Exposé. For the dissertation thesis:

Exposé For the dissertation thesis: Comparison of a global submission of new biological entity and a new chemical entity strategic decisions and criteria for implementation Submitted to apply for the application for a dissertation at Prof. Dr. rer. nat. habil. Harald G. Schweim At the professorship for Drug Regulatory Affairs of the Mathematisch-Naturwissenschaftlichen Fakultät of the Rheinischen Friedrich-Wilhelms-Universität Bonn presented by Andrea Hörner born at Mainz August 2005 1

TABLE OF CONTENTS 1. INTRODUCTION 2. STATUS AS OF TODAY 3. QUESTIONS AND AIM OF THE DISSERTATION 4. WORKING PLAN, TIME SCHEDULE 5. SUMMARY 6. REFERENCES 2

LIST OF ABBREVIATIONS ACTD ACTR AFR AR ASEAN AUS CADREAC CCP CHMP CP CPMP CTD DCP DRA EC EE EEC EMEA EU FDA Asean Common Technical Document ASEAN Common Technical Requirements Africa Assessment Report Association of South-East Asian Nations Australia Collaboration Agreement of Drug Regulatory Authorities in European Union Associated Countries Common CADREAC Procedure The Committee for Medicinal Products for Human Use Centralized Procedure The Committee for Proprietary Medicinal Products (now named: CHMP) Common Technical Document Decentralized Procedure Drug Regulatory Authority European Commission Eastern Europe European Economic Community European Medicines Agency (formerly: The European Agency for the Evaluation of Medicinal Products) European Union Food and Drug Administration 3

ICH LA MA MAA ME MHRA MRA MRP MS NBE NCE NDA NP NtA SEA TGA UK US USA International Conference of Harmonization Latin America Marketing Authorization Marketing Authorization Application Middle East Medicines and Healthcare products Regulatory Agency Mutual Recognition Agreements Mutual Recognition Procedure Member State New Biological Entity New Chemical Entity New Drug Application National Procedure Notice to Applicants South East Asia and Western Pacific Therapeutic Goods Administration United Kingdom United States United States of America 4

1. INTRODUCTION Today, the regulatory requirements in the various countries of the world are quite different. Therefore it is very difficult - especially for companies with global approach - to develop one single regulatory approach for a marketing authorization application (MAA) for a new medicinal product on the basis of one dossier submitted simultaneously to all countries in the world. On this background it is very important to know in detail and exactly the regulatory requirements in each concerned country where a MAA should be submitted to establish a suitable regulatory strategy before the submission in order to avoid any major difficulties and bad surprise. My dissertation topic Comparison of a global submission of new biological entity and a new chemical entity strategic decisions and criteria for implementation as a first focus includes the development of a global regulatory strategy MAA of a new chemical entity (NCE) as well as the MAA for a new biological entity (NBE). For this strategy a detailed analysis of the pharmaceutical legislations and regulatory requirements in the different areas (International Conference of Harmonization (ICH) countries (which are United States of America (USA), European Union (EU) and Japan) and Non-ICH-countries) and countries in the world was made, especially to identify and discuss the commonness and the main differences. Based on the result of the analyzes of the pharmaceutical legislation and regulatory requirements for NCEs and NBEs worldwide, a global regulatory strategy for submission of a new MAA of a NCE as well as the MAA for a NBE can be developed and established. 5

2. STATUS AS OF TODAY The world covers more than 100 countries, whereas at the moment in most of them pharmaceutical legislations and regulatory requirements are established and implemented, e.g. to describe the marketing authorization (MA) procedure for medicinal products. To be able to submit a MAA in all these countries, it is important to know exactly the pharmaceutical legislations (regulations, directives, guidelines) and the regulatory requirements in each of the country in advance. Differences in the pharmaceutical legislations and regulatory requirements can be found for example in the requirement for administrative data (e.g. type of documents which are requested, legalization necessary, etc.), in the pharmaceutical data (e.g. in the requirements for stability data (ICH versus ASEAN) and also in the clinical data (e.g. placebo-controlled studies or comparative studies). Therefore, it is very important to analyze and discuss especially the differences and commonness between the pharmaceutical legislations and regulatory requirements in the different countries of the world. Due to the fact that the United States (US) and the EU are the biggest and most potential markets for medicinal products in the world, global working companies focus and analyze the US and EU pharmaceutical legislations and regulatory requirements very detailed in advance and include these requirements from EU and US normally in their development concept of a new medicinal product and consequently in their global regulatory strategy for MAA of this product. In the last few years industry recognized that other regions of the world South East Asia and Western Pacific (SEA), Middle East/Africa (ME/AFR) and Latin America (LA) are becoming increasingly important for pharmaceutical companies in their global marketing strategies. The objective of the companies is to identify ways and factors that impede the efficient registration of new medicinal products and their timely access to patients. Therefore companies with global approach realize that it is not sufficient anymore to develop their global regulatory strategy based on the regulatory requirements in EU and US but also to take into consideration the other regions of the world. Consequently, the detailed analyze of the pharmaceutical legislations and regulatory requirements in SEA, LA and Eastern Europe (EE) are necessary - in addition to the detailed analyze of the pharmaceutical legislations and regulatory requirements in EU 6

and USA - to be finally able to develop a global regulatory strategy for a MAA of a NCE and NBE. The pharmaceutical legislations and regulatory requirements in the world were established during the last 100 years, often as results of some tragedies. 1937, in the USA 100 people died after consumption of a children s syrup (Diethylene glycol poisoning) and based on this in 1938 the first Food Drug and Cosmetic Act was implemented. The resulting Food Drug and Cosmetic Act of 1938 required that proof, in the form of a New Drug Application (commonly called an NDA) has to be submitted to a new department called the US Food and Drug Administration (FDA). Anyone wishing to market a "New Drug" had to show safety for intended use in the form of a NDA. In Germany, the first Drug Law was established in 1961 as a result of the thalidomide tragedy in Europe, which happened in the early sixties. Also in Japan the first drug law was established in 1961. In EU the first drug law was established in 1965 with the Directive 65/ 65. The aim of all the regulatory legislations (drug laws) and all drug regulatory authorities (DRAs) is to provide patients with safe medicinal products as fast as possible based on the proof of quality, safety and efficacy which has to be shown due to a submission of a MAA. The changing regulatory requirement and legislations have an impact on the regulatory strategy during drug development. Consequently, due to the fact that the pharmaceutical legislation in EU was changed in the last year accordingly to the EU Review 2004, a detailed analysis of the changes in the pharmaceutical legislations and regulatory requirements in EU due to the new EU legislation is necessary, especially the changes concerning the different regulatory procedures and requirements in EU which have an impact on the regulatory strategy. The changes in the EU legislation has also an impact on other countries in the world, e.g. in the Collaboration Agreement of Drug Regulatory Authorities in European Union Associated Countries (CADREAC) which are Bulgaria, Romania and Croatia because a lot of their regulations depend on EU legislation. As a result of the review 2004 several regulations and directives have been changed and replaced. 7

The council Regulation 2309/93 (cf. 6) describes the centralized procedure (CP) in the EU and it also has established the European Medicines Agency (EMEA) (formerly: The European Agency for the Evaluation of Medicinal Products) (also called Agency )) and the Committee for Proprietary Medicinal Products ((CPMP) (now named: Committee for Medicinal Products for Human Use (CHMP)), the scientific committee - which is responsible for the evaluation of new MAAs for medicinal products for human use - under the direction of the Agency. Due to the review 2004, the council Regulation 2309/93 (cf. 6) was replaced by the new council Regulation 726/2004 (cf. 7). This new regulation was adopted at 31st March 2004 and became valid on the 20th May 2004. Other parts of the regulation are not yet implemented but have to be implemented until 20th November 2005. After the full implementation of the revised community legislation in November 2005 several changes will be made with regard to the CP. These include an expansion of the scope of the procedure, establishment of a procedure for conditional MAs, formalization of an accelerated procedure and management of compassionate use programmes. In addition, assistance will be available for small and medium-sized enterprises. Next to the council regulation 2309/93 (cf. 6) also the directive 2001/83 (cf. 1) - the codification directive - was amended by Directive 2004/27 (cf. 2) and 2004/24 (for herbal drugs) (cf. 9). The two Directives 2004/27 and 2004/24 were adopted on 31 st March 2004 and have to be implemented into national law. Therefore a transition period of 18 months is foreseen. This means that the directives have to be implemented into national law of the EU member states (MSs) until November 2005. The changes in the EU legislation have also a big impact on the CADREAC countries and their legislations (cf. 3, 4, 5, 8) because the so-called CADREAC procedures are direct linked with the EU legislations and depend on the EU legislation and the EU regulatory procedures. Another important fact which should be mentioned and discuss in detail are the Association of Southern Asian Nations (ASEAN) (cf.10). The Association of Southeast Asian Nations (ASEAN) was established on 8 August 1967 in Bangkok by the five original member countries which are Indonesia, Malaysia, Philippines, Singapore and Thailand. On 8 January 1984 Brunei Darussalam joined ASEAN, 8

Vietnam on 28 July 1995, Laos and Myanmar on 23 July 1997, and Cambodia on 30 April 1999. The objective of the ASEAN Consultative Committee on Standards and Quality Pharmaceutical Product Working Group (ACCSQ PPWG) is the development of harmonization schemes of pharmaceutical regulations of the ASEAN member countries to complement and facilitate the objective of ASEAN Free Trade Agreement (AFTA), particularly, the elimination of technical barriers to trade posed by the regulations, without compromising on drug quality, efficacy and safety. The strategy of the ASEAN Consultative Committee on Standards and Quality Pharmaceutical Product Working Group (ACCSQ PPWG) is the exchange of information on the existing pharmaceutical requirements and regulation implemented by each ASEAN member countries, to study the harmonized procedures and regulatory systems implemented in the ICH region, development of common technical dossiers with a view of arriving at MRAs (Mutual Recognition Arrangements). ASEAN also established some the so called ASEAN Common Technical Document (ACTD) and the ASEAN Common Technical Requirements (ACTR) to create harmonized requirements and a common format for all submissions of dossiers in the ASEAN countries. The ACTS is a common format and content acceptable for an application in the ASEAN member countries. The ACTR are a set of written materials (requirements or guidelines) intended to guide applicants to prepare application dossiers in a way that is consistent with the expectations of all ASEAN DRAs. From August 2003 December 2004 each ASEAN country should implement a trial implementation period. The Full implementation of the ASEAN requirements were originally planned for January 1, 2005. The transition period for the ASEAN requirements were extended to further 1-2 years; so it is possible that the full implementation will be in 2006. The development of training modules for the countries is planned. All regulatory agencies in these 10 countries have a relatively week infrastructure and small resources. The agencies are structured differently and the standards of scientific guidelines are not well established. A big problem of the agencies is the lack of consistency and the lack of transparency. To solve these problems they are consistently improving with more dialogues with the industry. 9

In all ASEAN countries a CPP from the reference country is required and builds the basis of the drug approval. In 1999 a harmonization initiative was started among the 19 ASEAN countries. One aim of this harmonization should be to harmonize quality guidelines that are valid for all countries involved. Another focus lies in the technical co-operation. As mentioned before, it is important to know exactly the pharmaceutical legislations (regulations, directives, guidelines) and the regulatory requirements in each of the country in advance to be able to submit a MAA in all these countries. Based on the result of the analyzes of the pharmaceutical legislation and regulatory requirements for NCEs and NBEs worldwide, a global regulatory strategy for submission of a new MAA of a NCE as well as the MAA for a NBE can be developed and established before the submission in order to avoid any major difficulties and bad surprise. 10

3. QUESTIONS AND AIM OF THE DISSERTATION As mentioned before, the industry recognized in the last few years also that the other regions of the world South East Asia and Western Pacific (SEA), Middle East/Africa (ME/AFR) and Latin America (LA) are becoming increasingly important to pharmaceutical companies in their global marketing strategies. With my dissertation I would like to provide a scientific evaluation and recommendation for the development of a global regulatory strategy for the MAA of a new MAA of a NCE as well as the MAA for a NBE. To be able to develop a global regulatory strategy for MAA of a NCE and a NBE, the analyzes of the commonness and the main differences between the different areas (ICH, Non-ICH) and countries in the world are one major aspect. Therefore the pharmaceutical legislations and regulatory requirements of the following countries and regions are important: EU pharmaceutical legislations and regulatory requirements US pharmaceutical legislations and regulatory requirements CADREAC pharmaceutical legislations and regulatory requirements (on the example of Romania) SEA pharmaceutical legislations and regulatory requirements (on the example of Taiwan and Singapore (as one country belonging to ASEAN)) LA pharmaceutical legislations and regulatory requirements (on the example of Brazil) The different regulatory regulations, directives and guidelines of these countries and regions relating to new MAAs will be analyzed and described in detail especially concerning the following aspects: Dossier formats which are required for a MAA (e.g. old Notice to applicants (NtA)-format, the Common Technical Document (CTD)-format or ACTD) Dossier requirements (Documents which are requested for a MAA) Different registration procedures for MAAs (e.g. normal procedures, accelerated procedures, national procedures, CADREAC procedures), e.g.: in EU: - MAA via CP described in the Council Regulation 726/2004 (cf. 7) 11

- MAA via mutual recognition procedure (MRP) described in the Directive 2004/27 (cf. 2) - MAA via decentralized procedure (DCP) described in the Directive 2004/27 (cf. 2) - MAA via national procedure (NP) described in the Directive 2004/27 (cf. 2) in Singapore(cf.11): - Full evaluation of dossier which takes 210 working days (if product is not yet approved by any DRA) - Abridged evaluation of dossier which takes 120 working days (possible for products which are already approved by one DRA and for NBE) - Verification route which takes only 45 working days (If product is already approved by two bench market DRAs (which are US (FDA); EU (EMEA), Australia (AUS) (Therapeutic Goods Administration (TGA)), United Kingdom (UK) (Medicines and Healthcare products Regulatory Agency (MHRA)) and Canada (Health Canada)) and if Assessment Reports (ARs) from these two DRAs are available) - only possible for NCEs, not for NBEs due to the complexity of NBEs In this context also the aspects concerning confidentiality of the documentation submitted to the different authorities, the intellectual property rights and patent issues should be covered shortly. Due to the fact that the pharmaceutical legislations and regulatory requirements for NCEs and NBEs vary quite a lot in most of the countries (due to the difference in the product type), it is necessary that the pharmaceutical legislation and regulatory requirements for NCEs and NBEs will be discussed and analyzed separately. Then, a comparison of the pharmaceutical legislation and regulatory requirements for a MAA of a NCE compared with the pharmaceutical legislation and regulatory requirements for a MAA of a NBE will be made. Based on the result of the analyzes of the pharmaceutical legislation and regulatory requirements for NCEs and NBEs worldwide, a global regulatory strategy for submission of a new MAA of a NCE as well as the MAA for a NBE will be developed. 12

This will be compared with a historical MAA of a NCE and NBE submitted some time ago to show the differences in the development of the product and the differences in the regulatory strategy due to the regular changes in the pharmaceutical legislations and regulatory requirements worldwide. 13

4. WORKING PLAN, TIME SCHEDULE The time schedule for my dissertation covers approximately three years. The following working plan and time schedule is planned: ½ year: Searching for all of the pharmaceutical legislation and regulatory requirements (regulations, directives and guidelines) for MAAs for EU, USA; CADREAC (Romania), SEA (Singapore and Taiwan) and LA (Brazil) ½ year: Screening and analyzes of the pharmaceutical legislation and regulatory requirements (regulations, directives and guidelines) for MAAs for EU, USA; CADREAC (Romania), SEA (Singapore and Taiwan) and LA (Brazil) 1 year: Comparison of the different regulatory requirements of the different regions and countries in the world and comparison between requirements for NCEs and NBEs 1 year: Development of a global regulatory strategy for the submission of a MAA for a NCE and a NBE and comparison with the historical case During the whole period of my dissertation the current changes in the different pharmaceutical and regulatory legislations will be tracked and will be covered until a certain point of time, which has to be fixed in my dissertation. 14

5. SUMMARY The world covers more than 100 countries, whereas at the moment in most of them pharmaceutical legislations and regulatory requirements are established and implemented, e.g. to describe the marketing authorization (MA) procedure for medicinal products. To be able to submit a MAA in all these countries, it is important to know exactly the pharmaceutical legislations (regulations, directives, guidelines) and the regulatory requirements in each of the country in advance. Due to the fact that the United States (US) and the EU are the biggest and most potential markets for medicinal products in the world, global working companies focus and analyze the US and EU pharmaceutical legislations and regulatory requirements very detailed in advance and include these requirements from EU and US normally in their development concept of a new medicinal product and consequently in their global regulatory strategy for MAA of this product. But the industry recognized in the last few years also that the other regions of the world South East Asia and Western Pacific (SEA), Middle East/Africa (ME/AFR) and Latin America (LA) are becoming increasingly important to pharmaceutical companies in their global marketing strategies. With my dissertation I would like to provide a scientific evaluation and recommendation for the development of a global regulatory strategy for the MAA of a new MAA of a NCE as well as the MAA for a NBE. First, the different pharmaceutical legislations and regulatory requirements for a new MAA of a NCE and NBE on the examples of EU, USA, CADREAC (Romania), SEA (Singapore and Taiwan) and LA (Brazil) will be discussed and analyzed in detail especially concerning the aspects required and accepted dossier format, dossier requirements (documents required for a MAA) and different regulatory procedures for MAAs. Also the aspects concerning confidentiality of the documentation submitted to the different authorities, the intellectual property rights and patent issues should be covered shortly. 15

Afterwards the comparison between the different pharmaceutical and regulatory legislations in these countries and the comparison between MAAs for NCEs and NBEs will follow. Based on this comparison a global regulatory strategy for MAA of a NCE and a NBE will be developed. Finally, this will be compared with a historical MAA of a NCE and NBE submitted some time ago to show the differences in the development of the product and the differences in the regulatory strategy due to the regular changes in the pharmaceutical legislations and regulatory requirements worldwide. 16

6. REFERENCES 1 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 2 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 3 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 4 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 5 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 6 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 7 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 8 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 9 Directive 2004/24/EC of the European Parliament and of the Council of 31 March 2004 amending, as regards traditional herbal medicinal products, Directive 2001/83/EC on the Community code relating to medicinal products for human use 10 http://www.aseansec.org/64.htm 11 Guidance on Medicinal Product Registration in Singapore 17