020.
2020/56130 to postpone its implementation 6. Regulation (EEC) No. 726/2004 of the European Parliament
until May 2021, due to coronavirus crisis. and of the Council of 31 March 2004 laying down Union
Where a device incorporates a substance procedures for the authorisation and supervision of medici-
which, if used separately, may be considered nal products for human and veterinary use and establishing
a European Medicines Agency. EUR-Lex website. https://
to be a medicinal product within the meaning eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX-
of point 2 of Article 1 of Directive 2001/83/ :02004R0726-20190128&from=EN. Accessed 27 April 2020.
EC, including a medicinal product derived 7. Regulation (EC) No. 141/2000 of the European Parlia-
from human blood or human plasma, the doc- ment and of the Council of 16 December 1999 on orphan
medicinal products. EUR-Lex website. https://eur-lex.
umentation shall identify the source of that europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX-
substance and contain the data of the tests :02000R0141-20190726&from=EN. Accessed 27 April 2020.
conducted to assess its safety, quality and use- 8. Guideline on plasma-derived medicinal products (EMA/CHMP/
fulness, taking account of the intended purpose BWP/706271/2010). EMA website. https://www.ema.europa.
eu/en/documents/scientific-guideline/guideline-plasma-de-
of the device. rived-medicinal-products_en.pdf. Accessed 27 April 2020.
9. Guideline on the investigation of manufacturing processes for
Conclusion plasma-derived medicinal products with regard to variant
Creutzfeldt-Jakob disease risk (CPMP/BWP/CPMP/5136/03).
Medicinal products for human use derived from human EMA website. https://www.ema.europa.eu/en/documents/scien-
blood or plasma are regulated in the EU as medicinal tific-guideline/guideline-investigation-manufacturing-process-
products under Directive 2001/83/EC. Due to quality es-plasma-derived-medicinal-products-regard-variant_en.pdf.
and safety concerns about such products, extensive rules Accessed 27 April 2020.
10. Guideline on the replacement of rabbit pyrogen testing by an al-
and guidance are provided. These publications focus ternative test for plasma derived medicinal products (EMEA/
on two areas—starting material source and medicinal CHMP/BWP/452081/2007). EMA website. https://www.
product manufacture, including virus and TSE risk ema.europa.eu/en/documents/scientific-guideline/guideline-re-
assessments. placement-rabbit-pyrogen-testing-alternative-test-plasma-de-
rived-medicinal-products_en.pdf. Accessed 27 April 2020.
11. Guideline on requirements for plasma master file certification
References (CPMP/BWP/4663/03). EMA website. https://www.ema.
1. Commission Directive 2001/83/EC of the European Parliament europa.eu/en/documents/scientific-guideline/guideline-require-
and of the Council of 6 November 2001 on the Community ments-plasma-master-file-pmf-certification_en.pdf. Accessed
code relating to medicinal products for human use, amended 27 April 2020.
by Directives 2002/98/EC, 2003/63/EC, 2004/24/EC and 12. Note for Guidance on virus validation studies by CHMP’s prede-
2004/27/EC. EC website. https://ec.europa.eu/health/sites/ cessor, the Committee for Proprietary Medicinal Products (CPMP),
health/files/files/eudralex/vol-1/dir_2001_83_consol_2012/ CPMP/BWP/268/95. EMA website. https://www.ema.europa.
dir_2001_83_cons_2012_en.pdf. Accessed 27 April 2020. eu/en/documents/scientific-guideline/note-guidance-virus-vali-
2. Commission Directive 2002/98/EC of the European Parliament dation-studies-design-contribution-interpretation-studies-vali-
and of the Council of 27 January 2003 setting standards of dating_en.pdf. Accessed 27 April 2020.
quality and safety for the collection, testing, processing, storage 13. CHMP position statement on CJD and plasma- and urine-derived
and distribution of human blood and blood components and medicinal products, EMA/CHMP/BWP/303353/2010 Rev. 3.
amending Directive 2001/83/EC. EUR-Lex website. https:// EMA website. https://www.ema.europa.eu/en/documents/scien-
eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX- tific-guideline/chmp-position-statement-creutzfeldt-jakob-dis-
:32002L0098&from=EN. Accessed 27 April 2020. ease-plasma-derived-urine-derived-medicinal-products_en-0.
3. Commission Directive 2004/33/EC of 22 March 2004 pdf. Accessed 27 April 2020.
implementing Directive 2002/98/EC of the European 14. Note for guidance on minimising the risk of transmitting animal
Parliament and of the Council as regards certain technical spongiform encephalopathy agents via human and veterinary me-
requirements for blood and blood plasma, amended by Di- dicinal products (EMA/410/01 Rev. 3.) EMA website. https://
rective 2014/110/EU. EUR-Lex website. https://eur-lex.

www.ema.europa.eu/en/documents/scientific-guideline/ 22. Ibid.

minimising-risk-transmitting-animal-spongiform-encephalop- 23. Human OCABR Guidelines. EDQM website. https://www.
athy-agents-human-veterinary-medicinal_en.pdf. Accessed 27 edqm.eu/en/human-ocabr-guidelines. Accessed 27 April 2020.
April 2020. 24. Op cit 19.
15. Guideline on Epidemiological Data on Blood Transmissible In- 25. Op cit 23.
fections (EMA/CHMP/BWP/548524/2008 Rev. 1.) EMA 26. Directive 2010/84/EU of the European Parliament and the
website. https://www.ema.europa.eu/en/documents/scientif- Council of 15 December 2010 amending, as regards pharma-
ic-guideline/guideline-epidemiological-data-blood-transmissi- covigilance, Directive 2001/83/EC on the Community code
ble-infections-revision-1_en.pdf. Accessed 27 April 2020. relating to medicinal products for human use. EMA website.
16. Guideline on the scientific data requirements for a plasma master file http://ec.europa.eu/health/files/eudralex/vol-1/dir_2010_84/
(EMEA/CHMP/BWP/3794/03 Rev.1). EMA website. https:// dir_2010_84_en.pdf. Accessed 27 April 2020.
www.ema.europa.eu/en/documents/scientific-guideline/guide- 27. Regulation (EU) No. 1235/2010 of the European Parliament
line-scientific-data-requirements-plasma-master-file-pmf-revi- and of the Council of 15 December 2010 amending, as regards
sion-1_en.pdf. Accessed 27 April 2020. pharmacovigilance of medicinal products for human use, Regu-
17. Regulation (EU) No. 2017/745 of the European Parliament lation (EC) No. 726/2004 laying down Community procedures
and of the Council of 5 April 2017 on medical devices and for the authorisation and supervision of medicinal products for
amending Directive 2001/83/EC and Regulation (EC) No. human and veterinary use and establishing a European Medi-
178/2002 and Regulation (EC) No. 1223/2009 and repealing cines Agency, and Regulation (EC) No. 1394/2007 on advanced
Council Directives 90/385/EEC and 93/42/EEC. EUR-Lex therapy medicinal products. EC website. http://ec.europa.eu/
website. https://eur-lex.europa.eu/legal-content/EN/TXT/PD- health/files/eudralex/vol-1/reg_2010_1235/reg_2010_1235_
F/?uri=CELEX:02017R0745-20170505&from=EN. Accessed en.pdf. Accessed 27 April 2020.
27 April 2020. 28. Commission implementing Regulation (EU) No. 520/2012 of
18. European Commission. Eudralex: the Rules Governing Medicinal 19 June 2012 on the performance of pharmacovigilance activi-
Products in the European Union (European Commission, April ties provided for in Regulation (EC) No. 726/2004 of the Euro-
1998). EC website. http://ec.europa.eu/health/documents/eu- pean Parliament and of the Council and Directive 2001/83/EC
dralex/index_en.htm. Accessed 27 April 2020. of the European Parliament and of the Council. EC website.
19. Op cit 8. http://ec.europa.eu/health/files/eudralex/vol-1/reg_2012_520/
20. BWP Report on viral safety of plasma-derived and urine-derived reg_2012_520_en.pdf. Accessed 27 April 2020.
medicinal products with respect to Zika virus (15 September 2016, 29. Op cit 18.
EMA/CHMP/BWP/596747/2016). EMA website. http:// 30. Regulation (EU) 2020/561 of the European Parliament and
www.ema.europa.eu/docs/en_GB/document_library/Re- of the Council of 23 April 202 amending Regulation (EU)
port/2016/09/WC500213035.pdf. Accessed 27 April 2020. 2017/745 on medical devices, as regards the dates of appli-
21. European Directorate for the Quality of Medicines and Health- cation of certain of its provisions. EUR. Lex website. https://
Care. General European OMCL Network. EDQM website. eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX-
https://www.edqm.eu/en/general-european-omcl-network-geon. :32020R0561&from=EN. Accessed 29 April 2020.

Chapter 40

Chapter 41
Orphan Medicinal Products

OBJECTIVES □ Regulation (EC) No. 2049/2005 of the European

Parliament and of the Council of 16 December
□ Examine the special regulations for rare indica- 1999 on orphan medicinal products
tions involving small patient populations
□ Commission Notice 2016/C 424/03 of the
□ Obtain a basic understanding of the consid- European Parliament and of the Council of 16
erations for developing orphan medicinal December 1999 on orphan medicinal products
products (OMPs) for the EU market
□ Understand the EU incentives in place for OMPs

Introduction
□ Learn how to apply for OMP designation Orphan medicinal products (OMPs) are intended for
the diagnosis, prevention or treatment of life-threaten-
□ Understand the EU specificities associated with ing or very serious conditions affecting fewer than five
OMPs in 10,000 people in the EU. These products are called
“orphans” because the pharmaceutical industry has little
interest, under normal market conditions, in developing
DIRECTIVES, REGULATIONS AND GUIDELINES and marketing products intended for only a small num-
COVERED IN THIS CHAPTER ber of patients suffering from very rare conditions. Since
such a small proportion of the population is affected
□ Regulation (EC) No. 141/2000 of the European by these diseases, the pharmaceutical industry was
Parliament and of the Council of 16 December reluctant in the past to invest in the research and devel-
1999 on orphan medicinal products opment of medicinal products to treat them.
For this reason, governments and organisations
□ Commission Regulation (EC) No. 847/2000 of representing patients suffering from these rare diseases
27 April 2000 laying down the provisions for have emphasised the need for economic and regulatory
implementation of the criteria for designation incentives to encourage drug companies to develop and
of a medicinal product as an orphan medicinal market medicines to treat these rare conditions.
product and definitions of the concepts similar In response to this situation, a groundbreaking
medicinal product and clinical superiority precedent was set by the US when the Orphan Drug
Act came into effect in 1983. In the 1990s, Japan
adopted orphan medicines legislation, followed by
Parliament and of the Council of 16 December
Australia. Similarly, to stimulate orphan drug research
1999 on orphan medicinal products
and development, the EU introduced new legislation
□ Regulation (EC) No. 1901/2006 of the European in 2000, with the aim of providing incentives for OMP
Parliament and of the Council of 16 December development. To make this information available to
1999 on orphan medicinal products the public, a Community OMP register was created,

Chapter 41
which includes all drugs with orphan designation. As of Drug Administration (FDA) and EMA have agreed to
December 2019, 19 years after implementation, 2,233 harmonise their orphan drug designation application
orphan designations and 169 initial marketing authori- forms to simplify the process. The new application form
sations (MAs) have been granted.1 contains a section for common information required
by both agencies. It also contains a section for require-
Legal Framework in Europe ments unique to each agency. EMA and FDA will
On 16 December 1999, the European Parliament conduct independent reviews of such submissions to
approved Regulation (EC) No. 141/20002 of the ensure the data submitted meet each jurisdiction’s legal
European Parliament and the Council on orphan and scientific requirements.6
medicinal products. The regulation sets forth EU Due to their relatively small numbers, patients with
orphan designation criteria and describes available orphan diseases may be distributed around the world,
incentives, e.g., 10-year market exclusivity, protocol requiring a global regulatory strategy. The introduction
assistance and access to the Centralised Procedure (CP) of the joint US-EU orphan drug application is the first
for marketing authorisation to encourage research, step in simplifying the procedure.
development and marketing of medicines to treat, pre- If an application has not been submitted to the
vent or diagnose rare diseases. Japanese authorities before, EMA encourages the
In 2000, the Committee for Orphan Medicinal sponsor also to seek orphan designation from the
Products (COMP) was created to review designation Ministry for Health, Labour and Welfare (MHLW) in
applications from those intending to develop medicines Japan. Under the Japanese orphan designation system,
for rare diseases. This committee is responsible for MHLW provides consultation on orphan designations
evaluating orphan designation applications and giving before submission, whereas marketing authorisation
opinions on OMP designation. COMP also provides applications submitted following an orphan designa-
advice to the European Commission in discussions on tion are assessed by the Pharmaceuticals and Medical
orphan drugs. Devices Agency (PMDA). MHLW generally seeks
Other regulations and guidelines were adopted to scientific counsel from PMDA on orphan designation.
clarify specific concepts or provide procedural guidelines
following Commission Regulation (EC) No. 847/20003 OMP Incentives
of 27 April 2000 laying down the implementation pro- As stated earlier, the OMP legislation’s aim is to stimu-
visions of criteria for designating a medicinal product late research and development of medicinal products for
an orphan medicinal product and defining the concepts rare conditions by providing incentives to the pharma-
of “similar medicinal product” and “clinical superiority.” ceutical industry, including:
On 29 March 2006, the European Parliament • fee reductions
adopted Regulation (EC) No. 507/2006,4 which • development input through protocol assistance
provides the legal framework for the granting of a con- • access to the CP for the product’s evaluation
ditional marketing authorisation to medicines that fall • specific market exclusivity once authorised
within the scope of Regulation (EC) No. 726/2004. • additional incentives for micro-, small- and
It establishes that orphan medicines can be granted a medium-sized enterprises (SMEs)
conditional marketing authorisation within this legal • grants
framework.
On 12 December 2006, the European Parliament Member States can add their own inducements (tax
adopted Regulation (EC) No. 1901/20065 on medicinal incentives, grants and free scientific input) at the
products for paediatric use, extending the usual period national level.7
of market exclusivity for orphan medicines to 12 years
if study results are submitted in compliance with an Fee Reductions
agreed paediatric investigation plan at the time of mar- Companies applying for OMP designation pay reduced
keting authorisation. fees for regulatory activities, including protocol assis-
Relevant documents regarding orphan drug desig- tance, marketing authorisation applications (MAAs),
nation are provided on the European Medicines Agency inspections before authorisation, applications for MA
(EMA) website. changes after approval, inspections and reduced annual
fees. Fee reductions are revised annually.
Harmonisation Efforts
There is significant emphasis on transatlantic simplifi-
cation in the orphan designation area. For example, to
leverage some administrative burden, the US Food and

Protocol Assistance Each orphan designation has market exclusivity

EMA provides protocol assistance, a special form of potential for one particular indication. A medicine with
scientific advice, for orphan drug designation sponsors.8 several separate orphan designations for different indi-
This allows sponsors to get answers to questions on the cations can have several separate market exclusivities if
study types needed to demonstrate the medicine’s qual- they are for separate orphan-designated conditions.
ity, benefits and risks and information on the product’s The market exclusivity period is extended by two
significant benefit. years for medicines also complying with an agreed
Protocol assistance is available at a reduced charge pediatric investigation plan (PIP) granted at the time of
for designated orphan medicines, linked to a fee-reduc- review of the OMP designation. “Where an application
tion scale that depends on the sponsor’s status. There for a marketing authorisation is submitted in respect of
is no restriction on the number of times a sponsor can a medicinal product designated as an orphan product
request protocol assistance. pursuant to the OMP Regulation and that application
Protocol assistance can be requested at any OMP includes the results of all studies conducted in compli-
development stage. EMA provides protocol assistance ance with an agreed pediatric investigation plan, and the
in consultation with the Committee for Medicinal statement referred to in Article 28(3) of this Regulation
Products for Human Use (CHMP) and its Scientific is subsequently included in the MA granted, the
Advice Working Party (SAWP). The protocol assistance 10-year period referred to in Article 8(1) of Regulation
procedure is similar to that for scientific advice. The (EC) No. 141/2000 shall be extended to twelve years.”10
main differences between the two are: This extension is dependent only on completion of the
• Two COMP members and specific experts agreed-upon studies and not on their outcomes.
from the field (e.g., researchers in the orphan
indication’s field, methodologists, statisticians Additional SME Incentives
and patient representatives) participate in the Companies classified as SMEs benefit from further
process to provide an extended and collabo- incentives when developing medicines with orphan des-
rative forum that takes broad views and new ignation. These include administrative and procedural
ideas into consideration. assistance from EMA’s SME office and fee reductions.11
• An interactive dialogue is sought. In general,
sponsors are invited to present an oral explana- Grants
tion during the protocol assistance procedure. Unlike FDA, EMA does not offer research grants for
orphan medicinal product sponsors, but funding is
EMA protocol assistance is not binding on EMA, available from the European Commission and other
CHMP or the sponsor with regard to any future OMP sources.12,13
MAA.
EMA encourages sponsors to consider coordinat- Community OMP Register
ing the timing of protocol assistance with other regions All products designated as OMPs are listed on the
like the US. EMA and FDA have a program to request European Commission Community Register. It con-
parallel scientific advice.9 tains information on OMPs under market exclusivity.14
Scientific advice also is available from PMDA. At the end of a designated OMP’s market exclusiv-
ity period, the product is removed from the register.
Access to the Centralised Authorisation Procedure
All EU orphan medicine MAAs are subject to the CP. OMP Designation
This allows companies to make a single application to
Criteria for Orphan Designation
EMA, resulting in a single opinion and a single decision
To obtain EU OMP designation, an applicant must
from the European Commission, valid in all EU Member
establish the product meets the criteria described in
States. Sponsors also may have access via orphan designa-
OMP Regulation15 Article 3(1) (Figure 41-1):
tion to conditional approval, under the CP.
1. Condition rarity—The medicinal product
is intended for the diagnosis, prevention or
10-Year Market Exclusivity treatment of a life-threatening or chronically
Authorised OMPs, once approved, benefit from 10 debilitating condition affecting not more
years of market exclusivity. Market exclusivity is than five in 10,000 persons in the EU at the
awarded by the European Commission and is linked to time of submission. Or, the medicinal prod-
one specific orphan designation for which an MA has uct is intended for the diagnosis, prevention
been granted. or treatment of a life-threatening, seriously

Chapter 41
Figure 41-1. Simplified View of the Designation EMA provides the COMP secretariat. COMP consists
Criteria of:
• a chair, elected by serving COMP members
• one member nominated by each of the 27
Rare Condition (Prevalence <5 in 10,000)? Member States
• three members nominated by the European
Commission to represent patient organisations
YES • three members nominated by the European
Commission on the basis of EMA
recommendations
Serious or Life-Threatening Condition?
• one member nominated by each EEA-EFTA
state (Iceland, Norway, Liechtenstein and
Switzerland)
YES
Members are appointed for renewable three-year terms.

Existence of Satisfactory Treatment Methods?
OMP Designation Procedure
Application Procedure
NO YES EU’s OMP Regulation clearly states only medici-
nal products for human use, as defined in Directive
YES 2001/83/EC8 Article 2, as amended, are eligible for
Orphan Designation Significant Benefit? OMP designation. The scope includes drugs, biological
and biotechnological products and advanced therapy
medicinal products (ATMPs); it excludes medical
devices and certain tissue products.
debilitating, or serious and chronic condition Sponsors are no longer required to send a notifi-
in the EU, and without incentives, it is unlikely cation of intent to file an orphan drug application for
marketing this product in the EU would gen- designation to EMA. Instead, they should follow one of
erate sufficient financial return to justify the these two options:
necessary investment. • Submit the application to EMA through
2. Approved methods of diagnosis, prevention or the IRIS system, a regulatory and scientific
treatment—Applicants should demonstrate, information management platform: Sponsors
at the time of submission, that no satisfactory can send the application preferably a few
method of diagnosis, prevention or treatment days before any of the published submission
of the condition in question has been autho- deadlines available on the EMA website to
rised in the EU. If such a method has been allow more time for the validation process.
approved, the applicant should demonstrate its Applications for orphan designation are free
medicinal product will be of significant benefit of charge. (IRIS was established in 2018 and is
to those affected by the condition. part of EMA’s digital transformation process.
IRIS is a secure online portal that enables
Committee for Orphan Medicinal Products sponsors to submit their orphan designation
(COMP) applications and manage post-designation
OMP Regulation Article 4 established COMP, whose activities.)
tasks are: • Request a presubmission meeting or tele-
• examining any application submitted for a conference: Presubmission meetings are not
medicinal product’s designation as an OMP in mandatory, and sponsors are welcome to send
accordance with the OMP Regulation an application for orphan drug designation
• advising the European Commission on estab- without notice. If sponsors feel they could
lishing and developing an EU OMP policy benefit from a preliminary discussion before
• assisting the European Commission in liais- submitting an orphan drug application to
ing internationally and with patient support EMA, they should email a request for a pre-
groups on matters relating to OMPs submission meeting or teleconference at least
two months prior to their planned submission
date. This should allow enough time for the

organisation and any amendment of the appli- • The agency advises sponsors to use the com-
cation as recommended by EMA. Sponsors mon EMA/FDA orphan application form for
should send the draft application for the pre- orphan designation, particularly if an applica-
submission discussions one week in advance. tion has not been submitted before in the US.
• If an application has not been submitted
The agency strongly encourages sponsors to request a before to the Japanese authorities, EMA
presubmission meeting prior to filing an application. also encourages the sponsor to seek orphan
Presubmission meetings usually take place via telecon- designation from Japan’s MHLW. Under the
ference, unless the sponsor has a strong preference for Japanese orphan designation system, MHLW
meeting with the agency in person. Where possible, provides consultation on orphan designations
sponsors should request a presubmission meeting at before submission, whereas MAAs submitted
least two months prior to filing. Presubmission meet- following an orphan designation are assessed
ings for orphan designation are free of charge. by PMDA. MHLW generally seeks scien-
Presubmission meetings are useful, since the evalu- tific counsel from PMDA on the orphan
ation process has a fixed duration of 90 days and cannot designation.
be lengthened to accommodate the lack of data or other
omissions in the application. Experience has shown OMP Designation Application Evaluation
they have a positive impact on the success rate of the After submission, the two coordinators prepare a sum-
applications. mary report on the application, which is circulated to
Sponsors can view a flowchart (Figure 41-2) of all COMP members and discussed at COMP’s next
the application process and can find the following plenary meeting (Day 60), when members may raise
forms on EMA’s webpage “how to apply for orphan questions about the application.
designation:”16 At this stage, COMP will either adopt a positive
• application form for OMP designation opinion or raise a list of questions and invite the spon-
• common EMA/FDA application form (click sor to present an oral explanation at the next COMP
on the “clusters” link) or application form for plenary meeting.
orphan medicinal product designation COMP should adopt an opinion by Day 90 of
• template for sections A to E for the scientific the procedure. No opinions are discussed in the spon-
part of the orphan designation application sor’s presence. This opinion then is forwarded to the
European Commission to adopt a decision.
Once the request for designation is submitted, EMA If COMP’s opinion is negative, the sponsor can
appoints two coordinators: appeal. The sponsor should notify EMA in writing of its
• one COMP member intent to appeal within 15 days of receiving the negative
• one scientific administrator from the agency’s opinion. The reasoning for the appeal should be submit-
secretariat ted to EMA within 90 days of receiving the opinion.
EMA then forwards the grounds for appeal to COMP,
EMA will validate the application and send the spon- which considers them at its next meeting. The appeal
sor a validation issues letter, explaining whether the should be based only on the original data provided in
application is found to be invalid or incomplete. Once the application for orphan designation.17
validation is complete, the agency will send the sponsor
an evaluation procedure timetable. European Commission Decision
The agency advises sponsors developing ATMPs The European Commission will issue a decision on a
to apply separately to the Committee for Advanced COMP opinion within 30 days of receipt. Following a
Therapies (CAT) to have their medicines classified as decision:
ATMPs. • EMA publishes information on the orphan
Horizon 2020 is the biggest ever EU research and designation under its rare disease (orphan)
innovation funding programme, running from 2014 to designations webpage18
2020 • the European Commission enters the orphan
designation into the OMP Register19
Parallel Application with International Regulators
EMA encourages parallel applications for orphan desig- Since March 2002, EMA has published the public
nation with regulatory authorities outside the EU. summary of the COMP opinion after adopting any
The agency has special arrangements with regula- European Commission opinion. This document is
tors in the US and Japan for this purpose:

Chapter 41
Figure 41-2. EMA Orphan Drug Designation Guide
Start Not eligible*
No
Proposed condition
has distinct Prevalence: identification of
Yes Condition is seriously Yes
pathophysiological, European epidemiological
debilitating/life
histopathological, resources (e.g. papers,
threatening.
clinical characteristics. registries, databases).
No Yes
The specific
Prevalence is Yes product applied No
<5 in 10,000 for is under
Subset has a plausible
in EU** development for
Condition is Yes link to the condition AND
this condition.
subset of a distinct the product cannot exert
medical entity. pharmacodynamic effects
beyond the subset.
No Not ready
Yes
to apply*
No No
Not eligible*
Not eligible* Data available with the specific
product in relevant non-clinical
Grounds for potential models or patients affected by the
significant benefit based proposed condition, indicating
on data to support clinically clinically relevant outcomes.
relevant advantage and/or Satisfactory authorised
No major contribution to patient Yes methods for treatment,
care vis a vis the existing diagnosis or prevention
authorised products. Yes
exist within the EU.
Not ready to apply*. Consider Identification of

other frameworks (e.g. Yes existing methods of
No
paediatrics, advanced- treatment, diagnosis
Ready to apply for an
therapy medicinal products, or prevention of the
orphan designation.
micro-, small- and medium- condition within the EU.
Arrange a pre-
sized enterprises).
submission meeting.
*Contact the EMA orphan medicines office for more guidance.

**Article 3(1)(a) of Regulation (EC) No. 141/2000 provides an alternative criterion to the prevalence number, based on evidence of insufficient return to
justify the necessary investment.
available on EMA’s website and provides summary considered proprietary or commercially confidential is
information on the following topics: removed.
• orphan indication The sponsor may decide at any time during the
• available treatment methods procedure to withdraw an application. After a with-
• estimated prevalence or financial aspects drawal, the sponsor may resubmit the application.
(depending on the criterion used for the
application) Annual Report
• mode of action After OMP designation has been granted, sponsors
• stage of development are required to submit annual reports20 via IRIS yearly
• sponsor’s contact details until a marketing application is filed. This information
includes:
Before publishing the public summary, EMA consults • administrative update—provided as an updated
patient organisations to ensure readability. EMA also application form
consults with the sponsor to ensure any information • summary of product development—con-
cise summary of development plan advances

compared to the original application or pre- the medicinal product concerned from the
vious annual report. (A tabulated overview current sponsor (i.e., the date of transfer
including initiated, ongoing and completed implementation)
preclinical and clinical studies, as well as a o identification (i.e., name and address) for
short summary of the results, should be pro- both the existing and proposed sponsors
vided. Full reports should be provided only o proof the proposed sponsor is established
when requested. The summary also should in the EEA
include a brief description of the upcoming o depending on the orphan designation
year’s development plan and follow-up infor- approval date, translation of either the
mation on protocol assistance received.) active ingredient or subset name in all EU
• update on the product’s current regulatory languages, plus Icelandic and Norwegian
status—an update on the OMP’s regulatory
status in EU and non-EU countries, includ- EMA should adopt an opinion within 30 days of receiv-
ing active compassionate use programs and ing a valid application. The opinion will be forwarded
orphan designation request and MAA status to the existing sponsor, the proposed sponsor and the
(including those requested, rejected, granted European Commission. If it agrees, the Commission
and planned for each country, with submission will amend the decision granting the designation. The
dates) transfer is accepted from the date of notification of the
• incentives received—estimates of total finan- amended European Commission decision.
cial incentives directly related to the orphan
designation received during the reporting year Orphan Designation Expiry
and the incentive source(s) (Member States, When an indication’s market exclusivity period ends, its
European Commission, EMA) orphan designation expires, and it is removed from the
Community OMP register.
Sponsors of medicines with orphan designations in both Once all the orphan designations associated with
the EU and US can submit a single report to EMA and an approved medicine have expired or been withdrawn
FDA. Submitting a single report to the two agencies by the sponsor, the medicine ceases to be classified as an
is voluntary. EMA and FDA carry out independent orphan medicine and no longer benefits from orphan
reviews and assessments of the report’s contents. incentives.
Sponsorship Transfer OMP Designation Request Content

Once granted by the European Commission, an OMP The following documentation must be supplied in any
designation can be transferred from the currently OMP designation application:22
approved sponsor to a new sponsor in accordance with 1. cover letter (signed PDF)
OMP Regulation Article 5(11). The sponsor holding 2. EMA or Common EMA/FDA application
the designation should submit an application21 to EMA form, with the following:
that includes: • active substance name
• a copy of the Commission decision on the • proposed indication and ATC code (if
designation available)
• a comprehensive document (Template 1, avail- • proposed medicinal product details (if
able on EMA’s website) signed by both the available)
current and new sponsor, including: • sponsor or corporate contact person name
o sponsor identification of the designation and permanent address
to be transferred (“current sponsor”) and • active substance name and manufacturer
of the sponsor to whom the transfer is 3. Scientific Sections A-E of the application (i.e.,
to be granted (“new sponsor”), including the core dossier), with the following:
contact details • condition description
o a statement certifying a copy of the o condition details
complete and up-to-date designation o proposed orphan indication
application has been made available or o medical plausibility
transferred to the new sponsor o justification of the condition’s
o a statement as to the date on which the life-threatening or debilitating nature
new sponsor actually can assume responsi- • condition’s prevalence
bility for and rights of the designation for

Chapter 41
o orphan disease or condition’s preva- specific clinical, pathophysiological or histopathological

lence in the Community characteristics generally are acceptable. A subset of a
o orphan disease or condition’s frequent disease could be considered a valid condition
prevalence and incidence in the for orphan status if subset patients show distinct and
Community unique quantitative characteristics with a plausible link
• potential for return on investment to the condition. In addition, the following must apply:
• existence of other diagnostic, prevention • Patients’ characteristics are essential for the
or treatment methods medicinal product to carry out its action.
o details on existing methods • The absence of these characteristics in patients
o justification as to why methods are will render the product ineffective in the rest of
not satisfactory the population.
o justification of significant benefit
• development stage description Prevalence
o product development summary In June 2019, COMP updated Points to Consider on
o current regulatory status and market- Calculation and Reporting of the Prevalence of a Condition
ing history details in EU and non-EU for Orphan Designation.24 Prevalence is defined as the
countries number of people in the EU affected by the condition
• bibliography at the time of submission. Prevalence should not be
4. proof of sponsor’s establishment in the EU confused with incidence—the number of new cases of
5. if applicable, letter of authorisation from the a condition in a specified time period. Only in the case
sponsor for the person or company acting on of conditions with a very short duration (less than one
its behalf during the procedure year) has COMP adopted positive opinions on the basis
6. product name and proposed orphan indication of annual incidence rather than prevalence.
translated into the official EU languages, plus The sponsor should present precise evidence
Icelandic and Norwegian (including published literature and data from reference
7. bibliography databases) demonstrating prevalence is lower than five in
10,000 in the Community. The use of selected references
Medical Plausibility or databases in calculating prevalence should be justified.
In many cases, at the time of designation, little or no
clinical experience is available, so it is important to Significant Benefit
discuss the relevance of in vitro and in vivo preclinical The concept of significant benefit is unique to EU
models presented in the application in the context of orphan legislation. It is defined in the OMP Regulation
the condition, with appropriate reference to other prod- as a clinically relevant advantage or major contribution
ucts developed for the same condition. As a general rule, to patient care.25 When seeking orphan designation for
at least relevant in vitro and in vivo data in appropriate an authorised medicinal product, the sponsor should
preclinical models should be submitted. justify the assumption the product will provide sig-
In addition to the efficacy data, a summary of any nificant benefit to those affected by the condition. In
available important safety data obtained in preclinical general, any medicinal product already authorised in an
and clinical testing (both in the orphan condition and in EU Member State for the proposed orphan indication
other conditions) should be included in the application.23 will be viewed as a “satisfactory method,” and the spon-
Experience has shown a large proportion of unsuc- sor will be required to argue “significant benefit.”
cessful orphan designation applications were due to Because sponsors can submit an application at
so-called “salami slicing.” This refers to artificial subsets any development stage, COMP looks for justifica-
of conditions that, as a whole, have a greater prevalence tion of a potential benefit assumption rather than a
than five in 10,000 people in the Community. demonstration of it. The significant benefit should be
It is important to distinguish between the proposed demonstrated later to maintain the orphan designation
orphan indication, which is the designation application’s prior to MAA approval. Note COMP’s position is that
subject, and the proposed therapeutic indication, which a new mode of action (i.e., improved efficacy) or a new
is the MAA’s subject. The MAA’s proposed therapeutic method of administration (e.g., from intravenous to
indication should reflect clinical development results oral) could be acceptable as a justification for signifi-
and usually describes a specific population for whom cant benefit. In an EMA retrospective analysis on the
benefit has been demonstrated. However, the proposed grounds for product authorisation, significant benefit
orphan indication should be described as broadly as was granted much more often based on a “clinically
possible. Distinct medical entities defined according to relevant advantage” than on a “major contribution to

patient care.” This reflects the fact that a major contri- This is important because market exclusivity is
bution to patient care is based on “soft” endpoints (e.g., linked to orphan designation maintenance, when the
patients’ preference, compliance), usually not addressed product receives an MA for the concerned indication.
in the pivotal trials performed to support the MA or When an orphan designation application is pend-
self-evident advantages, the relevance of which might ing at the time of MAA submission, the medicinal
be difficult to establish.26 product still may be authorised as an OMP, provided
When the MAA is submitted, the significant COMP adopts the orphan designation and it is con-
benefit should be based on evidence from clinical data firmed by the Commission before granting the MA.
confirming the designation’s assumptions and hypoth- Prior to submitting the MAA, regardless of
eses. Methodological issues on significant benefit can whether the medicinal product in question has been
arise when the applicable condition’s population size designated as orphan, a sponsor is advised to check
does not allow randomised active control trials to be the Community OMP Register for information on
conducted or when the COMP assessment requires sig- the product’s orphan status designation under market
nificant benefit demonstration against a large number exclusivity protection.
of comparators. COMP encourages sponsors to request As required by OMP Regulation Article 8(1), if any
protocol assistance to discuss approaches to demon- of the designated OMPs has been granted a MA in
strate significant benefit and improve the chances for the EU, and a period of market exclusivity is in force, a
regulatory approval. sponsor should submit a similarity report addressing the
In a 2015 workshop, participants expressed possible similarity between the new medicinal products
their desire to see more interactions and information and any authorised OMP(s). Information on the sim-
exchange between COMP and CHMP to better define ilarity report’s content is available on EMA’s webpage
the relevant data required to demonstrate significant for presubmission guidance and in the EC guideline for
benefit, particularly regarding secondary endpoints assessment of similarities.
in relation to major contributions to patient care and Where an OMP MA is granted, EMA and the
different comparators.27 It was mentioned that patients Member States shall not, for a period of 10 years,
may have different opinions of what is relevant with accept another application for an MA or grant an MA
regard to significant benefit and whether there may be or accept an application to extend an existing MA, for
better ways of capturing patients’ views. There also was the same therapeutic indication, in respect of a sim-
a desire for more details on COMP’s significant benefit ilar medicinal product. OMP Regulation Article 8(3)
discussion, published in the EPAR. specifies that an MA may be granted, for the same ther-
Finally, during the development phase, sponsors apeutic indication, to a similar medicinal product if:
should be aware other diagnostic, preventive or treat- • the original orphan medicinal product’s mar-
ment methods for the same condition may be approved keting authorisation holder (MAH) has given
in the European Community or one of its Member consent to the second applicant
States. In such cases, it may be necessary to change the • the original orphan medicinal product’s MAH
OMP designation’s basis from “no authorised treatment is unable to supply sufficient quantities of the
available” to “significant benefit.” This change can be medicinal product
made in the annual report on OMP development. • the second applicant can establish in the appli-
In this context, when submitting an orphan cation that its product, although similar to the
designated product MAA, applicants should justify orphan medicinal product already authorised,
significant benefit and/or why the chemical or molecu- is safer, more effective or otherwise clinically
lar entity is not a similar active ingredient (as defined in superior
the orphan legislation).
Assessment of Similarities
MAAs The concepts of “similar medicinal product” and “clin-
When an orphan designation product’s sponsor sub- ical superiority” are defined in the OMP Regulation.28
mits an MAA or a new indication to EMA, an orphan The assessment of similarity between two medicinal
designation maintenance request should be submitted products takes into consideration:
in parallel. An orphan similarity evaluation also may be • principal molecular structural features
required. This enables EMA to determine whether the • mechanism of action
medicinal product can maintain its status as an OMP • therapeutic indication
and benefit from market exclusivity.
If significant differences exist within one or more of
these criteria, the two products will not be considered as

Chapter 41
similar. If CHMP concludes the MAA is not similar to interest. The sponsor should submit a letter of intent to
an authorised OMP or, if similar, one of the derogations request eligibility for review under accelerated assess-
provided in Article 8(3) of the OMP Regulation claimed ment. The decision to conduct the MAA review under
by the applicant applies, this will not prevent granting accelerated assessment is made by CHMP and com-
the MA or extension, provided the medicinal product’s municated to the sponsor before the review begins. If
quality, safety and efficacy are demonstrated.29 major objections are identified during the assessment,
Should CHMP conclude the MAA product is CHMP can decide to revert the review procedure to the
considered similar to an authorised OMP, and none of normal timetable, which is 210 days (EC Regulation
the derogations apply, it will adopt an opinion recom- 726/2014).
mending the refusal of the MA or extension, regardless As of March 2020, 23 OMPs have been approved
of the demonstration of the medicinal product’s quality, under accelerated assessment.
safety or efficacy (e.g., taliglucerase alfa).
Conditional and Exceptional Circumstances
Orphan Designation Review at Time of MAA Marketing Authorisations
Submission The EU has introduced two instruments to regulate
COMP reviews the maintenance of orphan designation early market access: conditional marketing authorisation
based on data available at the time and a report on the and authorisation under exceptional circumstances.32,33
designation criteria maintenance, which the sponsor
supplies with the MAA. This report includes data on: Conditional Marketing Authorisation
• the current prevalence of the condition to be This may be granted when, although comprehensive
diagnosed, prevented or treated, or the poten- clinical data have not been provided, all of the following
tial return on investment requirements are met:
• the condition’s life-threatening or debilitating • benefit-risk balance is positive, based on scien-
nature tific data, pending confirmation
• the existence of other methods for the condi- • comprehensive clinical data likely will be
tion’s diagnosis, prevention or treatment provided
• if applicable, a justification of the medicine’s • unmet medical needs will be fulfilled
significant benefit • benefit to public health or immediate availabil-
ity outweighs risks that additional data still are
COMP’s review is carried out independently of, but in required
parallel with, CHMP’s MAA evaluation. The COMP
opinion on orphan designation review follows CHMP’s Conditional MAs are subject to specific obligations to
positive MA opinion. The COMP opinion is sent to the complete ongoing studies or to conduct new studies
Commission, which has 30 days to endorse it. A report with the goal of confirming the positive benefit-risk
on whether the medicine still meets the orphan desig- balance. Upon fulfilling all specific obligations, the
nation criteria is published together with a European conditional MA may convert to a normal MA. A con-
public assessment report (EPAR) on EMA’s orphan ditional MA is valid for one year and can be renewed
designations webpage.30 annually. As of March 2020, there are 15 conditional
MAs. There are regulatory precedents where OMPs
Additional Regulatory Pathways to initially approved under conditional approval have con-
Expedite Development and Approval verted to regular MA (e.g., Sunitinib).34
Accelerated Assessment
Authorisation Under Exceptional Circumstances
Accelerated assessment was introduced in the revised
This has been available since the start of EMA’s CP. It
EU pharmaceutical legislation to help speed patient
applies to MAAs lacking comprehensive clinical data
access to new medicines.31 Companies can request
and depending on:
accelerated assessment if they are able to demonstrate
• disease rarity
their product responds to unmet medical needs or
• present state of scientific knowledge
constitutes a significant improvement over available
• ethical constraints
methods for a condition’s prevention, diagnosis or
treatment. Accelerated assessment offers the possibil-
An MA under exceptional circumstances should not be
ity of obtaining a positive opinion in 150 days instead
granted when a conditional MA is more appropriate.
of 210 days for medicinal products that demonstrate
The MA under exceptional circumstances is valid
therapeutic innovation and are of major public health
for five years. Then, the MA can be renewed under

exceptional circumstances for an unlimited period, Additional support is available to eligible development
unless EMA decides, on justified grounds relating to programmes in an additional presubmission meeting
pharmacovigilance, to proceed with one additional prior to the one foreseen by the parallel Scientific Advice
five-year renewal. However, annual CHMP benefit-risk procedure, allowing companies to discuss their options
balance reassessment is required. As of March 2020, and ideas before drafting the protocols that will be the
there are 19 exceptional circumstance MAs. subject of scientific advice. See Chapter 24 Adaptive
There are few OMPs for which, when all specific and Alternative Pathways for more information.
obligations were fulfilled, the CHMP considered there
were no remaining grounds for the MA to remain Conclusion
under exceptional circumstances. Consequently, follow- The EU OMP Regulation has been implemented suc-
ing the annual reassessment approval under exceptional cessfully throughout the European Community. Many
services review, the approval was converted to a standard companies are using the regulation to develop med-
marketing authorisation (e.g., Zavesca).35 icines for rare diseases, as demonstrated by the large
number of applications to COMP. By the end of 2019,
Adaptive Pathway approximately 192 OMPs had reached the market. In
In 2014, EMA announced the implementation of May 2015, during the event organised to celebrate the
the adaptive pathways approach, which is part of the OMP Regulation’s 15th anniversary, Eurordis, the associ-
agency’s efforts to improve timely patient access to new ation representing patients, called to changing attitudes
medicines. The adaptive pathway is managed by EMA’s toward risk:
Scientific Advice Office. EMA’s website has a page ded- “ The risk-benefit assessment of a medicine should
icated to the adaptive pathway.36 be more flexible by accepting more limited efficacy
Adaptive pathways are based on three principles: data and should follow a more adaptive pathway to
• iterative development, which means either: patients. When assessing the risks and benefits of
o approval in stages, beginning with a a new medicine, only patients, as experts of their
restricted patient population and then disease, can legitimately determine how much
expanding to wider patient populations uncertainty they are willing to accept in exchange
o confirming a product’s benefit-risk bal- for the proposed safety and benefit of a medicine.
ance, following a conditional approval Rare disease patients, who often don’t have access
based on early data (using surrogate end- to a satisfactory medicine or any treatment at all,
points) considered predictive of important may be willing to accept more risk than patients
clinical outcomes who live with diseases for which satisfactory treat-
• gathering evidence through real-life use to ments already exist.”37
supplement clinical trial data
• both early patients and health technology References
assessment (HTA) bodies are involved in dis- 1. Orphan Medicine Figures 2000–2014. EMA website.
http://www.ema.europa.eu/docs/en_GB/document_library/
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2. Regulation (EC) No. 141/2000 of the European Parliament and
This concept applies primarily to treatments in areas of of the Council of 16 December 1999 on orphan medicinal prod-
high medical need, where it is difficult to collect data ucts (Orphan Regulation). EUR-Lex website. https://ec.europa.
eu/health/sites/health/files/files/eudralex/vol-1/reg_2000_141_
via traditional routes and where large clinical trials cons-2009-07/reg_2000_141_cons-2009-07_en.pdf. Accessed
would unnecessarily expose patients who are unlikely to 27 April 2020.
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The approach builds on regulatory processes already the provisions for implementation of the criteria for designation
of a medicinal product as an orphan medicinal product and
in place within the existing EU legal framework. These definitions of the concepts ‘similar medicinal product’ and ‘clin-
include: ical superiority’. EUR-Lex website. https://ec.europa.eu/health/
• scientific advice documents/eudralex/vol-1_en. Accessed 27 April 2020.
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work for the granting of a conditional marketing authorisation
• the conditional approval mechanism (for med- to medicines that fall within the scope of Regulation (EC) No.
icines addressing life-threatening conditions) 726/2004. EC website. https://ec.europa.eu/health//sites/health/
• patient registries and other pharmacovigilance files/files/eudralex/vol-1/reg_2006_507/reg_2006_507_en.pdf.
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5. Regulation (EC) No. 1901/2006 on medicinal products for
risk management plan development for each paediatric use. EC website. https://ec.europa.eu/health//
medicine sites/health/files/files/eudralex/vol-1/reg_2006_1901/
reg_2006_1901_en.pdf. Accessed 27 April 2020.

Chapter 41
6. Procedural advice for orphan medicinal product designation, 4; 27 March 2014). European Commission website. https://
Guidance for sponsors. EMA/420706/2018 Rev. 6 (11 December ec.europa.eu/health//sites/health/files/files/orphanmp/2014-03_
2019). EMA website. http://www.ema.europa.eu/docs/ guideline_rev4_final.pdf. Accessed 27 April 2020.
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line/2009/09/WC500003769.pdf Accessed on 27 April 2020. ical plausibility and the assumption of significant benefit for
7. Orphan Medicinal Product Incentives. EMA website. https:// an orphan designation (EMA/COMP/15893/2009 Final; 2
www.ema.europa.eu/en/human-regulatory/research-develop- March 2010). EMA website. http://www.ema.europa.eu/docs/
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2020. line/2009/09/WC500003778.pdf. Accessed 27 April 2020.
8. Guidance for Applicants Seeking Scientific Advice and Protocol 24. Points to consider on the estimation and reporting on the prev-
Assistance (EMA/4260/2001 Rev.9; 30 June 2017). EMA web- alence of a condition for the purpose of orphan designation,
site. http://www.ema.europa.eu/docs/en_GB/document_library/ EMA/COMP/436/01 Rev. 1, dated 20 June 2019. EMA web-
Regulatory_and_procedural_guideline/2009/10/WC500004089. site. http://www.ema.europa.eu/docs/en_GB/document_library/
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9. General Principles EMA-FDA Parallel Scientific Advice pdf. Accessed 27 April 2020.
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document_library/Other/2009/11/WC500014868.pdf. Accessed opments. EMA website. http://www.ema.europa.eu/docs/
27 April 2020. en_GB/document_library/Report/2012/07/WC500130376.pdf.
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(EEC) 1768/92, Directive 2001/20/EC and Regulation (EC) Orphan Medicines: Concepts, Methodology and Impact on
No. 726/2004. EUR-Lex website. https://ec.europa.eu/health/ Access – 7 December 2015 (EMA/6690/2016; 22 July 2016).
documents/eudralex/vol-1_en Accessed 27 April 2020. EMA website (http://www.ema.europa.eu/docs/en_GB/docu-
11. Micro-, small- and medium-sized-enterprise (SME) office. ment_library/Report/2016/07/WC500210934.pdf. Accessed 27
EMA website. http://www.ema.europa.eu/ema/index. April 2020.
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Accessed 27 April 2020. 29. Guideline on Aspects of the Application of Article 8(1) and (3) of
12. Horizon 2020—The EU Framework Programme for Research Regulation (EC) No 141/2000: Assessing Similarity of Medicinal
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13. International Rare Diseases Research Consortium home page. Market Exclusivity (C(2008) 4077 final; 29 September 2008).
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http://ec.europa.eu/health/documents/community-register/ 30. Op cit 18.
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Accessed 27 April 2020. en_GB/document_library/Scientific_guideline/2016/03/
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Product Designation or Review of Orphan Designation Criteria 32. Guideline on the Scientific Application and the Practical
at the Time of Marketing Authorisation. EMA/2677/01 Rev. 2 Arrangements Necessary to Implement Commission Regulation
(8 May 2013). EMA website. http://www.ema.europa.eu/docs/ (EC) No. 507/2006 on the Conditional Marketing Authorisation
en_GB/document_library/Regulatory_and_procedural_guide- for Medicinal Products for Human use Falling Within the Scope of
line/2009/09/WC500003783.pdf. Accessed 27 April 2020. Regulation (EC) No. 726/2004 (EMA/CHMP/509951/2006,
18. Rare Disease (Orphan) Designations. EMA website. https:// Rev.; 25 February 2016). EMA website. http://www.ema.
www.ema.europa.eu/en/medicines/ema_group_types/ema_ europa.eu/docs/en_GB/document_library/Scientific_guide-
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20. Submitting annual reports on medicine development. EMA 15 December 2005). EMA website. http://www.ema.europa.eu/
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al-reports-medicine-development. Accessed 27 April 2020. 34. Sutent Scientific Discussion. EMA website. http://www.ema.
21. Checklist for Sponsors Applying for the Transfer of Orphan europa.eu/docs/en_GB/document_library/EPAR_-_Scientific_
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Rev. 6 (13 February 2020). EMA website. http://www.ema. Accessed 27 April 2020.
europa.eu/docs/en_GB/document_library/Regulatory_and_pro- 35. Zavesca Procedural steps taken and scientific information after
cedural_guideline/2009/09/WC500003786.pdf. Accessed 27 the authorization. EMA website. http://www.ema.europa.
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Designations From One Sponsor to Another (ENTR/6283/00 Rev.

36. Adaptive Pathways. EMA website. http://www.ema.europa.

eu/ema/index.jsp?curl=pages/regulation/general/general_con-
tent_000601.jsp&mid=WC0b01ac05807d58ce. Accessed 27
April 2020.
37. 15 Years of EU Orphan Medicines Regulation: The Next
Chapter. EURORDIS website. https://www.eurordis.org/
news/15-years-eu-orphan-medicines-regulation-next-chapter.

Chapter 41

Chapter 42
Combination Products
Updated by Claudia Ising, FRAPS, RAC
OBJECTIVES □ Regulation (EC) No. 1394/2007 on advanced

therapy medicinal products (ATMPs)
□ Understand definition and types of combination
products □ Community procedure for the authorisation
and supervision or medicinal products for
□ Understand the prerequisites for classifying human and veterinary use and establishing
combination products correctly in the EU European Medicines Agency, Regulation (EC)
No. 726/2004
□ Understand the regulatory pathway for combi-
nation products □ MEDDEV 2.1/3 Rev. 3 Borderline Products,
drug-delivery products and medical devices
□ Understand specific requirements for the qual-
incorporating as an integral part, an ancillary
ity management system
medicinal substance or an ancillary human
□ Obtain information related to classification and blood derivative
conformity assessment
□ Manual on Borderline and Classification in the
□ Review examples of products where medical community Regulatory Framework for Medical
device regulation applies Devices, Version 1.17
□ EMA/37991/2019, Rev. 1, 21 October 2019

Questions and Answers on Implementation
DIRECTIVES, REGULATIONS AND GUIDELINES of the EU MDR and EU IVDR (2017/745 and
COVERED IN THIS CHAPTER 2017/746)
□ European Medical Devices Regulation (EU MDR)
2017/745 (entered into force 25 May 2017, date
of application (DoA) 26 May 2020, prolonged by
Introduction
The conceptual delineation between medicinal products
regulation 2020/561 to 26 May 2021)
and medical devices is important, as this determines the
□ European In Vitro Diagnostic Medical Devices required regulatory approval pathway. When devices
Regulation (EU IVDR) 2017/746 (entered into and medicinal products are placed on the market
force 25 May 2017, (DoA) 26 May 2022) together, distinction is made by which component’s
action is principal and which is ancillary. EU MDR
□ Directive 2001/83/EC of the European Article 1(8) sets the regulatory framework for medical
Parliament and of the Council on the Community devices with ancillary medicinal substance.
code relating to medicinal products for human • Combination products with principal medic-
use, as amended inal substance are regulated as medicinal

Chapter 42
products under Medicinal Products Directive will determine which regulatory pathway to use,
2001/83/EC (MPD). depending on the product’s materials, mode of action
• For medicinal products with an integral med- and interaction with a patient. In addition to drug-de-
ical device Article 117 of EU MDR 2017/745 vice combinations, other examples include device-blood
amends Annex I to Directive 2001/83/EC, products, device-tissue products, device-cosmetics or
Point 12 of Section 3.2) and introduces a new device-nutritional supplements. However, this chapter
requirement for notified body involvement. discusses only combinations of medical devices and
• Combination products with ancillary devices, medicinal products and companion diagnostics.
e.g., for administration of medicinal products, Of the above configurations, drug-device combi-
are distinguished in: nation products are by far the most prolific, may be the
o single integral products (e.g., prefilled most controversial in terms of regulatory framework
syringes, pens, transdermal patches, pre- and present significant challenges to attaining market-
filled inhalers) ing approval.
o co-packaged devices (e.g., reusable pen for Systems and procedure packs, sometimes referred
insulin cartridges, tablet delivery systems) to as kits, as defined by EU MDR Article 22, are out-
o devices obtained separately (Article 1(9)) side the scope of this chapter.
• Devices with the intended purpose to be sys-
temically absorbed by the body (invasive device Developing a Regulatory Strategy to
via orifice or applied to the skin) require noti- Determine Registration Pathway
fied bodies (NBs) to obtain scientific opinion A regulatory professional must consider four areas when
from EMA or the competent authority. developing a drug-device combination product regula-
• Borderline products are unclear about the tory strategy:
applicable regulatory pathway. Under EU 1. primary mode of action (PMOA)
MDR and EU IVDR, EMA’s scientific com- 2. questions to consider
mittees may be consulted. 3. directives, regulations, guidance documents,
application selection
Novel technologies and different materials (e.g., 4. national regulations and guidance document
advanced cell therapy and tissue-engineered products) requirements
may lead to combined advanced therapy medicinal prod-
ucts (combined ATMPs), when devices are an integral With the numerous combination possibilities of devices
part of the product. Procedural advice on their evalu- with other products, EU MDR has not defined com-
ation in the Centralised Procedure is regulated under bination products per se, but does delineate which
(EC) No. 1394/2007 (not covered in this chapter). combination products fall under the EU MDR, EU
So-called ‘companion diagnostics’ are in vitro IVDR or MPD or other regulation. EU MDR, Article
diagnostics that identify suitable patients for safe and 1, Point 8 states “any device, that incorporates, as an
effective treatment by specific medicinal products. integral part that would be considered a medicinal
They are regulated under the IVDD and the EU In product that has an action ancillary to that medical
Vitro Diagnostic Regulation (EU IVDR) (2017/746) device, shall follow EU MDR requirements due to its
with (DoA) 26 May 2022. Under the EU IVDR, a new mode of action.” Further, Point 9 states “any device used
classification system and the obligation for conformity to administer a medicinal product shall be governed by
assessment by a NB are introduced. Details on the con- the EU MDR unless the product is formed of a single
sultation procedure involving the NB and competent integral product which shall be governed by the MPD.”
authority or EMA will be announced by EMA. It should be noted that Article 1, Point 10 states “prod-
The number of combination drug-device products incorporating tissues or cells of human origin also
ucts continues to grow, with transdermal patches and may comply with Regulation (EC) 1394/2007,”2 which
drug-eluting stents comprising most of the market, is not covered in this chapter.
which is expected to top $177 billion by 2024.1 This
growth signifies more companies are investing in novel
PMOA
technologies, which will prompt changes to EU regula-
A combination medical device-medicinal product’s clas-
tory requirements.
sification essentially is determined by its PMOA and
This chapter provides practical guidance on bor-
the product’s auxiliary component(s), how they inter-
derline issues concerning these combination products,
face, the nature of the nondevice component and, finally,
followed by an explanation of regulatory strategy. The
how it is labelled and marketed.
specific drug-device combination and its components

Definitions Related to PMOA Determination The legal definition of a “medicinal product” in

Although medical devices and medicinal products in Directive 2001/83/EC Article 1(2) is:
Europe have been defined in the respective regula- “any substance or combination of substances pre-
tions or directives, their use in combination is further sented as having properties for treating or preventing
described in the medical device guidance document, diseases in human being or any substance or com-
MEDDEV 2.1/3 Rev. 3, on borderline products, drug-de- bination of substances which may be used in or
livery products and medical devices incorporating, as an administered to human beings either with a view to
integral part, an ancillary medicinal substance or ancillary restoring, correcting or modifying physiological func-
human blood derivative. MEDDEV documents are non- tions by exerting a pharmacological, immunological
binding on the authorities and, therefore, not legally or metabolic action or making a medical diagnosis”
enforceable, making them comparable to harmonised
standards describing the current state of science. The PMOA is self-evident in the vast majority of com-
The legal definition of a “medical device” in EU bination products.
MDR Article 2, Point 1 is:
“Any instrument, apparatus, appliance, software, Borderline Products Definition:
implant, reagent, material or other article intended According to MEDDEV 2.1/3 Rev. 3, borderline prod-
by the manufacturer to be used, alone or in com- ucts are those for which it is unclear from the outset
bination for human beings for one or more of the whether they fall under the EU MDR (stated cur-
following specific purposes: rently as MDD and Active Implantable Medical Devices
• diagnosis, prevention, monitoring, predication, Directive (AIMDD), which have been consolidated into
prognosis, treatment or alleviation of disease the EU MDR) or the MPD. It is challenging to assess
• diagnosis, monitoring, treatment, alleviation of, combination product registration pathways and, there-
or compensation for, an injury or disability fore, nearly all combination products can be categorised
• investigation, replacement or modification of as borderline products.
the anatomy or of a physiological or pathologi- Note: borderline products not considered combina-
cal process or state tion products are outside the scope of this chapter.
• providing information by means of in vitro Changes from the MDD to EU MDR have real-
examination of specimens derived from the ised a new process for handling borderline products,
human body, including organ, blood and tis- described briefly in the regulation’s preamble. To estab-
sue donations and which does not achieve its lish a consistent process across all Member States, the
principal intended action by pharmacological, Commission shall consult with the Medical Device
immunological or metabolic means; in or on Coordination Group (MDCG) to determine whether
the human body, but which may be assisted in a product falls under the scope of the EU MDR or the
its function by such means MPD. Part of this process shall ensure an appropriate
level of consultation with the applicable agency, i.e.,
The following products also shall be deemed to be med- EMA. The MDCG is responsible for implementing
ical devices: ‘acts’ that make decisions on regulatory status, including
• devices for the control or support of whether a product falls under the definition of a medi-
conception cal device, medicinal product or both.
• products specifically intended for the clean-
ing, disinfection or sterilisation of devices as Questions to Consider
referred to in Article 1(4) and those referred to In addition to specific EU MDR requirements, a com-
in the first paragraph of this point.” pany wanting to market a combination product should
evaluate a series of regulatory questions to determine
To be classified as a medical device, the product must, which legal framework is applicable:
among other preconditions “…not achieve its principal
intended action by pharmacological, immunological or Question 1. Is a medicinal product included?
metabolic means; in or on the human body, but which The manufacturer should assess whether the product
may be assisted in its function by such means.” This contains, as an integral part, a medicinal product or
means the medical device function is achieved princi- is used to administer a medicinal product. Common
pally by mechanical means, including, but not limited examples include a product containing a medicinal
to, mechanical action, physical barrier or replacement coating or a drug-injection device. A medicinal prod-
of or support to organs or body functions (MEDDEV uct also may be co-packaged and marketed with the
2.1/3 Rev. 3 (A2.1.1.1)). device. If the medicinal product is sold separately (i.e.,

Chapter 42
not included in the device packaging), it is a medicinal “All devices incorporating, as an integral part, a
product and not a medical device. substance which, if used separately can be considered
to be a medicinal product as defined in Article 1 of
Question 2. Is the substance a medicinal product? Directive 2001/83/EC and which is liable to act upon
It must be determined whether a “substance, if used the body with action ancillary to that of the devices, are
separately is considered … a medicinal product.” Many in Class III.”
substances may be used in different ways and for differ- In addition, EU MDR Article 1, Point 8, second
ent indications. Examples include: paragraph states: “However, if the action of that sub-
• surface tension-reducing substances used to stance is principal and not ancillary to that of the device,
reduce foaming in bubble oxygenators but also the integral product shall be governed by Directive
used for the same purpose in treating certain 2001/83/EC or Regulation (EC) No. 726/2004 of
stomach conditions the European Parliament and of the Council(1), as
• vitamin E (alpha-tocopherol) used as an applicable. In that case, the relevant general safety and
oxygenation enhancer in certain pathogen performance requirements set out in Annex I to this
reduction processes Regulation shall apply as far as the safety and perfor-
• heparin solutions to rinse laboratory glassware mance of the device part are concerned.”
to prevent clotting when used with blood in Subtle but important differences exist between
the laboratory these two statements, primarily concerning the inter-
• human growth hormone in combination with pretation of what a medicinal product is “defined in” or
a mechanical scaffold to promote bone growth “within the meaning of.” There is a growing tendency
in large bone defects that will not heal com- to use an all-encompassing interpretation of what con-
pletely by themselves stitutes a medicinal product. As a result, a conformity
assessment consistent with Class III is performed in
National competent authorities and, consequently, NBs the majority of drug-device combination products. The
and courts of justice tend to consider any substance or resulting pharmaceutical consultation process is dis-
chemical with any pharmacological, metabolic, immu- cussed later in this chapter.
nological and, at times, even nutritional (as a precursor
to metabolic) property as falling within the medicinal Question 4. What is the principal component?
product definition. With differences in regulatory What is the product’s principal component, and what
requirements for the available pathways, a manufac- is its auxiliary component? Theoretically, the PMOA
turer designing a combination product should establish can be determined by deleting one component and
definitively the planned product’s correct classification. then assessing whether the intended use still is pos-
sible. If the intended use no longer is possible, the
Question 3. Does the substance act on the human deleted component provides the PMOA. For instance,
body? in a dressing releasing an antibiotic substance into the
A further consideration from Article 1, Point 8 is, “… wound to combat an infection, the PMOA clearly is a
and that has an action ancillary to that of the device …” pharmacological intervention. But a dressing with par-
This statement is more complicated than it first may affin to soothe and mechanically protect a burn wound
appear and is explained best by an example: a wound is a device, with paraffin as an auxiliary pharmaceutical.
dressing containing solidly embedded silver particles. If considered separately, the paraffin may be used as a
It has been demonstrated the silver is not released medicinal product.
into the wound. The manufacturer claims the silver is
used only to reduce microbial colonisation inside the Question 5. What are the intended product claims?
dressing to extend the dressing’s duration of use (not The product’s configuration is a primary factor in
to enhance pathogen load reduction in the wound), so determining the pathway to CE marking. Separately
this is not considered a combination product. However, packaged components of a drug-device combination
if any of these conditions is not met, a consensus pub- intended to be used together are likely to have major
lished by the European Commission (the Manual on consequences. For example, when a medicinal prod-
Borderline and Classification in the Community Regulatory uct and a syringe (drug-delivery device) are packaged
Framework for Medical Devices Version 1.17 09-2015,3 and sold separately, each requires individual approval
Section 8.15) categorises the product as Class III under or clearance. However, if the medicinal product and
MDD Rule 13, Annex IX, dealing with medical device syringe are packaged together as a prefilled syringe, the
classification (Rule 13 now may be considered under product is considered a combination product and will
EU MDR Rule 21, Annex VIII): be governed under the MPD. Therefore, the product’s

configuration when placed on the EU market plays an patch used to deliver a medicinal product.
important role in defining the PMOA and intended These are medicinal products governed
product claims. by the MPD, although the general safety
and performance requirements for medical
Directives, Guidance Documents Selection of devices also must be met.
Application • Article 1, Point 9 states, “Any device which is
In the EU, a combination product is regulated by either intended to administer a medicinal product
the EU MDR or the MPD. In general, the product’s as defined in Point 2 of Article 1 of Directive
PMOA or function determines how it is classified and 2001/83/EC shall be governed by this
regulated. In contrast to US regulations, in the EU, Regulation, without prejudice to the provi-
a combination product can never be both a pharma- sions of that Directive and of Regulation (EC)
ceutical product and a medical device. Adding to this No. 726/2004 with regard to the medicinal
complexity is that no clear definition or specific regula- product.”
tion exists for combination products. However, this does o An example is an insulin pump or syringe
not preclude meeting requirements from both regula- intended for parenteral administration of
tions, i.e., a medicinal product with a device component medicinal products. These medical devices
still must comply with EU MDR Annex I, General are governed exclusively by the EU MDR.
Safety and Performance Requirements. A regulatory • Point 9 further states, “However, if the device
professional must consider a complex framework of intended to administer a medicinal product
regulations before implementing an appropriate and and the medicinal product are placed on the
suitable regulatory strategy. market in such a way that they form a single
Key references to combination products in the cur- integral product which is intended exclusively
rent EU MDR are summarised as: for use in the given combination and which
• Article 1, Point 8 states, “Any device which, is not reusable, that single integral product
when placed on the market or put into service, shall be governed by Directive 2001/83/EC or
incorporates, as an integral part, a substance Regulation (EC) No. 726/2004, as applicable.
which, if used separately, would be considered In that case, the relevant general safety and
to be a medicinal product as defined in Point 2 performance requirements set out in Annex
of Article 1 of Directive 2001/83/EC, includ- I to this Regulation shall apply as far as the
ing a medicinal product derived from human safety and performance of the device part of
blood or human plasma as defined in point the single integral product are concerned.”
10 of Article 1 of that Directive, and that has o An example is a disposable syringe pre-
an action ancillary to that of the device, shall filled with insulin or another drug, or a
be assessed and authorised in accordance with disposable, prefilled drug delivery device
this Regulation.” such as a pen injector. These products are
o Some examples include heparin-coated classified as medicinal products but also
catheters, platelet irradiation solutions must meet additional device safety and
for the reduction of pathogen load, joint performance requirements. In addition,
replacements coated with bone growth a reusable pen injector used to dispense
factor or in vitro fertilisation media. insulin or another drug is classified as a
• Point 8 further states, “However, if the action medical device.
of that substance is principal and not ancil- • Article 117 amends Directive 2001/83/EC,
lary to that of the device, the integral product Point 12 of Section 3.2. and is replaced by the
shall be governed by Directive 2001/83/EC following: “‘(12) Where, in accordance with
or Regulation (EC) No. 726/2004 of the the second subparagraph of Article 1(8) or
European Parliament and of the Council (1), the second subparagraph of Article 1(9) of
as applicable. In that case, the relevant general Regulation (EU) 2017/745 of the European
safety and performance requirements set out in Parliament and of the Council (*), a product
Annex I to this Regulation shall apply as far as is governed by this Directive, the marketing
the safety and performance of the device part authorisation dossier shall include, where
are concerned.” available, the results of the assessment of the
o Examples include a photodynamic ther- conformity of the device part with the relevant
apy (PDT) drug activated using a specific general safety and performance require-
wavelength laser device or a transdermal ments set out in Annex I to that Regulation

Chapter 42
contained in the manufacturer’s EU declara- pathway, medicinal product registration pathway or a

tion of conformity or the relevant certificate combined medical device registration pathway/pharma-
issued by a notified body allowing the manu- ceutical consultation procedure.
facturer to affix a CE marking to the medical
device.” Registration Pathway
If the dossier does not include results of the This section is intended to discuss the overall regulatory
conformity assessment, the involvement of a pathways for combination products, including the phar-
notified body is required. maceutical consultation procedure.
Please refer to other chapters in this book for
Therefore, based on a marketed drug-device combination’s further details on medicinal product registration and
PMOA, intended use and configuration, either the EU medical device registration pathways.
MDR or the MPD is the governing regulation. Selecting
the correct regulatory pathway can be a complex pro- Medical Device Regulation and Classification
cess, and sources, such as definitions in the regulations, Classification of medical devices in the EU MDR is in
directives and supporting guidance documents, must Article 51, which is defined further by rules in Annex
be considered. Ultimately, it is possible to consult with VIII (see Chapter 15 in this book for more detail).
various entities for borderline drug-device combinations, Traditional combination product classifications have
particularly for new, novel products. This will be discussed been stated in different guidance documents as noted
further in the registration pathways section. previously, with no clear legal basis for categorising
these products. The EU MDR now includes rules for
National Regulations and Guidance Document borderline or combination products that in previous
Requirements directives left significant room for interpretation. With
EU Member States have varying opinions on classify- the addition of Rules 20 and 21, several previous bor-
ing specific product types or combinations thereof. In derline products now are considered medical devices
addition, a comprehensive set of well-defined rulings governed by the regulation, with supporting legal basis.
addressing both borderline and combination products is Rule 12 (this was MDD Rule 11) for active devices
not available. intended to administer and/or remove medicinal prod-
Therefore, manufacturers should not rely solely on ucts from the body remains the same.
specific national guidance when assessing borderline Interpretation within these rules still can vary;
products if the intention is to market a combination however, this has been clarified by guidance on devices
product throughout the EU. Drug-device combination intended to administer medicinal products and prod-
product requirements may be viewed differently across ucts absorbed or dispersed in the human body. A drug
Member States; however, the EU MDR defines these or device’s PMOA still must be considered in full
combination products more specifically, which should context of the EU MDR and the MPD, meaning all
remove most ambiguity. Manufacturers should consult requirements should be reviewed prior to determining
the legislation and determine classification in con- classification. When questions concerning the proper
junction with regulatory agencies and/or professional regulatory pathway remain, a more formal method has
advisers as needed. been introduced with the EU MDR.
A manufacturer must be aware that although a
CE Mark is valid in all EU jurisdictional territories Regulatory Classification Determination
and Switzerland, the notified body and its rulings are Given some combination products’ complexity, coupled
governed by the Member State in which it is located. In with not always clear definitions and regulations, addi-
other words, a German notified body is governed by its tional time may be needed to determine a clear pathway.
national competent authority, ZLG (BfArM), but the When the notified body and manufacturer disagree
resulting CE Mark is valid throughout the EU. If, for about a classification, the notified body will request a
instance, France or the Netherlands disagrees with the ruling through its Member State to be administered
combination product classification, it may invoke the by the MDCG. Marketed products’ regulatory status
EU MDR’s preventive health protection measures to in the EU is governed by Article 4, which outlines
protect its citizens’ (Article 98) health and well-being. whether they are regulated as a medical device, medical
Such a procedure may have various results, but those are device accessory or another category. When MDCG
outside the scope of this chapter. makes this determination, implementing ‘acts’ provide
Once the legal framework for combination product the product category and regulatory status. MDCG
registration in the EU is determined, the manufacturer is a coordination group that relies on individuals from
follows the appropriate medical device registration

each Member State and works with expert panels and/ report development and application of the scrutiny pro-
or technical working groups to determine classifica- cedure during technical documentation review.
tion. If necessary, the manufacturer can file a formal The pharmaceutical consultation procedure has
complaint against its notified body with the national been included as part of the EU MDR, with specific
competent authority, which then must review the case. requirements for devices incorporating a medicinal sub-
This should not be necessary, because when there is a stance. This procedure is detailed in Annex IX, Section
classification dispute, the notified body, MDCG and 5.2 and is summarised in the following section.
the Commission consult, resulting in a classification
ruling that determines which regulation would govern The Pharmaceutical Consultation Procedure
drug-device combination products. A product classified as a “device incorporating, as an
It should be noted that, at publication, this proce- integral part, an ancillary medicinal substance or an
dure is stated in the EU MDR article; however, a formal ancillary human blood derivative,” or combination
process has not been implemented yet. It is anticipated product, must be reviewed by any Member State’s
the MDCG will publish policy or instructions on national competent authority or EMA. The notified
administering each of its tasks defined under Article body may choose the reviewing agency but, in practice,
105. This includes methods of assisting Member States’ the choice is limited by two factors:
competent authorities in medicinal product and med- • manufacturer preference
ical device classification and regulatory status for the • national competent authority availability
European market.
The manufacturer also can lodge a formal com- Essentially, this may reduce the choice of authorities to
plaint against a national competent authority with the Netherlands, Germany or France. Other agencies
the European Commission. If the complaint’s result either refuse to perform the review or have extremely
is not acceptable, the manufacturer can go to the ulti- long waiting periods. The Dutch agency has descriptors
mate arbiter of appeals, the European Court of Justice of what they expect regarding data, format and docu-
in Luxembourg. Although the procedure itself is not mentation. Dossier criteria focus on product safety and
prohibitively expensive, by this point, most small and “usefulness,” with less emphasis on such other aspects
mid-sized manufacturers will have exhausted their as pharmacodynamics and pharmacokinetics. According
funds and abandoned the effort due to lost time and to MEDDEV 2.1/3 Rev. 3, “safety” is defined as the
sales opportunities. However, there always is a possibil- potential inherent risks assessed against the benefit
ity of a positive outcome. The important consequence to be obtained, and “usefulness” is the medicinal sub-
is that such adjudications are not only binding law in stance’s suitability to achieve its intended ancillary
all EEA countries and Switzerland, but they also set a action. As it is important to limit the dossier’s scope to
precedent through this decision process and become the data relevant to this assessment, these agencies actually
basis for regulatory status in subsequent cases. In addi- encourage the manufacturer to meet with them prior to
tion, for many Class I and IIa and some IIb products, submission. Such discussions’ results are binding on the
the verdict may have implications for submissions in manufacturer. To prevent future misunderstandings, the
Canada and Australia and countries with similar device manufacturer always should summarise these discus-
classification systems. sions in writing and share the summary with the agency
In conclusion, the best way to resolve any con- to ensure agreement.
tentious classification issues is to reach an outcome The submission’s format is described in some detail
satisfying all parties, even if the national competent in MEDDEV 2.1/3 Rev. 3, Section C3. The guidance
authority would prefer to escalate the matter. details specified drug submission parts in the Common
Technical Document (CTD) format.
Additional Conformity Assessment Requirements The manufacturer submits the documentation to
Conformity assessment routes for medical devices in the notified body, which verifies the substance’s use-
the EU MDR are stated in Article 52, which is further fulness as part of the combination product’s device
defined by Annex IX, X and XI (see Chapter 20 in this constituent. The device’s intended purpose and how
book). These annexes are covered in greater detail in drug-device constituents are used together are also
that chapter, but additional procedures in Annex IX and considered. The notified body then seeks a scien-
X are specific to products that fall under the category tific opinion from a selected competent authority or
of combination devices. As an example, Class IIb active EMA, referenced as ‘the medicinal product authority.’
devices intended to administer and/or remove medicinal Subsequently, the medicinal product authority checks
products from the body have additional requirements, the documentation’s completeness and format. If the
such as notified body clinical evaluation assessment submission is rejected, the manufacturer usually has

Chapter 42
one more opportunity to submit, but the review clock The notified body shall seek the medicinal product
stops between the original and updated submissions. authority’s opinion to ensure change(s) have no negative
If the submission is accepted, the review may lead to impact on the previously established risk or benefit.
multiple question-and-answer cycles. The overall review The medicinal product authority has 60 days to provide
process takes about 12 months, but can deviate signifi- its opinion. Whether the medicinal product authority
cantly from this timeframe. In France and Germany, provides a favourable or unfavourable opinion, the noti-
the review timeline is less predictable. Ancillary blood fied body shall deliver information to the applicant and
derivatives and certain new pharmaceuticals or exist- update the EC technical documentation assessment
ing products with a new use (e.g., drug-eluting stents) certificate as appropriate.
are subject to submission and review by EMA and its
Committee for Advanced Therapies (CAT). EU IVDR
Evidence of conformity with the EU MDR’s general Another category of combination products less preva-
safety and performance requirements is expected to be lent in the medical device industry is in vitro diagnostic
included in the product or product family’s technical doc- (IVD) devices used in conjunction with medicinal
umentation. EMA developed the Guideline on the quality products; these commonly are known as companion
requirements for drug-device combinations (EMA/CHMP/ diagnostics (CDx). The use and application of compan-
QWP/BWP/259165/2019),4 which provides guidance ion diagnostics, like drug-device combination products,
on quality requirements for drug-device combination are increasing in response to current personalised
products (DDCs) that are integral and nonintegral to medicine trends. These products are highlighted in this
the medicinal products, i.e., copackaged and separately chapter because, while they are regulated under the EU
obtainable. The guidance clarifies EMA’s expectations on IVDR, the classification, conformity assessment and
the documentation in the quality part of the dossier for technical documentation process is quite similar to that
marketing authorisation applications (CTD) or variation of medical devices. However, there is no defined consul-
applications, package leaflet and label. For nonintegral tation process for medicines and CDx at this time; they
and separately available devices, requirements depend are regulated separately. EMA has published a concept
on device specifics and potential risks for the medicinal paper on how medicinal products and CDx may be
product’s quality, safety and/or efficacy. linked in the future. CDx devices in the EU IVDR
The medicinal product authority must take the are classified as Class C, which requires a high level of
manufacturing process and data related to the incor- review similar to that of Class IIb medical devices. For
porated substance’s usefulness into consideration. This expected dossier content in combination with pharma-
opinion shall be provided within 210 days of receipt ceuticals, refer to Guideline on the quality requirements
of all necessary documentation. This is a consider- for drug-device combinations (EMA/CHMP/QWP/
able amount of time for medical device development. BWP/259165/2019).5 [For nonintegral and separately
However, it is a rather reliable timeline a manufacturer available IVDs, documentation requirements depend on
can use for planning purposes. The pharmaceutical con- product specifics and potential risks for the medicinal
sulting process may undergo further process refinement product’s quality, safety and/or efficacy. IVD products
or definition through EU MDR implementation. are covered in more detail in Chapter 13.
Once the national competent authority or EMA
review results are final, a “recommendation” will be Quality System Requirements
issued, which the notified body must follow. A negative One of the most challenging aspects of developing a
national competent authority opinion means a combi- combination product is determining the appropriate
nation product cannot be placed on the market. quality system requirements. As stated previously, in the
Several issues will impact the review: EU, a combination product cannot be both a medic-
• data submitted to other agencies, e.g., the US inal product and a medical device. However, during
Food and Drug Administration (FDA) combination product development, applicable quality
• use of an active substance master file (ASMF) system requirements for both medicinal products and
for pharmaceuticals as a “fast track” approach medical devices must be considered. As noted above,
• careful labelling development to avoid “drug” specific additional procedures must be applied as part of
claims conformity assessment to ensure general safety and per-
formance requirements are met. Manufacturing, testing
The applicant shall notify the notified body of changes and overall product realisation for combination devices
made to an ancillary substance incorporated into a may present more challenges, such as the need to com-
medical device. The consultation process for a change ply with specific quality system requirements related to
versus new product introduction is relatively the same.

medical devices, which may differ from medicinal prod- determining medical devices and medicinal products’
ucts’ requirements. These requirements are discussed in regulatory status in the EU. Some questions are answered
detail in other chapters of this book. in the “Questions and Answers on Implementation of
the Medical Devices and In Vitro Diagnostic Medical
Labelling Requirements Devices Regulations ((EU) 2017/745 and (EU)
A combination product with a medical device PMOA 2017/746).7
must meet EU MDR labelling requirements, while
a combination product with a medicinal product Case Studies
PMOA must meet MPD labelling. For DDCs, refer to A. Heparin Coating of an Active Implantable
Guideline on the quality requirements for drug-device com- Medical Device (Artificial Heart) Intended for
binations (EMA/CHMP/QWP/BWP/259165/2019). Auxiliary Heart Pump Function in Severe Cardiac
Labelling requirements for medicinal products Deficiency
shall follow EU legislation (Commission Implementing This combination product contained a tiny quantity
Regulation (EU) No. 520/2012 (Articles 25 and 26). (1/20,000th) of the daily heparin dosage to achieve
systemic anticoagulation and was bound solidly to the
Postmarket Surveillance Requirements pump material. However, its mere presence necessitated
Postmarket surveillance requirements for medical a pharmaceutical consultation procedure under the
devices and medicinal products use similar processes for MDD, Annex IX, Rule 13 (EU MDR, Annex VIII,
gathering information related to adverse event report- Rule 14), Class III procedures.
ing; however, there still are significant differences. A This example is quoted in MEDDEV 2.1/3 Rev. 3,
combination product under the medical device legal section B.4.1 (first example).
framework must implement a postmarket surveillance
system. Combination products using the medicinal B. In Vitro Fertilisation and Other Solutions to
product legal framework must gather postmarket expe- Transport Transplant Organs or Tissue (Simulated
rience. These requirements are discussed in detail in
Environment)
other chapters of this book.
These fairly complex and largely empirically formu-
lated products have been used in millions of EU and
Additional Comments for EU MDR/EU IVDR US patients over the last 25 years. Despite this, whistle
The new EU MDR and EU IVDR were published in blower action almost resulted in an (unintended) clas-
May 2017, with defined transition periods for their sification of one such product as a drug because several
application date on 26 May 2020 and 26 May 2022, national competent authorities maintained the media
respectively. As a response to the global COVID- had a metabolic action on the spermatocytes and fer-
19 crisis, the EU Commission adopted regulation tilised oocyte. After approximately three years of tough
2020/561, which amends EU MDR 2017/745 and also negotiations, the European Commission successfully
prolongs the entry into force date to 26 May 2021. forged a compromise, which is published in the Manual
While the regulations have been published, there still on Borderline and Classification in the Community
are procedures within the regulations that require full Regulatory Framework for Medical Devices, Section 4.3.
implementation. As mentioned, the regulatory status This compromise means products will be treated as
determination process through the Commission and Class IIb medical devices if no medicinal substance,
MDCG still needs to be defined further. ‘Acts’ and no blood derivative and no animal-based derivative is
potentially common specifications are expected to be used. If the product contains one or more of these com-
published that define how the EU MDR or MPD will ponents, the applicable route will apply. For example,
regulate combination products. the use of human serum albumin (HSA) necessitates
Specific guidance documents published as a review by EMA, which easily adds 18 months to the
MEDDEVs and other national guidance written to the review process and a sizeable fee. In addition, HSA is
AIMD, MDD and IVDD must be updated. Multiple subject to batch release.
sections of the regulations are inconsistent with require-
ments in the current directives. It is not clear at the C. Set for Local Anesthesia With Lidocaine
time of writing this chapter what will happen with the In this example, the packaging configuration plays a
aforementioned borderline manual6 or other combi- major role. Unlike the US, where such a product may be
nation product-related documents such as MEDDEV subject directly to a medical device registration process,
2.1/3. Updates of these documents most likely will in the EU, the classification depends on whether:
occur once the framework has been established for

Chapter 42
• the lidocaine has been approved as a generic professional’s expertise and contribution are paramount
or branded drug and is added as an approved, to product development. The regulatory professional will
labelled entity to the set provide functional guidance to ensure sound regulatory
• it is sold separately as a drug but may be used strategies, leading to expeditious product approval.
with the device set The subject of combination product regulation con-
• it is “embedded” in the device set and has not tinues to evolve as different, innovative products, often
been labelled as an approved separate drug integrating new technologies, are developed. While
entity it is likely these innovations will require revision to
regulations and guidelines, the current methodologies
In the latter case only, the combination will be classified explored in this chapter provide the regulatory profes-
as Class III under EU MDR Rule 14 and subject to a sional a strong foundation to assess any future change.
pharmaceutical consultation procedure. This is an excel-
lent exercise to test whether a packaging configuration References
1. Report Predicts Significant Growth Global Drug-Device
omission or modification would result in a different Combination Products. Medical Product Outsourcing
PMOA. website. https://www.mpo-mag.com/contents/
view_breaking-news/2016-10-17/report-predicts-signifi-
D. Sunblock Cream With Embedded Titanium cant-growth-for-global-drug-device-combination-market.
Oxide for Vitiligo (Barrier) 2. Procedural advice on the evaluation of combined advanced ther-
Even though the product would qualify as a straightfor- apy medicinal products and the consultation of Notified Bodies in
ward medical device because of the mechanical action, accordance with Article 9 of Regulation (EC) No. 1394/2007.
EMA website. http://www.ema.europa.eu/docs/en_GB/docu-
the titanium oxide may be considered a medicinal ment_library/Regulatory_and_procedural_guideline/2010/07/
substance and, consequently, subject the product to EU WC500095323.pdf. Accessed 1 May 2020.
MDR, Annex VIII, Rule 14. The PMOA, though, is 3. Questions and Answers on Implementation of the Medical
physical and, consequently, the MDR applies. Devices and In Vitro Diagnostic Medical Devices Regulations
((EU) 2017/745 and (EU) 2017/746) EMA/37991/2019,
Rev. 1, 21 October 2019. https://www.ema.europa.
Conclusion eu/en/documents/regulatory-procedural-guideline/
In conclusion, to register combination products success- questions-answers-implementation-medical-devices-vitro-diag-
nostic-medical-devices-regulations-eu/745-eu-2017/746-tracke
fully in the EU, it is critical to understand: d-changes_en.pdf. Accessed 27 April 2020.
• what the products are 4. Draft Guideline on the Quality Requirements for Drug-Device
• the prerequisites for their correct classification Combinations (EMA/CHMP/QWP/BWP/259165/2019).
in the EU https://www.ema.europa.eu/en/documents/scientific-guideline/
draft-guideline-quality-requirements-drug-device-combina-
• how to select an appropriate regulatory tions_en.pdf. Accessed 1 May 2020.
pathway 5. Ibid.
• how to manage the regulatory status determi- 6. Manual on Borderline and Classification in the Community
nation process, as needed Regulatory Framework for Medical Devices version 1.17, 09-2015.
EC website. http://ec.europa.eu/DocsRoom/documents/12867/
attachments/1/translations/en/renditions/pdf. Accessed 27 April
As the variety of combination products continues to 2020.
expand, and regulations evolve accordingly, the regulatory 7. Op cit 3.

Chapter 43
Regulatory Information
Resources
Updated by Meredith Brown-Tuttle, FRAPS and Gert Bos, MSc, PhD, FRAPS
OBJECTIVES a valuable objective for a compliant regulatory team. In

addition, within the regulatory field, the transition to
□ Become familiar with information resources digital transactions and electronic data has resulted in
relevant to the regulated healthcare industry increased reliability, trustworthiness, usability and por-
tability of online information technology tools.
□ Learn where to access, retrieve and appraise
Given the fluidity of the global regulatory environ-
publicly available government, industry and
ment, regulatory professionals are expected to develop
association resources to find regulatory infor-
a strategy based on a variety of data streams: print (e.g.,
mation and generate regulatory intelligence
books and magazines), static electronic (e.g., e-newslet-
□ Recognise the value of regulatory intelligence ters and government websites) and interactive electronic
for use in business strategy development and resources (i.e., social media and webinars). With all of
compliance for the healthcare industry us moving to social distancing, virtual tools are rap-
idly replacing face-to-face training and other personal
interactions. This chapter discusses the value of each
Introduction data stream and provides a comprehensive review of
The pharmaceutical sector is regulated extensively at resources available to build EU regulatory intelligence
the EU level to protect public health and strengthen and support product substantiation.
the industry’s competitiveness through the continued
development of a single EU healthcare product mar- The EU Regulatory System for Medicines
ket. Regulatory professionals in the healthcare product The European medicines regulatory system is based
industry are faced with an ever-changing landscape in on a network of around 50 regulatory authorities from
the form of new and modified regulations, standards the 30 European Economic Area (EEA) countries (27
and industry practices. Compounding this variability EU Member States plus Iceland, Liechtenstein and
are company structure and focus changes, such as merg- Norway, the European Commission (EC) and European
ers, acquisitions and new product development. With Medicines Agency (EMA). This network makes the EU
an increased presence of RA professionals supporting regulatory system unique. UK (Brexit), Turkey (Turkxit)
due diligence and product development in early stages, and Switzerland (Swixit) are departing largely from the
many professionals find it challenging to move beyond coordinated approach.
a company’s perspective on regulatory requirements EMA and the Member States cooperate and share
to understanding how to comply with requirements expertise in assessing new medicines and new safety
as they are presented in the actual regulations. For information. They also rely on one another for infor-
regulatory professionals, this results in a specific set of mation exchange in medicines’ regulation, for example,
challenges requiring a proactive and vigilant approach reporting medicines’ side effects, oversight of clinical
to stay abreast of relevant independent healthcare trials and inspecting medicines’ manufacturing facilities
industry information. As such, information resource and good clinical practice (GCP), good manufacturing
identification and management of said information is practice (GMP), good distribution practice (GDP) and

Chapter 43
good pharmacovigilance practice (GVP) compliance. Medicinal products for pediatric use, orphan diseases,
This works because EU legislation requires each Member herbal medicinal products and advanced therapies are
State to operate to the same rules and requirements governed by specific rules.
regarding medicines’ authorisation and monitoring. These volumes are available for reference on the
European Commission website’s public health section.
EU Legal Framework for Medicinal Products for The webpage’s right, bottom corner “useful link” button
Human Use gives direct access to Eudralex.
An integral component of a regulatory professional’s Volume 1 is a compilation of relevant information
work is staying informed of the latest regulatory and from the OJ with respect to medicinal products for
legislative developments. This chapter reviews readily human use under the subheadings: directives, regu-
accessible electronic regulatory and legislative documents. lations, non-legislative acts and miscellaneous (court
The EU legal framework for medicinal products for decisions, commission communications and guide-
human use is intended to ensure a high level of public lines) along with the version history. In similar format,
health protection and to promote the functioning of Volume 5 compiles the body of EU pharmaceutical
the internal market, with measures that also encourage legislation for medicinal products for veterinary use.
innovation. It is based on the principle that placing Volume 2 contains a list of regulatory guidelines
medicinal products on the market is subject to a compe- related to procedural and regulatory requirements, such
tent authority granting a marketing authorisation. as renewal procedures, dossier requirements for Type
A large body of legislation has developed around this IA and IB variation notifications, summary of product
principle, with the progressive harmonisation of require- characteristics (SmPC), package information and classifi-
ments for granting marketing authorisations since the cation, label readability and package leaflet requirements.
1960s, which has been implemented across the EEA.1 Notices to Applicants (NTA) are prepared by
the European Commission, in consultation with the
Medical Product Legislation Member States’ competent authorities and EMA. These
The body of EU legislation in the pharmaceutical sec- notices have no legal force and do not necessarily repre-
tor is compiled in Volume 1 and Volume 5 of the Rules sent the Commission’s final views. If there is any doubt,
Governing Medicinal Products in the European Union, therefore, reference should be made to the appropriate
commonly known as Eudralex:2 EU directives and regulations. The first NTA was pub-
• Volume 1—EU pharmaceutical legislation for lished in 1986 and is regularly updated. NTAs now are
medicinal products for human use published in the following volumes:
• Volume 5—EU pharmaceutical legislation for • Volume 2A dealing with marketing authorisa-
medicinal products for veterinary use tion procedures
• Volume 2B dealing with application dossier
The basic legislation is supported by a series of guide- presentation and format
lines published in the following volumes of Eudralex: • Volume 2C dealing with regulatory guidelines
• Volume 2—Notice to applicants and regu-
latory guidelines for medicinal products for Volume 2A includes chapters on marketing authorisa-
human use tions, mutual recognition and referral procedures. The
• Volume 3—Scientific guidelines for medicinal chapter on the Centralised Procedure was deleted from
products for human use the NTA in July 2015. EMA is now responsible for the
• Volume 4—Guidelines for Good scientific evaluation of Centralised Procedure applica-
Manufacturing Practices for medicinal prod- tions for EU marketing authorisations for human and
ucts for human and veterinary use veterinary medicines.
• Volume 6—Notices to applicants and regu- This NTA volume also includes a chapter pro-
latory guidelines for medicinal products for viding guidelines on various variation category
veterinary use details. Information regarding human medicinal
• Volume 7—Scientific guidelines for medicinal products authorised centrally and nationally (Mutual
products for veterinary use Recognition Procedure or Decentralised Procedure)
• Volume 8—Maximum residue limits contained in NTA Chapter 7 has been transferred to
• Volume 9—Guidelines for pharmacovigilance the EMA and CMDh websites respectively.
for medicinal products for human and veteri- For CMDh, see ‘Transfer of information contained
nary use in Notice to Applicants, Volume 2A, Chapter 7.’
• Volume 10—Guidelines for clinical trial For EMA, see the webpages on:
• presubmission

Regulatory Information Resources
• postauthorisation for active substances used as starting materials. Part III

contains GMP-related documents, which clarify regula-
Any reference to Chapter 7 should be interpreted as a tory expectations.
reference to these webpages. However, guidelines and Volume 8 contains guidance on the application of
other interpretative documents that reference this chap- Council Regulation (EEC) No. 2377/90, as amended,
ter may be provided, as they represent the views of their which provides the legal framework for the establish-
authors. ment of maximum residue limits (MRLs) for medicinal
Volume 2B is concerned with the presentation of products for veterinary use.3
the application dossier and was first published as a sepa-
rate volume in 1998. It provides guidance for compiling European Device Regulation
EU MAA dossiers and is applicable to the Centralised, Approval processes for medical devices also followed
Mutual Recognition and Decentralised Procedures. The a harmonisation path in Europe with establishment
update takes international agreements on the common of the EU, but medical device regulation does not fall
technical document (CTD) structure and format into solely to any one agency.
account, which were agreed in November 2000 within Three EC directives that have been subject to peri-
the International Council on Harmonisation (ICH) odic amendment address approval of medical devices:
framework and includes further documents and revised 1. Implantable devices are regulated under
guidelines agreed since that time. Directive 90/385/EC.
Volume 2C provides various legally nonbinding 2. Most other devices are regulated under
regulatory guidelines related to procedural and regula- Directive 93/42/EC.
tory requirements. 3. In vitro diagnostic devices (IVDs) (i.e., used on
In similar format to Volume 2, Volume 6—Notice to substances produced by the body) are regulated
applicants and regulatory guidelines for medicinal products under Directive 98/79/EC.
for veterinary use, contains a list of regulatory guidelines
related to procedural and regulatory requirements, such The system is largely overhauled after several decades
as renewal procedures, dossier requirements for Type of functioning, and following a detailed process of
IA/IB variation notifications, summary of product char- stakeholder engagement, on 5 April 2017, two new
acteristics (SPC), package information and classification regulations on medical devices and IVDs were adopted.
for the supply, label readability and package leaflet Regulation (EU) 2017/745 of the European Parliament
requirements. and of the Council of 5 April 2017 on medical devices
Volume 3 contains scientific guidelines prepared by will replace Directive 90/385/EC and Directive 93/42/
the Committee for Medicinal Products for Human Use EC, the EU Medical Devices Regulation (EU MDR),
(CHMP), and Volume 7 contains scientific guidelines will cover all medical devices and implantable devices
prepared by the Committee for Medicinal Products for in the EU. Regulation (EU) 2017/746 if the European
Veterinary Use (CVMP) in consultation with the EU Parliament and of the council of 5 April 2017 on in
Member State competent authorities, to help applicants vitro diagnostic medical devices, the EU IVD Regulation
prepare MAAs for medicinal products for human and (EU IVDR), will replace Directive 98/79/EC. A transi-
veterinary use. Guidelines provide a basis for practical tional period applies to both regulations. The EU MDR
harmonisation of the manner in which the EU Member will become applicable in 2021; the EU IVDR in 2022.
States and EMA interpret and apply the requirements Until then, the directives remain in effect.
to demonstrate the directives’ quality, safety and efficacy The European Commission provides a range
criteria. They also help ensure MAAs are prepared in a of guidance documents to assist stakeholders in
manner EMA will recognise as valid. Volumes 3 and 7 implementing directives related to medical devices.
can be accessed directly via EMA’s website for scientific The Commission has adopted several implement-
guidelines for research development under human regu- ing measures based on the MDD. Most of the initial
latory and veterinary regulatory, respectively. guidance was focused on getting the new system
Volume 4 contains guidance for interpreting GMP started, including notified body designation, UDI,
principles and guidelines for medicinal products for central database, etc. More recent guidance on reg-
human and veterinary use laid down in Commission ulations related to technology are beginning to be
Directives 91/356/EEC, as amended by Directive developed. The key documents on recommendations,
2003/94/EC, and 91/412/EEC respectively. The guid- classification and other amending and implement-
ance is presented in three parts and supplemented by a ing legislation are provided by EC and can be
series of annexes. Part I covers GMP principles for the accessed on the Commission’s website under medical
manufacture of medicinal products. Part II covers GMP device sector.4 New publications are easily tracked

Chapter 43
on the docs-room: https://ec.europa.eu/docsroom/ of the relevant EU directive provisions.8 A complete list

documents?locale=en&keywords=medical%20device. of all MEDDEVs covering scope, field of application,
Eudamed is the European databank on medical definition, essential requirements, medical device clas-
devices. Its purpose is to strengthen market surveillance sification, conformity assessment procedures, clinical
and transparency for medical devices by providing investigations, clinical evaluations, notified bodies, mar-
national competent authorities with fast access to ket surveillance, transitional period, IVDs and more can
information. It also contributes uniform application of be found on the Commission website, as it is changing
the directives. Eudamed is a secure, web-based portal, on a very regular basis.
which serves as a central repository for information A number of committees and working groups play
exchanged among national competent authorities and a role in implementing the medical device directives
the Commission. It is not available yet, but once avail- and regulations.9 Practical working structures for imple-
able, will display several levels of access; some data will menting the medical device directives is described in
become publicly accessible.5 the Guidelines on Medical Devices, MEDDEV 2.15 Rev.
The list of published harmonised standards for 3 published by the European Commission Enterprise
medical devices is available on the standardisation and Industry Directorate General. An overview of the
website. The purpose of this website is to provide committee and working group structure is provided on
access to the latest lists of harmonised standards and the Commission website.
other European standards published in the OJ. In
Europe, standards are developed and agreed by three European Union Law
officially recognised EU standardisation organisa- EUR-Lex is an official website of EU laws and other
tions: the European Committee for Standardization public documents, published in the EU’s 24 official lan-
(CEN), the European Committee for Electrotechnical guages. The Official Journal of the European Union (OJ)
Standardization (CENELEC) and the European also is published on EUR-Lex.10
Telecommunications Standards Institute (ETSI).6 The OJ is a periodical published every day from
At this stage, the harmonised standards list is geared Tuesday to Saturday and includes information in all
toward the existing older legislation. Harmonisation of official EU languages. The linguistic coverage is greater
standards with the new regulations has begun but will for the four official languages of the founding Member
take several years to complete. States—Dutch, French, German and Italian. For the
The new approach notified and designated organ- other languages, translations are provided for the leg-
isations (NANDO) information system includes EU islation in force at the time of the accession of the
Member States, EFTA countries (EEA members) country in question and the texts adopted after this
and other countries with which the EC has concluded date. Some texts, particularly the older ones, are not
mutual recognition agreements (MRAs) and protocols available in the languages that were added during the
to the Europe agreements on conformity assessment and later accessions. It is the official compendium of all EU
acceptance of industrial products’ (PECAs) designated legal acts.11
notified bodies, established per directive. Lists of notified There are OJ series, subseries and special edi-
bodies can be searched on the NANDO website, which tions. There are two series: L—Legislation and
can be accessed from the European Commission’s web- C—Information and Notices (C stands for French
site. The lists include each notified body’s identification ‘communications’). Within these series, there are three
number and the tasks for which it has been notified; subseries: A—an OJ that is an annex of another, I—a
the lists are subject to regular updates. Member States one-off (isolated) OJ and M—a special edition in
shall designate a notifying authority to be responsible Maltese or an edition that is part of a backlog in a given
for setting up and carrying out the necessary proce- language. An OJ number comprises: the letter denoting
dures for notified body assessment, notification and the series (L or C), followed by up to three digits in
subsequent monitoring. A country-by-country list of some cases, followed by the letter denoting the subseries
notifying authority and accreditation bodies also is A and P for legislative acts published before 1967. CE
provided on NANDO’s website.7 Recently, NANDO denotes electronic documents published between 1999
started displaying triangles with exclamation marks to and 2014, the historical series.12
indicate designation is still formally in place, but some Several legal texts initially and officially published
supporting documents have not been updated to the in different OJ issues are combined as a ‘consolidated
Commission. This could be an early sign of poten- family’ in one easy-to-read document, including the
tial trouble. In addition, legally nonbinding guidance current status of the EU law. If any corrigendum is
documents or MEDDEVs, consensus statements and published after the last amending act was incorporated,
informative documents help ensure uniform application it will be consolidated immediately, unless it provides

only a minor change. In the latter instance, it will be EMA communications on important changes
included in the next consolidation. The publications to medicines’ authorisation to improve patient safety,
office consolidates EU regulations, directives and deci- which have been recommended by the Committee
sions. However, legal acts that will be in force for only a for Medicinal Products for Human Use (CHMP),
short time are not consolidated. Minor corrigenda in a the Coordination Group for Mutual Recognition
few languages are consolidated with the next modifier.13 and Decentralised Procedures—Human (CMDh) or
The EUR-Lex database covers many types of the Pharmacovigilance Risk Assessment Committee
texts produced mostly by EU institutions, but also by (PRAC), can be accessed via the patient safety page on
Member States, the European Free Trade Association the agency’s website.17
(EFTA), etc. The content is divided into sectors: 1— Summaries of opinion for medicines evaluated by
Treaties, 2—International agreements, 3—Legislation, the Committee for Medicinal Products for Veterinary
4—Complementary legislation, 5—Preparatory acts, Use (CVMP) and CHMP and those medicines cur-
6—Case-law, 7—National transposition measures, rently pending an EC decision can be accessed via this
8—References to national case-law concerning EU page. These summaries are replaced by full EPARs once
law, 9—Parliamentary questions, 0—Consolidated acts, the Commission has decided—taking EMA’s opinion
C—Other documents published in the OJ C series and into consideration—whether to grant the MA.18,19
E—EFTA documents.14 This page also provides information on human
Legislative procedures also are included in the medicines related to withdrawn applications, pae-
EUR-Lex database. A particular legislative proposal’s diatrics, rare disease designations, medicines under
lifecycle from the moment it is launched until it becomes evaluation, medicines for use outside the EU, refer-
law can be followed. It provides access to the documents rals, periodic safety update report single assessments,
involved, details about the procedure stage, each institu- postauthorisation safety studies, shortages catalogue
tion’s decisions, departments responsible, etc.15 and recommendations on medication errors. MRL
assessment reports, pending EC decisions on maximum
EU Agencies and Committees residue limits and referrals for veterinary medicines can
EMA is at the core of the EU’s medicine and health be accessed via this page as well.20,21
system and aims to protect human and animal health. EMA has seven scientific committees and a num-
To ensure the system works effectively, the agency ber of working parties and related groups that conduct
works closely with its partners and stakeholders and is a the agency’s scientific work (Table 43-1).
proactive member of important networks in Europe and • CHMP
beyond. • PRAC
EMA and the national competent authorities have • CVMP
built their own specialised databases to monitor specific • Committee for Orphan Medicinal Products
regulatory issues and provide public access to biomedi- (COMP)
cal, clinical and other useful government resources. The • Committee on Herbal Medicinal Products
beginning of this chapter discusses databases housing (HMPC)
EU legislation. This section highlights repositories useful • Committee for Advanced Therapies (CAT)
for manufacturer and device registrations, submission • Paediatric Committee (PDCO)
preparation and postmarket surveillance. It focuses pri-
marily on the EU health authorities’ databases. The committees’ evaluations of MAAs submitted
EMA’s website features spotlighted links on the through the Centralised Procedure provide the basis for
latest news, patient safety, new medicines, public con- medicines’ authorisation in Europe. The committees and
sultations, resources targeting pharmaceutical industry, working parties also contribute to the development of
patients and care providers, media, academia, healthcare medicines and medicine regulation by:
professionals and animal healthcare professionals. It also • providing scientific advice to companies
provides several convenient listings, which include but researching and developing new medicines
are not limited to safety monitoring, side effect reports, • preparing scientific guidelines and regulatory
clinical data publication, priority medicines, ISO’s guidance to help pharmaceutical companies
IDMP standard, EU clinical trials register and EU prepare MAAs
telematics. Under the ‘find medicine’ section on EMA’s • contributing to the harmonisation of
website, information related to human, veterinary and regulatory requirements in the EU and
herbal medicines can be accessed through European internationally
public assessment reports (EPAR) for every medicine
granted a centralised MA.16

Chapter 43
Table 43-1. EMA’s Committees and Working Parties
Committee/Working Responsibilities More Information

Party
Committee for CHMP plays a vital role in human medicines’ authorisation in the http://www.ema.europa.eu/ema/
Medicinal Products for EU. In the Centralised Procedure, CHMP is responsible for: index.jsp?curl=pages/about_us/
Human Use (CHMP) • conducting the initial EU-wide MAA assessment general/general_content_000094.
• assessing modifications or extensions (‘variations’) to an jsp&mid=WC0b01ac0580028c79
existing MA
• considering the recommendations of the Pharmacovigilance
Risk Assessment Committee on the safety of medicines
on the market and, when necessary, recommending MA
changes, product suspension or withdrawal to the European
Commission
Pharmacovigilance PRAC is responsible for assessing all risk management aspects of http://www.ema.europa.eu/ema/
Risk Assessment human medicines, including: index.jsp?curl=pages/about_us/
Committee • adverse effect risk detection, assessment, minimisation and general/general_content_000537.
(PRAC) communication, while taking the medicine’s therapeutic jsp&mid=WC0b01ac058058cb18
effect into account
• design and evaluation of postauthorisation safety studies
• pharmacovigilance audit
Committee for CVMP plays a vital role in the veterinary medicines’ authorisation http://www.ema.europa.eu/ema/
Medicinal Products for in the EU. In the Centralised Procedure, CVMP is responsible for: index.jsp?curl=pages/about_us/
Veterinary Use (CMVP) • conducting the initial EU-wide MAA assessment general/general_content_000262.
• postauthorisation and maintenance activities, including the jsp&mid=WC0b01ac0580028dd8
assessment of any modifications or extensions (‘variations’)
to an existing MA
• safety monitoring of veterinary medicines on the market and,
when necessary, recommending MA changes, product sus-
pension or withdrawal to the European Commission. For more
information, see Veterinary pharmacovigilance.
Committee for Orphan COMP is responsible for evaluating applications for orphan http://www.ema.europa.eu/ema/
Medicinal Products designation. This designation is for medicines to be developed index.jsp?curl=pages/about_us/
(COMP) for diagnosing, preventing or treating rare diseases that are general/general_content_000263.
life-threatening or very serious. In the EU, a disease is defined jsp&mid=WC0b01ac0580028e30
as rare if it affects fewer than 5 in 10,000 people across the EU.
The European Commission decides whether to grant an orphan
designation for the medicine based on COMP’s opinion.
Committee on Herbal HMPC prepares the agency’s opinions on herbal substances and http://www.ema.europa.eu/ema/
Medicinal Products preparations, along with information on recommended uses and index.jsp?curl=pages/about_us/
(HMPC) safe conditions. general/general_content_000264.
This work supports the harmonisation of the European market: jsp&mid=WC0b01ac0580028e7c
national competent authorities are able to refer to one unique
set of information on an herbal substance or preparation when
evaluating MAAs for herbal medicines.
To support EU Member States, HMPC focuses on two main tasks:

• establishing EU monographs covering the therapeutic uses
and safe conditions of well-established and/or traditional use
for herbal substances and preparations
• drafting an EU list of herbal substances, preparations and
combinations thereof for use in traditional herbal
medicinal products
Committee for CAT’s main responsibility is preparing a draft opinion on each http://www.ema.europa.eu/ema/
Advanced Therapies ATMP application submitted to EMA, before CHMP adopts a final index.jsp?curl=pages/about_us/
(CAT) opinion on the concerned medicine’s MAA. general/general_content_000266.
jsp&mid=WC0b01ac05800292a4
At the request of EMA’s executive director or the European
Commission, CAT also can draw up an opinion on any scientific
matter relating to ATMPs.

Table 43-1. EMA’s Committees and Working Parties (cont.)
Committee/Working Responsibilities More Information

Party
Paediatric Committee PDCO’s main role is assessing Paediatric Investigation Plans’ (PIPs) http://www.ema.europa.eu/ema/
(PDCO) content, which determines the studies companies must conduct index.jsp?curl=pages/about_us/
in children when developing a medicine. This includes assessing general/general_content_000265.
applications for a full or partial waiver and for deferrals. jsp&mid=WC0b01ac0580028e9d
The committee’s other roles include:

• assessing data generated in accordance with agreed PIPs
• adopting opinions on a medicine’s quality, safety or efficacy
for use in the paediatric population, at the request of CHMP
or a medicines regulatory authority in an EU Member State;
PDCO can give an opinion if the data have been generated in
accordance with an agreed PIP
• advising Member States on the content and format of data
to be collected through surveys on the uses of medicines in
children
• advising and supporting the development of the European
Network of Paediatric Research at EMA (Enpr-EMA)
• providing advice on questions on paediatric medicines, at the
request of the Agency’s executive director or the European
Commission
• establishing and regularly updating an inventory of paediatric
medicine needs
• advising the agency and the European Commission on how
to communicate the arrangements available for conducting
research into paediatric medicines
Coordination Group CMDh examines questions relating to the marketing authori- http://www.ema.europa.eu/ema/
for Mutual Recognition sation of human medicines in two or more EU Member States index.jsp?curl=pages/about_us/
and Decentralised in accordance with the Mutual Recognition or Decentralised general/general_content_000310.
Procedures - Human Procedure, and questions concerning variations of these marketing jsp&mid=WC0b01ac058074758f
(CMDh) authorisations.
Coordination Group CMDv examines question relating to the marketing authorisation http://www.ema.europa.eu/ema/
for Mutual Recognition of veterinary medicines in two or more EU Member States in accor- index.jsp?curl=pages/about_us/
and Decentralised dance with the Mutual Recognition or the Decentralised Procedure. general/general_content_000311.
Procedures - jsp&mid=WC0b01ac058074c450
Veterinary (CMDv)
EudraVigilance The EudraVigilance Expert Working Group (EV-EWG) advises the http://www.ema.europa.eu/ema/
Expert Working Group pharmacovigilance governance structure of the EU regulatory net- index.jsp?curl=pages/contacts/
(EV-EWG) work on aspects of the EudraVigilance system. PRAC/people_listing_000128.
jsp&mid=WC0b01ac0580a959a6
Information on these committees’ roles and compo- adopts implementing measures and ensures the correct
sition and the details of their meetings, agenda and application of EU law and collaborates with relevant
reports are available on EMA’s website under the international partners and promotes the EU system
Committees tab.22 globally.24 The following documents can be directly
EMA has close ties with all of the EU institutions, accessed from the EC website:
EC, European Parliament and Council of European • The Rules Governing Medicinal Products in the
Union involved in developing EU laws concerning European Union (Eudralex), which contains
medicines and the regulation of medicines.23 EU legislation on medicinal products for
The European Commission makes binding deci- human and veterinary use
sions on medicines’ authorisation valid throughout the • the Community register, which contains a list
EU. It bases its decisions on EMA’s scientific commit- of all medicinal products for human and veter-
tees’ assessments, ensuring medicines comply with high inary use, as well as orphan medicinal products,
quality, safety and efficacy standards. that have received a centralised MA
The European Commission also proposes or • reports of the pharmaceutical committee, an
amends legislation for the pharmaceutical sector, advisory committee of senior experts from EU

Chapter 43
countries entrusted with examining questions Safety (ENVI) deals with issues concerning EMA.
relating to proprietary medicinal products, and ENVI follows the work of EMA closely. By invitation,
in particular, preparing proposals for directives EMA’s executive director and senior staff attend ENVI
• judgments of the European Court of Justice of meetings to provide updates on EMA’s work to mem-
interest to the pharmaceutical sector bers of the European Parliament and exchange views on
• news archives (DG Health and Consumers) issues of interest.
concerning pharmaceuticals The Member States’ health ministers meet in the
• High Level Group on Innovation Employment, Social Policy, Health and Consumer
and the Provision of Medicines: G10 Affairs Council (EPSCO). EPSCO may seek EMA’s
Medicines—Report opinion on public health issues, in particular on those
• Transparency Directive (89/105/EEC) concerning communicable diseases.26
EMA has formal working arrangements with its
EC also provides links to following EU services and main EU agency partners, laying out the nature of their
agencies as well as pharmaceutical agencies: collaboration and mutual consultation in areas of com-
• Directorate-General for Internal Market, mon interest. These agencies regularly run joint projects
Industry, Entrepreneurship and SMEs and participate in each other’s events and meetings.
o Medical devices sector The European Centre for Disease Prevention and
o Cosmetics Control’s (ECDC) mission is to identify, assess and
• Directorate General for Health and Food communicate current and emerging threats to human
Safety health posed by infectious diseases. Collaboration
o The Public Health Portal of the European between EMA and ECDC relates primarily to informa-
Union tion on vaccines, antimicrobial resistance and antiviral
o International Activities medicines. These agencies monitor the benefit-risk bal-
• Directorate General for Research and ance of vaccines and substances of human origin, such as
Innovation the use of human tissue or cells in medicines.
o Nanotechnology The European Food Safety Authority (EFSA) pro-
• Council of Europe: European Directorate for vides independent scientific advice and communication
the Quality of Medicines on existing and emerging risks relating to the safety of
• EMA food and animal feed. Collaboration between EMA and
• Innovative Medicines Initiative EFSA relates mainly to potential conflicts in scientific
opinions, the use of antibiotics in food-producing ani-
Pharmaceutical agencies mals, joint scientific guidance, risk communication and
• The Heads of Medicines Agencies website governance and reporting.
o Human Medicines Agencies The European Chemicals Agency (ECHA) seeks
o Veterinary Medicines Agencies to help companies comply with chemicals’ legislation,
advance the safe use of chemicals, address chemicals
EMA has daily contact with the Commission’s of concern and provide information on chemicals, all
Directorate General for Health and Food Safety (DG for the protection of human health and the environ-
SANTE), which deals with issues concerning the reg- ment. Collaboration between EMA and ECHA relates
ulation of medicines. DG SANTE is represented on primarily to information on chemicals’ evaluation and
EMA’s Management Board, and its officials regularly authorisation or restriction, relevant to EMA’s activi-
attend the agency’s scientific and stakeholder meetings ties, information concerning risk management through
as observers. EMA participates in the EC’s pharmaceu- substances’ classification, labelling and packaging, tox-
tical committees and relevant expert groups for human icological assessments by predictive methods and new
and veterinary medicines and participates in its Health methodologies, biocides, in particular the establishment
Security Committee.25 of MRLs for pharmacologically active substances con-
EMA also provides input to the Commission on tained in biocidal products used in animal husbandry
major European public health issues, including support and environmental risk assessments for both human
for drafting relevant legislation. and veterinary medicines and ecotoxicology.
The European Parliament and the Council of the The European Monitoring Centre for Drugs
European Union adopt EU legislation concerning the and Drug Addiction (EMCDDA) provides factual,
regulation of medicines proposed by the European objective, reliable and comparable information con-
Commission. Within the European Parliament, the cerning drugs, drug addiction and their consequences.
Committee for Environment, Public Health and Food Collaboration between EMA and EMCDDA relates to

information on new psychoactive substances and abuse regulatory burden. It covers both human and veterinary
of medicines, including illicit drugs, validated signals domains and consists of regulatory, business and IT
with medicines related to drug abuse, definition of risk experts from the regulatory network as core members,
management plans of selected medicines on an ad-hoc and representatives of the innovative, generic and non-
basis and potential conflicts over scientific opinions. prescription industry as nonvoting participants.31
The European Environment Agency (EEA) Detailed information on the working arrangements
provides independent, reliable and comparable envi- and memorandums between EMA and its partners can
ronmental information on the state and trends of the be accessed via the agency’s website.32
European environment for those involved in developing, The national competent authorities provide
adopting, implementing and evaluating environmental information on additional national requirements for
policy, and for the general public.27 medicinal products for human and veterinary use,
The Heads of Medicines Agencies (HMA) is a net- medical devices, herbal and traditional medicines and
work of the heads of the national competent authorities, cosmetics. The information on the website includes, but
the agencies responsible for the regulation of human is not limited to scientific and procedural guidelines,
and veterinary medicines in the individual countries of information related to agency fees, withdrawals, com-
the European Economic Area (EEA).28 plaints and recalls, adverse event reporting, forms and
The national competent authorities are responsible templates, referrals, updated product information and
for authorising medicines available in the EU that do inspection. Regulatory agencies have designed various
use the Centralised Procedure. This unique collaborative channels for providing scientific and regulatory advice to
model, known as the European Medicines Regulatory applicants and information related to the MAA proce-
network, enables Member States to pool resources and dure can be accessed via national competent authorities’
coordinate work to regulate medicines efficiently and websites. Member States also publish information on
effectively. The Member States also are represented on nationally authorised products and export products.
EMA’s Management Board.29 A list of EEA national
competent authorities (human and veterinary) is EU and International Organisations
provided in Table 43-2. The HMA website provides As international markets expand and companies operate
national competent authorities’ contact details, includ- more and more internationally, regulatory authorities’
ing direct links to their websites. tasks of assessing compliance with legislation and mon-
One of the most frequently used HMA databases itoring medicines’ safety becomes increasingly difficult
is the MRI product index of medicines approved in EU and resource-intensive. In response to this overall sit-
Member States through the Mutual Recognition or uation and to address the challenges of globalisation,
Decentralised Procedures.30 The page lists the 20 latest which can pose potential risks to public health, the
products and allows a search for products using multiple European Commission has intensified global coopera-
criteria e.g., MR number, active substance and product tion on different levels.
name, etc., to obtain product details, SmPCs, public EMA works closely with organisations that estab-
assessment report summary (PARSUM), final pack- lish standards for regulatory processes. These include the
age leaflet (PL), final labelling and finalised product International Organization for Standardization (ISO),
information. HMA also provides a list of documents International Council for Harmonisation of Technical
published on the CMDh website, including procedural Requirements for Registration of Pharmaceuticals for
guidance, templates, recommendations and referrals. Human Use (ICH) and International Cooperation
HMA works to foster an effective and efficient on Harmonisation of Technical Requirements for
European medicines regulatory system. It is supported Registration of Veterinary Medicinal Products (VICH).
by working groups covering specific areas of respon- ISO is a key nongovernmental standards-pro-
sibility and by the HMA management group and ducing organisation, comprising a network of national
permanent secretariat. EMA is a member of HMA. standards institutes representing 162 countries, 3,368
EMA and HMA have jointly organised the EU technical bodies and a coordinating central secretariat
network training centre (EU NTC), with the aim of in Geneva, Switzerland. ISO’s catalog includes more
ensuring the exchange of good scientific and regulatory than 21,000 published international standards related
practices across the European medicines regulatory to quality management, risk and many other drug and
network by harmonising training standards and offering device lifecycle facets.33
high-quality and relevant training opportunities. ICH brings together EU, US, Japanese, Canadian
The Regulatory Optimisation Group (ROG) is an and Swiss regulatory bodies and pharmaceutical indus-
HMA subgroup co-chaired by EMA, focused on opti- try experts to discuss scientific and technical product
mising regulatory and business operations and reducing registration aspects. ICH’s safety, efficacy, quality and

Chapter 43
Table 43-2. National Competent Authorities
Pharmaceutical Regulatory
Country Ministry of Health Medical Device Registration
Authority
EU Member States
European Medicines Agency (EMA),
EU DG Health and Food Safety
European Commission (EC)
Federal Office for Safety in Health
Austrian Medicines and Medical
Austria Care (BASG), Austrian Medicines and Federal Ministry of Health
Devices Agency (AGES MEA)
Medical Devices Agency (AGES MEA)
Federal Agency for Medicines and Federal Public Service Health, Food Federal Agency for Medicines and
Belgium
Health Products (FAGG) Chain Safety and Environment Health Products (FAGG)
Bulgaria Bulgarian Drug Agency (BDA) Ministry of Healthcare Bulgarian Drug Agency (BDA)
Agency for Medicinal Products and Republic of Croatia Ministry of Agency for Medicinal Products and
Croatia
Medical Devices of Croatia (HALMED) Health Medical Devices of Croatia (HALMED)
Ministry of Health - Pharmaceutical Cyprus Medical Devices Competent
Cyprus Ministry of Health
Services Authority
Czech State Institute for Drug Control Ministry of Health of the Czech Ministry of Health of the Czech
Republic (SÚKL) Republic Republic
Danish Health and Medicines Danish Health and Medicines
Denmark Ministry of Health
Authority (SST) Authority (SST)
State Agency of Medicines (SAM)
Estonia Ministry of Social Affairs Ministry of Health—The Health Board
RAVIMIAMET
National Supervisory Authority for
Finland Finnish Medicines Agency (Fimea) Ministry of Social Affairs and Health
Welfare and Health
French National Agency of Medicine French National Agency of Medicine
France Ministry of Health and Social Affairs
and Health Products Safety (ANSM) and Health Products Safety (ANSM)
Federal Institute for Drugs and Federal Institute for Drugs and
Germany Federal Ministry of Health
Medical Devices (BfArM) Medical Devices (BfArM)
National Organization for Medicines National Organization for Medicines
Greece Ministry of Health and Welfare
(EOF) (EOF)
Office of Health Authorization and
Hungary National Institute of Pharmacy (NIP) Ministry of Human Resources
Administrative Procedures
The Health Products Regulatory The Health Products Regulatory
Ireland Department of Health
Authority (HRPA) Authority (HRPA)
Italy Italian Medicines Agency (AIFA) Ministry of Health Ministry of Health
Latvia State Agency of Medicines (ZVA) Ministry of Health State Agency of Medicines (ZVA)
State Medicines Control Agency State Health Care Accreditation
Lithuania Ministry of Health
(VVKT) Agency
Luxembourg Ministry of Health Ministry of Health Ministry of Health
Malta Competition and Consumer
Malta Medicines Authority Ministry of Energy and Health
Affairs Authority
Ministry of Health, Welfare and
Netherlands Medicines Evaluation Board Ministry of Health—CIBG
Sport
Office for Registration of Medicinal
Office for Registration of Medicinal
Products, Medical Devices
Poland Ministry of Health Products, Medical Devices and
and Biocidal Products, Main
Biocidal Products
Pharmaceutical Inspectorate
National Authority of Medicines and National Authority of Medicines and
Portugal Ministry of Health
Health Products Health Products
National Agency for Medicines and National Agency for Medicines and
Romania Ministry of Health
Medical Devices Medical Devices

Table 43-2. National Competent Authorities (cont.)
Pharmaceutical Regulatory
Country Ministry of Health Medical Device Registration
Authority
State Institute for Drug Control State Institute for Drug Control
Slovakia Ministry of Health
(SÚKL/SIDC) (SÚKL/SIDC)
Agency for Medicinal Products and Agency for Medicinal Products and
Slovenia Medical Devices of the Republic of Ministry of Health Medical Devices of the Republic of
Slovenia Slovenia
Spanish Agency for Medicines and Ministry of Health, Social Services Spanish Agency for Medicines and
Spain
Medical Devices and Equality Medical Devices
Sweden Medical Products Agency Ministry of Health and Social Affairs Medical Products Agency
Medicines & Healthcare products Medicines & Healthcare products
UK Department of Health
Regulatory Agency (MHRA) Regulatory Agency
EFTA Member States
Iceland Icelandic Medicines Agency (IMA) Ministry of Welfare Icelandic Medicines Agency (IMA)
Office of Health—Department of Office of Health—Department of
Liechtenstein Office of Public Health
Pharmaceuticals Pharmaceuticals
Directorate for Health and Social
Norway Norwegian Medicines Agency Ministry of Health and Care Services
Affairs
Swiss Agency for Therapeutic Swiss Agency for Therapeutic
Switzerland Federal Office of Public Health
Products (Swissmedic) Products (Swissmedic)
multidisciplinary guidelines help pharmaceutical and it. The ICH observers (Argentina, India, Cuba, Mexico,
biologics regulatory professionals (and medical device Columbia, Israel, Jordon, Russia, Moldova, Malaysia,
professionals, with Q9 Quality Risk Management and Kazakhstan, South Africa, Saudia Arabia, Armenia,
guidelines on clinical trials and human subject protec- Turkey and WHO, et al.) also are part of the GCG. For
tion) evaluate proposed products and ensure regulatory a complete list see www.ich.org/page/observers. The
compliance. ICH representatives include drug reg- GCG serves as a forum for discussing harmonisation
ulatory authorities from Australia, Brazil, Canada, topics and practices.
China, Chinese Taipei, Republic of Korea, Japan, ICH’s success in harmonising regulatory require-
Singapore, Switzerland, the EU and the US, as well ments for human medicines led to the 1996 launch of
as the World Health Organization (WHO), which a similar harmonisation drive for veterinary medicines
serves as an official observer. Six regional harmonisa- (VICH) under the auspices of the World Organisation
tion initiatives (RHIs) also are active participants in for Animal Health (OIE). Besides the EU, Japan and
ICH meetings: Asia-Pacific Economic Cooperation the US, VICH includes Australia, Canada and New
(APEC), Association of Southeast Asian Nations Zealand, as observers.
(ASEAN), East African Community (EAC), Gulf EMA also contributes to the Codex Alimentarius.
Cooperation Countries (GCC), Pan American Network The Codex Alimentarius aims to protect consumer
on Drug Regulatory Harmonization (PANDRH) and health and ensure fair trade practices in the food trade
South African Development Community (SADC). and promote the coordination of all food standards
Representatives from the EU, Japan, Canada, the US, work undertaken by international governmental and
WHO, the Pharmaceutical Research and Manufacturers nongovernmental organisations. The agency’s main
of America (PhRMA) and International Federation interaction with the Codex Alimentarius is in setting
of Pharmaceutical Manufacturers and Associations acceptable limits for residues of veterinary medicines,
(IFPMA) serve on the ICH steering committee.34 such as antibiotics, in animal foodstuffs and in risk
To promote mutual understanding of regional har- assessment methodologies.35
monisation initiatives and facilitate the harmonisation The European Commission has very close working
process, the ICH Global Cooperation Group (GCG) relations with the Council of Europe in the area of the
was formed in 1999. Its role is to make information on quality control of medicines, through the European
ICH activities and guidelines available to regulatory department for the quality of medicines and healthcare
authorities and pharmaceutical companies that request (EDQM). EDQM is an organisation that protects

Chapter 43
public health by enabling the development, supporting and industry now are committed to work jointly toward
the implementation and monitoring the application of creating a European research area (ERA).38
quality standards for medicines and their safe use. EU
pharmaceutical legislation makes direct reference to the Professional Organisations
European Pharmacopoeia (Ph. Eur.) and other activities Of the many professional organisations in the EU
under EDQM’s responsibility, such as certification of region, some are discussed below. EMA maintains a
suitability to Ph. Eur.’s monographs and coordinating complete list of eligible industry stakeholder organisa-
the European network of Official Medicines Control tions, which is provided in Table 43-3.
Laboratories (OMCL). The most frequently used The innovative medicines initiative (IMI) is
EDQM databases are provided later in this chapter.36 Europe’s largest public-private initiative aiming to
The World Health Organization (WHO) is an speed up the development of better and safer medi-
important partner for contacts with regulatory authori- cines for patients. IMI supports collaborative research
ties, particularly those with whom EMA does not have a projects and builds networks of industrial and academic
confidentiality arrangement. Collaboration with WHO experts to boost pharmaceutical innovation in Europe.
is highlighted specifically in the legislation establishing IMI is a joint undertaking between the EU and the
the agency, with reference to scientific harmonisation, European Federation of Pharmaceutical Industries and
technical cooperation and international collaboration Associations (EFPIA).39
on pharmacovigilance. The European Commission is EFPIA represents the pharmaceutical industry
an active member of WHO’s International Medical operating in Europe. Through its direct membership of
Products Task Force (IMPACT).37 national associations and leading pharmaceutical com-
EMA works with the OIE to promote initiatives to panies, EFPIA is the EU voice of companies committed
improve and harmonise standards for veterinary medi- to researching, developing and bringing new medicines
cines at a global level. to the market to improve health and the quality of life
EMA is a member of the International Coalition of around the world.40
Medicines Regulatory Authorities (ICMRA). ICMRA The European Industrial Pharmacists Group
is a voluntary, executive level entity of medicines (EIPG) is a European association representing the
regulatory authorities worldwide providing strategic national, professional organisations of pharmacists
coordination, advocacy and leadership. ICMRA acts as employed in the pharmaceutical or allied industries in
a forum to support international cooperation among the EU Member States, the EEA or European coun-
medicines regulatory authorities. It aims to avoid dupli- tries with a mutual recognition agreement with the EU
cation and promote informed, risk-based allocation of on compliance control of regulated medicines.41
resources to strengthen dialogue, facilitate the wider The European Association of Euro-Pharmaceutical
exchange of reliable and comparable information and Companies (EAEPC) is a Brussels-based nonprofit
encourage greater leveraging of its members’ resources organisation, which represents the European licensed
and work products. parallel distribution industry, championing the indus-
EMA also is a recognised partner of the try’s achievements and the benefits of its products.
Pharmaceutical Inspection Convention and Through national associations and individual company
Pharmaceutical Inspection Co-operation Scheme membership, it encompasses more than 80 firms in
(PIC/S). PIC/S are two international instruments 23 EEA countries. All products handled by EAEPC
among countries and pharmaceutical inspection author- members have national or EU regulatory approvals and
ities. They aim to lead the international development, are sourced exclusively from and sold to EEA countries
implementation and maintenance of harmonised GMP using authorised trade channels.42
standards and quality systems of inspectorates in the The European Confederation of Pharmaceutical
field of medicines. Entrepreneurs (EUCOPE) provides a platform for
The directorate-general for research and innovation pharmaceutical entrepreneur discussions. On a regular
defines and implements European research and inno- basis, pharmaceutical company owners and CEOs and
vation (R&I) policy. High-level research is increasingly associations discuss solutions to improve patients’ qual-
complex and interdisciplinary, costly and requires a con- ity of life and strengthen the European pharmaceutical
stantly increasing “critical mass,” and virtually no research industry’s competitiveness.43
team, company or Member State can reasonably claim The Association of Research-Based Pharmaceutical
to be able to respond to these challenges. Taking up this Companies (vfa), is the trade organisation of research-
challenge, the European Commission, Member States based pharmaceutical companies in Germany. It
and the European Parliament, the scientific community represents 43 leading research-based pharmaceutical
companies that, together with their more than 100

Table 43-3. Eligible Industry Stakeholder Organisations
Organisation Name Acronym Website

Active Pharmaceutical Ingredients Committee APIC http://apic.cefic.org/
Animal Health Europe AnimalhealthEurope www.animalhealtheurope.eu
Association of Clinical Research Organizations ACRO www.acrohealth.org
Association of the European Self-Medication Industry AESGP www.aesgp.eu/
Association of Veterinary Consultants AVC www.avc-eu.de
European Association for Bioindustries EuropaBio www.europabio.org/
European Association for Logistics and Transport in EALTH www.ealth.org/
Healthcare
European Association of Euro-Pharmaceutical Companies EAEPC www.eaepc.org
European Biopharmaceutical Enterprises EBE www.ebe-biopharma.eu/
European Coalition on Homeopathic & Anthroposophic ECHAMP www.echamp.eu/
Medicinal Products
European Confederation of Pharmaceutical Entrepreneurs EUCOPE www.eucope.org/
European Contract Research Organization Federation EUCROF www.eucrof.eu/
European Federation of Pharmaceutical Industries and EFPIA www.efpia.eu/
Associations
European Federation of Statisticians in the Pharmaceutical EFSPI www.efspi.org
Industry
European Group for Generic Veterinary Products EGGVP www.eggvp.org/
European Healthcare Distribution Association GIRP www.girp.eu/
European Industrial Pharmacists Group EIPG www.eipg.eu
Europharm SMC Europharm SMC www.europharmsmc.org/
Eye-Care Industries European Economic Interest Grouping ECI-EEIG www.eci-eeig.org
Medicines for Europe N/A www.medicinesforeurope.com/
Plasma Protein Therapeutics Association PPTA www.pptaglobal.org/
Vaccines Europe VE www.vaccineseurope.eu/
subsidiaries and affiliated companies, employ nearly and a world in which public health issues go beyond
78,000 people in Germany.44 national borders. The agency has agreements in place
The Association of the British Pharmaceutical with regulators in several countries, including the US,
Industry (ABPI) represents innovative research-based Canada, Japan, Switzerland, Australia, New Zealand
biopharmaceutical companies, large, medium and small, and Israel. Details on these agreements are provided on
leading biosciences in the UK. ABPI is recognised by EMA’s website under partners and networks.
government as the industry body negotiating on behalf
of the branded pharmaceutical industry for statutory Online Commercial and Government
consultation requirements including the UK medicines’ Databases
pricing scheme.45 An integral component of a regulatory professional’s
work is to stay informed about the latest regulatory and
Regulators Outside the EU legislative developments. The resources reviewed in this
EMA cooperates with many of the world’s largest reg- section highlight noteworthy governmental database
ulatory bodies in areas such as inspections, medicines’ tools to support these monitoring and surveillance
safety and exchange of information on issues of mutual responsibilities. Numerous commercial, fee-based,
concern. International cooperation is a key agency work web-based databases and free, government, web-
area in an increasingly globalised pharmaceutical market based databases are available to support the regulatory

Chapter 43
professional’s legislative tracking and regulatory analysis Public Assessment Reports (PARs) on its Infarmed
responsibilities. database along with the authorisation information
EUDRANET is a European human and veterinary and product information. Medicinal product Agency
pharmaceutical telecommunication network offering of Sweden publishes product information and Public
information and communication technology (ICT) Assessment Reports (PARs) for some products under
services allowing scientific experts, those working on its ‘Drug Facts’ database, Läkemedelsfakta. The Dutch
pharmaceutical business processes and policy makers to Medicines Evaluation Board publishes this information
have a secure and well-structured electronic environ- on a searchable database, ‘Medicine information back,’
ment to ‘meet,’ exchange information and work together and UK’s Medicines and Healthcare products Regulatory
on a pan-European scale.46 Agency (MHRA) publishes ‘Medicines Information’ in
Although managed by EMA, the Eudra ‘family’ of alphabetical order by active substances.48-53
applications (such as EudraVigilance and EudraTrack) Clinically oriented databases include EudraCT,
comes under the overall responsibility of the phar- EU Clinical Trials Register and EudraPharm. EMA
maceuticals and cosmetics unit within the European is responsible for developing, maintaining and coor-
Commission’s DG Enterprise. These applications are dinating the EudraCT database. This database is used
provided in collaboration with EMA and the national by national competent authorities to enter data from
authorities responsible for pharmaceuticals, which total clinical trial sponsors and Paediatric Investigation Plan
28 organisations. (PIP) information. A subset of this data is made avail-
EudraVigilance is a system designed to collect reports able through the EU Clinical Trials Register, which
of suspected side effects. These reports are used to evalu- EMA manages on behalf of EU Member States and
ate medicines’ benefits and risks during development and forms part of EudraPharm, the EU database of med-
monitor their safety following their EEA authorisation. It icines. Users are able to view the description of Phase
has been in use since December 2001. EudraVigilance is a 2–Phase 4 adult clinical trials with investigator sites in
single repository for reports of suspected adverse reactions the EEA, the description of any paediatric clinical trials
seen in healthcare practice and clinical trials. It is used by with investigator sites in the EU and any trials that are
Member States, EMA and industry.47 part of a PIP, including those with investigator sites
For centrally authorised medicines, access to outside the EU.
adverse event reports is available by the medicine’s The Czech Republic’s State Institute for Drug
name or the active substance’s name. For medicine not Control’s (SÚKL) Drug Pages (lecich.cz) are intended
approved from the Centralised Procedure, only the for the general public. Their aim is to educate and
active substance’s name can be used. EMA launched inform the public about drug issues and protect com-
this website in 2012 to provide public access to reports panies from unauthorised and inaccurate information
of suspected side effects (also known as suspected from the drug field. SÚKL makes a database of clinical
adverse drug reactions). These reports are submitted trials authorised in the Czech Republic available on the
electronically to EudraVigilance by national medi- Czech register of clinical trials via this website.
cines regulatory authorities and by the pharmaceutical The EDQM databases include Pharmeuropa, which
companies that hold the medicines’ MAs. The website provides public inquiries on draft European texts or
also provides a link to contact information for national matters of general policy, the latest official announce-
safety and side effect reporting. ments on freshly adopted monographs and Certification
EPARs play a pivotal role in the drive for increased database for information on Certificates of Suitability
EU regulatory transparency. As mentioned earlier, EMA (CEPs) granted by EDQM. The information on
publishes EPARs for centrally authorised products on Pharmeuropa Reference Standards, WHO International
its website, and assessment reports for those products Chemical Reference Substances (ICRS) and WHO
approved via Mutual Recognition and Decentralised International Standards for Antibiotics (ISA) also can
Procedures are available on HMA’s MRI product index. be searched in EDQM databases (Table 43-4).54
More recently, this has been expanded to national regu- This EDQM page provides access to the electronic
latory agencies. France publishes EPARs under reports Ph. Eur. The English and French electronic editions are
on Agence national de sécurité du medicament et des produits cumulative and compiled from the same texts used to
de santé (ANSM) website. Ireland’s Health Products produce the paper versions. A new edition is published
Regulatory Authority (HPRA) publishes Medicinal every three years, and supplements are published three
Product Public Assessment Reports (IPARs) on its times a year. In Switzerland, the Pharmacopoeia Helvetica
website and under the ‘find medicine’ section along (Ph. Helv.) exists alongside the Ph. Eur., and together,
with product information and educational material for the two form the legally binding pharmacopoeia. In
patients and healthcare professionals. Portugal publishes France, the pharmacopoeia consists of the texts of the

Table 43-4. EDQM Databases
Pharmeuropa provides public inquiries on draft European texts or matters of general policy,
Pharmeuropa the latest official announcements on freshly adopted monographs, the latest news on
pharmacopoeial harmonisation and a readers’ tribune.
Pharmeuropa Bio
Pharmeuropa Bio & Scientific Notes contains all the news in the biological standardisation area
and& Scientific
and scientific articles linked to the work of the European Pharmacopoeia.
Notes
Knowledge is a searchable database of information on a given substance or general analysis
method and also contains information such as: monograph revision history; the chromatogram
Knowledge in pdf format; links to the reference standard catalogue number; some reagents’ trade names,
such as chromatography columns and biological kits; and access to the list of Certificates of
Suitability to European Pharmacopoeia (CEPs) monographs granted for this substance.
Ph. Eur. Reference
Continuously updated database for information on Ph. Eur. Reference Standards.
Standards
WHO ICRS Information on WHO International Chemical Reference Substances (ICRS).
WHO ISA Information on WHO International Standards for Antibiotics (ISA).
Certification Database of information on Certificates of Suitability (CEPs) granted by EDQM.
Database containing terms and definitions for pharmaceutical dosage forms, routes and
Standard Terms methods of administration, containers, closures and administration of devices, and patient-
friendly terms.
Database on the legal classification of medicines regarding their supply: conditions and details
Melclass
of prescription status.
Ph. Eur. and the French Pharmacopoeia, including the Española) and National Formulary are available electroni-
“overseas” pharmacopoeia. Other countries, e.g., the UK, cally in La Tienda del BOE via subscription.55-61
have decided to fully integrate the texts of the Ph. Eur. The EudraGMDP database is the community data-
into their national pharmacopoeia; hence, the British base on manufacturing, import and wholesale distribution
Pharmacopoeia (BP) contains the Ph. Eur.’s texts in addi- authorisations, and GMP and GDP certificates. The
tion to the BP’s national texts. Every new edition of the database has been available publically since 2011, which
Croatian Pharmacopoeia implements requirements from allows public access to database information that is not
a particular edition of the Ph. Eur. The Czech Republic’s of a commercial or personal confidential nature. EMA
Ministry of Health’s Pharmacopoeia Commission cooper- maintains and operates the EudraGMDP database.62
ates with the European Pharmacopoeia Commission and
is responsible for the correctness of the pharmacopoeia’s Databases with Global Regulatory Coverage
texts. The Czech Pharmacopoeia (Český lékopis) is a member Databases providing global coverage of country-specific
of the Czech Republic’s Pharmacy Commission and its regulations and guidelines also play an essential role in
expert sections. The rules contained in the Pharmacopoeia the regulatory professional’s ability to monitor legis-
Deutsches Arzneibuch (DAB) are decided by the German lative developments, conduct regulatory analyses and
Pharmacopoeia Commission (Arzneibuch-Kommission) understand compliance requirements for all phases of
or the European Pharmacopoeia Commission or the the drug, biologic and device product lifecycles. These
German Homeopathic Pharmacopoeia Commission are invaluable tools when used in conjunction with
(Deutsche Homöopathische Arzneibuch-Kommission). The other sources of regulatory expertise, from networking
DAB is published in the Federal Gazette by the Federal with colleagues to contacting consultants and/or com-
Institute for Drugs and Medical Devices, mention- municating directly with regulatory agency authorities.
ing the relevant Pharmacopoeia source. The Portuguese This section discusses several databases offering interna-
Pharmacopoeia (Farmacopeia Portuguesa) has a fundamental tional regulatory information.
role in defining and establishing standards and technical Publicly launched in September 2014, the National
requirements for raw materials, pharmaceutical substances, Institute of Allergy and Infection Diseases’ (NIAID)
analytical methods and pharmaceuticals used in Europe. ClinRegs is designed to help clinical researchers nav-
The Spanish Royal Pharmacopoeia (Real Farmacopea igate country-specific, regulatory information as they

Chapter 43
plan and implement clinical trials. ClinRegs is an online drug delivery and development, drug discovery, labora-
database, which is a central resource providing the tory; manufacturing and engineering, medical devices,
research community with up-to-date regulatory infor- quality assurance, regulations and standards and training
mation for multiple countries. Organised by country and validation. Similarly, John Wiley & Sons produces
and topic areas, the site also allows users to compare regulatory publications on drug submissions, clinical
countries’ requirements side by side. Topic areas the trials, drug safety evaluation, pharmaceutical manufac-
website addresses include: clinical trial lifecycle, compe- turing regulations, quality and preclinical development.
tent authority oversight, Ethics Committee oversight, Springer, by comparison, covers regulatory and toxicology
informed consent, investigational products, specimens issues, such as pharmaceutical safety evaluation, in its
and sponsorship. ClinRegs currently includes clinical pharmaceutical science area. The following keywords are
research regulatory information summarised in English effective for searching these online catalogs:
for Brazil, China, India, Kenya, Liberia, Malawi, Peru, • regulatory
South Africa, Tanzania, Thailand, Uganda, Vietnam, • regulatory affairs
Liberia, Sierra Leone, Guinea, the UK and the US.63 • regulatory healthcare
Thomson Reuters Cortellis’ Intelligent Regulatory • pharmaceutical
Database (IDRAC) and Tarius are a fee-based global • biotechnology
regulatory intelligence database of regulatory, legal • medical device
and scientific information accessed by professionals • pharmacology
who develop and register human drug and biologics
products.64 IDRAC and Tarius frequently update its Other industry publishers focus on such specific areas
documents and provides expert analyses on key regula- as quality assurance and standards. For example, the
tory topics for 75 countries. European Association for Quality Assurance (ENQA)
In the device field, some trade associations share in Quality Press publishes books, standards and training
information with its members; most other data is avail- materials relating to quality issues.66 Several industry
able from commercial resources. publishers specialise in publications focusing entirely or
largely on regulatory and compliance issues. Concept
Book Publishers Heidelberg and European Compliance Academy
Several companies specialise in print and electronic (ECA) publish periodicals and journals addressing
publications focused on healthcare regulatory topics. professionals in quality assurance, qualified persons and
This section reviews industry, government, associa- GMP representatives in the pharmaceutical and active
tion and standards publishers targeting the healthcare pharmaceutical ingredient industry, covering informa-
regulatory profession and explains how to retrieve the tion on GMPs and regulatory compliance, picking up
most relevant resources using online catalogs. Because emerging GMP challenges.67
regulatory is an interdisciplinary profession, publishers The Eurofins Group publishes a pharma services
concentrating primarily on scientific research and devel- newsletter, presenting new services and analytical tech-
opment (R&D), law, medicine, business or government niques, research projects, major events and other related
or possibly all of the above, also may produce publica- topics. The newsletter is published three times per year.
tions with a regulatory focus. MedTech Europe has a resource library focused on
The compendium of EU pharmaceutical law information related to the medical device industry.68
(EudraBook) compiles the most recent versions of the Many associations, such as the Regulatory Affairs
key legal instruments on medicinal products for human Professionals Society (RAPS), publish materials
use. It provides a useful overview for stakeholders, espe- intended for regulatory professionals, available in their
cially the pharmaceutical industry, regulatory authorities online bookstores. This book is a key example of one
and legal practitioners, but also interested citizens, such RAPS product. In addition, RAPS publishes reg-
patients and healthcare professionals.65 ulatory affairs certification (RAC) preparatory materials
CRC Online Press, John Wiley & Sons, Lippincott for RAC drugs and RAC devices, self-assessment exams
Williams & Wilkins/Wolters Kluwer Health, Majors. for these certifications and books on topics key to the
com and Springer are major publishing firms providing development of regulatory professionals.69
broad subject coverage and featuring numerous publica- EMA’s staff and experts publish articles on the
tions for the regulatory professional. The CRC Online agency’s scientific activities in scientific publications,
Press website contains regulatory publications under the such as journals or textbooks.
general category of pharmaceutical science, divided into
subcategories: biotechnology/biopharmaceutical, clean-
ing and sterilisation, clinical trials, computer software,

Electronic Newsletters, Magazines and legislation, pharmacovigilance, pharmacoeconomics

Journals and drug safety. Informa Healthcare also produces a
broad range of fee-based industry news sources (e.g.,
Industry Resources
Scrip World Pharmaceutical News), business and market
In addition to books, reports and standards, a number
research reports, R&D analytical tools and databases
of industry resources are available to regulatory pro-
(e.g., Pharmaprojects and TrialTrove) and research jour-
fessionals to monitor current events and advance their
nals (e.g., Clinical Research & Regulatory Affairs, Drug
knowledge of healthcare product regulation. Regulatory
Development and Industrial Pharmacy).71
professionals can stay informed and save time by
The medical device industry also receives excellent
reviewing these industry-specific publications, as the
web coverage through a number of free publications.
sources reviewed in this section cover a range of drug,
Med-Tech Innovation News is the UK and Ireland’s
device and biologic regulatory publications.
leading publication for medical design and manufactur-
Many publishers produce multiple newsletters
ing technology and innovation. It delivers daily news,
directed at different healthcare product sectors. For
technical content, analysis, case studies and high-profile
example, EMA publishes three newsletters to provide
interviews with industry experts and thought leaders.
updates on various topics to patients, healthcare pro-
The list of free and fee-based regulatory publications is
fessionals and the pharmaceutical industry. Human
long and varied, ranging from industry newsletters and
medicines highlights, published monthly, contains key
peer-reviewed journals to association magazines. This
information on human medicines and changes to reg-
section provides a snapshot of some of these resources.
ulatory processes in the past month. The newsletter for
These publications, although not exhaustive of all avail-
micro-, small- and medium-sized enterprises (SMEs),
able resources, provide regulatory professionals a solid
published four times a year, provides key updates to
basis for further independent research.
SMEs on the European regulatory environment. What’s
new in pharmacovigilance, also published four times a
year, updates Qualified Persons for pharmacovigilance Association Resources
on guidance, regulations and events. The majority of association publications are free with
Health-EU e-newsletter by the European membership but require nonmembers to pay an annual
Commission is published twice a month with a selection membership fee. RAPS is one such association, pub-
of the latest news and activities in the field of public lishing a monthly electronic magazine, Regulatory Focus,
health at both the European and international level. which is available to its members, with limited online
ECA’s GMP Newsletter is a free service published on guest access to selected articles. The magazine focuses
a weekly basis. The newsletter reviews the latest develop- on current regulatory issues affecting the drug, med-
ments and trends with regard to GMP and US Food and ical device and biological healthcare product sectors.
Drug Administration (FDA) compliance topics. As an offshoot from the magazine, RAPS provides
The European Pharmaceutical Review is the leading daily (weekdays only) news briefings via RF Today
source for up-to-the-minute information on all aspects and Regulatory Recon, featuring summaries of the top
of drug analysis, formulation, delivery, manufacturing regulatory news stories from around the world relating
and regulation. The magazine is published bi-monthly, to pharmaceuticals, medical devices, biotechnology
and each issue delivers high-level technical and business and the agencies that regulate them. Another RAPS
contributions from the world’s leading pharmaceutical member-based resource is a weekly e-newsletter,
scientists and business experts, coupled with a variety of RAPS Weekly Update. Similarly, The Organisation for
features including interviews, updates and profiles.70 Professionals in Regulatory Affairs (TOPRA) pub-
Another key regulatory publication by Informa is lishes a members-only international journal, Regulatory
SCRIP Regulatory Affairs (SRA, formerly Regulatory Rapporteur, which provides current news and analyses
Affairs Journal Pharma/Devices). SRA is a source of on regulatory and legislative topics. TOPRA also issues
global news, commentaries and analyses of regulation a quarterly member newsletter, In Touch, which serves as
in the pharmaceutical and biotechnology industries. an association news digest covering member and organ-
The publication provides pharmaceutical regula- isational activities.72,73
tory intelligence on global regulations governing the DIA publishes its official bimonthly journal,
development, launch and postmarket surveillance of Therapeutic Innovation & Regulatory Science (formerly
medicines and combination products. Areas of coverage the Drug Information Journal). This journal encompasses
include: regulatory agencies and legislation, application drug, device and diagnostic innovations, global regulatory
requirements and guidelines, R&D, patents and intel- topics as well as pharmaceutical research and develop-
lectual property, international harmonisation, pediatric ment issues. DIA produces Global Forum, a bimonthly
magazine dedicated to global coverage of pharmaceutical

Chapter 43
and medical products, from discovery and development • access to member directories and online
to regulation, marketing and surveillance. Global Forum forums
also delivers up-to-date association and member news. In • participation in meetings, trade shows and/or
addition, DIA’s e-newsletter, DIA Daily, provides news conferences
highlights and information about the pharmaceutical, • involvement in special partnerships and/or
biotechnology and medical device fields from thousands meetings with direct interaction with compli-
of global news sources. ance bodies and regulatory agencies
The Parenteral Drug Association’s (PDA) mem- • networking with other professionals with simi-
bership publication, PDA Letter, reports on science, lar expertise or regulatory interests
technology, quality, regulatory affairs, association news • assistance with business and/or regulatory
and updates relevant to the PDA community. PDA’s activities
Journal of Pharmaceutical Science and Technology is a • advocacy for the professional and/or an organi-
bimonthly publication containing peer-reviewed scien- sation’s professional interests
tific and technical papers covering the pharmaceutical • participation on committees influencing the
and biotech industries. The journal is distributed as a organisation’s vision and direction
member benefit and also is available by subscription.
PDA Technical Reports are global consensus documents Participation in these associations grants access and
addressing a range of topics relating to pharmaceutical opportunities for learning through professional net-
production, validation and quality assurance. Expert task working, committee involvement and educational tools.
forces prepare the reports, which then are reviewed by Regulatory professionals can maintain their knowledge
technical forums and ultimately evaluated and approved of the regulatory healthcare industry and/or fulfill core
by an advisory board and the PDA board of directors.74 competency requirements by participating in e-learn-
ing courses, web-based training, interactive web-based
Associations and Continued Learning webinars and/or online certificate programs.
Knowledge garnered from publications, government Webinars may be open to members and nonmem-
databases and other agency resources unquestionably bers, depending on the organisation. These webinars
has an integral place in a regulatory professional’s career offer live, virtual group learning sessions, in which the
development. These resources enable the regulatory pro- presenter(s) and subject matter experts focus on a spe-
fessional to monitor the latest news, track the status and cific topic and open the floor to attendees for discussion
development of laws, regulations and guidelines and and questions. Typically, the presentation is in Microsoft
engage in effective strategic product development. PowerPoint format but also may reference a regulatory
In addition, associations are indispensable educa- document, database or any other pertinent resource.
tional resources for regulatory professionals. Through Alternatively, e-learning resources provide archived
the active participation of their members, these asso- learning sessions accessible at the regulatory profes-
ciations embody the immediate focus and future sional’s convenience, where the learner sets the pace of
direction of the specific interest areas they serve. The the online coursework. RAPS, DIA,the World Medical
organisations mentioned earlier in the chapter, includ- Device Organization (WMDO) and a growing number
ing RAPS, DIA and TOPRA, offer a broad variety of of larger consultancy firms provide e-learning curricula
learning opportunities to their members. Most associ- culminating in a certificate. DIA offers certificates in
ations require a nominal membership fee, which grants clinical research, regulatory affairs, clinical safety and
individuals (or, in some cases, designated company pharmacovigilance, project management and medi-
representatives) access to member-only resources. These cal communications. WMDO provides educational
resources may include: opportunities to regulatory professionals in the medical
• discounts on the organisation’s resources, i.e., device arena, with certificates in clinical evaluation,
webinars and publications Asia-Pacific and EU medical device regulatory affairs
• access to knowledge databases, reports, and medical device monitoring. A combined medical
directories device and pharmaceutical regulatory affairs certificate
• access to the latest news specific to the organ- is offered by RAPS, as well as individual certificates
isation’s focus via periodic newsletters, email within each topic. Formal postgraduate degree pro-
updates and/or social media outlets grams (online and classroom settings) are offered by
• access to education tools, i.e., e-learning and several universities.
seminars
• access and/or discounts to partner associations’
resources

Social Networking and Mobile Apps In addition, regulatory professionals can participate
Social networking and other forms of dynamic and in sites such as LinkedIn to establish public profes-
interactive information-sharing by users has become sional profiles, search for jobs, interact with colleagues,
pervasive in the healthcare industry through the use search for other regulatory professionals and join online
of smart phones, tablets and other innovations in web regulatory groups. LinkedIn operates the world’s larg-
and mobile technology, making on-demand access to est professional network on the Internet, with more
current information the standard. Data users also expect than 300 million members in over 200 countries and
opportunities for community-based input and daily or territories.75 Joining the network is free and simply
minute-to-minute content sharing in their respective requires the user to create a profile summarising his
professional fields. To complement the networking or her professional experience and accomplishments.
benefits of industry association memberships, regulatory The information a user chooses to make available pub-
professionals now can connect with colleagues through licly can be searched by other professionals within the
blogs and social networking websites. The regulatory LinkedIn network and used for the purpose of meeting
professional has several options through which to and collaborating with other members.
receive information: LinkedIn hosts a multitude of regulatory groups
• Tumblr/Blogs/Microblogs—regularly updated supporting regulatory professionals’ interaction. The
journal entries designed to be read by a pro- Quality and Safety Regulatory Network on LinkedIn
fessional audience and representing the unique supports professionals working in quality assurance, reg-
personality of the author or website; multime- ulatory and compliance in highly regulated industries.
dia postings with commenting features (more This group allows professionals to share experiences
information provided below) and expand their networks of people and ideas in qual-
• LinkedIn—microblogging/networking tool ity, regulatory, safety, health, sustainability, risk and
for professionals, organisations and businesses compliance for continuous improvement across mul-
(more information provided below) tiple industries.76 Similarly, the reg-info.com group on
• RSS feeds—automated tracking of updates to LinkedIn allows pharmaceutical professionals to share
favourite websites (more information provided ideas and participate in a forum for issues related to
below) regulatory intelligence and information gathering. This
• Twitter—microblogging of videos, photos community also assists pharmaceutical professionals in
and status/activity updates, with commenting finding regulatory intelligence information through links
features to key regulatory and related information sources.77
• YouTube—public video sharing with caption- RAPS members can connect on the Regulatory
ing and commenting features Exchange (RegEx) by joining communities, establishing
• Facebook—microblogging/networking tool connections with other members, contributing to the
for sharing videos, photos and status/activity resource library and participating in discussions.78 RegEx
updates with commenting features also provides information about upcoming RAPS events
and publications, as well as volunteer opportunities.
RSS news feeds automatically track website content Other social networking sites, such as Pinterest,
updates (news, blogs, audio, video and images) and then Instagram, Flickr and Foursquare, are not covered
send content to subscribers. RSS allows users to collect in this discussion, as they have not yet been adopted
and organise information from websites, commonly widely as useful platforms for regulatory intelligence
referred to as feeds. The RSS feed can be synched to and/or information sharing. Notably, mobile applica-
Microsoft Outlook to receive scheduled email updates. tion technology has emerged within the last decade as
RSS feed aggregators (also referred to as readers) are a tool for quick, user-friendly information retrieval on
available for download, both commercially and open smartphones. The adoption of downloadable mobile
access. The RSS feed tool, along with direct email applications (“apps”) for regulatory content still is in its
subscriptions to government websites, organisations/ nascent stage but growing.
societies and blogs, offers the regulatory professional
convenient periodic updates. Conclusion
Some of the more popular blogs within the regu- Regulatory professionals have improved their produc-
latory healthcare sector include: official MHRA blog, tivity, effectiveness and expertise significantly through
Royal Pharmaceutical Society blog and European ever-increasing access to an array of web-based reg-
Journal of Hospital Pharmacy blog. This list does not ulatory resources. The ease with which regulatory
begin to scratch the surface of the widely available regu- information can be acquired is profound, compared to
latory information; however, it is a good starting point. less than a decade ago when the only way to acquire

Chapter 43
similar information was through mail, fax and/or tele- 15. Ibid.
phone. This chapter reviews a wide range of information 16. European Medicines Agency website. http://www.ema.europa.
eu/ema/. Accessed 28 April 2020.
resources and social networking tools available to reg- 17. Ibid.
ulatory professionals. The number of publications and 18. Pending EC decisions. EMA website. http://www.ema.europa.
databases, and government, association and industry eu/ema/index.jsp?curl=pages/medicines/landing/smop_search.
web-based tools, as well as social networking opportuni- jsp&mid=WC0b01ac058001d127. Accessed 28 April 2020.
19. European public assessment reports (EPARs): veterinary medi-
ties developed in just the past few decades, is staggering. cines. EMA website. https://www.ema.europa.eu/en/medicines/
The new challenge for regulatory professionals is to ema_group_types/ema_medicine/field_ema_web_catego-
distill the essential knowledge they require from the vast ries%253Aname_field/Veterinary. Accessed 28 April 2020.
storehouse of information available to perform their 20. Op cit. 16.
21. Op cit. 19.
jobs as effectively as possible. This will require managing 22. Committees, working parties and other groups. EMA website.
subscriptions carefully, becoming skilled in using rele- http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/
vant government and industry databases, making use of general/general_content_000217.jsp&mid. Accessed 28 April
associations’ educational resources to advance profes- 2020.
23. EU Institutions. EMA website. http://www.ema.europa.eu/
sional knowledge, leveraging the expertise of consulting ema/index.jsp?curl=pages/partners_and_networks/general/
firms as needed and using social networking tools with general_content_000216.jsp&mid=WC0b01ac058003174c.
discipline and discernment. In this way, regulatory pro- Accessed 28 April 2020.
fessionals will be certain to reap the greatest benefit from 24. Ibid.
25. Ibid.
the abundant resources available, and thereby ensure 26. Ibid.
the public receives safe, effective and quality healthcare 27. European Union agencies. EMA website. http://
products. The key challenge is to choose trustworthy www.ema.europa.eu/ema/index.jsp?curl=pages/part-
sources when seeking information from authorities and ners_and_networks/general/general_content_000218.
jsp&mid=WC0b01ac058003174d. Accessed 28 April 2020.
institutes. It is important to compare information from 28. Heads of Medicines Agencies. EMA website. http://www.ema.
different sources when evaluating positions related to europa.eu/ema/index.jsp?curl=pages/partners_and_networks/
regulatory changes and developments. general/general_content_000228.jsp&mid=WC0b01a-
c058007e1a6. Accessed 28 April 2020.
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59. s.r.o. Q. Czech Pharmacopoeia. State Institute for Drug 78. RAPS Regulatory Exchange. RAPS website. https://connect.
Control website. http://www.sukl.eu/pharmaceutical-industry/ raps.org/home. Accessed 28 April 2020.
informace-o-historii-a-soucasnosti-ceskeho-ekopisu?highlight-
Words=Czech+Pharmacopoeia+%28%C4%8Cesk%C3%B-
D+l%C3%A9kopis%29. Accessed 28 April 2020.

Chapter 43

Comparative Matrix of
EU Legislation Across
Product Lines
Authorities
Source* Authorities and Standards Organisations
Devices www.cen.eu European Committee for Standardization
http://ec.europa.eu/growth/sectors/ European Commission—Enterprise—Medical Devices
medical-devices_en EUR-Lex—European law and other documentation
http://eur-lex.europa.eu International Medical Device Regulators Forum
www.imdrf.org/ International Organization for Standardization
www.iso.org International Electrotechnical Commission
www.iec.ch European Committee for Electrotechnical
www.cenelec.eu Standardization
www.who.int/ World Health Organization
Drugs www.edqm.eu European Directorate for the Quality of Medicines
www.ema.europa.eu and HealthCare
http://ec.europa.eu European Medicines Agency (EMA)
http://eur-lex.europa.eu European Commission
https://ec.europa.eu/health/home_en EUR-Lex—European law and other documentation
https://ec.europa.eu/health/home_en International Conference on Harmonisation
www.ich.org/ Heads of Medicines Agencies
www.hma.eu World Health Organization
www.who.int/
Biologics Same as drugs
*These websites are accurate at the time of publication (May 2020).

Comparative Matrix of EU Legislation Across Product Lines
Major Regulations and Directives

Source Directives and Regulations
Devices • Directive 2007/47/EC amending Directive 90/385/EEC, Directive 93/42/EEC and Directive
98/8/EC
• Medical Devices Directive (MDD) 93/42/EEC
• Active Implantable Medical Devices Directive (AIMDD) 90/385/EEC
• In Vitro Diagnostic Devices Directive (IVDD) 98/79/EC
• Blood Directive 2002/98/EC
This matrix is based on the content of the above Directives.
• Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017
on medical devices, amending Directive 2001/83/EC, Regulation (EC) No. 178/2002 and
Regulation (EC) No. 1223/2009 and repealing Council Directives 90/385/EEC and 93/42/
EEC (5 May 2017), as last amended by Regulation (EU) 2020/561 of 23 April 2020
• Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017
on in vitro diagnostic medical devices and repealing Directive 98/79/EC and Commission
Decision 2010/227/EU (5 May 2017)
These regulations were adopted on 5 April 2017 and will apply after a transitional period of
four years after entry into force for the EU MDR (May 2021) and five years after entry into force
(May 2022) for the EU IVDR. Note Regulation (EU) 2017/745 (EU MDR) replaces both the MDD
and the AIMDD.
Drugs The Rules Governing Medicinal Products in the European Union: Medicinal Products for
Human and Veterinary Use lists both pharmaceutical legislation (Volumes 1 and 5) and vari-
ous guidance documents (Volumes 2-4 and 6-10) (Volume # below)
• Legislation:
o Volume 1 EU pharmaceutical legislation for medicinal products for human use
o Volume 5 EU pharmaceutical legislation for medicinal products for veterinary use
• Guidelines:
o Volume 2 Notice to applicants and regulatory guidelines for medicinal products for
human use
o Volume 3 Scientific guidelines for medicinal products for human use
o Volume 4 Guidelines for good manufacturing practices for medicinal products for
human and veterinary use
o Volume 6 Notice to applicants and regulatory guidelines for medicinal products for
veterinary use
o Volume 7 Scientific guidelines for medicinal products for veterinary use
o Volume 8 Maximum residue limits
o Volume 9 Guidelines for pharmacovigilance for medicinal products for human and
veterinary use
o Volume 10 Guidelines for clinical trials
Medicinal products for paediatric use, orphan, herbal medicinal products and advanced
therapies (biologics, including gene therapy, somatic cell therapy and tissue engineered
medicines) are governed by specific rules.

Major Regulations and Directives

Source Directives and Regulations
Drugs Directives and Regulations
• Council Directive 2001/83/EC on the Community code relating to medicinal products of
human use, as amended by:
o Directive 2003/63/EC
o Regulation (EC) No. 1901/2006
o Directive 2010/84/EU
o Directive 2012/26/EU
• Directive 2001/82/EC on the Community code relating to veterinary medicinal products,
as amended by:
o Commission Regulation (EC) No. 540/95—Reporting Serious Adverse Reactions
o Commission Regulation (EU) No. 1235/2010 amending Regulation (EC) No. 726/2004
o ICH Guidelines
Biologics Same as drugs plus:
• Directive 2002/98/EC
• Regulation (EC) No. 1394/2007
ICH Guidelines specific to biologics:

• ICH Q5B Analysis of the expression construct in cell lines used for production of r-DNA
derived protein products (CPMP/ICH/139/95)
• ICH Q5D Derivation and characterisation of cell substrates used for production of bio-
technological/biological products (CPMP/ICH/294/95)
• ICH Q5A Viral safety evaluation of biotechnology products derived from cell lines of
human or animal origin (CPMP/ICH/295/95)
• ICH Topic Q5E Comparability of biotechnological/biological products (CPMP/
ICH/5721/03)
• ICH 5QC Stability testing of biotechnological/biological products (CPMP/ICH/138/95)
• ICH Q6B Specifications: Test procedures and acceptance criteria for biotechnological/
biological products (CPMP/ICH/365/96)
• General principles to address the risk of inadvertent germline integration of gene therapy
vectors (CHMP/ICH/469991/2006)
• General principles to address virus and vector shedding (EMEA/CHMP/
ICH/449035/2009)
• ICH S6 (R1) Preclinical safety evaluation of biotechnology-derived pharmaceuticals
(CHMP/ICH/731268/1998)

Product Classification
Source Product Classification
Devices Directive 93/42/EEC and Active Implantable Medical Devices—all one classification
Directive 90/385/EEC
Amended by Directive Medical Device Classification
2007/47EEC and • Class I—nonsterile, non-measuring
Directive 98/79/EC • Class I sterile and/or Class I with a measuring function
• Class IIa
Regulation (EU) • Class IIb
2017/745 on medical • Class III
devices and Regulation
(EU) 2017/746 on in IVD Classification
vitro diagnostic medical • Annex II List A and List B devices
devices • Self-testing devices
• Non-Annex II and Non-self-testing devices (“Other” IVDs)
CE Marking
• Symbolises the conformity of a product with the applicable European
Community requirements imposed on the manufacturer
• A declaration by the person responsible for the product conforms to all
applicable Community provisions and the appropriate conformity assess-
ment procedures have been completed
• CE Mark must be on the label when conforming products are placed on
the market
• CE Mark must be on the device itself or the sterile pack (where practica-
ble and appropriate)
• CE Mark also must be included on the Instructions for Use
• CE Mark must:
o be legible
o be visible
o be indelible
o include notified body number (except Class I and non-Annex II/non-
self-testing IVDs)
o be in the exact proportions given in the directive
• Custom-made and devices used in clinical trials need not bear the CE
Mark
Classification of Medical Devices is based on:

• Device’s intended purpose
• Duration of contact with patient
o transient—normally intended for continuous use for less than 60
minutes
o short-term—normally intended for continuous use for not more than
30 days
o long-term—normally intended for continuous use for more than 30
days
• Invasiveness of device
o body orifice
o surgically invasive device—which penetrates inside the body
through the surface of the body
• Implantability of device
• Active device (power source)
• Devices incorporating a measuring function
• In vitro diagnostic device

Devices Classification Rules—Applicable only to medical devices under Directive
93/42/EEC; to determine the class, apply the highest class for the character-
istics or a combination of characteristics of the medical device:
• Noninvasive device—Rules 1, 2, 3, 4
• Invasive device—Rules 5, 6, 7, 8
• Active devices—Add Rules 9, 10, 11, 12
• Special rules—Rules 13, 14, 15, 16, 17, 18
The Rules (see full rules for exceptions)

• Rule 1—Either does not touch patient or contacts only intact skin—Class I
• Rule 2—All noninvasive devices intended for channelling or storing blood,
body liquids or tissues, liquids or gases for the purpose of eventual infu-
sion, administration or introduction into the body are Class IIa
• Rule 3—All noninvasive devices intended for modifying the biological
or chemical composition of blood, other body liquids or other liquids
intended for infusion into the body are Class IIb
• Rule 4—All noninvasive devices that come into contact with injured skin
are in Class I if they are intended to be used as mechanical barriers, for
compression or for absorption of exudates, or are in Class IIb if they are
intended to be used principally with wounds that have breached the der-
mis and can only be healed by secondary intent
• Rule 5—All invasive devices with respect to body orifices, other than sur-
gically invasive devices, and are not intended for connection to any active
medical device are in Class I if they are intended for transient use, in
Class IIa if they are intended for short-term use and in Class IIb if they are
intended for long-term use
• Rule 6—All surgically invasive devices intended for transient use are in
Class IIa
• Rule 7—All surgically invasive devices intended for short-term use are in
Class IIa
• Rule 8—All implantable devices and long-term surgically invasive devices
are in Class IIb
• Rule 9—All active therapeutic devices intended to administer or exchange
energy are in Class IIa
• Rule 10—All active devices intended for diagnosis are in Class IIa
• Rule 11—All active devices intended to administer and/or remove medi-
cines, body liquids or other substances to or from the body are in Class
IIa
• Rule 12—All other active devices are in Class I
• Rule 13—All devices incorporating, as an integral part, a substance
which, if used separately, can be considered to be a medicinal product as
defined in Article 1 of Directive 65/65/EEC, and which is liable to act on
the human body with action ancillary to that of the device, are in Class III
• Rule 14—All devices used for contraception or the prevention of the trans-
mission of sexually transmitted diseases are in Class IIb
• Rule 15—All devices intended specifically to be used for disinfecting,
cleaning, rinsing or, when appropriate, hydrating contact lenses are in
Class IIb; those intended specifically for disinfecting medical devices are
in Class IIa
• Rule 16—Non-active devices specifically intended for recording of X-ray
diagnostic images are in Class IIa
• Rule 17—All devices manufactured utilising animal tissues or derivatives
rendered non-viable are Class III except where such devices are intended
to come in contact with intact skin only
• Rule 18—Blood bags are in Class IIb

Devices The new EU MDR and EU IVDR will extend to devices currently not regulated
as medical devices, including contact lenses, cosmetic implants and invasive
laser equipment, as well as products utilising nonviable human tissues or
cells. The EU MDR will absorb the AIMD, and those devices and any accesso-
ries will fall into the EU MDR’s highest risk class. The classification rules will
change somewhat and have additions, with a resulting total of 22 rules.
For IVDs, the current list-based classification will be replaced by four risk
classes (A–D). The EU IVDR includes a new regime for laboratory-developed
tests (home brew tests) and companion diagnostics.
Drugs Directive 2001/83/EC, as Prescription Only
amended • Are likely to present a danger either directly or indirectly, even when used
correctly, if utilised without medical supervision
Directive 2001/82/EC, as or
amended • Are frequently and to a very wide extent used incorrectly, and as a result
are likely to present a direct or indirect danger to human health
or
• Contain substances or preparations thereof, the activity and/or side
effects of which require further investigation
or
• Are normally prescribed by a doctor to be administered parenterally
Nonprescription
• All drugs not subject to prescription (such as OTC)
Other Medicinal Product Designations Include:

• Orphan
• Herbal
• Medicinal products for paediatric use
• Advanced therapy medicinal products
• Veterinary medicinal products
• Radiopharmaceuticals

Format and Content of Applications

Source Format and Content of Applications
Devices Directive 93/42/EEC and Quality System Application to Notified Body Requirements
Directive 90/385/EEC • Manufacturer name and address
Amended by Directive • Class or category of products to be manufactured
2007/47/EC and • Statement that no application has been lodged with another
Directive 98/79/EC notified body for the same product-related quality system
• Quality system documentation
Regulation (EU) 2017/745 • How the manufacturer will fulfil the approved quality system
on medical devices and obligations
Regulation (EU) 2017/746 on • How the manufacturer will maintain the approved quality sys-
in vitro diagnostic medical tem to ensure adequacy and efficacy
devices • How the manufacturer will institute and maintain the postmar-
keting surveillance system
• The manufacturer must ensure products conform to the direc-
tive provisions and apply them at every stage from design to
final controls through quality objectives, organisation of the
business, procedures for monitoring and verifying the design
of the products, inspection and quality assurance techniques,
and appropriate tests and trials before, during and after
manufacture
Clinical Trial Documentation

EN ISO 14155:2011 • A statement must be made to the competent authority of the
Clinical Investigation of Member State(s) where the trials are to take place prior to com-
Medical Devices for Human mencement of clinical trials, containing the following elements
Subjects—Good Clinical (in addition to elements required in application below):
Practice o data allowing the devices to be identified
o an investigational plan identifying the purpose, scope and
number of devices concerned
Clinical Evaluation: o name and doctor of institution responsible for the
A Guide for Manufacturers investigation
and Notified Bodies (MEDDEV o the place, date of commencement and duration scheduled
2.7.1 Rev. 4) for the investigations
o a statement affirming the device in question complies with
the Essential Requirements and stating what precautions
have been used to protect the health and safety of the
patient


Devices Design Dossier Application to Notified Body (Class 3, Annex II, List A
and Self-testing IVDs)
• Manufacturer name and address
• Authorised Representative name and address (if applicable)
• A written declaration the application has not been made to
another notified body
• General description of the device
• Design drawings
• Methods of manufacture envisioned (sterilisation, diagrams of
parts, subassemblies, circuits, etc.)
• Description and explanations necessary for understanding the
drawings and diagrams and the product’s operation
• Results of design calculations, investigations and technical
tests carried out
• Design specifications, including standards applied
• If standards are not being used, describe the test methods used
• Clinical trial data
• Draft instruction leaflet
• Additional data requested by notified body
Modification to Device Design

• The notified body issuing the EC Design Examination
Certification or EC Type-Examination Certificate shall be notified
of any modifications made to the approved design.
• Supplementary approval must be obtained for any design
modifications.
Possible Decision Outcome From Notified Body

• If the dossier complies with all relevant provisions of the direc-
tive, the device will be allowed to be placed on the market and
an EC Design Examination Certification shall be issued. The
certification shall contain:
o conclusions of the examination
o conditions of its validity
o data needed for identification of the approved design
o description of the product’s intended use
• Allowed to be placed on the market with restrictions
• Refusal to allow the device to be placed on the market
Renewal of the EC Design Examination Certification is applied for

every five years.
For restrictions and refusals, remedies are allowed.
CE Marking
• Once necessary notified body certificates are in place for quality
systems and product evaluation and the necessary Technical
Documentation is in place, the manufacturer will be able to sign
a Declaration of Conformity and CE Mark the product.
• Class I medical devices or non-Annex II, non-self-testing IVDs
may be self-declared to conform to the requirements of the
necessary directive and placed on the market directly without
intervention from a notified body.


Drugs Directive 2001/83/EC, as European Dossier
amended
Common Technical Document (CTD)
The CTD is organised into five Modules. Module 1 is region specific.
Modules 2, 3, 4 and 5 are intended to be common for all regions.
• Module I: Region Specific Administrative and Product
Volume 2B, Notice to Information
Applicants, Presentation and o Cover letter
content of the dossier o Comprehensive Table of Contents
o Application Form
o Product Information Documents
o Information About the Experts
o Environmental Risk Assessment
o Pharmacovigilance System Description
o Risk Management Plan
o Clinical Trial Information
o Paediatric Information
• Module 2: Common Technical Document Summaries

o Table of Contents (Modules 2–5)
o Introduction
o Quality Overall Summary
o Nonclinical Overview
o Clinical Overview
o Nonclinical Written and Tabulated Summary
– Pharmacology
– Pharmacokinetics
– Toxicology
o Clinical Summary
– Biopharmaceutics and Associated Analytical Methods
– Clinical Pharmacology Studies
– Clinical Efficacy
– Clinical Safety
– Synopses of Individual Studies
• Module 3: Quality
o Table of Contents (Module 3)
o Body of Data
o Literature References
• Module 4: Nonclinical Study Reports

o Study Reports
• Module 5: Clinical Study Reports

o Tabular Listing of All Clinical Studies
o Clinical Study Reports


Drugs ICH: M4 (M4, M4Q, M4E, Application Renewals
M4S)—Common Technical • A renewal application should be submitted no later than six
Document months before the end of the five-year period (or no later than
nine months for centrally authorised products). The following
documentation should be submitted:
• An updated CTD: Module I, including current manufacturing
authorisation and GMP declarations, product Information and
other information such as dates of authorisation in all Member
States, chronological list of all the variations of any type
approved since the grant of the marketing authorisation or last
renewal, including the CHMP opinion number
• An updated Module 2 (2.3 Quality overview and 2.5 Clinical
overview). The clinical overview should include any actions
taken as a result of the PSURs.
• Update of studies requested in the CHMP opinion
Biologics Volume 2B, Notice to Appli- Same as drugs (with some specific extra information)
cants
Extra information required for biotech products covers such topics
as schematic amino acid sequence, cell bank and cell culture, har-
vest(s), purification and modification reactions, filling, storage and
shipping conditions, among others.

Marketing Authorisation Procedures

Source Marketing Authorisation Procedures
Devices Directive 93/42/EEC and CE marking is the only prerequisite to placing products on the EU mar-
Directive 90/385/EEC ket. While it is necessary to communicate with the national competent
Amended by Directive authorities when placing medical devices on the market—including
2007/47/EC and all Class I and custom-made devices and, in some countries, Class IIa,
Directive 98/79/EC Class IIb and Class III devices—this communication does not constitute
or convey approval by these authorities. The details of the communi-
Regulation (EU) 2017/745 cation and whether there are specific requirements and forms to be
on medical devices and submitted vary from country to country.
Regulation (EU) 2017/746
on in vitro diagnostic Under the EU MDR and EU IVDR, the market access mechanism for
medical devices low- and medium-risk devices will largely stay the same, but details
will change. High-risk devices will face stricter control through a new
premarket scrutiny mechanism from experts at EU level. IVDs will have
additional requirements, going from only 10–20% CE-certified and the
rest self-certified, to 80–90% needing to be CE-certified by a notified
body.
MD and IVD notified bodies will need expert employees rather than
using contractors. They will have to conduct unannounced manu-
facturing inspections. All notified bodies will need to re-apply for
accreditation under stricter rules.
Drugs Directive 2001/83/EC, as Marketing Authorisation Exempted for:
amended • Medicinal products prepared on the basis of magisterial or offici-
nal formula
Regulation (EC) No. • Medicinal products intended for research or clinical trials
726/2004 • Intermediate products intended for further processing by an
authorised manufacturer
Four Routes for Marketing Authorisation: National, Mutual

Recognition, Decentralised and Centralised
National Procedure for EU Member States

• Submit a marketing authorisation application (MAA) to only one
Member State (usually targeted for the initial marketing authori-
sation or as a basis for the application to be mutually recognised
by other Member States).
Mutual Recognition Procedure

• Submit an MAA in one Member State and, once the MA has been
granted (serial), make applications in other Member States con-
cerned requesting them to mutually recognise the MA already
granted.
• If recognition of the national authorisation is requested in another
Member State, the Mutual Recognition procedure must be used.
The Reference Member State (RMS) is the first Member State to which
an application is submitted. Once marketing authorisation (MA) has
been granted by the RMS, identical applications can be submitted
to the Concerned Member States (CMS) requesting them to mutually
recognise the MA already granted. An identical dossier translated into
the language of the CMS should be submitted.


Drugs Timeframe
• RMS has 210 days from receipt of the application to issue a
decision.
• If the parallel procedure is used, CMS can suspend their decisions
until the RMS decision is issued.
• CMS have 90 days to mutually recognise the RMS authorisation
once the marketing authorisation holder (MAH) applies; CMS also
can mutually recognise an application within 90 days without the
MAH’s request.
MAH Must Ensure:

• Dossier is identical (including any approved variations) to that
accepted by the RMS or identify any additions.
• Summary of product characteristics (SmPC) is identical.
• Dossier and SmPC as submitted are identical in all CMS.
If concerns are raised that cannot be resolved within the 90-day period
for mutual recognition a referral procedure will be triggered. See
https://www.ema.europa.eu/en/human-regulatory/post-authorisa-
tion/referral-procedures for referral procedures.
Decentralised Procedure
The Decentralised Procedure is used for medicinal products for which
there is no existing MA in any EU Member State at the time of appli-
cation. It covers all medicinal products not authorised in the EU (for
which the Centralised Procedure is not mandatory). Like the Mutual
Recognition Procedure, the applicant can select the RMS and list
the CMS. The Decentralised Procedure was introduced by Directive
2004/27/EC. Decision by Day 210.
Council Regulation (EEC) No. 2309/93 (now replaced by Regulation
(EC) No. 726/2004) created a centralised Community procedure for
the authorisation of medicinal products and established the European
Medicines Agency (EMA). An MA granted under the Centralised
Procedure is valid for the entire Community market.
• Obligatory for:
o Medicinal products developed by means of biotechnological
processes such as:
– recombinant DNA technology
– hybridoma and monoclonal antibody methods
o veterinary medicinal products, including those not derived
from biotechnology, intended primarily for use as perfor-
mance enhancers
o orphan medicinal products
o medicinal products containing a new active substance
intended for the treatment of
– acquired immune deficiency syndrome (AIDS)
– cancer
– neurodegenerative disorders
– diabetes


Drugs o Optional for the following, where it can be demonstrated
central registration is an added value for the Community:
o innovative products
o has a significant benefit for the society; this also applies to
OTC products intended for human use
Submission and Dossier Evaluation

• Submit an application to EMA.
• Scientific evaluation is carried out by Committee for Medicinal
Products for Human Use (CHMP), which prepares and issues a
scientific opinion within 210 days after receiving the dossier.
• The opinion is sent to the European Commission, which drafts a
decision and consults with a Standing Committee.
Potential Opinions
• Positive
• Approvable under exceptional circumstances
• Conditional approval, with obligations
• Negative—major deficiencies identified and approval unlikely
(this can be appealed within 15 days)
Usually, the European Commission will adopt the decision. If favour-

able, an MA will be granted. The Community Marketing Authorisation
is valid in all Member States and confers the same rights and obliga-
tions in each Member State as if granted by that Member State.
Variations to an Approved Marketing Authorisation
Type IA and Type IB

Type IA notifications are listed in Annex II of Regulation (EC) No.
1234/2008. Certain Type IA variations are labelled IAIN (IN = immediate
notification) must be notified to the authority immediately after imple-
mentation due to administrative circumstances. A variation that is not
an extension and classification of which is undetermined after appli-
cation of the rules provided in Regulation (EC) No. 1234/2008 shall by
default be considered a minor variation of Type IB. These types of vari-
ations concern an amendment to the contents of a document as they
were at the moment of the decision on the marketing authorisation.
Type II
Any change to the documentation proposed by the MAH, which is not
a Type IA or Type IB notification and is not regarded as an extension
to the MA, is considered a Type II variation. Type II variations have a
significant impact on the quality, safety or efficacy of the medicinal
product concerned. Changes that require a new application procedure
are defined in Annex II of the regulations. Type II variations are listed
in Annex II of Regulation (EC) No. 1234/2008.


Drugs Regulation (EC) No. Urgent Safety Restriction
726/2004 An urgent safety restriction can only be used by the applicant or holder
of a certificate of registration to amend the package insert of a medic-
inal product based on new information that has a bearing on the safe
use of the product. It involves an interim change to product informa-
tion by the MAH restricting the indication(s) and/or dosage and/or
target species of the medicinal product; or adding a contraindication
and/or warning due to new information having a bearing on the prod-
uct’s safe use. Such an urgent safety restriction may be imposed by
either the MAH or by the competent authorities.
Extension Applications
Regulation (EC) No. An application for an extension to the MA can be made, provided the
1234/2008, amended conditions reflected in Annex I of Regulation (EC) No. 1234/2008 are
by Regulation (EU) No. met. These applications fall outside the scope of the definition of a
712/2012 variation to an MA and, consequently, such applications are exam-
ined by the competent authority/Community in accordance with the
procedure for granting a new MA. Therefore, an extension or a mod-
ification of the existing MA will have to be granted by the competent
authority/Community. Further guidance on whether a change leads
to a new application or variation can be found in the EC guidance,
Categorisation of New Application Versus Variations Applications.
Action by Application
The detailed actions for each type of variation and procedure are listed
in Regulation (EC) No. 1234/2008.


Biologics Directive 2001/83/EC, as New biologics can be submitted through the Mutual Recognition or
amended Centralised Procedure like drugs (see above) with some restrictions
Annex of Regulation (EC) (below).
No. 726/2004
Centralised Procedure is Optional for:
• A medicinal product, which constitutes a significant therapeutic,
scientific or technical innovation or that the granting of authorisa-
tion is in the interest of patients at Union level.
Centralised Procedure is Obligatory for:

• Medicinal products, including biosimilars, developed by means of
one of the following biotechnological processes:
o recombinant DNA technology
o hybridoma and monoclonal antibody methods
o controlled expression of genes coding for biologically active
proteins in prokaryotes and eukaryotes including trans-
formed mammalian cells
• Advanced therapy medicinal products (gene therapy, somatic cell
therapy and tissue engineered products)
• Veterinary medicinal products, including those not derived
from biotechnology, intended primarily for use as performance
enhancers
• Orphan medicinal products
• Medicinal products for human use containing a new active sub-
stance for which the therapeutic indication is the treatment of any
of the following diseases:
o acquired immune deficiency syndrome (AIDS)
o cancer
o neurodegenerative disorders
o diabetes
o Auto-immune diseases and other auto-immune dysfunctions
o Viral diseases
Variations/Changes (same as drugs)

Requirements for Clinical Investigations/Investigators (GCP)

Source Requirements for Clinical Investigations
Devices EN ISO 14155:2011 Notification/Approval Prior to Trial Initiation
Clinical Investigation • The manufacturer or authorised representative must submit a statement
of Medical Devices to the competent authority of its intention to conduct a clinical trial with a
for Human medical device prior to commencement.
Subjects—Good • In some countries, the study may not commence until the competent
Clinical Practice authority provides approval. In other countries, if a specific time period has
elapsed (generally 60 days) without query from the competent authority,
Directive 93/42/EEC the study can begin.
and • No clinical trial can begin until Ethics Committee approval is also obtained.
Directive 90/385/
EEC Purpose of a Clinical Investigation
Amended by • To verify, under normal conditions of use, the device’s performance com-
Directive 2007/47/ plies with the conditions indicated in the statement required for clinical
EC and investigations.
Directive 98/79/EC • To determine any undesirable side effects, under normal conditions of use,
and assess whether they are acceptable risks with regard to the device’s
Clinical Evaluation: intended performance.
A Guide for
Manufacturers and Ethics
Notified Bodies • All clinical trials must be conducted according to the Declaration of Helsinki.
(MEDDEV 2.7.1 Rev.
4) Methods
• Investigational plan must be designed to confirm or refute the claim for the
Regulation (EU) device.
2017/745 on med- • An adequate number of observations should be included to guarantee the
ical devices and scientific validity of the conclusions.
Regulation (EU) • Procedures used to perform the investigation must be appropriate to the
2017/746 on in vitro device being investigated.
diagnostic medical • The clinical investigation must have equivalent circumstances to the
devices device’s normal conditions of use.
• All features, including the device’s safety and performance and its effects
on patients, must be examined.
• All adverse events should be recorded.
• The clinical investigation should be performed by a qualified medical spe-
cialist in an appropriate environment.
• The qualified medical specialist shall have access to the technical data
regarding the device.
Literature Review as Basis for Approval (for nonimplantable or devices equiva-

lent to existing CE-marked devices)
• Identify hazards in the clinical part of the risk analysis
• Published literature should be taken from recognised scientific publications
including unfavourable and favourable data
• Other scientific data including in vitro and bench testing
• Documented expert opinions
• Description of the device and any variants
• Product specifications
• Data that may have been submitted to regulatory bodies for approval


Devices Adverse Event Reporting
All serious adverse events must be fully recorded and immediately notified to all
competent authorities of the Member States in which the clinical investigation is
being performed.
The new EU MDR and EU IVDR contain requirements for clinical evidence (both
pre- and postmarket) using existing MEDDEVs. The regulations will not ‘grand-
father’ existing devices, so manufacturers will have to collect additional clinical
evidence for devices already CE-marked and they will need to be recertified.
Drugs Regulation No. The European Clinical Trial Regulation (Regulation No. 536/2014) was adopted
536/2014 of the on 16 June 2014 with an implementation deadline no earlier than 28 May
European Parliament 2016, and at least six months after the new EU Database and EU Portal become
and of the Council available. On 16 June 2017, EMA’s management board announced that “due to
on clinical trials technical difficulties with the development of IT systems has delayed the imple-
on medicinal prod- mentation of the regulation. Current estimates say the earliest the systems will
ucts for human be available will be mid-2021, with implementation of the Regulation at least six
use, and repealing months after that.
Directive 2001/20/
EC (NOTE- Not yet Under the ECTR, one application dossier will be submitted through a single sub-
implemented, mission portal, grouping all the clinical trial’s information. A two-part parallel
unlikely to be imple- scientific and ethical review will be conducted:
mented before 2022) • Part I, assessment coordinated between the relevant MS and a reporting
MS, with a single decision.
Clinical Trials • Part II, assessment performed by each relevant MS and national EC, with a
Directive 2001/20/ national decision.
EC
The information below describes the process based on the 2001 Clinical Trials
Directive 2001/83/ Directive.
EC, as amended
Protection of Subjects
ICH E1, E2A, E2B, • Right to privacy, integrity and withdrawal at any time is required.
E2F, E3, E4, E5, E6, • For children and incapacitated adults, legal representative consent is
E7, E8, E9, E10, E11 required and can be revoked at any time (no incentives are allowed in this
population).
• Provision should be taken to minimise pain, fear, risk and distress.
• All clinical trials must be conducted according to the Declaration of Helsinki.
Regulatory Notification/Approval Prior to Trial Initiation

• Parallel notification/submission of regulatory authority and Ethics
Committee is allowed.
• No clinical trial can begin until both competent authority and Ethics
Committee approval is obtained.
• The regulatory authority has 60 days from the submission of a valid dossier
to notify the sponsor of no objections or nonacceptance of dossier.
o If no objections are raised after 60 days, the trial shall be authorised.
o If grounds for nonacceptance are issued, a sponsor can file a one-time
amendment.
o If no amendment is filed, the request is rejected.
• The notification time cannot be extended except for certain biologic prod-
ucts (see below).


Drugs Competent Authority Responsibilities
• Review of existing nonclinical and clinical data to ensure proposed protocol
is based on available date.
• Review of protocol to ensure safe and meaningful trial design, including
appropriate use of placebo or comparator drugs
• Review of quality of proposed investigational medicinal product (IMP)
• Ensure IMP manufactured in compliance with GMP
• Review of plans for safety reporting/pharmacovigilance
• Evaluate benefit risk ratio
• Each member state requires the approval of the competent authority
approval of that member state.
Ethics Committee Responsibilities

• Review of trial design
• Review trial benefit-risk evaluation
• Review of informed consent
• Review investigator’s brochure and protocol
• Review patient recruitment
• Review quality of investigator, staff and facilities
• Provision for compensation in case of injury
• Review all information provided to patient before consent
• Review of patient or investigator incentives
• An opinion should be issued within 60 days after a valid application is
received
o The clock stops if additional information is requested from the sponsor.
• Metacentre trials in one Member State can obtain one Ethics Committee
approval
• Multi-state trials require a single Ethics Committee opinion per Member
State
Conduct of Trials
Substantial amendments to the conduct of the clinical trial may arise from
changes to the protocol or from new information relating to the scientific
documents in support of the trial. Amendments to the trial are regarded as “sub-
stantial” where they are likely to have a significant impact on:
• Safety or physical or mental integrity of the subjects
• Scientific value of the trial
• Conduct or management of the trial
• Quality or safety of any IMP used in the trial.
• Substantial amendments need both regulatory and Ethics Committee
approval before being implemented.
• Competent authority and Ethics Committee opinion on amendments should
be issued in 35 days.
• End of clinical trial—competent authorities and Ethics Committee need to be
notified of the global end of a clinical trial within 90 days.
• Early termination of a clinical trial—competent authorities and Ethics
Committee need to be notified of the early termination of a clinical trial
within 15 days.
• Trial must comply with good clinical practice (GCP).
• A clinical study report (CSR) detailing all aspect of the study and the results
must be prepared and finalised within one year of the end of the study.
• The results of all clinical trails must be uploaded to the EudraCT database
within one year of the end of the study (or within six months for paediatric
studies). Some Member States also require the CSR to be submitted to
Ethics Committees and competent authorities.


Drugs Suspension of a Trial
• A trial may be prohibited or suspended if the Member State has doubts
about the trial’s safety or scientific validity or if the conditions for the
request for authorisation are not being met.
• If the competent authority has objective grounds for considering that the
sponsor or investigator or any other person involved in the conduct of the
clinical trial is no longer meeting his obligations, it shall inform the sponsor
or investigator of the actions needed to remedy the situation. The compe-
tent authority also will notify the Ethics Committee and the other competent
authorities of its actions.
Manufacture of Clinical Supplies (See GMP Section)

• Clinical supply manufacturer must comply with GMP requirements.
• A manufacturing authorisation should have been granted.
• Import/free movement is authorised upon certification by a Qualified
Person.
Adverse Event Reporting

• The investigator shall report all serious adverse events to the sponsor
immediately, except those that the protocol or investigator’s brochure iden-
tifies as not requiring immediate reporting.
• The immediate report shall be followed by detailed, written reports.
• The immediate and follow-up written reports shall identify subjects by
unique code numbers.
• Adverse events or laboratory abnormalities identified in the protocol as
critical to safety evaluations shall be reported to the sponsor according to
the reporting requirements and within the time periods specified within the
protocol.
• Detailed records shall be kept for all adverse events; these records shall be
submitted to the Member States (if requested) in whose territory the clinical
trial is being conducted.
Suspected Unexpected Serious Adverse Reaction (SUSAR) Notification

• The sponsor shall ensure t all relevant information about serious unex-
pected adverse reactions that are fatal or life-threatening is recorded and
reported as soon as possible to the competent authorities in all Member
States concerned and to the Ethics Committee, no later than seven calendar
days after learning about the event, and a follow-up report with all relevant
information is submitted within an additional eight calendar days.
• All other serious adverse reactions shall be reported to the competent
authorities in all Member States concerned and to the Ethics Committee, as
soon as possible but within a maximum of 15 calendar days after the spon-
sor first learns of the event.
• Each Member State shall ensure all suspected unexpected serious adverse
reactions are recorded.
• The sponsor shall inform all investigators of unexpected serious adverse
reactions.
• Once a year, during the conduct of the clinical trial, the sponsor shall pro-
vide the Member States and Ethics Committee in whose territory the clinical
trial is being conducted with a list of all suspected serious adverse reactions
that have occurred during the period and a report of the subjects’ safety via
the development safety update report (DSUR).


Biologics Regulation No. Same as drugs (except where noted below)
536/2014 of the
European Parliament Ethics Committee Responsibilities
and of the Council • An opinion will be issued 60 days after a valid application is received,
on clinical trials on except for gene or cell therapy where an extension of 30 days is granted.
medicinal products • There is no set time limit for clinical trial notification for clinical trials
for human use, and involving gene therapy, cell therapy, xenogeneic cell therapy, biotechnolo-
repealing Directive gy-derived or any biological product.
2001/20/EC • A trial cannot begin until a favourable opinion is issued by an Ethics
Committee.
Clinical Trials
Directive 2001/20/ Notification/Approval Prior to Trial Initiation
EC • A dossier can be submitted to the competent authorities at the same time it
is submitted to the Ethics Committee.
Directive 2001/83/ • For biologics classified as genetically modified organisms (GMOs) there
EC, as amended is a requirement to submit a GMO application to an additional competent
authority. The GMO dossier can be submitted in most countries (but not in
Directive 2009/41/ all) in parallel to the CTA dossier submissions to the competent authorities
EC on the contained and Ethics Committee.
use of geneti- • For classic medicinal products, a clinical trial can be initiated 60 days after
cally modified submission of the CTA dossier.
microorganisms • Regulatory authorisation is needed to begin a clinical trial and is granted
within 90 days for gene therapy, cell therapy products, genetically modified
Directive 2001/18/ organisms and xenogeneic cell therapy medicinal products, unless the clock
EC on the deliberate is stopped for additional information requests. An additional 90 days may
release of GMOs into be added to this timeline if experts are consulted.
the environment • GMO approval is needed to begin a clinical trial with GMOs. Procedures and
timelines are highly variable between countries.

Reporting/Recordkeeping Requirements for Clinical Investigators and Sponsors

Source Reporting/Recordkeeping Requirements for Clinical Investigators
Devices EN ISO 14155-1 • ISO 14155-1 states it should be the sponsor’s responsibility to
Clinical Investigation of “collect, store, guard and ensure completion by relevant parties
Medical Devices for Human of all the documentation from clinical investigations.” This shall
Subjects—Good Clinical include:
Practice o clinical investigator’s brochure
o clinical investigation plan
o CVs for all investigators
o name of the institution(s) where investigation will be held
o Ethics Committee opinion
o correspondence with authorities
o agreements between sponsor and investigator
o informed consent forms
o case report forms
o forms for reporting adverse incidents
o monitor(s) names/contact details
o copies of signed and dated case report forms
o records of any adverse incidents reported during the
investigation
o statistical analyses and underlying supporting data
o final report
• Arrangements for the storage of such records should be part of
the sponsor/investigator agreement.
• Since this type of data supports the information put into the tech-
nical file for devices, it should be retained for at least the same
length of time as the rest of the technical file (i.e., the lifetime of
the device plus five years minimum). The sponsor should there-
fore specify the retention period required.

Reporting/Recordkeeping Requirements for Clinical Investigators and Sponsors

Source Reporting/Recordkeeping Requirements for Clinical Investigators
Drugs Directive 2001/83/EC, as General
amended • The sponsor shall arrange with the investigator for the retention
of patient identification codes for at least 15 years after the com-
Clinical Trial Regulation pletion or discontinuation of the trial.
(EU) No. 536/2014)—not • Patient files and source data shall be kept for the maximum
yet implemented as of April period of time permitted by the hospital, institution or private
2020. practice.
• The sponsor or other owner of the data shall retain all other doc-
umentation pertaining to the trial for as long as the product is
authorised and shall include:
o clinical protocol
o details of the investigational product, including the refer-
ence medicinal product and/or the placebo used
o standard operating procedures
o all written opinions on the protocol and procedures
o investigator’s brochure
o case report forms on each trial subject
o final study report
o audit certificate(s), if available
Note: When the Clinical Trial Regulation (EU) No. 536/2014) is imple-
mented, the following will apply unless other Union law requires
archiving for a longer period:
• The sponsor and the investigator shall archive the content of the
clinical TMF for at least 25 years after the end of the clinical trial.
However, the medical files of subjects shall be archived in accor-
dance with national law.
• The final report shall be retained by the sponsor or subsequent
owner for five years after the product is no longer authorised
(discontinued marketing).

Packaging and Labelling

Source Labelling
Devices Directive 93/42/EEC and Information supplied by the manufacturer must include:
Amended by Directive Labelling on device, outer packaging and instructions for use must
2007/47/EC and include:
Directive 98/79/EC • Manufacturer name or trade name and address
• If imported into the Community
• Authorised representative (if appropriate)
ISO/TC 145 Graphical Symbols • Device and packaging contents identification
• “Sterile” when appropriate
Medical Device Symbols • Batch code or serial number preceded by the word, “LOT”
ISO 15223-1:2016 • Use-by date specified by year and month
ISO 15223-2:2010 • Indication the device is for single use (if appropriate)
• “Custom-made device” if the device is custom made
EN ISO 11607-1:2019 • “Exclusively for clinical investigations” if device is intended for
Packaging for terminally ster- clinical investigations
ilized medical devices • Any special storage and/or handling conditions
• Any special operating instructions
Principles of Labelling for • Any warnings and/or precautions to take
Medical Devices and IVD • Year of manufacture for active devices (this may be included in
Medical Devices (IMDRF) the serial or batch number)
• Sterilisation method (where applicable)
AIMDD Annex 1 Essential • Device’s intended purpose (unless obvious)
requirements 12–15 • Identification of device components (when reasonable and
practical)
MDD Annex 1 Essential
requirement 13 Instructions for Use
• May be omitted for Class I and Class IIa devices if the manufac-
IVDD Annex 1 Essential turer can ensure they can be used safely without instructions
requirement 8
In addition to requirements (above), labelling must contain, when
Regulation (EU) 2017/745 practical:
on medical devices and • Device performance standards
Regulation (EU) 2017/746 on • Undesirable side effects
in vitro diagnostic medical • Whether the device must be installed or used with other compo-
devices nents in order to operate as required for its intended purpose
• How to verify the device is properly installed and can operate
safely and correctly
• Nature and frequency of needed maintenance, including cal-
ibration needed to ensure the device operates properly and
safely at all times
• Information on how to avoid certain risks in connection with
implantation of devices (where appropriate)
• If the device is reusable, how to process the device to allow for
re-use


Source Labelling
Devices Use-by Date
• All medical devices must contain a statement about any time
limitations on their safe use.
• The “use-by” time limit relates to the period before the first use
of the device and does not relate to the number or period of
subsequent uses.
• The manufacturer must demonstrate via relevant performance
the device characteristics are maintained over the claimed shelf
life reflected by the “use-by” date, by:
o prospective studies on accelerated aging, validated with
real time degradation correlation
o retrospective studies using real-time experience, involving
testing of stored samples, review of complaints history or
published literature
• The lack of a “use-by” date implicitly implies the product has an
infinite shelf life.
The new EU MDR and EU IVDR require new information on labels,

e.g., UDIs, number of reprocessing cycles, and sterile packaging
information.
Drugs Directive 2001/83/EC, as Controlled at the National Level
amended
All labelling should be easily legible, clearly comprehensible and
indelible and shall appear in the official language(s) of each Member
State where the medicinal product is placed on the market.
Investigational Products
ICH Q7 Good Manufacturing • Must be in accordance with GMP Guidelines (see Annex VI of
Practices for Active Regulation (EU) No. 536/2014).
Pharmaceutical Ingredients • Particulars must be in at least the language of the Member
State on outer packaging and on the immediate packaging if
Readability Guidelines there is no outer packaging.
https://ec.europa.eu/
health/sites/health/ Marketed Products
files/files/eudralex/
vol-2/c/2009_01_12_read- Outer Pack Required Information
ability_guideline_final_en.pdf • Product name (trade name, international nonproprietary name)
• Strength
• Pharmaceutical form
• Qualitative and quantitative composition of active ingredients
• Qualitative list of excipients
• Method and route of administration
• Expiry date in clear terms (month/year)
• Storage conditions
• Precautions for disposal of unused product or waste materials
• MAH name and address
• Special warnings (e.G., “Keep out of reach of children”)
• Manufacturer’s batch number
• Marketing authorisation number
• Instructions for self-medication (where applicable)
• May include symbols or pictograms designed to clarify certain
information
• Trade name and strength in Braille


Source Labelling
Drugs Minimum Requirement on Immediate Packaging
• Product trade name
• Strength and route of administration
• Method of administration
• Batch expiry date
• Batch number
• Contents (weight, volume and dosage)
Package or User Leaflet Must Contain:

• Product identification (name and common name)
• Strength
• Quantitative composition of the active ingredient
• Quantitative list of excipients
• Contents per dose
• Product’s group
• MAH name and address
• Therapeutic indications
• Contraindications
• Precautions
• Interactions
• Warnings
• Instructions for use
o dosage
o method
o frequency
o overdose
o side effects
o warning regarding expiry and storage
o date of last revision
Centralised Procedure Marketing Authorisation

• Package leaflet and all packaging materials must be identical
except for language.
• Identical colour schemes, layout and design must be used
across the EU.
• Information specific to Member State is allowed on outer pack
inside a blue box.
Mutual Recognition Marketing Authorisation

• Minor differences are accepted among the package leaflet,
packaging and labelling materials.
• The SmPC (between applications) needs to be identical except
the:
o MAH
o authorisation number
o pack-size presentation used in the specific country
• Differences are accepted for:
o label
o package/patient leaflet
o outer pack


Source Labelling
Biologics Directive 2001/83/EC, as Same as drugs. There are special provisions for the labelling of
amended advanced therapy medicinal products:
Regulation 1394/2007 Labelling of Outer/Immediate Packaging

By way of derogation from Articles 54 and 55(1) of Directive
2001/83/EC, the particulars listed in Annex III to Regulation
ICH Q7 Good Manufacturing 1394/2007 shall appear on the outer packaging of advanced therapy
Practices for Active medicinal products or, where there is no outer packaging, on the
Pharmaceutical Ingredients immediate packaging.
Special Immediate Packaging

In addition to the particulars mentioned in Article 55(2) and (3) of
Directive 2001/83/EC, the following particulars shall appear on the
immediate packaging of advanced therapy medicinal products:
• The unique donation and product codes, as referred to in Article
8(2) of Directive 2004/23/EC
• In the case of advanced therapy medicinal products for autol-
ogous use, the unique patient identifier and the statement ‘for
autologous use only’
Package Leaflet
• By way of derogation from Article 59(1) of Directive 2001/83/
EC, the package leaflet for an advanced therapy medicinal
product shall be drawn up in accordance with the summary of
product characteristics and shall include the information listed
in Annex IV to Regulation 1394/2007, in the order indicated
therein.
• The package leaflet shall reflect the results of consultations
with target patient groups to ensure that it is legible, clear and
easy to use.

Promotion and Advertising

Source Promotion and Advertising
Devices No specific documented Marketing claims must match those in the clinical trial and technical docu-
requirements mentation. Advertising is regulated in some countries through the national
transpositions of the directives.
Drugs Directive 2001/83/EC, as Controlled at the National Level
amended
Advertising Directive Covers
• Advertising only permitted for products with a marketing
authorisation
• Advertising to healthcare professionals and suppliers
o compliance with the product’s SmPC
o compliance with supply classification
• Behaviour of sales representatives
o representatives need to be trained correctly
o they shall supply the SmPC to the physician
o they shall supply information on price and reimbursement to the
physician (if required by local legislation)
o they shall report any adverse reactions reported to them during
their visit
• Supply of samples to physicians
o is limited
o written request from the physician is needed
o no larger than the smallest pack size available labelled, “Free
Medical Sample—Not for Sale” will be provided and accompanied
by the SmPC
o all samples need to be traceable
• Healthcare professionals shall not solicit or accept any inducement to
prescribe
o Any gifts or benefits in kind must be inexpensive and relevant to
the practice of medicine or pharmacy.
o Hospitality must be for purely professional and scientific
purposes.
• Sponsorship of meetings and participation by healthcare profession-
als including travel expenses
A company must be able to provide to the authorities samples of all adver-

tisements issued by the company, stating to whom it was addressed, how
the advertisement was disseminated and the date of dissemination.
Advertising prescription products to the public is prohibited.


Postmarketing Surveillance and Pharmacovigilance

Source Form Postmarketing Surveillance and Pharmacovigilance
Devices Guidelines on a Medical Postmarketing surveillance covers the requirement to
Devices Vigilance System have a proactive systematic procedure in place to gather
(MEDDEV 2.12/1) information about the product in its postmarketing
phase. This should include a process on how to handle
Clinical Evaluation— vigilance incidents that need to be reported to the compe-
Guidelines on Postmarket tent authorities.
Clinical Follow-up Studies
(MEDDEV 2.12/2) Postmarketing surveillance data can come from complaint
monitoring, feedback from sales representatives, reports
from regulatory authorities, literature reviews and ser-
Regulation (EU) 2017/745 vice/repair information.
on medical devices and
Regulation (EU) 2017/746 on For vigilance incidents, the manufacturer makes an initial
in vitro diagnostic medical report to the competent authority for recording and evalu-
devices ation. Each initial report should lead to a final report, but
not every initial report will lead to a corrective action.
Corrective action includes:

• Device recall
• Issue of advisory notice
• Additional surveillance/modification of devices in
use
• Modification to future device design
• Components or manufacturing process
• Modification to labelling or instructions for use
Submit a vigilance report to the competent authority

when:
• An incident (or potential incident) has occurred that
led to:
o a death
o a serious deterioration in health (the deter-
mination of serious should be made in
consultation with a medical practitioner)
– life-threatening illness or injury
– permanent impairment of a body function
or permanent damage to a body structure
– condition necessitating medical or surgical
intervention to prevent permanent impair-
ment of a body function or permanent
damage to a body structure
• The manufacturer’s device is associated with the
incident:
o incident led, or might have led, to one of the
following outcomes:
– death of a patient, user or other person
– serious injury of a patient, user or other
person


Devices A vigilance report does not need to be submitted when:
• Adverse incident is caused by patient conditions
(e.G., Pre-existing conditions)
• Service life of medical device exceeded
• Protection against a fault functioned correctly
• Remote likelihood of occurrence of death or serious
injury
• Expected and foreseeable side effects
• Adverse incident described in advisory notice
• Reporting exemption granted by competent authority
An Initial Report must contain:

• Manufacturer’s name, address, contact point, tele-
phone and fax number
• Date the incident came to the manufacturer’s
attention
• Medical device
o commercial name
o catalogue number/model
o serial/batch/lot number
o software version
o identification number of the notified body
involved in the Conformity Assessment
Procedure (if any) and the dates of attestation(s)
• Associated devices and/or accessories involved in
the incident
• Details of the incident (to the extent known) includ-
ing date, patient and user outcome
• Current location of the device involved in the incident
(if known)
• Contact point of user where incident occurred
• Manufacturer’s preliminary investigation and
comments
• Manufacturer’s proposed next action and timeframe
• Statement of whether the manufacturer is aware of
similar incidents having an impact on the current
report, and when and to whom these were reported
• Any other EEA state in which the device is known to
be on sale
Reporting Time Frames (based on the guidelines)

Incidents: 10 Calendar Days (serious public health threat:
two Calendar Days)
Near Incidents: 30 Calendar Days
Typical events are:

• Malfunction or deterioration in the characteristics of
performance
• Inadequate design or manufacture
• Inaccuracy of labelling, instructions for use and/or
promotional materials
• Significant health concern
• Other information becoming available


Devices If the initial report is made by telephone or fax, it must be
followed up by a written confirmation (hard copy posted
to competent authority). The competent authority will
acknowledge receipt of the report.
Reports can be made to the manufacturer or the compe-

tent authority or both.
Member States may supplement reports received from

manufacturers with reports from other sources.
The new EU MDR and EU IVDR introduce requirements

regarding:
• Incorporation of MEDDEV 2.12 Rev. 8 into the
regulation
• Reporting of serious incidents and FSCA to Eudamed
• PSUR requirements
• Centralised evaluation of the same/similar incidents
• New electronic surveillance system
• Binding procedure for noncompliant and compliant
devices
Drugs Directive 2001/83/EC, as Individual Guidelines on Good Pharmacovigilance Practices (GVP)
amended, including Directive Case Safety New legislation for pharmacovigilance applies in the
2010/84/EU as regards Reports European Union (EU) since July 2012, and to
Pharmacovigilance (ICSRs) support its implementation, a set of guidelines for the
conduct of pharmacovigilance in the EU has
Regulation (EU) No. been developed which, as they have been adopted,
1235/2010 amending, as replaced the previous set in Volume 9A of the
regards pharmacovigilance of Rules Governing Medicinal Products in the EU.
medicinal products for human This new guidance on good pharmacovigilance practices
use, Regulation (EC) No. (GVP) is organised into two types of chapters, namely
726/2004 Modules on pharmacovigilance processes and Product- or
Population-Specific Considerations.
Regulation (EU) No.
1027/2012 amending System Requirements and Noncompliance
Regulation (EC) No. 726/2004 All MAHs must have an appropriate pharmacovigilance
as regards pharmacovigilance system in place (with the 2010 regulation, must have a
pharmacovigilance system master file (PSMF) perma-
Directive 2012/26/EU amend- nently available for submission or inspection by the
ing Directive 2001/83/EC as national competent authority). The system should be
regards pharmacovigilance capable of:
• Expedited reporting
European Medicines Agency: • Periodic safety update reporting
Good Pharmacovigilance • Responding to requests for information from compe-
Practices 2012 tent authorities
• Handling urgent safety restrictions for safety
ICH E2A – E2F variations
Pharmacovigilance • Continuously monitoring the authorised medicinal
product’s safety profile and notifying competent
authorities and healthcare professionals of changes
to the product’s benefits-risks
• Meeting CHMP commitments (where MAHs hold a
centralised marketing authorisation)
• Internal audit of the pharmacovigilance system


Drugs Qualified Person Responsible for Pharmacovigilance
Person responsible for placing a medicinal product on the
market shall have a qualified person for pharmacovigi-
lance. This person shall be responsible for:
• Establishing and maintaining a system to ensure that
all suspected adverse reactions are reported
• Preparing a report within 15 days to the competent
authorities
• Addressing any requests made for additional infor-
mation by the competent authorities
Serious Adverse Reaction

An adverse reaction that:
• Results in death
• Is life-threatening
• Requires in-patient hospitalisation or prolongation
of existing hospitalisation
• Results in persistent or significant disability or
incapacity
• Is a congenital anomaly/birth defect
Unexpected Adverse Reaction

An adverse reaction, the nature, severity or outcome of
which is not consistent with the SmPC.
Expedited Adverse Drug Reactions

• MAHs are required to report all suspected serious
adverse drug reactions (causal relationship) occur-
ring within and outside of the EU and Member States
within 15 days through the EudraVigilance system,
EU’s electronic database for suspected adverse
reactions.
PSURs
A periodic safety update report (PSUR) is intended to pro-
vide an update of a medicinal product’s worldwide safety
experience to competent authorities at defined times,
postauthorisation. A worldwide safety update summary
should be prepared and submitted to the competent
authorities and EMA for all medicinal products authorised
at the following intervals unless the MA makes different
provisions:
• At least every six months during the first two years
following authorisation
• Every six months during the first two years after
being placed on the market
• Once a year for the following two years
• Afterward, every three years or as requested by the
competent authority
Each safety report should cover the period of time since

the last update report and should be submitted within 60
days of the data-lock point.


Biologics Same as drugs. There are additional requirements for
advanced therapy medicinal products (Articles 14 and 15,
Regulation 1394/2007):
Postauthorisation follow-up of efficacy and adverse reac-

tions and risk management
• In addition to the requirements for pharmacovig-
ilance laid down in Articles 21 to 29 of Regulation
(EC) No. 726/2004, the applicant shall detail, in the
marketing authorisation application, the measures
envisaged to ensure the follow-up of efficacy of
advanced therapy medicinal products and of adverse
reactions thereto.
• Where there is particular cause for concern, the
Commission shall, on the advice of the agency,
require as part of the marketing authorisation that
a risk management system designed to identify,
characterise, prevent or minimise risks related to
advanced therapy medicinal products, including an
evaluation of the effectiveness of that system, be set
up or that specific post-marketing studies be carried
out by the holder of the marketing authorisation and
submitted for review to the agency.
• In addition, the agency may request submission of
additional reports evaluating the effectiveness of any
risk management system and the results of any such
studies performed.
• Evaluation of the effectiveness of any risk man-
agement system and the results of any studies
performed shall be included in the periodic safety
update reports referred to in Article 24(3) of
Regulation (EC) No. 726/2004.
• The agency shall forthwith inform the Commission if
it finds that the marketing authorisation holder has
failed to comply with the requirements referred to in
Paragraph 2.
• The Agency shall draw up detailed guidelines relat-
ing to the application of Paragraphs 1, 2 and 3.
• If serious adverse events or reactions occur in
relation to a combined advanced therapy medici-
nal product, the agency shall inform the relevant
national competent authorities responsible for
implementing Directives 90/385/EEC, 93/42/EEC
and 2004/23/EC.


Biologics Traceability
1. The holder of a marketing authorisation for an
advanced therapy medicinal product shall estab-
lish and maintain a system ensuring the individual
product and its starting and raw materials, including
all substances coming into contact with the cells
or tissues it may contain, can be traced through
the sourcing, manufacturing, packaging, storage,
transport and delivery to the hospital, institution or
private practice where the product is used.
2. The hospital, institution or private practice where
the advanced therapy medicinal product is used
shall establish and maintain a system for patient and
product traceability. That system shall contain suf-
ficient detail to allow linking of each product to the
patient who received it and vice versa.
3. Where an advanced therapy medicinal product
contains human cells or tissues, the marketing
authorisation holder, as well as the hospital, insti-
tution or private practice where the product is used,
shall ensure that the traceability systems estab-
lished are complementary to, and compatible with,
the requirements laid down in Articles 8 and 14 of
Directive 2004/23/EC as regards human cells and tis-
sues other than blood cells, and Articles 14 and 24 of
Directive 2002/98/EC as regards human blood cells.
4. The marketing authorisation holder shall keep the
data referred to in Paragraph 1 for a minimum of 30
years after the expiry date of the product, or longer if
required by the Commission as a term of the market-
ing authorisation.
5. In case of bankruptcy or liquidation of the marketing
authorisation holder, and if the marketing authori-
sation is not transferred to another legal entity, the
data referred to in Paragraph 1 shall be transferred to
the agency.
6. If the marketing authorisation is suspended, revoked
or withdrawn, the holder of the marketing authorisa-
tion shall remain subject to the obligations laid down
in Paragraphs 1, 3 and 4.

Quality Management Systems/Good Manufacturing Practices (GMPs)

Source GMP
Devices ISO 9001:2008 and ISO 9001:2015 A manufacturer must be audited by a notified body (for all
AIMDs, Class I sterile and Class I with measuring function,
EN ISO 13485:2016 Class IIa, Class IIb and Class III medical devices, and Annex II
listed and self-test IVDs) to ensure compliance with the quality
Regulatory Auditing of Quality system.
Management Systems of Medical
Device Manufacturers www.imdrf. Quality System
org: SG4/84:2010, SG4/83:2010 Mandatory documented procedures and mandatory records in
accordance with EN ISO 13485.
EN ISO 19011:2011 Guidelines for
Auditing Management Systems Design
• Devices must be designed to minimise risk.
ISO 9000:2015 Quality • All devices must be designed to comply with the essential
Management Systems— requirements of the applicable directive(s).
Fundamentals and Vocabulary • Manufacturing, storage and quality control criteria
• Quality control
ISO 14971 Application of Risk
Management to Medical Devices Symbols
• “Sterile” (on a sterile pack)
Directive 93/42/EEC and • Sterilisation method
Directive 90/385/EEC • “Do not re-use”
Amended by Directive 2007/47/EC • Lot or serial number
and Directive 98/79/EC • Use by date
• Manufacturer
Regulation (EU) 2017/745 on med-
ical devices and Regulation (EU) Device Technical Documentation
2017/746 on in vitro diagnostic • Product documentation and related data
medical devices • Description of the device and any variants
• Product specifications
• Data that may have been submitted to regulatory bodies
for approval
Risk Analysis
• Identification and documentation of any potential hazards
that may exist with the device design and how that risk has
been minimised or eliminated
• Record of how long the device has been in use, number of
units sold, and number and classification of complaints
received
• Critical appraisal of the scientific literature
Documentation must uniformly interpret quality policies and

procedures, such as quality programs, quality plans, quality
manuals and quality records. Documentation must include:
• Manufacturer’s quality objectives
• Organisational structure of business
• Procedures for monitoring and verifying product design
• Appropriate tests used before, during and after production
The manufacturer shall inform the notified body of any plans to

alter the system.


Source GMP
Devices Design changes should be reported to the notified body when
“substantial” or “significant.”
• All changes made to a device should be documented and
classified as substantial or not substantial.
• Changes considered “substantial” are:
o product changes that would affect conformity with the
essential requirements or the conditions prescribed
for the intended use
o changes to the quality system that would affect com-
pliance of the device or would mean an addition to the
product range covered by the quality system
• The manufacturer shall inform the notified body of all
planned substantial changes.
All documents must be kept for five years after the last date
of manufacture of the product. For implantable devices, the
period is at least 15 years after the last product has been man-
ufactured. All records should be kept for the foreseen device
lifetime but not less than two years from the date of delivery.
The EU MDR and EU IVDR include 23 general safety and per-

formance requirements for medical devices (20 for in vitro
diagnostic devices) in Annex I, compared to the previous
version’s 13. Another significant change is that manufactur-
ers will be required to update the technical documentation,
declarations of conformity and labelling, making the technical
documentation is a set of living documents that evolves with
the postmarket surveillance.


Source GMP
Drugs Eudralex Volume 4, Good Manufacturing authorisation is granted/maintained by the
Manufacturing Practice (GMP) authority of the Member State. A manufacturing authorisation
Guidelines application is granted for specific products and the facilities
specified for their production.
Directive 2001/83/EC and
2001/82/EC, as amended. GMP Requirements
Directive 2003/94/EC Directive • Quality management (quality assurance, quality control)
91/412/EEC • Personnel (key personnel, training, personnel hygiene)
• Documentation (required documents, specifications for
Commission Directive (EU) starting and packing materials, specifications for inter-
2017/1572 of 15 September 2017 mediate and bulk products, specifications for finished
supplementing Directive 2001/83/ products, manufacturing and validation processes, manu-
EC of the European Parliament facturing formulae and processing instructions, packaging
and of the Council as regards instructions, batch processing records, batch packaging
the principles and guidelines of records, procedures and records for: receipt, sampling and
good manufacturing practice for testing)
medicinal products for human use • Production (prevention of cross-contamination in produc-
tion, validation, starting materials, processing operations:
Commission Delegated Regulation intermediate and bulk products, packaging materials,
(EU) 2017/1569 of 23 May 2017 packaging operations, finished products, and rejected,
supplementing Regulation (EU) recovered and returned materials)
No. 536/2014 of the European • Quality control (good quality control laboratory practice,
Parliament and of the Council documentation, sampling, testing)
by specifying principles of and • Contract manufacture and analysis (the contract giver, the
guidelines for good manufacturing contract acceptor, the contract)
practice for investigational • Complaints and recalls
medicinal products for human use • Self-inspection
and arrangements for inspections
GMP Requirements for Investigational Medicinal Products
ICH Q1A, Q1B, Q1C, Q1D, Q1E, Q1F, • Quality management (quality assurance, quality control)
Q2(R1), Q3A, Q3C, Q6A, Q6B, Q7, • Personnel (key personnel, training, personnel hygiene)
Q8, Q9, Q10 • Premises and equipment
• Documentation (order, product specification file, manu-
facturing formulae and processing instructions, packaging
instructions, labelling instructions, and manufacturing and
packaging batch records)
• Production (starting materials, manufacturing operations,
principles applicable to comparator product, randomisa-
tion code)
• Quality control
• Release of batches
• Free movement
• Contract manufacturer and contract analysis
• Complaints
• Recalls and returns
• Shipping, returns, destruction


Source GMP
Drugs Manufacturing authorisation is based on compliance with the
following:
• Identification of the medicinal product and pharmaceutical
forms to be manufactured
• Name and address of manufacturing and control plants
• Suitability and adequacy of the facilities
• Equipment and premises must comply with legal require-
ments (production, control and storage)
• Have at the manufacturer’s disposal the services of a qual-
ified person, a staff complying with the manufacturing and
control requirements of the Member State where the facili-
ties are located
• Informing the authorities of any proposed changes to the
product qualified person, facilities, equipment, processes,
etc.
• Giving the qualified person the tools needed to fulfil his
responsibilities
• Complying with the principles of GMP applicable in the EU
The decision to grant manufacturing authorisation shall take

place within 90 days of the initial application. All decisions
regarding applications for changes to the current authorisation
shall be made within 30 days. The clock will stop if the author-
ity asks for additional information from the applicant.
Distribution
• A distribution authorisation is needed to hold, supply or
export medicinal products.
• Member States grant distribution authorisations.
• A distributor must comply with the following specific
conditions:
o appropriate facilities and equipment to ensure ade-
quate storage and distribution of the product
o a qualified person
• A distributor can distribute products to all Member States.
Qualified Person
• A manufacturer must have at its disposal the permanent
services of a Qualified Person who:
o ensures and certifies each lot manufactured is
produced in accordance with the manufacturing
authorisation and these certifications are recorded
in a register that is to be made available during an
inspection
o controls the quality of imported product


Source GMP
Biologics Volume 4, Good Manufacturing Same as drugs, including:
Practice (GMP) Guidelines
Annex 2 - Manufacture of Biological Active Substances and
ICH same as drugs plus Q5A – Q5E Medicinal Products for Human Use
• Personnel
• Premises and equipment
• Animal quarters and care
• Documentation (specifications for starting materials, spec-
ifications required for intermediate and bulk biological
medicinal products)
• Production
• Starting and raw materials
• Seed lot and cell bank
• Operating principles
• Quality control
Manufacture of Radiopharmaceuticals
• Personnel
• Production
• Quality control
• Distribution and recalls
Manufacture of Products Derived from Human Blood or Human

Plasma
• Quality management (quality assurance, blood collection
control and procedures)
• Traceability and post collection measures
• Manufacturing (starting material, certification/release of
plasma for fractionation as starting material, processing of
plasma for fractionation)
• Quality control
• Release of intermediate and finished products
• Retention of plasma pool samples
• Disposal of waste

Complaints
Source Complaints
Devices Guidance on the Quality Systems Any complaint received from the supplier about a product that
for the Design and Manufacture of either fails to conform to its specification or conforms to its
Medical Devices (GHTF/IMDRF) specification but nevertheless causes a problem in use shall be
recorded and investigated.
EN ISO 13485:2016, Clause 8.5.1
Complaint documentation system should include:
• Establish responsibility for complaint handling system
• Complaint evaluation
• Records and statistical summaries, to determine the major
causes of complaints
• Documentation of any corrective action taken
• Desegregation and disposition, or reprocessing, of cus-
tomer returns and faulty stock (with special attention given
to decontamination)
• Filing of customer correspondence and other relevant
records; define retention time for these items
• Determine if a death or serious injury occurred
Complaint and investigation documentation should include:

• Product name
• Date the complaint was received
• Any control number used
• Complainant name and address
• Nature of the complaint
• Results of the investigation including:
o corrective action taken
o justification if no action was taken
o dates of investigation
o name of investigator
o the reply (if any) to the complainant

Complaints
Source Complaints
Drugs Directive 2001/83/EC, as amended All complaints and other information concerning potentially
Directive 2003/94/EC defective products must be reviewed carefully according to
written procedures.
Commission Directive (EU) 2017/1572
of 15 September 2017 supplementing Complaint documentation system should include:
Directive 2001/83/EC of the • Designated person responsible for handling complaints
European Parliament and of the and deciding measures to be taken, with sufficient sup-
Council as regards the principles and porting staff
guidelines of good manufacturing • Written procedure describing the action to be taken,
practice for medicinal products for including the need to consider a recall (for a complaint
human use concerning a possible product defect)
• Procedure for recording a complaint concerning a prod-
See also Matrix 11 - Quality uct defect with all the original details and a thorough
Management Systems Good investigation
Manufacturing Practices • If a product defect is discovered or suspected in a batch,
consideration should be given to checking other batches to
determine whether they also are affected
• All decisions and measures taken as the result of a
ICH Q7 Good Manufacturing Practices complaint should be recorded and referenced to the corre-
for Active Pharmaceutical Ingredients sponding batch records
• Complaint records should be reviewed regularly for any
indication of specific or recurring problems requiring atten-
tion and possibly the recall of marketed products
• Competent authorities should be informed if a manu-
facturer is considering action following possibly faulty
manufacture, product deterioration or any other serious
quality problems with a product
Complaint records should include:

• Complainant name (title, where appropriate) and address
• Telephone number of person submitting the complaint
• Date complaint is received
• Product name
• Complaint nature (including name and batch number)
• Action initially taken (including dates and identity of per-
son taking the action)
• Any follow-up action taken
• Response provided to the originator of complaint (includ-
ing date response sent)
• Final decision on intermediate, or batch or lot
• Results of the investigation including corrective action taken
Records of complaints should be retained to evaluate trends,

product-related frequencies and severity with a view to taking
additional and, if appropriate, immediate corrective action.
In the event of a serious or potentially life-threatening situa-

tion, local, national and/or international authorities should be
informed and their advice sought.
The conclusions of any investigation carried out in relation to a
complaint should be discussed between the manufacturer and
sponsor to assess any potential impact on the trial and on the
product development.

Quality System Assessment/Inspection

Source Quality System Assessment/Inspection
Devices Regulatory Auditing of Quality The manufacturer shall authorise the notified body to carry out all
Management Systems of necessary inspections and shall supply it with all appropriate informa-
Medical Device Manufacturers tion, including:
www.imdrf.org: SG4/84:2010, • Quality system documentation
SG4/83:2010 • Data stipulated in quality system relating to design, e.G., Result
of analyses, calculations, tests, etc.
• Data stipulated in quality system relating to manufacture, e.g.,
reports concerning inspections, tests, standardisations/calibra-
tions and staff qualifications
The notified body shall periodically carry out appropriate inspections

and evaluations to ascertain whether the manufacturer is applying
the approved quality systems. The manufacturer will receive a written
evaluation report of the inspection from the notified body. The notified
body may conduct an inspection of the manufacturer without notice.
Audits
A manufacturer will be audited to ensure compliance to the quality
system. There are four types of audits:
1. Initial audit
2. Surveillance audit
3. Special audit
4. Unannounced audit
Drugs Directive 2001/83/EC, as Good Clinical Practice/Manufacturing Audits
amended • A Member State’s competent authority can inspect:
Regulation (EC) No. 726/2004 o clinical trial/investigator’s site
o investigational product manufacturing site
o laboratory used for analysis during the clinical trial
o sponsor’s premises
• A report will be prepared after the inspection and made available
to the sponsor.
• Inspection findings will be shared and recognised by all Member
States.
GMP inspections for manufacturing sites and control laboratories are

carried out regularly by national authority representatives:
• Manufacturing plant and equipment are inspected.
• Inspectors may take samples.
• Inspectors may review relevant documents and control processes
to validate the medicinal product is being manufactured in accor-
dance with marketing authorisation.
Inspections required for:

• Intermediate products
• Finished products
Outcome of an inspection:
• Written report is prepared and sent to manufacturer
• A decision on granting or maintaining the manufacturing authori-
sation is made

Traceability Requirements
Source Traceability Requirements
Devices EN ISO 13485/2016: 7.5.3 Product traceability involves the ability to trace the history,
application or location of an item or activity by means of recorded
Directive 93/42/EEC and identification.
Amended by Directive Each individual product must have an identifier (e.g., serial number,
2007/47/EC and date code, batch code, lot number, etc.) unique to the source of
Directive 98/79/EC operation. Separate identifiers are required for changes in operative
personnel, raw materials, tooling; new or different machine set ups;
Regulation (EU) 2017/745 changes in process methods, etc.
on medical devices and
Regulation (EU) 2017/746 on The product should be traceable up to the point of device use or
in vitro diagnostic medical implantation.
devices
Traceability records should be maintained throughout the product’s
lifetime.
The new EU MDR and EU IVDR have defined the requirements for
implementation of a Unique Device Identification (UDI) system,
including requirements for labelling, data submission, and storage/
traceability.
Drugs Directive 2011/62/EU Packagers, repackagers, wholesale distributors, pharmacies/retailers
Prevention of and possibly others must be able to verify the medicinal product’s
the entry into the legal authenticity, uniquely identify individual packs and maintain a reposi-
supply chain of falsified tory system in which to store identification data.
medicinal products
(Falsified Medicines Product Samples
Directive) All samples distributed to physicians need to be traceable.
ICH Q7 Good Manufacturing Record Maintenance

Practices for Active • Blending process batch records should allow traceability back to
Pharmaceutical Ingredients the individual batches that make up the blend.
• Manufacturer name; identity and quantity of each batch ship-
Volume 4, Good ment of raw materials, intermediates, or labelling and packaging
Manufacturing Practice materials for APIs; supplier name; supplier’s control number(s), if
for Active Pharmaceutical known, or other identification number; the number allocated on
Ingredients receipt; and the date of receipt must be recorded, along with:
o results of any test or examination performed and the conclu-
See also Matrix 11 - Quality sions derived from this
Management Systems Good o records tracing the use of materials
Manufacturing Practices o documentation of API labelling and packaging materials
examination and review for conformity with established
specifications
o final decision regarding rejected raw materials, intermedi-
ates or API labelling and packaging materials
Biologics Regulation 1394/2007 Same as drugs (except where noted below)
Donations from blood/plasma collection establishments to the manu-

facturer need to be traceable.
See Matrix 10 Postmarketing There are also special traceability requirements (as post authorisation
Surveillance and requirement) for advanced therapy medicinal products (Regulation
Pharmacovigilance 1394/2007)

Import/Export Requirements
Source Import/Export Requirements
Devices Regulation (EU) No additional requirements. Products must be CE marked to come into the EU.
2017/745 on medical In some countries, importers must hold a licence or authorisation issued by the
devices and Regulation national authorities to retrieve devices from customs when the devices origi-
(EU) 2017/746 on in nate outside the EU.
vitro diagnostic medical
devices Under the new EU MDR and EU IVDR, each economic operator must verify that
a previous economic operator has complied with the EU MDR requirements.
Where, in the past, this applied to manufacturer, with the new regulations,
importers and distributors must ensure independently that, prior to placing a
medical device on the market, the manufacturer, importer and the device itself
meet the stipulated EU MDR regulatory requirements. In addition, importers
will be responsible to register imported devices in an electronic database sys-
tem on the registration of devices and economic operators (which will reside in
the Eudramed database).
Drugs Directive 2001/83/EC, Import Finished Product
as amended A manufacturing import authorisation (MIA) is required for importing medicinal
products or bulk product from a country outside the EU. An import authorisa-
tion is granted by the competencies of the Member States. Importing authori-
sation also is required for products being brought into the EU for exportation
outside the EU.
Any batch of medicinal products imported into the EU must be batch tested by
an independent laboratory based in the EU and found to be within the market-
Eudralex Vol. 4 Annex ing authorisation registered specifications before it can be released by an EU
16 QP Batch Release QP to be used in the EU. Imported products from outside the EU where there is
a MRA in place do not need to undergo EU importation testing provided trans-
portation studies have validated the route.
Import API
API and intermediates need to be made under GMP/ICH Q7 and the exporting
country if outside the EU must supply a GMP certificate for each batch which
confirms that the manufacturing site have been inspected and approved to
GMP by the local regulatory authority. The EU based importing company must
apply to its local competent authority to add the manufacturer to the authori-
ties list of approved API manufacturers based outside the EU.
Investigational Drug
GMP must be applied to the manufacturer of products used in clinical trials.
Product batches imported from a country outside the EU need to be certified by
a qualified person. Some Member States will accept certification, without fur-
ther retesting, if a qualified person formally releases the batch.
The batch must undergo a two-stage release, first by the QP to confirm com-
pliance in manufacture to GMP and the CTA specification, and second by the
sponsor to the clinical trial site.
Parallel Import
Parallel import is the import of medicinal product from one Member State into
another Member State. To use parallel import, the products must be therapeu-
tically equivalent, and a valid MA must be in place in both the importing and
exporting Member States. The parallel imported product must be relabelled
to comply with the new countries national language and released by the local
QP. Now with the implementation of the Falsified Medicines Directive, the in-
dividual packs serialisation must be decommissioned in the EU portal prior to
repacking and a new tamper evident seal and 2D serialisation code applied to
each pack and then uploading to the EU portal.

Drugs Export
• To export a product from the EU to outside the EU, a manufacturer’s
import authorisation must be held, but a marketing authorisation is not a
requirement.
• Manufacturer must request/apply for certification from a Member State
the product being exported complies with the MA by supplying the
Member State with:
o SmPC (if product is authorised)
or
o declaration explaining why no marketing authorisation is available
Certain EU countries have a product export ban register that must be checked
prior to exporting a product which is linked to national shortages of individual
drugs.

Product Recalls
Source Product Recalls
Devices EN ISO 13485:2016 Where there is risk of death or serious deterioration of the state of health, a
recall is implemented by:
Guidance on the Quality • Returning a medical device to the supplier
Systems for the Design • Supplier modification of the device at the site of installation
and Manufacture of • Exchanging the device
Medical Devices (GHTF/ • Destroying the device
IMDRF)
A manufacturer must notify the competent authority via the vigilance system
MEDDEV 2.12-1 Rev. 8 of any technical or medical reason for a systemic recall. The classification and
wording of the recall should be agreed with the competent authority before
Regulation (EU) commencing the recall.
2017/745 on medical
devices and Regulation Removal from the market for purely commercial reasons is not considered a
(EU) 2017/746 on in recall.
vitro diagnostic medical
devices When implementing recalls, the manufacturer shall:
• Issue an advisory notice or recall which will provide:
o medical device description and model designation
o serial numbers or other identification (batch or lot numbers) of the
medical device concerned
o reason for the issue of a notice/recall
o advice on possible hazards and consequent action(s) to be taken
• Monitor the progress of the recall and reconcile the number of products
received
• Send a copy of the advisory notice to competent authorities in the appli-
cable countries
o for Class II and III devices, the notified body that attested to the CE
Mark shall be notified
o for Class I devices, only the competent authority where the manufac-
turer is located shall be notified
o when a serious deterioration in health occurs (the determination of
serious should be made in consultation with a medical practitioner)
Under the new EU MDR and EU IVDR, importers and distributors also have
responsibilities for keeping a register of complaints, of non-conforming devic-
es and of recalls and withdrawals, and provide the manufacturer, Authorised
Representative and distributors with any information requested by them, in
order to allow them to investigate complaints.
API and Directive 2001/83/EC, General
Finished as amended • To provide for all contingencies, a system should be designed to recall
Dosage from the market, if necessary—promptly and effectively—products known
Forms Regulation (EC) No. or suspected to be defective.
726/2004 • There should be established written procedures, regularly checked and
updated when necessary, to organise any recall activity.
• The recall procedure should designate who should be involved in eval-
ICH Q7 Good Manu- uating the information, how a recall should be initiated, who should
facturing Practices for be informed about the recall, and how the recalled material should be
Active Pharmaceutical treated.
Ingredients (Eudralex • A person should be designated as responsible for executing and coordi-
Vol. 4 Part 2) nating recalls and should be supported by sufficient staff to handle all
Finished Dosage Forms aspects of recalls with the appropriate degree of urgency.
Eudralex Vol. 4 Part 1 • Recall operations should be capable of being initiated promptly and at
Chapter 8 any time.

Product Recalls
Source Product Recalls
API and • Distribution records should be readily available to the person(s) respon-
Finished sible for recalls and should contain sufficient information on wholesalers
Dosage and directly supplied customers (with addresses, phone and/or fax num-
Forms bers inside and outside working hours, batches and amounts delivered),
including those for exported products and medical samples.
• Recalled products should be identified and stored separately in a secure
area while awaiting a decision on their fate.
• Recall process progress should be recorded and a final report issued,
including a reconciliation between the delivered and recovered quantities
of products.
• Recall arrangements’ effectiveness should be evaluated periodically.
• All competent authorities of all countries to which products may have
been distributed should be informed promptly if products are intended to
be recalled because they are, or are suspected of being defective.
• Prior to initiating the recall, the local competent authority must be con-
tacted and the categorisation of the level and urgency of recall and the
recall wording and means of notification to users must be agreed upon.
Procedures for retrieving investigational medicinal products and documenting
this retrieval (e.g., for defective products recall, returns after trial completion
or expired products return) should be in place. This should be understood by
the sponsor, investigator and monitor in addition to the person(s) responsible
for recalls.
Recall Classification
Class 1: Potentially life-threatening defects or those that could cause serious
risk to health:
• Wrong product (label and contents are different product)
• Correct product but wrong strength, with serious medical consequences
• Microbial contamination of sterile injectable or ophthalmic product
• Chemical contamination with serious medical consequences
Class 2: Defects that could cause illness or mistreatment but are not Class 1:
• Mislabelling (wrong or missing text or figures, wrong or missing batch
numbers or expiry date)
• Missing or incorrect information (leaflets or inserts)
• Microbial contamination of noninjectable, nonophthalmic sterile product
with medical consequences
• Chemical/physical contamination
Class 3: Defects that may not pose a significant hazard to health but where
a recall has been initiated for other reasons, not necessarily required by the
competent authority, but are not Class 1 or 2:
• Faulty packaging
• Faulty closure
• Contamination (microbial spoilage)
The MHRA also issues “Caution in Use” notices which are called Class 4 Drug
Alerts, where there is no threat to patients or no serious defect likely to impair
product use or efficacy.

Product Withdrawal
Source Product Withdrawal
Devices AIMDD Article 14, as Withdrawal by a Member State or Community
amended Member State may withdraw medical devices from the market at any time
MDD Article 19, as amended • If time allows (due to safety concerns) the Member State will notify
IVDD Article 18 the manufacturer (or authorised representative) of the reasons for
the product withdrawal and the available remedies and time limits to
Regulation (EU) 2017/745 which the remedies are subject.
on medical devices and • If time does not allow, the Member State can withdraw the product first
Regulation (EU) 2017/746 on and then notify the manufacturer (or authorised representative) of the
in vitro diagnostic medical reasons for the product withdrawal.
devices
Under the new EU MDR and EU IVDR, importers and distributors also have
responsibilities for keeping a register of complaints, of non-conforming
devices and of recalls and withdrawals, and provide the manufacturer,
authorised representative and distributors with any information requested
by them, in order to allow them to investigate complaints.
Drugs Directive 2001/83/EC, as Withdrawal by a Member State or Community
amended Member States shall take all appropriate measures to ensure the supply of
the medicinal product shall be prohibited and the medicinal product with-
drawn from the market if:
• The medicinal product proves to be harmful under normal conditions
of use
or
• It is lacking in therapeutic efficacy
or
• Its qualitative and quantitative composition is not as declared
or
• The controls on the medicinal product and/or on the ingredients and
the controls at an intermediate stage of the manufacturing process
have not been carried out or if some other requirement or obligation
relating to the grant of the manufacturing authorisation has not been
fulfilled
Member States can decide to refuse or revoke a marketing authorisation

or withdraw a product from the market. This decision and the reasons for it
are sent to EMA. Any Member State, due to public health concerns (such as
adverse drug reactions which present an unacceptable level of risk under
normal conditions of use) can suspend or withdraw the medicinal prod-
uct and refer the matter to CHMP for a decision. The MAH shall notify the
Member States concerned of any action taken to suspend the marketing
of a product or to withdraw the product from the market, together with the
reasons for such action if the latter concerns the efficacy of the product or
the protection of public health. CHMP shall publish a list of medicinal prod-
ucts annually that are prohibited in the Community.
Biologics Directive 2001/83/EC, as Same as drugs (except where noted below)
amended
The competent authority may limit the prohibition to supply the product,
or its withdrawal from the market, to those batches that are the subject of
dispute.

Retention of Product Samples

Source Retention of Product Samples
Devices No documented requirements. The need for retained samples is the
manufacturer’s decision.
Drugs ICH Q7 Good Manufacturing Samples from each batch are to be retained for one year after the batch
Practices for Active expiry date assigned by the manufacturer, or for three years after dis-
Pharmaceutical Ingredients tribution of the batch, whichever is longer. For active pharmaceutical
ingredients (APIs) with retest dates, similar reserve samples should be
retained for three years after the batch is distributed by the manufac-
turer. The reserved samples should be stored in the same packaging
system in which the API is stored or in one that is equivalent to or more
protective than the marketed packaging system. Sufficient quantities
should be retained to conduct at least two full compendial analyses or,
when there is no pharmacopoeial monograph, two full specification
analyses.
Biologics Same as drugs (except where noted below)
Samples of each pool of plasma should be stored under suitable condi-

Directive 2001/83/EC, as tions for at least one year after the finished product’s expiry date with
amended the longest shelf life.
Member States may require samples of each bulk and finished product
batch of certain immunological products (vaccines, toxins, serums,
allergens) and products derived from human blood and plasma to be
submitted to and controlled by an official laboratory of a Member State
prior to being placed on the market.
The batch should be released by the Official Medicines Control

Laboratory (OMCL) of a Member State within 60 days; other Member
States are not allowed to control the same batch and should recognise
the certificate issued by the first OMCL stating the batch complies with
the approved specifications.
Also Eudralex Vol. 4 Annex 19 8.1 A retention sample should represent a batch of finished products as
distributed in the EEA and may need to be examined in order to confirm
non-technical attributes for compliance with the marketing authorisa-
tion or EU legislation. Therefore, retention samples should in all cases
be located within the EEA. These should preferably be stored at the site
where the qualified person (QP) certifying the finished product batch is
located.
8.2 In accordance with 8.1 above, where an operational MRA is in place
and reference samples are retained at a manufacturer located in a coun-
try outside the EEA, separate retention samples should be kept within
the EEA.
8.3 Retention samples should be stored at the premises of an autho-
rised manufacturer in order to permit ready access by the competent
authority.
8.4 Where more than one manufacturing site within the EEA is involved
in the manufacture importation/packaging/testing/batch release, as
appropriate of a product, the responsibility for taking and storage of
retention samples should be defined in a written agreement(s) between
the parties concerned.

Glossary
A Active Implantable Medical Devices Directive

(AIMDD) First EU medical device legislation;
ABPI Code
sets general requirements relating to the design,
Association of the British Pharmaceutical Industry
construction and CE-marking of these devices and
Code. Regulates the advertising of prescription
their accessories.
medicines to health professionals and administrative
staff. It also covers information about prescription-only
Active Substance Master File
medicines made available to the general public.
(ASMF) Procedure to allow valuable confidential active
substance manufacturer (ASM) intellectual property
Abridged Application
or ‘‘know-how’ to be protected, while at the same time
An application for marketing authorisation that, based
allowing the applicant or Marketing Authorisation
upon demonstrating essential similarity or by detailed
Holder (MAH) holder to take full responsibility for
references to published scientific literature, does not
the medicinal product and the active substance’s quality
contain the results of pharmacological and toxicological
and quality control. National competent authorities and
tests or the results of clinical trials.
EMA thus have access to the complete information
necessary to evaluate the active substance’s suitability
Accessory
in the medicinal product. (Formerly known as the
An article that while not being a device is intended
European Drug Master File (EDMF)).
specifically by its manufacturer to be used together with
a device to enable it to be used in accordance with the
Adaptive Pathway Approach
device’s use intended by the device manufacturer.
Part of EMA’s efforts to improve timely patient access
to new medicines by allowing medicinal products to
Acquis Communautaire
receive approval for use in a “well-defined patient
Usually referred to as the Acquis, the collection of
subgroup” or narrow indication, followed by a gradual
European laws to which all EU Member States must
expansion of the indication using postapproval and
adhere.
“real-world data.”
Active Implantable Medical Device
ADR
Intended to be totally or partially introduced, surgically
Adverse Drug Reaction
or medically, into the human body or by medical
intervention into a natural orifice, and which is
intended to remain after the procedure.

Glossary
Advanced Therapy Medicinal Product B

(ATMP) A medicinal product that is either a gene
Bibliographic Application
therapy medicinal product as defined in Part IV of
Also known as “well established use applications.” The
Annex 1 to Directive 2001/83/EC, a somatic cell
applicant prepares a product dossier based on literature
therapy medicinal product as defined in Part IV
available in the public domain. The drug product
of Annex 1 to Directive 2001/83/EC or a tissue-
concerned needs to have been on the market for at least
engineered product as defined in Article 2.1(b) of the
10 years. This application type is especially important
ATMP Regulation.
to newer Member States, as it allows them to keep
their current generic products on the market where no
AESGP
reference product exists.
Association Européenne des Spécialités
Pharmaceutiques Grand Public, Association of the
Biosimilar
European Self-medication Industry
A biological medicinal product that contains a version
of active substance of an already authorised (in the
AIMDD
EEA) original biological medicinal product (reference
See Active Implantable Medical Devices Directive
medicinal product). A biosimilar demonstrates
similarity to the reference medicinal product in terms
Alliance for Safe Online Pharmacy
of quality characteristics, biological activity, safety
(ASOP EU) Comprises patient organisations, internet
and efficacy, based on a comprehensive comparability
intermediaries, healthcare providers, pharmaceutical
exercise.
companies and supply chain stakeholders united in a
campaign to make the internet a safer place to obtain
Biosimilar Medicinal Products Working Party
medicines. It aims to become a trusted partner of the
(BMWP) Provides recommendations to the Committee
authorities in combatting the illegal sale of medicines
for Medicinal Products for Human Use (CHMP)
online.
on clinical or non-clinical matters relating directly or
indirectly to biosimilar medicines, and on the conduct
API
of tests on biosimilar medicinal products.
Active Pharmaceutical Ingredient
Blood Products Working Party
Applicant
(BPWP) Provides recommendations on all matters
See Marketing Authorisation applicant
relating directly or indirectly to blood products’ efficacy
and safety.
ASMF
See Active Substance Master File
Blue Guide
Explains the New Approach and Global Approach to
ASOP-EU
technical harmonisation and standardisation.
See Alliance for Safe Online Pharmacy
Borderline Products
Assessment Report
Complex healthcare products for which there
Assessment of the medicinal product by the Reference
is uncertainty over which regulatory framework applies.
Member State, including the reasons for its conclusions
during the Mutual Recognition Procedure. During the
BSE
Centralised Procedure, CHMP prepares an assessment
Bovine spongiform encephalopathy
report released as the European Public Assessment
Report (EPAR).
BSI
British Standards Institution
ATMP
See Advanced Therapy Medicinal Product
BPWP
See Blood Products Working Party
Authorised Representative
A natural or legal person established in the EU who,
BWP
explicitly designated by a non-European manufacturer,
Biotechnology Working Party, Biologics Working Party
acts on the manufacturer’s behalf in carrying out certain
tasks required in the applicable directives.

Glossary
C Certificate of Suitability
(CEP) Certificate granted by the EDQM Certification
CAMD
Secretariat certifying a substance’s quality is suitably
Competent Authorities for Medical Devices
controlled by the relevant European Pharmacopoeia
monographs with, if necessary, an annex appended.
CAPs
A CEP can be granted for active substances or
Conformity Assessment Procedures; see Conformity
excipients and for substances or preparations with
Assessment
a risk of transmitting agents of animal spongiform
encephalopathies.
CAT
See Committee for Advanced Therapies
CESP
See Common European Submission Portal
CDx
Companion diagnostics
CHMP
See Committee for Medicinal Products for Human Use
CE Marking
European Conformity, Conformité Européenne,
CIOMS
marking. Mandatory European marking for products
Council for International Organisations of Medical
falling under one of the New Approach directives
Sciences
(including medical devices) to indicate conformity with
the essential health and safety requirements.
CIP
See Clinical Investigation Plan
CEN
See European Committee for Standardization
CJEU
Court of Justice of the European Union
CENELEC
See European Committee for Electrotechnical
Clinical Investigation Plan
Standardization
(CIP) Document stating a clinical investigation’s
rationale, objectives, design and proposed analysis,
methodology, monitoring, conduct and recordkeeping.
Submission of a dossier to EMA to obtain marketing
authorisation from the European Commission valid
Clinical Trials Directive
in all EU Member States. The Centralised Procedure
Directive setting clinical trials’ analytical, pharma-
is compulsory for orphan medicinal products; any
toxicological and clinical standards and protocol
medicinal product for human use containing an entirely
requirements.
new active substance; those manufactured using
biotechnological processes; and medicinal products
Clock Stop
for the treatment of AIDS, cancer, neurodegenerative
Refers to a period of time during a medicinal product’s
disorders, auto-immune diseases and other immune
evaluation when the “clock” calculating a procedure’s
dysfunctions and viral diseases or diabetes. It also
timeframe stops while the applicant prepares answers to
may be used on a voluntary basis for other innovative
questions from the regulatory authority.
products. Products are assessed by the CHMP (human)
and CVMP (veterinary).
CMC
Chemistry, Manufacturing and Control
CEP
Certificate of European Pharmacoepeia. See Certificate
CMDh
of Suitability
See Coordination Group for Mutual Recognition and
Decentralised Procedures (human)
CMDv
See Coordination Group for Mutual Recognition and
Decentralised Procedures (veterinary)

Glossary
Co-decision Procedure COMP

Procedure by which the Council of the European Union See Committee for Orphan Medicinal Products
and the European Parliament—the two institutions
responsible for EU legislation—adopt legislative Competent Authority
acts. It applies to virtually all legislation regarding For medicinal products, a Member State’s governmental
pharmaceutical law. body responsible for authorising and supervising
such products. For medical devices, the organisation
COE authorised by a Member State’s government to act
See Council of the European Union on its behalf to ensure all medical devices meet the
Essential Requirements laid down in the medical device
Combination Product directives.
Product that shares the attributes of two product
categories such as medical devices and medicinal Concerned Member State
products. A Member State included in a Mutual Recognition
Procedure or Decentralised Procedure application.
Committee for Advanced Therapies
(CAT) A multidisciplinary committee advising EMA, Conformity Assessment
comprising the best available experts in Europe to assess The systematic examination of evidence generated and
ATMPs’ quality, safety and efficacy and follow scientific procedures undertaken by the manufacturer, under
developments in the field requirements established by the regulatory authority, to
ensure a medical device is safe and performs as intended
Committee for Medicinal Products for Human Use by the manufacturer and, therefore, conforms to the
(CHMP) A committee providing scientific advice Essential Principles of Safety and Performance for
to EMA on questions relating to the evaluation of Medical Devices.
medicinal products for Human Use. (Formerly, the
CPMP—Committee for Proprietary Medicinal Coordination Group for Mutual Recognition and
Products) Decentralised Procedures (human)
(CMDh) Coordinates and facilitates the operation of
Committee for Orphan Medicinal Products the Decentralised and Mutual Recognition Procedures
(COMP) A committee providing scientific advice for medicinal products for human use. (Replaced the
to EMA on questions relating to the designation of informal Mutual Recognition Facilitation Group
“orphan drugs” for rare diseases. (MRFG)).
Committee for Veterinary Medicinal Products Coordination Group for Mutual Recognition and
(CVMP) A committee providing scientific advice Decentralised Procedures (veterinary)
to EMA on questions relating to the evaluation of (CMDv) Coordinates and facilitates the operation of
veterinary medicinal products. the Decentralised and Mutual Recognition Procedures
for medicinal products for veterinary use.
Committee on Herbal Medicinal Products
(HMPC) A committee providing scientific advice Cost-Based Pricing Model
to EMA on questions relating to herbal medicinal (CbP) Allows a pharmaceutical product’s price to be
products. based primarily on its production cost.
Common European Submission Portal Council of the European Union

(CESP) An online delivery system, capable of accepting Sometimes referred to as the Council of Ministers,
information from stakeholders through one portal and the EU’s main decision-making institution and final
distributing it to one or more agencies. legislative authority. It comprises one representative
per Member State. The representative usually is a
Common Technical Specifications government minister and varies depending on the
(CTS) A set of requirements published in the Official matters being discussed, e.g., the minister for health for
Journal of the European Union and currently applicable pharmaceutical issues.
only to the Annex II List A IVD products.

Glossary
Counterfeit Medicines Decentralised Procedure

Any medicinal product that does not comply with Procedure that may be used for medicinal products for
intellectual property rights and/or infringes on which there is no existing Marketing Authorisation
trademark law. in any EU Member State. The applicant can select
the Reference Member State and list the Concerned
Crisis Management Plan Member States.
Comprises various methods to respond to a crisis,
establishing metrics to deal with crises, including Declaration of Conformity
defining what scenarios constitute a crisis and possible A document whereby the manufacturer ensures either
response mechanisms. A crisis management plan should the product safety component satisfies the Essential
include possible worst-case scenarios and solutions in Requirements of the applicable directives, or the
the form of a contingency plan. product is in conformity with the type for which a type-
examination certificate has been issued and satisfies the
CS Essential Requirements of the applicable directives. This
Common Specifications declaration is issued after completion of all relevant
conformity assessment procedures and must, in any
CTA case, be drawn up before the product is placed on the
Clinical Trial Application market; as a general rule, it accompanies the product
bearing the CE marking.
CTD
Common Technical Document DHCP
See Direct Healthcare Professional Communication
CTFG
Clinical Trials Facilitation Group DIBD
Developmental international birth date
CTMP
Somatic cell therapy medicinal product Direct Healthcare Professional Communication
(DHCP) A letter sent directly to individual healthcare
CTS professionals by a marketing authorisation holder or a
See Common Technical Specifications regulatory authority, containing information or advice
regarding the use of a medicine.
Custom-Made Device
Any device specifically made in accordance with Directive
the written prescription of a duly qualified medical An EC decision binding on EC institutions and
practitioner or any other person authorised by virtue of Member States that must be transposed into national
professional qualifications to do so that gives, under the legislation. However, the way in which it is implemented
prescriber’s responsibility, specific design characteristics is left to the discretion of individual Member States.
and intended for the sole use of a particular patient.
Distributor
CVMP Any natural or legal person in the supply chain, other
See Committee for Veterinary Medicinal Products than the manufacturer or importer, who makes a product
available on the market.
D
DG-SANCO
DAR
Directorate-General for Health and Consumers
Draft Assessment Report
DG-SANTE
DDC
Directorate-General for Health and Food Safety
Drug-device combination product
DLP
Data lock point
DMF
Drug Master File

Glossary
DMRC ENCePP
See Defective Medicines Report Centre European Network of Centres for
Pharmacoepidemiology and Pharmacovigilance
E
Enpr-EMA
EATB
European network of research networks, investigators
European Association of Tissue Banks
and centres with recognised expertise in performing
clinical studies in children to facilitate studies
EC
to increase the availability of medicinal products
See European Commission
authorised for use in the paediatric population.
ECJ
Enterprise Directorate-General
European Court of Justice
Enterprise DGs are the principal administrative
agencies of the European Commission. Their objective
eCTD
is to supply policy ideas that promote a supportive
Electronic Common Technical Document
business environment for all European enterprises—
including pharmaceutical companies.
ECTR
European Clinical Trial Regulation
EPAR
See European Public Assessment Report
EDQM
See European Directorate of Quality of Medicines and
ERA
Healthcare
Environmental risk assessment
EEA
ERP
See European Economic Area
See External Reference Pricing
EEC
Essential Requirements
See European Economic Community
Technical requirements defined in each New Approach
directive (usually Annex 1) with which a product must
EFPIA
comply to qualify for CE marking.
European Federation of Pharmaceutical Industries and
Associations
ESM
See European Stakeholder Model
EFSA
European Food Safety Authority
ESPEN
European Society for Clinical Nutrition and
EFTA
Metabolism
European Free Trade Association, composed of Iceland,
Liechtenstein, Norway and Switzerland.
eTACT
EDQM anti-counterfeiting traceability service for
EMA
medicines.
See European Medicines Agency
Ethics Committee
EMVS
A committee organised, generally at the hospital level,
See European Medicines Verification System
to approve, review and monitor clinical trials taking
place, to protect the rights and wellbeing of trial
EMVO
participants.
See European Medicines Verification Organisation
ETSI
EN
See the European Telecommunications Standards
See European Standard
Institute

Glossary
EU EU MDR
See European Union EU Medical Devices Regulations
Eudamed EUnetHTA
European Database on Medical Devices European Network for Health Technology Assessment;
emerged as a pilot programme co-funded by the
Eudralex European Commission and industry members to
Compilation of EU pharmaceutical legislation and collaborate on Health Technology Assessment.
guidelines accessible from the European Commission
Pharmaceuticals Unit website. EUnetHTA Joint Action 3
Aims to define and implement a sustainable model
EudraCT for the scientific and technical cooperation on
Database of all clinical trials commencing in the HTA in Europe, and is co-funded by the European
Community from 1 May 2004 onward, established in Commission.
accordance with Directive 2001/20/EC.
EuPFI
EudraGMP Database European Initiative for Paediatric Formulations
The Community database on manufacturing, import
and wholesale-distribution authorisation and Good EURD
Manufacturing Practice (GMP) and Good Distribution European Union Reference Dates
Practice (GDP) certificates. A public version of the
database has been available since 2011, which allows European Commission
public access to the database information not of a (EC) The executive branch of the European Union,
commercially or personally confidential nature. composed of 28 commissioners led by a Commission
President. The body is responsible for proposing
EudraPharm legislation, implementing decisions, upholding the
A source of information on all medicinal products for Union’s treaties and the general day-to-day operation of
human or veterinary use that have been authorised the EU.
in the EU and the EEA, and information on clinical
trials of medicinal products, including products with or European Committee for Electrotechnical
without a marketing authorisation. Standardization
(CENELEC) EU standards body that establishes
EudraVigilance voluntary electrotechnical standards.
A data processing network and management system for
reporting and evaluating suspected adverse reactions European Committee for Standardization
during the development and following the marketing (CEN) Comité Européen de Normalisation promotes
authorisation of medicinal products in the European voluntary harmonisation of European technical
Economic Area (EEA). standards across a wide range of products, processes and
appliances.
EU IVDR
EU In Vitro Diagnostic Medical Devices Regulations European Community
The collective body formerly designated as the
EU Legal Representative European Economic Community (EEC). The plural
(EU-LR) An individual, company, institution, or term European Communities also is used widely.
organisation authorised to act on behalf of the sponsor
of a clinical trial when the sponsor is not legally European Council
established in the EU. The Legal Representative must The heads of state of governments of the European
be based in the EU or the EEA, which includes Iceland Union Member States who meet regularly. It is the
and Norway (Article 15 of Dir 2001/20/EC). most senior manifestation of the Council of the
European Union.
EU LR
See EU Legal Representative

Glossary
European Directorate of Quality of Medicines and European Parliament

Healthcare The EU’s directly elected parliamentary body. Together
(EDQM) Part of the administrative structure of the with the Council of the European Union (the Council),
Council of Europe, its responsibilities include the it forms the bicameral legislative branch of the Union’s
Technical Secretariat of the European Pharmacopoeia institutions. The highest EU legislative body.
Commission, the unit for certifying the suitability of Ph.
Eur. monographs, developing the European network of European Pharmacopoeia
the Official Medicines Control Laboratories (OMCL) (Ph. Eur.) Pharmacopée Européenne is a pharmacopoeia
and providing the secretariat for this network. whose monographs are common to all concerned
European nations.
European Economic Area
(EEA) A free-trade area, in all but agriculture, European Public Assessment Report
comprising the EU Member States plus Iceland, (EPAR) Report on CHMP’s scientific conclusion at the
Liechtenstein and Norway. Previously called the end of the centralised evaluation process, summarising
European Economic Space. the grounds for the CHMP Opinion on granting
a marketing authorisation for a specific medicinal
European Economic Community product. EMA makes this information available to
(EEC) One of three communities created by the the public after deleting commercially confidential
Treaty of Rome in 1957 to establish a common market. information.
The 1967 merger of the EEC, Customs Union and
European Atomic Energy Community created the European Stakeholder Model
European Communities. Precursor to the European (ESM) Partnership of organisations involved in the
Union. pharmaceutical supply chain, overseen by a not-for-
profit stakeholder organisation called the European
European Federation of Pharmaceutical Industries Medicines Verification Organisation (EMVO). The
and Associations ESM’s aim is to develop a safe, cost-effective and
(EFPIA) Represents more than 2,000 pharmaceutical partnership-based pan-European medicines verification
companies involved in research, development and system using 2-D barcodes to address FMD needs.
manufacturing medicinal products for human use in
Europe. European Standard
(EN) Standards harmonised across the EU whose use,
European Medicines Agency in theory, is voluntary. They address product health or
(EMA) The agency responsible for coordinating the safety aspects, as well as such other characteristics as
scientific evaluation of human and veterinary medicinal durability, appearance, quality levels or even cultural
products’ safety, efficacy and quality undergoing the preferences. These standards may be test methods or
Centralised Procedure as well as arbitration during measurement guides.
the Mutual Recognition Procedure. It comprises the
CHMP, CVMP, COMP, CAT, HMPC, PDCO, a European Telecommunications Standards Institute
Secretariat, the Executive Director and a Management (ETSI) Develops standards for information and
Board. communications technologies.
European Medicines Verification Organisation European Union

(EMVO) A nonprofit organisation representing (EU) Political body comprising 27 Members States
stakeholders united in securing the legal supply chain established by the 1993 Treaty of Maastricht. It is the de
from falsified medicines. facto successor to the European Economic Community
founded in 1957 by the Treaty of Rome.
European Medicines Verification System
(EMVS) A measure in the EU to prevent falsified EUTCD
medicines entering the legal supply chain. European Union Tissue and Cells Directives
EVDAS
EudraVigilance Data Warehouse and Analysis System

Glossary
EVPM FMD
EudraVigilance Postauthorisation Module See Falsified Medicines Directive
EVTCM Follow-up Measures

EudraVigilance Clinical Trial Module (FUMs) Minor safety, quality and/or efficacy
questions, which remain outstanding at the time of the
Expert Report Committee’s opinion but do not prevent the granting of
Report drawn up for a Marketing Authorisation a Community Marketing Authorisation.
applicant by an expert, on the applicant’s behalf, on
the quality (chemical, pharmaceutical and biological Foods for Specific Groups
documentation), safety (pharmaco-toxicological) or (FSG) Regulation intended to strengthen provisions
efficacy (clinical) of a medicinal product, including a on foods for vulnerable population groups needing
tabulation, written summary (optional) and critical particular protection.
discussion of the product’s properties. The clinical
and nonclinical Expert Report has been replaced in FSCA
the Common Technical Document by the respective See Field Safety Corrective Action
overviews (modules 2.4 and 2.5).
FSD
External Reference Pricing Food Supplements Directive. Establishes harmonised
(ERP) The practice of using the price(s) of a medicine rules for food supplement labelling and introduces
in one or several countries to derive a benchmark or specific rules on vitamins and minerals in food
reference price for the purposes of setting or negotiating supplements. The aim is to harmonise the legislation
the price of the product in a given country. and ensure these products are safe and appropriately
labelled, so consumers can make informed choices.
F
FSG Regulation
Falsified Medicine
See Foods for Specific Groups
Medical products that deliberately/fraudulently
misrepresent their identity, composition or source.
FSMPs
Dietary Foods for Special Medical Purposes
Falsified Medicines Directive
Introduces tougher rules to improve the protection of
FSN
public health with new harmonised, pan-European
See Field Safety Notice
measures to ensure medicines are safe and the trade in
medicines is rigorously controlled.
Full-Mixed Application
Allows submission of published literature either in
FBO
support or in lieu of some of the nonclinical/clinical
Food business operator
data to be presented in Module 4 and/or 5 of the
Marketing Authorisation Application (MAA).
Field Safety Corrective Action
(FSCA) An action taken by a manufacturer to reduce
FUMs
the risk of death or serious deterioration in the state
See Follow-up Measures
of health associated with the use of a medical device
already placed on the market.
FVAR
Final Variation Assessment Report
Field Safety Notice
(FSN) A communication from a manufacturer or its
representative to customers and/or users in relation to a G
Field Safety Corrective Action. GCP
Good Clinical Practice
Fixed Combination Medicinal Product
Medicinal products containing active substances used in GDP
the composition of authorised medicinal products (but Good Distribution Practice
not to be used in combination for therapeutic purposes

Glossary
General Product Safety Directive GVP

(GPSD) Intended to ensure product safety throughout Good Pharmacovigilence Practice
the EU for consumer products not covered by specific
sector legislation (e.g., toys, chemicals, cosmetics, GxPs
machinery). Good practice regulations and principles that govern
various areas of the research, development, testing,
General Safety and Performance Requirements manufacturing, and distribution of medicines.
(GSPRs) Under the new EU Medical Devices
Regulations and EU In Vitro Diagnostic Medical H
Devices Regulations, the set of requirements stipulating
Healthcare Technology
the safety principles for medical device design and
Any intervention for use in promoting health,
manufacture to ensure patient, user and third party’s
preventing, diagnosing or treating diseases or
health and safety are protected.
for rehabilitation long-term care, including
pharmaceuticals, devices, procedures and organisational
Generic Medicinal Product
systems used in healthcare.
A medicinal product with the same qualitative and
quantitative composition in active substances and
Health Technology Assessment
pharmaceutical form as the reference medicinal product,
(HTA) Policy research that systematically examines
and whose bioequivalence with the reference medicinal
short- and long-term consequences, in terms of health
product has been demonstrated by appropriate
and resource use, of a health technology’s application, a
bioavailability studies.
set of related technologies or a technology-related issue.
Genetically Modified Organism
Helsinki Procedure
(GMO) An organism in which the genetic material has
Used by a national competent authority to request other
been altered in a way that does not occur naturally by
national competent authorities to provide an opinion on
mating and/or natural recombination.
a specific borderline or classification issue.
Global Medical Device Nomenclature Code
High Level Pharmaceutical Forum
(GMDN Code) A comprehensive system of
(HLPF) Intended to serve as a platform for the best
internationally recognised coded descriptors of preferred
practice exchange and examining efficiency gains in the
terms with definitions used to identify medical devices
area of Health Technology Assessments.
and related healthcare products generically.
HLPF
GLP
See High Level Pharmaceutical Forum
Good Laboratory Practice
HMPC
GMDN Code
See Committee on Herbal Medicinal Products
See Global Medical Device Nomenclature Code
HTA
GMO
See Health Technology Assessment and Human Tissue
See Genetically Modified Organism
Authority
GMP
HTAB
Good Manufacturing Practice
Health Technology Assessment Body
GPSD
Human Tissue Authority
See General Product Safety Directive
Regulates organisations removing, storing and using
human tissue for research, medical treatment, post-
GSPRs
mortem examination, education and training, and
See General Safety and Performance Requirements
display in public.
GTMP
Gene therapy medicinal product

Glossary
Hybrid Medicine Individual Case Safety Report

A medicine that is similar to an authorised medicine (ICSR) A document providing the most complete
containing the same active substance, but where there information on an individual case at a certain time
are certain differences between the two medicines, such point. An individual case is the information provided
as in their strength, indication or pharmaceutical form. by a primary source to describe suspected adverse
reaction(s) related to the one or more medicinal
I product’s administration to an individual patient at a
particular point of time.
ICH
International Council on Harmonisation of Technical
Informed Consent Application
Requirements for Registration of Pharmaceuticals for
Based on a permission, which allows the applicant
Human Use
to make use of the quality, nonclinical and clinical
documentation contained in the dossier of another
ICSR
medicinal product.
See Individual Case Safety Report
Innovation Task Force
Identification of Medicinal Products
(ITF) A multidisciplinary group that includes scientific,
(IDMP) An ISO standard that specifies the use
regulatory and legal competences. It was set up to
of standardised definitions for the identification
ensure coordination across EMA and to provide a
and description of medicinal products for human
forum for early dialogue with applicants.
use. (Replaces EudraVigilance Medicinal Product
Dictionary (XEVMPD)).
In Vitro Diagnostic Devices Directive (IVDD)
Covers devices used in vitro to examine specimens
IDMP
derived from the human body, including reagents,
See Identification of Medicinal Products
instruments and specimen receptacles.
IEC
INN
International Electrotechnical Commission
International Nonproprietary Name
IFPMA
International Medical Device Regulators Forum
International Federation of Pharmaceutical
(IMDRF) A voluntary group of medical device
Manufacturers’ Associations
regulators from around the world who have come
together to build on the strong foundational work of the
IFU
Global Harmonization Task Force on Medical Devices
Instructions for use. Applies to medical devices.
(GHTF) and aims to accelerate international medical
device regulatory harmonization and convergence.
IMP
Investigational medicinal product
IQWIG
Institute for Quality and Efficiency in Health Care
IMPD
(Germany)
Investigational medicinal product dossier
IRIS
IMDRF
EMA’s secure online platform for regulatory and
See International Medical Device Regulators Forum
scientific procedures.
Importer
ISO
Any natural or legal person established within the
International Organization for Standardization
Community who places a product from a third country
on the Community market.
ISPE
International Society of Pharmacoepidemiology
INAHTA
International Network of Agencies for Health
ITF
Technology Assessment
See Innovation Task Force

Glossary
IVDD Marketing Authorisation Application

In vitro diagnostic medical device (MAA) The application submitted to a Member
State(s) for a Decentralised or Mutual Recognition
IVDD Procedure or to EMA for the Centralised Procedure
In Vitro Diagnostic Devices Directive seeking permission to place a new product on the
market.
IVF/ART
In-vitro fertilisation/assisted reproductive technologies Marketing Authorisation Holder
(MAH) The person or company holding the marketing
J authorisation for placing a medicinal product on the
market and responsible for marketing the product. The
JAP
MAH must be established in the EEA.
See Joint Audit Programme
MDCG
Joint Audit Programme
Medical Device Coordination Group
( JAP) Validates and verifies the implementation
of relevant EU directives’ provisions into national
MDD
laws; manufacturers’ authorisation/licensing systems;
See Medical Devices Directive
GMP compliance certification; administration of
inspections; inspectorate; resources; complaints; rapid
MDEG
alerts including laboratory support, enforcement and
See Medical Device Expert Group
internal quality assurance. The JAP covers all EEA
GMP inspectorates for human and veterinary medicinal
MedDRA
products.
Medical Dictionary for Regulatory Activities developed
under the auspices of ICH. It is a medical terminology
JPMA
coding dictionary, important in the electronic
Japan Pharmaceutical Manufacturers Association
transmission of adverse event reporting as well as in the
coding of clinical trial data.
L
LOA Medical Devices Directive
Letter of Access (MDD) The Medical Devices Directive (Directive
93/42/EEC) sets general requirements relating to the
M design and construction of medical devices and their
accessories.
MA
Marketing Authorisation Medical Device Expert Group
(MDEG) A group of Member State, industry and
MAA other stakeholder representatives in the medical device
See Marketing Authorisation Application area for implementing the directive. This is the umbrella
group for other working groups in the field and
MAH coordinates and oversees their activities.
See Marketing Authorisation Holder
Medicines and Healthcare products Regulatory
MAID Agency
Manufacturer, Authorised Representative, Importer and (MHRA) The UK agency responsible for ensuring
Distributor (medical devices). The economic operators medicines and medical devices work and are acceptably
covered by the new supply chain regime under the safe.
IVDD.
Medicines for Europe
Marketing Authorisation The official representative body of the European generic
(MA) Authorisation to place a medicinal product on and biosimilar medicines pharmaceutical industry.
the market in a Member State issued by its competent (Formerly European Generic Association).
authority or by EMA for the EU market.

Glossary
MEDICRIME Convention NeeS

Drafted by the Council of Europe, a binding Non-eCTD electronic submission
international instrument in the criminal law field on
counterfeiting of medical products and similar crimes New Approach Directives
involving threats to public health. The European Council’s Decision of 7 May
1985 established a “New Approach” for technical
Member State harmonisation and standardisation to remove technical
An EU member nation. EFTA States have adopted the trade obstacles within the EU. The New Approach
complete Acquis Communautaire on medicinal products serves inter alia as the basis for the European Council
and consequently are parties to Community procedures; medical devices directives issued thus far with the object
therefore, for the purposes of this book, the term of removing existing trade obstacles and achieving high
Member State also shall include EFTA countries. unified security standards.
MHRA New Legislative Framework

See Medicines and Healthcare products Regulatory (NLF) A package of measures aimed at improving
Agency market surveillance and boosting conformity assessment
quality. It also clarifies the use of CE marking and
MPD creates a toolbox of measures for use in product
Medicinal Product Directive legislation.
MRA NFR
See Mutual Recognition Agreement Novel Foods Regulation
MRL NfG
Maximum residue limit Notes for Guidance
MSOG NHCR
Market Surveillance Operations Group Nutrition and Health Claims Regulation
Mutual Recognition Agreement NLF

(MRA) International agreement by which two or more See New Legislative Framework
countries agree to recognise one another’s conformity
assessments. NMVO
National Medicines Verification Organisation
Mutual Recognition Procedure
Applicable to most conventional medicinal products, the NIMP
Mutual Recognition Procedure is based on extending Noninvestigational medicinal product
national marketing authorisations to one or more
additional Member States. Applicants may select the Notice to Applicants
Reference Member State to conduct the assessment and (NTA) Procedures for marketing authorisation,
applicable Concerned Member States where the product regulatory guidelines and application dossier
would be put on the market if approved. presentation and content for medicinal products for
human use (Volume 2) and veterinary medicinal
N products (Volume 6). The NTA has no legal force.
Name Review Group
Notified Body
(NRG) Established by the Committee for Medicinal
Certification organisation (e.g., independent testing
Products for Human Use (CHMP) to perform reviews
house, laboratory or product certifier) authorised by
of the (invented) names of medicinal products being
the relevant Member State’s competent authority to
assessed by the Agency.
perform conformity assessment procedures specified in
the medical devices directives.
NBOG
See Notified Body Operations Group

Glossary
NBCG Orphan Medicinal Product

Notified Body Coordination Group (previously NB- A medicinal product with a limited target population
Med) or treating a rare disease, thus limiting its commercial
and financial potential. In the EU, the Orphan
Notified Bodies Operations Group Medicinal Product Regulation was adopted much later
(NBOG) Contributes to improving the overall (in December 1999), to stimulate the development
performance of notified bodies in the medical devices of medicinal products for diagnosing, preventing and
sector primarily by identifying and promulgating treating some 5,000 diseases classified as “rare” and
examples of best practice to be adopted by both notified affecting not more than 5 in 10,000 persons in the EU.
bodies and those organisations responsible for their
designation and control. OTC
Over-the-Counter (products available without a
NPAR prescription)
National Public Assessment Report
P
NRG
Paediatric Committee
See Name Review Group
(PDCO) Scientific committee within EMA assessing
the content of paediatric investigation plans (PIPs)
NTA
and adopting opinions on them in accordance with
See Notice to Applicants
Regulation (EC) 1901/2006, as amended. This includes
assessing applications for a full or partial waiver and
O applications for deferrals.
OBL
Own-brand labelling Paedriatric Investigation Plan
(PIP) Development plan aimed at ensuring the
OCABR necessary data are obtained through studies in children,
Official Control Authority Batch Release for medicinal when it is safe to do so, to support the authorisation of a
products derived from human blood or plasma. medicine for children.
Official Journal Paediatric Regulation

(OJ) Official Journal of the European Union. Contains Regulation passed in 2006 to encourage the
details of all EU legislation, as well as draft legislation, development and authorisation of medicinal products
information, notices and advertisements for public to meet the special therapeutic needs of the paediatric
works and supplies contracts. population.
OJ PAES
See Official Journal Postauthorisation efficacy studies
OMCL PAGB
Official Medicines Control Laboratories (see EDQM) UK trade association representing the manufacturers of
branded over-the-counter medicines, self care medical
OMP devices and food supplements.
See Orphan Medicinal Product
PAM
Oral Explanation Postauthorisation Measure
(OE)

Glossary
Parallel Consultation PIL

The European Medicines Agency (EMA) offers Patient Information Leaflet
consultations in parallel with the European Network
for Health Technology Assessment (EUnetHTA) as PIP
of July 2017. This aims to allow medicine developers to See Paedriatric Investigation Plan
obtain feedback from regulators and health technology
assessment (HTA) bodies on their evidence-generation Plasma Master File
plans to support decision-making on marketing (PMF) A compilation of all required scientific data
authorisation and reimbursement of new medicines at on human plasma’s quality and safety relevant to the
the same time. medicines, medical devices and investigational products
using human plasma in their manufacture. These data
PARNUTS cover all aspects of plasma use, from collection to
Food for Particular Nutritional Uses plasma pool.
PASS PMF
Postauthorisation Safety Studies See Plasma Master File
PBRER PMCF
Periodic Benefit-Risk Evaluation Report See Postmarket Clinical Follow-up
PDCO PMCPA
See Paediatric Committee Prescription Medicines Code of Practice Authority
(Finland)
Periodic Safety Update Report
(PSUR) A periodic report, submitted at defined PMOA
postauthorisation times, on a medicinal product’s Primary mode of action
worldwide safety experience.
PMS
Pharmacovigilance See Postmarket Surveillance
The science and activities relating to detecting,
assessing, understanding and preventing adverse effects POM
or any other drug-related problems. Prescription-only medicine
Pharmacovigilance Risk Assessment Committee Postmarket Clinical Followup

(PRAC) Provides advice to the CHMP and CAT (PMCF) A study carried out following a device’s CE
regarding the risk of products, both for new applications marking and intended to answer specific questions
and with ongoing pharmacovigilance, including relating to a device’s clinical safety or performance
management and mitigation of known and potential when used in accordance with its approved labelling.
safety risks, Postauthorisation Safety (PAS) studies and
pharmacovigilance audits. Postmarket Surveillance
(PMS) Systematic procedure by which a manufacturer
PhRMA records, evaluates and reports any incidents, proactively,
Pharmaceutical Research and Manufacturers of by gathering product experience in the postmarketing
America phase. Used as the basis for any necessary corrective
actions.
PIC
Pharmaceutical Inspection Convention. The PIC and PPRS
the Pharmaceutical Inspection Co-operation Scheme Pharmaceutical Price Regulation Scheme
(PIC Scheme) operate together as PIC/S.
PRAC
PIF See Pharmacovigilence Risk Assessment Committee
Product Information File
PrAR
Preliminary Assessment Report

Glossary
PRIME R
A scheme launched by the European Medicines Agency
Randomised Controlled Trial
(EMA) to enhance support for the development of
An experiment in which two or more interventions,
medicines that target an unmet medical need. This
possibly including a control or no intervention, are
voluntary scheme is based on enhanced interaction and
compared by being randomly allocated to participants.
early dialogue with developers of promising medicines,
to optimise development plans and speed up evaluation
Rapporteur and Co-Rapporteur
so these medicines can reach patients earlier.
Members of the CHMP, CVMP or COMP who
assume responsibility for assessing marketing
Protocol Assistance
authorisation applications, community referrals and
A special form of scientific advice available for
requests for orphan drug designation.
developers of designated orphan medicines for rare
diseases.
RATC
Rapid alert system for tissues and cells
PSMF
Pharmacovigilance System Master File (replaces
RCT
Detailed Description of the Pharmacovigilance System
See Randomised Controlled Trial
(DDPS)).
REA
PSRPH
See Relative Effectiveness Assessment
Potential Serious Risk for Public Health
Relative Effectiveness Assessment
PSUR
(REA) A specific health technology assessment element
See Periodic Safety Update Report
focusing on an intervention’s clinical implications.
PUMA
REACH
Paediatric Use Marketing Authorisation
Regulation on the Registration, Evaluation, Authorisation
and Restriction of Chemicals
Q
QbD Reference Medicinal Product
Quality by Design A medicinal product that has been granted a marketing
authorisation by a Member State or by the Commission
Qualified Person for Pharmacovigilance on the basis of a complete dossier, i.e., with submission
(QPPV) Responsible for overall pharmacovigilance for of quality, preclinical and clinical data in accordance
all medicinal products for which the company holds with Directive 2001/83/EC Articles 8(3), 10a,
marketing authorisations within the EU. 10b or 10c and to which the MAA for a generic/
hybrid medicinal product refers, by demonstration of
QPPV bioequivalence, usually through the submission of the
See Qualified Person for Phamacovigilance appropriate bioavailability studies.
QRD Reference Member State

See Working Group on Quality Review of Documents The European Member State conducting the
primary MAA review in the Mutual Recognition or
Qualified Person Decentralised Procedure and whose assessment report is
A person at the Marketing Authorisation Holder’s used as the basis for mutual recognition.
disposal responsible for ensuring the quality of each
medicinal product is in accordance with the marketing Regulation
authorisation’s requirements. A legal act entirely and directly binding on Member
States. Unlike a directive, it does not require
transposition into national law and its provisions can
come into force immediately.

Glossary
Risk Management Plan Scientific Advice Working Party

(RMP) A set of pharmacovigilance activities and (SAWP) A standing working party with the sole remit
interventions designed to identify, characterise, prevent of providing scientific advice and protocol assistance.
or minimise risks relating to a medicinal product, It was established by the Committee for Medicinal
including the assessment of the effectiveness of those Products for Human Use (CHMP).
interventions.
Scientific Advisory Group
RMP (SAG) Provides advice in connection with a specific
See Risk Management Plan and Reference Medicinal medicine or treatment’s evaluation. Consists of EU
Product experts selected according to their particular expertise
on the basis of CHMP or EMA nominations.
RMS
See Reference Member State SDR
Signal of disproportionate reporting
RP
See Responsible Person SEC
Single European Code
RPN
See Risk Priority Number SF Medicines
Substandard and falsified medicines
S
SMEs
Safe and Timely Access to Medicines for Patients
Small and medium-sized enterprises
(STAMP) Expert group set up to provide advice and
expertise to the Commission services in relation to the
SmPC
implementation of the EU Pharmaceutical legislation,
See Summary of Product Characteristics and
as well as programmes and policies in this field.
Supplementary Protection Certificate
Safeguard Clause
SOP
A rapid reaction measure a Member State may invoke
Standard Operating Procedure
to withdraw a device from the market, or prohibit or
restrict its placement on the market, if the device, when
STAMP
correctly installed, maintained and used for its intended
See Safe and Timely Access to Medicines for Patients
purpose, may compromise health or safety.
Substandard Medicine
SAG
Authorised medical products that fail to meet either
See Scientific Advisory Group
their quality standards or specifications, or both.
SAWP
Summary of Product Characteristics
See Scientific Advice Working Party
(SmPC) A document describing the properties and
the officially approved conditions of use of a medicine.
Scientific Advisory Group
Summaries of product characteristics form the basis of
(SAG) Provides advice in connection with a specific
information for healthcare professionals on how to use
medicine or treatment’s evaluation. Consists of EU
the medicine safely and effectively.
experts selected according to their particular expertise
on the basis of CHMP or EMA nominations.
Sunset Clause
The cessation of a medicinal product’s marketing
Scientific Advice
authorisation, if the product is not placed on the market
EMA advice to a developer on the appropriate tests
within three years of the authorisation being granted,
and studies in the development of a medicine. This is
or where a medicinal product previously placed on the
designed to facilitate the development and availability
market is no longer present on the market for three
of high-quality, effective and acceptably safe medicines,
consecutive years.
for the benefit of patients.

Glossary
Supplementary Protection Certificate Type I Variation

(SPC) An SPC protects intellectual property rights Any of the “minor” documentation variations listed in
following patent expiration and is available in the Annex I of Regulations (EEC) 1084/2003 (formerly
EU for medicinal products and plant protection 541/95) and (EEC) 1085/2003 (542/95) to an approved
products. An SPC can come into force only after the marketing authorisation. A Type IA or Type IB
corresponding patent expires and for a maximum of variation notification must be filed with EMA for any
five years, to grant a product not more than 15 years such change. Type IAIN requires immediate notification.
of market exclusivity. It is intended to compensate
the holder for the extended period required for some Type II Variation
products to be approved. Any change to an approved MA’s documentation that is
not a Type IA or Type IB Variation and is not regarded
SUSAR as an extension to the MA.
Suspected unexpected serious adverse reactions
U
T UDI
TCD Unique device identifier
See Tissues and Cell Directive
UMI
TEAM-NB Unique medicine identifier
The European Association for Medical Devices of
Notified Bodies Urgent Safety Restriction
(USR) An interim change to SmPC product
TEP information by the Marketing Authorisation Holder
Tissue Engineered Product concerning indications, dosage, contraindications,
warnings, target species and withdrawal periods
THMPD resulting from new information about a medicinal
See Traditional Herbal Medicinal Products Directive product’s safe use.
Tissues and Cell Directive V

Sets quality and safety standards for human tissue
Vaccine Antigen Master File
and cell donation, procurement, testing, processing,
(VAMF) A standalone part of the MAA dossier for a
preservation, storage and distribution.
vaccine containing all relevant information of biological,
pharmaceutical and chemical nature for one given
Traditional Herbal Medicinal Products Directive
vaccine antigen common to several vaccines from the
Requires traditional, over-the-counter herbal remedies
same MA applicant or MAH.
to be manufactured to assured safety and quality
standards.
VAMF
See Vaccine Antigen Master File
Transparency Directive
Aims to ensure the transparency of Member States’
Value-Based Pricing Model
measures to control medicinal product pricing and
Allows a pharmaceutical product’s price to be set based
reimbursement.
on its added therapeutic value when compared with the
existing standard of care.
Treaty on European Union
The 1992 document that restructured the EC,
VHP
formally established the EU and committed the EC to
Voluntary Harmonisation Procedure
Economic and Monetary Union (EMU) by 1999 at the
latest. Also known as the Maastricht Treaty.
VICH
International Cooperation on Harmonisation of
TSE
Technical Requirements for Registration of Veterinary
Transmissible spongiform encephalopathies
Medicinal Products

Glossary
Vigilance
Adverse incident reporting requirements and system for
devices.
VWP
Vaccine Working Party
W
WHO
World Health Organisation
Working Group on Quality Review of Documents

(QRD) Provides assistance to EMA’s scientific
committees and companies on linguistic aspects of
the product information for medicines. This includes
SmPCs, labelling and package leaflets.

Glossary

Index
Tables, figures, and case studies are indicated by active pharmaceutical ingredients (API)
appending “t”, “f”, or “c” to the page number. EDQM inspection process, 369
Contents of tables are not indexed separately. in generic products, 377
Active Substance Master File (ASMF)
A with combination products, 550
generic medicinal products, 384
absorption, distribution, metabolism and excretion
IGDRP work on, 384
(ADME)
MA dossier quality section, 280
gene therapy products, 466, 468
medicinal product registration, 350
preclinical testing, 302–303
acute/repeat dose toxicity studies, 303
accelerated assessment
Ad Hoc Expert Group
additional pathways for, 538–539
MAA review, 54
ATMPs, 452, 453t
meeting of, 56
CAT request for human tissues, 480
adaptive and alternative pathways
CHMP recommendation for, 35
accelerated access initiatives by EMA, 295–296
conditional authorisation, 475
eligibility for, 295, 297f, 346
EMA advice meetings, 44t
HTA/EMA collaboration for, 88–89
EMA initiatives, 101
legal framework for, 296–298
for orphan designation products, 538
medicinal products, 296–298
prepandemic influenza vaccines, 496
for orphan designation products, 539
procedures for, 475
principles of, 296
registration of medicinal products, 347
procedural guidance for, 298
regulatory mechanisms for, 3–4
product eligibility for, 297f
requests for, 283
Addition of Vitamins and Minerals and of Other
See also PRIME (PRIority MEdicines)
Substances to Food Regulation, 504
Active Implantable Medical Device Directive (AIMDD)
Advanced Therapy Medicinal Products (ATMPs)
repeal of, 184–185
authorised in EU, 455t
transition from, 178
borderline and criteria precluding from, 457–460
See also EU MDR and EU IVDR
certification of, 460
active implantable/active medical devices
characterisation and quality control, 462
classification change for, 146
classification of, 456–457, 457t, 477–478
classification rules for, 191t
classification procedures for, 456–460
legal framework for, 165–170
GTMP, 461–462, 464–465, 466
MDR rules
legal framework, 480
medical device legislation and classification,
MA procedures for, 480
191t
pharmaceutical regulation evolution, 21–22

Index
preclinical development, 465–466 animal models

product characterisation, manufacturing and nonclinical testing, 235c
quality control of, 462–463 pharmacodynamic testing, 395–396
regulation, 451–470, 480 preclinical device testing, 235c
risk management for, 466–467 tissue-engineered product, 495
sCTMPs, 460–461, 462, 463–464, 465–466 Annual Safety Reports (ASRs), 311
subcategories of, 452–453 authorisation procedures for medicinal products
summary, 467–468 Centralised and Mutual Recognition Procedures
supply without MA grant, 455–456 for, 278–279
TEPs, 461, 463, 465, 466 Centralised Procedure, 281–285
Adverse Drug Reactions (ADRs)/reporting Decentralised Procedure, 287–289, 290t
for biosimilar medicinal products, 401 eCTD format and acceptability, 281
defined, 313 legal framework for MAA, 278–279
Eudra Vigilance databases, 318, 401 MA dossier quality section, 280
from healthcare professionals, 438 MA system, 278–279
human blood or plasma products, 525 Mutual Recognition Procedure, 285–287
nonprescription medicinal products, 409 national authorizations, 289
for paediatric product development, 100 Notice to Applicants (NTA) for medicinal products,
PRAC activities for, 387 278–279
requirements of Member States, 386–387 referrals, 292, 293
See also pharmacovigilance Authorised Representatives, 216, 255–256, 255t
advertising and promotion, 103–114
abbreviated ads as reminders, 106 B
comparative advertisements, 110
Belgium
contents for HCPs, 105–106
advertising preapproval, 111
EFPIA goals and code, 104–105
BeNeLuxA, 23
enforcement by competent authorities, 120
bench testing for devices, 234–235c
to general public, 108
bibliographic applications/well-established use,
general public content, 107–108
291–292
biocompatibility testing
HCPs, 105–106
nonclinical studies, 234c, 235c
to healthcare professionals, 105
preclinical test plan, 229
healthcare professionals (HCPs), 105, 106–107
requirements from standards and risk
Internet media, 109
management, 230–231
jurisdictions for, 111–112
in tissue-engineered products, 465
market surveillance, 110–111
bioequivalence, 378, 380–381
medical devices, 112
Biologics Working Party (BWP), 21, 522
nonauthorised products, 109–110
biosimilar medicinal products
nonprescription medicinal products, 408–409
administration route and dosage parameters, 397
off-label information, 109–110
authorised active substance in, 394
OTCs, 108
clinical comparability demonstration for, 396–
preapproval of material, 111–112
397
press releases, 108–109
comparability to reference product, 394–395
regulatory framework, 103–104
comparative development of, 399f
regulatory strategy for, 138
development processes for, 395f, 396f
sales representatives/sample distribution,
effects of change to reference product, 399
105–106
GLPs for, 396
scientific service by MAA, 111
immunogenicity testing for, 397
self-regulation, 104–105
MAA data package for, 400t
affiliated countries and competent authorities,
MAA submission for, 397–398
161–163t
pharmaceutical regulation evolution, 22
American Association of Tissue Banks (AATB), 473
pharmacovigilance and safety reporting, 400
Anatomic, Therapeutic, Chemical Classification
postapproval lifecycle management, 399–400
(ATC) code, 282

Index
preclinical study program for, 395 ATMP MAA timetable, 481–483t

registration of, 397–399 authorisation system, 20
safety reporting for, 400–401 biosimilar medicinal product registration, 397,
therapeutic interchangeability, 22, 399 401
timeline for development of, 397f biosimilar medicinal products, 397
types of biological medicinal products, 393–394 biotechnology-derived product marketing
urgent safety restrictions for, 400 authorisation, 407–408, 413
biotechnology-derived products Brexit effects for UK, 10
accelerated assessment procedure, 415 combination products, 544
centralised procedure for, 415–416 comparison of pathways for nonprescription
clinical information, 419 products, 406f
conditional authorisation, 415 DNA and therapeutic vaccines, 497
development processes for, 394, 416 dossier assessment procedures, 354
developmental pharmaceutics, 416 dossier requirements, 433
exceptional circumstances application procedure, eligibility request for generic medicinal products,
415 386
GLP for preclinical testing, 418–419 EMA committee evaluation of products, 7, 14
MA maintenance, 416 EMA presubmission guidance, 414
manufacturing information for, 417 evaluation of products, 14
pathways to marketing authorisation, 413–414 generic medicines, 379
pharmacovigilance and safety reporting, 419 human blood/plasma product registration, 523
postapproval lifecycle comparability, 419 human blood/plasma product renewal and
postapproval variations, 419 pharmacovigilance, 525
registration procedures for, 414–415 Information and Work Sharing projects, 386
release testing in Europe, 418 inspection process with, 366
TSE and viral clearance data for, 417–418 labelling and package leaflet (PL), 388
Blood Products Working Party (BPWP), 522 MA issued under, 285
borderline products classification, 200–201 MAA evaluation by EMA, 2
Brexit. See United Kingdom (UK) MAA procedures, 281–283, 355f
British Pharmacopoeia (BP) medicinal product authorisation, 381
quality systems and inspectorate process, 373 medicinal product authorisation procedures,
281–285
C medicinal product clinical trials, 385
national competent authorities medicine
carcinogenicity studies, 303
authorisation, 561
CE Mark
for nonprescription medications, 405
compliance confirmation with, 155
orphan medicinal products, 525
countries requiring, 272
pan-European generic authorisation, 391
for IVDs, 213–214
pan-European registration system, 19
central individual case study report (ICSR)
postauthorisation assessment procedure, 426
electronic submissions, 449
in PMSF, 440
prescription to nonprescription reclassification,
processing center performance, 441
407–408
submission and processing requirements, 443,
product criteria for use, 19, 287, 293, 414
445, 445f
product exclusivity under, 291
centralised marketing authorisation
registration of medicinal products, 341, 344
MAA review for, 53–60
regulatory dossier assessment, 354
medicinal products, 278–279
regulatory information resources for, 554, 557,
Centralised Procedure (CP)
574
advantages and disadvantages for biotechnology
scientific advice and parallel meeting for, 48
products, 415, 419
vaccine licensure, 492
advantages/risk comparison for nonprescription
variation assessment and notifications, 433–435
medicines, 406t
certificate of analysis, 369, 490
application evaluation timetable for, 284t

Index
Certificate(s) of Suitability (CEP) clinical trials for medicinal products, 309–340

for APIs, 380 amendment notifications, 320–323
EDQM issue of, 280, 352 biological product guidance, 490
GMP inspections, 367–369 clinical trial application scientific assessment,
registration of medicinal products, 352 327f
significance of, 369–370 clinical trial authorisation procedure, 326f
Chemical Abstracts Service (CAS) number, 305 clinical trial regulatory telematics structure
Clinical Effectiveness (EFF) HTA model, 80 transitions, 317–318
clinical evaluation and clinical investigations DSUR contents, 334t
bench testing, 234c, 235c ECTR and Clinical Trials Directive definitions,
CE Mark requirements, 238 316–317t
Clinical Evaluation Report (CER), 238 ECTR implementation
clinical pathway review, 241 clinical trial application process, 324
clinical strategy plan, 240 clinical trial authorisation, 324
clinical trial essentials, 241 CTA dossier contents, 329f
common mistakes in, 241–242 EU Clinical Trials Register (EUCTR), 319
elements of device evaluation, 238–239 EU Telematics, 317–318
equivalence to existing device, 239 Part II CTA assessment, 328f
GCP and quality in, 241 serious adverse event reporting, 332f
objectives of clinical investigation, 239 Coding Directive, 485
performing clinical investigation, 240–241 combination products, 543–552
planning the evaluation, 239–240 borderline products, 545
report required, 238 conformity assessment requirements, 549
Clinical Evaluation Report (CER), 238–240 determination of registration pathway, 544
Clinical Investigation Protocol (CIP), 171, 241 directives and guidance documents, 547–548
clinical investigations vs clinical trials heparin and AIMD, 551c
MDD, EU MDR definitions of, 116 IVDs and CDx, 550
See also specific products labelling requirements, 551
Clinical Trial Application (CTA) medicinal product/device delineation, 543–544
EU laws and regulations, 39 pharmaceutical consultation procedure, 549–550
vaccines, 490 postmarket surveillance requirements, 551
clinical trial authorisation process product classification by PMOA, 544–547
application to national competent authority, 320 quality system requirements, 550–551
Ethics Committee evaluation and Member State regulatory classification determination, 548
competent authority, 319–320 set for local anaesthesia with lidocaine, 551–552c
Ethics Committee opinion application, 320 sunblock cream/embedded barrier for vitiligo,
GMO-based products, 463, 497–498 552c
Clinical Trials Directive (CTD), 310–312 in vitro fertilisation/transplant organs or tissue,
amendment of in-progress clinical trial, 323 551c
Annual Safety Reports (ASR) requirements of, 312 combined ATMPs (cATMPs), 452, 456, 467
application to IMPS, 315–317 Committee for Advanced Therapies (CAT)
clinical trial end declaration, 323–324 ATMP classification and certification by, 457t,
CTA process and authorisation process, 319–323 460, 477, 533
declaring end of clinical trial, 323–324 ATMP Regulation and, 453–457
ECTR significant changes from, 314–315t combination products, 550, 557
EudraCT changes, 318–319 EMA responsibility for, 164
EudraPharm function, 319 feedback during MA review, 54, 55f
objectives and transition to ECTR, 310, 312 MAA evaluation by, 480
serious adverse reaction (SAR) reporting, 313 MAA review, 53–54, 54t
Clinical Trials Facilitation Group (CTFG), 313 PRAC advise to, 56
PRIME rapporteur appointment from, 36–37
rapporteur appointment from, 282, 430
representation in, 54
responsibilities of, 4, 8, 54t

Index
Committee for Medicinal Products for Human Use postmarket surveillance procedures, 259
(CHMP) risk management in device industry, 260
ATMP marketing authorisation, 480 surveillance and control provisions, 267–268
conditional marketing authorisation grant, 35 trend reporting, 265
GCP adoption by, 330, 445 Concerned Member States (CMS)
human blood or plasma product regulation, 522, application review timeline in, 322
531 authorisation of clinical trials under ECTR,
inspection requests from, 366 324–325
MAA review, 53–54, 54t clinical trial acceptability, 324–325
meeting preparation timeline, 57f clinical trial management and notifications, 328
PDCO appointments, 95 clinical trial safety procedures, 323
PRAC recommendation endorsements, 119 clinical trials for medicinal products, 311
responsibilities of, 7 communications with Reference Member State,
Committee for Medicinal Products for Veterinary Use 355–356
(CVMP), 8, 366, 555, 557 decentralised procedure applications, 345
Committee for Orphan Medicinal Products (COMP), decentralised procedure referral, 293
343 decentralised procedures, 288, 355–356
orphan designation request review, 38 dossier validation in, 354
rare disease designation review, 530 DSUR submission, 333
responsibilities of, 8, 343, 532 IMPD cross-referencing, 330
scientific advice from, 37, 48 inspection report submission by sponsor, 330
Common European Submission Portal (CESP), manufacture and importation, 388
323–324 MRP, 356–357
Common Specification (CS): GSPRs verifications, Mutual Recognition Procedure phase 2 timeline,
225 286
Common Technical Document (CTD) national law application in, 337
biotechnology-derived product pharmaceutics, RMS evaluation for MA, 19
416–417 scientific advice for IMPs, 324
eCTD envelope, 351–352, 352t scientific advice from competent authority, 322
eCTD format and acceptability for medicinal sponsor selection of, 345
products, 281 vigilance procedures in, 478
MAA EU format and content, 280–281 conditional authorisation
medicinal product registration, 351–352, 351t accelerated assessment, 475
for vaccines, 490 biotechnology-derived products, 415
Common Technical Specifications (CTS) for IVDs, 214 by CHMP, 35
Communication and Tracking System (CTS) data for orphan designation products, 538
base, 288–289 registration of medicinal products, 346
community interest referral, 293 conformity assessment
competent authorities. See national competent AIMDD documentation, 246
authorities AIMDD procedure, 250f
Competent Authorities for Medical Devices (CAMD), Authorised Representatives, 216, 255–256, 255t
116, 164 CE marking process, 244–245
Complete/Full and Independent application, 289 Class I device, self-declaration/self-certification,
compliance and postmarket surveillance (devices) 250f
clinical followup for AIMDs and MDs, 260–261 Class IIa procedure, 249f
Eudamed, 266–267 Class III device options, 248f
feedback mechanisms for, 257–258 Class IIIb procedures, 249f
Field Safety Corrective Action (FSCA), 258 conformity assessment in, 136
follow-up investigation, 264–265 documentation for, 247
FSCAs and FSNs, 265 EC-type examination, 252, 254t
GPSD, MDD, and EU MDR relationship, 258–259 full quality assurance system, 253, 254t
incidents and criteria for reporting, 262–264 high-risk IVD procedure, 253f
medical device global vigilance, 266 internal production control, 252, 254t
PMS vs vigilance, 266–267 IVD procedure, 251f

Index
IVDD Annex II list b procedure, 252f Declaration of Conformity (DoC)

IVDD documentation, 247t authorised representative signature, 187
for IVDs, 216 CE Mark for conformity, 155
MDD conformity assessment documentation, Essential Requirements for, 213
247t under EU IVDR, 216
Notified Bodies in, 255 for placing on the market, 170
procedures for, 246t responsible person for regulatory compliance,
product quality assurance, 253, 254t 145
product risk class and, 245, 248, 251–252 See also conformity assessment
product verification, 253, 254t Declaration of Helsinki, 311, 390
production quality assurance, 252–253, 254t delegated act definition, 366
quality system requirements, 253, 255 Description and Technical Characteristic of
self-testing IVD procedure, 251f Technology (TEC) HTA model, 80
Cost and Economic Evaluation (ECO), 80 Design Traceability Matrix, 231
cost-based pricing (CbP model), 63–64 Development International Birth Date (DIBD), 333
custom-made devices Development Safety Update Report (DSUR)
Essential Requirements for, 171 contents of, 334t
EU MDR and EU IVDR, 170–171 EVCTM for submission, 335
medical device legal system, 165–171 format for, 443, 444t
ICH guideline for, 313, 332–333
D ICH replacement for annual report, 312
Directive defined, 184, 366
Danish Centre for HTA (DACEHTA), 78
Directorate- General for Health and Consumers (DG
Danish Promotion Code, 106
SANCO), 522
Decentralised Procedure (DCP)
Directorate-General for Health and Food Safety (DG
applications to other Member States, 286
SANTE), 522, 560
ATC code and, 282
divergent decision referral, 293
biosimilar medicinal product registration, 397
dossier. See regulatory dossier
biotechnology-derived product marketing
Draft Assessment Report (DAR), 355
authorisation, 413
drug and biologic regulatory pathways
CMDh, 8, 10
MAA, 32
EU regulatory bodies for, 341
product development, 31–32
flow chart for, 290t
drug product process validation scheme, 351–352
generic medicinal products, 381, 382
drug-device combination products (DDCs)
human blood/plasma postmarket requirements,
classification, 193–194
525
Drug-Eluting Stent (DES) and medicinal substance,
human blood/plasma product registration, 523
234–235c
Information and Work Sharing projects, 386
initial MAA, 356f
market access mechanism, 19, 279, 285, 287– E
289 electrical magnetic disturbance testing, 233
medicinal product authorisation procedures, electrical safety, 233
287–289 Electrotechnical Commission (CENELEC), 225
medicinal product registration, 344–345, 355– EMA meeting preparation, MAA review
356 CHMP meeting preparation timeline, 57f
nonprescription medicinal products, 405 core briefing materials for, 57–58
pathways for nonprescription products, 406f early preparation for, 57
postauthorisation requirements for face-to-face meetings, 54–56
pharmaceuticals, 424 Q&A preparation, 58
referrals, 293 rehearsals for, 59
regulatory dossier assessment, 355–356 rehearsals in Amsterdam, 59
regulatory information resources for, 554 representation and feedback from, 55f
variation assessment and notifications, 431, Scientific committee role in, 53
433–434 scripting/developing core presentation, 58

Index
slide development and management, 58–59 Clinical Trials Regulation (536/2014), 39

Standard Assessment Review Timeline, 55f codification/clarification of pharmaceutical
steps for preparation, 56–57 directives, 19
understand committee members, 57 CTA, 38–39
written briefing document, 58 current regulation evolution, 17–19
EMA meetings Directive 2001/83/EC, 165, 184
advice meetings, 43–44t Directive 200427/EC, 165
communications for MAA, 41–52 economic issues, 16–17
general preparation for, 47–48 falsification and counterfeiting, 17
for MAA, 41–52 General Data Protection Regulation (GDPR), 138
MAA procedural steps and, 42–47 information availability and transparency, 16
during MAA review, 53–60 IVDD, 26
MAA review, 53–60 medical device regulation evolution, 23–24
scientific advice review, 48 medical product regulation development, 14–15
steps required for, 45t orphan medicinal products (OMPs), 38
timelines for, 46t paediatric development programs, 38
See also specific meeting types Paediatric Regulation, 121
enforcement patient advocacy and involvement, 16
CE marking errors, 117 pharmaceuticals regulation, 20
Eudamed communications, 118 PRIME, 36–37
medicinal product advertising and promotion, product innovation, 15–16
119–120 scientific advice and protocol assistance, 37–38
medicinal product GMP compliance, 119 traditional herbal medicinal products, 23
medicinal product pharmacovigilance, 119 unsafe product consequences, 15
medicinal products recalls, 119 EU MDR and EU IVDR
notified bodies, 118 ATMPs, 480–484
Safeguard Clause, 117 authorised representative, 173
Enpr-EMA, 101, 559t authorised representative agreement contract
Essential Requirements (ER) forms, 179
clinical investigation vs clinical evaluation, classification and conformity assessment, 146
238–239 clinical evidence, trials, and regulatory
compared to GSPRs, 230 compliance, 144–145
conformity assessment for, 187 clinical investigation devices, 171
consensus standards definition by, 225 Commission recommendation, 174, 174t
custom-made devices, 171 custom-made devices, 170–171
GHRF Essential Principles concept, 222–224 delegated and implementing acts, 148
harmonised technical standards for, 177 EC working groups, 165, 166–167t
intended purpose and, 167 Essential Requirements vs GSPRs, 238
for IVD manufacturer processes, 211 governance structure, 147–148, 147f, 176f
legal documents, 18 healthcare establishments, 164
legislative harmonisation and compliance, 155, human tissues, cells and derivatives, 484
213–214 implementation of MAID goods package, 142–143
manufacturer GSPR demonstration, 238 implications of, 148–149
safety and performance vs technical importers and distributors, 164
documentation, 23–24 improved elements, 173–174
Ethical Analysis (ETH) HTA model, 80–81 industry representation/trade associations, 165,
Ethics Committees (ECs) 167t
application for opinion on clinical trial, 320 institutional cooperation and consensus
contents of application to, 321t building, 164–165
EU Clinical Trials Register (EUCTR), 319 interpretation of device law
EU In Vitro Diagnostic Medical Devices Regulation Commission as an arbitrator, 177
(EU IVDR), 138 Commission guidance, 175–176
EU laws and regulations courts, 174
basic legislation for, 14 guidance from Member States, 177

Index
guidance from other sources, 177 submissions, 41–52

key directives, 165 medical device compliance/postmarket
legal system evolution, 178 requirements, 257–269
manufacturer, 171–173 medical device conformity assessment
manufacturers and authorised representatives, procedure, 243–256
164 medical device legislation and classification,
market access mechanism, 144 183–206
MDD and EU MDR device definitions, 168t medical device national particularities, 271–276
MEDDEV guidance documents, 172–173t medical device preclinical testing, 229–236
medical devices and active implantable medical medical devices legal system, 151–182
devices, 142, 165–170 medicinal product authorisation procedures,
national enforcement, 177–178 277–294
NBOG Best Practice Guide, 175t medicinal product clinical trials, 309–339
notified bodies changes with, 144 medicinal product registration procedures,
overview, 180 341–362
own-brand labelling and reprocessing, 146–147 new MDR and IVDD regulation, 141–150
postmarket surveillance and vigilance, 145–146 nonprescription medicinal products, 403–412
product liability, 178–179 orphan medicinal products (OMPs), 529–542
proposed IVDR classification rules, 145f Paediatric Regulation, 93–102
scope of device directives, 165 pharmaceutical postauthorisation requirements/
significance of technical standards, 177 compliance, 423–436
stakeholders, 159 pharmaceutical quality systems and inspectorate
supply chain controls, 142f process, 363–376
supply chain vigilance obligations, 179–180 pharmacovigilance, 437–450
timeline for adopting/transitional regime, 148 preclinical testing and GLP, 301–308
traceability, 143–144 pricing and reimbursement, 61–76
EU MDR and EU IVDR regulatory information resources, 553–573
ISO 13485 in transition to, 255 regulatory strategy, 135–140
QMS requirements and ISO 13485, 252–253 safety and performance requirements/technical
EU Medical Devices Regulation (EU MDR), 480–481 documentation, 221–228
EU regulatory affairs vaccines, 489–500
adaptive and alternative pathways, 295–300 in vitro diagnostic devices (IVDDs), 207–220
advertising and promotion, 103–114 EU Tissue and Cell Directives (EUTCD), 471–473. See
ATMP regulatory framework, 451–470 also specific tissue and cell products
biosimilar medicinal products, 393–402 EU Treaty, 14
clinical evaluation and clinical investigations, Eudamed
237–242 competent authority communications, 118
combination products, 543–552 market surveillance and vigilance, 267–268
drug and biologic regulatory pathways, 31–40 Eudra Vigilance databases, 318, 566
EMA and other regulatory bodies, 1–12 EudraCT paediatric clinical trial records, 319
enforcement and competent authorities, 115–120 EudraGMDP inspection information in, 369
Falsified Medicines Directive (FMD), 121–134 EudraVigilance Clinical Trial Module (EVCTM), 332,
food for special medical purposes, 511–518 335
food supplements, 501–510 EudraVigilance medicinal product dictionary
generic medicinal products, 377–392 (xEVMPD), 440
Health Technology Assessment (HTA), 77–92 EudraVigilance Postauthorisation Module (EVPM),
history of regulations, 13–30 493
human blood or plasma products, 519–528 Eurasian Economic Union Member States, 374
human tissue regulation, 471–488 European Association of Tissue Banks (EATB), 473
MAA for biotechnology derived products, 413– European Blood and Marrow Transplantation Group
422 (EBMT), 473
Marketing Authorisation Application (MAA) European Clinical Trial Database (EudraCT)
review, 53–60 clinical trial databases, 38, 100
Marketing Authorisation Application (MAA) SUSAR reporting, 318

Index
European Clinical Trial Regulation (ECTR) HTA parallel consultation, 88

adverse reactions in, 313 marketing recommendation for medicinal
application to IMPS, 315–317 products, 278–279
electronic reporting, 319 regulatory authorities, pharmaceutical quality,
EU Clinical Trials Register (EUCTR), 317–318 365
EU Portal, 317 European Medicines Verification Organisation
EU portal and database, and associated legacy (EMVO), 131
systems, 311 European Medicines Verification System (EMVS), 131
EU Telematics Strategy and Implementation European Network for HTA (EUnetHTA)
Roadmap, 317 EMA collaboration, 88–89
EudraVigilance Clinical Trial Module (EVCTM), HTA assessments, 78–88
317–318 MAA evaluation, 50, 65–67
evaluation for duplication, 318 European Network of Centres for
implementation guidance documents, 312–313 Pharmacoepidemiology and Pharmacovigilance
Member States national laws and, 311 (ENCePP), 445–446
significant changes from Clinical Trials Directive, European Pharmacopoeia (Ph. Eur.), 373
314–315t European Public Assessment Report (EPAR), 283,
European Commission (EC) 398–399
demonstration of GSPRs, 225 European Society of Human Reproduction and
initiatives and models for pricing, 63–64 Embryology (ESHRE), 473
Notice to Applicants (NTA) for medicinal products, European Standardization Committee (CEN), 225
278–279 European Transplant Coordinators Organisation,
regulatory authorities, pharmaceutical quality, 473
365 European Union (EU)
Task Force for Relations with the United Kingdom medical product regulatory bodies, 341–342
(UKTF), 364, 366 pricing and reimbursement, 61–76
European community referral, 292 European Union Reference Dates (EURD)
European Directory for the Quality of Medicines active substances, 388
(EDQM) PSURs and PSUSAs scheduling, 360, 445
API assessment by, 380 exceptional circumstances
CEP issued by, 280 medicinal product registration, 346–347
European Economic Area (EEA) for orphan designation products, 538–539
CE marking requirements, 272 expedited evaluation programs
European Eye Banking Association (EEBA), 473 ATMPs, 453t
European Federation of Pharmaceutical Industries decision tree for pathways, 454f
and Associations (EFPIA See also Adaptive Pathways; alternative
CE marking requirements, 272 pathways; PRIME (PRIority MEdicines)
codes of conduct, 104–105 External Reference Pricing (ERP)), 63, 64f. See also
falsified medicines legislation, 123t pricing and reimbursement
product distribution, 106–107, 111
regulatory information from, 564 F
European Food Safety Authority (EFSA)
facility requirements
food supplement assessment by, 504–505
medicinal requirements, 305
foods for special medical purposes, 513–514
Falsified Medicines Directive (FMD), 121–134
scientific advice, 560
active substance GMP, 128
European Generics Medicines Association (EGA),
active substances and excipient definitions, 128t
379
combination therapies, 132
European Initiative for Paediatric Formulations
companion diagnostics, 132
(EuPFI), 100
defining, 122
European Medicines Agency (EMA)
detection and management goals of, 132
accelerated access initiatives, 295–300
EMVS in, 131–132
early access initiatives, 88–89
examples of SFFC medicines, 126
EUnetHTA collaboration, 88–89, 88f
falsified active substances in routes in supply
falsified medicine defined, 121

Index
chain, 125f general principles of regulation, 512

harmonisation of regulation, 124 for specific groups, 512
implementation of, 124–125 Foods for Specific Groups (FSG) Regulation, 512–
implementation process for, 128–129 513, 516
implications and challenges of, 129–131 France
initiatives relevant to, 129t advertising preapproval, 111
key term definitions, 124t HTA in, 82t, 83t
online logo requirements, 128f HTA process in, 85f
problem scope, 122 pricing/reimbursement procedures, 68–69
stakeholder requirements, 124 pricing/reimbursement-HTA assessment
stakeholder requirements under FMD, 127t competent authorities, 68
third countries requirements under, 125, 128, Universal Health Coverage Act (CMU), 67
129t
unique product identifiers and information flow, G
131f
gene therapy medicinal products (GTMPs)
Field Safety Corrective Action (FSCA), 258
clinical development, 466
Field Safety Notices (FSNs), 265
decision tree for classification, 459f
first-in-human (FIH) trials guidance documents, 322
intended use and manipulation criteria, 461
fixed-combination application, 292
manufacturing process, 461–463
follow-up referral, 292
preclinical development, 464–465
Food and Drug Administration (FDA)
General Electrical Safety Standard, 233
collaboration on paediatric products, 100
General Product Safety Directive (GPSD), 259
PSA for MAA/EMA meetings, 49
general safety and performance requirements
Food for Special Medical Purpose (FSMP)
(GSPRs)
Regulation, 512–513
applicable standards identification, 226
food for special medical purposes (FSMPs)
checklist for, 223–224t
communications and claims for, 516
device registration requirements, 216
competent authority notification of marketing,
historical foundations for, 221–222
516
IVDD revision by EU IVDR, 216–217
compositional requirements for, 514–515
manufacturer GSPR demonstration, 187, 238
definition of, 513
predicate device requirement, 227
food information and nutrition information,
referencing applicable standards, 227
515–516
regulatory status of European standards, 225
FSMP critical concepts, 513–514
requirements for, 222, 223
history of use, 511–512
standards and common specifications use for,
legal framework for regulation, 512–514
225
reimbursement, 516
technical documentation, 226–227
single-use plastics directive for, 516
terminology change, 238
food supplements, 501–510
generic medicinal products, 377–392
competent authority notification of marketing,
advertising and promotion, 389
504
biosimilar applications, 383
for food supplements, 505–507
biosimilar medicines, 380
harmonisation of, 507
comparison with innovator medicines and
health claims for, 505
reference products, 377–378
labelling (information to consumers), 503–504
compendial monographs for, 380
legal framework for regulation, 505–507, 512–513
dossier requirements for, 383–386
quality requirements, 503
electronic submission of information for, 390
regulatory summary, 507–508
GCP for, 390
safety assessment of ingredients, 504
GDP for, 389, 390
scope and definitions for regulation, 502–503
GLP for, 390
vitamin/mineral content for safety, 504
GMP for, 389–390
Food Supplements Directive (FSD), 502–504
Good Pharmacovigilance Practices for, 386–387,
foods for special medical purposes (FSMPs),
390
511–518

Index
GPMs for, 379–380 facility requirements, 305

international regulations for, 386 for generic medicinal products, 390
labelling and package leaflet, 388–389 inspections and compliance, 307
legal basis for generic application for MA, medicinal product requirements, 302
381–383, 381t pharmacokinetic studies in vitro, 302–303
manufacture and importation for, 388 pharmacology safety studies, 302
postauthorisation surveillance of, 380 preclinical studies required by, 302–303
PSURs for, 387–388 products covered, 304
RMP for, 387 purpose and relevance guidance, 306–307
supervision and sanctions for, 390–391 Quality Assurance programme, 305
WHO definition of, 377 regulations and guidelines for
wholesale distribution of, 389 toxicity studies, 302
generic/Abridged application, 289–290 reporting study results
genetically modified organisms (GMO) content of study plan, 306
GTMPs, 463 revisions for harmonisation, 307–308
vector use in, 497–498 SOPs for test facility, 306
genotoxicity studies, 303 study performance
Germany study plan and content, 306
competent authorities for pricing// test and reference items
reimbursement and HTA, 69 characterization, 305–306
Gesetzliche Krankenversicherung (GKV), 69 receipt, handling, sampling and storage, 305
HTA in, 82t, 83t test facility organisation
HTA process in, 86f management, 304
medicinal product pricing under AMNOG, 70f principal investigator, 305
pricing/reimbursement procedures, 69–71 study director, 304–305
Safeguard Clause action (catgut), 267 test systems, 305
Global Harmonization Task Force (GHTF) in vivo feasibility and dose testing under, 303
Essential Principles concept, 222 Good Manufacturing Practice (GMP)
guidance document from, 240 biotechnology-derived products, 416
IMDRF succession to, 266 certificate, 119, 369, 390–391
IVD risk classification of IVDs, 212–213 in drug life cycle, 364
risk-based device classification, 206 foods for special medical purposes, 512
STED developed by, 226 for generic medicinal products, 389–390
See also International Medical Device Regulators for herbal medicines, 410
Forum MAH compliance, 119
Good Clinical Practice (GCP) Good Pharmacovigilance Practices (GVPs)
biological product guidance, 490 for biosimilar medicinal products, 400–401
biosimilar clinical comparability demonstration in drug life cycle, 364
for, 396–397 for generic medicinal products, 390
biotechnology-derived products, 416 GVP overview and modules, 439–449, 439t
clinical investigation of devices, 240–241 MA maintenance, 360
in drug life cycle, 364 Module I: PV systems and quality systems,
for generic medicinal products, 390 439–440
legal framework and, 370–371 Module II: PV system master file, 440
Good Distribution Practice (GDP) Module III: PV inspections, 440–442
in drug life cycle, 364 Module IV: PV audits, 442–443
for generic medicinal products, 389, 390 Module IX: signal management, 446–447
inspections for, 371 Module V: risk management systems (RMS), 443
Good Laboratory Practice (GLP) Module VI: adverse reaction management/
ancillary quality system components, 306 reporting, 443
for biosimilar medicinal products, 396 Module VII: PSURs, 443–445
biotechnology-derived products, 416 Module VIII: post authorisation safety studies,
definition, 301 445–446
in drug life cycle, 364 Module X: additional monitoring, 447–448

Index
Module XV: safety communications, 448 role in product market, 78–80

Module XVI: risk minimisation measures, 448– heated sleep apnea device, 234c
449 herbal medicinal product MAA, 292
nonprescription medicinal products, 409 human blood or plasma products, 519–528
Guidance documents batch-release requirements, 525
European Commission Consensus Statements, CHMP working groups, 522
174t Council of Europe publications on, 523
European Commission documents, 174t, 175–176 DG SANTE, 522
MDCG, 185 donation testing for, 523–524
MEDDEV Commission guidance, 172–173t guidelines and documents for, 523–524
NBOG Best Practice Guide, 175t legal framework, 522–523
TEAM-NB, 177 marketing authorisation dossier for, 524–525
plasma master file, 525
H plasma-derived medicinal products, 520–521,
521t
harmonisation
postmarketing pharmacovigilance for, 525
EURD in, 388
registration procedures for, 523
of food supplements, 507
Single European Code structure, 476t
GLP regulations, 307–308
transition to new regulations, 525–526
GSPR compliance demonstration, 225–226
TSE safety evaluation, 524
medical device regulation, 24–25
virus safety evaluation, 524
of SmPC, 342, 345
Human Organ Transplantation Directive, 485
standards for IVDs, 213–216
human tissue products, 471–487
Heads of Medicines Agencies (HMA), 311
ATMP classification, 477
Health Claims (HCs)
classification of, 477–478
food supplements, 505–506, 507
contiguous legislation, 484–485
foods for special medical purposes, 513, 516
distribution and import, 476
health monitoring measures
donation of, 474
actions against general threats to public health,
donor selection and testing, 474–475, 475t
117
EUTCD requirements, 473–474
comparison with Safeguard Clause, 267–268,
legislation on, 473–474
267t
licensing and inspections, 478
Health Problem and Current use of Technology (CUR)
MA authorisation for, 480
HTA model, 80
MA procedure for, 480
Health Technology Assessment (HTA), 77–92
as medical device, 483
comparison in EU countries, 81–84, 83t
pharmacovigilance (PV), 477–478
decision timeline, 87t, 88f
processing and storage, 475–476
EMA and EUnetHTA collaboration, 88
procurement, 474
harmonisation, 84–88
quality system for establishment and responsible
HTA in Member States, 82t
person, 478–479
legal framework, 77–78
regulation, 473, 480–484
models used for: CUR, 80
regulatory framework for, 484t
models used for: ECO, 80
responsible person qualifications/
models used for: EFF, 80
responsibilities, 479t
models used for: ETH, 80–81
tissue establishments and banks, 478
models used for: LEG, 81
traceability, 476–477
models used for: ORG, 81
hybrid applications, 291
models used for: SAF, 80
models used for: SOC, 81
models used for: TEC, 80 I
organisation and structure in EU, 81–84 Identification of Medicinal Products (IDMP), 359
parallel advice for MAA, 49–51 immunogenicity data
pricing and reimbursement, 65–66 advanced therapy medicinal products, 465
role in decision making, 84 biosimilar medicinal product development, 395

Index
biotechnology-derived products, 417–419 International Coalition of Medicines Regulatory

comparability exercise for biosimilars, 396–397, Authorities (ICMRA), 374–375
398 International Conference on Harmonisation (ICH)
pre-licensing product testing, 349 coordination and cooperation enhancement, 117
vaccines, 494, 496 Development Safety Update Report, 312
immunotoxicity studies, 303 guidelines for biotechnology-derived products,
Impact on Clinical Research of European Legislation 416–417
(ICREL), 310 harmonisation of preclinical testing, 302
Importing Directive, 485 pharmaceutical quality systems, 365
In Vitro Diagnostic Medical Devices Regulation (EU PSUR format revision and scheduling, 445
IVDR), 141–149, 189–200 International Electrotechnical Commission (IEC)
in vitro diagnostic (IVD) medical device, 207–220 medical device standards, 230–231, 233–234
accessories, 210 standard use in EU, 164, 177
classification disputes, 203 International Federation of Pharmaceutical
classification process, 201–203 Manufacturers Association (IFPMA)
companion diagnostic (CoDx), 211–212 code of ethics, 103, 105, 107
device performance testing, 210 promotional material approval, 111
essential requirements for, 213 International Generic Drug Regulators Pilot (IGDRP),
EU laws and regulations, 26 386
in-house developed, 211 International Medical Device Regulators Forum
IVD use, 209 (IMDRF)
IVDD and IVDR classification rules, 204–205 consensus standards, 225–226
IVDD and IVDR scope, 208–209 coordination and cooperation enhancement, 117
IVDD revision, 216–217 GHTF basis for, 266
laboratory use products and IVD devices, 210t inspection guidelines, 374
manufacturer process, 211 medical device global vigilance, 266
medical device legislation and classification, International Medical Products Anti-Counterfeiting
208–209 Taskforce (IMPACT), 122, 123t
pan-European requirements, 207 International Organization for Standardization (ISO)
regulations for safety, 217 consensus standards definition by, 225
research-only, 210–211 standard harmonisation, 164, 561
risk-based classification lists for, 212–213 use in preclinical testing, 230
specimen receptacles, 209–210 See also specific standards
specimens examined, 209 International Society of Pharmacoepidemiology
In Vitro Diagnostic Medical Devices Directive (IVDD), (ISPE), 374, 445
184–185 invasive devices: classification rules for (MDR), 190t
In Vitro Diagnostic Medical Devices Regulation (EU Investigational Medicinal Product Dossier (IMPD)
IVDR), 189, 544 biological product guidance, 490
influenza vaccines, 494–496, 495f content requirements for, 490
Information and Work Sharing projects, 386 submission, 330–331
informed consent applications, 292 investigational medicinal products (IMPs), 317
in-house produced devices, 147 Clinical Trials Directive definition of, 315
innovator medicines (originator products), 378–379 clinical trials for, 310
inspection process CTD information in dossier, 330
in drug approval process, 367f documentation requirements for, 490
EudraGMDP database entries, 369 DSURs for, 332
GLP regulations, 307 for FIH trials, 322
pharmaceuticals, 366–369 GMP requirements for, 331
tissue establishment inspections, 478 manufacturing requirements for, 498
installation qualification (IQ), 306 risk-benefit amendment notification, 322
Instructions for Use (IFU) SUSARs/DSURs for, 332
contents for IVDs, 215 ISO 13485
device evaluation and, 238 gap assessment for EU MDR and EU IVDR
international birth date (IBD), 333 transition, 255, 258

Index
harmonised quality system model, 214–215, 226 pharmacovigilance (PV), 438–439

production quality assurance model, 252–253 product legislation, 17–18
QMS requirements, 215 Recommendation, 184
review of feedback, 259, 266, 268 Regulation defined, 184
ISO 14971 lifecycle of drugs
FSCA warning methods, 265 regulations in, 364f
harmonised standards for risk management, 214 research and development (R&D), 22–23
postmarket surveillance and vigilance, 258 local tolerance studies, 303
risk management requirements, 226, 266, 268
Italian Farmaindustria Code, 106 M
Italy
Market Surveillance Operations Group (MSOG), 267
advertising preapproval, 111
Marketing Authorisation Application (MAA)
competent authorities for pricing//
accelerated assessment for, 35
reimbursement and HTA, 72
approval types, 34, 36t
HTA in, 82t
for biosimilar medicinal products, 397–398
pricing/reimbursement procedures, 72–73
for biotechnology derived products, 292
Servizio Sanitario Nazionale (SSN), 72
clarification and discussion meetings, 54–55
communications to EMA, 41–52
J dossier quality section, 280
Joint Action on Market Surveillance (JAMS), 3, 116 EMA meetings during review, 53–60
Joint Immediate Action Plan, 118 EU format and content of, 280
human-veterinary variations, 20–21
L legal basis and dossier requirements, 32–34
legal basis for generic application for MA,
labelling requirements
381–383
combination products, 551
medicinal product application types, 289–292,
food for special medical purposes (FSMPs),
290t, 291–292
515–516
for medicinal products, 279–284
for food for special medical purposes (FSMPs),
PIP requirements, 94–95, 98–100
516
prior EMA meetings for, 41–52
food supplements, 503–504
procedural steps and EMA meetings, 42–47
language for IVDs, 215–216
procedure timelines for, 55f, 57f
Legal Aspects (LEG) HTA model, 81
procedures for, 34–35
legal framework/legislation
scientific advice and protocol assistance, 37–38
for adaptive and alternative pathways, 296–298
Scientific Advice review, 54
Advanced Therapy Medicinal Products (ATMPs),
Scientific committee role in review, 53, 54t
451–470, 480
Marketing Authorisation Holder (MAH)
ATMP Regulation, 453–456
advertising to general public, 108
clinical trial improvements, 312f
advertising to healthcare professionals, 105
clinical trials, 311
definition of, 279
Directive defined, 184
EMVO, 119
for food supplements, 505–507
GMP compliance, 119
foods for special medical purposes and special
MA maintenance, 359
groups, 512–514
obligations for medicinal products, 282, 284,
herbal medicinal products, 409–410
289
human blood or plasma products, 522–523
paediatric products, 99–100
PIP preparation, 94–95
MAA, 32–34
product failure responsibility and liability, 342
mechanism for medicinal products for human
renewal date agreement with Reference Member
use, 18–19
State, 424
medical devices, 141–149, 150–182, 183–206
responsibilities and obligations for medicinal
medical product, 18
products, 279–280
Opinion, 184
role in various application types, 292
orphan medicinal products, 530

Index
scientific service implementation, 111 legislative process, 150 –152, 153f

submission of information for generic products, manufacturer role in, 171
390 market surveillance, 117–118
worksharing, 359 MDD and EU MDR device definitions, 168t
Marketing Authorisation (MA) MEDDEV guidance documents, 171–172t
adaptive and alternative pathways, 295–300 medical device laws, 165–170
food supplements, 504 national enforcement, 177–178
for generic medicinal products, 391 new approach regulatory philosophy, 153–154,
human tissue products, 480 154t
regulatory strategy for, 138 new legislative framework (NLF), 157
See also Centralised Procedure; Mutual regulation evolution and harmonisation, 23–25
Recognition Procedure; National Procedure See also EU MDR and EU IVDR; specific devices
maximum tolerated dose (MTD), 302 medical device legislation and classification,
MEDDEV guidance documents 183–206
authorised representatives, 143 basic principles of application, 189–190
clinical evidence, trials, and regulatory classification disputes, 203
compliance, 144, 146 classification matrix, 188t
revisions and updates, 118 comparison of EU MDR and MDD rules, 195–200t
Medical Device Coordination Group (MDCG) EU MDR and MDD rules, 200–201
borderline combination products, 545 human tissue/cell products with, 483
centralised governance, 159, 165 IVD classification process, 201–203, 202t
classification disputes, 203–205 IVDD and IVDR rule comparison, 204–205t
CTS adoption by implementing act, 214 key concepts for classification, 191, 193
decisions on product qualification, 142 MDR rules for invasive devices, 190t
device classification determination, 142 MDR rules: special, 192t
enforcement and surveillance, 146–148, 159, 178 medical devices directives, 184–185
regulatory classification determination, 545, medical devices definition and expansion of,
548–549, 551 185–186
regulatory strategy development, 138 non-invasive devices rules, 189t
regulatory strategy information, 138 regulatory framework definitions, 184
responsibilities of, 176–177 requirements, 186–187
revised guidance from, 230 rule-based approach for, 187–189
Medical Devices Directive transition to EU MDR and EU IVDR, 185
repeal of, 184–185 unclassified devices, 188
transition from, 178 (see also EU MDR and EU in vitro diagnostic regulation, 189
IVDR) medical device national particularities
medical device legal system CE marking for, 271
adaptive and alternative pathways, 298 directives and regulations for, 272t
clinical evaluation cycles, 159f EU outermost regions, 272t
Commission as an arbitrator, 177 language and labeling, 272–274
compliance verification, 155 national languages, 274t
conformity assessment for AIMDs, 157f notification requirements, 274–275
conformity assessment for IVD, 158f translation requirements, 273t
conformity assessment procedures, 156f See also pricing and reimbursement
custom-made devices, 165–171 Medical Device Vigilance System, 258, 261
development, 25–26 Medical Devices Coordination Group (MDCG), 159
EC working groups and activities, 166–167t Medical Devices Regulation (EU MDR), 141–149
EMA in, 164 Medicinal Product Directive (MPD), 18, 32, 506
enforcement, 117 medicinal products for human use
enforcement and competent authorities, 117–118 adaptive and alternative pathways, 296–298
Essential Requirements and technical standards, bibliographic applications/well-established use,
177 291–292
essential requirements compliance, 155–159 clinical trials for, 309–340
industrial trade associations, 167t Complete/Full and Independent, 289

Index
decentralised procedures, 290t comparison of pathways for nonprescription

enforcement, 119–120 products, 406f
enforcement and competent authorities, 118–120 criteria for use of, 19, 285
factors affecting pricing, 62f evaluation of products, 14
fixed-combination application, 292 flowchart for, 287f
generic/Abridged, 289–290 for generic products, 381
herbal medicinal products, 292 human blood/plasma postmarket
hybrid applications, 291 pharmacovigilance, 525
informed consent applications, 292 MAA procedure with, 357f
legislation in EU, 18–19 medicinal product registration, 341
Marketing Authorisation Application, 289–292 for medicinal products, 287t
mixed marketing, 292 multiplication/duplication of applications, 289
medicinal products MAA applications nonprescription products, 405
bibliographic applications/well-established use, phases and timeline for medicinal products,
291–292 285–287
Complete/Full and Independent, 289 postauthorisation requirements for
decentralised procedures, 290t biotechnology products, 424–425
fixed-combination application, 292 product registration, 356–357
generic/Abridged, 289–290 Reference Member State selection, 287–288
herbal medicinal products, 292 registration for human blood/plasma products,
hybrid applications, 291 523
informed consent applications, 292 registration for medicinal products, 289, 345,
mixed marketing, 292 356
Medicines and Healthcare products Regulatory regulatory dossier assessment, 356–357
Agency (MHRA) regulatory information resources for, 554
joint inspection programs, 372–373 submissions and Reference Member State role
Medicines for Europe, 379 and timeline, 286–287
Member States Mutual Recognition Regulation, 502–503, 506
clinical trial authorisation procedures in, 324 mutual recognition/decentralised procedure
clinical trial safety procedures, 323 referral, 293
competent authorities and affiliated countries,
161–163t N
competent authorities marketing guidelines,
national authorizations, medicinal products, 289
278–279
national competent authorities, 115–120
enforcement by competent authorities, 115–120
action on medical device safety, 117–118
EU MDR and ER IVDR significance for, 159–164
application for clinical trial authorisation,
GLP regulations in, 302
320–323
interim device actions under Safeguard Clause,
clinical trial application, 321t
267
cooperation and coordination for enforcement,
Marketing Authorisation Application in, 19
116–117
See also Concerned Member States; national
coordination and cooperation enhancement, 117
competent authorities
generic medicinal product safety, 390–391
mixed marketing, 292
inspection process, 366
Mutual Acceptance of Data (MAD) system, 302, 370
listing of, 562–563t
Mutual Recognition Agreements (MRAs)
medical devices, 117
for generic product GMP inspections, 379–380
member states and affiliated countries, 161–163t
for inspections, 371
national regulatory bodies, 116
Mutual Recognition Facilitation Group (MRFG), 286
pharmaceutical quality and inspections, 365–369
Mutual Recognition Procedure (MRP)
pricing and reimbursement and HTA, 366
application format for, 281
tissue establishment inspections, 478
authorisation of medicinal products, 285–287
National Medicines Regulatory Authorities (NMRA),
biosimilar medicinal product registration, 381
130
biotechnology-derived product marketing
National Medicines Verification Organisations
authorisation, 413

Index
(NMVOs), 132 Official Control Authority Batch Release (OCABR)

National Procedure batch-release requirements, 493
biosimilar medicinal product registration, 397 EDQM procedures for, 522
comparison of pathways for nonprescription plasma products, 525
products, 406f Official Medicines Control Laboratories (OMCL)
generic medicinal products, 381 blood/plasma product testing, 522
human blood/plasma products, 523 postmarketing lot release, 493
MAA procedure with, 357f vaccine testing by, 490
marketing authorisation for medicinal products, operational qualification (OQ), 306
19 Opinion, defined, 184
medical product registration, 345–346 Oral Explanation (OE) meeting
medicinal product registration, 357 purpose of, 55
nonprescription medicinal products, 405 Organisation for Economic Co-operation and
product registration, 345–346, 356–357 Development (OECD)
regulatory dossier assessment, 357 EMA collaboration, 10
variability of, 285 GLP guidelines, 327, 375, 390
new chemical entity (NCE): preclinical test plan, 302 harmonisation of preclinical testing, 302–304
new legislative framework (NLF) for devices, 157 mutual acceptance of data system, 370
nonclinical pharmacodynamics, 235c Organisational Aspects (ORG) HTA model, 81
nonclinical studies. See Good Laboratory Practice; Orphan Drug Act, 529
preclinical testing Orphan Medicinal Products (OMP) Regulation
non-invasive devices: classification rules for (MDR), COMP established by, 531–532
189t product designation procedure, 535
noninvestigational medicinal products (NIMPs) significant benefit concept in, 536–537
defined, 315 similar medicinal product and clinical superiority
SUSARs for, 332 in, 537
nonprescription medicinal products, 403–412 orphan medicinal products (OMPs), 529–542
advertising and promotion, 408–409 annual report requirement, 534
advertising to general public, 409 application evaluation and timetable for, 533
common uses of, 405t conditional marketing authorisation for, 538
definition of, 404 designation expiry, 535
herbal medicinal products, 409–410 designation procedure application, 532–533
legal basis of MAA, 405 designation request content, 535–536
legislation of, 404 EU laws and regulations, 38
marketing access pathways for, 404–405, 406t European Commission decision, 533–534
pharmacovigilance and safety reporting, 409 harmonisation efforts, 530
product information and labelling, 405–407 incentives for development, 530–531
reclassification from prescription to, 407–408 legal framework, 530
role in self-care, 404 MAA for designation product, 536–537, 538
successful switch strategy for, 408 medical plausibility for request and prevalence,
warning statements and guidance for, 407 536
Notified Bodies: responsibilities of, 118 orphan designation benefits, 342
Notified Body Operations Group (NBOG) orphan designation benefits and criteria, 8, 38,
best practices guides, 175t 530, 534f
guidance document from, 175, 185–186 parallel applications, 533
Novel Foods Regulation, 504 pathways for expedited development and
Nutrition and Health Claims Regulation (NHCR) approval, 538
(Regulation (EC) No. 1924/2006), 505 significant benefit concept in, 536–537
Nutrition Claims (NCs), 505 similar medicinal product and clinical superiority
in, 537
O sponsorship transfer, 535
over-the-counter (OTC) medicines. See
office based evaluation and risk assessment
nonprescription medicinal products
(OBERA), 371
advertising to general public, 108

Index
Own-Brand Labelling (OBL), 146–147 codification/clarification, 19

development of regulatory system, 20
P human-veterinary MAA variations, 20
Pharmaceutical Inspection Convention (PIC), 117,
Paediatric Committee (PDCO), 95, 343
373
Paediatric Investigation Plan (PIP)
Pharmaceutical Inspection Co-operation Scheme
Marketing Authorisation Holder, 94–95
(PIC/S)
submission procedures in, 97–99, 98f
for generic products, 379–380
paediatric product regulation
participants in (list), 373–375
application procedure, 97–99
pharmacodynamic (PD) testing: biosimilars, 395
background and scope, 93–94
pharmacokinetic (PK) testing
compliance check, 99
for biosimilar medicinal products, 395
deferrals, 96–97
with combination product, 235c
Marketing Authorisation Holder, 99–100
pharmacovigilance (PV)
PDCO, 95
EC definition and development of, 438
PIPs, 94–95
fees, 449
population and product definitions, 94
GVP overview and modules, 439t
product development under, 100–101
research incentives, 99
ICSR expedited submission requirements, 445f
waivers, 95–96
legal framework, 438–439
Paediatric Regulation, 93–94
notification of withdrawn products, 449
Paediatric Use Marketing Authorisation (PUMA), 94
risk management plan modules, 444t
Parallel Scientific Advice (PSA), 49
signal management lifecycle, 447f
particular nutritional uses (PARNUTs), 512
system master file (PSMF) contents, 441f
Patients and Social Aspects (SOC) HTA model, 81
vaccines, 493
performance qualification (PQ), 306
Pharmacovigilance Regulation, 493
Periodic Benefit-Risk Evaluation Report (PBRER)
Pharmacovigilance Risk Assessment Committee
EU format for, 445
(PRAC)
format for, 443, 444t
communications, 56
ICH guideline for, 445
coordination and cooperation enhancement, 117
Periodic Safety Update Report (PSUR)
MA maintenance, 360
benefit-risk balance, 387–388, 401, 425–426,
MAA review, 53–54, 54t
449
photo-safety testing, 303
Plasma Master File (PMF), 280
device technical documentation, 227
plasma master file (PMF), 280, 525
frequency of, 416
Post Market Clinical Follow-up (PMCF), 238
MAH submission of, 443
postauthorisation requirements (pharmaceutical)
PMCF in, 261
annual re-assessment
postmarketing safety assessment, 425, 428, 429
assessment procedures, 431
PSUR format revision and scheduling, 445
dossier requirements for, 430–431
renewal procedures and, 436
for biotechnology-derived products, 424–425
requirements for, 440
centrally approved product renewal
RMP update, 447
assessment procedure, 429–430
sharing through Eudamed, 118
dossier requirements for, 426
submission and review process for, 360
legal framework for, 421, 424–425
submission of, 443–445
major changes/extension application, 435
submission to EMA, 353
MRP/DCP product renewal, 424–425
synchronization with other reports, 333, 426, 445
assessment procedures, 426
for technical documentation, 227
dossier requirements for, 425
validated signals in, 447
other postauthorisation measures and
Periodic Safety Update Single Assessment (PSUSA)
enforcement, 431
submission to EMA, 353
re-examination, 430
pharmaceutical directives
vaccines, 492–493
ATMPs, 21–22
variations

Index
assessment/notifications for, 433–435 61–62

dossier requirements for, 431–433 food for special medical purposes (FSMPs), 516
postauthorisation safety studies (PASS), 324 legal framework, 62–63
for biosimilar medicinal products, 401 link between models and HTA, 67–74
postmarket clinical follow-up (PMCF) models and HTA case studies, 67–74
Class III and implantable devices, 238–239, models for, 64
260–261 cost-based pricing, 63–64
for clinical efficacy evaluation, 298 reference-based, 63, 65t
manufacturer’s obligations for, 157 value-based pricing, 64
use in clinical strategy, 240 pricing factors for, 62f
postmarket surveillance (PMS), 260 reference pricing system for generic products,
device technical documentation, 227 377–378
for generic medicinal products, 380 reimbursement, 65–67
manufacturer, 117–118 vaccines, 498
postmarket surveillance requirements primary mode of action (PMOA), combination
combination products, 551 products, 544–545
Potential Serious Risk for Public Health (PSRPH) PRIME (PRIority MEdicines)
application withdrawal in DCP, 345 HTA/EMA collaboration for, 89
preclinical testing laws and regulations, 36–37
GLP regulations in, 301 promotion. See advertising and promotion
OECD GLP principles, 303–304
See also Good Laboratory Practice; medical Q
device preclinical testing
Qualified Person (QP/QPPV)
preclinical testing of devices
biocompatibility testing, 231, 234c, 235c
GMP certification, 331
Design Traceability Matrix for, 231
for human tissues/ATMPs, 479t
electrical safety and magnetic disturbance
pharmacovigilance (PV), 439
testing, 233
pharmacovigilance for medicinal products, 280
nonclinical studies, 231, 235
postmarket pharmaceutical compliance, 426–427
packaging validation, 232
PSMF and, 387
performance testing, 231
in recall decisions, 119
preclinical test plan
signal management, 446
regulatory requirements, 230
tissue establishment, 479
standards requirements, 230
vaccine development, 490
user requirements, 230
vaccine release, 490
risk management requirements, 230
See also responsible person (RP)
shelf life (aging) studies, 233
Quality Assurance (QA) programme
software verification and validation, 233
GLP requirements, 305
statistical methods, 234
Quality Management System (QMS)
sterilisation validation, 232–233
assessors and inspector relationship in, 364–
transport studies, 232
365, 365f
usability (human factors) studies, 233
for clinical evaluation procedures, 240
predicate device
in clinical investigation and evaluations, 240
GSPRs requirements, 227
in clinical trial protocol, 330
preliminary assessment report (PrAR)
for combination products, 550–551
Reference Member State (RMS) authoring of,
in conformity assessment, 248
355–356
conformity assessment in, 136
Prescription Medicines Code of Practice Authority
EU IVDR requirements, 215
(PMCPA), 111
human tissue products regulation, 473
pricing and reimbursement, 61–76
ICH QMS requirements, 365
containment policies of Member States, 67f
pharmacovigilance factors for, 440
current trends, 67
PMS requirements, 118
economic evaluations, 66, 66f
postmarket surveillance in, 117–118, 259
factors affecting pricing for medicinal products,

Index
regulatory strategy for, 138 Mutual Recognition Procedure (MRP), 345,

technical documentation for, 226 356–357
quality review of documents (QRD) Mutual Recognition Procedure phase 2 timeline,
labelling templates, 407, 415 286
medicinal product authorisation procedures, 281, Mutual Recognition Procedure role, 286
351, 358 PrAP from, 355
SmPC information requirements, 388, 448 renewal date agreement with MAH, 424
templates in Centralised Procedure, 415 selection for MAA, 285
quality systems and inspectorate process selection of, 336
assessors and inspector relationship in, 365f worksharing for MA maintenance, 359
British Pharmacopoeia (BP), 373 reference-based pricing model, 63, 65t
EDQM inspection process, 369 referrals
Eurasian Economic Union, 374 community interest referral, 293
European Pharmacopoeia (Ph. Eur.), 373 divergent decision referral, 293
GCP inspections, 370–371 European community referral, 292
GDP inspections, 371 follow-up referral, 292
for generic medicinal products, 390 generic medicinal product evaluation, 381
GLP inspections, 370 mutual recognition/decentralised procedure
GMP inspections, 367–369 referral, 293
GMP/GDP Inspectors Working Group, 370 registration of medicinal products, 341–362
ICMRA, 374 accelerated assessment, 347
industry associations, 374 adaptive pathway, 346
for IVDs, 214–215 ASMF for, 350
joint inspection program participants, 372–373 bibliographic applications/well-established use,
legal framework for, 366, 366f 349
list of other agency inspections, 371 of biosimilar medicinal products, 397–399
MRAs for inspections, 371 biosimilar medicinal products, 397–399
OECD, 375 for biotechnology-derived product, 414–415
pharmaceutical regulation evolution, 363–364 for biotechnology-derived products, 414–415
pharmacopeial compendia, 373 Certificate(s) of Suitability, 352
PIC/S, 373 combination products, 544
requirements for EU, 365 conditional approval, 346
Swiss Pharmacopoeia (Ph. Helv.), 373 conditional authorisation, 346
Quality-Adjusted Life Years (QUALYs) content of submissions, 351, 351t
in HTA assessment, 84 eCTD envelope and CTD format, 351–352
in pricing and reimbursement, 66 exceptional circumstances, 346–347
fixed combination, 349
R full registration, 348
generic products, 391
reference medicine, 377
generic registration, 348
pharmacopoeial compendia for API, 380
for human blood or plasma products, 523
Reference Member State (RMS)
hybrid registration, 348
business validation and checklist for, 354
informed consent, 349
DCP role of, 355–356
MA maintenance, 359–360
Decentralised Procedure applications role and
MAA application types, 347–350
timeline, 287–288
MAH liability and, 342
decentralised procedure role, 344
materials of human/animal origin, 352
follow-up referral, 292
mixed marketing, 350
initial product assessment, 342
orphan medicinal products, 342–343
MAA evaluation, 19
other documentation, 358–359
MAA presubmission meetings, 347
paediatric investigations, 343–344
mutual recognition and decentralised procedure
presubmission meeting request, 347
referrals, 293
procedure types, 344–345
PSURs and PSUSAs, 360

Index
questions on dossier, 358 medical product legislation in Eudralex, 554–555

referrals, 360 national competent authorities listing, 562–563t
regulatory dossier changes/variations, 359 professional association/organisations, 564
regulatory dossier submission, 352–353 regulators outside the EU, 565
regulatory dossier validation, 353–354 regulatory system for medicines, 553–554
routes for, 523 social networking and mobile apps, 571–572
scientific advice, 343 regulatory strategy
scientific advice application, 350–351 confirming strategy, 138–139
similar biological registration, 348–349 developing and implementing, 136–138
urgent safety restrictions, 360 documentation of, 138–139
Regulation defined, 184, 366 information resources for development, 138
regulatory authorities key questions during development, 137t
Council of Europe, 365 market considerations in, 135–136
EMA, 1–5, 7–10 prescription to nonprescription strategy, 408
European Commission (EC), 365 review/update of, 139
European Medicines Agency (EMA), 365 reimbursement. See pricing and reimbursement
European Medicines Regulatory Network, 5–7 Reporting Member State
Task Force for Relations with the United Kingdom clinical trial authorisation process, 311, 324–326
(UKTF), 364, 366 low-intervention clinical trial determination, 329
regulatory dossier reprocessing, 147
for blood/plasma products, 524–525 reproductive studies, 303
Centralised Procedure, medicinal products, 354 responsible person (RP)
changes/variations for medicinal products, 359 generic products, 386
Decentralised Procedure (DCP), medicinal tissue quality systems, 478–479, 479t
products, 355–356 See also Qualified Person (QP)
for IVD design, 215 risk management plan (RMP), 425
Mutual Recognition Procedure (MRP), medicinal adaptive pathways and, 346
products, 356–357 for Advanced Therapy Medicinal Products
National Procedure, medicinal products, 357 (ATMPs), 466–467
submission for medicinal products, 352–353 for ATMPs, 466–467
validation for medicinal products, 353–354 biocompatibility testing, 230–231
REgulatory FITness and performance programme in device industry, 260
(REFIT), 502, 506 generic medicinal products, 387
regulatory information resources, 553–574 pharmacovigilance modules, 444t
agencies and committees, 557–561 preclinical device testing, 230
association electronic media, 569–570 requirements for, 440
book publishers, 567–568 See also ISO 14971; pharmacovigilance
commercial and government databases online,
565–567 S
continued learning and associations, 570
Safeguard Clause
core SmPC guidance for vaccines, 496
action by Member States, 267
Council of Europe publications on blood/plasma
action on conforming devices, 117
products, 523–524
comparison of health monitoring measures,
device regulation, 555–556
267–268, 267t
EDQM databases, 567t
Safety (SAF) HTA model, 80
EMA committees and working parties, 558–559t
safety measures in clinical trials, 323
EU and international organisations, 561–564
scientific advice and protocol assistance
EU laws and regulations, 556–557
for MAA, 37–38
framework for medicinal products, human use,
review before EMA meeting, 48
554
Scientific Advice Working Party (SAWP), 37
global regulatory coverage databases, 567–568
Scientific Advisory Group (SAG) meeting, 55–56
industry resources in electronic newsletters, 569
scientific committees (EMA)
industry stakeholder organisation, 565t
MAA review, 53, 54t
innovative medicines initiative (IMI), 564

Index
scientific service implementation, 111 paediatric medicinal products, 94

serious adverse events (SARs) for IMPs and NIMPs, protection of innovator medicine by, 379
332 supply chain controls: new MDR and IVDD
Single European Code (SEC), 476t, 485 regulation, 142–143
single-use plastics directive, 516 suspected unexpected serious adverse reactions
software (SUSARs)
EU MDR and EU IVDR reclassification of, 142, 146, electronic reporting, 318
167 reporting, 332–333
GSPRs requirements, 222, 231 Swiss Pharmacopoeia (Ph. Helv.)
with medical devices, 26, 186, 200–201, 208, quality systems and inspectorate process, 373
545
preclinical device testing, 233 T
verification and validation of, 233, 234c
technical documentation
vigilance for, 261
of Essential Requirements compliance, 215
somatic cell therapy medicinal products (sCTMPs)
EU MDR and EU IVDR, 226–227
clinical development, 465–466
for IVDs, 215
intended use and manipulation criteria, 460–461
“the garlic case”, 506
manufacturing process, 462
therapeutic interchangeability
preclinical development, 463–464
biosimilar medicinal products, 22, 399
Spain
tissue-engineered products (TEPS)
competent authorities for pricing//
clinical development, 466
reimbursement and HTA, 71
decision tree for classification, 458f
HTA in, 82t, 83t
intended use and manipulation criteria, 461
National Health Service (SNS), 71
manufacturing process, 463
pricing/reimbursement procedures, 71–72
preclinical development, 465
Spurious/Falsely-Labelled/Falsified/Counterfeit
toxicity studies
(SFFC) medicines, 121, 126, 129t, 132
Standard Assessment Review Timeline
preclinical device testing, 235c
EMA meeting preparation, MAA review, 55f
preclinical testing, 302
Standard Operating Procedures (SOPs), 306
traceability
Summary of Product Characteristics (SmPC)
new regulations, 143–144
advertising and promotion compliance, 104–107,
SEC for tissues/ATMPs, 485
109
Traditional Herbal Medicinal Product Directive
changes affecting safety, 360, 399–401, 424–
(THMPD), 409–410, 503, 506
425, 432 (see also pharmacovigilance)
traditional herbal medicinal products: regulation
generic and reference products, 33, 379, 382–
evolution, 23
383
Transmissible Spongiform Encephalopathy (TSE)
human blood or plasma products, 522
biotechnology-derived products, 417–418
as IMPD, 331
blood and plasma evaluation for, 15, 524
in MAA, 35
Transparency Directive, 17, 62–63, 498, 560
medicinal product MA maintenance, 279–280,
Treaty on the Functioning of the EU, 62
286–289, 292
trend reporting, 265
national competent authority product
authorisation, 320
product labelling, 388, 407, 427 U
QRD review, 358–359 unique device identifiers (UDI), 138, 143, 215, 268,
for vaccines, 491, 492, 496 485
See also specific application procedures United Kingdom (UK)
Summary of Safety and Clinical Performance (SSCP), advertising and promotion, 111–112
238 assessors and inspector relationship in, 364–365
Summary Technical Documentation (STED), 226– Brexit effects for quality management, 364–365
227 Brexit impact on medical devices, 272
Supplementary Protection Certificate (SPC) competent authorities for pricing/reimbursement
paediatric investigation incentives, 344 and HTA, 73

Index
HTA in, 82t, 83t pharmaceutical regulation evolution, 22–23

implementation of ECTR in, 315 regulatory agencies for, 2–3, 4–5, 365–366
National Health Service (NHS), 73 regulatory principles, 22–23
pricing/reimbursement procedures, 73–74 scientific advice and protocol assistance, 48
United States (US): GLP regulations in, 302 variations to MAAs, 20–21
Urgent Safety Restriction (USR) See also specific application procedures
biosimilar medicinal products, 400 vigilance procedures for IVDs, 214–215
dossier requirements for, 426 viral clearance, 418
timeframe for implementation, 432–433 Voluntary Harmonisation Procedure (VHP)
variation classification and, 436 CTFG and, 336
usability testing, 234c implementation and guidance for, 313
V W
vaccine adverse event reporting system (VAERS), worksharing in market authorisation maintenance,
493 359
Vaccine Antigen Master File (VAMF) World Health Organization (WHO)
development processes for, 491, 492 falsified medicine initiative/IMPACT, 122, 564
EU regulations, 21 generic medicinal product definition, 377
veterinary vaccines, 23 Global Surveillance and Monitoring System
vaccines, 489–500 (GSMS), 130
adjuvants in, 496–497 HTA definition by, 66
classification and development pathway, 489– International Clinical Trials Registry Platform
490 (WHO ICTRP), 335
clinical studies, 492 paediatric medicine initiative, 100
CTA for, 490–491 pandemic vaccine development and, 496
DNA and therapeutic vaccines/GMO-based, wrongly affixed CE-marking, 117
497–498
GMO-based vaccines, 497–498
guidance on, 496
immunomodulators in, 497
licensure, 492–498
lot release, 492
manufacturing process, 490–491
nonclinical studies, 491–492
overview, 498
pandemic influenza, 496
pharmacovigilance (PV), 493
pricing and reimbursement, 498
seasonal influenza vaccines, 494–495, 495f
for special populations, 494
vaccines, 492–493
VAMF, 491
VAMF certification, 491t
VAMF certification and requirements, 21
vector use in, 497
value-based pricing model, 64
veterinary medicinal products
CMDv, 18
CVMP role in authorisation, 8
GMP inspections for, 373–374
national competent authorities for, 6–7
OMCLs testing, 522

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Fundamentals of EU Regulatory Affairs 9th Edition

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Regulatory Affairs Professionals Society i

Sharry Arora, MPharm Kell Cannon Kate Dion

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Chapter 2 History of Regulations........................................................................................................................13

Chapter 3 Overview of Drug and Biologic Regulatory Pathways........................................................................31

Chapter 6 Pricing and Reimbursement................................................................................................................61

Chapter 7 Health Technology Assessment (HTA)..............................................................................................77

Chapter 8 The Paediatric Regulation...................................................................................................................93

Chapter 9 Advertising and Promotion...............................................................................................................103

Chapter 10 Enforcement and Competent Authorities........................................................................................115

Chapter 11 Falsified Medicines Directive: Requirements and Implications for

Chapter 12 Regulatory Strategy..........................................................................................................................135

Section II: Medical Devices

Chapter 14 The European Medical Devices Legal System..................................................................................151

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Chapter 16 In Vitro Diagnostic Medical Devices................................................................................................207

Chapter 17 General Safety and Performance Requirements and Technical Documentation

Chapter 18 Medical Device Preclinical Testing...................................................................................................229

Chapter 19 Clinical Evaluation and Clinical Investigations................................................................................237

Chapter 20 Medical Device Conformity Assessment Procedure.........................................................................243

Chapter 21 Medical Device Compliance: Postmarket Requirements..................................................................257

Chapter 22 Medical Device National Particularities............................................................................................271

Section III: Medicinal Products

Chapter 24 Adaptive and Alternative Pathways..................................................................................................295

Chapter 25 Preclinical Testing and Good Laboratory Practice Regulations........................................................301

Chapter 26 Medicinal Product Clinical Trials.....................................................................................................309

Chapter 27 Registration Procedures for Medicinal Products...............................................................................341

Chapter 28 Quality Systems and Inspectorate Process—Pharmaceuticals..........................................................363

Chapter 29 Generic Medicinal Products.............................................................................................................377

Chapter 30 Biosimilar Medicinal Products..........................................................................................................393

Chapter 31 Nonprescription Medicinal Products................................................................................................403

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Chapter 33 Pharmaceutical Postauthorisation Requirements and Compliance With the

Chapter 35 Regulatory Framework for Advanced Therapy Medicinal Products .................................................451

Chapter 36 Human Tissue Regulation................................................................................................................471

Section IV: Foods

Chapter 39 Food for Special Medical Purposes...................................................................................................511

Section V: Other Product Classifications

Chapter 41 Orphan Medicinal Products.............................................................................................................529

Chapter 42 Combination Products......................................................................................................................543

Section VI: Resources

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EMA and Other

OBJECTIVES □ Directive 2012/26/EU of the European

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Figure 1-1. EMA Mission

Protect Human and Animal Health

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• Ministry of Health, Via Giorgio Ribotta 5, • Medical Products Agency, Dag

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Pharmacovigilance Risk Assessment Committee focuses on establishing EU monographs covering the