Table of Contents

SECTION I: Fundamentals of US Medical Device Regulations

Chapter 1 History of Food, Drug and Cosmetic Laws......................................................................................................................1
Updated by Meredith Brown-Tuttle, RAC, FRAPS

Chapter 2 Overview of Drug, Biologic, Device, Combination Product or Food Regulatory Pathways............................................13
Updated by Michael R. Hamrell, PhD, RQAP-GCP, CCRA, FACRP, RAC, FRAPS

Chapter 3 Clinical Trials: GCPs, Regulations and Compliance for Drugs, Biologics and Medical Devices......................................45
Updated by Monique Carter, MS, RAC and Samantha Zappia, MS, RAC

Chapter 4 Current Good Manufacturing Practices and Quality System Design..............................................................................83

Updated by Joscelyn Bowersock, MS-RA, and Richard Vincins, CQP, MCQL, CBA, CQA, RAC

Chapter 5 Medical Device Submissions..........................................................................................................................................99

Updated by Maria Connolly, MPharm and Thomas McNamara, MSE, RAC

Chapter 6 Medical Device Compliance and Postmarketing Activities...........................................................................................127

Updated by Ryan Burke, RAC and Elizabeth Goldstein, RAC

Chapter 7 In Vitro Diagnostics Submissions and Compliance......................................................................................................139

Updated by Jocelyn Jennings, MS, RAC

Chapter 8 Advertising, Promotion and Labeling for Medical Devices and In Vitro Diagnostics (IVDs)........................................149
Updated by Carol M. Cooper, MS, IM(ASCP), RM(AAM), RAC

Appendices
Glossary of Terms...............................................................................................................................................................................159
Index of Laws and Guidances.............................................................................................................................................................183
Index by Subject.................................................................................................................................................................................187

FIgures
Figure 2-1. Decision Tree for Drug and Device Development and Approval When FDA Premarket Review is Required..................21
Figure 2-2. CTD Organization........................................................................................................................................................27
Figure 3-1. Types of Pharmaceutical and Biologic Clinical Trials and Typical Pathway.....................................................................54
Figure 3-2. Types of Medical Device Clinical Trials and Typical Pathway.........................................................................................67
Figure 4-1. Quality System Documentation Elements......................................................................................................................85
Figure 4-2. Design Control “V” Model Process Flow.......................................................................................................................86

Tables
Table 1-1. Electronic Resources for US Laws and Regulations..........................................................................................................3
Table 1-2. Other Laws, Regulations and Guidelines........................................................................................................................10
Table 2-1. Title 21 CFR Parts.........................................................................................................................................................20

Fundamentals of Medical Device Regulations iii

Table 2-2. Key Questions in a Drug Development Program...........................................................................................................23
Table 2-3. IND Safety Reporting Timeframes................................................................................................................................29
Table 2-4. Summary of Device Classification System......................................................................................................................36
Table 3-1. Significant Legislation Relevant to Clinical Trials in the US...........................................................................................48
Table 3-2. Comparison of 21 CFR and ISO-GCP Requirements for Protocol Deviations in Medical Device Clinical Trials...........52
Table 3-3. Comparison of 21 CFR and ISO GCP Requirements for Investigator Responsibilities in Medical Device
Clinical Trials.................................................................................................................................................................73
Table 3-4. Comparison of 21 CFR and ISO-GCP Requirements for Recordkeeping in Medical Device Clinical Trials...................74
Table 3-5. Comparison of 21 CFR and ISO-GCP Requirements for Device Accountability in Medical Device Clinical Trials ������75
Table 5-1. Device Classification Summary of Requirements..........................................................................................................103
Table 5-2. Typical Data Requirements Based on Device Class.......................................................................................................105
Table 5-3. Typical Device Studies Covered Under the IDE Regulation.........................................................................................106
Table 6-1. Domestic Establishments.............................................................................................................................................129
Table 6-2. Foreign Establishments................................................................................................................................................130
Table 6-3. Annual Registration Process.........................................................................................................................................136

SECTION II: Fundamentals of EU Medical Device Regulations

Chapter 1 EMA and Other Regulatory Bodies...................................................................................................................... 1
Updated by Ratinder Dhami, MSRA, RAC

Chapter 2 History of EU Regulations................................................................................................................................... 13

Updated by Sabina Hoekstra-van den Bosch, PharmD, FRAPS

Chapter 3 Advertising and Promotion.................................................................................................................................. 31

Updated by Karen Zhou, JD, MS, RAC

Chapter 4 Enforcement and Competent Authorities............................................................................................................ 43

Updated by Sabina Hoekstra-van den Bosch, PharmD, FRAPS

Chapter 5 Regulatory Strategy.............................................................................................................................................. 49

Updated by Karen Fan, MSc, PEng, RAC

Chapter 6 The New Medical Devices Regulation and In Vitro Diagnostic Medical Devices Regulation............................. 55
Updated by Gert Bos, MSc, PhD, FRAPS and Erik Vollebregt, LLM

Chapter 7 The European Medical Devices Legal System..................................................................................................... 65

Updated by Gert Bos, MSc, PhD, FRAPS and Erik Vollebregt, LLM

Chapter 8 Medical Devices: Legislation and Classification.................................................................................................. 97

Updated by Ruthanne Vendy, RAC and Chauneen Leah Wood, MS, RAC

Chapter 9 In Vitro Diagnostic Medical Devices................................................................................................................. 121

Updated by Erik Vollebregt, LLM

Chapter 10 General Safety and Performance Requirements and Technical Documentation

(EU MDR, EU IVDR)....................................................................................................................................... 135
Updated by Darin Oppenheimer, DRSc, RAC, Suraj Ramachandran, MS, RAC and George Cusatis, MS, RAC

Chapter 11 Medical Device Preclinical Testing.................................................................................................................... 143

Updated by Jan-Paul van Loon, MSc, PhD and Gert Bos, MSc, PhD, FRAPS

Chapter 12 Clinical Evaluation and Clinical Investigations.................................................................................................. 151

Updated by Loes Pelgrim, MSc and Gert Bos, MSc, PhD, FRAPS

Chapter 13 Medical Device Conformity Assessment Procedure........................................................................................... 157

Updated by Gert Bos, MSc, PhD, FRAPS

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Chapter 14 Medical Device Compliance: Postmarket Requirements.................................................................................... 171
Updated by Tran Do and Gert Bos, MSc, PhD, FRAPS

Chapter 15 Medical Device National Particularities............................................................................................................. 185

Updated by Robert Falcone, PhD

Chapter 16 Combination Products....................................................................................................................................... 191

Updated by Claudia Ising, FRAPS, RAC

Appendices
Comparative Matrix of EU Legislation Across Product Lines.................................................................................................... 201
Glossary ............................................................................................................................................................................ 249
Index ............................................................................................................................................................................ 269

Figures
Figure 1-1. EMA Mission.......................................................................................................................................................3
Figure 1-2. EMA Organisational Structure............................................................................................................................9
Figure 6-1. Supply Chain Controls.......................................................................................................................................57
Figure 6-2. Proposed EU IVDR Classification Rules............................................................................................................59
Figure 6-3. Governance Structure for the EU MDR and EU IVDR......................................................................................61
Figure 7-1. Simplified EU Legislative Process......................................................................................................................67
Figure 7-2. Flow Chart for the Conformity Assessment Procedures in Directive 93/42/EEC on Medical Devices............70
Figure 7-3. Flow Chart for the Conformity Assessment Procedures Provided for in Directive 90/385/EEC
on Active Implantable Medical Devices.............................................................................................................71
Figure 7-4. Flow Chart for the Conformity Assessment Procedures Provided for in Directive 98/79/EEC
on in Vitro Diagnostic Medical Devices.............................................................................................................72
Figure 7-5. Clinical Evaluation Cycle ..................................................................................................................................73
Figure 7-6. EU MDR and EU IVDR Governance Structure.................................................................................................90
Figure 13-1. Class III Device Conformity Assessment Procedure Options..........................................................................162
Figure 13-2. Class IIb Conformity Assessment Procedures..................................................................................................163
Figure 13-3 Class IIa Conformity Assessment Procedure....................................................................................................163
Figure 13-4. Class I Device, Self-Declaration or Self-Certification......................................................................................164
Figure 13-5. AIMDD Conformity Assessment Procedure....................................................................................................164
Figure 13-6. IVD Conformity Assessment Procedure..........................................................................................................165
Figure 13-7. Self-Testing IVD Conformity Assessment Procedure......................................................................................165
Figure 13-8. IVDD Annex II List B Conformity Assessment Procedures............................................................................166
Figure 13-9. High-Risk IVD Conformity Assessment Procedure........................................................................................167

Tables
Table 5-1. Regulatory Key Questions During Development................................................................................................51
Table 7-1. New Approach Areas...........................................................................................................................................68
Table 7-2. EU Member States and Affiliated Countries Competent Authorities.................................................................75
Table 7-3. European Commission Working Groups and Their Activities.............................................................................80
Table 7-4. European Industrial Trade Associations...............................................................................................................81
Table 7-5. Comparison of MDD and EU MDR Definition of a Medical Device ...............................................................82
Table 7-6. MEDDEV Guidance Documents.......................................................................................................................86
Table 7-7. European Commission Consensus Statements....................................................................................................88
Table 7-8. Informative Documents Issued by the European Commission............................................................................88
Table 7-9. NBOG Documents (NBOG Best Practice Guides)............................................................................................89
Table 8-1. MDR Annex VIII, Chapter III Classification Matrix........................................................................................102
Table 8-2. MDR Classification Rules for Non-Invasive Medical Devices..........................................................................103
Table 8-3. MDR Classification Rules for Invasive Medical Devices...................................................................................104
Table 8-4. MDR Classification Rules for Active Medical Devices......................................................................................105
Table 8-5a. Special MDR Rules: Medical Devices...............................................................................................................106
Table 8-5b. Special MDR Rules: Medical Devices...............................................................................................................106
Table 8-6. Comparison of MDD and MDR Device Classification Rules...........................................................................108
Table 8-7. IVDR Annex VIII, I Classification Matrix ........................................................................................................116
Table 8-8. Comparison of IVDD and IVDR Device Classification Rules...........................................................................118
Table 9-1. Examples of General Laboratory Use Products and IVD Medical Devices.......................................................124

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Table 10-1. General Safety and Performance Requirements Checklist (Annex I of EU MDR and EU IVDR).....................137
Table 11-1. Basic Design Traceability Matrix (DTM) for Connecting Requirements to Test Results.................................145
Table 13-1. Conformity Assessment Procedures...................................................................................................................160
Table 13-2. AIMDD Conformity Assessment Documentation............................................................................................160
Table 13-3. MDD Conformity Assessment Documentation................................................................................................161
Table 13-4. IVDD Conformity Assessment Documentation................................................................................................161
Table 13-5. Internal Production Control...............................................................................................................................168
Table 13-6. EC Type-Examination.......................................................................................................................................168
Table 13-7. Production Quality Assurance...........................................................................................................................168
Table 13-8. Product Quality Assurance................................................................................................................................168
Table 13-9. Product Verification...........................................................................................................................................168
Table 13-10. Full Quality Assurance System..........................................................................................................................168
Table 13-11. Authorised Representatives................................................................................................................................169
Table 14-1. Provisions for Providing Feedback about Medical Devices................................................................................173
Table 14-2. Eudamed Data Repository.................................................................................................................................176
Table 14-3. Comparison of Safeguard Clause and Health Monitoring Measures................................................................181
Table 15-1. EU Outermost Regions.....................................................................................................................................186
Table 15-2. Current Directives and New Regulations for Medical Devices, AIMDs and IVDs..........................................186
Table 15-3. Translation Requirements for Medical Devices, AIMDs and IVDs..................................................................187
Table 15-4. National Languages of the EU, Iceland, Liechtenstein and Norway..................................................................188

SECTION III: Fundamentals of International Medical Device Regulations

Chapter 1 Medical Device Premarket Requirements.........................................................................................................................1
Updated by Amina Abdal, MS, MBA

Chapter 2 Technical and Regulatory Requirements.........................................................................................................................19

Updated by Robin Stephens and Echo (Yuanyuan) Yu, MS, RAC

Chapter 3 Device Quality Systems..................................................................................................................................................27

Updated by Sharad Mi. Shukla, RAC, and Rajaram Balasubramanian, RAC

Chapter 4 In Vitro Diagnostic Medical Devices..............................................................................................................................37

Updated by Gert Bos, PhD, FRAPS, and Jocelyn Jennings, MS, RAC

Chapter 5 Active Implantable Medical Devices...............................................................................................................................57

By Gert Bos, PhD, FRAPS

Chapter 6 Software.........................................................................................................................................................................67
Updated by Echo (Yuanyuan) Yu, MS, RAC, and Raajdeep (Raaj) Venkatesan, MS (EE BME, MDDE), RAC

Chapter 7 Postmarket Requirements...............................................................................................................................................79

Updated by Pei-Ting S. Chou, RAC

Appendices
Comparative Matrix of Regulations Across Product Lines....................................................................................................................89
Glossary.............................................................................................................................................................................................115
Index..................................................................................................................................................................................................131

Figures
Figure 1-1. Decision Tree for Noninvasive Device Classification......................................................................................................12
Figure 1-2. Decision Trees for Invasive Device Classification............................................................................................................13
Figure 1-3. Decision Tree 2 for Invasive Devices...............................................................................................................................14
Figure 1-4. Decision Tree 1 for Active Device Classification.............................................................................................................15
Figure 1-5. Decision Tree 2 for Active Device Classification.............................................................................................................16
Figure 1-6. Decision Tree for Device Classification With Additional Rules.......................................................................................17
Figure 2-1. Premarket Use of the STED...........................................................................................................................................21

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Figure 2-2. Postmarket Use of the STED.........................................................................................................................................22
Figure 3-1. Influence of Design Controls on the Design Process......................................................................................................30
Figure 3-2. Process Validation Decision Tree....................................................................................................................................32
Figure 3-3. Key Activities for Supplier Control ...............................................................................................................................33
Figure 4-1. General GHTF Classification System for IVD Medical Devices.....................................................................................39
Figure 4-2. Regulatory Requirements Related to the Device Risk Class............................................................................................39
Figure 6-1. MDD Decision Tree......................................................................................................................................................70
Figure 6-2. IVDD Decision Tree......................................................................................................................................................72

Tables
Table 1-1. Class A Device.................................................................................................................................................................5
Table 1-2. Class B Device.................................................................................................................................................................6
Table 1-3. Class C Device.................................................................................................................................................................6
Table 1-4. Class D Device.................................................................................................................................................................7
Table 1-5. Noninvasive Devices .......................................................................................................................................................7
Table 1-6. Invasive Devices...............................................................................................................................................................8
Table 1-7. Active Devices ...............................................................................................................................................................10
Table 1-8. Additional Rules............................................................................................................................................................11
Table 4-1. Classification Rules for IVDs.........................................................................................................................................40
Table 4-2. Classification Rules for IVDs.........................................................................................................................................41
Table 4-3. Class A Device...............................................................................................................................................................42
Table 4-4. Class B Device...............................................................................................................................................................42
Table 4-5. Class C Device...............................................................................................................................................................43
Table 4-6. Australian Classification Scheme....................................................................................................................................51
Table 4-7. Conformity Assessment Stages.......................................................................................................................................53
Table 4-8. Rule 9 Special Classification...........................................................................................................................................54
Table 6-1. Examples of Software Types and Their EU Qualification as General Medical Devices....................................................76

SECTION IV: Fundamentals of Canadian Medical Device Regulations

Chapter 1 Health Canada..............................................................................................................................................1
Updated by Don Boyer, RAC, FRAPS

Chapter 2 Investigational Testing and Special Access Programme...................................................................................9

By Annie Levesque, MSc, RAC (CAN) and Jennifer Cabralda, RAC (US, CAN)

Chapter 3 Medical Device Submission and Approval Process.......................................................................................19

By Dinar Suleman RAC (US, Can) and Karen Long RAC (US, EU, Can, GS)

Chapter 4 In Vitro Diagnostic Medical Devices...........................................................................................................39

By Ugbaad Elmi and Sabrina Sharif

Chapter 5 Medical Device Quality System Requirements............................................................................................47

Updated by Karen Fan, MSc, RAC, Peng, Charles Tam, MBA, and Danuta Zylka

Chapter 6 Medical Device Classification......................................................................................................................61

Updated by Melissa Lake, RAC (US, CAN) and Janice Wright

Chapter 7 Medical Device Labelling, Advertising, Promotion......................................................................................75

By Karen Long, RAC (US, EU, Can, GS) and Dinar Suleman RAC (US, Can)

Chapter 8 Medical Device Postmarketing Activities.....................................................................................................85

Updated by Kathryn Ronalds, RAC and Ana Bascom, MSc

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Chapter 9 Medical Device Establishment Licensing...................................................................................................107
Updated by Danuta Zylka, RAC

Index.............................................................................................................................................................................111

Figures
Figure 1-1. Health Canada..............................................................................................................................................2
Figure 1-2. Branches with Responsibility for the Regulation of Healthcare Products.......................................................3
Figure 5-1. MDSAP Audit Sequence.............................................................................................................................54
Figure 5-2. MDSAP Nonconformity Grading Overview...............................................................................................55
Figure 5-3. MDSAP Nonconformity Grading Matrix...................................................................................................56
Figure 5-4. MDSAP Post-Audit Activities and Timeline................................................................................................57
Figure 7-1. Sample Letter of Attestation........................................................................................................................82
Figure 7-2. Flowchart H—Changes to Labelling...........................................................................................................83
Figure 8-1. Export Certificate........................................................................................................................................88
Figure 8-2. Complaint Form.........................................................................................................................................95

Tables
Table 2-1. Stages of Product Development for Medical Devices...................................................................................10
Table 2-2. Record Requirements per MDR Section 81................................................................................................11
Table 2-3. Content of an ITA Application for Non-IVDDs and IVDDs......................................................................12
Table 2-4. Examples of Additional Information that May be Requested from the Manufacturer..................................15
Table 3-1. Types of Medical Device Licence Applications............................................................................................22
Table 3-2. Required Information for Medical Device Licence (MDL) Application Form ............................................24
Table 3-3. Accepted Formats for Device Submissions...................................................................................................27
Table 3-4. Table of Contents (ToC) Submission Folder Structure and Naming Conventions ......................................28
Table 3-5. Specific Content Requirements for Devices in ToC Format ........................................................................29
Table 3-6. Class III Medical Device Health Canada Non-IVDD Submission Folder Structure and
Naming Conventions..................................................................................................................................30
Table 3-7. Health Canada IVDD Submission Folder Structure and Naming Conventions...........................................31
Table 3-8. Class IV Medical Device Health Canada Non-IVDD Submission Folder Structure and
Naming Conventions..................................................................................................................................32
Table 3-9. STED-Based IVDD Submission Folder Structure and Naming Conventions..............................................33
Table 3-10. STED-Based non-IVDD Submission Folder Structure and Naming Conventions......................................36
Table 4-1. IVDD Classifications..................................................................................................................................40
Table 6-1. Classification Examples...............................................................................................................................63
Table 6-2. Classification Rules and Associated Device Classes—Non-IVDDs..............................................................68
Table 6-3. Classification Rules and Associated Device Classes—IVDDs.......................................................................70
Table 7-1. Directions for Use Sections.........................................................................................................................77
Table 7-2. Schedule 2 Implant Devices (Require Implant Registration Cards)..............................................................77
Table 7-3. Additional Requirements for Some Devices.................................................................................................78
Table 7-4. IVDD Package Insert Information..............................................................................................................80
Table 8-1. Type of TPD Authorization Required for the Importation of Devices for Various Uses...............................87
Table 8-2. Regulatory Requirements Assessed During HPFB Inspection of Medical Device-Related Companies.......102

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