The rules governing medicinal products in the European Union Volume 2B Notice to Applicants Medicinal products for human use Presentation and content of the dossier 1998 Edition EUROPEAN COMMISSION Directorate General III Industry Pharmaceuticals and cosmetics
THE RULES GOVERNING MEDICINAL PRODUCTS IN THE EUROPEAN UNION Volume 1 Pharmaceutical legislation Medicinal products for human use Volume 2 Notice to applicants Medicinal products for human use Volume 3 Guidelines Medicinal products for human use Volume 4 Good manufacturing practices Medicinal products for human and veterinary use Volume 5 Pharmaceutical legislation Veterinary medicinal products Volume 6 Notice to applicants Veterinary medicinal products Volume 7 Guidelines Veterinary medicinal products Volume 8 Maximum residue limits Veterinary medicinal products Volume 9 Pharmacovigilance Medicinal products for human use and veterinary medicinal products
FOREWORD This Notice to Applicants (NTA) has been prepared by the European Commission, i n consultation with the competent authorities of the Member States and the European Agency for the Evaluation of Medicinal Products. This Notice has no legal force and does not necessarily represent the final views of the Commission. In case of doubt, therefore, reference should be made to the appropriate Community Directives. It is important when reading this text to appreciate that the legal requirements of the Directives and the Regulation must be met and that this Notice presents the harmonised views of the Member States on how those requirements may be met. The Notice to Applicants (Volume 2 in the series The Rules governing Medicinal Products in the European Union ) was first published in 1986. A revised and completed version, the second edition, was issued in January '89. Since then, the procedures for applications for a marketing authorisation have been amended in order to introduce the centralised and mutual recognition procedures. The resulting size of NTA has meant that it has been divided into parts Volume 2A dealing with procedures for marketing authorisation; Volume 2B dealing with the presentation and content of the application dossier. Volume 2B is concerned with the structure and content of the application dossier (Parts I, II, III, IV). It provides guidance for the compilation of dossiers for applications for marketing authorization, and is applicable for the centralised procedure and national procedures, including mutual recognition. The requirements for the content of the application dossier are set out in Directive 75/318/EEC as amended, i.e. the particulars and documents accompanying an application for marketing authorization pursuant to Article 4 of Council Directive 65/65/EEC shall be presented in four parts, in accordance with the requirements set out in the Annex to that directive, taking account of the guidance published by the Commission in The rules governing medicinal products in the European Union, Volume 2: Notice to applicants for marketing authorisations for medicinal products for human use. The content of the dossier (Volume 2B) has not been changed since 1989 with the exception of additions in order to take account of those medicinal products brought within the scope of Directive 65/65/EEC as a result of the extension directives i.e. radiopharmaceuticals, medicinal products derived from human blood and plasma and homeopathics; as well as occasional clarifications as requested by the pharmaceutical industry. In order to provide regulatory authorities and the pharmaceutical industry with a single source document, the current text of the 1989 edition of the Notice to Applicants has been re-presented, with those additions and clarifications already (consulted upon and) adopted duly incorporated. Therefore, the text of the 1989 edition is replaced by this volume. In order to facilitate the preparation of the dossier, particularly the tabular presentations, this volume is also available on a diskette.
OVERVIEW INTRODUCTION i PART I SUMMARY 1 PART II CHEMICAL, PHARMACEUTICAL AND BIOLOGICAL DOCUMENTATION 175 PART III TOXICO-PHARMACOLOGICAL DOCUMENTATION 205 PART IV CLINICAL DOCUMENTATION 207 NOTES 209 v
TABLE OF CONTENTS Foreword INTRODUCTION iii xix PART I SUMMARY OF THE DOSSIER 1 PART I A SUMMARY OF THE DOSSIER 1 Administrative data 1 Fees, declaration and signature 1 Type of application 1 1. This application concerns: 2 2. The application is in accordance with the following legal base: 2 3. This is an application for: 3 Marketing authorization particulars 9 PART I B 1 SUMMARY OF PRODUCT CHARACTERISTICS 17 Summary of the product characteristics: list of headings 18 1. Trade name of the medicinal product 19 2. Qualitative and quantitative composition 19 3. Pharmaceutical form 19 4. Clinical particulars 19 5. Pharmacological properties 21 6. Pharmaceutical particulars 22 7. Marketing authorization holder 23 8. Marketing authorization number 23 9. Date of first authorization/renewal of authorization 23 10. Date of (partial) revision of the text 23 PART I B 2 PROPOSAL FOR PACKAGING, LABELLING & PACKAGE LEAFLET 23 PART I B 3 SPCS ALREADY APPROVED IN THE MEMBER STATES 23 PART I C EXPERT REPORTS 24 A. Introduction 24 B. Presentation of the expert report 24 C. Expert reports for abridged applications 26 PART I C 1 EXPERT REPORT ON THE CHEMICAL, PHARMACEUTICAL AND BIOLOGICAL DOCUMENTATION 28 A. Introduction 28 Product profile 28 Expert report 28 Appendices to the expert report 28 B. Expert report on the chemical, pharmaceutical and biological documentation 29 C. General aspects 30 vii
Table of contents viii D. Critical assessment 31 1. Composition of the product: 31 2. Development pharmaceutics: 31 3. Stereoisomerism: 31 4. Method of preparation: 32 5. Process validation: 32 6. Control of pharmacopoeial active substance(s) : 32 7. Control of non-pharmacopoeial active substance(s): 32 8. Excipients: 33 9. Packaging material (immediate packaging): 33 10. Control tests on intermediate products: 33 11. Control tests on the finished product: 33 12. Stability of the active substance(s): 33 13. Stability of the finished product: 33 14. Other information: 33 15. Reference list: 34 16. Information on the qualifications and experience of the pharmaceutical expert: 34 E. Tabular formats 35 F. Tabular formats for radiopharmaceutical products 36 PART I C 2 EXPERT REPORT ON THE TOXICO-PHARMACOLOGICAL (PRE- CLINICAL) DOCUMENTATION 79 A. Introduction 79 Product profile 79 Expert report 79 Appendices to the expert report 79 B. Expert report on the toxico-pharmacological documentation 80 C. General aspects 81 D. Critical assessment 82 1. Pharmacodynamics 82 2. Pharmacokinetics 82 3. Toxicity 82 4. Conclusions 83 5. Reference list 83 6. Information on the toxico-pharmacological (pre-clinical) experts 83 E. Tabular formats 84 PART I C 3 EXPERT REPORT ON THE CLINICAL DOCUMENTATION 159 A. Introduction 159 Product profile 159 Expert report 159 Appendice to the expert report 159 B. Expert report on the clinical documentation 160 C. General aspects 161 D. Critical assessment 162 1. Clinical pharmacology (Part IV A) 162 2. Pharmacodynamics 162 3. Pharmacokinetics 162 4. Clinical trials (PART IV B) 164
Table of contents 5. Post marketing experience 166 6. Other information 167 7. Conclusion 167 8. Reference list 167 9. Information on the clinical expert 167 E. Tabular formats 168 PART II CONCERNING CHEMICAL. PHARMACEUTICAL AND BIOLOGICAL DOCUMENTATION FOR CHEMICAL ACTIVE SUBSTANCE(S) 175 PART II A: COMPOSITION 175 1. Composition of the medicinal product 175 2. Container (brief description) 175 3. Clinical trial formula(e) 175 4. Development pharmaceutics 175 PART II B: METHOD OF PREPARATION 176 1. Manufacturing formula (including details of batch size) 176 2. Manufacturing process 176 3. Validation of the process 176 PART II C: CONTROL OF STARTING MATERIALS 176 1. Active substance(s) 176 2. Excipient(s) 177 3. Packaging material (immediate packaging) 177 PART II D: CONTROL TESTS ON INTERMEDIATE PRODUCTS (IF NECESSARY) 178 PART II E: CONTROL TESTS ON THE FINISHED PRODUCT 178 1. Specifications and routine tests 178 2. Scientific data 178 PART II F: STABILITY 178 1. Stability tests on active substance(s) 178 2. Stability tests on the finished product 179 PART II H: DATA RELATED TO THE ENVIRONMENTAL RISK ASSESSMENT FOR PRODUCTS CONTAINING, OR CONSISTING OF GENETICALLY MODIFIED ORGANISMS (GMOS) 180 PART II Q: OTHER INFORMATION 180 PART II CONCERNING CHEMICAL. PHARMACEUTICAL AND BIOLOGICAL DOCUMENTATION FOR RADIOPHARMACEUTICAL PRODUCTS 181 PART II A: COMPOSITION 181 1. Composition of the medicinal product 181 2. Container (brief description) 181 ix
Table of contents 3. Clinical trial formula(e) 181 4. Development pharmaceutics 182 PART II B: METHOD OF PREPARATION 182 1. Manufacturing formula (including details of batch size) 182 2. Manufacturing process 182 3. Validation of the process 182 PART II C: CONTROL OF STARTING MATERIALS 182 1. Active substance(s) 182 2. Excipient(s) 184 3. Packaging material (immediate packaging) 184 PART II D: CONTROL TESTS ON INTERMEDIATE PRODUCTS (IF NECESSARY) 184 PART II E: CONTROL TESTS ON THE FINISHED PRODUCT 184 1. Specifications and routine tests 184 2. Scientific data 184 PART II F: STABILITY 185 1. Stability tests on active substance(s) 185 2. Stability tests on the finished product 185 PART II G: BIOAVAILABILITY/BIOEQUIVALENCE 185 PART II H: DATA RELATED TO THE ENVIRONMENTAL RISK ASSESSMENT FOR PRODUCTS CONTAINING, OR CONSISTING OF GENETICALLY MODIFIED ORGANISMS (GMOS) 186 PART II Q: OTHER INFORMATION 186 PART II CONCERNING CHEMICAL. PHARMACEUTICAL AND BIOLOGICAL DOCUMENTATION FOR BIOLOGICAL MEDICINAL PRODUCTS 187 PART II A: COMPOSITION 187 1. Composition of the medicinal product 187 2. Container (brief description) 187 3. Clinical trial formula(e) 187 4. Development pharmaceutics 187 PART II B: METHOD OF PREPARATION 188 1. Manufacturing formula 188 2. Manufacturing process 188 3. Validation of the process 188 PART II C: PRODUCTION AND CONTROL OF STARTING MATERIALS 188 1. Active substance(s) 188 2. Excipient(s) 188 x
Table of contents 3. Packaging material (immediate packaging) 191 PART II D: CONTROL TESTS ON INTERMEDIATE PRODUCTS 191 PART II E: CONTROL TESTS ON THE FINISHED PRODUCT 191 1. Specifications and routine tests 191 2. Scientific data 192 PART II F: STABILITY 192 1. Stability tests on active substance(s) 192 2. Stability tests on the finished product 192 PART II G: BIOAVAILABILITY/BIOEQUIVALENCE 192 PART II H: DATA RELATED TO THE ENVIRONMENTAL RISK ASSESSMENT FOR PRODUCTS CONTAINING, OR CONSISTING OF GENETICALLY MODIFIED ORGANISMS (GMOS) 194 Part IIH-1. 194 Part IIH-2. 194 Part IIH-3. 194 Part IIH-4. 194 Part IIH-5. 194 Part IIH-6. 194 PART II Q: OTHER INFORMATION 194 PART II V: VIROLOGICAL DOCUMENTATION 194 1. Brief presentation of the finished product 195 2. Starting materials and biological reagents used in production 195 3. Production process 196 4. Validation studies on the process 196 5. Virological control tests during the production process 197 6. Pharmacovigilance (surveillance of the viral safety) 197 7. Expert report 197 PART II CONCERNING CHEMICAL. PHARMACEUTICAL AND BIOLOGICAL DOCUMENTATION FOR VEGETABLE MEDICINAL PRODUCTS 199 PART II A: COMPOSITION 199 1. Composition of the medicinal product 199 2. Container (brief description) 199 3. Clinical trial formula(e) 199 4. Development pharmaceutics 199 PART II B: METHOD OF PREPARATION 200 1. Manufacturing formula (including details of batch size) 200 2. Manufacturing process 200 3. Validation of the process 200 xi
Table of contents PART II C: CONTROL OF STARTING MATERIALS 200 1. Active substance(s) 200 2. Excipients 200 3. Packaging material (immediate packaging) 200 PART II D: CONTROL TESTS ON INTERMEDIATE PRODUCTS (IF NECESSARY) 203 PART II E: CONTROL TESTS ON THE FINISHED PRODUCT 203 1. Specifications and routine tests 203 2. Scientific data 203 PART II F: STABILITY 204 1. Stability tests on active substance(s) 204 2. Stability tests on the finished product 204 PART II G: BIOAVAILABILITY/BIOEQUIVALENCE 204 PART II H: DATA RELATED TO THE ENVIRONMENTAL RISK ASSESSMENT FOR PRODUCTS CONTAINING, OR CONSISTING OF GENETICALLY MODIFIED ORGANISMS (GMOS) 204 PART II Q: OTHER INFORMATION 204 PART III TOXICO-PHARMACOLOGICAL DOCUMENTATION 205 PART III A: TOXICITY 205 PART III B: REPRODUCTIVE FUNCTION (FERTILITY AND GENERAL REPRODUCTIVE PERFORMANCE) 205 PART III C: EMBRYO-FOETAL AND PERINATAL TOXICITY 205 PART III D: MUTAGENIC POTENTIAL 205 PART III E: CARCINOGENIC POTENTIAL 205 PART III F: PHARMACODYNAMICS 206 PART III G: PHARMACOKINETICS 206 PART III H: LOCAL TOLERANCE (WHERE APPROPRIATE) 206 PART III Q : OTHER INFORMATION 206 PART III R: ENVIRONMENTAL RISK ASSESSMENT / ECOTOXICITY 206 PART IV CLINICAL DOCUMENTATION 207 xii
Table of contents PART IV A: CLINICAL PHARMACOLOGY 207 1. Pharmacodynamics 207 2. Pharmacokinetics 207 PART IV B: CLINICAL EXPERIENCE 208 1. Clinical trials 208 2. Post-marketing experience (if available) 208 3. Published and unpublished experience (other than 1.) 208 PART IV Q: OTHER INFORMATION 208 NOTES 209 xiii
INTRODUCTION 1. PRESENTATION OF THE APPLICATION The Community application dossier, which should be submitted in either a Community or national procedure (i.e. to competent authorities of the Member States and the European Agency for the Evaluation of Medicinal Products), consists of administrative information and the necessary demonstration of quality, safety and efficacy of the product. This is presented in four Parts (I, II, III, IV). Part I Summary of the dossier Part II Chemical/pharmaceutical/biological tests Part III Toxico-Pharmacological tests Part IV Clinical documentation. 2. PART 1 Part I is divided into 3 sub-sections: Part IA consists of the administrative data, packaging, samples, manufacturing and marketing authorisations applied for or obtained elsewhere (previously in Part V of the dossier). A harmonised format for Part IA has been agreed. Part IB consists of the proposed Summary of Product Characteristics (SPC) and package leaflet, in accordance with Article 4a of Directive 65/65/EEC. The sequence given in the guideline has been accepted by the competent authorities of all Member States, and places the clinical data in a more prominent location. Part IC consists of the Expert Reports and their Annexes. Parts IA, IB and IC are always required. Part IB must be in the language(s) of the Member State concerned or in all Community languages for centralised applications. 2.1 Experts Reports in the application dossier Directive 75/319/EEC as amended requires that the particulars and documents submitted i n the application dossier are drawn up and signed by experts, with the necessary technical or professional qualifications. The chemical/pharmaceutical/biological, toxicopharmacological and clinical parts of the dossier should each include an Expert Report. The Expert Reports, their tabular formats and written summaries are placed in Part IC of the dossier. It is important to emphasise that well prepared Expert Reports greatly to facilitate the task of the competent authority in evaluating the dossier and contribute towards the speedy processing of applications. For these reasons particular care should be taken in the preparation of Expert Reports, following the guidance on the preparation of Expert Reports given in this volume. Where relevant Community guidelines on the conduct of tests, studies and trials on a medicinal product exist, these should be taken into consideration when Expert Reports are prepared. Any deviation from guidelines should be discussed and justified. In particular, the xv
Introduction experts should give a justification for the statements in the proposed summary of product characteristics (SPC), taking into account the submitted data and the SPC guideline and also considering the need for bioavailability studies with reference to the guideline on bioavailability and bioequivalence in Volume III of the Rules governing medicinal products in the European Union. 2.2 Presentation of the Expert Report Experience has shown that many applications, particularly for new active substances, have included a written summary as well as the tabulations to the Expert Reports. Competent authorities have generally found these to be helpful. However, it is considered important to clarify the purpose of the appendices to the Expert Reports in order to avoid duplication and overlap. It is important to avoid duplication, repetition between the Expert Report and the written summary. Equally, experience has shown that a good tabular presentation with a short written summary is an effective method of communication. Therefore, where tabular formats suffice, it is not necessary to duplicate the message in writing. Quality For the quality part of the dossier, the tabular formats are considered to fulfil the function of a written summary (except in the case of biotechnology medicinal products and medicinal product which contain or consists of genetically modified organisms where a written summary of not more than 30 pages would be helpful). The assessment report prepared by the competent authority on Part II of the dossier consists of three parts: annotations on the tabulated formats of the Expert Report; annotations on the critical part of the Expert Report (including a critical appraisal section of the Active Ingredient Manufacturers restricted part (of a DMF file); a critical evaluation by the assessor of key features of the dossier. When the assessment report is to serve as the basis of mutual recognition, the applicant will be invited to provide a revised and updated version of the critical discussion and the tabulated formats of the Expert Report, based on an updated Part II of the dossier. These revisions would take into account all of the points raised during the assessment. It is these revised and updated documents which will form the basis of the (updated) assessment report referred to in Article 9.3 of Directive 75/319/EEC as amended. Safety For the toxicological section of the dossier, the tabular formats are considered to fulfil the function of a written summary. For the pharmacological section of Part III of the dossier, a written summary could be useful. Normally, the written summary would not be more than 10 pages. It is considered helpful to have an overview table which would precede a written summary. This overview table would form part of the assessment report. xvi
Introduction The assessment report would include a critical analysis of the Part III Expert Report, tabular formats, overview table, written summary, in the light of knowledge of the detail of the submitted dossier of study reports. Efficacy A written summary can be helpful for large, complex clinical documentation. In order to aid clarity, an overview table of clinical studies should precede the written summary. This overview table would form part of the assessment report. The written summary should be factual, complete (i.e. covering all studies) and concise. Normally, it would not be longer than 30 pages. However, in cases of complex dossiers, with multiple indications and/or large numbers of patients evaluable for safety and efficacy, a larger summary (up to 100 pages) could be necessary. 3. TECHNICAL DOCUMENTATION Parts II, III, and IV of the application dossier consist of the chemical, pharmaceutical and biological documentation; the toxicological and pharmacological documentation; and the clinical documentation respectively. In Part IV, Clinical Documentation, case report forms are always required to be available. Although it is not necessary to include these in the submission, applicants should be prepared to supply them normally within 48 hours of any request by the competent authority and i n any event within 7 calendar days of the request. This applies (for submission of case report forms) also to the time during the evaluation procedure unless a significant change of the SPC arises from single case reports. 3.1 Overview tables Given the pivotal role of the overview tables for Parts III and IV, applicants are strongly urged to include these in submissions, as quickly as possible. In any event, consideration of a dossier in any of the Community procedures would be greatly facilitated by the presence of such overview tables. A written summary, for the relevant sections of Part III and Part IV would facilitate mutual recognition by concerned Member States, and also consideration by the members of the Scientific Committee of the European Agency for the Evaluation of Medicinal Products. xvii