Analysis of requirements for a new marketing authorization application for new chemical entities and new biological entities

Doktorantenkolloquium im Rahmen der Dissertation im Fachbereich Drug Regulatory Affairs an der Uni Bonn am 04.04.2008

Andrea Hörner, MDRA
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Topics
General requirements for a new marketing authorization application Special requirements per region (EU / USA / Non-ICH selected countries) Conclusion

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ICH / Non-ICH countries
International Conference of Harmonization (ICH)
European Union USA Japan

Non-ICH countries covers all countries outside ICH includes also Canada, Switzerland & Australia The ICH countries developed a common format for submissions of new marketing authorization applications (MAAs) CTD format
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ICH - CTD structure

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General requirements for a new marketing authorization application (1)
CTD Dossier:
Complete ICH CTD dossier requested for ICH countries and some Non-ICHcountries (like Canada, Switzerland, Australia, Croatia) For most of the non-ICH-countries it is advisable not to submit the complete ICH CTD dossier due to confidentiality reasons
Delete the documents with highly confidential information (e.g. Middle East, Latin America) Prepare documents with abbreviated content (e.g. ASEAN countries)
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General requirements for a new marketing authorization application (2)
CTD dossier (Module 2, 3 4, and 5)
Module 2: Overviews and Summaries Module 3: Quality Data Module 4: Preclinical Data Module 5: Clinical Data

Module 1 / Administrative documents
Labeling texts and mock-ups CAVE: For ASEAN countries the ASEAN CTD will become mandatory from 2009 onwards!
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General requirements for a new marketing authorization application (3)
NCEs
Small molecules Clearly defined by the product itself Preparation of the dossier according to NCE guidelines NBEs
Often big and complex molecules (like monoclonal antibodies) A biotech product is defined not only by the product but also by the process. Viral safety profiles requested Preparation of the dossier according to NBE guidelines
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Andrea Hörner

Topics
General requirements for a new marketing authorization application Special requirements per region (EU / USA / Non-ICH selected countries) Conclusion

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Andrea Hörner

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Additional requirements per country - EU
Clinical studies:
Investigator Medicinal Product should be tested against comparator Clinical data with progression-free-survival (PFS) as primary endpoint acceptable for anticancer drugs

Module 1 according to European legislation 1.2 Application form 1.3 Summary of product characteristics, labelling and package leaflet 1.4 Information about the experts 1.5 Specific requirements for different types of applications 1.6 Environmental Risk Assessment 1.7 Information relating to orphan market exclusivity 1.8 Description of the Pharmacovigilance System 1.9 Risk Management Plan
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Additional requirements per country - USA
Clinical studies:
Should be tested against placebo whenever possible Clinical data with PFS as primary endpoint acceptable for anticancer drugs Quality requirements for Regional Information: Comparability Protocol Methods Validation Package Environmental Assessment Manufacturing Batch Records for Drug Substance and Drug Product
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Additional requirements per country – USA (2)
Module 1 according to US legislation
Form 356h Cover letter Labeling Case Reports Tabulations (CRTs) Case Reports Forms (CRFs) Patent Information Patent Certification Debarment Certification User Fee Cover Sheet Financial Information
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Additional requirements per country - CADREAC
CADREAC: Centralized Procedure (CP)
Dossier identical to the dossier submitted in EU Assessment report of EU CHMP opinion and EU commission decision All variations performed after approval of MAA CHMP opinions and EU commission decisions for all variations CADREAC information sharing letter Declaration of the applicant List of variations submitted and approved in EU

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Additional requirements per country – CADREAC (2)
CADREAC: Decentralized Procedure (DCP) and Mutual Recognition Procedure (MRP)
Dossier identical to the dossier submitted in EU Assessment report of RMS Approval letter of RMS All variations performed after approval of MAA Approval letters of all variations CADREAC information sharing letter Declaration of the applicant List of variations submitted and approved in RMS History of MRP or DCP
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Additional requirements per country - Brazil
Stability requirements different from ICH
Data for 30°C / 75% rh requested for long term stability

Phase III clinical studies requested to get an approval without Phase III data no approval can be obtained! Administrative documents, e.g.
CPP GMP certificates Letter of authorizations (Power of Attorneys) Labeling documents CoAs of Drug Substance (DS) and Drug Product (DP)

Batch Records requested for Drug Product (!)
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Additional requirements per country – Singapore (ASEAN)
Special documents requested:
Appendix 8: Singapore Quality Overall Summary for Biologic Validation sheet Singapore Stability sheet

Stability requirements different from ICH, valid for NCEs (not for NBEs):
Long term testing:
Products packed in semi-permeable containers: 30°C ± 2°C / 75% RH ± 5% RH – mind. 12 months 30°C +/- 2°C, humidity not specified (for products in impermeable containers), 12 mo

Accelerated studies: 40°C ± 2°C / 75% RH ± 5% RH – min. 6 months Stress studies: 40°C ± 2°C / 75% RH ± 5% RH
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Additional requirements per country – Singapore (ASEAN) (2)
Administrative documents, e.g.
CPP GMP certificates Letter of authorizations (Power of Attorneys) Labeling documents EU approval letters EU Assessment Reports (from benchmarking countries) TGA approval letters, if available Patent declaration form CoAs of DS and DP
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Additional requirements per country – Taiwan
Plant Master File registration required before MAA can be submitted Administrative documents, e.g.
CPP GMP certificates Letter of authorizations (Power of Attorneys) Labeling documents CoAs of DS and DP

Batch Records requested for DP (!) Detailed information about quality part requested, even very confidential information

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Additional requirements per country - China
Detailed information about quality part requested, even very confidential information Administrative documents, e.g.
Application Forms CPP GMP certificates Letter of authorizations (Power of Attorneys) Labeling documents SOPs for test methods CoAs of DS and DP

Only one manufacturer can be registered for DS and DP
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Topics
General requirements for a new marketing authorization application Special requirements per region (EU / USA / Non-ICH selected countries) Conclusion

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Conclusion
ICH CTD dossier is the basis for new MAAs worldwide – Module 2 to 5 can be used in general for global submissions For some countries it might be advisable to submit not the whole CTD dossier due to confidentiality reasons documents with non confidential (abbreviated) content can be prepared Each country has additionally special requirements which needs to be considered before submission of MAAs to the authority – otherwise a rejection of the application or a deficiency letter may be obtained Be proactive Talk to the agencies as a partner
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Back Up

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Topics
Legal background List of abbreviations

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Legal background
European Union (EU):
Directive 2001/83/EEC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use COMMISSION DIRECTIVE 2003/63/EC of 25 June 2003 amending Directive 2001/83/EC of the European Parliament and of the Council on the Community code relating to medicinal products for human use Directive 2004/27 EEC of the European Parliament and of the Council of 31 March 2004 amending Directive 2001/83/EC on the Community code relating to medicinal products for human use Andrea Hörner 23

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Legal background
EU (con’t):
Council Regulation (EEC) No 2309/93 of 22 July 1993 laying down Community procedures for the authorization and supervision of medicinal products for human and veterinary use and establishing a European Agency for the Evaluation of Medicinal Products Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down Community procedures for the authorization and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency
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Legal background
EU (con’t):
Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use Notice to applicants

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Legal background
USA
CFR Title 21 - Food and Drugs “CHAPTER I FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED)”
Part 310 – New drugs Part 312– Investigational new drug application (INDA) Part 314 – Applications for FDA approval to market a new drug PART 316 – Orphan drugs PART 600 – Biological products - General
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Legal background
CADREAC:
Procedure on the granting of MAs by CADREAC Drug Regulatory Authorities for human medicinal products already authorized in EU member states following the decentralized procedure Procedure on the granting of MAs by CADREAC Drug Regulatory Authorities for medicinal products for human use authorized in the EU following the centralized procedure and the variation and renewal of such marketing authorizations
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Legal background
CADREAC (con’t):
Guidance for simplified procedure for MA of medicinal products authorized in the European Union following the Centralized procedure and for variations and renewals to these MAs in CADREAC area Common CADREAC Procedure (CCP) for retrospective inclusion of centrally authorized MPs for human use in the Common CADREAC Simplified System - in force since May 2001
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Legal background
Brazil: Resolution stability Brazil_RDC137 2003-05-29 Brazil_RDC140 2003-05-29 Brazil_RDC1548 2003-09-23 Brazilian Guideline on new biological entities (NBEs) RDC 136.03 (registro medicamentos novos)
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Legal background
Singapore (ASEAN):
Guidance on Medicinal Product Registration in Singapore Guidance For Drug Registration In Singapore_Effective1Nov2004 Guidelines for the conduct of Bioavailability and Bioequivalence Studies DR Guide main for circulation (041206)

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Legal background
Singapore (ASEAN) (con’t):
Appendix 4 - Application checklist (ACTD & ICH CTD) Appendix 6A - Singapore Quality Overall Summary for Chemical Drugs Appendix 6B - Singapore Quality Overall Summary for Biologics Appendix 8 - Guideline on Submission Requirements for Non-Prescription Medicines
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Legal background
Taiwan:
New Chemical Entity (NCE) GuidelineChap 1-13 (revised) gNDA CDE draft 07-29-05 (English) Stability guideline Register of NDA dossier The revised draft of the “Guidance on the Preparation of Plant Master File (PMF)”
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Legal background
China:
DRUG REGISTRATION REGULATION (SFDA Order 28) with the 6 annexes:
Annex 1: Registration Categories and Application Information Requirements of TCM and Natural Drugs Annex 2: Registration Categories and Application Information Requirements of Chemical Drugs Annex 3: Registration Categories and Application Information Items Requirements of Biological Products Annex 4: Registration Items and Application Information Requirements of Supplemental Application of Drug Registration Annex 5: Application Information Items of Drug ReRegistration Annex 6: Timeframe for monitoring period of New Drugs (notes, no note: no monitoring period will be established for the drugs other than those listed) (table 1-3)
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Topics
Legal background List of abbreviations

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List of abbreviations (1)
ACTD = ASEAN Common Technical Document ASEAN = Association of Southeast Asian Nations CADREAC = Collaboration Agreement of Drug Regulatory Authorities in European Union Associated Countries CFR = Code of Federal Regulations CHMP = The Committee for Medicinal Products for Human Use CP = Centralized Procedure CPP = Certificate of a Pharmaceutical Product CTD = Common Technical Document
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List of abbreviations (2)
DCP = Decentralized Procedure DP = Drug Product DS = Drug Substance EU = European Union GMP = Good Manufacturing Practise ICH = International Conference of Harmonization MA(A) = Marketing Authorization (Application) MRP – Mutual Recognition Procedure NDA = New Drug Application NBE = New Biological Entity NCE = New Chemical Entity
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List of abbreviations (3)
PFS = Progression Free Survival PMF = Plant Master File RMS = Reference Member State SFDA = State Food and Drug Administration SOP = Standing Operating Procedure TCM = Traditional Chinese Medicines TGA = Therapeutic Goods Administration USA = United States of America VAR = Variation
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