MARKETING AUTHORIZATION of PHARMACEUTICAL PRODUCTS with SPECIAL REFERENCE to MULTISOURCE (GENERIC) PRODUCTS: a MANUAL for DRUG REGULATORY AUTHORITIES Preface

WHO/DMP/RGS/98.5 Original: English Distribution: General MARKETING AUTHORIZATION OF PHARMACEUTICAL PRODUCTS WITH SPECIAL REFERENCE TO MULTISOURCE (GENERIC) PRODUCTS: A MANUAL FOR DRUG REGULATORY AUTHORITIES Preface This text was developed in consultation with national drug regulatory authorities within WHO’s Member States. The draft was circulated for comment and discussed at two informal consultations convened by the WHO Division of Drug Management and Policies in Geneva from 7 to 8 April and 6 to 8 July 1998. Contributions were made by. Dr K. Bremer, Regulatory and Quality Assurance Capacity, Action Programme for Essential Drugs, WHO, Geneva Dr A. Broekmans, Medicines Evaluation Board, Ministry of Health Welfare and Sport, Rijswijk Netherlands Miss M. Cone, International Federation of Pharmaceutical Manufacturers Associations (IFPMA), Geneva, Switzerland Dr M. Couper, Drug Management and Policies, WHO, Geneva Mr M.N. Dauramanzi, Medicines Control Authority of Zimbabwe, Harare, Zimbabwe Dr E. Griffiths, Biologicals, Drug Management and Policies, WHO, Geneva Mr R. Hislop, Boots Healthcare International, Nottingham, United Kingdom Dr J. Idänpään-Heikkilä, Director, Drug Management and Policies, WHO, Geneva Ms A. Jenoevari, (IFPMA) Eli Lilly Export SA, Vernier, Switzerland Ms P. Jude, Drug Regulatory Support, Drug Management and Policies, WHO, Geneva Mr E. Kkolos, Pharmaceutical Services, Ministry of Health, Nicosia, Cyprus Dr S. Kopp-Kubel, Quality Assurance, Drug Management and Policies, WHO, Geneva Professor U.F. Krylov, Pharmacopoeial Committee, Ministry of Health, Moscow, Russian Federation Dr A. Mechkovski, formerly Quality Assurance, Drug Management and Policies, WHO, Geneva Dr A. Padilla, Biologicals, Drug Management and Policies, WHO, Geneva Dr R. Patnaik, Center for Drug Evaluation and Research, Rockville, USA Mr G. Perry, European Generic Medicines Association, Brussels, Belgium Professor L. Rago, State Agency of Medicines,Tartu, Estonia Dr V. Reggi, Drug Regulatory Support, Drug Management and Policies, WHO, Geneva Mr D. Sato, Pharmaceutical and Medical Safety Bureau, Ministry of Health and Welfare, Tokyo, Japan Ms M. Schmid, Quality Assurance, Drug Management and Policies, WHO, Geneva Dr R. Schraitle, (WSMI) Bundesfachverband der Arzneimittel-Hersteller (BAH),Bonn, Germany Dr M. Spino, International Generic Pharmaceutical Alliance, Weston, Ontario, Canada Dr M. ten Ham, Drug Safety, Drug Management and Policies, WHO, Geneva Professor A. Toumi, Directorate for Pharmacy and Medicines, Ministry of Public Health, Tunis Belvedere, Tunisia Ms A. Wehrli, Drug Regulatory Support, Drug Management and Policies, WHO, Geneva Mr E. Wondemagegnehu, Regulatory and Quality Assurance Capacity, Action Programme for Essential Drugs, WHO, Geneva. Special thanks go to Dr S. Walters (Head, Pharmaceutical Chemistry Evaluation, Therapeutic Goods Administration, Woden, Australia), who drafted the text and acted as Rapporteur at the consultations. Finally, we should like to thank Dr D. Thompson for his invaluable contribution in editing this document. Table of Contents I. INTRODUCTION 1 II. PROVISIONS AND PREREQUISITES FOR REGULATORY CONTROL 2 A. Political will and commitment 2 B. Legislation 3 C. Accountability3 D. Resources for the marketing authorization function 4 E. Fees and cost recovery 8 F. Inventory of existing products on the market 8 G. Rational selection of products9 H. Special access schemes 11 I. Postmarketing activities 11 III. OPERATING ACTIVITIES 11 A. Transparency 11 B. Policies 12 C. Administrative procedures 12 D. Guidelines for applicants 12 E. Model application form 14 F. Communication among departments within the DRA 14 G. Relationship of evaluators with GMP inspectors 14 H. Relationship of evaluators with the quality control laboratories 14 I. Functional relationship of the evaluators with the expert advisory body 15 K. Meetings with applicants 16 L. Procedures for appeals 17 M. Collaboration with other DRAs 17 N. Collaboration with WHO 18 O. Use of external experts as evaluators 19 P. Timeframes for processing of applications 19 Q. Publication of marketing authorization decisions 20 IV. REVIEW OF APPLICATIONS FOR MARKETING AUTHORIZATION OF MULTISOURCE (GENERIC) PHARMACEUTICAL PRODUCTS 20 A. Applicability 20 B. Initial decisions on options for premarket evaluation21 C. Evaluation of data on quality 22 D. Quality of starting materials 27 E. Container labelling 27 F. Toxicological, pharmacological and clinical data 27 G. Product Information 28 H. Interchangeability 29 V. ISSUE OF WRITTEN MARKETING AUTHORIZATION 29 VI VARIATIONS 30 VII. PERIODIC REVIEWS 31 iii VIII. SUSPENSION AND REVOCATION OF MARKETING AUTHORIZATION 32 GLOSSARY 33 ABBREVIATIONS 40 REFERENCES 42 ANNEXES 45 Annex 1: National drug regulatory legislation: guiding principles for small drug regulatory authorities 47 Annex 2: Guidelines for Implementation of the WHO Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce 85 Annex 3: Multisource (Generic) Pharmaceutical Products: Guidelines on Registration Requirements to Establish Interchangeability 109 Annex 4: Model Guidelines on Conflict of Interest and Model Proforma for a Signed Statement on Conflict of Interest 147 Annex 5: Model Contract between a Regulatory Authority and an External Evaluator of Chemistry, Pharmaceutical and Bioavailability Data 151 Annex 6: Model Application Form for new Marketing Authorizations, Periodic Reviews and Variations, with Notes to the Applicant 155 Annex 7: Detailed Advice on Evaluation of Data by the Drug Regulatory Authority 169 Annex 8: Ethical criteria for medicinal drug promotion 183 Annex 9: Model marketing authorization letter 191 Annex 10: Model List of Variations (Changes) to Pharmaceutical Aspects of Registered Products which may be made without Prior Approval 195 Annex 11: Guidelines for stability testing of pharmaceutical products containing well established drug substances in conventional dosage forms 197 4 1 I. INTRODUCTION As outlined in WHO's Guiding Principles for Small National Drug Regulatory Authorities (1) an important task for a drug regulatory authority (DRA) is to institute a system which subjects all pharmaceutical products to premarketing evaluation, marketing authorization and postmarketing review to ensure that they conform to required standards of quality, safety and efficacy. Because it has responsibilities in public health, in most countries the DRA is located in, linked to or reports to the Ministry of Health. This manual is intended to provide guidance to countries which do not already have a fully functioning system of premarket evaluation and market authorization, and have a particular interest in the assessment and authorization of multisource (generic) pharmaceutical products. Many of the principles apply to other groups of medicines (such as complex biologicals and ‘alternative’ preparations), but the details may be specific to multisource products. For the purposes of this manual, the term drug regulatory authority means a network that administers the full spectrum of drug regulatory activities, including at least the following functions and others: C Marketing authorization for new products and variation of existing authorizations; C Quality control laboratory testing; C Adverse drug reaction monitoring; C Provision of drug information and promotion of rational drug use; C Good Manufacturing Practice (GMP) inspections and licensing of manufacturers, wholesalers and other distribution channels; C Enforcement operations; C Monitoring of Drug Utilization. In some regulatory systems the functions of an individual DRA may be more limited. The manual may still be used when, for example, the DRA is confined to marketing authorization activities. This manual provides detailed guidance on the structure and operation of those functions of a DRA that deal with premarket evaluation and marketing authorization, also known as drug registration. The other activities are a necessary complement to the marketing authorization function but are not discussed in detail in this document. The principles underpinning premarket evaluation and the marketing authorization process are discussed in WHO’s Guiding Principles for Small National DRAs (1). The advice in this manual is intended to be independent of local political and legal structures. Instead of being prescriptive, it describes options from which governments can select the most suitable path, depending on current circumstances. Marketing authorization applications can be classified broadly in three groups, which comprise applications for: 1. Products containing new chemical or biological active pharmaceutical ingredients (APIs); 2. Multisource pharmaceutical products (generic products): that is, new marketing authorization holders, formulations, or sources of well established drugs; 3. Variations to existing marketing authorizations. Evaluation of the complex toxicological and clinical data which accompany new chemical entities requires resources and experience that are usually found only in national DRAs with substantial funding and skills. Countries with more limited resources may wish to give 1 2 priority to well established drugs. They can then await the outcome of detailed premarketing evaluation of safety and efficacy, and postmarketing surveillance of safety, by the well resourced authorities before considering issuing marketing authorizations for newer drugs (see Part III “Collaboration with other DRAs”). If a new drug appears to be important

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