International Cooperation, Convergence, and Harmonization of Pharmaceutical Regulations

INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

A GLOBAL PERSPECTIVE

Pierre-Louis Lezotre, MS, PhD

To contact the Author: [email protected]

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First published 2014

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14 15 16 17 10 9 8 7 6 5 4 3 2 1 To Isabelle, Cléo and Noah

“Wisdom is to have dreams that are big enough not to lose sight when we pursue them.”

Oscar Wilde Preface

The preparation of this book has been a long journey!

It is the outcome of 5 years of serious research and reflection on cooperation, convergence and harmonization in the pharmaceutical domain. In fact, it is even more than that. It represents the knowledge acquired during 15 years of practical experience as a professional involved in global pharmaceutical regulation and, even more importantly, the result of many discussions with experts and friends on this fascinating topic.

Many people contributed to this book in numerous ways, and I am grateful to all of them.

My several professional positions, in both Europe and the United States, allowed me to meet many people that shared my passion for this topic. I particularly remember certain “debates” with Ms. Marie Dray in Washington DC or a late evening phone conversation with Dr. Murray Lumpkin where we exchanged points of view on this subject. These discussions stimulated me to further explore this particular topic and to finally write a book on it!

I would like to sincerely thank and acknowledge each of the following people who helped me in the preparation of this document:

- Mr. Maher Aljaser, MSc, Senior Pharmacist, Licensing Department, Drug Sector, Saudi Food and Drug Authority, Riyadh, Saudi Arabia - Dr. Samvel Azatyan MD, PhD, Manager, Medicines Regulatory Support Programme [MRS], Quality Assurance and Safety: Medicines, Department of Essential Medicines and Health Products (EMP), World Health Organization, Switzerland - Prof. Saleh A. Bawazir, PhD, Vice President for Drug Affairs, Saudi Food and Drug Authority, Riyadh, Saudi Arabia - Mrs. Hilde Boone, European Medicines Agency Liaison Official at the US FDA, Silver Spring, Maryland, United States of America - Prof. Sir Alasdair Breckenridge, CBE, MD, Chairman of the Board of the MHRA, London, United Kingdom - Ms. Marie Allison Dray, MBA, President of International Regulatory Affairs Group, LLC, Naples, Florida, United States of America - Dr. Hajed M. Hashan, PhD, Executive Director of Licensing Department, Drug Sector, Saudi Food and Drug Authority, Riyadh, Saudi Arabia - Dr. Christina Lim, PhD, Senior Director, International Relations, Health Products Regulation Group, Health Sciences Authority, Singapore - Dr. Murray M. Lumpkin, MD, Commissioner’s Senior Advisor and Representative for Global Issues, US FDA, Silver Spring, Maryland, United States of America xi xii PREFACE

- CAPT Justina A. Molzon, MS Pharm., JD, Associate Center Director for International Programs, Center for Drug Evaluation and Research, US FDA, Silver Spring, Maryland, United States of America - Mr. Joseph Mthetwa, MSc (Medicine), Senior Programme Officer for Health and Pharmaceuticals, Directorate of Social, Human Development and Special Programmes, SADC, Gaborone, Botswana - Ms. Margareth Ndomondo-Sigonda, MBA, MSc, Pharmaceutical Coordinator, African Union-NEPAD Planning and Coordinating Agency, Johannesburg, South Africa - Prof. Jean-Yves Pabst, PhD, PharmD, Professeur de droit et économie pharmaceutique, Doyen de la Faculté de Pharmacie de Strasbourg, Strasbourg, France - Prof. Anne-Catherine Perroy Maillols, PhD, PharmD, Professeur de droit et économie pharmaceutique, Faculté de Pharmacie, Université Lille 2, Lille, France - Dr. Lembit Rago, MD, PhD, Coordinator, Quality Assurance and Safety: Medicines, Essential Medicines and Pharmaceutical Policies, WHO, Geneva, Switzerland - Dr. Tomas Salmonson, PhD, CHMP Chair, European Medicines Agency, London, United Kingdom - Dr. Dean K. Smith, PhD, Senior Evaluator, Bacterial & Combination Vaccines Division, Biologics and Genetic Therapies Directorate, Health Canada, Ottawa, Canada - Mrs. Marie Tham, Advisor, International Collaboration, Health Products Regulation Group, Health Sciences Authority, Singapore - Prof. Daniel Vion, PharmD, Doyen de la Faculté de Pharmacie de Lille, Lille, France - Mr. Mike Ward, Manager International Programs at Health Canada and APEC RHSC Chair, Ottawa, Canada - Prof. Stuart Walker, PhD, Professor of Pharmaceutical Medicine, School of Pharmacy, Cardiff University, Wales & Founder of CMR International & the Centre for Innovation in Regulatory Science, London, United Kingdom - Dr. Cheryl Watton, MD, MBA, VP, Head of Global Safety & Epidemiology, Allergan Inc., Irvine, California, United States of America

This list includes the best international experts in the field, representing academia, regulatory authorities, and industry. Most of them have been dedicated to international cooperation and harmonization of pharmaceutical regulations for many years. They are well recognized for their incredible efforts and significant value added to several bilateral, regional, and/or global harmonization initiatives. However, despite their significant responsibilities and busy schedules, they did not hesitate and accepted with enthusiasm the opportunity to assist me.

The support from all of these international experts allowed me to have accurate and up- to-date nonproduct-related information on the ongoing worldwide harmonization and cooperation activities (Part I of this document). Follow-up discussions with some of them have also been extremely beneficial. It helped me to further develop my analysis on the matter, to challenge my ideas and proposal so that I could improve them, and to focus on the critical items. Their expert support, enthusiasm, and kindness were very much appreciated. PREFACE xiii

I would also like to express my sincere gratitude to Dr. Susan Garabedian-Ruffalo and Ms. Barbara Swenson, my two linguistic experts! The content and accuracy of a scientific or technical book is obviously important, but the form, the way you express and structure your ideas, and the clarity of the explanation and argumentation are critical. Susan and Barbara’s unconditional continuous support and constructive advice over the past years have added significant value to this book!

I hope my work will bring another piece to the puzzle and contribute to the increase of cooperation in the pharmaceutical domain. I am looking forward to further exchanges and debates on this fascinating and important subject, which is critical to protect and promote global public health!

Pierre-Louis Lezotre, MS, PhD. About the Author

Doctor Pierre-Louis Lezotre, MS, PhD, is presently Director of Global Regulatory Affairs at Allergan Inc., California, USA. He specializes in global regulatory strategy, and is recognized for his passion and expertise on international cooperation, convergence, and harmonization of regulations for pharmaceutical and biotechnology products. He has worked in different cultural environments and lived in both Europe and the United States.

Dr. Lezotre studied biology (University of Sciences, Saint- Etienne, France) and drug development (University of Pharmacy, Montpellier, France) from 1992 to 1998. He then received his Master in Regulatory Sciences in 1999 (University of Pharmacy, Lille, France). He also recently completed his PhD in Law with honors (Doctoral School of “Law, Politics and Management,” University of Law, Lille, France).

Since 1998, Dr. Lezotre has worked for several international pharmaceutical and biotechnology companies, with increasing levels of responsibility. He has served as a regional and then global regulatory leader for small molecule and biologic/biotech programs in various stages of research and development (from early discovery to life cycle management). He successfully led many global regulatory teams in supporting global registrations of major products and numerous development projects in several therapeutic areas, including dermatology, urology, neurology, and pain. He has been responsible for communications with worldwide Drug Regulatory Authorities and has also worked with external partners/ companies through co-development agreements and business development programs.

Dr. Lezotre has recently been invited to teach courses on international regulation in the Regulatory Sciences programs of the University of Southern California (USC).

xv Foreword by Professor Stuart Walker

Professor Stuart R Walker BSc PhD (Lond) MFPM FRSC FIBiol FRCPath, is an Independent Consultant in Pharmaceutical Medicine and Founder of both CMR International and the Centre for Innovation in Regulatory Science. For the past thirty years he has also held the position of Professor of Pharmaceutical Medicine, University of Wales, Cardiff, and he is a Fellow of the School of Pharmacy, London University. Professor Walker spent ten years at London University, which included lecture- ships in biochemical pharmacology at St Mary’s Hospital Medical School and Clinical Pharmacology at the Cardiothoracic Institute. This was followed by eight years with Glaxo Group Research in the UK where he had international responsibility for several major clinical research programmes. His current research interests include studies to improve productivity, efficiency, and decision making in global drug development and the regulatory review process, developments in the regulatory environment in the emerging markets of the Asia-PacificRegion, Latin America, Africa, and the Middle East, as well as public policy issues that relate to these research activities. During his research career, Professor Walker has supervised over 25 PhD programs, co-authored 250 research papers, and co-edited 24 books in the fields of toxicology, drug discovery , clinical development, regulatory policies, and more recently in the benefit/risk assessment of medicines. Professor Walker has been a member of a number of academic, professional, and industrial committees and sits on the editorial boards of several scientific journals. He was given the Drug Information Association Outstanding Service Award in 2001 and received a Lifetime Achievement Award from Informa in the same year and the TOPRA lifetime achievement award in 2011. He is frequently involved in the organization of national and international meetings on key issues that concern the pharmaceutical industry and regulatory review and has lectured extensively throughout Europe, the United States, Japan and the Asia-Pacific Region, Latin America, and the Middle East.

The international cooperation and harmonization of pharmaceutical regulations are the critical factors for the successful development and review of medicines to ensure their timely availability for patients. The past 25 years have witnessed major challenges in this area, but also significant changes, particularly in the 1990s with the advent of the ICH initiative between pharmaceutical companies and regulatory agencies in Japan, Europe, and the USA. I was privileged to be involved in this program and sat on several of the working parties that saw the reduction in animal requirements, resources, and time that resulted from more than 50 harmonized regulatory requirements. Subsequently, I was pleased to see many other countries and regions were given the opportunity to join and they have benefitted from this initiative. One of the keys to the future has to be the possibility of regional reviews for medicines to maximize the limited resources and expertise in the world rather than every country endeavoring to become a competent authority.

xvii xviii FOREWORD BY PROFESSOR STUART WALKER

It is for this reason I welcome the publication of this book by Pierre-Louis Lezotre. It is the most comprehensive account that I have read on the harmonization of regulatory requirements and processes for the development and review of medicines. The reader will find that the book is well laid out and structured in a way that is easy to read and to follow the relevant arguments. Pierre-Louis has conveniently divided it into three parts, by first providing the current status of cooperation and harmonization within the pharmaceutical sector. This is followed by a critique and an evaluation of the critical parameters and influencing factors from a variety of initiatives in this area. Finally he has included several recommendations for action and measures to support the next steps for cooperation and harmonization.

One of the objectives for writing this book has been to argue for the establishment of a global coalition of regulators and to respond to an increasing demand for further cooperation within the pharmaceutical sector. I thought it was of particular value to have a comprehensive up-to-date review of both the key global harmonization initiatives such as the World Health Organization (WHO) and the International Conference on Harmonization of Technical Requirements for the Registration of Pharmaceuticals for Human Use (ICH), and a number of important regional harmonization initiatives which have had varying degrees of success to date. The uniqueness of this book is also found in the section on the value of harmonization in the pharmaceutical domain as well as identifying the critical parameters for harmonization and the influencing factors.

However, the true value of this book lies in the significant amount of time and attention that has been given to several well thought out recommendations that are clearly laid out and presented in a logical coherent fashion with the relevant arguments in support of these suggestions and the challenges that would be faced were they to be implemented. To write a book like this is very ambitious. However, it is of such fundamental importance with regard to the future of drug development and patients’ access to medicines worldwide that I believe that this book is long overdue.

The review that Pierre-Louis provides is particularly significant in that the first half of the book is descriptive, whereas the second part underlines the lessons that are to be learned from regional and global initiatives while at the same time reviewing the challenges that they present going forward. I was particularly pleased to see an overview of the key principles of the proposed global pharmaceutical system that should be put in place as a basis for considering the recommendations that are made.

This book provides a well argued global perspective for international cooperation and harmonization of pharmaceutical regulations and will make a major contribution to the literature in this field. It is a book that should be on the shelves of every pharmaceutical company and regulatory authority and must be read by all stakeholders who are interested in seeing patients have improved access to innovative medicines that are fundamental to the health of our nations. Introduction

Pharmaceutical productsa are not usual “commodities.” In fact, they are some of the most regulated marketable products as they provide fundamental health needs to the public, and their evaluation and control require a high level of expertise.

Access to essential and quality medicines is indeed considered an integral component of the right to health, which is a basic human right that first emerged as a social right in the World Health Organization (WHO) Constitution in 1946b and in the Universal Declaration of Human Rights in 1948 [1]. This right to health was then recognized in several international and regional texts [2–8]. In 2000, the United Nations (UN) reemphasized that health is a fundamental human right indispensable for the exercise of other human rights, and that this right to health includes certain components that are legally enforceable. They also outlined the principles of accessibility, availability, appropriateness, and assured quality to goods and services, which include medicines [9]. In 2011, access to essential, high-quality, and affordable medical products as one aspect of equity in public health was reemphasized again [10].

To meet this fundamental human right of access to high-quality, safe, and effective medicines, many countries have proactively developed pharmaceutical regulations to control their pharmaceutical market [11]. In many cases, the revision and improvement of national pharmaceutical regulations was also driven by tragedies.c

Pharmaceutical regulations, or medicines regulations, have been defined as the combination of legal, administrative, and technical measures that governments take to ensure the safety, efficacy, and quality of medicines, as well as the relevance and accuracy of product information [12,13]. The term “regulation” includes a variety of texts (e.g. guidelines, recommendations, procedures, policies, etc.) that have different legal bases and authority.

a The terms “pharmaceutical product,” “medicine,” “medicinal product,” and “drug” are interchangeable in this book. b The WHO Constitution states: “The enjoyment of the highest attainable standard of health is one of the fundamental rights of every human being without distinction of race, religion, political belief, economic or social condition.” c For example, in the United States (US), the tragic incident with Elixir Sulfanilamide that killed more than 100 people in 1937 was the trigger for enactment in 1938 of the Federal Food, Drug & Cosmetic Act. In many countries in Europe, the trigger was the thalidomide tragedy of the 1960s.

International Cooperation, Copyright © 2014 Pierre-Louis Lezotre. Convergence and Harmonization of Pharmaceutical Regulations 1 Published by Elsevier Inc. All rights reserved. 2 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

It is important to note that most countries differentiate between pharmaceutical legislation and pharmaceutical regulations [14,15] as follows:

▸ “Legislation” refers specifically to the creation of laws that are usually written in fairly general terms to meet present and possible future needs. They have language that enables the government to issue regulations based on the law. Passing new laws requires a lengthy process and involves a country’s legislative body.

▸ “Regulations” are the rules established by an agency that interprets the laws to facilitate their practical implementation. They can be passed more quickly and simply than laws. For example, the United States Food and Drug Administration (US FDA) has the rule-making responsibility for the “Food, Drug, and Cosmetic Act” of 1938 in the United States (US). Regulations have a way of expanding far beyond the size of the enabling law. For example, the “Food, Drug, and Cosmetic Act” consisted of a mere 19 pages. Today, Code of Federal Regulations Title 21, which enforces the law, requires nine volumes containing over 4,000 pages.

The objective of this book is to analyze and discuss the international convergence and harmonization of pharmaceutical regulations. The harmonization of national pharmaceutical legislation, which is limited to the situations where countries initiate a process of integration, although briefly discussed in some sections (e.g. the section on Europe), is not in the scope of this analysis. Also, other regulated health products (e.g. medical devices, cosmetics, and veterinary products) are not covered, though certain harmonization initiatives have also been established for these products.d

All national pharmaceutical regulations in the world have the same objectives, which are to guarantee and promote public health. The vast majority of national assessments of medicines are based on the same criteria of quality, safety, and efficacy. However, the implementation of processes and systems to achieve these same objectives has been very different, and national regulations and technical requirements have varied, sometimes significantly. Different models for regulation of medicines exist across the world, and these are determined by the size of the pharmaceutical market and the availability of resources, as well as the public health needs. Varied histories, cultures, and political experiences, as well as economic profiles of countries, have determined the construction of different institutional pharmaceutical systems. Moreover, despite some progress in past years, there remain major differences between developed and developing countries in terms of regulatory capacity. The level of development of pharmaceutical systems and regulations, and the availability of medicines, vary a lot between different regions of the world. This gap among regulatory systems is in fact increasing rather than decreasing due to the human and financial resources gap that exists between well-resourced and resource-constrained regions [16]. There are also major differences within regions or subregions. For example, the number of d Acknowledging the increase of combination products that incorporate both a medicine and a medical device, it is critical that all these harmonization efforts be done in parallel to avoid divergences between countries on one aspect that might impact the availability of these combination products. INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 3 medicines registered varies widely from country to country in the “Southern African Devel- opment Community” (SADC), from 1,407 in Mozambique to a maximum of 12,000 in South Africa [17]. Many developing countries still lack effective pharmaceutical regulations and systems due to lack of resources and expertise. In these countries, patients still do not have access to the fundamental right to health.

In addition, in the past several decades, the pharmaceutical environment has radically changed, and the regulatory systems in place today are challenged by the rapid evolution of societies worldwide, including factors such as [18]: ▸ Increased globalization of the general economy and trade and the pharmaceutical market ▸ Reorganization of the pharmaceutical industry, which increased its international presence and began to globalize its activities ▸ The declining number of new medicines and increasing research and development (R&D) costs ▸ Development of new technologies ▸ Increasing public concerns about safety and demands for more transparency, which require better communication strategies to keep the public informed ▸ The global financial crisis that increased pressure on all players in the pharmaceutical sector ▸ The rise of new emerging economies, which do not always have stable regulatory systems with appropriate resources, capacity, and expertise

First, the divergences in regulations became an important problem for an industry that desired to market its products globally as it required duplication of studies and testing. Reg- ulatory professionals need to take into account many different regulations, and sometimes conflicting requests, to develop global regulatory strategies. Second, as international markets expand and companies operate more and more internationally, the task of Drug Regulatory Authorities (DRAs) to assess compliance with legislation and monitor the safety of medicines becomes increasingly difficult and resource intensive. In response to this overall situation and to address the challenges of globalization, which can pose potential risks to public health, it became increasingly important that regulators communicated and exchanged information with other worldwide counterparts. However, the differences in regulation and pharmaceutical systems impeded this communication and exchange.

This rapid and important change of environment, creating new opportunities but also new challenges, prompted the need for strategic partnerships. It triggered an increase of cooperation between countries that understood that working together was essential in order to respond to these new challenges.

The basic principle of international cooperation is to establish bilateral and multilateral efforts to leverage the human, scientific, and financial resources and the knowledge and experience of other key regulatory authorities to avoid duplication of efforts; this makes activities more efficient and allows limited resources to be focused on higher-risk areas of concern [19]. This increased cooperation between worldwide regulators necessitates proactive, deliberate 4 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS efforts towards the harmonization of regulations, practices, and requirements to eliminate or reduce differences.

Harmonization of pharmaceutical regulations has been defined as the process of inte- grating national standards with international standards in a manner universally acceptable to participating countries in order to facilitate efficient global drug development and local registration. This process encompasses technical and scientific requirements, the format and content of dossiers, and also the assessment and review of practices [20]. This process has to be distinguished from regulatory convergence, which is an approach whereby regulatory requirements across countries/regions become more similar or aligned over time as a result of the gradual adoption of internationally recognized technical guidance documents, standards, and best practices. This convergence approach, defined by the Life Sciences Innovation Forum of the Asia-Pacific Economic Cooperation (APEC) initiative, does not require harmonization of regulations [21-1, 21-2].

The aim of both harmonization and convergence is to eliminate duplication and to ensure the efficient use of resources in order to allow faster access to safe and effective medicines of good quality.

Harmonization of pharmaceutical regulations requires strong cooperation between worldwide regulators, but also with other stakeholders. Cooperation and harmonization are indeed interdependent. Cooperation requires harmonization of standards and languages, and harmonization implies cooperation. It would not be logical to discuss harmonization without cooperation and vice versa. Therefore, this book analyzes both aspects: the harmonization of pharmaceutical regulations and the international cooperation scheme.

Cooperation and harmonization of standards in the pharmaceutical domain are already a reality and have become increasingly important during the past several decades with a high level of commitment to these activities by all stakeholders. In certain countries, cooperation and harmonization of requirements were established by law as a priority of the DRA. For example, in the US, legislators decided that such activities are an integrated part of the US FDA’s mission. Indeed, the “Food and Drug Administration Modernization Act” of 1997 stated that one of the missions of the FDA is to “participate through appropriate processes with representatives of other countries to reduce the burden of regulation, harmonize regulatory requirements, and achieve appropriate reciprocal arrangements” [22].

Over the past several years, many cooperation and harmonization initiatives have been initiated at the bilateral, regional, and global levels as a response to the current geo-economic-political situation. Even if the objectives of the regulators participating in these processes are always to safeguard global public health and continue to ensure availability of safe and effective products, all these initiatives have taken a variety of forms, from informal cooperation to full integration of regulatory mechanisms and systems. All these multiple worldwide cooperation and harmonization programs have also evolved rapidly over the past several decades. INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 5

As previously mentioned, cooperation, convergence, and harmonization is not an end in itself. Elimination of differences, agreement on common standards, and the increase of cooperation are needed to protect and promote global public health. It is therefore important to thoroughly analyze the value and impact of the harmonization and cooperation process, and to determine if all the efforts have indeed met expectations. After many years of experience, it seems important to have a thorough evaluation to answer several important questions: ▸ What has been the benefit of the multiple harmonization and cooperation initiatives so far? ▸ Should such processes continue? Are there any other alternatives to resolve current challenges? ▸ Should current initiatives and projects be improved? If so, how and what are the priorities? ▸ Would greater harmonization and closer cooperation be beneficial? Is it possible? Is it necessary? What are the limits of this process? How should this increased cooperation and harmonization be structured and organized globally?

This book goal is to answer the important questions listed above. It provides the current status of this complex and broad phenomenon of cooperation, convergence, and harmonization in the pharmaceutical sector (Part I),e and thoroughly evaluates the added value of cooperation, convergence, and harmonization and its critical parameters and influencing factors (Part II) in order to recommend actions and measures to support the next steps for cooperation, convergence, and harmonization (Part III).

e The objective of this review is not to produce an exhaustive list of all worldwide harmonization initiatives or to list all the harmonized topics from each initiative, but to have an overall understanding of the global situation. P A R T I State of Play and Review of Major Cooperation Initiatives

There are topics that are global in nature for which resolution of related issues and problems cannot be restricted to any one country or region. These topics require cooperation between countries and harmonization of standards. Climate change, pollution, and water supply are good examples of issues that need to be resolved at a global level as they extend across borders. Public health, which includes availability of relevant medicines, is another topic that needs to be considered at a global level, as demonstrated by recent pandemic crises.

Many aspects of increased globalization also have profound implications on pharmaceutical regulation worldwide. In general, globalization of the economy (with increased travel of people and exchange of goods, finance, and information), and also globalization of the pharmaceutical market (including development, manufacture, and distribution activities), requires increased cooperation and harmonization of pharmaceutical standards and regulation. Pharmaceutical industries have asked for better harmonization of requirements for the development and manufacture of pharmaceutical products to avoid duplication of work that ultimately creates delays in drug availability [23].

In this context, harmonization of pharmaceutical regulations has naturally become an important topic of discussion among worldwide Drug Regulatory Authorities (DRAs). Over the past several decades, they have been working to end an isolationist attitude that cannot resolve current worldwide issues and challenges. As a result, many cooperative initiatives (bilateral, regional, and global) were established, and harmonization efforts have been enhanced. All these initiatives can be very different in scope (some are part of a broader harmonization initiative), level of harmonization (depending on the political support/commitment), organization (well structured versus simple discussion), or advancement (established process versus pilot projects), but they all work towards harmonization of requirements and/or practices. Increased exchange of information on a regular basis (e.g., more than 26 countries and international organizations from Australia to Vietnam now have agreements to share information with the United States Food and Drug Administration [US FDA]) [24] also contributes to the natural convergence of requirements and practices.

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Harmonization models can be distinguished by their scope and objectives. Indeed, the spectrum of collaborations varies from simple technical cooperation to full integration of systems and regulations:

▸ Simple technical and scientific intergovernmental cooperation model: In this type of cooperation model, countries agree to exchange expertise and experience to accelerate the availability of medicines (e.g., the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use [ICH], the Pan American Network for Drug Regulatory Harmonization [PANDRH], the European Union [EU]/United States of America [US] bilateral agreement).

▸ Integration model: In this type of agreement, most of the time driven by political decision, deeper harmonization of regulation is achieved with the creation of supranational central authorities in order to support integration and/or creation of a single market (e.g., EU, the Association of Southeast Asian Nations [ASEAN]). In this case, harmonization of standards and regulations is critical in reducing trade barriers. In this model, countries give up some of their autonomy on certain matters by transferring the power to make decisions to the common supranational authority or by automatically recognizing decisions from the other party (via mutual agreement mechanisms).

The African Medicines Registration Harmonization (AMRH) initiative has defined five iden- tifiable levels of harmonization (Figure 1).

FIGURE 1: Levels of Harmonization.

Not Harmonized Fully Harmonized

Working Collaborate on Harmonized Recognition of Centralized independently selected topics standards and decisions made registration broad collaboration elsewhere

Member States Member States Member States have National verification Centralized operate collaborate on common technical based on information registration on independently to selected topics (e.g., requirements and about decisions made behalf of strengthen regulatory certain technical collaborate broadly elsewhere and/or participating capacity and each guidelines, Good (e.g., from Mutual Recognition Member States country has its own Manufacturing intensified Agreements technical Practice inspection, information requirements and information exchange including format for exchange, etc.) sharing assessment registration and inspection applications reports to joint evaluations and inspection)

Source: New Partnership for Africa's Development (NEPAD) and WHO, “African Medicines Registration Harmonization (AMRH) Initiative: Summary, Status and Future Plans,” November 2009.

To facilitate cooperation, a Mutual Recognition Agreement (or Arrangement) (MRA) can be signed by one or more parties to mutually recognize or accept some or all aspects of one another’s requirements. They can be concluded at the technical level (e.g., the INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 9 confidentiality arrangements between the US FDA and European Medicines Agency [EMA], or the MRA between EU and Australia) or at the government level (e.g., European Treaty).

I-1) GLOBAL INITIATIVES

These multilateral initiatives are major projects as they involve multiple organizations and countries and represent the highest degree of harmonization. The objective of this technical and scientific intergovernmental cooperation is to globally discuss scientific issues that support the decisions made by individual governments and international regulatory bodies in order to achieve global scientific consensus. The goal is to facilitate the development of new medicines and to make them available to the maximum number of people worldwide. There is no intent of full integration of systems and regulations. The main difficulty faced by these initiatives is the complexity and management of the structure due to the important number of participants (e.g., the World Health Organization [WHO] has 194 Member States) and the diversity of needs, challenges, and level of development of its members.

I-1.1) World Health Organization The World Health Organization (WHO) was established in 1948 as a specialized agency of the United Nations (UN) [25]. It is accountable to its Member States and works closely with other entities of the UN system.

This agency has a very broad scope of responsibilities as it is the directing and coordinating authority for international health matters and public health within the UN system. WHO is well known for some of its work (e.g., the coordination of influenza surveillance and monitoring activities, emergency assistance to people affected by disasters, mass immunization campaigns or actions against Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome [HIV/AIDS], tuberculosis, and malaria). However, WHO undertakes many more activities because it is responsible for providing leadership on global health matters, shaping the health research agenda, setting norms and standards, articulating evidence-based policy options, providing technical support to countries, and monitoring and assessing health trends. Most of these core functions, as further defined in its “11th General Programme of Work,” [26] rely on cooperation and harmonization of standards.

This focus on regional and global collaboration, and especially aid from developed countries to developing countries, is aligned with the UN Millennium Development Goals (MDGs).a a The United Nations Millennium Development Goals (MDGs) are eight international goals that UN Member States (and international organizations) have agreed to achieve by the year 2015. They are derived from the United Nations Millennium Declaration, signed in September 2000, which endorsed a framework for development and commits world leaders to combat poverty, hunger, disease, illiteracy, environmental degradation, and discrimination against women. These MDGs are interdependent and several relate either directly or indirectly to health. WHO is therefore very involved in this process and works with countries to achieve the health-related MDGs. 10 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

Indeed, the objective of these MDGs is that countries and development partners work together to improve the global situation and resolve major issues. A number of specific targets and indicators have been identified to monitor progress towards the goals. Goal 8 (“Develop a global partnership for development”) specifically recognizes the role of developed nations and addresses global cooperation and partnerships.

WHO has worked in the area of pharmaceuticals since its creation approximately 60 years ago. During this time, many products and services have been created that are widely recognized as core functions of WHO.

The role of WHO in pharmaceutical regulations is based on its constitutional mandate and various World Health Assembly (WHA) resolutions. This support is twofold. One aspect relates to the development of internationally recognized norms, standards, and guidelines. The second relates to providing guidance, technical assistance, and training in order to enable countries to implement global guidelines to meet their specific medicines regulatory environment and needs [27].

I-1.1.1) Membership All countries that are members of the UN may become members of WHO by accepting its constitution. Other countries may be admitted as members when their application has been approved by a simple majority vote of the World Health Assembly (WHA). Territories that are not responsible for the conduct of their international relations may be admitted as associate members upon application made on their behalf by the member or other authority responsible for their international relations. Members of WHO are grouped according to regional distribution.

WHO’s strength lies in its neutral status and nearly universal membership. Today, it represents 194 countries and two associate members (Puerto Rico and Tokelau). One country is an observer (Vatican) [28,29].

I-1.1.2) Structure The organization is headed by the Director-General,b but the WHA is the supreme decision- making body for WHO. It generally meets in Geneva, Switzerland in May of each year, and is attended by delegations from all Member States. Its main function is to determine the policies of the organization. The Health Assembly also appoints the Director-General (on the nomina- tion of the Executive Board), supervises the financial policies of the organization, and reviews and approves the proposed budget.

b The Director-General is WHO’s chief technical and administrative officer and oversees the policy for the organization's international health work. INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 11

The work of the Assembly is supported by the Executive Board, which it elects. This executive arm of the Assembly is composed of 34 members technically qualified in the health field. Members are elected for three-year terms. The main board meeting, at which the agenda for the forthcoming Health Assembly is agreed upon and resolutions for forwarding to the Health Assembly are adopted, is held in January. A second shorter meeting in May, immediately after the Health Assembly, is held to address more administrative matters. The primary functions of the Board are to give effect to the decisions and policies of the Health Assembly, to advise it, and generally to facilitate its work.

Under the leadership of the Director-General,c more than 8,000 people from more than 150 countries work for WHO. This WHO staff includes health professionals (including medical doctors, public health specialists, epidemiologists, and scientists) as well as managers, economists, administrators, and other professionals. They are located in country offices, six regional offices, and at the headquarters in Geneva, Switzerland [30].

One of the unique aspects of WHO is its decentralized structure. WHO’s work is a great combination of actions at the country, regional, and global levels. These efforts to decentralize its structure are aimed at getting closer to the ground (field) where decisions made can be more responsive to actual needs. Indeed, this decentralized and regionalized structure provides WHO with multiple opportunities for engaging with countries.

I-1.1.2.1) Corporate Level WHO’s global headquarters is located in Geneva, Switzerland.

The team based at the global headquarters supports and builds on all of the regional and local efforts. It sets global policies and standards, facilitates technical support to regions and countries, monitors and publicizes progress, and helps mobilize political and financial support.

At the WHO headquarters, medicine activities are conducted within the cluster of Health Systems and Services (HSS) and are coordinated by the Department of Essential Medicines and Health Products (EMP). This department (which employs about 100 staff members [31]) is involved in the harmonization of pharmaceutical regulations because it coordinates various activities in the areas of quality assurance (e.g., the International Pharmacopoeia, International Nonproprietary Names [INN], prequalification of medicines, counterfeit medicines), regulation and legislation (e.g., International Conference of Drug Regulatory Authori- ties [ICDRAs]), and safety and efficacy (e.g., drug alerts). These activities comprise guideline development, workshops, and training courses, coordination and promotion of pharmacovigilance for global medicine safety, regulatory and other information exchange, and review of narcotic and psychotropic substances.

c Dr. Margaret Chan is the current Director-General of WHO. She was first appointed by the World Health Assembly on November 9, 2006 and then appointed for a second term in 2012. 12 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

I-1.1.2.2) Regional Level WHO Member States are grouped into six regions, each of them having a regional office: ▸ WHO Regional Office for Africa in Brazzaville, Republic of Congo. ▸ WHO Regional Office for Europe in Copenhagen, Denmark. ▸ WHO Regional Office for Southeast Asia in New Delhi, India. ▸ WHO Regional Office for the Americas/Pan American Health Organization (PAHO) in Washington DC, United States. ▸ WHO Regional Office for the Eastern Mediterranean in Cairo, Egypt. ▸ WHO Regional Office for the Western Pacific in Manila, The Philippines.

Each of WHO’s regional offices are the first point of contact for country offices that need extra technical or financial help. These regional offices also give special attention to adapting global policies to fit specific needs in their regions. Indeed, the regional level is important in the WHO organization as it links the global strategy and plan with the country’s reality and needs.

They play a key role in the implementation of WHO norms and standards by ensuring that: ▸ Country and regional needs are taken into consideration when WHO norms and standards are developed ▸ Global guidelines and internationally recognized norms and standards are appropriately implemented in their regions (in the context of their own specific regulatory environment and challenges) by providing guidance, technical assistance, and training

In addition to global activities coordinated from WHO headquarters, WHO regional and country offices can also carry out a variety of medicine-related activities specific to their regions.

I-1.1.2.3) Country Level In addition to the regional and headquarters offices, WHO has 145 country offices that cover 159 Member States.d There are also two field offices (the WHO Humanitarian Assistance Office in Pristina, Kosovo and the West Bank and Gaza Office) and offices covering two different areas, the US–Mexican border field office in El Paso, Texas (US), and the Office of Carib- bean Program Coordination in Barbados. WHO has also established “WHO liaison offices” in key locations (e.g., at the European Union in Brussels, Belgium, at the African Union and the Economic Commission for Africa in Addis Ababa, Ethiopia, in Washington DC, US, and at the UN in New York City) and more than 10 “technical offices” (e.g., the European Observatory on Health Systems and Policies in Berlin, Germany) [32].

d Some countries that do not have a physical WHO country office are served by the WHO Representative of another country (for instance, the WHO Representative to Malaysia covers not just Malaysia, but also Brunei, Darussalam, and Singapore). INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 13

Approximately 40% of WHO country offices are either owned or supported by the government and ministries of health. Some of these WHO country offices are located in independent premises either rented or owned by WHO, while others are located within ministries of health or UN common premises.

These country offices are led by the Head of WHO Office (HWO), who are designated by the Director-General and by the respective regional Directors. The HWO manages WHO core functions at the country level and provides leadership in the following key functional areas: ▸ Advocacy, partnership, and representation ▸ Support for policy development and technical cooperation ▸ Administration and management

It is important to note that WHO is focused on needs of countries and emphasizes in particular the decentralization process that is aimed at increasing WHO’s impact on health and development at the country level. This country focus tailors WHO’s technical collaboration to the needs and capacities of each Member State, with a special emphasis on the poorest countries and most fragile contexts.

The key principles guiding WHO cooperation in countries are [33]: ▸ Ownership of the development process and projects by the country ▸ Alignment with national priorities and strengthening national systems ▸ Harmonization with the work of sister UN Agencies and other partners in the country towards better aid effectiveness ▸ Collaboration as a two-way process that fosters Member States’ contributions to the global health agenda

WHO’s country presence is the platform for effective cooperation with countries for advancing the global agenda, contributing to national health strategies and planning, and bringing country realities and perspectives into global policies and priorities. Accord- ing to the above principles and its structure, WHO is indeed able to focus on countries’ needs and better define its priorities to actively support the development, implementation, monitoring, and assessment of national health policies, strategies, and plans. But it also allows for better monitoring implementation of global agreements such as the Millennium Development Goals (MDGs) and the International Health Regulations (IHR [2005]).

These activities in countries are governed by the Country Cooperation Strategy (CCS), which is WHO’s key instrument to guide its work in countries. It is a medium-term vision (generally covering four to six years) for its technical cooperation with a given Member State, in support of the country's national health policy, strategy, or plan. It is an organization-wide reference that guides partnership, planning, budgeting, and resource allocation.

WHO also established the Department of Country Focus (CCO) to support and advocate for WHO country offices, develop the capacity of WHO country teams for effective engagement 14 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS in partnership platforms, and facilitate and monitor WHO’s engagement in the aid effectiveness agenda at the country level. For example, CCO provides support for the development, dissemination, and use of the Country Cooperation Strategy.

I-1.1.2.4) Supporting Bodies

▸ Expert Committees: Expert committees have an important role in WHO activities. They are defined in the WHO constitution.e In addition to the constitution, regulations for expert advisory panels and committees are also included in the WHO document entitled “Regulations for Expert Advisory Panels and Committees.”f

An expert committee is the highest official advisory body to the Director-General of WHO as well as to all the organization’s Member States. It is established by the WHA or by an Executive Board decision. There are various types of WHO expert committees. For example, the WHO Expert Committee on Specifications for Pharmaceutical Preparations (ECSPP) has been providing, for more than 60 years, recommendations and tools to assure the quality of medicines from their development phase to their final distribution to patients. There is also the Expert Committee on Biological Standardization (ECBS), which is as old as the ECSPP.

▸ WHO Collaborating Centers: In addition to its structured organization, the WHO has been supported since its creation by its “collaborating centers.” These are institutions such as research institutes and parts of universities or academies that are designated by the Director-General to carry out activities in support of WHO programs. Currently there are over 800 WHO collaborating centers in over 80 Member States working with WHO in several areas (one of them being “Pharmaceu- ticals”). Several collaborating centers may exist for the same topic (e.g., international classifications or traditional medicines) and form a specific network to help WHO regarding this specific topic.

The function of these collaborating centers is manyfold, and may include the following: ▸ Collection, collation, and dissemination of information ▸ Standardization of terminology and nomenclature of technology, diagnostics, therapeutic and prophylactic substances, and methods and procedures ▸ Development and application of appropriate technology ▸ Provision of reference substances and other services ▸ Participation in collaborative research developed under the Organization’s leadership, including the planning, conduct, monitoring, and evaluation of research, as well as promotion of the application of research results ▸ Training, including research training ▸ Coordination of activities carried out by several institutions on a given subject e Reference is made to Expert Committees in Chapter V, Article 18, as well as in Chapter VIII, Articles 38–40. f See Annex, “Rules of Procedure for Expert Committees.” INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 15

WHO collaborating centers are an essential and cost-effective cooperation mechanism that enable the organization to fulfill its mandated activities and to harness resources far exceeding its own. WHO gains access to top centers worldwide and the institutional capacity to ensure the scientific validity of global health data. In addition to providing resources and support, these collaborating centers also enhance national participation and collaboration in WHO activities and therefore facilitate implementation of agreements and projects. In line with the WHO policy and strategy of technical cooperation, they also participate in the strengthening of country resources in terms of information, services, research, and training, in support of national health development.

I-1.1.3) History When diplomats met in San Francisco, California, US to form the UN in April 1945, one of the things they discussed was the idea to set up an international health organization following a proposal from representatives of Brazil and China [34].

On February 15, 1946, the Economic and Social Council of the UN instructed the Secretary- General to convene a conference to frame the constitution of this new international organization. The Technical Preparatory Committee met in Paris from March 18 to April 5, 1946 and drew up proposals for the constitution that were presented to the International Health Conference in New York City, New York, US between June 19 and July 22, 1946. On the basis of these proposals, the Conference drafted and adopted the constitution of WHO, signed July 22, 1946 by representatives of 51 members of the UN and of 10 other nations. The Conference also established an Interim Commission to carry out certain activities of the existing health institutions until the entry into force of the Constitution of the WHO on April 7, 1948g when the 26th of the governments who had signed it ratified its signature [35].

The first WHA opened in Geneva, Switzerland on June 24, 1948. Delegates from 53 of WHO’s 55 original Member States came to agreement on WHO’s top priorities.

It is important to note that as early as 1949, the 2nd WHA laid down the policy (which has been constantly followed since) that the organization should not consider “the establishment, under its own auspices, of international research institutions” and that “research in the field of health is best advanced by assisting, coordinating and making use of the activities of existing institutions.” This policy has been very important, as it influenced the way WHO has been structured (with the most importance given to its collaborating centers).h

At its creation, WHO took over responsibility for the International Classification of Dis- eases (ICD),i which dates back to the 1850s and was first known as the International List

g April 7 has since been designated “World Health Day” to celebrate this event. h There is, however, an exception to that policy in the WHO Region of the Americas, where a number of “international health centers,” some with regional (hemisphere-wide), others with subregional functions, have been set up, and are financed and administered by the Pan American Health Organization. i The ICD is used to classify diseases and other health problems, and has become the international standard used for clinical and epidemiological purposes. 16 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS of Causes of Death. WHO also started to publish its Bulletin, which is today an international peer-reviewed monthly journal of public health with a special focus on developing countries.j

In its early years, WHO’s priority was the prevention and control of specific diseases (e.g., malaria, tuberculosis, smallpox, yaws, onchocerciasis, and venereal disease), some of which are still a problem today. They also focused on women’s and children’s health and nutri- tion, and environmental sanitation. WHO’s work has since grown to cover other (sometimes new) health problems (including polio, HIV/AIDS, and Severe Acute Respiratory Syndrome [SARS]), but it also works to control tobacco and alcohol use and to promote diet and physical activity to prevent the four main noncommunicable diseases (cardiovascular disease, cancer, chronic lung diseases, and diabetes) [36].

WHO has also been increasingly involved in the global regulation and control of medicines. In 1977, the first essential medicines list was released two years after the WHA introduced the concepts of “essential drugs” and “national drug policy.” One hundred and fifty-six countries today have a national list of essential medicines. WHO has also funded many projects over the years to facilitate global cooperation and harmonization of standards. The purpose of all these activities in the pharmaceutical domain is aimed at increasing global and equitable access to safe, effective medicines of assured quality. This specific goal is derived from the overall objective of WHO to improve and maintain global public health. This objective has been regularly reiterated in several WHA resolutions and during other events such as the ICDRAs. In 1978, the International Conference on Primary Health Care (Alma-Ata, Kazakhstan) set the historic goal of “Health for All,” to which WHO continues to aspire. More recently, the UN MDGs have further clarified the objectives and priorities of global cooperation derived from the UN Millennium Declaration signed in September 2000.

I-1.1.4) Harmonization and Cooperation Process One of WHO’s mandates is “to develop, establish and promote international standards with respect to food, biological, pharmaceutical and similar products” [37]. WHO Member States (especially developing countries) rely on WHO for expertise and guidance in regulation, safety, and quality assurance of medicines through development and promotion of international norms, standards, guidelines, and nomenclature.

To achieve this goal, WHO relies on cooperation and uses its decentralized organization to facilitate implementation of projects and agreed-upon standards.

The harmonization activities are initiated according to the WHO’s Medicines Strategy. Trig- ger actions to initiate a new project or development of a standard are given at different levels and bodies (i.e., the WHA, Executive Board Resolutions, ICDRAs, or WHO programs and j Since it was first published in 1948, theBulletin has become one of the world’s leading public health journals. As the flagship periodical of WHO, the Bulletin draws on both WHO experts (as editorial advisors, reviewers, and authors) and external collaborators. INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 17 clusters). These projects and standards are then developed through a vast global consultation process involving WHO Member States, national and regional authorities, international agencies, and with specialists from industry, national institutions, nongovernmental organizations, etc. Project updates and approved standards become publically available through the extensive list of WHO publications to support national, regional, and global health strategies.k Because the global dissemination and exchange of information is important, WHO secures the broad international distribution of its publications and encourages their translation.l This ensures the widest possible availability of authoritative information and guidance on health matters.

The Department of EMP, based at the WHO global headquarters in Geneva, works closely with expert committees, other regulators, and relevant WHO collaborating centers to develop and implement these harmonization activities. This department coordinates these activities globally with the support of WHO’s regional advisors and country project staff in each of the regional offices and many country offices. Each of the regional offices has two to five professionals coordinating the Medicines Strategy, and 40 WHO country offices have full-time pharmaceutical policy experts [38].

It is worth mentioning that in addition to its normative activities and harmonization projects, WHO also assists countries in capacity building by assessing regulatory systems. It does this by facilitating cooperation and information exchange between countries and by providing technical support. It is very important to involve all countries (whatever their development level), and to facilitate the implementation of norms and standards.

Finally, WHO has developed relationships with a lot of nongovernmental and civil society organizations on a global basis via the Civil Society Initiative (CSI), and also at regional and national levels. The objectives of WHO’s relations with nongovernmental organizations (NGOs) are to promote the policies, strategies, and activities of WHO to facilitate their implementation.

I-1.1.5) Harmonization and Cooperation Projects WHO has a large repertoire of global normative work relevant for all levels of development. In the area of medicines, a lot of standards, norms, and classifications have been developed, and forums/networks have been created to enhance global cooperation. Important initiatives are presented below.

k WHO publishes practical manuals, handbooks, and training material; internationally applicable guidelines and standards; reviews and analyses of health policies, programs, and research; and state-of-the-art consensus reports that offer technical advice and recommendations for decision makers. Also, the WHO Technical Report Series makes available the findings of various international groups of experts that provide WHO with the latest scientific and technical advice on a broad range of medical and public health subjects. l In 1978, the World Health Assembly turned multilingualism into a WHO policy by establishing six official languages (Arabic, Chinese, English, French, Russian, and Spanish). Since the adoption of a 1998 resolution, all governing bodies’ documents and corporate materials have been made available online in all official languages. 18 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

I-1.1.5.1) International Conference of Drug Regulatory Authorities The International Conference of Drug Regulatory Authorities (ICDRAs) provides drug regulatory authorities of WHO Member States with a forum to meet and discuss ways to strengthen collaboration and harmonization of pharmaceutical regulations. This is a key accomplishment of WHO that has been instrumental in guiding DRAs, WHO, and interested stakeholders to develop national, regional, and international medicines regulation, and it continues to be a cornerstone of international harmonization of medicines regulation.

These conferences have been held since 1980, and they have involved both developed and developing countries. The 14th ICDRAs, held in Singapore from November 30 to December 3, 2010, involved 345 participants from over 90 agencies. The 15th ICDRAs, which took place in Tallinn, Estonia from October 23 to 26, 2012, was attended by over 300 participants from 100 countries.

The aim of these conferences is to promote the exchange of information and collaborative approaches to issues of common concern. Topics discussed include quality issues, herbal medicines, homeopathy, regulatory reform, medicine safety, counterfeiting, regulation of clinical trials, harmonization, new technologies, and e-commerce. Recommendations are proposed for actions to take among agencies, WHO, and related institutions. It is worth mentioning that the idea to create ICH began to formulate after background discussions between the US, the European Union (EU), and Japan during the 5th ICDRAs conference in Paris, France in 1989 [39].

As a platform was established to develop international consensus, the ICDRAs continues to be an important tool for WHO and DRAs in their efforts to harmonize regulation and improve the safety, efficacy, and quality of medicines on a worldwide basis.

I-1.1.5.2) International Classifications The WHO constitution mandates the production of international classifications on health. These internationally endorsed classifications, developed through the WHO networkm are very important as they facilitate the storage, retrieval, analysis, interpretation, and comparison of data. They support global cooperation and harmonization by providing a consensual framework that governments, healthcare providers, and consumers can use as a common language. They also permit the comparison of data not only within populations over time, but also between populations.

WHO reference classifications are the International Classification of Diseases (ICD), the Inter- national Classification of Functioning, Disability and Health (ICF), and the International Classification of Health Interventions (ICHI). In addition, related and derived classifications (based on the reference classifications) have also been developed (e.g., the Anatomical Therapeutic Chemical Classification with Defined Daily Doses (ATC/DDD) that classifies m WHO has designated a number of collaborating centers to work with it in the development, dissemination, maintenance, and use of the WHO International Classifications. INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 19 therapeutic drugs according to the organ/system on which they act, and their chemical, phar- macological, and therapeutic properties).

I-1.1.5.3) International Clinical Trials Registry Platform The WHO International Clinical Trials Registry Platform (ICTRP) is a global initiative that aims to make information about all worldwide clinical trials involving humans publicly available. This activity was launched during the 58th WHA in 2005n following discussions and recommendations from a Ministerial Summit on Health Research in Mexico City, Mexico in November 2004.

The ICTRP is not itself a clinical trials registry, but a central repository that can be searched using the WHO search portal (http://apps.who.int/trialsearch/). All items in the trials registration data set are copied from individual registries onto the WHO central repository, and data is updated regularly. Indeed, details on clinical trials come directly from one of the primary registrieso in the WHO Registry Network (e.g., the European Clinical Trials Register that became a member of the Network in September 2011p).

By consolidating clinical trials information from several worldwide sources using standardized data set format/criteria, and by implementing unambiguous identification (i.e., a Uni- versal Trial Number [UTN]), the ICTRP not only facilitates the exchange of information, but also promotes harmonization of this information. Harmonization is also further achieved because WHO proactively supports countries/regions in establishing WHO-compliant clinical trials registries or policies on trial registration.

I-1.1.5.4) Quality Assurance of Pharmaceutical Products Quality assurance is a wide-ranging concept covering all matters that individually or collectively influence the quality of a product. This is a major public health challenge, particularly in light of growing cross-border health issues and the growing international dimensions of trade. The quality of pharmaceuticals has been a concern of WHO since its inception. The development of norms, standards, and guidelines to promote quality assurance is an integral part of WHO’s constitution, and has been endorsed and supported through numerous WHA resolutions. More recently, the WHO Medium-Term Strategic Plan for 2008–2013 requested that the organization develop international standards, recommendations, and instruments to assure the quality of medicines, whether produced and traded nationally or internationally.

n Resolution WHA 58.34 called on the global scientific community, international partners, the private sector, civil society, and other relevant stakeholders to “establish a voluntary platform to link clinical trials registers in order to ensure a single point of access and the unambiguous identification of trials with a view to enhancing access to information by patients, families, patient groups and others.” o A Primary Registry in the WHO Registry Network is a clinical trial registry with at least a national remit that meets WHO Registry criteria for content, quality and validity, accessibility, unique identification, technical capacity, and governance and administration. p The European Clinical Trials Register provides public access to information extracted from the EU clinical trial database (“EudraCT”). 20 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

The WHO Medicines Quality Assurance Program, which is part of the EMP Department, produces norms, standards, and guidelines on the quality assurance of pharmaceuticals. These regulatory tools are prepared through a vast global consultative process, and are ultimately approved by the WHO ECSPP,q which meets annually. The report of each meeting (Technical Report Series) includes newly adopted guidelines in its annexes. When adopted, the norms, standards, and guidelines become international harmonized standards intended for use by national DRAs, manufacturers, and other interested parties.

Many important international standards and projects have been developed in this area: ▸ Good manufacturing practice (GMP) ▸ Guidelines for regulatory approval (e.g., the guidelines on stability testing or on registration requirements to establish the interchangeability of multisource generic pharmaceutical products and the proposal to waive in vivo bioequivalence requirements) ▸ Prequalification of medicines, laboratories, and supply agencies ▸ Model certificates for quality assurance–related activities ▸ Quality control testing ▸ New specifications for inclusion in the Basic Tests Series and the International Pharmacopoeia ▸ International Chemical Reference Substances (ICRS)r ▸ The INN program

Some of these international guidelines and projects are further developed below.

▸ Good Manufacturing Practice: Good Manufacturing Practice (GMP) is the part of quality assurance that ensures products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the marketing authorization. GMP is aimed primarily at diminishing the risks involved in any pharmaceutical production that cannot be elimi- nated through testing of the final product.s GMP covers all aspects of production: from the starting materials, premises, and equipment, to the training and personal hygiene of staff. Detailed, written procedures are essential for each process that could affect the quality of the finished product.

q The WHO Expert Committee on Specifications for Pharmaceutical Preparations (ECSPP) was established in the very first World Health Assembly in 1948, and its members were selected from the members of the WHO Expert Advisory Panel on the International Pharmacopoeia and Pharmaceutical Preparations. r ICRS are used by laboratories to test pharmaceuticals for the purpose of quality control. These substances are mainly used for validating the results from specific tests, and as primary standards for calibrating secondary standards. WHO’s collection of ICRS is now maintained by the Council of Europe’s European Directorate for Quality of Medicines and HealthCare (EDQM), which also distributes the substances worldwide. EDQM is responsible for obtaining candidate material, testing it to ensure its purity and suitability, and reporting results with recommendations to WHO. s The main risks are the following: unexpected contamination of products causing damage to health or even death; incorrect labels on containers, which could mean that patients receive the wrong medicine; and insufficient or too much active ingredient resulting in ineffective treatment or adverse effects. INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 21

Recognizing the importance of GMP in international commerce of pharmaceutical products, WHO developed requirements early on. The first WHO draft text on GMP was prepared in 1967 by a group of consultants at the request of the 20th WHA [40]. It was subsequently submitted to the 21st WHA under the title “Draft Requirements for Good Manufacturing Practice in the Manufacture and Quality Control of Medicines and Pharmaceutical Special- ties” and was accepted. In 1968, the revised text was discussed by the WHO ECSPP and published as an annex to its 22nd report. The text was then reproduced, with some revisions, in 1971 in the Supplement to the 2nd edition of the International Pharmacopoeia (Ph. Int.).

Since then, WHO has further defined its general principles and requirements regarding GMP [41], and it has also established several detailed guidelines covering specific needs for GMP of active pharmaceutical ingredients [42], pharmaceutical excipients [43], sterile pharmaceutical products [44], biological products [45], blood establishments [46], pharmaceutical products containing hazardous substances [47], investigational pharmaceutical products for clinical trials in humans [48], herbal medicinal products [49], radiopharmaceutical products [50], and water for pharmaceutical use [51]. Finally, it also developed guidelines of a more general scope such as validation [52], risk analysis [53], technology transfer [54], and inspection [55], and has created appropriate training materials for countries.

Many countries have formulated their own requirements for GMP based on the WHO GMP.

▸ The International Pharmacopoeia: The International Pharmacopoeia (Ph. Int.) comprises a collection of quality specifications for pharmaceutical substances (i.e., active ingredients and excipients) and dosage forms together with supporting general methods of analysis. It is intended to serve as source material for reference or adaptation by any WHO Member State. Clearly defined steps are followed in the development of new monographs.

The Ph. Int. is published by WHO with the goal of achieving a wide global harmonization of quality specifications for selected pharmaceutical products, excipients, and dosage forms. The Ph. Int., or any part of it, has legal status whenever a national or regional authority expressly introduces it into appropriate legislation.

The history of the Ph. Int. dates back to 1874 when the need to standardize terminology and to specify dosages and composition of drugs led to attempts to produce an international pharmacopoeia compendium. The first conference, called by the Belgian Government and held in Brussels in 1902, resulted in an agreement for the unification of the formulae of potent drugs, which was ratified in 1906 by 19 countries. The outcome considerably influenced the subsequent publication of national pharmacopoeias.

In 1947, the Interim Commission of the WHO took over the work on pharmacopoeias previously undertaken by the Health Organization of the League of Nations. The 3rd WHA, held in May 1950, formally approved the publication of the “Pharmacopoea Internationalis” and recommended, in accordance with Article 23 of the WHO Constitution, “the eventual inclusion of its provisions by the authorities responsible for the pharmacopoeias.” It was thus 22 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS recommended that the “Pharmacopoea Internationalis” not be used as a legal pharmacopoeia in any country unless adopted by the pharmacopoeial authority of that country. This first edition, published with the aim of creating a worldwide, unified pharmacopoeia, relied on collaboration with national pharmacopoeia commissions for its preparation.

In 1975, the purpose of the Ph. Int. was reconsidered. It was decided that the publication should focus more on the needs of developing countries (because developed countries had established their own pharmacopoeias), and recommended only simple, classical chemical techniques that had been shown to be sound. Since 1979, the drugs appearing in the Ph. Int. have therefore been selected from the list of essential drugs based on the first report of the WHO Expert Committee on the Selection of Essential Drugs. Also, whenever possible, classical procedures are used in the analytical methods so that the use of expensive equipment is minimized in the application of the Ph. Int. to facilitate its implementation by developing countries.

The work on the Ph. Int. is carried out by the WHO ECSPP in collaboration with members of the WHO Expert Advisory Panel on the International Pharmacopoeia and Pharmaceutical Preparations and other specialists [56]. The process involves consultation with, and input from, WHO Member States and DRAs, WHO collaborating centers and national drug quality control laboratories in all six WHO regions, standard-setting organizations and parties including regional and national pharmacopoeias, and manufacturers around the world.

▸ International Nonproprietary Names: In 1950, The WHA adopted a resolution [57] to create the International Nonproprietary Names (INN) Program in order to identify pharmaceutical substances unambiguously on a worldwide basis, and to provide a universal, unique, nonproprietary name to be used in Pharmaco- poeia monographs. It began operating in 1953 when the first list of INNs for pharmaceutical substances was published. Today, this program is coordinated by the WHO EMP department.

The selection of a new INN relies on a strict procedure [58,59]. This process is supported by the Expert Advisory Panel on the International Pharmacopoeia and Pharmaceutical Prepa- rations, which provides advice on proposed names following an application made by the manufacturer or inventor. The procedure also involves the WHO Secretariat, which examines the suggested names for conformity with the general rules, similarities with published INNs, and potential conflicts with existing names. After a time period for objections has lapsed, the name will obtain the status of a recommended INN and will be published as such in “WHO Drug Information” if no objection has been raised. To make INNs universally available, they are formally placed by WHO in the public domain, hence their designation as “nonproprietary” names (also known as “generic names”).

The existence of this international nomenclature for pharmaceutical substances is important for the clear identification, safe prescription, and dispensing of medicines to patients, but also for communication and exchange of information among health professionals and scientists and regulators worldwide. It provides them with a unique and universally available designated name to identify each pharmaceutical substance. INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 23

Today, INN names are widely used and globally recognized. At present, more than 8,000 INNs have been published, and this number is growing every year. The majority of pharmaceutical substances used in medical practice are designated by an INN, and their use is already common in research and clinical documentation. Nonproprietary names are intended for use in pharmacopoeias, labeling, product information, advertising and other promotional material, drug regulation and scientific literature, and as a basis for product names (e.g., for generics).

Also INN collaborates closely with numerous national drug nomenclature bodies. The use of INN names is normally required by national authorities and also by the European Commu- nity. As a result of ongoing collaboration, national names such as British Approved Names (BAN), Dénominations Communes Françaises (DCF), Japanese Adopted Names (JAN), and United States Adopted Names (USAN) are nowadays, with rare exceptions, identical to the INN.

I-1.1.5.5) Safety of Pharmaceutical Products In addition to the quality standards, WHO also developed norms and standards for pharmacovigilance, and promotes information exchange on medicine safety. The aim is to assure the safety of medicines by ensuring reliable and timely exchange of information on drug safety issues, promoting pharmacovigilance activities on an international basis, and encouraging participation in the WHO Program for International Drug Monitoring [60].

In 1968, WHO established its Program for International Drug Monitoring in response to the thalidomide disaster in 1961. At the end of 2010, 134 countries were part of the WHO Phar- macovigilance Program.

An international system for monitoring adverse drug reactions (ADRs) using information derived from Member States was established in 1971. This allows WHO to issue a rapid Drug Alert whenever a serious problem in the safety of any medicinal product arises. WHO headquarters in Geneva is responsible for policy issues, while the operational responsibility for the program rests with the WHO Collaborating Centre for International Drug Monitoring, Uppsala Monitoring Centre in Sweden. A common reporting form was developed, agreed- upon guidelines for entering information were formulated, common terminologies and classifications were prepared, and compatible systems for transmitting, storing and retrieving, and disseminating data were created. The ADRs database in Uppsala currently contains over three million reports of suspected ADRs.

In 2003, a WHO Advisory Committee on Safety of Medicinal Products (ACSoMP) was established to guide WHO on general and specific issues related to pharmacovigilance. Addition- ally, a network of “information officers” was established in 1980 to allow a direct relationship between WHO and all national DRAs in Member States. Each national information officer is charged with providing information to WHO on the safety and efficacy of pharmaceutical preparations, and with securing prompt transmission to national health authorities regarding new information on serious adverse effects. 24 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

I-1.1.5.6) Certification Scheme on the Quality of Pharmaceutical Products This certification scheme was initially adopted by the 22nd WHA in 1969 [61], but since then it has been amended. It is an administrative instrument that requires each participating Mem- ber State, upon application by a commercially interested party, to attest to the competent authority of another participating Member State whereby: ▸ A specific product is authorized for placement on the market within its jurisdiction, or if it is not authorized, the reason why that authorization has not been accorded. ▸ The manufacturing plant in which it is produced is subject to inspections at suitable intervals to establish that the manufacturer conforms to GMP as recommended by WHO. ▸ All submitted product information, including labeling, is currently authorized in the certifying country.

The primary document delivered under this scheme is the Certificate of Pharmaceutical Product (CPP), but two other documents can be requested within the scope of the scheme. The first is a statement of licensing status of pharmaceutical product(s), and the second is a batch certificate of a pharmaceutical product (this document is rarely applied other than to vaccines, sera, and biologicals). These documents are used by DRAs of importing countries in their decision to approve, renew, extend, or vary a license.

WHO created models for these confidential documents and listed the information that such certificates need to include. Obligations that certifying authorities need to fulfill in order to be able to deliver a certificate have also been defined [62]: ▸ Possess an effective national licensing system, not only for pharmaceutical products, but also for responsible manufacturers and distributors. ▸ Have GMP requirements, in agreement with those recommended by WHO, to which all manufacturers of finished pharmaceutical products are required to conform. ▸ Effective controls must be in place to monitor the quality of pharmaceutical products registered or manufactured within its country, including access to an independent quality control laboratory. ▸ Have a national pharmaceuticals inspectorate, operating as an arm of the national DRA, and having the technical competence, experience, and resources to assess whether GMP and other controls are being effectively implemented, and the legal power to conduct appropriate investigations to ensure that manufacturers conform to these requirements by, for example, examining premises and records and taking samples. ▸ Support administrative capacity to issue the required certificates, to institute inqui- ries in the case of complaint, and to notify expeditiously both WHO and the competent authority in any Member State known to have imported a specific product that is subsequently associated with a potentially serious quality defect or other hazard.

GMP standards provide the basis for the WHO Certification Scheme that relies on the capacity, experience, and expertise of the certifying authority of the exporting country. This scheme INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 25 is a great example of cooperation between countries and is an important tool to support a regulatory system in developing countries that do not have enough capacity, resources, or expertise.

I-1.1.5.7) Biological Standardization Biological medicinal products, such as vaccines, blood and blood products, diagnostics, gene therapy, biotechnology products, cytokines and growth factors, and cell and tissue products, rely heavily on international standardization to ensure their quality and their equivalence across manufacturers. This is especially true due to the increasing globalization in the production and distribution of these biological medicines.

Over the past 50 years, WHO has worked to standardize these biological materials by establishing international biological reference materialst as well as developing international guidelines and recommendations on the production and control of biological products and technologies. Guidelines provide more general information on a range of topics of interest to national DRAs and manufacturers (e.g., “Guidelines on Evaluation of Similar Biothera- peutic Products, SBPs”), whereas recommendations establish the technical specifications for manufacturing and quality control of specific products (e.g., “Recommendations to Assure the Quality, Safety and Efficacy of BCG Vaccines”). WHO has also released many other documents on general topics (such as “Regulation and Licensing of Biological Products in Countries with Newly Developing Regulatory Authorities” [63] and “Good Manufacturing Practices for Biological Products” [64]) or on a specific type of product (e.g., blood products and related biologicals, cells and tissues, cytokines, or vaccines) to facilitate control of these biological products on a worldwide basis.

These norms and standards have been developed to assist WHO Member States in ensuring the quality and safety of biological medicines and related in vitro biological diagnostic tests worldwide. By adopting these guidance documents in their pharmacopoeias or equivalent legislation, each country ensures that the products produced and used in their country conform to current international standards. By advising national DRAs and manufacturers on the control of biological products, regulatory guidance documents also establish a harmonized regulatory framework for products in international markets.

WHO accomplishes its biological program through the WHO collaborating centers and the WHO ECBS. Members of the ECBS are scientists from national control agencies, academia, research institutes, public health bodies, and the pharmaceutical industry acting as individual experts and not as representatives of their respective organizations or employers. Its work is based on scientific consensus achieved through this international consultation and collaboration. This committee, which directly reports to the Executive Board, has met on an annual t Reference materials are required to standardize potency, purity, and identity measurements for complex biological materials. The WHO Biological Reference Materials provide a global standard against which experimental values can be compared and expressed, thereby allowing direct comparisons between products and measurements across different methodologies and assays in use around the world. They define an internationally agreed-upon unit to allow comparison of biological measurements worldwide. 26 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS basis since 1947 and is responsible for the establishment of the WHO International Biological Reference Preparations and for adoption of the WHO Recommendations and Guidelines that are published in the WHO Technical Report Series.u

Additionally, WHO has been particularly active in the specific field of blood products and related biologicals. It has provided technical guidance and quality assurance tools to DRAs, National Control Laboratories, and manufacturers to support implementation of quality and safety systems for the production and control of blood products and related in vitro diagnostic devices worldwide. Indeed, many countries have significant difficulties in ful- filling their responsibilities in this field because processing blood (with inherent variability due to the nature of the source materials) is a highly specialized process that requires a high degree of expertise. This development of WHO International Reference Materials and Guidelines supports the technical capacity of national DRAs and assures the compliance of manufacturers to quality and safety measures globally in order to prevent transmission of diseases via blood products. It also contributes to technology transfer, global cooperation, and harmonization of regulations via the Blood Regulators Network (BRN).

Finally, the WHO has been very involved in the development of standards and guidelines regarding vaccines due to the importance of these products in public health.v Moreover, WHO established the “prequalification of vaccines” (regarding the acceptability, in principle, of vaccines from different sources for supply) to help the United Nations Chil- dren’s Fund (UNICEF) and other UN agencies that purchase vaccines. Finally, through its regulatory pathways initiative it also helps to address the challenges faced by developing countries that are targets for clinical trials or introduction of new vaccines not registered in the country of manufacture. The objective is to support the establishment of regulatory mechanisms for the licensing of products in those countries that have not yet fully developed the expertise for the review of technical applications. This is achieved via workshops and technical assistance in collaboration with the European Medicines Agency (EMA) through its Article 58 Scientific Opinion procedure,w the US FDA, and other national DRAs in developed countries. A Developing Countries’ Vaccine Regula- tors Network (DCVRN) was created in September 2004, and regional initiatives were also established.

I-1.1.5.8) Pediatric Medicines Regulators’ Network (PmRN) As part of WHO’s Better Medicines for Children initiative, a Pediatric Medicines Regula- tors’ Network (PmRN) was set up with representatives from national DRAs from all u The WHO Technical Report Series provides updated information on the establishment, discontinuation, and replacement of the WHO International Biological Reference Preparations as well on the adoption of Guidelines and Recommendations. v Vaccination is recognized as one of the most important public health interventions. WHO estimates that between two and three million deaths are averted through immunization each year. w Article 58 of Regulation (EC) No. 726/2004 allows the Agency’s Committee for Medicinal Products for Human Use (CHMP) to give opinions, in cooperation with WHO, on medicinal products for human use that are intended exclusively for markets outside of the European Union. INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 27 regions [65]. This PmRN is a prime example of a global cooperation model that WHO can offer to facilitate information sharing globally and the development of global standards.

In many countries (developed and undeveloped), there is recognition of the significant need for research and development of medicines specifically for pediatric use (or data from pediatric studies using medicines that have been developed for adults). This lack of pediatric data became an important problem despite many initiatives from different regions or countries. The lack of suitable pediatric medicines, paired with inconsistent regulatory frameworks, poses significant risks to a particularly vulnerable patient population.

The overall aim of the PmRNx is to promote availability of quality medicines (including biological medicines and vaccines) for children by facilitating communication, collaboration, and regulatory harmonization across manufacturing, licensing, and research [66]. More specifically, among several objectives, this network tries to: ▸ Provide a forum for discussion between worldwide DRAs to build awareness of pediatric medicines regulatory considerations ▸ Facilitate the collaboration, discussion, and work towards consensus on regulatory standards for pediatric medicines (i.e., the development of international recommendations and common standards for clinical trials and registration of medicines for children based on the existing ICH, EMA, and US FDA guidelines) ▸ Strengthen licensing (approval) systems for pediatric medicines by increasing regulatory cooperation, information sharing, and training

I-1.1.5.9) Traditional Medicines Traditional medicinesy have been used in many countries throughout the world over many centuries. Today, these medicines still represent an important part of healthcare in some countries.z For example, more than 100 countries have regulations for herbal medicines, but practices of traditional medicine vary greatly from country to country and from region to region, as they are influenced by factors such as culture, history, personal attitudes, and philosophy. However, while it is often necessary to tailor legislation and delivery to reflect the needs and traditions of the individual countries, a number of themes and issues are common, such as the importance of practitioner training, the issues

x Established in response to the World Health Assembly Resolution WHA60.20 from May 23, 2007 on “Better Medicines for Children” and a recommendation from the 13th International Conference of Drug Regulatory Authorities (ICDRA) held in Bern, Switzerland, in 2008. y WHO defines “Traditional Medicine” as the sum of the knowledge, skills, and practices based on the theories, beliefs, and experiences indigenous to different cultures, whether explicable or not, used in the maintenance of health as well as in the prevention, diagnosis, improvement or treatment of physical and mental illness (WHO General Guidelines for Methodologies on Research and Evaluation of Traditional Medicine, WHO/EDM/TRM/2000.1, 2000). z In some Asian and African countries, 80% of the population depends on traditional medicine for primary health care (WHO Fact sheet No 134, December 2008). 28 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS related to safety, the need to enhance research into both products and practices, and the importance of labeling.

Also, the use of traditional medicines has expanded globally and has gained popularity in the last few decades. Specifically, these practices have not only continued to be used for primary healthcare of the poor in developing countries, but have also been used in other countries where conventional medicines are predominant in the national healthcare system.aa With this tremendous expansion in the use of traditional medicines worldwide, safety and efficacy as well as quality control of herbal medicines and traditional procedure-based therapies have become important concerns for many of these countries. For this reason, WHO has been increasingly involved in developing international standards and technical guidelines for these types of medicines, and also in increasing communication and cooperation between countries [67]. The challenge now is to ensure that traditional medicines are used properly, and to determine how research and the evaluation of traditional medicines should be carried out.

Supported by several WHA and Executive Board resolutions, WHO has developed and issued a series of technical guidelines (e.g., guidelines for the assessment of herbal medicines, research guidelines for evaluating the safety and efficacy of herbal medicines, and guidelines for clinical acupuncture research). In 1997, WHO developed draft guidelines for “methodology on research and evaluation of traditional medicine” that was finally approved in April 2000 [68]. The purpose of this document is to promote the proper development, registration, and use of traditional medicines and to harmonize the use of certain terms in traditional medicine. Moreover, in 2006, WHO established a global network (called the International Regulatory Cooperation for Herbal Medicines [IRCH]) to allow communication and exchange between worldwide regulatory authorities responsible for the regulation of herbal medicines.

I-1.1.5.10) Prequalification Program The UN Prequalification Program, managed by WHO and launched in 2001, involves two types of assessments: ▸ A comprehensive evaluation of the quality, safety, and efficacy of products, based on information submitted by the manufacturers, and inspection of the corresponding manufacturing and clinical sites ▸ The prequalification of pharmaceutical quality control laboratories

This program focuses on a selection of products that have been identified by the respective WHO disease departments as essential for treatment of HIV/AIDS, tuberculosis, malaria, and other diseases, and for reproductive health. This prequalification evaluation has also been extended to active pharmaceutical ingredients [69].

aa In many developed countries, 70% to 80% of the population has used some form of alternative or complementary medicine such as acupuncture (WHO Fact sheet No 134, December 2008). INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 29

The mission of this program is “to make quality priority medicines available for the benefit of those in need.” This is achieved through evaluation and inspection activities, and in cooperation with national DRAs and partner organizations. The list of prequalified medicinal products (updated regularly) is used principally by UN agencies (including UNICEF and the Joint United Nations Programme on HIV/AIDS [UNAIDS]) to guide their procurement decisions. But, the list has also become a vital tool for any agency or organization involved in bulk purchasing of medicines, as demonstrated by the Global Fund to Fight AIDS, Tuberculosis and Malaria.

The strategy is to apply unified standards of acceptable quality, safety, and efficacy and to build the capacity of staff from national DRAs, quality control laboratories, and from manufacturers or other private companies, to ensure quality medicines. Technical assistance, training, and capacity building are an important part of the program [70].

When a product is included on the WHO list, the relevant product dossier has been evaluated and the manufacturing sites inspected by WHO-appointed assessors and inspectors and found to comply with WHO standards. WHO also recognizes the evaluation of products by some major DRAs that apply stringent standards for quality, including, but not limited to, the US FDA, EMA, and Health Canada.bb However, it is important to note that the inclusion of a product (or a laboratory) on this list does not imply any approval by WHO because it is the sole prerogative of national authorities.

WHO inspections are done by a team of inspectors, including: ▸ An inspector/expert from one of the Pharmaceutical Inspection Co-operation Scheme (PIC/S) countries ▸ A WHO representative (inspector/expert) ▸ An inspector (or inspectors) as an observer from the national DRA of the country in which the laboratory is located

At the end of 2011, the WHO list of prequalified medicines included 269 products (manufactured in 25 countries); a total of 23 quality control laboratories had been prequalified (covering all WHO 6 regions). The program had also prequalified its first active pharmaceutical ingredients (APIs) [71].

I-1.1.5.11) Others The above projects are specifically related to the harmonization of pharmaceutical regulations and regulatory standards related to medicinal products. However, it is important to note that several other WHO projects not directly related to the harmonization of pharmaceutical

bb When a product is listed with a reference to US FDA or EMA, the alternative listing procedure was used, and the products have been added to the list relying on the assessment and inspections conducted by the US FDA or EMA. 30 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS regulationscc have been or are also very important because they facilitate implementation of common systems, agreements on terminology, and the establishment of a forum for exchange of not only information, but also expertise and experience. These other WHO projects ultimately facilitate overall dialogue, cooperation, convergence, and harmonization between countries and regions.

Moreover, other more general projects can also promote regional and subregional collaboration and harmonization of the regulation. For example, one of the principles of the general EC-ACP-WHO Partnership established in 2004dd was to “strengthen existing collaborative arrangements (e.g. pooled procurement in the Caribbean) and catalyse the creation of new ones, which can work together to achieve pooled procurement, common policies and harmonization of legislation.”

In addition, WHO publishes many documents regarding pharmaceuticals and regulations (i.e., newsletters, periodicals, reports status, or special publications such as the WHO Blue Book [72]) that allow the diffusion and exchange of information and data everywhere in the world. For example, “WHO Drug Information” is a quarterly journal, launched in 1987, which provides an overview of topics relating to medicine development and regulation that is targeted to a wide audience of health professionals and policymakers. It communicates the latest international news and trends.

Finally, some other specific WHO projects are also very important in facilitating the implementation of the international standards. These following projects need to be reviewed even though they are not directly related to the harmonization of pharmaceutical regulations because they demonstrate the key role of WHO in the global regulatory system, and therefore show how this organization has the legitimacy to further coordinate global harmonization.

▸ WHO Review of Drug Regulatory Systems: To ensure that public health is appropriately supported, national regulatory capacity needs to be regularly assessed, areas of weakness need to be identified, and necessary measures need to be taken.

WHO provided technical advice on how to conduct this review of regulatory systems [73] and developed a standardized Data Collection Tool [74] to help DRAs perform assessments. It is interesting to note that Module 16 of this tool evaluates the involvement of the national systems in the international cooperation and harmonization initiatives. cc Such as the WHO support of the health system strengthening activities within Global Fund proposals, the WHO coordination of global actions against influenza, the WHO integrated global alert and response system for epidemics/ health emergencies, the capacity building in GCP and Bioethics sponsored by the WHO Initiative for Vaccine Research, the International Medical Products Anti-Counterfeiting Taskforce (IMPACT), or the WHO knowledge management initiative. dd The EC–ACP–WHO Partnership on Pharmaceutical Policies was a partnership between the European Union, WHO, and the African, Caribbean, and Pacific Island (ACP) countries in the development and implementation of essential medicines strategies in ACP countries. INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 31

The objectives of this review are to strengthen national regulatory and control capacity through the identification of specific needs and the provision of appropriate technical support and training. This is done via the evaluation of existing legal framework, regulations, and control activities in order to assess the national regulatory capacity against a set of predefined parameters. WHO can then provide technical input if gaps are identified.

This activity is very important, especially in developing countries, to ensure that international standards can be appropriately implemented at the national level. It is also an important tool to have a clear status of national regulatory systems to evaluate appropriate needs from developing countries and therefore necessary support from regional and international organizations. The WHO multicountry study (involving only 10 countries) also showed that such assessments represent significant opportunities to learn more about the strengths and weaknesses of DRAs and the different strategies used to improve drug regulation performance [75].

▸ The International Health Regulations: The International Health Regulations (IHR), first adopted by the Health Assembly in 1969 and then significantly revised in 2005 in consideration of the growth in international travel and trade and the emergence or reemergence of international disease threats and other public health risks [76], were finally adopted by the 58th WHA on May 23, 2005 and entered into force on June 15, 2007. The IHR is an international legal instrument that is binding on all the WHO Mem- ber States. These global rules were developed and implemented to enhance national, regional, and global public health security. Its aim is to help the international community prevent and respond to acute public health risks that have the potential to cross borders and threaten people worldwide. The stated purpose and scope of the IHR are “to prevent, protect against, control and provide a public health response to the international spread of disease in ways that are com- mensurate with and restricted to public health risks, and which avoid unnecessary interference with international traffic and trade.” The IHR has been used for the H1N1 pandemic crisis [77].

The revised IHR requires countries to strengthen their core surveillance and response capacities so that they can report certain disease outbreaks and public health events to WHO. Build- ing on the unique experience of WHO in global disease surveillance, alert, and response, the IHR defines the rights and obligations of countries to report public health events, and establishes a number of procedures that WHO must follow in its work to uphold global public health security.

As mentioned above, this document was not specifically developed for pharmaceutical products, but is an important global tool that enhances cooperation between all countries in the world. Indeed, even if this agreement does not specifically relate to the harmonization of pharmaceutical regulations, it is very interesting for many reasons. First, this project helps strengthen worldwide capacities for public health and global cooperation in general, which is important for the implementation of harmonized global standards. More importantly, this is one of the first agreements that manages public health as a truly global issue and proposes further action using an integrated international approach and network. It shows that further integrated global cooperation in the area of health (with WHO being at the center of this cooperation to coordinate this effort) is possible and beneficial [78]. 32 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

I-1.1.6) Conclusion The mission of WHO’s program on medicines and pharmaceutical policies is to support the achievement of the health-related MDGs by assisting governments and organizations to ensure global and equitable access to safe, effective medicines of assured quality. Goal 8ee and Target 8Eff are particularly applicable to WHO harmonization activities in the pharmaceutical domain.

Many of WHO’s activities in the pharmaceutical domain support the achievement of these MDGs because they globalize the resolution of major public health issues (that cannot be resolved at the national/local level), they promote collaboration between countries and regions, and they provide tools and standards to allow such international collaboration. Since its creation, WHO has indeed played a significant role in the global harmonization of pharmaceutical regulations. As per its mandate and the responsibilities defined in its constitution, it has developed and maintained numerous international standards, norms, guidelines, classifications, and nomenclatures through a rigorous, international, and independent scientific consultative process. In addition to this normative role, WHO has also established important networks to facilitate global cooperation. For example, ICDRAs has been an important player in global regulatory harmonization. It launched many projects that have facilitated and promoted harmonization and cooperation between countries [79].

Cooperation projects have also been pioneered over the years with a specific interest in essential medicines.gg The WHO Prequalification Program has been an important step since it demonstrated that cooperation in the domain of medicine evaluation is possible and beneficial. Indeed, this program has been very positive and its scope has continually been extended since its creation in 2001. It has clearly accelerated the access of essential medicines worldwide (especially in low and middle income countries) [80]. This model should be used to further develop regional and global collaboration for medicine evaluation. The example of the 2010/2011 pilot WHO/East African Community (EAC) collaborative procedure initiated to facilitate registration of prequalified medicines in the EAC [81] was positive. The overall aim was to identify a framework for WHO/EAC, for joint evaluation and approval of dossiers and inspections of medicine manufacturing sites, and to ensure that these assessments are integrated into national regulatory decision making. Two assessors each from three EAC countries (Kenya, Tanzania, and Uganda) and six WHO assessors jointly assessed two product dossiers submitted by a single manufacturer. The dossiers were submitted in parallel, and with identical content, to each participating EAC country and to WHO. The products were both prequalified. The principal benefit of this joint assessment was that once the products had been jointly assessed and approved by WHO/EAC, they were granted immediate access to the markets of each of the countries that had participated in the joint assessment. Also, such joint assessment contributes to harmonization of regulatory requirements at the regional level.

ee Goal 8: Develop a global partnership for development. ff Target 8E: In cooperation with pharmaceutical companies, provide access to affordable essential drugs in developing countries. gg Essential medicines are those that satisfy the priority health care needs of the population. They are selected by WHO with due regard to public health relevance, evidence on efficacy and safety, and comparative cost-effectiveness. INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 33

This pilot WHO/EAC project also exemplifies the role of WHO in providing technical assistance to countries and supporting local capacity building. Indeed, by acknowledging the important role of adequate systems to implement sound and effective pharmaceutical regulation, WHO has supported developing countries in addressing their deficiencies or capacity problems through various types of training, assessment of regulatory capacity, and the recommendation of institutional development plans. These activities have been very beneficial in the past, but work needs to continue and grow in this domain, as problems still exist. Indeed, the extent of implementation of standards varies from one region to another. There are a number of factors that explain observed weaknesses of medicine regulation, and these differ from country to country and depend also on the individual health systems. Countries may vary regarding their registration system, and not all of them can implement a comprehensive medicine evaluation and registration system.

Also, WHO encourages regional and international collaboration among national DRAs in order to promote the harmonization of requirements and practices, and to strengthen professional competence [82]. However, as recognized in its Medicine Strategy Plan, cooperation with regional harmonization initiatives and organizations should be further enhanced [83]. Closer cooperation and coordination should also be sought with other global initiatives such as ICH.

Further assistance to countries and cooperation with other regional and global initiatives are indeed possible and can be facilitated by WHO’s regionalized structure. This specific three- level organization provides multiple opportunities for engaging with countries. The headquarters focus on initiation, development, and global coordination of harmonization projects, while regional offices focus on technical support and building national capacities to support implementation. WHO’s presence in countries also allows a close relationship with ministries of health and its partners inside and outside of government. This work at the regional and country levels is critical in ensuring that local and regional needs and challenges are taken into consideration when international standards and projects are developed.

To conclude, although some improvements may address current challenges, WHO has been very successful and beneficial for all Member States (developing and also developed countries). It has promoted evidence-based debate, analysis, and recommendations for health through its own work and that of the numerous formal and informal networks and collaborating centers around the world. These networks facilitate lively cooperation between scientists across nations and allow governments to jointly tackle global health problems. Development and promotion of global norms and standards in medicine is one of WHO’s efforts that is widely perceived as being in an area in which WHO has a comparative advantage. This advantage is due to the recognition of WHO as the global leader and coordinating authority on global public health. The achievement of the MDGs and the renewal of primary healthcare are indeed unthinkable without WHO’s norms and standards, policy guidelines, and technical cooperation. This is why the development and promotion of global norms and standards are an area of continued focus for WHO [84]. It is indeed critical that WHO continue its work towards better harmonization and cooperation in the pharmaceutical domain. Acknowledging the unique neutral and independent role of WHO, its numerous successes in the past, and its nearly universal membership, it would be appropriate to further extend the leadership of WHO in this domain. This increased responsibility in the coordination of medicines would also further fulfill its mandate “to act as the directing and co-ordinating authority on international health work.” [85] 34 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS I-1.2) International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) is a 20-year-old program. This unique initiative was established with the objective to bring together the DRAs of Europe, Japan, and the United States and experts from the pharmaceutical industry in these three regions to discuss scientific and technical aspects of pharmaceutical product registration.

The drug regulatory systems in all three regions share the same fundamental concerns for the safety, efficacy, and quality of medicines. However, many time-consuming and expensive experiments have been repeated in all three regions to meet specific regional requirements. The goal of ICH has been to increase harmonization of technical requirements to ensure that safe, effective, and high-quality medicines are developed and registered in the most efficient and cost-effective manner in order to be delivered to the maximum number of patients in the world without delay.

These activities have been undertaken to promote public health, prevent unnecessary duplication of clinical trials in humans, and minimize the use of animal testing without compromising safety and effectiveness. By making recommendations on ways to achieve greater harmonization of technical requirements for product registration, the objective is indeed to reduce or obviate the need to duplicate the testing carried out during the research and development of a new product.

Since its inception in 1990, ICH has evolved, through its Global Cooperation Group (GCG), to respond to the increasingly global face of drug development, so that the benefits of international harmonization for better global health can be realized worldwide.

This ICH mission is embodied in its current Terms of Reference: ▸ To maintain a forum for a constructive dialogue between regulatory authorities and the pharmaceutical industry on the real and perceived differences in the technical requirements for product registration in the EU, US, and Japan in order to ensure a more timely introduction of new medicinal products, and their availability to patients; ▸ To contribute to the protection of public health from an international perspective (added upon revision in 2000); ▸ To monitor and update harmonized technical requirements leading to a greater mutual acceptance of research and development data; ▸ To avoid divergent future requirements through harmonization of selected topics needed as a result of therapeutic advances and the development of new technologies for the production of medicinal products; ▸ To facilitate the adoption of new or improved technical research and development approaches which update or replace current practices, where these permit a more economical use of human, animal, and material resources, without compromising safety; ▸ To facilitate the dissemination and communication of information on harmonized guidelines and their use such as to encourage the implementation and integration of common standards. INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 35

I-1.2.1) Membership I-1.2.1.1) Founding Members of ICH ICH is comprised of representatives from six parties (the founding members of ICH) that represent the regulatory bodies and research-based industry in the EU, Japan, and the US:

▸ In Japan, the members are the Ministry of Health, Labour and Welfare (MHLW) and the Japan Pharmaceutical Manufacturers Association (JPMA): • The Ministry of Health, Labour and Welfare (MHLW) has the responsibilities for approval and administration of drugs, medical devices, and cosmetics. Technical and scientific support for ICH activities are provided by the Pharmaceuticals and Medical Devices Agency (PMDA; established in April 2004 as a new administrative agency for scientific review for drug approval), and by the National Institute of Health Sci- ences (NIHS) and other experts from academia. • The Japan Pharmaceutical Manufacturers Association (JPMA) was established in 1968, and represents approximately 70 members (including foreign affiliates). Mem- bership includes all the major research-based pharmaceutical manufacturers in Japan. ICH work is coordinated through its specialized committees of industry experts who also participate in the expert working groups. Among the objectives of JPMA is the development of a competitive pharmaceutical industry with a greater awareness and understanding of international issues. As a member of the International Federation of Pharmaceutical Manufacturers & Associations (IFPMA), JPMA is engaged with various global issues in the pharmaceutical and healthcare sector, and promotes the adoption of international standards by its member companies.

▸ In Europe, the members are the EU and the European Federation of Pharmaceutical Industries and Associations (EFPIA): • The European Commission (EC) represents the 28 members of the EU and promotes the common interest within the Union. The Commission works through harmonization of legislation and technical requirements and procedures to achieve a single market in pharmaceuticals allowing for free movement of products throughout the EU. The Euro- pean Medicines Agency (EMA) was established by the Commission and is located in London, England. Technical and scientific support for ICH activities are provided by the Committee for Medicinal Products for Human Use (CHMP) of the EMA. • The European Federation of Pharmaceutical Industries and Associations (EFPIA) is a nonprofit organization that was founded in 1978. It is located in Brussels, Belgium and has as its members over 30 national pharmaceutical industry associations and 40 leading pharmaceutical companies involved in the research, development, and manufacturing of medicinal products in Europe. A wide network of experts and country coordinators has been established through member associations to ensure that EFPIA’s views within ICH are representative of the European industry.

▸ In the US, the members are the US Food and Drug Administration (US FDA) and the Pharmaceutical Research and Manufacturers of America (PhRMA): • The US Food and Drug Administration (US FDA) is an agency within the Department of Health and Human Services. This Agency has a wide range of 36 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

responsibilities for drugs, biologicals, medical devices, cosmetics, radiological items, veterinary products, and the nation’s food supply. The US FDA is the largest of the world’s Drug Regulatory Authorities (DRAs) and is responsible for the approval of all drug products used in the US. The US FDA consists of administrative, scientific, and regulatory staff organized under the Office of the Commissioner, and has several centers with responsibility for various regulated products. Technical advice and experts for ICH work are drawn from the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER). • The Pharmaceutical Research and Manufacturers of America (PhRMA) represents the pharmaceutical research-based industry in the US. The members of this association are involved in the discovery, development, and manufacture of prescription medicines. PhRMA coordinates its technical input to ICH through its scientific and regulatory sections. Special committees of experts from PhRMA companies have been set up to address ICH topics.

I-1.2.1.2) Additional Members Since 1990, when ICH was initiated, members have been added:

▸ The International Federation of Pharmaceutical Manufacturers & Associations (IFPMA), the global nonprofit, nongovernmental organization, founded in 1968 to represent the research-based pharmaceutical, biotech, and vaccine sectors. Its members are comprised of over 20 leading international companies and over 40 national and regional industry associations covering both developed and developing countries. IFPMA is very involved in all subjects related to the improvement of global health. It has been closely associated with ICH since its inception to ensure contact with the research-based industry (especially outside the ICH regions). IFPMA provides the ICH Secretariat.

▸ Observers from: • The World Health Organization (WHO) • The European Free Trade Association (EFTA) currently represented at ICH by Swiss- medic (Switzerland) • Canada represented at ICH by Health Canada

This important group of nonvoting members was established as a link between ICH and non- ICH countries and regions.

I-1.2.2) Structure The ICH organization consists of the ICH Steering Committee, ICH Coordinators, ICH Sec- retariat, and ICH Working Groups. The ICH Global Cooperation Group (GCG) and the ICH Medical Dictionary for Regulatory Activities (MedDRA) Management Board are subcommittees of the ICH Steering Committee.

The Steering Committee is the body that governs the ICH, determines the policies and procedures, selects topics for harmonization, and monitors the progress of harmonization initiatives. This committee, established at the first ICH meeting in April 1990, has met at least twice a year INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 37 since, with the location rotating between three regions (EU, Japan, and US). During these committee meetings, new topics are considered for adoption, reports are received on the progress of existing topics, and maintenance and implementation of the guidelines are discussed. Each of the six ICH parties has two seats on the ICH Steering Committee. Each of the observers nomi- nates nonvoting participants to attend the ICH Steering Committee Meetings. IFPMA also participates as a nonvoting member. Meetings of the ICH MedDRA Management Board, ICH GCG, and the Regulators Forum also occur during the same week as the Steering Committee meeting.

ICH Working Groups are the key players of the ICH harmonization process. They are responsible for the development, implementation, or maintenance of ICH guidelines. Each of the six ICH parties is represented in every working group. The official membership of an Expert Working Group/Implementation Working Group (EWG/IWG) is usually limited to two officials per party (one Topic Leader and one Deputy Topic Leader). One of these topic leaders is nominated Rapporteur (and sometimes a second is nominated Co-Rapporteur) by the Steering Committee. ICH Observers and Interested Partieshh can also nominate one representative. The pharmacopoeial authorities and representatives from the self-medication industry and the generic industry were invited to participate in the various Working Groups. Finally, the three regulatory parties of the Steering Committee officially designate a Regula- tory Chair when a new ICH topic is formally adopted. The Regulatory Chair, designated among the three regulatory parties, regularly presents reports to the Steering Committee and ensures, in close collaboration with the Rapporteur, timely execution of the ICH process and adherence to the concept paper and business plan, including scope and timelines.

Depending on the type of harmonization activity required, the Steering Committee will endorse the establishment of one of three types of Working Groups: ▸ Expert Working Group (EWG): These Working Groups are appointed by the Steering Committee when new topics are accepted for harmonization. The objective of each EWG is to review the differences in requirements between the three regions and develop scientific consensus required to reconcile those differences. It is charged with developing a harmonized guideline that meets the objectives defined in the concept paper and business plan. ▸ Implementation Working Group (IWG): An IWG’s task is to develop questions and answers (Q&A) to facilitate implementation of existing guidelines. ▸ Informal EWG/IWG: These Working Groups are formed prior to any official ICH harmonization activity. Their objective is to develop a concept paper and business plan.

Working Groups meet in the same week as the Steering Committee and report on their progress to the Committee. These one-week meetings are key for the ICH organization as they allow for a regular review of efforts and achievements and adjust them if necessary. They include an important number of experts from the ICH and non-ICH regions. Each of the biannual meetings is attended by approximately 10 to 15 EWGs, and 200 to 300 experts. hh ICH defines Interested Parties as “Organizations that are expected to implement or to be regulated by the outcome of ICH efforts (World Self-Medication Industry -WSMI, International Generic Pharmaceutic Alliance - IGPA, and other interested parties as determined by the Steering Committee over time).” 38 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

ICH Discussion Groups are established to discuss specific scientific considerations or views (e.g., Gene Therapy Discussion Group) to facilitate the exchange of information on a specific topic, and ultimately the harmonization of the requirements.

The Coordinators are fundamental to the smooth running of the ICH and are nominated by each of the six parties. An ICH coordinator acts as the main contact with the ICH Secretariat and ensures that ICH documents are distributed to the appropriate persons within the area of their responsibility.

Each party has also established a contact network of experts within their own organization or region in order to ensure that, in the discussions, they reflect the views and policies of the co- sponsor they represent. The way this network operates differs according to the administrative structure of the party concerned. Due to structural differences within the EU and MHLW, ICH technical coordinators are also designated from the EMA and PMDA, respectively. They support the ICH coordinator and facilitate every action of the Steering Committee members in the region, mainly by applying their scientific knowledge. Their roles include acting as a contact point between the experts within the EMA and PMDA and the ICH coordinator at the main regulatory body, and as a contact point with the ICH Secretariat.

The ICH Secretariat operates from the IFPMA offices in Geneva (Switzerland), and provides support to the ICH Steering Committee. The Secretariat is primarily concerned with preparations for, and documentation of, meetings of the Steering Committee, as well as coordination of preparations for Working Group (EWG, IWG, and Informal WG) and Discussion Group meetings. The Secretariat also provides administrative support for the GCG and the MedDRA Management Board, and maintains the ICH website.

The MedDRA Management Board, appointed by the ICH Steering Committee, has overall responsibility for direction of MedDRA, an ICH standardized dictionary of medical terminology. The Board oversees the activities of the MedDRA Maintenance and Support Services Organi- zation (MSSO), which serves as the repository, maintainer, developer, and distributor of Med- DRA. The Management Board is composed of the six ICH Parties, the Medicines and Healthcare Products Regulatory Agency (MHRA) of the UK, Health Canada, and WHO (as Observer). The IFPMA acts as a nonvoting observer on the Management Board and also chairs the Board.

The ICH Global Cooperation Group (GCG) was formed on March 11, 1999, as a subcommittee of the ICH Steering Committee. The GCG is not a technical body. In 1999, this group was made up of one representative from each of the six parties on the ICH Steering Com- mittee, plus the ICH Secretariat at IFPMA. The ICH Observers were also part of the GCG. In 2003, other regional harmonization initiatives, namely the Asia-Pacific Economic Cooperation (APEC), Association of Southeast Asian Nations (ASEAN), Gulf Cooperation Council (GCC), Pan American Network on Drug Regulatory Harmonization (PANDRH), and Southern African Development Community (SADC), were invited to join the group and to designate permanent representatives to the GCG. Since then, these Regional Harmonization Initiatives (RHIs), and the East African Community (EAC), which joined the GCG in 2011 [86–90], have also been invited to participate in Steering Committee meetings (as Observers) and EWG meetings. Finally in autumn 2007, the Steering Committee decided to invite representatives of individual countries INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 39 from outside the ICH regions to participate in the GCG. Australia, Brazil, China, Chinese Taipei, India, South Korea, Russia, and Singapore have current representation at the GCG.

As stated in its mission statement adopted by all parties in May 2005, this group “promotes a mutual understanding of regional harmonization initiatives in order to facilitate the harmonization process related to ICH guidelines regionally and globally, and to facilitate the capacity of drug regulatory authorities and industry to utilize them.” This group ensures that the benefits of ICH harmonization extend beyond the three ICH regions (Japan, EU, and US).

The role of the GCG has changed over time as the focus on collaboration with the non-ICH regions increased. From its creation to today, three phases can be differentiated:

▸ First Phase (1999 to 2003): Information Sharing Outside ICH: During these first three years, the GCG mandate was to share information outside ICH (via preparation of brochures, presentations at international meetings, etc.). The objectives were to make available to any country or pharmaceutical company that requested it information on ICH, ICH activities, and ICH guidelines. To this end, the group created a series of brochures intended to guide its activities as it answers requests for information and responds to non- ICH regulators and industry: • Principles of the Global Cooperation Group (October 2000) • Questions & Answers about ICH (October 2000) • ICH Information Brochure (May 2001) • Synopsis of ICH Guidelines and Topics (last update in May 2004)

▸ Second Phase (2003 to 2007): Integration and Collaboration with RHIs: On November 9, 2003, the ICH GCG released their terms of reference in which they extended their action to act as the primary representative of the ICH Steering Commit- tee outside the ICH regions, and equally as such as a conduit for non-ICH parties to the ICH Steering Committee. To do so, the group developed a privileged relationship with other non-ICH harmonization initiatives. This key activity of the GCG had three advantages: • To share ICH discussions and actions with the non-ICH regions (allowing, when possible, harmonization and implementation of ICH activities on a worldwide basis) • To promote and organize the involvement of the non-ICH regions experts in ICH discussions (via expert meetings, comments on Step 2 Guidelines, and training on Guidelines) • To facilitate interregional collaboration in order to promote transparency, better understanding of challenges and potential solutions to harmonization issues, leverage collective experience and knowledge (allowing easier standardization and development of Good Harmonization Practice)

When, in 2003, the GCG decided to include representatives from the non-ICH regions, the relationship with the non-ICH regions became more collaborative and proactive, and the focus shifted from information sharing to a two-way dialogue to set up training and work on implementation. 40 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

The results of these collaborations allowed the organization of workshops in the regions (e.g., APEC Workshops on Clinical Research Inspections in 2008 and 2009 in Thailand, the SADC Quality Guideline Workshop in 2008 in Zambia, and the APEC Quality Guideline Workshop in 2008 in China). As an example, the GCG also endorsed the APEC Life Sciences Innovation Forum (LSIF) sponsored workshop on ICH Quality Guidelines (Q8, Q9 and Q10), held in September 2007 in Seoul, South Korea. This workshop was a great success for the spread of ICH concepts and recommendations in this region as it was attended by more than 400 participants (i.e., regulators, policymakers, academia, and industry) from 17 countries. This type of workshop allows for practical explanation of ICH guidelines, but also opens up discussion and exchange on the anticipated challenges and opportunities associated with the implementation of ICH guidelines in order to better prepare implementation.

▸ Third Phase (2007 to Present): Second Expansion of GCG (to Individual Countries) and Establishment of the Regulators Forum to Focus on Implementation: The third phase of extension began on October 2007 in Yokohama, Japan when the ICH Steering Committee decided to expand the GCG beyond the RHIs and to invite a number of individual DRAs (or Departments of Health) of countries that are a source of active pharmaceutical ingredients (APIs), medicinal products, or clinical data for the ICH regions [91–1].

The participation of these individual countries is distinct and complementary to the participation of official RHI representatives.

In June 2008, the inaugural meeting of the expanded GCG occurred. Today, the key focus of the GCG continues to be the implementation of ICH guidelines via the organization of training that began in 2007. This training is indeed an important means for the promotion of better understanding of ICH and ICH guidelines beyond the ICH regions. It developed a framework and mechanism for policy [91–2], a procedure for selection and prioritization, a template for training requests, definitions of roles and responsibilities for the organization and coordination of training activities, and a clearinghouse of training events for public access. These training activities (most of the time coordinated with the respective RHIs) involve ICH experts.

During the meeting in October 2007 in Yokohama, Japan, the ICH Steering Committee also decided to complement the GCG with the Regulators Forum.

The ICH Regulators Forum is the latest idea implemented by ICH to increase communications and sow relationships between worldwide DRAs in order to ensure adoption and implementation of ICH guidelines. Following a proposal from the US FDA in 2007, the first meeting occurred in Portland, Oregon, US in June 2008. This is a good complement to the GCG activities and includes authorities from the three ICH regions, the Observers, the RHIs, and individual DRAs such as Australia, Brazil, China, Chinese Taipei, India, Korea, Russia, and Singapore. This ICH Regulators Forum allows frank discussion and the sharing of expertise among DRAs regarding best practices and challenges related to the implementation of ICH guidelines and their impact on regulatory systems. This discussion assists in identifying training and capacity needs for action by the GCG. More importantly, it also builds mutual understanding, relationships, and trust. INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 41

I-1.2.3) History

I-1.2.3.1) The Birth of ICH In the 1980s, many varied efforts of harmonization of pharmaceutical regulatory requirements were conducted. First, the European Community, who was developing a single market for pharmaceuticals, had shown that harmonization among different countries (with different medical cultures/practices and regulatory systems) was possible. At the same time, bilateral discussions between Europe, Japan, and the US on the possibility for harmonization were ongoing. The concretization of these ad hoc discussions happened during the World Health Organi- zation (WHO) International Conference of Drug Regulatory Authorities (ICDRAs) in Paris in 1989, where specific plans were agreed to. Following this meeting, the three authorities approached IFPMA to discuss a joint regulatory–industry initiative on international harmonization. The spirit and concept of ICH was then agreed on between the different parties.

In April 1990, ICH was officially created at its inaugural Steering Committee meeting, hosted by the EFPIA in Brussels, Belgium. Representatives of the regulatory agencies and industry associations of Europe, Japan, and the US met primarily to plan an international conference, but at the meeting the wider implications and terms of reference of ICH were also discussed. During this first meeting, the structure (including a Steering Committee and Expert Working Groups) and the focus of ICH activities (harmonization of safety, efficacy, and quality guidelines for human drugs and biological products) were agreed on. Eleven topics were selected for discussion at the first conference. Finally, it was agreed to expand the membership of the Steering Committee to include representatives from WHO, EFTA, and Canada as observers because the harmonized guidelines could be useful to other non-ICH regions. Additionally, agreement was reached on the full name of ICH. This name was chosen because one of the objectives of this group was to organize international conferences on harmonization. Today, this name is associated with the overall initiative.

The ICH members officially confirmed their commitment to ICH in a statement following the 2nd Steering Committee Meeting:

The Parties cosponsoring this Conference, represented at the 2nd Steering Committee Meeting in Tokyo, 23–24 October 1990 re-affirmed their commitment to increased international harmonization, aimed at ensuring that good quality, safe, and effective medicines are developed and registered in the most efficient and cost-effective manner. These activities are pursued in the interest of the consumer and public health, to prevent unnecessary duplication of clinical trials in humans and to minimise the use of animal testing without compromising the regulatory obligations of safety and effectiveness.

This Conference will provide a unique opportunity for regulators and industry to reach consensus on the steps needed to achieve this objective through greater harmonization of technical requirements and to set out practical and realistic targets for harmonising requirements where significant obstacles to drug development and the regulatory process have been identified. 42 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

Recognising the substantial progress which has already been made in achieving harmonization within Europe and through bilateral contacts between Europe, Japan, US, and other regions, the Conference will seek to make further progress through a trilateral approach, with clearly defined priorities, methods of work and recommendations to both industry and regulatory authorities.

Whilst the Conference will be an important step forward, it is not seen as an end in itself, but as a stage in a developing process, at a high level, between regulators and industry.

The Conference, its preparations, and follow-up activities will be conducted in an open and transparent manner and the presence of observers from other regulatory authorities and WHO is welcomed as a means of ensuring that the benefits of progress towards harmonization can be utilized world-wide.

The Conference will not only look at existing issues but will, based on past experience, seek to minimise future divergence of new registration requirements, as a consequence of technical progress.

This initial ICH statement is important because it provides the spirit of ICH that has been followed and implemented in all subsequent ICH activities since.

I-1.2.3.2) The First ICH Phase (1990–2000): Creation of Consensus Guidelines among ICH Regions From its creation in 1990 to 2000, the initial focus of ICH was to promote technical and scientific exchanges and discussions in order to find consensus on divergent technical requirements for registration of medicinal products in the ICH regions. The goal was indeed to remove redundancy and duplication in the development and review process, such that a single data set could be generated to demonstrate the quality, safety, and efficacy of new products. During this first phase of its activities, the ICH structure and process were defined, a lot of harmonization activities started, and several guidelines/standards developed. These first harmonization discussions were directed to both technical scientific content (related to quality, safety, or efficacy topics) and to format and communication tools (development of E3 and the start of MedDRA, Electronic Standards for Transmission of Regulatory Information (ESTRI) and Common Technical Document (CTD) projects).

During these first 10 years, there was a growing interest in ICH products beyond ICH countries, and ICH recognized early that harmonization within the ICH regions would not suffice. How- ever, during these first years, discussions and activities focused mainly on harmonization among ICH parties (even though ICH agreed to include observers as a link to the non-ICH regions) because it was important to start the process with a limited number of committed parties.

In November 2000, the 5th International Conference on Harmonization (ICH5) in San Diego, California, US marked the end of the first 10 years of ICH activity. This conference provided an opportunity to evaluate results and to identify future needs in the area of international harmonization. At the conference, results were presented of a survey on utilization of ICH guidelines confirming the positive contribution of ICH in improving the international drug regulatory approval process, thus speeding the availability of new medicines to the public. INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 43

In its statement titled “The Future of ICH” released at ICH5, the Steering Committee emphasized its intentions to focus the second phase of ICH on implementing and maintaining existing guidelines, preventing disharmony, encouraging scientific dialogue and harmonization in new areas, and undertaking efforts towards global cooperation with non-ICH regions and countries.

I-1.2.3.3) The Second ICH Phase (since 2000): Implementation/Maintenance of Guidelines and Collaboration with Non-ICH Regions During its second phase, ICH continues to develop and implement tripartite guidance on specific technical requirements, and also increase its effort on the implementation of harmonized regulatory communication tools (i.e. MedDRA, CTD, ESTRI, etc.) between authorities and industry.

Indeed, one of the areas of focus of this second phase is to ensure adequate implementation and maintenance of all the guidelines developed since 1990. Today, new guidelines continue to be developed, but less frequently. These new guidelines cover important technical subjects related to pharmacovigilance (i.e., guidelines E2D, E2E, and E2F) or improvement of quality systems (i.e., guidelines Q8, Q9, and Q10). New emerging topics (such as gene therapy) have also been discussed. However, the main challenge of ICH is now to maintain and update the collection of guidelines already developed (i.e., follow the evolution of science, the experience gained, etc.).

The second focus and priority of this ICH phase has been, and continues to be, the extension of relationships with non-ICH regions. It began with the creation of the GCG as a subcommittee of the ICH Steering Committee in 1999. Since this time, ICH has developed its relationship with non-ICH regions and tried to facilitate the implementation of its standards and guidelines on a broader territory via collaboration and training. Even if some relationships existed before, the GCG has been key for this geographical extension, and its role increased over time by moving from information sharing (via preparation of brochures, presentations at international meetings, etc.) to a collaborative and proactive dialogue (via the incorporation of non-ICH regions and countries in the group). Further evolution of the ICH structure and the GCG’s Terms of Reference are expected to continue to promote greater involvement of global regulators [92–1,92–2].

I-1.2.3.4) Conferences and Workshops The first activity of ICH was to organize the ICH1 Conference in 1991, one year after its creation, in order to exchange points of view and discuss divergences among different parties involved. Since ICH1, five additional conferences have been organized (Table 1). These regular, well-attended conferences helped communicate the results of the harmonization activities to the largest possible audience. They were designed as an open forum (in breakout sessions) to gather additional public comments and provide updates on ICH’s scientific activities.

These six conferences were well attended (e.g., 2,400 participants representing industry and authorities of over 40 countries for ICH3 and 1,300 participants representing industry and authorities of over 140 countries for ICH5). 44 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

Table 1: List of ICH Conferences

Conference Date Location

ICH1 November 1991 Brussels, Belgium ICH2 October 1993 Orlando, Florida, US ICH3 November/December 1995 Yokohama, Japan ICH4 July 1997 Brussels, Belgium ICH5 November 2000 San Diego, California, US ICH6 November 2003 Osaka, Japan

The early ICH conferences were very important in increasing visibility on the process of harmonization and for ensuring that the process was carried out in a transparent manner. ICH5 focused primarily on the finalization and completion of the CTD guideline. The last ICH conference organized, ICH6, focused on areas such as new technologies and global cooperation with regulatory harmonization initiatives outside the ICH regions. The three satellite sessions (related to “Partnerships in Harmonization,” “Gene Therapy,” and “MedDRA Users’ Group”) also confirmed the priorities of the meeting. During this conference, opportunities and new challenges for regulatory harmonization were discussed. The practical implementation of the CTD was also reviewed.

After ICH6, no additional international conferences were scheduled. ICH7 was planned to have taken place in Europe in 2007, but it was then canceled. Instead, in May 2007, the ICH Steering Committee decided to replace these large international ICH conferences with smaller and more frequent regional public meetings at the time of the ICH Steering Committee meetings in the region (in order to benefit from the presence of Steering Committee Members and ICH Experts). Now that the ICH process is well recognized, these smaller regional meetings allow for a better focus on regional issues and challenges. It also provides everyone the opportunity to meet with regulators and industry experts involved in ICH activities, to be regularly informed on recent developments, and to exchange information on different hot topics.

Following this decision, regional meetings have been organized: ▸ In Europe, the first EU regional public meeting took place in Brussels, Belgium in November 2008. ▸ In North America, the first regional public meeting took place in Washington, DC, US in October 2008. ▸ In Asia, the first regional public meeting took place in Tokyo, Japan in November 2007.

I-1.2.4) Harmonization and Cooperation Process The ICH Process was first drawn up at the Steering Committee meeting in Washington, DC in March 1992, and amended in Tokyo, Japan in September 1992. Since then, the ICH procedures have been revised several times [91–2]. Moreover, the new principles of governance, agreed to at the ICH Steering Committee meeting in June 2012, have revised the role of regulator and INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 45 industry parties in the development of ICH guidelines [92–3]. Further modifications of ICH procedures can be expected following this revision of responsibilities [92–4].

I-1.2.4.1) Initiation of a New Harmonization Action Suggestions for new harmonization initiatives may arise in a number of forums (ICH Regional Guideline Workshops; regional and international conferences, workshops, and symposia dealing with research and development (R&D) and regulatory affairs; recognized associations; testing and registration of medicines, etc.). From the suggestion of a new harmonization action to the development of a new guideline (or modification of an existing guideline), there are three sequential steps: • Submission of a Concept Paper to the ICH Steering Committee by an ICH party or an Observer • Endorsement by the Steering Committee • Establishment of a Working Group

▸ Development of a New Concept Paper: The Concept Paper is the start of all ICH harmonization activities. This document provides a short summary of the proposal (maximum two pages) and provides the information indicated below: • Type of Harmonization Action Proposed: For example, a new harmonized tripartite guideline and recommendation, or a revision of an existing guideline (indicating the category of procedure). • Statement of the Perceived Problem: Brief description with an indication of the magnitude of the problem currently caused by a lack of harmonization, or anticipated if harmonization action is not taken. • Issues to be Resolved: A summary of the main technical and scientific issues that require harmonization. • Background to the Proposal: Further relevant information (e.g., the origin of the proposal, references to publications, and discussions in other forums). • Type of Expert Working Group: Recommendation on whether the EWG should be a six-party group (for topics related to the R&D of a new drug substance and product) or an extended EWG (e.g., GMP).

If necessary, further documentation and reports may be added to the Concept Paper. Depend- ing on the category of harmonization activity, a Business Plan may also be required. The Busi- ness Plan outlines the costs and benefits of harmonizing the topic proposed by the Concept Paper.

▸ Endorsement by the Steering Committee: Only when the ICH Steering Committee endorses a Concept Paper, and where appropriate a Business Plan, can the harmonization activity be initiated.

A preliminary determination will be made on whether the topic is of sufficient interest to all parties and can be accommodated within the ICH work schedule. 46 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

The Steering Committee takes the following points into account when discussing a Concept Paper: • Objectives and Expected Outcome of the harmonization action • Categories of the ICH process • Composition of the EWG or IWG appointed to discuss the technical issues • Setting a Timetable and Action Plan for the EWG/IWG

The Concept Paper may need to be revised and updated to reflect the Steering Committee discussions and conclusions.

If the Steering Committee agrees that a topic may warrant further consideration and a Busi- ness Plan needs to be developed, an informal EWG/IWG will be formed and the group will work through e-mail, teleconference, and rarely, face-to-face meetings. The first tasks of the informal EWG/IWG will be to finalize a Concept Paper and develop a Business Plan. The revised Concept Paper and Business Plan will be sent prior to, and presented at, the next Steering Committee meeting.

At its meeting in Yokohama, Japan (in June 2006), the ICH Steering Committee agreed to have the final versions of the Concept Papers and Business Plans available on the ICH website, for public information.

▸ Establishment of a Working Group: Depending on the type of harmonization activity proposed, the ICH Steering Committee will endorse the establishment of either an EWG or an IWG.

I-1.2.4.2) ICH Harmonization Procedures ICH harmonization activities fall into four categories. As presented in Table 2, these four categories cover the creation and development (stepwise progression), implementation, revision, and maintenance of guidelines.

Table 2: Type of ICH Procedures

Technical Category Type of Procedure Discussion Group Activity Example

1 Formal ICH procedure EWG Development of a Most of the ICH new guideline Technical Guidelines 2 Q&A procedure IWG Creation of Q&As to CTD assist the implementation of existing guidelines 3 Revision procedure EWG Revision/modification E2B (R3) of existing guidelines 4 Maintenance procedure EWG Adding standards to Q3C existing guidelines and/ M2 Recommendations or recommendations INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 47

No procedure is in place for the withdrawal of existing ICH guidelines because it happens very rarely. When Guideline Q1F (Stability Data Package for Registration Applications in Climatic Zones III and IV) was withdrawn, an explanatory note was released following the endorsement of the withdrawal by the ICH Steering Committee at its meeting in Yokohama, Japan in June 2006. Withdrawal notifications were also released by the EMA, MHLW, and US FDA.

▸ The Formal ICH Procedure: The formal ICH procedure follows a stepwise approach consisting of five steps with “decision points” at Step 2 and Step 4 that enable the Steering Committee to monitor the progress of the harmonization topics. This procedure is followed for the harmonization of all new ICH topics. A streamlined procedure is also available when necessary.

The procedure is initiated with the endorsement, by the Steering Committee, of a Concept Paper and Business Plan. An EWG with membership as specified by the Concept Paper is subsequently established.

The EWG works to develop a draft guideline and bring it through the various steps of the procedure that culminate in Step 5 and the implementation in the ICH regions of a harmonized tripartite guideline.

• Step 1: Consensus Building When the Steering Committee adopts a Concept Paper as a new topic, then the process of consensus building begins. The EWG prepares an initial consensus technical document, based on the objectives set out in the Concept Paper and in consultation with experts designated to the EWG. The initial draft and successive revisions are circulated for comments within the EWG, providing fixed deadlines for receipt of those comments. Work is conducted via e-mail, teleconferences, and web conferences. If endorsed by the Steering Committee, the EWG will also meet face-to-face at the biannual Steer- ing Committee meetings. Interim reports on the progress of the draft are made to the Committee on a regular basis. When consensus is reached among all EWG members, the EWG signs the Step 1 Experts Signoff sheet. The Experts Document with EWG signatures is submitted to the Steering Committee to request adoption under Step 2a of the ICH process.

• Step 2: Confirmation of Consensus Step 2a is reached when the Steering Commit- tee agrees, based on the report of the EWG, that there is sufficient scientific consensus on the technical issues for the technical document or recommendation to proceed to the next stage of regulatory consultation.This technical document is made public on the ICH website. On the basis of the technical document, the three ICH regulatory parties take the actions they deem necessary to develop the “Draft Guideline.” The consensus text approved by the three regulatory ICH parties is signed off by the three regulatory ICH parties as the Step 2b Draft Guideline. 48 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

• Step 3: Regulatory Consultation and Discussion Regional Regulatory Consultation: At this stage, the guideline embodying the scientific consensus leaves the ICH process and becomes the subject of normal wide-ranging regulatory consultation in the three regions. In the EU it is published as a draft CHMP Guideline, in Japan it is translated and issued by the MHLW for internal and external consultation, and in the US it is published as draft guidance in the Federal Reg- ister. Step 2 guidelines released for consultation are also available on the ICH website. DRAs and industry associations in non-ICH regions may also comment on the draft consultation documents by providing their comments to the ICH Secretariat. Discussion of Regional Consultation Comments: After obtaining all regulatory consultation results, the EWG that organized the discussion for consensus building will be resumed. The same procedure described in Step 1 is used to address the consultation results into the Step 2 final document. The draft document to be generated as a result of Step 3 is called the Step 4 Draft Guideline. The Step 4 document with regulatory EWG signatures is submitted to the Steering Committee to request adoption as Step 4 of the ICH process.

• Step 4: Adoption of an ICH Harmonized Tripartite Guideline Step 4 is reached when the Steering Committee agrees, on the basis of the report from the regulatory chair and the regulatory rapporteur of the EWG, that there is sufficient scientific consensus on the draft guideline. This endorsement is based on the signatures from the three regulatory parties to ICH affirming that the guideline is recommended for adoption by the regulatory bodies of the three regions. In the event that one or more parties representing industry have strong objections to the adoption of the guideline on the grounds that the revised draft departs substantially from the original consensus, or introduces new issues, the regulatory parties may agree that a revised document should be submitted for further consultation. In this case, the EWG discussion may be resumed. The Step 4 final document is signed off on by the Steering Committee signatories for the regulatory parties of ICH as an ICH harmonized tripartite guideline at Step 4 of the ICH process.

• Step 5: Implementation Having reached Step 4, the harmonized tripartite guideline moves immediately to regulatory implementation, the final step of the process. This step is carried out according to the same national or regional procedures that apply to other regional regulatory guidelines and requirements in the EU, Japan, and the US. Information on the regulatory action taken and implementation dates are INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 49

reported back to the Steering Committee and published by the ICH Secretariat on the ICH website. In the EU, ICH guidelines are submitted to the CHMP for endorsement and the timeframe for implementation is established (usually six months). ICH Guidelines are available on the EMA website. In Japan, ICH texts are translated into Japanese and subsequent Pharmaceutical and Medical Safety Bureau notification for the promulgation of guidelines written in Jap- anese is issued with an implementation date. The notifications on guidelines in Japa- nese and also English attachments (ICH Texts) are available on the PMDA website. In the US, the US FDA publishes a notice with the full text of the guidance in the Federal Register. Step 4 guidance is available for use on the date it is published in the Federal Register. They are available on the US FDA website.

▸ The Q&A Procedure: The Q&A procedure is followed when additional guidance is considered necessary to aid in the interpretation of certain ICH harmonized tripartite guidelines and ensure a smooth and consistent implementation in the ICH regions and beyond.

The Q&A Procedure is initiated with the endorsement of the Steering Committee of a Con- cept Paper. In the case of major implementation activities, the Steering Committee may also consider the need for a Business Plan. An IWG with membership as specified by the Concept Paper is subsequently established.

The development and adoption of the Q&A follow an established process. Questions received from stakeholders are collected, analyzed, reformulated, and ultimately used as model questions for which standard answers are developed and posted on the ICH website. The incoming questions are not answered individually, rather they serve to highlight areas that need additional clarification and are then used to develop a model question that will be answered in the Q&A document.

Based on the level of guidance given by the answers, the IWG will assess whether the Q&A document should be a Step 2b document and published for comments or a Step 4 document and published as final. The document should be Step 2b if, based on the answers provided, it sets forth substantial new interpretations of the guideline(s). The document should be a Step 4 if, based on the answers provided, it sets forth existing practices or minor changes in the interpretation or policy of the guideline(s).

The document then follows the normal path of a Step 2b/Step 4 document as per the formal ICH procedure.

▸ The Revision Procedure: The revision procedure applies when an existing adopted guideline needs to be revised or modified. It is almost identical to the formal ICH procedure (i.e., five ICH steps). The only 50 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS difference is that the final outcome is a revised version of an existing guideline rather than a new guideline.

The revision of a guideline is designated by the letter R1 after the usual denomination of the guideline. When a guideline is revised more than once, the document will be named R2, R3, R4, and so on with each new revision.

▸ The Maintenance Procedure: The maintenance procedure is used to add standards to existing guidelines and/or recommendations or to provide an update based on new information.

This procedure has been used to amend the addendum of Guideline S5(R2), “Detection of Toxicity to Reproduction for Medicinal Products & Toxicity to Male Fertility,” and Guide- line M3(R1), “Maintenance of the ICH Guideline on Non-Clinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals,” on November 9, 2000. It is currently applicable for changes to the Q3C Guideline on Residual Solvents, the Q4B Annexes, and M2 Recommendations. In each case, the procedure is used when there is new information to be added or when the scientific/technical content is out-of-date or no longer valid.

For the Q3C guideline, this maintenance procedure is used to revise the permitted daily exposure (PDE) as new toxicological data for solvents become available.

I-1.2.5) Harmonization and Cooperation Projects Since its creation, and pursuant to its main goal, ICH has released a number of guidances, each harmonizing technical requirements for registration of medicinal products. For each technical topic, the relevant EWG discussed the important question of whether there is scientific justification for the different regional requirements, and whether it would be possible to develop a mutually acceptable guidance. The objective of this scientific discussion is to reach a scientific consensus whatever the time and effort it requires [93] (and not a “compromise” that would be an unacceptable decrease of certain regional requirements without scientific justification/ basis). ICH has also worked on broader projects (e.g., MedDRA and CTD), which have been critical for the international exchange of information.

I-1.2.5.1) ICH Guidelines The ultimate goal of ICH activities is to remove redundancy and duplication in the development and review process such that a single set of data could be generated to demonstrate the quality, safety, and efficacy of a new medicinal product. The Steering Committee has given priority to harmonizing the technical content of the sections of the reporting data. The first ICH Guideline to deal with harmonizing the format of reporting data was E3, “Content and Format of Clinical Study Reports.” This Guideline describes a single format for reporting the core clinical studies that make up the clinical section of a registration dossier.

The goal of developing a harmonized format has led to the creation of the ICH Guideline M4, “The Common Technical Document” (CTD), further described below. INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 51

At the first ICH Steering Committee meeting it was decided that the topics selected for harmonization would be divided into Safety, Quality, and Efficacy in order to reflect the three criteria that are the basis for approving and authorizing new medicinal products. Since then, ICH has created a fourth category called Multidisciplinary, which covers crosscutting topics that do not fit uniquely into one category or another. Therefore, today ICH topics are divided into four categories (Quality, Safety, Efficacy, and Multidis- ciplinary) and ICH topic codes are assigned according to these categories. A summary of harmonized topics is provided below. An updated list of these guidances (including their status) can also be downloaded from the ICH website (and also from the US FDA, PMDA, and EMA websites).

▸ Quality Topics: The guidelines under this category provide harmonization of information related to the development, manufacturing, and testing of medicines. They specifically cover stability testing (Q1), validation of analytical procedures (Q2), impurities testing (Q3), pharmacopoeial text harmonization and interchangeability (Q4), quality information on biotechnological products (Q5), specifications (test procedures and acceptance criteria) (Q6), GMP (Q7), pharmaceutical development (Q8), quality risk management (Q9), and pharmaceutical quality systems (Q10).

In addition, the ICH Steering Committee endorsed on April 11, 2008 the development of a new Q11 guidance related to the development and manufacture of drug substances (chemical entities and biotechnological/biological entities).

▸ Safety Topics: The guidelines under this category provide harmonization of information related to in vitro and in vivo preclinical studies. They cover all preclinical studies performed during the development of new pharmaceutical products, such as carcinogenicity studies (S1), genotoxicity studies (S2), toxicokinetics and pharmacokinetics studies (S3), toxicity studies (S4), reproductive toxicology studies (S5), pharmacology studies (S7), and immunotoxicology studies (S8). Guideline S6 specifically addresses preclinical safety evaluation for the biotechnological products. The ICH Steering Committee also endorsed on May 10, 2007 the development of a new S9 guideline that provides preclinical guidelines on oncology therapeutic development. Finally, the photosafety evaluation of pharmaceuticals was endorsed as a new topic (S10) by the ICH Steering Committee in June 2010.

▸ Efficacy Topics: The guidelines under this category provide harmonization of information pertaining to the clinical evaluation of pharmaceutical products.

Most of these guidelines relate to the assessment and management of safety data (E1 and E2 Guidelines). These guidelines cover: • Extent of Population Exposure to Assess Clinical Safety for Drugs Intended for Long-Term Treatment of Non-Life Threatening Conditions (E1) • Definitions and Standards for Expedited Reporting (E2A) • Data Elements for Transmission of Individual Case Safety Reports (E2B) 52 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

• Periodic Benefit-Risk Evaluation Report (E2C) • Post-Approval Safety Data Management (Definitions and Standards for Expedited Reporting; E2D) • Pharmacovigilance Planning (E2E) • Development Safety Update Report (E2F), recommended by CIOMS VI and VII to replace the different periodic safety reports (US IND [Investigational New Drug] Annual Report and EU Annual Safety Report)

However, the following additional topics are also covered to avoid duplication of clinical studies or clinical documentation for different ICH regions: • Structure and Content of Clinical Study Report (E3) • Design, Conduct and Interpretation of Dose–Response Studies (E4) • Influence of Ethnic (extrinsic and intrinsic) Factors on Clinical Results (E5) • Good Clinical Practice (E6) • Generalities for the Conduct of Clinical Studies: General Considerations (E8), Statisti- cal Principles (E9), Choice of Control Group and Related Issues (E10), and Clinical Evaluation of QT/QTc Interval Prolongation (E14) • Clinical Investigation in Specific Populations: Geriatric Population (E7) and Pediatric Population (E11) • Pharmacogenomics (E15) and Genomic Biomarkers Related to Drug Response (Con- text, Structure, and Format of Qualification Submissions) (E16)

All the above Efficacy guidelines can be applied to all therapeutic classes of drugs. Until now, ICH has focused the discussion on general (i.e., nontherapeutic class-specific) guidances. However, there are, in some therapeutic classes, individual drug evaluation guidelines among the three regions. Differences between guidelines can result in obstacles to the mutual use and acceptance of clinical data. At the Steering Committee meeting in September 1998, it was agreed that this should be adopted as a new area of work for ICH, with the first such guideline being undertaken as a "pilot study" to assess the feasibility of extending work in this area. It was agreed to develop the first therapeutic class-specific guideline for antihypertensive drugs. No other guideline for clinical evaluation of a specific therapeutic category has been developed since this guideline (E12).

▸ Multidisciplinary Topics: This category was created to include guidelines covering topics that do not fit uniquely into one of the above three categories.

In addition to the technical guidelines described in previous sections, ICH set up EWGs to harmonize Medical Terminology (M1: MedDRA), Drug Dictionaries (M5), and the format and organization of data in regulatory applications (M4: CTD) in order to ease the exchange of information. The creation of electronic standards (M2: ESTRI) was also critical for the quick exchange of common, agreed-upon data. In November 2010, the ICH Steering Committee endorsed the establishment of an EWG for the Electronic Common Technical Document (eCTD) and assigned the topic code “M8” (even though work in relation to the eCTD had previously been undertaken by the M2 EWG). INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 53

All these harmonization initiatives are critical achievements that required a lot of effort from their respective working groups. They are important activities that greatly contributed to the international harmonization of pharmaceutical regulations because they harmonized and facilitated the exchange of information between regulators and pharmaceutical companies. Due to the importance of these initiatives, each of them is detailed in the specific subsections below.

Guideline M3 covers a specific topic relating to both safety and efficacy issues. For this reason, it has been classified as a “Multidisciplinary Topic.” This joint safety and efficacy guideline provides principles for nonclinical strategies (i.e., scope, timing, and duration of nonclinical safety studies) in relation to the conduct of clinical trials. It helps to reduce the differences between the ICH regions and it also provides recommendations to reduce animal use during research and development (e.g., inclusion of any in vivo evaluations as additions to general toxicity studies instead of performing separate studies). This guideline is definitively aligned with the overall ICH objectives, as its purpose is to facilitate the timely conduct of clinical trials, reduce the use of animals in accordance with the 3Rs (reduce/refine/replace) principles, and reduce the use of other drug development resources. It clearly promotes the safe and ethical development and availability of a new pharmaceutical as quickly as possible.

Finally, the ICH Steering Committee endorsed (in June 2010) the “Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk” as a new topic (M7).

I-1.2.5.2) The Medical Dictionary for Regulatory Activities (MedDRA) MedDRA was developed by an ICH EWG in the early 1990s. It was designed to support the classification, retrieval, presentation, and communication of medical information internationally and throughout the product regulatory cycle.

Prior to MedDRA, different medical dictionaries (and also different versions of these dictionaries) were used, such as the World Health Organization Adverse Reaction Terminology (WHO-ART), the Coding Symbols for a Thesaurus of Adverse Reaction Terms (COSTART) from the US FDA, and the Japanese Adverse Reaction Terminology (J-ART) from the MHLW. At that time, several worldwide authorities were looking for a more cost- and time-efficient way of processing suspected adverse reaction reports (e.g., the United Kingdom Medicines Control Agency [UK MCA] were developing a new system of coding called ADROIT). It became obvious that this activity should fall under the auspices of ICH.

The goal of ICH in developing MedDRA was to have an internationally recognized standard, and medically rigorous and well-maintained terminology to facilitate communication. It is indeed one of the most important ICH projects for ensuring the global exchange of clinical information. This international medical terminology is particularly important in the electronic transmission of adverse event reporting (both in the pre- and post-marketing areas), as well as in the coding of clinical trials data.

The MedDRA dictionary is a multi-axial terminology that provides a set of terms that consistently categorizes medical information. It includes terminology for symptoms, signs, diseases 54 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS and diagnoses, and therapeutic indications. It is organized by System Organ Class (SOC), divided into High-Level Group Terms (HLGT), High-Level Terms (HLT), Preferred Terms (PT), and finally into Lower-Level Terms (LLT). The MedDRA dictionary has been translated into many languages.

As the terminology itself does not contain specific guidelines for its use, an ICH working group has been charged to develop two guides: ▸ “MedDRA Term Selection: Points to Consider”: This document was created to achieve consistency in the way users assign particular terms to particular symptoms, signs, diseases, etc. ▸ “MedDRA Data Retrieval and Presentation: Points to Consider”: This document provides guidance on retrieval and on sorting and presenting data in the most under- standable and reproducible way for the benefit of drug development, pharmacovigilance, and risk management.

These two documents provide a best practice approach for the use of MedDRA. They are revised for each new MedDRA version release.

In addition, the MedDRA dictionary includes Standardized MedDRA Queries (SMQs) that were developed (in collaboration with CIOMS) to facilitate the retrieval of MedDRA-coded data as a first step in investigating drug safety issues in pharmacovigilance and clinical development. SMQs are groupings of terms from one or more MedDRA System Organ Classes (SOCs) that relate to a defined medical condition or area of interest. They are intended to aid in case identification.

Because the terminology requires constant updating and maintenance, it was agreed that a Maintenance and Support Services Organization (MSSO) would be needed to carry out this task and to distribute the terminology, on license, to users in industry and regulatory agencies. The MSSO, contracted by ICH with technical and financial oversight by the MedDRA Management Board, is tasked to maintain, develop, and distribute Med- DRA.

Since the release of version 1.0 in 1994, MedDRA has become the accepted international standard for all worldwide regulatory activities (MedDRA is not yet mandatory in the US). As a single global, standardized medical terminology, MedDRA speeds the exchange of clinical information, facilitating research and safety monitoring, and making the regulatory approval process more efficient and responsive. Different translations of MedDRA have been released. In March/April 2008, MedDRA was also implemented in the WHO VigiBase, providing a global repository of MedDRA-coded safety data that can be used as a substantial tool for pharmacovigilance.

During a meeting on October 27–28, 2007 in Yokohama, Japan, the MedDRA Management Board announced fee reductions for lower revenue subscribers. These reductions are in keeping with the MedDRA Management Board’s goal of facilitating the use of Med- DRA for all users. Since January 2007, access to MedDRA has been free for academic INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 55 organizations, hospitals, healthcare providers, and other users involved in noncommer- cial activities.

I-1.2.5.3) Electronic Standards for Transmission of Regulatory Information (ESTRI) The objective of the Electronic Standards for Transmission of Regulatory Information (ESTRI) project was to facilitate international electronic communication. To this end, an ICH Mul- tidisciplinary Expert Working Group (called M2 EWG) was established during the ICH meeting of 1994 in Brussels, Belgium. The M2 EWG was to evaluate and recommend ESTRI that meet the requirements of the pharmaceutical companies and DRAs from the three ICH regions. Since 1994, the M2 EWG has developed the technological framework and recommended solutions for international information exchange. This was obtained by gathering requirements, assigning specific tasks, evaluating international standards and products, and recommending a functional architecture. This project included the verification of procedures for consistent, accurate information transfer, and the evaluation of encryption technologies and key certification procedures for the transfer of regulatory information. The working group has undertaken test projects to define logical electronic communication standards in order to ensure the integrity of information and data exchange between pharmaceutical companies and authorities.

To allow flexible change, some of the activities of the EWG result in recommendations that do not follow the formal ICH step process. They are agreed upon in the EWG, signed by all parties of the EWG, and are endorsed by the ICH Steering Committee at its different meetings. These recommendations, which have been modified and improved over time, provide various open international standards that allow for the international transmission of information regardless of the technical infrastructure. To facilitate the use of these recommendations, the M2 EWG has also developed a glossary for the technical terms.

Today, six M2 Recommendations are available. They cover and standardize general aspects, but also the choice of file format and information transfer as described in Table 3.

Table 3: ICH M2 Recommendations

Implemented Recommendation Category Title/Topic Current Version Date Endorsed EU Japan US Canada

General Procedure 2.0 Nov 2005 Yes Yes Yes Yes General ESTRI Gateway 2.0 Nov 2005 Yes Yes Yes Yes File Format PDF 2.0 Apr 2011 Yes Yes Yes Yes File Format XML 1.0 Nov 2005 Yes Yes Yes Yes Information EDIINT AS1/AS2 2.2 June 2010 Yes Yes Yes Yes Transfer File Integrity MD5 1.0 June 2010 Yes Yes Yes Yes 56 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

Recommendations were also prepared for the choice of physical media (i.e., floppy disks, CD-R, and DVD-RAM). Because these physical media are not relevant anymore, these recommendations were retired in June 2008.

In addition to the Recommendations, the M2 EWG also developed several specifications with regard to the electronic exchange of information:

▸ The first specification developed by the M2 EWG was related to the electronic transfer of the Individual Case Safety Report (ICSR) presented in ICH Guideline E2B (Data Elements for Transmission of Individual Case Safety Reports). Following the development of the E2B guideline, it became necessary to work on an electronic specification to guide the pharmaceutical companies on how to provide the information required by the E2B guideline. Indeed, successful electronic transmission of ICSR relies on the definition of common data elements (provided in the E2B guideline), but also a standard electronic transmission procedure. The first version of this specification was approved by the Steering Committee under Step 2 in 1997. Since then this specification has been modified because its implementation and use had to be aligned with the evolution of the ICH E2B and M1 (MedDRA) guidelines. As a result of this activity, adverse event (AE) data can be extracted, populated, and electronically transmitted in the manner specified by the ICH ICSR message from safety and surveillance databases. Even if it has required a lot of work, the implementation of electronic reporting of ICSRs based on the ICH E2B, M1, and M2 standards progressed very rapidly across the ICH regions. Thanks to these standards, pharmaceutical companies can now exchange case reports electronically via gateway with some DRAs (such as the US FDA or EMA).

▸ The second specification developed by the M2 EWG was the Electronic Common Technical Document (eCTD) created as the electronic message for the Common Technical Document (CTD) detailed in ICH Guideline M4. This specification has since been maintained by the eCTD IWG. The eCTD specification, based on XML (Exten- sible Markup Language) technology, allows for the electronic submission of the CTD from applicant to regulator, taking into consideration the facilitation of the creation, review, lifecycle management, and archiving of electronic submissions. While the table of contents is consistent with the harmonized CTD, the eCTD also provides a harmonized technical solution to implementing the CTD electronically. This eCTD specification is applicable to all modules of initial registration applications and for other submissions of information throughout the lifecycle of the product, such as variations and amendments. The backbone has been developed to handle both the regional and common parts of submissions. Implementation of eCTD has begun across the ICH partner and observer regions. For example, since January 1, 2008, all electronic submissions to the US FDA are required to be in eCTD format.

▸ In 2003, the M2 EWG published the first version of the Study Tagging File (STF) specification, which is supplemental to the eCTD. This specification has since been modified several times. For each study included in Modules 4 and 5 of an eCTD submission, the STF includes information allowing for the identification of all the files INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 57

associated with this specific study. This is additional information to the eCTD backbone files that already include many items, but do not contain enough information on the subject matter of several documents (e.g., study report documents) to support efficient processing and review of applications.

In June 2006, the Steering Committee agreed that the M2 EWG should collaborate with Standards Development Organizations (SDOs) through the establishment of a consortium. This consortium (composed of the International Organization for Standardization [ISO], Health Level 7 [HL7], the European Committee for Standardization [CEN], and ICH) is now in charge of the development of electronic standards. ICH participates to ensure that these electronic standards meet ICH standards. This decision followed a US FDA proposal (at the Steering Committee in November 2005) that wanted to develop standards in a wider context. This allows the utilization of the same standards for all products under US FDA responsibility (human medicines, but also veterinary medicines, medical devices, and food). This initiative should also help to elevate ICH standards to global standards. In Chicago, Illinois, US, the Steering Committee approved that E2B(R) and M5 messages enter the new SDO process. Then, during its November 2008 meeting in Brussels, Belgium, the Steering Committee decided to progress with the next major version of the eCTD through the ISO/CEN/HL7 Joint Initiative Project.

I-1.2.5.4) The Common Technical Document The Common Technical Document (CTD) is one of the major and most well-known achievements of ICH, and like all other big harmonization projects of ICH, required much effort. It provides a harmonized structure and format for regulatory applications. The objective is to reduce the time and resources needed to compile applications for registration of medicines in the different ICH regions. Additionally, this new common format allows DRAs to have more consistent reviews, helping them to perform analysis across applications and to exchange information among them.

Before the development of the CTD, each region had its own requirements for the organization of technical reports in the submission and for the preparation of the summaries and tables. In Japan, applicants had to prepare the GAIYO, which organized and presented a summary of the technical information. In Europe, expert reports and tabulated summaries were required, and written summaries were recommended. The US FDA had specific guidelines regarding the format and content of the New Drug Application (NDA).

In 1996, the ICH industry representatives proposed assembling the information generated during the development of a product in the same order. This proposal followed an industry survey in May 1996 that assessed the time and resources needed to convert an EU Market- ing Authorization Application (MAA) into a US NDA (and the reverse). This survey showed that an average of three to four months and 20 to 30 people were required for the conversion from one format to the other. With the acceptance in all three regions, the CTD now avoids the need to generate and compile different regional versions of most of the registration dossier sections. 58 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

The CTD was adopted as an ICH topic at the Steering Committee Meeting that took place just before the ICH4 meeting (July 1997). The CTD specifications reached Step 2 of the ICH process at the Steering Committee meeting in July 2000. After public consultation, Step 4 was achieved at the ICH5 Conference in San Diego, California in November 2000. On September 12, 2002 (at the Washington, DC meeting), numbering and section headers were then edited for consistency and use in the eCTD.

The CTD consists of five modules (Module 1 is region specific, and Modules 2, 3, 4, and 5 are intended to be common for all regions): ▸ Module 1 includes administrative information (i.e., application form) and proposed prescribing information. ▸ Module 2 summarizes data included in Modules 3, 4, and 5 and is organized in seven subsections: • CTD Table of Contents • CTD Introduction • Quality Overall Summary (QOS) • Nonclinical Overview • Clinical Overview • Nonclinical Written and Tabulated Summaries • Clinical Summary ▸ Module 3 provides quality information. ▸ Module 4 includes the nonclinical study reports. ▸ Module 5 encompasses the clinical study reports.

The CTD is defined by a general ICH Guideline (M4) and three specific technical guidelines (M4Q, M4S, and M4E, which cover the quality, safety, and efficacy parts of the CTD, respectively). A Q&A document is associated with each of these four guidelines to facilitate implementation of the CTD.

The ICH parties agreed to implement this harmonized format in the three regions by July 2003. It is indeed used today in the three ICH regions: it is mandatory in the EU and Japan, and “highly recommended” in the US (the current legislation does not allow the US FDA to make it mandatory). Moreover, this format is also used in other countries (e.g., Australia, Canada, Turkey, etc.), and derivatives of the CTD have been developed in other regions (e.g., the ACTD developed by the ASEAN countries).

This harmonized format is indeed one of the great successes of the ICH process. While the realization of the CTD took many years, there is now a common format for the regulatory submissions across the three ICH regions (Europe, Japan, and the US) and beyond. This facilitates pharmaceutical companies in making simultaneous filings in the ICH regions as it elimi- nates the extensive work previously required to convert from one format to another.

However, the CTD is not a “Global Dossier.” It remains only a harmonization of format instead of a harmonization of content. This initial misunderstanding, certainly created by the desire of many people to accelerate the harmonization of technical requirements, INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 59 led to a lot of criticism against this new format. However, the CTD cannot be a truly global identical dossier (including the same information/data/level of detail) if all technical requirements are not fully harmonized. Moreover, the submission’s content may also be different for several reasons, such as different individual regulations, legal status, or requirements, and different manufacturing situations for the three regions. Indeed, although the CTD provides a common format for regulatory applications, the actual content must still meet local regulations, laws, and statutes. As a result, despite being presented in the same order, the required content of Modules 2 to 5 may vary by region. For example, the Integrated Summary of Efficacy/Integrated Summary of Safety (ISE/ ISS) that were requested by the US FDA before the implementation of the CTD are still needed. Because these integrated summaries are unique to the US, the Table of Contents of the CTD does not specifically include them. A specific US FDA guidance was released in June 2007 to help pharmaceutical companies decide where to place these US-specific ISE/ISS documents within the structure of the CTD.

To conclude, even if the CTD is “only” an agreed-upon common format for the modular presentation of summaries, reports, and data, it provides obvious advantages. The CTD allows companies and DRAs to harmonize the terms and way of communication [94]. Having the same “language” will certainly help the harmonization of content, and ultimately the harmonization of technical requirements. Indeed, regulatory reviews and communication with the applicant will be facilitated by a standard document of common elements. In addition, exchange of regulatory information between DRAs will be simplified. This increase of communication between authorities and between authorities and pharmaceutical companies will obviously facilitate expertise and opinion sharing (related to the safety, efficacy, and quality of the development product) in a timely manner that will ultimately provide benefits to patients by providing quality medicines more quickly on the market.

I-1.2.5.5) Data Elements and Standards for Drug Dictionaries (M5 Guideline) Like MedDRA, the objective of this project was indeed to support all aspects of pre- and post-approval pharmacovigilance activities as well as communication of regulatory information. For example, MedDRA and the harmonization of drug dictionaries are critical in the transmission of the ICSR presented in ICH guideline E2B (Data Elements for Transmission of Individual Case Safety Reports). The transmission of structured data (especially electronically) does imply the use of controlled vocabularies.

Before the ICH initiative, there was no harmonized standard to document information and data on medicinal products. Regulators in the different regions had established their own standards, which differed in data format, content, language, and applied standard terminology (e.g., terminology used for substances, routes of administration, pharmaceutical forms, etc.). The WHO Drug Dictionary, or a modified version of this product, was sometimes used. This lack of internationally harmonized standards related to core sets of medicinal product information and medicinal product terminology made the scientific evaluation, comparison, and exchange of drug data (especially in the area of pharmacovigilance) very difficult. 60 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

The activity on the M5 Guideline only began in 2003. Following the example and success of MedDRA, the ICH Steering Committee at its meeting in November 2003 agreed to launch this new harmonization initiative and to develop a new tripartite guideline that defines the Data Elements and Standards for Drug Dictionaries. During the ICH meeting in Tokyo, Japan in February 2003, WHO presented a white paper regarding the concepts of a global drug-coding dictionary. During this meeting, the Steering Committee agreed to convene an informal discussion group in Brussels, Belgium during the ICH meeting in July 2003 to allow for a discussion of this proposal. An Informal Working Group was then established to develop a Concept Paper and prepare a Business Plan.

The M5 Guideline was released for consultation at Step 2 of the ICH process on May 10, 2005, along with controlled vocabulary lists for routes of administration and units of measurement. This Guideline was subsequently submitted to the ISO for development under this process.

The M5 Step 2 Guideline was updated based upon feedback received during consultation in 2005, as well as additional considerations following its submission to ISO for development as an international standard. Key parts of this updated guideline will be incorporated into the ICH “Implementation Guide for Identification of Medicinal Products Message Specification,” which is currently undergoing development as an ISO standard.

I-1.2.6) Conclusion

▸ Achievements So Far: For two decades, the ICH process has achieved much success and benefited both DRAs [95–1] and pharmaceutical industries [95–2]. More importantly, this harmonization has been pursued in the interest of patients and public health to prevent unnecessary duplication of clinical trials in humans and to minimize the use of animal testing without compromising the regulatory obligations of safety and effectiveness. To achieve this objective, the goal of ICH has been to promote international harmonization by bringing together representatives from the EU, Japan, and US to discuss and establish common guidelines and standards.

Through the ICH process, considerable harmonization has been achieved in the technical requirements for the registration of pharmaceuticals for human use. This is now a mature harmonization initiative. Since its creation, over 50 harmonized guidelines have been developed in the areas of quality, safety, and efficacy in order to eliminate duplication in the development and registration process. Moreover, common harmonized tools for regulatory communication (MedDRA, CTD, ESTRI) have also been made available. This represents an extraordinary contribution to the global harmonization of pharmaceutical regulations. These guidelines already form a solid basis for harmonized application of technical requirements during the registration process.

While the technical output of the ICH process has been very positive, the importance of the unique way in which ICH operates should also be noted. Indeed, in addition to the practical INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 61 harmonization of specific technical items, one of the major outcomes of ICH has been to create a forum that allows experts from different countries and with different backgrounds to communicate, exchange, discuss, and share their experience and information in a structured manner. This is of course an essential first step to any harmonization.

Finally, another important achievement of ICH is to be well recognized on a worldwide basis. ICH guidelines have been adopted and are now followed outside the ICH regions (e.g., Switzerland, Canada, and Australia, and also many RHIs). Although ICH’s initial focus was the development of guidelines for use in the ICH regions, increased globalization drastically modified the international cooperation environment. In response to a growing interest from beyond the ICH regions in the use of ICH guidelines, the ICH Steering Committee took the first step in March 1999 of establishing the ICH GCG. In November 2003, new terms of reference and rules were endorsed for the GCG with the aim of establishing partnerships beyond the ICH regions to promote a better understanding of ICH guidelines globally. Since then, RHIs from across the globe, but also representatives from DRAs and Departments of Health (DoH) that are either a major source of API or clinical trials data have been invited to participate in the GCG meetings and listen to technical topics at the level of the Steering Committee (at the biannual ICH meetings). In addition, as per a decision of the ICH Steering Committee in November 2010, invited RHIs and DRAs/DoH may now also nominate technical experts as active members of ICH EWGs. The implementation of ICH recommendations and standards outside the three ICH regions is indeed very important as it allows industry to better develop medicinal products for the global market.

As a consequence of this expansion to non-ICH regions, training and capacity building have become a key focus of the ICH GCG. In 2006, the GCG implemented a strategy for addressing training and capacity needs to help ensure the most effective use of resources, opportunities, and the realization of desired outcomes. Over the past few years, the GCG has responded to numerous requests for training, providing ICH expertise both for the development of training programs and for the delivery of the training itself. Today, the GCG and the ICH Steering Committee continue to implement new tools to promote a better understanding and use of ICH guidelines and recommendations [92–2, 96].

▸ Success Drivers: One of the drivers of this success is in the fact that this harmonization process is based on scientific consensus developed between industry and DRA experts. Before ICH, the industry and regulators never sat at the same table in an international forum to discuss the science of drug development in order to develop best practices across different regions. This joint effort allows not only for the involvement of the best experts (from both the authorities and pharmaceutical industries) in specific technical discussions, but also for ensuring that discussions take into account both the regional legislations and the practical impact on the development of pharmaceutical products. This inclusion of both industry and regulators increases commitments to the common goal (i.e., implementation of the ICH tripartite, harmonized guidelines, and recommendations) that has obviously been a key factor in the success of ICH. The results of a survey on the impact of ICH, presented during the ICH6 Conference in Osaka, Japan, showed 62 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS a high degree of satisfaction by both DRAs and industry with the completed ICH guidelines, and continuous support from both sides for ICH activities.

The second driver of ICH’s success is linked to its well-defined structure and process. In the beginning years of ICH, the Steering Committee organized its structure around the working groups, which included world-recognized experts. This decision was critical because it allowed ICH to have very robust scientific and technical recommendations, most of the time accepted and implemented without fundamental criticism. The Steering Committee has of course also been key as the governing body that gives direction, selects the topics for harmonization, and ensures completion of projects in a timely manner (not always easy when one’s goal is consensus). In addition to the structure, the Steering Committee has also been able to define a process that supported this incredible harmonization task in a structured and organized way, supported by different players such as the ICH Secretariat and coordinators. Indeed, the stepwise approach that has been put in place for the development of guidelines (the defined five-step process with decision points at Step 2 and Step 4) has been very important. This approach allowed for the creation of comprehensive drafts by a small number of experts (the best environment for facilitating focused discussion and development of consensus) and public review before implementation (which promotes transparency, and avoids surprises and post-approval issues). The creation of Concept Papers and Business Plans that the Steering Committee put in place at a later stage are also fundamental to (1) define clear goals, and (2) help to monitor progress towards the predefined goals. Finally, the review of progress during regular meetings also ensures commitment, follow-up, and therefore the seriousness of this initiative.

Finally, the extension of ICH beyond the ICH regions was possible because the Steering Com- mittee understood early on that its activity could not be restricted to the ICH regions with the increasing globalization of drug development and manufacture. Indeed, research and manufacture of new products is not confined to the three ICH regions any longer. Clinical trials are carried out throughout the world and many non-ICH countries are involved in the development and manufacture of pharmaceutical products. To increase transparency and promote collaboration outside ICH regions, the Steering Committee accepted observers (e.g., Canada), worked with other international organizations (EFTA and WHO), and involved other regions/countries in this process via the ICH GCG, which evolved over time. All these actions allowed the ICH work to be expanded to most of the regions/countries in the world, and its harmonization benefits to be available worldwide. The collaboration with non-ICH regions is today one of the priorities of ICH in order to increase commitment of these regions and facilitate worldwide implementation of ICH recommendations.

▸ Limitations and Challenges for the Future: As mentioned above, ICH has been an incredible contributor to the international harmonization of pharmaceutical regulations. ICH has been successful in achieving harmonization (initially of technical guidelines and then on the format and content of registration applications), and has positively impacted the global development of new drugs. All parties agree that there is a need to maintain this harmonization in the interest of the patient and public health. Now that the process and networks are in place, it seems indeed obvious that ICH needs to continue its activities as one of the major players in the international harmonization of pharmaceutical INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 63 regulations. Further harmonization activities should be continued in a focused manner. However, in an evolving international environment, some aspects of this initiative need to be reviewed as new approaches may be needed. Indeed, some aspects of this initiative may be optimized in order to better handle new and future challenges.

The first challenge of ICH, which the Steering Committee has already acknowledged, is the implementation and maintenance of already developed guidelines. The current magnitude of successful harmonization actions and the need for these to remain current in a rapidly changing environment calls for focusing more effort on the implementation and monitoring of ICH commitments. Development of IWGs or task forces to manage this challenge will be key to its success. This focus on implementation and maintenance should not, however, impact the work on new harmonization topics that still need to be discussed. These new topics for harmonization need to be rigorously assessed for need (i.e., scientific merit/emerging science) and feasibility (i.e., expected outcome, timeline, and resource requirements).

Another major challenge for ICH is to confirm its worldwide expansion and to continue to develop and strengthen its collaboration and partnership outside the ICH regions in order to better integrate these regions into the ICH process. At the time of ICH establishment, it was agreed that its scope would be confined to registration of new drugs and medicines in Western Europe, Japan, and the US because the vast majority of the new drugs were developed and manufactured in these three regions. However, since then, there has been strong involvement of other parts of the world. Canada and Australia are key markets for pharmaceuticals, and are often involved in global clinical studies. More recently, the emergence of other countries has been recognized in all areas, including the pharmaceutical industry. As already recognized by the ICH Steering Committee, the success of ICH in the ICH regions only will not be relevant any longer. The modification of the landscape obliges ICH to review and broaden its objectives. The current organization (with the GCG) that initially responded to this increased globalization may not be the most appropriate solution for future stages of development. The ICH organization and systems need to be reviewed and revised to better serve these broader objectives.

In 2000 (during ICH5), the ICH Steering Committee reviewed its structure and concluded that this structure continues to be appropriate. However, in order to increase transparency, they welcomed appropriate participation of other interested parties in a flexible and ad hoc manner on topics that also affected them. A decade later, the new evolving environment requires a bigger revision of its structure and process. The ICH Steering Committee understands this urgent need and has declared that a new ICH organizational structure will be adopted. The Steering Committee will set the framework for new rules on governance, decision making, and membership [92–1].

Finally, ICH has to become more proactive in new emerging topics to prevent future disharmony. The gene therapy topic is an interesting example that demonstrates the previous lack of commitment of ICH to “proactive harmonization.” In September 2002, the ICH Steering Com- mittee established a Gene Therapy Discussion Group (GTDG) in recognition of the rapidly evolving area of gene therapy medicines. The GTDG developed several ICH consideration 64 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS documents in this area. Despite this first positive step/outcome, the development of these consideration papers and the activities towards the development of a new multidisciplinary guideline (Guideline M6) was discontinued in September 2011 because “currently the ICH regions do not have the resources to support the development of further ICH consideration documents” in this domain [97–1]. Recently, the ICH Steering Committee started to define a new proactive approach to identify and creatively pursue advancements in science [97–2].

If ICH succeeds in these challenges, it will certainly become a real international organization/forum (vs. a multiregional initiative) where proactive discussion on all past and new technical requirements for registration of pharmaceuticals for human use will be discussed. However, some of these challenges are not new. ICH acknowledged these challenges years ago and has already tried to resolve them without succeeding (e.g., proactivity), confirming the difficulties of this task. To face these challenges, ICH needs to revise its structure and engage a new phase in order to address the evolution of regulations and the globalization of drug development and manufacturing, and to promote better proactivity in harmonization. The ongoing ICH reform [92–4] is obviously an important milestone toward resolution of current limitations.

I-2) REGIONAL INITIATIVES

Europe was the first major regional bloc established after World War II. Following this, there have been many regional harmonization activities throughout the world, especially over the past 30 years. Countries in different regions of the globe have organized themselves into closer economic and political entities. These movements have transformed the world, both economically and politically, as they create new opportunities and also new challenges (e.g., the management of regulations and standards disharmony).

These regional harmonization initiatives include members with closer interests and needs, compared to global initiatives, allowing further harmonization and cooperation. This level of harmonization is also essential for developing countries that may not have access to all global harmonization discussions due to sparse resources or lack of expertise. Regional cooperation can represent their interests and challenges and allow them to be heard at the global level.ii This level of cooperation is also essential for establishing region-wide pooled procurement systems.

Very diverse initiatives (each with a different scope, objective, structure, and working model) were established due to different cultural, historical, and political contexts. They range from a simple technical and scientific intergovernmental cooperation model to an advanced integration model.

ii Although all countries are part of WHO, many countries are not represented at ICH where global standards are developed. However, most of the major regional harmonization initiatives are today represented via the ICH GCG group. INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 65

The political and economic development of each region, and sometimes subregions, has indeed shaped the level of harmonization in the pharmaceutical area:

▸ Scenario 1 – Pharmaceutical harmonization in the context of an economical and political integration: In certain regions, economic integration among countries implies integration of pharmaceutical regulations and the harmonization of technical standards. This degree of integration varies from one region to another (and sometimes from one subregion/country to another), but the harmonization of regulations and policies and standards are very important to create a consistent regional legislative framework and a common certification system for products across regions. Europe is the best example in terms of advanced harmonization and integration with the development of a centralized system, institutions, and procedures for the registration of medicines to be marketed in the single market.jj

▸ Scenario 2 – Pharmaceutical harmonization in the context of a general political agreement: Other initiatives follow a general political agreement, mostly signed to avoid conflicts or wars in certain areas in the world or to facilitate economic growth and trade within a region (e.g., Asia-Pacific Economic Cooperation [APEC]), without an integration goal. The output of this harmonization initiative is variable, but most of the time does not produce a deep harmonization of pharmaceutical regulations because it is not the primary objective of the agreement and therefore the resources and efforts from the countries for this pharmaceutical regulation harmonization are variable.

▸ Scenario 3 – Pharmaceutical harmonization based on a specific intergovernmental agreement: In other regions, a simple technical and scientific intergovernmental cooperation has been established, focusing solely on the harmonization of pharmaceutical regulations. This is the case of the PANDHR initiative in the Americas where regional integration has not been the objective because countries continue to present very different systems and degrees of development, and there are no political commitments to create a single market. Countries only cooperate to promote harmonization without creating common legislation and procedure. This is a scenario that produces good harmonization of pharmaceutical regulations because this is the focus of the initiative, compared to Scenario 2 above, which is a derivative of a broader political agreement. However, the risk and difficulty of this scenario is its implementation. Because there is not an ultimate economic and political goal (e.g., developing a single market as in Scenario 1), implementation of the agreed-upon recommendations in the national law is somewhat difficult. Its success clearly depends on the commitment of each country.

It is important to understand that the scenarios discussed above can also be considered as steps. Harmonization is a moving process and harmonization initiatives evolve over time. For example: jj This central system is supported by the national DRAs that also continue to operate their own registration systems for products limited to national markets. 66 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

• The European model was initiated to stop war between its countries (Scenario 2), but has in the time since evolved to an integration model to create further economic and political bonds (Scenario 1). • ASEAN is another evolving initiative that may follow the European model. Today, it is between Scenario 1 and 2.

This evolution to a more integrated model is obviously easier when the members are somewhat limited in number and share common geographical, historical, and cultural roots. It is indeed very difficult to imagine that APEC or PANDRH will evolve towards integration models such as Europe or ASEAN.

I-2.1) The European Union The European Community was created after World War II in order to develop a more peaceful Europe by promoting cooperative projects. Since then, it has rapidly evolved to become a unique partnership between 28 European countries. The main goal of the community is the progressive integration of Member States’ economic and political systems, and the establishment of a single European market based on the free movement of goods, people, money, and services.

The European Union (EU) is not a federation like the United States of America (US), nor is it simply an organization for cooperation between governments like the United Nations. It is, in fact, unique in that the countries that make up the EU (its “Member States”) remain independent sovereign nations, but pool their sovereignty in order to gain a strength and world influence that none could have on their own.kk With approximately 500 million people (representing 7% of the world’s population), the EU is today the world’s third largest population after China and India, representing a huge single market. The EU’s Gross Domestic Product (GDP) is now bigger than that of the US, and it is the world’s biggest exporter and importer [98].

Diversity is an important characteristic of the EU as symbolized by its motto, “United in Diversity,” with many differences existing among its Member States. This diversity is a positive attribute of the Union. However, considering the 24 official languages and the major historic, social, cultural, and economic differences between Member States, its development has not been easy. Its diversity has also influenced its organization and the way the harmonization process has been structured. It is therefore very important to understand the history and organization of the EU in order to understand how the European pharmaceutical regulation has been structured over time.

Member States have the main responsibility for health policy and providing healthcare to EU citizens. Each EU country is free to decide on the health policies best suited to national circumstances and traditions. However, there are areas where Member States cannot act kk Pooling sovereignty means, in practice, that the Member States delegate some of their decision-making powers to shared institutions they have created so that decisions on specific matters of joint interest can be made democratically at the European level. The constituent treaties have indeed transferred a number of national powers and responsibilities to the Community Institutions. Therefore, European laws take precedence over national law and are binding on national authorities. INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 67 effectively alone and where cooperative action at the community level is indispensable. These include major health threats and issues with a cross border or international impact, such as pandemics and bioterrorism, as well as issues relating to free movement of goods, services, and people. Acknowledging that all countries share common values (i.e., ensure high standards of public health and equity in access to quality healthcare), it is therefore logical that the EU has developed common standards for medicines. Moreover, the implementation of a single market requires harmonization of the pharmaceutical market. The ability to travel freely, or to live and work anywhere in the EU, only makes sense if EU citizens can be sure to obtain the same level of healthcare wherever they go. Therefore, a number of European Com- munity rules have been adopted to ensure the highest possible degree of protection of public health while promoting the free movement of medicines in an internal market without barriers. The European Commission (EC)’s role is not to mirror or duplicate national activities, but to coordinate them. Work on healthcare at the community level adds value to Member States’ actions, particularly in the area of illness prevention, including activity on the safety and efficacy of medicines [99].

Today, the European pharmaceutical system is well developed and the vast majority of requirements have been harmonized. This successful European cooperation in pharmaceuticals is also recognized on a worldwide basis due to its major contribution to the global harmonization of pharmaceutical regulations (via its active involvement in international initiatives such as ICH and WHO).

I-2.1.1) Membership Today the EU is composed of 28 Member States, but the size of the EU has changed over time as it has continually expanded since European integration first began in 1951 with only six countries (Table 4).

Table 4: Membership Country and Year of Addition into the EU

Year of Membership Countries

1951 Belgium, Germany,* France, Italy, Luxembourg, the Netherlands 1973 Denmark, Ireland, United Kingdom 1981 Greece 1986 Spain, Portugal 1995 Austria, Finland, Sweden 2004 Czech Republic, Estonia, Cyprus, Latvia, Lithuania, Hungary, Malta, Poland, Solvakia, Slovenia 2007 Romania, Bulgaria 2013 Croatia

* The eastern part of Germany only joined the EU in October 1990, following the fall of the Berlin Wall in 1989 and the reunification of the country. 68 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

The final three enlargements (in 2004, 2007, and 2013) expanded the EU Member States from 15 to 28, and were rooted in the collapse of communism. It was a historic advancement that offered an unexpected and unprecedented opportunity to extend the Union into Central and Eastern Europe. Today, the landmass of the EU covers 4 million km2ll and can rightly claim to represent a continent (Plate 1). Stretching from the Atlantic Ocean to the Black Sea, it reunites Western and Eastern Europe for the first time since they were separated by the Cold War.

In the future, the EU will continue to grow as an increasing number of countries express interest in membership. The Treaty on European Union sets out the conditions for such accession (Articles 6 and 49): Any European country which respects the principles of liberty, democracy, respect for human rights and fundamental freedoms, and the rule of law may apply to become a member of the Union. The applicant country must meet a core of criteria (e.g., having stable institutions and a functioning market economy) in order to ensure that EU principles will be respected and that EU rules and procedures will be effectively implemented. This is a long and rigorous process that starts when the country submits an application to the Council. Today, Iceland, the former Yugoslav Republic of Macedonia, Montenegro, Turkey, Albania, Bosnia and Herzegovina, Kosovo, and Serbia are candidates to join the EU, some of these countries being in more advanced stages of negotiation with the EU than others.

Membership is only granted when the necessary requirements are met and when candidate countries have demonstrated that they will be able to fulfill their part as members. Acknowl- edging that the EU follows an integration model towards a supranational entity, it is important to note that the Member States relinquished part of their sovereignty in favor of the Community. This model creates dependencies between Members States. For example, the European pharmaceutical system is now based on the evaluation of a Marketing Authoriza- tion Application (MAA) by either the European Medicines Agency (EMA) (for Centralized Procedures) or by a Reference Member State (for the Mutual Recognition Procedure [MRP] and Decentralized Procedures) on behalf of the other Member States. It is therefore critical to ensure that new accessing countries know and are able to follow EU rules when they integrate into the Community.

In order to prepare for the adhesion of new countries, the EC has launched several assistance programs to support preparatory measures for participation of EU candidate countries in pre-accession activities. The Collaboration Agreement between Drug Regulatory Authorities in European Union Associated Countries (CADREAC) procedure was first established in 1998 (and then strengthened through the Pan European Regulatory Forum [PERF] project). It facilitated the EU adhesion of the Central and Eastern European countries via intense cooperative activities and the harmonization of technical requirements and administrative procedures [100–102]. In 2007, after the end of the PERF project, the Instru- ment for Pre-accession Assistance (IPA) program was launched (in 2008) in order to support the participation of the candidate countries in the work of selected EU agencies such as the EMA. The aim of this program was to build contacts and relationships between the EMA and the candidate countries in preparation for these countries’ future collaboration ll By surface area, France is the biggest EU country and Malta the smallest. INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 69 in the EU regulatory network. For example, the IPA program supported the participation of nominated representatives of the concerned countries in selected meetings and training courses as observers. The program also supported the organization of conferences to prepare the countries for integration into the European regulatory network for medicines. These activities helped identify areas where additional action might be needed to ensure the smooth transposition of the EU “acquis communautaire”mm into the national legislation of these future EU Member States.

▸ The Specific Case of Iceland, Liechtenstein, and Norway: In July 2009, Iceland submitted its application for EU membership and the accession negotiations have now been opened. Norway, despite two failed attempts by referendum to enter the European Community in 1972 and the EU in 1994, remains undecided whether or not it will apply once again for EU membership. Presently, however, neither Norway nor Liechtenstein are candidates for EU membership.

However, even if these three countries are currently not part of the EU, it is important to note that they have a specific strong relationship with the Union through the European Economic Area (EEA) Agreement that entered into force on January 1, 1994. This agreement allows these three EEA European Free Trade Association (EFTA) Statesnn to participate in the EU internal market on the basis of their application of internal market relevant acquis.oo All new relevant Community legislation is dynami- cally incorporated into the Agreement and thus applies throughout the EEA, ensuring the homoge- neity of the EU internal market. Also, the EEA Agreement allows for EEA-EFTA States to participate in the internal market’s relevant Community programs and agencies, albeit with no right to vote.

In the pharmaceutical sector, Norway, Iceland, and Liechtenstein have adopted the complete Community acquis on medicines, and are consequently parties to the European procedures. In the case of the Centralized Procedure, the representatives from these three countries do not vote, but their position is stated separately in the opinion, where relevant, in the minutes of the Committee and in the case of divergent opinions appended to the Committee’s opinion. Their position is not counted in reaching the Committee’s opinion [103]. According to Decision No. 74/1999 of the EEA Joint Committee (which entered into force on January 1, 2000), when decisions on approval of medicinal products are accepted by the Community, these three countries will accept corresponding decisions on the basis of the relevant acts. The Liechtenstein authorities have transposed into their national legislation a provision that makes Commission Decisions automatically applicable on their territory. However, legally mm “Acquis communautaire” is a French term referring to the cumulative body of EU laws, comprising the EC’s objectives, substantive rules, policies, and in particular, the primary and secondary legislation and case law – all of which form part of the legal order of the EU. nn The European Free Trade Association (EFTA) is an intergovernmental organization set up for the promotion of free trade and economic integration to the benefit of its four Member States: Iceland, Liechtenstein, Norway, and Switzerland. Although Switzerland has many agreements with the EU, it is today not part of the EEA Agreement due to the rejection of accession by the Swiss people. oo The EEA Agreement is concerned principally with the four fundamental pillars of the internal market, “the four freedoms” (i.e., freedom of movement of goods, persons, services, and capital). 70 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS binding acts from the Community (e.g., Commission Decisions) do not directly confer rights and obligations in Norway and Iceland, but first have to be transposed into legally binding acts in these states [104].

I-2.1.2) Structure Since the end of World War II, the EU has steadily become more established and organized.

The unique European model (not a federation but a more integrated than simple cooperation between governments) requires a complex organization that not only protects the independent sovereignty of the Member States, but also allows for the delegation of some of decision-making powers to shared supranational institutions. Today, the structure in place was specifically designed to represent the interests of the Community, the Member States, and the European citizens. Within this overall European structure and context, many special domains have been harmonized and organized to support the functioning of the single market.

A number of institutions, committees, and technical bodies (Table 5) play a significant role in the European pharmaceutical system.

The roles and characteristics of these are briefly described in the following sections.

I-2.1.2.1) Institutions

▸ The European Parliament is the directly elected EU institution that represents the interests of the EU’s citizens. Its 766 members are elected once every five years. Its origins go back to the 1950s and the founding treaties, but the Lisbon Treaty significantly increased its role in the decision-making process and budget approval. Its legislative powers were reinforced by the extension of the co-decision procedure. Today the Euro- pean Parliament is firmly established as a co-legislator, has budgetary powers, and exer- cises democratic control over all the European institutions. Its work is organized through a system of specialized committees that review and prepare legislative proposals and reports to be presented at the plenary assembly. The Committee on the Environment, Public Health and Food Safety is responsible for the legislation covering pharmaceutical products and the EMA. The European Parliament has three working locations: Brussels (Belgium), Luxembourg, and Strasbourg (France). Luxembourg is home to the administrative offices of the General Secretariat. Meetings of the entire Parliament, known as “plenary sessions,” take place in Strasbourg and sometimes in Brussels. Committee meetings are also held in Brussels.

▸ The Council of the European Union represents the individual Member States. It meets in different configurations and is attended by one minister from each of the EU’s national governments (depending on the agenda). Health-related discussions are handled by the Employment, Social Policy, Health and Consumer Affairs Council (EPSCO). As with the INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 71

Table 5: Summary of the Structure of the European Union and Roles/Responsibilities

Organization Role and Responsibility

Institutions European Parliament Represents interests of EU citizens. Is a co-legislative power that has budgetary powers and democratic controls over other Institutions. Council of the European Union Represents individual Member States. Defends national interests at the EU level and is a key decision- making body that shares lawmaking and budgetary powers with European Parliament as well as coordinating EU’s economic policies and foreign and security policies. European Commission Represents and upholds interests of the EU and represents them in international negotiations. Acts as the “Guardian of the Treaties” and functions to draft proposals for new European laws, implements the decisions of the European Parliament and the Council of the EU.

Technical Bodies European Medicines Agency (EMA) Key component of the European Pharmaceutical Network. Responsible for coordinating existing national scientific resources to protect and promote public and veterinary health. Evaluates, supervises, and performs pharmacovigilance analyses with a broad spectrum of assigned tasks and responsibilities. Pharmaceutical Committee Advisory committee attached to the EC. Consults for questions relating to proprietary medicinal products and preparation of proposals for Directives. European Directorate for the Quality of Functions as a directorate of the Council of Europe and is a key Medicines and HealthCare (EDQM) component of the European pharmaceutical system. Responsibilities include establishing high quality standards and ensuring the quality of medicinal products in Europe.

European Parliament, the Council was set up by the founding treaties in the 1950s. It is a key decision-making body that, among other responsibilities (e.g., coordination of the EU’s economic policies and foreign and security policy) shares lawmaking and budgetary powers with the European Parliament. Its work is facilitated by the Committee of Permanent Representatives (COREPER), which is responsible for preparing the work of the Council of the European Union (all issues must pass through COREPER before they can be included in the agenda for an EU Council meeting). This committee consists of the Member States’ ambassadors to the EU. These permanent national representatives and their team are located in Brussels, Belgium, and protect national interests at the EU level.

▸ The European Commission (EC) is independent of national governments as it represents and upholds the interests of the EU as a whole. It acts as the “guardian of the Treaties” but remains politically accountable to the Parliament. Like the Parliament and Council, the EC was set up in the 1950s under the EU’s founding treaties. A new 72 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

Commission, which is formed by a President (designated by the Member States and approved by the Parliament) and the “commissioners” (each of them responsible for a specific policy area), is appointed every five years. Its role is to draft proposals for new European laws (which are presented to the European Parliament and the Council for adoption). It is also the EU’s executive arm because it is responsible for implementing the decisions of the Parliament and the Council. This means managing the day-to-day business of the EU: implementing its policies, running its programs, allocating its funds, and representing the EU in international negotiations. The day-to-day running of the Commission is done by its administrative officials, technical experts (via its various committees and groups), translators, interpreters, and secretarial staff (which represent more than 20,000 people). This staff is organized in departments, known as Director- ates-General (DG), and “services” (such as the Legal Service). The overall coordination is provided by the Secretariat-General. Each DG is responsible for a particular policy area and is headed by a Director-General who is answerable to one of the commissioners. The regulation of medicinal products was previously under the DG Enterprise and Industry, but this policy area has been transferred to the DG Health and Consumers (SANCO) as of March 1, 2010. The Commission is based in Brussels (Belgium), but it also has offices in Luxembourg, representation in all EU countries, and delegations in many capital cities around the world.

This “institutional triangle” produces the policies and laws (such as European pharmaceutical legislation) that apply throughout the EU. The Court of Justice upholds the rule of these European laws and makes sure that this EU legislation is interpreted and applied in the same way in all EU countries.

The other institutions of the EU (the European Council and the Court of Auditors) are critical for the functioning of the EU, but are not directly involved with the development and harmonization of pharmaceutical legislation.

I-2.1.2.2) Technical Bodies The EU institutions are supported by a number of other bodies (e.g., the European Central Bank, the European Ombudsman, etc.). Specialized agencies (e.g., the EMA, the European Centre for Disease Prevention and Control, and the Executive Agency for Health and Consum- ers) have also been established to handle certain technical, scientific, or management tasks.

The core technical bodies and agencies forming the European pharmaceutical system are the European Medicines Agency, the Pharmaceutical Committee, and the European Directorate for the Quality of Medicines and Healthcare. The roles and characteristics of these Agencies and Committees are detailed below.

▸ The European Medicines Agency (EMA) is a key component of the European pharmaceutical network, and in line with new EU legislation, its sphere of responsibilities has gradually expanded over time [105]. Established in 1995, it is a decentralized body of the EU which has its headquarters in Canary Wharf (London, UK). This community INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 73

agencypp has the responsibility of coordinating the existing scientific resources, put at its disposal by Member States, to protect and promote public health. This is achieved through the evaluation, supervision, and pharmacovigilance of medicines [106] for human (and veterinary) use. More specifically, the EMA has a broad spectrum of assigned tasks and responsibilities such as: • The preparation and publication of guidelines on quality, safety, and efficacy testing requirements • Providing scientific advice and protocol assistance to companies for the development of new pharmaceutical products • The scientific evaluation of European Marketing Authorization Applications (MAAs) for pharmaceutical products (Centralized and Community Referral Pr ocedures) • The constant monitoring of the safety of medicines through a pharmacovigilance network (the EMA takes appropriate actions if adverse drug reaction reports suggest changes to the benefit–risk balance of a pharmaceutical product) • The coordination of inspections (i.e., Good Manufacturing Practice [GMP], Good Labo- ratory Practice [GLP], Good Clinical Practice [GCP], and Pharmacovigilance [PhV])qq • Providing support to the Commission (and especially to the DG SANCO) on major European public health issues such as the 2009 (H1N1) influenza virus, as well as providing support to drafting of relevant legislation • Overseeing a number of the EU international activities through its work with the European Pharmacopoeia (EP), the WHO, and the ICH, among other international organizations and initiatives

This Agency is headed by an Executive Director (who is its legal representative responsible for all operational and staffing matters) and has a staff of about 900 full-time members [107]. The Management Board is the supervisory body responsible for setting the Agency’s budget, approving the annual work program, and ensuring that the Agency works effectively and cooperates successfully with partner organizations across the EU and beyond.

In addition to its staff, the EMA is composed of seven committees that conduct the main scientific work of the Agency. These committees and their characteristics are reviewed below:

• The Committee for Medicinal Products for Human Use (CHMP), established by Regulation (EC) No 726/2004, replaced the former Committee for Propri- etary Medicinal Products (CPMP). This Committee (composed of a chair, co- opted members selected for their expertise, and one member and an alternate from each of the EU Member States, and Iceland and Norway) is responsible for preparing the Agency’s opinions on all questions concerning medicines for pp A body governed by European public law, distinct from the Community Institutions, and has its own legal personality as it is set up by an act of secondary legislation in order to accomplish a very specific technical, scientific, or managerial task. qq According to Article 57 (1)(i) of Regulation (EC) No 726/2004, the European Medicines Agency has a coordinating role for these inspections while the responsibility for carrying them out rests with the national competent authorities. 74 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

human use. The CHMP plays a vital role in the EU marketing procedures as it is responsible for: - Conducting the initial scientific assessment and issuing opinions on an MAA for medicines registered via the Centralized Procedure (these opinions are used by the EC as a basis for its legally binding decisions) - Coordinating post-marketing activities for medicines registered via the Centralized Procedure - Arbitrating disagreements between Member States during Mutual Recognition and Decentralized Procedures (Arbitration Procedure) - Acting in referral cases, initiated when there are concerns relating to the protection of public health or where other community interests are at stake (Community Referral Procedure) This Committee (and its working parties) also provides assistance to companies during development, prepares scientific and regulatory guidelines, and cooperates with international partners on the harmonization of regulatory requirements for medicines.

• The Committee for Orphan Medicinal Products (COMP), established by Regula- tion (EC) No 141/2000, is charged with reviewing applications from companies seek- ing “orphan medicinal product designation” for products they intend to develop for the diagnosis, prevention, or treatment of rare diseases (so-called “orphan drugs”). This committee is also responsible for advising the European Commission on the establishment and development of a policy on orphan medicinal products in the EU, and assists the Commission in drawing up detailed guidelines and liaising internationally on matters relating to orphan medicinal products.

• The Committee on Herbal Medicinal Products (HMPC) was established in Sep- tember 2004 (in accordance with Regulation (EC) No 726/2004 and Directive 2004/24/ EC), replacing the CPMP Working Party on Herbal Medicinal Products. The HMPC’s activities are aimed at assisting the harmonization of procedures and provisions concerning herbal medicinal products laid down in EU Member States, and further integration of herbal medicinal products within the European regulatory framework for medicines. To achieve this goal, the HMPC provides scientific opinions on traditional herbal medicines. It is also charged with establishing a Community list of herbal substances, preparations, and combinations for use in traditional herbal medicinal products, as well as the establishment of Community herbal monographs.

• The Pediatric Committee (PDCO) was established in accordance with Regula- tion (EC) No 1901/2006 as amended. The mandate of this Committee is to coordinate the EMA’s work on medicines for children and to support the development of such medicines in Europe by providing scientific expertise and defining pediatric medicine needs. Its main role is to determine the studies that pharmaceutical companies must carry out as part of Pediatric Investigation Plans (PIPs),rr which are rr A PIP is a development plan aimed at ensuring that the necessary data is obtained through studies in children to support the authorization of the medicines for children. INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 75

submitted by pharmaceutical companies, and to adopt opinions on these plans. This includes assessing applications for full or partial waivers and assessing applications for deferrals of pediatric studies. This Committee also assesses data generated in accordance with the agreed-upon PIPs, provides opinions on the quality, safety, or efficacy of a medicine for use in the pediatric population (at the request of the CHMP or a Member State), and supports the development of the European Network of Pedi- atric Research at the European Medicines Agency (Enpr-EMA).ss

• The Committee for Advanced Therapies (CAT) is a multidisciplinary committee established in accordance with Regulation (EC) No 1394/2007. It is responsible for providing scientific opinions on advanced-therapy medicinal products (ATMPs) and any scientific questions related to this field. For example, it prepares a draft opinion on each ATMP application before the CHMP adopts a final opinion on the granting, variation, suspension, or revocation of a marketing authorization for the medicine concerned.

• The Committee for Medicinal Products for Veterinary Use (CVMP) is responsible for preparing the Agency’s opinions on all questions concerning veterinary medicinal products.

• The Pharmacovigilance Risk Assessment Committee (PRAC) is the last committee established by the EMA to implement the new EU pharmacovigilance legislation. It is responsible for assessing and monitoring safety issues for human medicines. This includes the detection, assessment, minimization, and communication relating to the risk of adverse reactions, while taking the therapeutic effect of the medicine into account. It also has responsibility for the design and evaluation of post-authorization safety studies and pharmacovigilance audits. Its recommendations are considered by the CHMP when it adopts opinions for centrally authorized medicines and referral procedures, and by the CMDh when it provides a recommendation on the use of a medicine in Member States.

These EMA scientific committees are comprised of members of all EU and EEA-EFTA states (Iceland, Liechtenstein, and Norway); some committees include patients’ and doctors’ representatives. They are supported by a number of working parties and related groups that have expertise in a particular scientific field. The Committees consult with them on scientific issues relating to their particular field of expertise and delegate to them certain tasks associated with the scientific evaluation of an MAA or drafting and revision of scientific guidance documents. In particular, the CHMP is supported by an important number of groups (i.e., the Biologics Working Party, the ss The European Network of Pediatric Research at the European Medicines Agency (Enpr-EMA) is a network of research networks, investigators, and centers with recognized expertise in performing clinical studies in children, which is coordinated by the Agency. It aims to foster high-quality ethical research on quality, safety, and efficacy of medicines to be used in children. It does this through networking and stakeholder collaboration with members from within and outside the EU. 76 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

Scientific Advice Working Party, or the numerous scientific advisory groups specialized by therapeutic area); some are standing parties and some temporary groups. All these groups are made up of members selected from the European expert list maintained by the EMA. Indeed it is worth noting that the EMA evaluation system works through a network of European experts made available to the Agency by the national DRAs of all EU Member States and of the three EEA-EFTA States (Iceland, Liechtenstein, and Norway). This system brings together the scientific resources and expertise of all these countries in a network of over 4,500 European experts who serve as members of the Agency’s scientific committees, working parties, or scientific assessment teams. The EMA is today considered as the model of fruitful cooperation between national DRAs, working together within a Community body to serve Community purposes.

Also, to ensure that the European system is accessible to everyone, in 2005 the EMA launched a dedicated office to provide special assistance to small- and medium-sized enterprises (SMEs) [108].

For 2012, the total budget of the EMA was €222.5 million. It is estimated that €79.8 million has been paid to the national DRAs to compensate them for the work and involvement of their staff members in the Agency’s scientific committees, working groups, and other activities [109]. On average, 80% of the Agency’s budget is derived from fees and charges, and 20% from the EU contribution for public health issues.

▸ The Pharmaceutical Committee is an advisory Committee established on May 20, 1975 (by Council Decision 75/320/EEC) and attached to the EC. It is consulted for any question relating to proprietary medicinal products and the preparation of proposals for Directives. This advisory Committee consists of senior experts in public health matters from the Member States’ administrations and is chaired by a Commission representative. It facilitates implementation of European Directives by ensuring: • Adequate communication between the Commission and Member States on new pharmaceutical legislation and legislative issues and on major activities within the European network • Interpretation and clarification of legislation if necessary • Adequate communication on international activities (new and modification of agreements with other countries, new ICH guidelines, etc.)

▸ The European Directorate for the Quality of Medicines & HealthCare (EDQM) is not a body of the EU but a Directorate of the Council of Europe that was created in 1996.tt However, several agreements and contracts have been signed between the EU (EU Commission and EMA) and the Council of Europe. Today the EDQM is a key component of the European pharmaceutical system, and plays an important role in ensuring the quality of medicines in Europe. Located in Strasbourg (France), its mission is to establish high quality standards by [110]: tt Some of the activities that are today managed by the EDQM started in 1964. INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 77

• Establishing and providing official standards for the manufacture and quality control of medicines via the publication of the European Pharmacopoeia. • Providing a central supply of chemical and biological reference standards to be used in the testing of products. The EDQM also took over the responsibility for the establishment, preparation, storage, and distribution of WHO International Chemical Ref- erence Substances (ICRS). • Performing the evaluation of applications for Certificates of Suitability of the Mono- graphs of the European Pharmacopoeia (CEPs) and coordination of related inspections. So far, more than 3,500 certificates have been granted to manufacturers in nearly 50 countries from every continent for approximately 850 substances or preparations, used in the manufacture of medicines. • Coordinating the network of Official Medicines Control Laboratories (OMCL) to collaborate and share expertise among Member States. This network includes approximately 80 Official Medicines Control Laboratories (from 40 countries), which exchange information optimizing the use of expertise, laboratory resources, and analytical data available. It also organizes collaborative studies on the validation of methods. • Participating in risk prevention and management regarding counterfeiting of medicines. • Proposing ethical, safety, and quality standards: - For the collection, preparation, storage, distribution, and appropriate use of blood components in blood transfusions - For the transplantation of organs, tissues, and cells

The role of the EDQM is essential in Europe in facilitating mutual recognition of quality control tests carried out on medicines and ensuring that patients receive the same quality of pharmaceutical products throughout Europe.

There is a substantial amount of interaction between the EMA and the EDQM. For example, the EDQM representatives participate as observers of the EMA’s Quality Working Party (QWP) and Biologics Working Party (BWP) meetings, the GMP Inspec- tion Services Group meetings, as well as HMPC meetings at the EMA.

I-2.1.2.3) Member States It is important to note that the European Member State plays a significant role in the Euro- pean pharmaceutical system.

The EMA works closely with the 28 EU Member States as well as the EEA-EFTA countries (Norway, Iceland, and Liechtenstein). Member State representatives are members of the Agency’s management board while the Agency’s scientific committees and its network of 4,500 scientific experts are nominated by the Member States. Without their support and expertise, the EMA would be unable to deliver on its responsibilities and mandate as laid down in European legislation. 78 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

It is also important to realize that many medicines available in Europe are not authorized by the EC on the recommendation of the EMA. Many products are still approved and supervised by the national DRAs via the Mutual Recognition Procedure, the Decentralized Procedure, or National Procedure.

To coordinate their efforts, the Member States established the Heads of Medicines Agencies (HMA) group, which is a network of the heads of the national DRAs. This HMA is comprised of more than 40 national agencies, some also having responsibility for veterinary products, medical devices, and cosmetics, and also pricing and reimbursement of products. The EMA is also a member of the HMA. The first meeting of the HMA took place in Amsterdam (The Netherlands) at Schiphol Airport, on February 20, 1996.

The HMA is focused on EU coordination and harmonization, decision making, and consensus on strategic issues of the European Medicines Regulatory Network. Its aim is to foster an effective and efficient European Medicines Regulatory system. More specifically, it works towards the following key objectives [111]: ▸ Addressing key strategic issues for the European Medicines Regulatory Network, such as the exchange of information and sharing of best practices ▸ Collectively being responsible for all areas of medicines regulation, including the Mutual Recognition and Decentralized Procedures ▸ Focusing on the development, coordination, and consistency of the Network ▸ Supporting the Network by providing high-quality professional and scientific resources ▸ Providing a focus for making the most effective use of scarce resources across the Network, such as developing and overseeing arrangements for work sharing

To fulfill these objectives, the HMA has been working on both general issues (i.e., strategy for telematics, and regulatory and scientific training) and technical and scientific topics (i.e., harmonization of clinical trials, coordination of products testing, and European Risk Man- agement Strategy) is support of the European Medicines Regulatory Network. The HMA’s website contains the MRI Product Index database, which includes all medicines approved in the Member States according to the Mutual Recognition Procedure. One interesting program that has been developed is the Benchmarking of European Medicines Agencies (BEMA). The BEMA program assesses the systems and processes in individual agencies against a set of agreed-upon indicators. This is a good opportunity to exchange best practices and ensure harmonization of practices (i.e., assessment, inspection, etc.) between regulators within the Network.

Coordination among the national competent authorities is not a simple task due to the heterogeneity of these national organizations. Indeed, these authorities differ in size, historic origins, roles, resources, expertise, and funding. Acknowledging these differences and also the legal, scientific, social, political, and financial challenges facing the Network, the HMA adopted a strategic paper that provides a plan of action for 2011–2015 [112]. This second plan (the first one covered 2006–2010), highlights a number of key themes and areas of focus (i.e., INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 79 pharmacovigilance, clinical trials, and communication) and also the need for international cooperation.

The HMA is supported by the Heads of Medicines Agencies Management Group, the Perma- nent Secretariat, and working groups covering specific areas of responsibility.

It is worth mentioning the Co-ordination Group for Mutual Recognition and Decentralized Procedures – Human (CMDh). This group is critical for the good functioning of the Network and for ensuring adequate communication between Member States. The CMDh was set up by Directive 2004/27/EC (amending Directive 2001/83/EC) for the examination of any question relating to marketing authorization of a medicinal product when it involves two or more Member States. This group (and its subgroups) ensures consistency of standards by preparing guidelines and Q&A that present a harmonized view and interpretation of Directives and Regulations. Also, the CMDh is involved, in the case of disagreement between the Member States, in a Mutual Recognition or Decentralized Procedure. Finally, it is in charge of laying down, annually, a list of medicinal products for which a harmonized summary of product characteristics should be drawn up, promoting harmonization of marketing authorizations and information across the European Community. The CMDh started its activities in Novem- ber 2005 and replaced the informal Mutual Recognition Facilitation Group, which was operational for over 10 years, to coordinate and facilitate the operation of the Mutual Recognition Procedure. It is composed of one representative per EU Member State (as well as Norway, Iceland, and Liechtenstein) appointed for a renewal period of three years. Observers from the European Commission and accession countries also participate in the meetings. It also has many interactions with the EMA to facilitate harmonization in several areas (i.e., pediatric regulation, variation regulation, and pharmacovigilance). It holds monthly meetings at the EMA (which also provides the Secretariat of the CMDh). In practice, approximately half of the time of the CMDh meeting is dedicated to discussions on procedural and regulatory issues, development of guidance documents, and oversight of the activities of the various CMDh subgroups and working groups, while the other half is devoted to trying to reach agreement for applications referred to the CMDh in the case of disagreement between Member States.

I-2.1.3) History The gradual harmonization of pharmaceutical regulation in the EU has been dictated by the development and expansion of the community. It represents a good example of successful harmonization and also demonstrates the influence of the political and economical decisions on the harmonization process and its outcomes.

I-2.1.3.1) The European Union

▸ The Birth of the European Union: The historical roots of the EU lie in World War II. Following this bloody, horrific war, several leaders in Europe wanted to ensure that war could never happen again. Their goal was to develop a peaceful Europe and to stop the frequent wars via the promotion of cooperative 80 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS projects. This initiative has been critical but not easily accomplished due to the post-war geopolitical situation and the beginning of the 40-year-long Cold War that split Europe into East and West.

On September 19, 1946, Winston Churchill called for a “kind of United States of Europe” in a speech given at the Zurich University. Many attempts at cooperation were made in the following years (e.g., the Customs Convention between Belgium, Luxembourg, and the Neth- erlands, and the Organization for European Economic Cooperation). In 1949, West European nations created the Council of Europe.uu It was a first step towards cooperation between them, but some countries wanted to go ever further.

On May 9, 1950, France’s Foreign Minister Robert Schuman presented a plan for deeper cooperation and for the creation of an organized Europe, which would prove indispensable to the maintenance of long-term peaceful relations. This proposal (known as the “Schuman Decla- ration”) is considered to be the beginning of the creation of what is now the EU. May 9 has since been designated as “Europe Day” to celebrate this event. The idea of this plan (inspired by Jean Monnet, top advisor of the French government) was to promote European peace by (1) eliminating the age-old opposition of France and Germany, and (2) creating a framework and organization open to the participation of the other countries in Europe. It proposed that the Franco-German production of coal and steel be placed under a common high authority and that this new productive unit be open to all European countries willing to participate. The double objectives of this proposal were (1) to set up common foundations for economic development as a first step in the federation of Europe, and (2) to make war materially impossible [113].

Based on the Schuman plan, six countries (Germany, France, Italy, The Netherlands, Belgium, and Luxembourg) signed the Treaty of Paris on April 18, 1951 to establish the European Coal and Steel Community (ECSC) in order to run their coal and steel industries under a common management. It is important to note that the independence and the powers of the high authority have been critical, and differentiated the EU from other traditional intergovernmental organizations. Indeed, the establishment of the ECSC was the first step towards a supranational Europe. For the first time the six Member States of this organization relinquished part of their sovereignty, albeit in a limited domain, in favor of the European Community.

▸ Development and Enlargement of the Single Market: Building on the success of their first treaty, the six countries decided to expand cooperation to other economic sectors. On March 25, 1957, under the encouragement of uu The Council of Europe, based in Strasbourg (France), is one of the oldest international organizations, which seeks to develop, throughout Europe, common and democratic principles based on the European Convention on Human Rights and other reference texts on the protection of individuals. It was founded on May 5, 1949 (with the signature of the Treaty of London) by 10 countries to ensure that the horror and suffering of the 20th century’s two world wars would never be repeated. Since then, the 10 original members (Belgium, Denmark, France, Ireland, Italy, Luxembourg, the Netherlands, Norway, Sweden, and the United Kingdom) have been joined by almost all of Europe’s other countries, and this intergovernmental organization now has 47 member states. INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 81

Belgian Minister for Foreign Affairs, Paul-Henry Spaak, they signed the Treaty of Rome, establishing the European Economic Community (EEC) (or “common market”) allowing persons, goods, services, and capital to move freely across borders. The same day, they also signed a second treaty to create the European Atomic Energy Community (EURATOM).

Despite the construction of the Berlin Wall in August 1961, which increased the division between the East and the West, the cooperation between European countries continued to increase in different areas (e.g., food and agriculture, aerial navigation, the environment, etc.). On July 1, 1968, the six countries created the world’s largest trading group by removing customs duties on goods imported from each of the six countries to the others, allowing free cross-border trade for the first time. They also applied the same duties on their imports from outside countries. This EU Internal Market was reinforced in 1986 with the adoption of the “Single European Act” (which entered into force on July 1, 1987) to remove the final obstacles. In 1993, the single market and its four freedoms (movement of goods, services, people, and money) had finally been fully established. Additional agreements, such as the Schengen Agreement in 1995, have since been signed to further facilitate movement within Europe. Today, this single market represents the core of the EU.

In 1991, following the collapse of communism across Central and Eastern Europe and the dissolution of the Pacte de Varsovie, a decade began that would be critical for the future of Europe. On December 13, 1997, EU leaders agreed to start the process of membership negotiations with 10 countries of Central and Eastern Europe (Bulgaria, the Czech Republic, Estonia, Hungary, Latvia, Lithuania, Poland, Romania, Slovakia, and Slovenia). The Mediterranean islands of Cyprus and Malta were also included. In December 2000, treaty changes agreed to in Nice (France) and finally signed on February 26, 2001 were entered into force on Febru- ary 1, 2003 and opened the way for enlargement of the EU by reforming its institutions and voting rules. This enlargement to the Eastern European countries became effective on May 1, 2004 and January 1, 2007. Six years later, on July 1, 2013, the accession of Croatia brought the number of Member States to 28 countries.

▸ A Single Currency: A single currency (Euro [€]) was introduced on January 1, 1999 in 11 countries (joined by Greece in 2001) for commercial and financial transactions only. Notes and coins were introduced in January 2002. This introduction of the single currency followed a long stepwise process that started in the 1970s with the creation of the “Exchange Rate Mechanism” to maintain monetary stability.

▸ From the Economic Community to the Political Union: The next important step of integration (i.e., development of a political union with fully functioning institutions) took time and faced many challenges. The debate on the “constitutionalization” of Europe started in 1984 when the European Parliament adopted Altiero Spinelli’s report proposing, in a “draft treaty on European Union,” a fundamental reform of the European Community. 82 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

In the 1990s, two important treaties transformed the community: ▸ The Treaty on European Union (signed in Maastricht [The Netherlands] on February 7, 1992, entered into force on November 1, 1993) represented a new stage in European integration as it opened the way to political integration. It was a major EU milestone, introducing the concept of European citizenship and setting clear rules for the future single currency and for foreign and security policy. Under the treaty, the name “Euro- pean Union” officially replaced “European Community.” ▸ The Treaty of Amsterdam (signed on October 2, 1997, entered into force on May 1, 1999), built on the achievements of the treaty from Maastricht, laid down plans to reform EU institutions, gave Europe a stronger voice in the world, and concentrated more resources on employment and the rights of EU citizens.

Building on this transformation of the Community, the adoption of a European constitution and major institutional reform became an important topic of discussion for two reasons: ▸ Succeeding treaties have spurred progress in the building and reforming of Europe and its institutions. This long process marked by ever-closer integration progressively transformed Europe from an economic community to a political union. ▸ The combination of the various treaties and protocols signed over 50 years has made the European structure and legislation more and more complex.

After three years of debates and negotiations, a Treaty Establishing a Constitution for Europe was signed on October 29, 2004 by the 25 Heads of State and Government but never ratified (due to a negative citizen’s vote during referendum in both France and The Netherlands in 2005). Following this ratification issue and a period of reflection, the EU leaders agreed (during the European Council meeting on June 21 and 22, 2007) to finalize and adopt, not a constitution, but a reform treaty for the EU. The final text of the treaty was approved at the informal European Council in Lisbon, Portugal on October 18 and 19, 2007. This Treaty of Lisbon was finally signed by the 27 Member States on December 13, 2007 and entered into force on December 1, 2009 (despite a first negative referendum in Ireland in June 2008). This new treaty amended the previous ones, without replacing them, and reformed the EU institutions. It strengthened the role of the European Parliament, modified the voting rules for the Council, and created two new positions, the President of the European Council and the High Representative for the EU in Foreign Affairs and Security Policy. It also reinforced the values and objectives upon which the EU is built, and better defined the relationship between the Member States and the EU.

On November 20, 2009 at a meeting of the European Council, Herman Van Rompuy was appointed the first permanent President of the EU Council, and the British Trade Commis- sioner, Catherine Ashton, was appointed “High Representative of the Union for Foreign Affairs and Security Policy.”

Although the EU will certainly continue to grow, it is difficult to predict the next steps of integration due to the current geopolitical situation and the instability caused by the financial crisis. INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 83

I-2.1.3.2) Pharmaceutical Regulation in the European Union The evolution of pharmaceutical regulation harmonization and cooperation in Europe represents an excellent example and model that needs to be analyzed in detail as it shows the different important steps necessary for harmonization success.

A large body of legislation has been developed, with progressive harmonization requirements since the 1960s.

The first European Directive related to pharmaceutical products (Directive 65/65/EEC [114]) was signed on January 26, 1965. This text provides the European definitions of a “Medicinal Product” and a “Substance” and set up some fundamental principles for the creation of the European pharmaceutical system such as: ▸ No medicine may be placed on the market of a Member State unless a marketing authorization has been issued by the competent authorities following the review of an application submitted by the person responsible for placing that product on the market. ▸ Quality, safety, and efficacy are the basis for the evaluation of an application by the competent authorities. ▸ The information included in the application should be updated on a regular basis.

Following this first Directive, many texts followed over the years to further detail the Euro- pean principles and requirements led by Directive 65/65/EEC, to organize and structure the European system, and to add new requirements related to specific types of products or emerging problems. Major texts and important steps in the development of the European pharmaceutical system are discussed below. However, it is important to note that many other legislative texts, guidelines, and other recommendations (including harmonized quality, and nonclinical and clinical requirements) have been prepared and released over the years to support the major legislatives texts listed in this section.

Directive 65/65/EEC was complemented by two additional Directives (Directives 75/318/EEC and 75/319/EEC) in May 1975 to provide further details on the analytical, nonclinical, and clinical standards and protocols to be applied during the development of medicines, and how the results of such studies should be presented in the MAA. Directive 75/319/EEC also established the idea of Expert Reports (that would later influence the structure of the CTD), the CPMP (that would later be part of the EMA), and the first Multi-State Licensing Procedure, which would then evolve progressively to become the current Mutual Recognition Procedure (MRP).

Further clarification of requirements was provided by Directive 83/570/EEC (which also modified the Multi-State Licensing Procedure to facilitate its use), and Directive 87/21/ EEC (which established the notion of combination products and created a route for abridged applications in case of generics and literature-based applications).

In 1987, Directive 87/22/EEC established the Concertation Procedure, which provided a simple community-wide licensing opinion (via a mandatory referral to the CPMP) for all new biotechnology products and optionally for high technology medicinal products [115]. It was an important new step in building the European pharmaceutical system as this new 84 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS procedure (the forerunner of the current Centralized Procedure) required further cooperation between National DRAs compared to the Multi-State Licensing Procedure previously established. However, both procedures were still based on voluntary cooperation between the relevant national authorities, and each Member State remained solely responsible for granting the Marketing Authorization.

In 1989, legislators extended the scope of the previous Directives to specific types of products: vaccines, toxins or serums, and allergens (Directive 89/342/EEC); radiopharmaceuticals (Directive 89/343/EEC); and products derived from human blood or human plasma (Direc- tive 89/381/EEC). Additionally, on April 23, 1990, Directive 90/219/EEC laid down the first common measures related to genetically modified organisms (GMOs); several additional texts have since then been released on this topic over the years. Finally, extension of the scope of the harmonization of homeopathic products was only made in 1992 via the adoption of Directive 92/73/EEC.

In 1991, Directive 91/356/EEC, which laid down the principles and guidelines of GMP, was adopted.

In 1992, four new Directives covering the distribution of medicines were adopted to further establish the EU Internal Market and facilitate the free movement of products. They especially harmonized wholesale distribution (Directive 92/25/EEC), the classification of products as subject to medical prescription or not (Directive 92/26/EEC), the labeling of products (Directive 92/27/EEC), and advertising principles (Directive 92/28/EEC).

Despite all these texts adopted since 1965, the resulting progress of completing the single market in pharmaceuticals was not satisfactory. It was therefore decided to fundamentally improve the authorization procedures. A new European pharmaceutical system was then created in 1993 (but only implemented in January 1995). This new system, still in place today, is based on two major texts that established, for the first time, “European decisions” binding to the Member States: ▸ Directive 93/39/EEC modified the Multi-State Licensing Procedure to create the Mutual Recognition Procedure (MRP) still in place today. This text also established the Arbitration Procedure (if the Member States cannot reach agreement during the MRP), leading to a single European Commission decision on the area of disagreement binding on the Member States concerned. ▸ Regulation 2309/93 has been an important and strong political decision (it is a Regula- tion and not a Directive that needs to be transposed in national laws); it created: • The European Agency for the Evaluation of Medicinal Products (EMEA; renamed the European Medicines Agency (EMA) in 2009), incorporating the CPMP. • The Centralized Procedure replacing the Concertation Procedure (Directive 87/22/ EEC establishing the Concertation Procedure had been repealed by Directive 93/41/ EEC in June 1993). This procedure’s ultimate objective is for the creation of a single market allowing a single Pan-European Marketing Authorization by the EC, valid in all European countries. INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 85

Following the adoption of these European procedures, it was necessary to harmonize the system to vary the terms of marketing authorization. This was done via the adoption of two Regulations in 1995: Regulation 541/95 (for the MRP) and Regulation 542/95 (for the Central- ized Procedure).

Additionally, acknowledging the increased complexity of the European pharmaceutical legislation, it was agreed to assemble all previous Directives in one single text. This codifying Directive, Directive 2001/83/EC adopted on November 6, 2001, was necessary because all the Directives adopted since 1965 had been frequently and substantially amended. Therefore, this Directive regroups all legal requirements agreed-upon since 1965 (except requirements and legal provisions provided by Regulation 2309/93). This new Directive has already been amended several times since its adoption, some of these amendments being the result of a major general review of the legislation and system discussed below.

In 2000, as directed by Regulation 2309/93 (Article 71), the Commission conducted a major review of the operation of the new system implemented in 1995. The goal of this audit, contracted out to independent auditors, was to review the extent to which the results achieved over the first five years have met the objectives (namely to enhance the creation of a single market in medicinal products, while ensuring the protection of public health and the development of the pharmaceutical industry). The audit report [116], known as the “Cameron McKenna Andersen Report,” includes the results of the extensive consultation carried out involving individual companies, all DRAs responsible for the authorization of medicines and the EMEA, patient and professional associations, trade associations, and relevant ministries.

This audit highlighted the overall satisfaction with this new system, as both procedures had been perceived as contributors in both a qualitative and quantitative way to create a harmonized European Community pharmaceutical market. Ninety-two percent (92%) of companies and 97% of DRAs in the EU were satisfied or very satisfied with the Central- ized Procedure. There was also general recognition of the very considerable contribution made by the EMEA and the EU telematics strategy to the successful operation of the system. However, this report also identified several issues and listed several possible improvements to the system. These criticisms were primarily directed towards the MPR for which it was agreed that the lack of real supervisory, management support, and liaison between Member States had altered the application of the central principle of mutual recognition. Concerned Member States were continuing to assess applications. Regarding the Centralized Procedure, it was felt that it should be opened up to a broader range of products and that the “decision-making process” of the Commission (post-CPMP opinion) should be reduced and improved. Finally, it was also interesting to note that the European procedures had not yet produced any real dividends in terms of cost efficiencies through economy of scale. There was also a need to reduce the administrative burden where there were no public health implications (e.g., in relation to minor variations to existing approvals). 86 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

This evaluation of the regulatory processes was not only very timely with the emerging technical challenges (e.g., gene therapies, etc.), but also with the political challenges in preparation for EU expansion [117]. Indeed, there was little doubt that the upcoming major enlargement of the EU (in 2004, and involving 10 additional countries) would accentuate the weaknesses of the system if both the structural and process issues were not resolved by then.

Based on this review of the EU pharmaceutical legislation and various public hearings, the EC concluded that on the whole the system had proven appropriate and suitable for its purpose and therefore it was recommended that it keep its main principles and structures. How- ever, the EC also proposed several adaptations of the system and legislation in order to better achieve four major objectives [118]: ▸ Assure a high level of public health protection, notably by increased supervision of the market through the strengthening of inspection procedures and of pharmacovigilance. ▸ Complete the single market for pharmaceutical products, taking into account the stakes of globalization, and establish a regulatory and legislative framework that favors the competitiveness of European industry. ▸ Respond to the challenges of the future enlargement of the EU. ▸ Rationalize and simplify the system and improve its overall coherence and visibility and the transparency of its procedures.

These proposals, such as opening up the Centralized Procedure to a broader range of products, establishment of a fast track procedure and conditional authorization, improvement of the transparency of the system, strengthening pharmacovigilance and supervision requirements, abolition of the renewal, control of the effective use of marketing authorization with the “Sunset Clause,” improvement of the decision-making process after CPMP opinion, re-organization and increase of the role of the EMEA and its committees, major modifications to the MRP and creation of the Decentralized Procedure, and harmonization of data protection periods [119,120], have been further debated with the Parliament and the Coun- cil over subsequent years. Most of them have finally been implemented via the adoption of new or revised legislation and/or guidelines. One of the major legislative impacts has been the adoption of Regulation (EC) No 726/2004 on March 31, 2004, which replaced Regula- tion 2309/93. This new regulation (amended several times since 2004), together with the amended Directive 2001/83/EC, today forms the two pillars of the European pharmaceutical legislation.

Finally, in addition to these critical texts that created the European system and general requirements, it is worth mentioning the following additional legislative texts adopted over the past 10 years on important specific subjects (see Part I-2.1.5.3 for more details): ▸ Regulation (EC) No 141/2000 (adopted on December 16, 1999) on orphan medicinal products ▸ Directive 2001/20/EC (adopted on April 4, 2001) harmonizing the requirements for the conduct of clinical trials in Europe. ▸ Regulation (EC) No 1901/2006 (adopted on December 12, 2006) providing measures on the development and authorization of medicines for pediatric use. INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 87

▸ Regulation (EC) No 1394/2007 (adopted on November 13, 2007) related to advanced therapies (i.e., medical products based on genes [gene therapy], cells [cell therapy], and tissues [tissue engineering]).

I-2.1.4) Harmonization and Cooperation Process The current European pharmaceutical system has progressively developed over the years via the adoption of agreed-upon policies. Since 1985 many texts have been adopted with the aim of achieving a single market for pharmaceutical products. As noted above, several European institutions and technical bodies, together with the EU Member States, are involved in the harmonization of European pharmaceutical regulation.

The European harmonization process lies in the adoption of EU laws [121] that can be catego- rized as follows:

▸ The “primary” legislation: The Treaties are binding agreements between EU member countries. They state EU objectives, rules for EU institutions, how decisions are made, and the relationship between the EU and its Member States. They also form the basis or ground rules for all EU actions. This means that every action taken by the EU is founded on treaties that have been approved voluntarily and democratically by all EU member countries. For example, if a policy area is not cited in a Treaty, a law cannot be proposed in that area.

▸ The “secondary” legislation: This is derived from the principles and objectives set out in the Treaties. It includes the following texts: • Regulations are the most direct form of EU law. As soon as they are passed, they have binding legal force throughout every Member State and must be applied in its entirety across the EU. National governments do not have to take action themselves to implement EU regulations (i.e., regulations do not require any transposition by the national authorities). • Directives are legislative acts that set out a goal that all EU countries must achieve. National authorities have to adapt their laws to meet these goals, but are free to decide how to do so.vv Directives are used to bring different national laws in line with each other, and are particularly common in matters affecting the operation of the single market (e.g., product safety standards). They may concern one or more Member States, or all of them. • Decisions are individual acts relating to specific cases and are addressed to specific parties. They are binding only on those to whom they are addressed (e.g., an EU country or an individual company), and are directly applicable (no need for implementation into national law). Decisions can come from the EU Council (sometimes jointly with the European Parliament) or the EC. vv Each directive specifies the date by which the national laws must be adapted (giving national authorities room to maneuver within the deadlines necessary to take account of differing national situations). 88 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

• Recommendations are not binding, but allow the institutions to make their views known and to suggest a line of action (without imposing any legal obligation on those to whom it is addressed). • Opinions are not binding. They are an instrument that allows the institutions to make a statement in a nonbinding fashion; in other words, without imposing any legal obligation on those to whom it is addressed. They can be issued by the main EU institutions (Commission, Council, Parliament), the Committee of the Regions, and the European Economic and Social Committee.

The European Parliament and the Council of the EU share legislative power, which means they are empowered to adopt European laws (directives and regulations). In principle, it is the Commission that proposes new “legislative texts,”ww but it is the Parliament and Council that adopt them. The Commission and the Member States then implement them, and the Commission ensures that the laws are correctly applied.

The vast majority of European laws are adopted jointly by the European Parliament and the Council using a procedure known as “co-decision.”xx This means that the directly elected European Parliament has to approve EU legislation together with the Council (the governments of the 28 EU countries). In addition to this “ordinary legislative procedure,” there are also other special legislative procedures (which apply only in specific cases) where the Parlia- ment has only a consultative role.

The requirements and procedures for the marketing authorization of medicinal products, as well as the rules for variations to the terms of marketing authorizations and for the constant supervision of products after they have been authorized, are primarily laid down in Directive 2001/83/EC and Regulation (EC) No 726/2004 (and their subsequent amendments). These texts additionally lay down harmonized provisions in related areas such as the manufacturing, wholesaling, or advertising of medicinal products for human use. In addition, various laws have been adopted to address the particularities of certain types of medicinal products and promote research in specific areas.

In addition to the legal texts, many additional Community or international documents and recommendations have been developed and support the harmonization and cooperation in the EU. The “Introduction and General Principles” of Annex 1 of Directive 2001/83/EC, as ww The European Commission is the only institution empowered to initiate legislation. Before proposing a new text, it assesses the potential economic, social, and environmental consequences that they may have by preparing “impact assessments” (which set out the advantages and disadvantages of possible policy options) and by consulting interested parties. The Commission will propose action at the EU level only if it considers that a problem cannot be solved more efficiently by national, regional, or local action. This principle of dealing with things at the lowest possible level is called the “subsidiarity principle,” and has been reaffirmed in the Lisbon Treaty. xx The co-decision procedure was introduced by the Maastricht Treaty on European Union (1992), and strengthened and made more effective by the Amsterdam Treaty (1999). With the Lisbon Treaty that took effect on December 1, 2009, this procedure has been renamed “ordinary legislative procedure” and has become the main legislative procedure of the EU’s decision-making system. INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 89 amended, acknowledged these scientific and technical recommendations (i.e., “The rules governing medicinal products in the European Community,” ICH guidelines, and monographs of the European Pharmacopoeia).

All Community rules in the area of medicinal products for human (and veterinary) use are compiled in “The Rules Governing Medicinal Products in the European Union” (EudraLex), published by the EC. Volume 1 of this publication contains the body of the EU pharmaceutical legislation (i.e., Regulations, Directives, Decisions, etc.). The subsequent volumes include guidelinesyy developed to support this basic legislation:zz ▸ Volume 2 (also known as “Notice to Applicants”), first published in 1986, contains all regulatory guidelines related to procedural and regulatory requirements (i.e., the presentation and content of the dossiers), and also the application forms. It was prepared and is regularly updated by the European Commission in consultation with competent authorities of the Member States and the EMA. This Notice has no legal power. In case of doubt, therefore, reference should be made to the appropriate Community Directives and Regulations. Also, in July 2012, the information contained in Chapter 7 of Volume 2A (concerning general information on procedures for marketing authorization) was transferred to EMA and CMDh websites. ▸ Volume 3 consists of all the scientific guidelines for medicinal products for human use prepared by the Committee for Medicinal Products for Human Use (CHMP) in consultation with the competent authorities of the EU Member States. The guidelines are intended to provide a basis for practical harmonization in the manner in which the EU Member States and the EMA interpret and apply the detailed requirements for the dem- onstration of quality, safety, and efficacy contained in the Community Directives. An updated list of scientific guidelines is accessible on the EMA website.

yy To facilitate the interpretation of the legislation and its uniform application across the EU, numerous guidelines of regulatory and scientific nature have additionally been developed. An EU guideline is a Community document with explicit legal basis referred to in the legislative framework as intended to fulfill a legal obligation laid down in the Community pharmaceutical legislation. It provides advice to applicants or marketing authorization holders, competent authorities, and/or other interested parties on the best or most appropriate way to fulfill an obligation laid down in the community pharmaceutical legislation. Guidelines can be of different types (such as regulatory guidelines, scientific guidelines, pharmacovigilance guidelines, etc.), and therefore cover a lot of different areas. In the case of scientific guidelines, these may relate to specific scientific issues reflecting a harmonized EU approach and based on the most up-to-date scientific knowledge (see “Procedure for European Union Guidelines and related documents within the pharmaceutical legislation framework, EMEA/P/24143/2004 Rev. 1 corr, 18 March 2009”).Within the framework of the pharmaceutical legislation, guidelines do not have legal force, and the definitive legal requirements are those outlined in the relevant Community legislative framework (Directives, Regulations, Decisions, etc.) as well as appropriate national rules. Guidelines are “soft law” non-legally binding but quasi-binding character that can derive from the legal basis when the guideline intends to specify how to fulfill a legal obligation (example Article 106 of Directive 2001/83/EC concerning pharmacovigilance). However, guidelines are to be considered as a harmonized Community position, which if they are followed by relevant parties, such as the applicants, marketing authorization holders, sponsors, manufacturers, and regulators, will facilitate assessment, approval, and control of medicinal products in the European Union. Nevertheless, alternative approaches may be taken, provided that these are appropriately justified. zz The volumes of this publication not listed below relate specifically to veterinary products. 90 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

▸ Volume 4 contains guidance for the interpretation of the principles of GMPs for medicinal products for human and veterinary use. ▸ Volume 9 contained pharmacovigilance guidelines for medicinal products for both human use (Volume 9A) and veterinary use (Volume 9B). Volume 9A was replaced by the EMA “Guidelines on Good Pharmacovigilance Practice (GVP)” in 2012 [122]. ▸ Volume 10 contains guidance documents applying to clinical trials.

Finally, in addition to the published rules listed above, a lot of other documents that do not have the status of a law or guideline (i.e., questions and answers [Q&A], recommendations, public statements, position papers, reflection papers, etc.) are released by the EMA to provide additional guidance. Moreover, templates (e.g., assessment templates and guidance), internal standard operating procedures (SOPs), work instructions (WINs), and policy covering both general and specific topics (e.g., pharmacovigilance, inspection, etc.) have been developed by the EMA to improve consistency in activities and evaluations and to help ease the exchange of information.

I-2.1.5) Harmonization and Cooperation Projects

I-2.1.5.1) Harmonization of Technical Requirements Many technical requirements have been harmonized and published in Europe to ensure that medicinal products throughout Europe are of equal quality, safe, and efficacious. These are the three basic criteria that are always evaluated and taken into consideration when establishing the risk and benefit ratio. These criteria are evaluated through the quality, nonclinical, and clinical information included in all applications. Of course, the level of quality/nonclinical/clinical documentation varies depending upon the type of products and the level of development, but they are always the basis of approval for the registration of a clinical trial or a new product.

Legal provisions related to these technical requirements are included in Annex 1 of Directive 2001/83/EC and other relevant Regulations or Directives. In addition, scientific and technical guidelines are also prepared by the EMA’s Committees (i.e. CHMP, COMP, PDCO, etc.) and its Working Parties (in consultation with the competent authorities of the EU Member States). Guidelines developed by other technical bodies (e.g., the European Pharmacopoeia) or international bodies are also used in Europe. For example, Europe is a founder and member of ICH, and therefore all ICH guidelines are also applicable in Europe.

▸ Quality: Many European requirements are in place regarding the quality of the products (active substance, excipients, and finished products). Detailed scientific guidelines have been developed to adequately cover pharmaceutical development, manufacture, packaging, control (i.e., specifications, analytical procedures and validation, and impurities), stability evaluation, and post-approval changes. Moreover, guidelines for certain types of products (i.e., biologics, radiopharmaceuticals, medicinal gases, or herbal medicinal products) have been specifically released to take into account their specific challenges. INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 91

These technical and scientific guidelines, together with the Q&A document, provide a common interpretation of the European legislation and ensure harmonization of quality requirements. Also, in addition to these guidelines, it is worth mentioning two other publications that have been critical in the harmonization of the quality aspect of medicinal products available on the European market:

• Good Manufacturing Practice (GMP) is one of the most important harmonized requirements that have been issued. As per Directive 2001/83/EC and Directive 2001/20/EC, all products (including investigational medicinal products) have to comply with the principles and guidelines of GMP. These GMP principles are laid down in Directive 2003/94/EC. In addition, the EC has published detailed GMP guidelines in line with those principles in EudraLex (Volume 4). This volume covers both the basic requirements for Medicinal Products (Part I) and for Active Substances used as Starting Materials (Part II). Particular considerations and conditions for specific products (biological products, radiopharmaceuticals, medicinal gases, products derived from human blood or plasma, herbal medicinal products, excipients, etc.) are also in place or under discussion. Under this EU system, manufacturers and importers of medicines located in the EEA are subject to a manufacturing authorization and come under the supervision of the competent authorities of the Member States (the Supervisory Authorities), who are responsible for issuing the authorizations for those activities taking place in their territories. • The European Pharmacopoeia (EP), established on July 22, 1964 by eight countries,aaa is a collection of standardized specifications, so-called monographs, which define the quality reference standard for medicines. Today, the Convention has been ratified by more than 35 European countries and the EU. European Directive 2001/83/EC refers to the mandatory character of EP monographs in the preparation of dossiers for MAA in the EU. The EP is also applicable in all the signatory states of the Convention for the elaboration of an EP, and is used as a reference by many other countries (there are more than 20 Observers). The EP is published by the EDQM and covers active substances, excipients, substances or preparations for pharmaceutical use of chemical, animal, human or herbal origin, homoeopathic preparations and stocks, antibiotics, as well as dosage forms and containers. The texts of the European Pharmacopoeia also apply to biologicals, blood and plasma derivatives, vaccines, and radiopharmaceutical preparations.

▸ Nonclinical: All aspects of nonclinical testing and programs are covered under general guidelines (e.g., GLP)bbb or discussions on nonclinical strategies to identify and mitigate risks for first-in-human clinical trials or guidelines specific to a type of testing (i.e., pharmacology, aaa Belgium, France, Germany, Italy, Luxembourg, the Netherlands, Switzerland, and the United Kingdom. bbb The principles of Good Laboratory Practice define a set of rules and criteria for a quality system concerned with the organizational process and the conditions under which nonclinical health and environmental safety studies are planned, performed, monitored, recorded, reported, and archived. 92 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS pharmacokinetics, single and repeat dose toxicity, genotoxicity, carcinogenicity, reproductive and developmental toxicity, and local tolerance). Most of these guidelines have in fact been developed under the auspices of ICH.

As for the quality requirements, specific nonclinical guidelines have also been developed for certain types of products.

▸ Clinical Efficacy & Safety: Numerous clinical guidelines are available, which cover all phases of clinical development, from early on (i.e., clinical pharmacology and pharmacokinetics studies) to the design of Phase 3 studies (disease and patient characteristics, advice on selection of endpoint, duration, control groups, and choice of comparator, etc.). Due to the specificities of each group of products, guidelines have been organized by therapeutic area, and some focus on certain types of products (herbal medicinal products or radiopharmaceuticals and diagnostic agents). Additionally, general guidelines have also been released to provide advice on general considerations and topics during drug development that are not disease-specific (e.g., “Guideline on Missing Data in Confirmatory Clinical Trials,” “Extrapolation of Results from Clinical Studies Conducted Outside Europe to the EU Population,” “Clinical Trials in Small Populations,” “Data Monitoring Committee,” “Choice of a Non-Inferiority Margin,” and “Excipients in the Label and Package Leaflet of Medicinal Products for Human Use”).

In addition to these numerous scientific guidelines, it is worth mentioning the development and implementation of GCP in Europe for investigational medicinal products. This harmonization of GCP has been critical for the recognition of data between European countries, and therefore cooperation on clinical aspects of drug development. Directive 2001/20/EC is the framework legislation that provides for additional directives, accompanying guidelines, and detailed guidance documents. These guidelines and guidance documents are published in EudraLex (Volume 10).

Finally, it is important to note that there has been a lot of effort put forth in past years regarding harmonization of the European pharmacovigilance system. This system is coordinated by the EMA, but also involves national competent authoritiesccc and the European Commis- sion. It includes a broad range of activities such as the review of Risk Management Plans (RMPs) and PSURs, the development and maintenance of the EU reporting and data ware- house system for case reports (EudraVigilance), signal-identification activities in the EU, and the coordination of EU rapid alert and incident management systems for timely and adequate responses to new safety data.

The EU legal framework of pharmacovigilance was provided in Regulation (EC) 726/2004 and Directive 2001/83/EC. Additionally, relevant ICH guidelines have been implemented, and Volume 9 of EudraLex has been dedicated to this key public health function. It included a number of detailed guidelines, definitions, standards, and information regarding the precise execution of pharmacovigilance-related procedures. ccc In some Member States, regional centers are in place under the coordination of the national competent authority. INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 93

In December 2008, following a public consultation, the EC decided to further harmonize the system (to ensure it is optimally effective, robust, and transparent) via the adoption of two additional texts [123,124]. The final new legislation [125] was finally published on December 31, in the Official Journal of the European Union. On June 19, 2012, the Commission Implementing Regu- lation (EU) 520/2012 was adopted, complementing the 2010 pharmacovigilance legislation that started to apply in July 2012. Finally, some pharmacovigilance incidents in the Union have shown the need for further improvements of the 2010 legislation. These issues have been addressed by Directive 2012/26/EU and Regulation No 2012/1027/EU, which started to apply in 2013.

Due to the number and importance of improvements that need to be implemented [126,127], many observers consider this new pharmacovigilance legislation as the biggest change to the EU legal framework since the creation of the EMA in 1995.

The implementation of this new pharmacovigilance legislation required a lot of effort from the EMA [128]. This was a major activity because several processes needed to be established or amended (e.g., the establishment of a new Pharmacovigilance Risk Assessment Committee [PRAC] replacing the CHMP Pharmacovigilance Working Party). Also, an important change of the new legislation is the increased direct involvement of the EMA in the pharmacovigilance of nationally authorized products, in addition to the centrally authorized products. For example, the EMA has released the “Guidelines on Good Pharmacovigilance Practice (GVP)“, which replace Volume 9 of EudraLex [129]. This new set of guidelines applies to all medicines authorized in the EU, whether centrally or nationally authorized.

The EMA is also working with other groups to continuously improve the safety monitoring of medicines. This includes its central coordinating role in PROTECT,ddd its support of the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP),eee its work with the US FDA on AE signal detection activities, and its notifications to the WHO of any measures taken in the EU on medicines that may have a bearing on public health protection in third-world countries.

Finally, the Heads of Medicines Agencies have also put in place a multi-annual program (called the European Risk Management Strategy [ERMS]) which aims to strengthen European pharmacovigilance systems by putting in place efficient measures allowing for the early detection, assessment, minimization, and communication of a medicine’s risk throughout its lifecycle.

▸ Multidisciplinary: These guidelines apply to more than one specific area and have been prepared through the collaboration of several working parties. They provide advice and guidance on specific

ddd PROTECT is a project of the Innovative Medicines Initiative (IMI), which is aimed at strengthening the monitoring of the benefits and risks of medicines in Europe by developing innovative tools and methods that will enhance the early detection and assessment of adverse reactions. eee ENCePP is a network that supports independent, post-authorization studies on the safety and benefit/risk aspects of specific medicines. 94 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS important topics (i.e., pediatrics, cell therapy and tissue engineering, vaccines, biosimilars, gene therapy, and pharmacogenomics).

The EU harmonization activities related to certain of these topics are further discussed in the following sections.

It is also important to note that cooperation in the areas of inspection (e.g., GMP, GLP, GCP, or PhV) is critical. Although the responsibility for carrying out inspections rests with the national competent authorities of Member States, the coordination of these inspections by the EMA (and the agreement of common standards) has been an important step that allows for: • Increased cooperation between Member States • Reduced duplication of work (due to the recognition of inspections performed by other Member States) • Ensuring the same level of quality of medicinal products, and the data generated during their development, wherever the location of the manufacturing site or studies

I-2.1.5.2) Harmonization of Procedures for the Authorization of Medicinal Products A European system for the authorization of medicinal products has been created with the objective of ensuring that safe, effective, and high-quality medicines can quickly be made available to all citizens across the EU.

Today, the European system offers several routes for the authorization of medicinal products:

▸ The Centralized Procedure (laid down in Regulation (EC) No 726/2004) is compulsory for certain types of products: products derived from biotechnology processes, advanced therapy medicines, orphan medicines, or products intended for the treatment of certain specific diseases. For medicines that do not fall within these categories (the “mandatory scope”), companies can also submit an application if the medicinal product constitutes a significant therapeutic, scientific, or technical innovation, or if it is in any other respect in the interest of public health. Applications for the Centralized Procedure are made directly to the EMA and lead to European marketing authorization. This authorization, binding in all Member States, is granted by the EC (based on the opinion of the relevant EMA committee). It is valid for the entire Community market, which means the medicines may be put on the market in all Member States. This is the ultimate integration model in this domain because there is a single application, a single evaluation, and a single authorization allowing direct access to the single market of the Community.

▸ The Mutual Recognition Procedure (MRP) (laid down in Directive 2001/83/EC), applicable to the majority of conventional medicinal products, is based on the principle of recognition of an already existing national marketing authorization by one or more Member States. Should any Member State refuse to recognize the original INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 95

national authorization on the grounds of potential serious risk to public health, the issue is referred to the CMDh to find a consensus. In that case, the CMDh uses its best efforts to reach an agreement on the action to be taken (within the 60-day time period foreseen in the legislation). When this fails, the matter is then referred to the EMA/CHMP for arbitration (see below for details).

▸ The Decentralized Procedure (introduced with the legislative review of 2004 and laid down in Directive 2004/27/EC) is also based on recognition by national authorities of a first assessment performed by one Member State. The difference lies in that it applies to medicinal products that have not received a marketing authorization at the time of application. Through this procedure, an application for the marketing authorization of a medicinal product is submitted simultaneously in several Member States, one of them being chosen as the Reference Member State (RMS).

At the end of the MRP and Decentralized Procedure, national marketing authorizations are granted in the Member States involved, whereas the Centralized Procedure results in a single marketing authorization (called a “Community marketing authorization”) that is valid across the EU, as well as in the EEA-EFTA states (Iceland, Liechtenstein, and Norway). Purely national authorizations are still available, but are limited to medicinal products to be marketed in one Member State only.

In addition to the above registration procedures, another European procedure called “referral” has been established. This Community Referral Procedure is used to resolve disagreements (e.g. between Member States during an MRP or a Decentralized Procedure), address specific concerns relating to the safety or efficacy of a medicine or a class of medicines, or when there is a need to harmonize national decisions across the EU. In a Referral Procedure, the EMA is requested to conduct, on behalf of the European Community, a scientific assessment of a particular medicine or class of medicines. The problem is “referred” to the CHMP so that the Committee can make a recommendation for a harmonized position across the EU. Referral Procedures can be started by the EC, any Member State, or by the pharmaceutical company. At the end of the referral, the Committee makes a recommendation, and the Euro- pean Commission issues a decision to all Member States reflecting the measures to take to implement the CHMP recommendation.

Finally, it is important to note that, in addition to the harmonization of procedures for the authorization of medicines, the system also ensures harmonization and coordination of the pre- and post-authorization activities:

▸ Pre-authorization activities: Companies can request scientific advice (or protocol assistance in the case of medicines for “orphan” or rare diseases) from the EMA at any stage of medicine development, whether the medicine is eligible for the Centralized Procedure or not. This European procedure helps the company to make sure that it performs the appropriate tests and studies so that no major objections regarding the design of the tests are likely to be raised during evaluation of the marketing authorization application. 96 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

▸ Post-authorization regulatory activities (i.e., variations or extensions and trans- fers of marketing authorizations, renewals, PSURs, and notifications) have also been harmonized and are coordinated via the Centralized, MRP, or Decentral- ized Procedures. This ensures that the same quality, safety, and efficacy of products are maintained during the entire lifecycle management of the products throughout Europe (e.g., availability of new formulations, extension of indications, etc.).

I-2.1.5.3) Special Harmonized Areas

▸ Regulation on the Development and Authorization of Medicines for Pediatric Use: After years of extensive discussions involving ethical aspects [130], the European Commission adopted a proposal on September 29, 2004 [131]. This proposal led to new legislation (Regulation (EC) No 1901/2006) that entered into force in the EU on January 26, 2007. Today, this amended text (and its several associated guidelines and other published information) [132] sets up a system of requirements, rewards, and incentives together with lateral measures to ensure that medicines are researched, developed, and authorized to meet the therapeutic needs of children (representing over 20% of the total European population [133]). In practice, this new regulation established an expert Pediatric Committee (PDCO) within the EMA, which is responsible for providing opinions on the development of medicines for pediatric use. The key objectives of the regulation are: • To ensure high-quality research in the development of medicines for children aged 0 to 17 years of age • To ensure, over time, that the majority of medicines used by children are specifically authorized for such use • To ensure the availability of high-quality information about medicines used by children

In 2008, a communication from the EC (Communication 2008/C 243/01) provided guidelines on the format and content of applications for agreement or modification of a pediatric investigational plan. Many additional procedural and scientific guidance documents have also been released by the EMA to facilitate the implementation of this new regulation.

▸ Orphan Medicinal Products Regulation: The EU introduced a new Orphan Medicinal Product legislation in 2000 in order to provide incentives for the development of medicinal products for rare disorders. Harmonization of requirements for these types of products is critical to allow for multinational clinical studies and to limit the development challenges due to the small number of patients. Prior to this European legislation, a number of Member States had adopted specific measures to increase knowledge on rare diseases and improve their detection, diagnosis, prevention, and treatment. However, these initiatives were few and did not lead to any significant progress in research on rare diseases.

EU Regulation (EC) No 141/2000 established a Centralized Procedure for the designation of orphan medicines with the technical Committee for Orphan Medicinal Products (COMP), INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 97 which is responsible for the scientific examination of applications. Designated orphan medicines are assessed centrally on a European level by the CHMP, rather than in each Member State separately. This regulation also put in place incentives for the research, marketing, and development of such products (e.g., fee waivers, a 10-year market exclusivity period post- authorization, and scientific assistance for marketing authorizations). Following its entry into force and its associated rules and guidelines, the number of orphan medicines authorized has increased significantly [134].

▸ Regulation for Advanced Therapies: Legislation on advanced therapy medicines (i.e., medicines based on genes [gene therapy], cells [cell therapy] and tissues [tissue engineering]) came into force in the EU on December 30, 2008 (Regulation [EC] No 1394/2007). The legislation defines what products are to be considered advanced therapy medicines, and lays down the rules on how they are to be authorized, supervised, and monitored to ensure that they are safe and effective. The legislation also establishes within the EMA a new committee dedicated to advanced therapies. The Committee for Advanced Therapies (CAT) plays a central role in the scientific assessment of advanced therapy products. On September 14, 2009, Directive 2009/120/EC amended Directive 2001/83/ EC to further reflect new scientific and technical progress in this field.

▸ Herbal Medicinal Products Regulation: EU legislation on medicines for human use also applies in general to traditional herbal medicines. However, in order to overcome difficulties encountered by Member States in applying pharmaceutical legislation to this specific type of medicine, a simplified national registration procedure was introduced in March 2004 with Directive 2004/24/EC (amending Directive 2001/83/EC regarding traditional herbal medicinal products).

This Directive’s aim is to protect public health while securing the free movement of herbal medicines within the Community. While most individual herbal medicines will continue to be licensed nationally by Member States, the process for licensing and information on herbal substances and preparations will be increasingly harmonized across the EU. For example, in order to further integrate these special medicines in the European regulatory framework, a Committee for Herbal Medicinal Products (HMPC) was established at the EMA in September 2004 (replacing the CPMP Working Party on Herbal Medicinal Products). The major tasks of this scientific Committee are to establish Community monographs for traditional herbal medicines, and to prepare and maintain a list of herbal substances that have been in medicinal use for a sufficient period of time, and so are not considered to be harmful under normal conditions of use [135].

▸ Clinical Trials Regulation: The procedures for clinical trials in Europe used to vary from one country to another. There were different national approaches regarding the approval and notification systems, documentation requirements, and timelines [136].

Requirements for the conduct of clinical trials in Europe had first been harmonized with the introduction of Directive 2001/20/EC, signed on April 4, 2001 (but implemented in May 2004). This first Clinical Trials Directive has since been complemented by Directive 2005/28/ 98 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

EC and several guidelines, published by the European Commission and the EMA, which provide further details on the practical implementation of these principles, such as: • Information to be submitted to the DRAs and to the ethics committees • Requirements on safety monitoring and the reporting of adverse reactions • Requirements regarding GCP • Specific requirements regarding the products • Inspections of competent authorities and the applicable procedures • Information on the European database (EudraCT), which includes all clinical trials commencing in the Community from May 1, 2004 forward

The harmonization of requirements for clinical trials was important because approximately 60% of all clinical trial applications (CTAs) in the Member States relate to clinical trials performed in more than one EU Member State [137].

In October 2004, in order to coordinate the implementation of the new harmonized requirements across the Member States, the HMA established the Clinical Trials Facili- tation Group (CTFG). The CTFG (attended by representatives from the National DRAs, EC, and the EMA) acts as a forum for discussion on the agreement of common principles and processes to be applied throughout Europe. It also promotes harmonization of clinical trial assessment decisions and administrative processes across the national DRAs. This group established a Voluntary Harmonization Procedure (VHP) for the assessment of multinational CTAs [138]. During this three-phase procedure, DRAs from all Mem- ber States involved assess the application, though each Member State remains ultimately responsible for the approval of the CTA in its own country. However, there is a coordinated validation phase (phase 1) and voluntary cooperation of the Member State during the assessment phase (phase 2) before the usual formal national process (phase 3). Phases 1 and 2 of the procedure are coordinated by a VHP coordinator. The “acceptability statement” obtained through this VHP procedure is then included in the subsequent national CTA applications.

From March 2009 to April 2010, 30 applications were evaluated through the pilot VHP procedure; 23 of these applications received a positive opinion [139]. The average procedural time was 52 days (which is significantly less than the average time of standard national procedures). The overall feedback from sponsors was positive, except that: • The time for phases 1 and 2 varied significantly from one procedure to another (range 1 to 45 days) • The time for national approval was significantly different between countries (from 1 to 80 days)

Early in 2010, the CTFG implemented a VHP version 2 with an enlarged scope and developed the concept of the leading Member State. The implementation of the leading Member State, in order to consolidate the list of questions of all the participated Member States and to avoid redundancy of questions, resulted in an average reduction of initial questions by approximately 50% prior to being sent out to the applicant [140]. As of January 30, 2013, 250 applications have been submitted through this procedure. These applications concerned mostly INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 99

Phase 2 and 3 clinical trials. The mean time of the completed procedures was 52 days (including the time for responses from companies), with a minimum of 12 days and a maximum of 67 days [141]. A third version of the guidance document was finally released in June 2013.

Directive 2001/20/EC and its associated texts and guidelines are a very important step in the harmonization of procedure for the registration and conduct of clinical trials in Europe. Implementation of this Clinical Trials Directive into national legislation of all 27 EU Mem- ber States was completed in 2006. Principles like Clinical Trial Authorization by the national DRAs within defined maximum timelines led to significant harmonization of the clinical trial approval process. However, it has been agreed that this new system needs further harmonization in order to achieve the ultimate objective [142]. Indeed, the actual assessment of a request for authorization of a clinical trial is done independently by the Member States concerned. The legislation does not provide for a mechanism whereby the Member States are obliged to reach a common conclusion regarding a clinical trial involving different Member States. This lack of obligation and detailed direction implied different interpretation from Member States and therefore created implementation issues. As a consequence, sponsors have to respond to the various required changes and adapt their protocol in view of diverging assessments by the DRAs. This situation requires additional time and effort by the pharmaceutical industry (without added value for the patients).

In 2010, following a public consultation and a long and thorough impact assessment (initiated in 2008 and led by the EC DG SANCO), the European Commission proposed further harmonization and drastic legislation modifications regarding the resolution of the numerous problems created by the implementation of the Clinical Trials Directive and to ensure adequate application of the harmonized principles [143]. Several guidelines have been revised following this review (such as the guidance on adverse reaction reporting released on June 17, 2010 [144]). These revisions can certainly help to clarify definitions and processes, but are not completely sufficient. Indeed, these improvements are logically limited to what is possible under the current legal framework. A more dramatic medium/ long-term change aimed at more structural improvements of the situation is needed to achieve the original objective, to harmonize the rules for the conduct of clinical trials within the community [145].

Understanding the continued criticism voiced equally by patients, academics, researchers, and industry on the implementation of the Clinical Trials Directive,fff the EC has finally decided to prepare a new Regulation for clinical trials. The objective is to streamline the submission process, create a single submission portal (information on one clinical trial should be submitted only once), and increase collaboration between Member States for the assessment of the application [146]. In 2011, a new round of consultations was conducted by the EC to further evaluate concrete ideas and proposed modifications [147]. Most of these EU Commis- sion proposals have been positively received by all stakeholders (143 responses have been received) [148]. fff There has been a decline in clinical trials in the EU in recent years of about 15%. At the same time, costs for bureaucracy and resource requirements to handle paperwork have doubled, and delays have increased by 90%. 100 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

On July 17, 2012, the Commission adopted a “Proposal for a Regulation of the Euro- pean Parliament and of the Council on Clinical Trials on Medicinal Products for Human Use, and repealing Directive 2001/20/EC.” [149] The proposal has been submitted to the European Parliament and the Council who engage in ordinary legislative procedure. This proposal, once adopted by the EU-legislator, is going to replace the 2001 Clinical Trials Directive. It is expected to come into effect in 2016 and to provide major revisions to the current system (e.g., single assessment outcome, simplified reporting procedures, etc.).

▸ Others: Finally, it must be noted that other important topics related to the regulation of medicines are also coordinated at the community level (by the EC and the EMA) in order to have harmonized regulatory actions and enforcements, and to complete the single pharmaceutical market. These harmonization initiatives are at different stages of development: • Fight against falsified and counterfeit medicines (with the signature of Directive 2011/62/EU in June 2011) • Development of quality access to reliable information about medicines by the Euro- pean citizens • Special financial and administrative provisions for small- and medium-sized enterprises (SMEs) to support innovation in Europe (Regulation (EC) No 2049/2005 of December 15, 2005) • Parallel distribution • Community patent protection

I-2.1.5.4) Telematics Program To support cooperation and harmonization activities, the EU needed systems and knowledge management support. The implementation of this telematics (the integrated use of telecommunications and informatics) strategy, coordinated by the EMA, is critical to increase efficiency and transparency across the European Medicines Regulatory Network.

In addition to the standards for Electronic Submissions (eSubmissions) that were developed and published, a central set of Pan European systems and databases was created. These systems and databases exchange information with systems of external stakeholders and DRAs, while staying separate from them. They also help provide high-quality information on medicinal products to the general public and support the monitoring of the post-authorization risk and benefit balance of medicines in the EU.

The following critical projects and tools have been developed under this program (some of them are still under development): ▸ EudraCT: The Community’s electronic database for clinical trials containing information submitted by sponsors. It informs DRAs of ongoing clinical trials in all Member States and EEA countries, enabling an overview of multi-state trials. The system also alerts DRAs in the case of early interruption or termination. INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 101

▸ EudraGMP: Community database on manufacturing and import authorizations and GMP certificates. The EMA launched the first release in April 2007. This system is used by EU GMP inspectors to share information (i.e., GMP authorization, noncompliance with GMP information resulting from inspection activity, planned inspection activity, and “rapid alerts” arising out of faulty manufacture). ▸ EudraNet: Private electronic network linking the members of the European Medicines Regulatory Network and EMA. It ensures that both electronic mail between members of the Network and their access to the EU telematics systems is secure. ▸ EudraLink: The European Medicines Regulatory Network’s secure file transfer system used for exchanging information for regulatory purposes. It operates independently of EudraNet, so that it can be used by applicants and marketing authorization holders, as well as the regulatory organizations within the network to transfer files. ▸ EudraPharm: The Community’s database of authorized medicinal products. Some functionalities of this database are still under development. ▸ EudraVigilance: System monitoring the post-authorization safety of medicines through safety reports (i.e., suspected adverse reaction reports). It is designed to receive, process, store, and make available information. One of the objectives of this system is the early detection of possible safety signals to facilitate the regulatory decision-making process (based on a broader knowledge of the adverse reaction profile of medicines). ▸ European Review System (EURS): System that enables DRAs in Member States and the EMA to receive, validate, store, and make available information for review marketing authorization applications. The system’s key benefit is its ability to take advantage of the lifecycle management functionality built into the eCTD by easily allowing the full extent of the current valid documentation as well as its submission history. ▸ EU Telematics Controlled Terms (EUTCT): Central repository and publication system for a controlled term list used in the European Medicines Regulatory Network.

I-2.1.6) Conclusion The establishment of the EU has not been easy, but it has represented the desire to end conflicts in Europe. Since its creation, the EU has been successful in delivering peace between Member States and has reunited a fractured continent via the promotion of cooperative projects (i.e., economic and social). This cooperative initiative went beyond the initial objectives of its founders. Ever deeper integration has been pursued while embracing new members. The membership of the EU has grown from 6 to 28 nations, bringing the EU’s population to half a billion people. It has created stable institutions, a single market, and a single currency. Despite numerous challenges,ggg the EU has survived, and is today a major economic and commercial power. Although improvements are still needed in certain areas, the EU represents a unique ggg For example, fear and hatred developed between countries during the previous wars, the Euroscepticism of certain parts of the European population, the Cold War between West and East, the difficult acceptance by Europeans of their new treaties that increased cooperation, the nonratification of the “treaty establishing a Constitution for Europe” due to a negative citizen vote during referendum in both France and the Netherlands in 2005, the nonacceptance of the Euro by some countries, the doubts on the stability of a common money, the financial crisis, the divergences on how to help Greece, the different positions on the membership of Turkey, etc. 102 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS model of successful cooperation, harmonization, and integration between countries of different languages, cultures, history, and levels of development.

In the pharmaceutical sector, much has been achieved towards the consolidation of the Euro- pean system of evaluation and supervision of medicines. Several challenges have already been overcome, but outstanding issues still need to be resolved to further support and improve public health in Europe, free movement and access to medicines in the community, and the competitiveness of the Union.

Taking into consideration its successes and challenges, this section provides a balanced evaluation of the current situation. It demonstrates that harmonization of pharmaceutical regulation in Europe can be considered a real and quick success in general (considering the major changes it required), but acknowledges some specific areas where work is still needed. For all these reasons, the development of the EU and its European pharmaceutical “regulation/ system” is a great example that needs to be further evaluated and discussed. Although this model of harmonization and integration may not be fully applicable to other cases, this experience can certainly help other regional or global harmonization initiatives.

I-2.1.6.1) Achievements and Successes in Harmonizing European Pharmaceutical Regulation Since the adoption of the first pharmaceutical directive in 1965, many topics have been harmonized. The past 50 years have seen a gradual convergence of pharmaceutical legislation in Europe. Today, a considerable package of harmonized legislation (in the form of the pharmaceutical “acquis communautaire”) is in place to support two objectives: the protection of public health and the free movement of products. These provisions/texts applicable to medicinal products are included in EudraLex. They include binding legislation (i.e., Regulations and Directives), but also numerous technical guidelines and recommendations to facilitate the implementation of these common principles.

A well-structured European pharmaceutical system has also been established. In addition to the European institutions necessary to harmonize and create the European pharmaceutical legislation, technical European bodies have also been established. Today, the evaluation and supervision of medicines in Europe is shared between European and national bodies that form a complex but well-organized network of approximately 5,000 technical and regulatory experts. Words like “networking,” “work sharing,” and “harmonization” became common and remain crucial for the future.

The establishment of the EMA as a key coordinator of this system was an important decision for the integration and harmonization of practices and standards to support and promote the single European pharmaceutical market. The primary aim of this centralized system was to create conditions in which a single scientific evaluation of the highest possible standard would lead to rapid access to an integrated market of innovative and good cost-effective treatments. This objective, in large measure, has been achieved. The EMA, which is comprised of experts provided by national DRAs, has today established itself as a leading world agency INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 103 for the evaluation of medicines. Its contribution to the effectiveness and efficiency of the EU system, and therefore to the protection of public health and to the achievement of an operational internal market, is well recognized by all stakeholders. The effectiveness of the system has been maintained despite its growing complexity. Indeed, the increase in the number of centralized applicationshhh and other procedures, EU enlargement, and new regulations have led to an increased workload and an enlarged scope of responsibility for the EMA over the past 10 years. These changes have led to the creation of new committees (COMP, PDCO, CAT, HMPC, PRAC) that require the implementation of additional procedures and new tools. These structural changes and increased responsibilities should be monitored closely in the future to avoid risks of inconsistencies, overlapping, bureaucracy, and rigidity. Also, it is critical to continue to monitor financial compensation of national DRAs and to regularly assess the involvement of each Member State in the EU pharmaceutical system to ensure availability of appropriate resources and expertise [150,151].

Within this legal framework and European pharmaceutical system, community authorization procedures (Centralized, MRP, or Decentralized) have been in place since the mid-1990s. The centrally coordinated tasks include assessments led by rapporteurs and co-rapporteurs, inspections, and pharmacovigilance through the medicine’s lifecycle. Although the national DRAs have prime responsibility for the efficient operation of MRPs and Decentralized Procedures, national marketing authorizations, and clinical trial authorizations for human medicines, the EMA has an important role in supporting these noncentralized functions. For example, the EMA maintains the Eudravigilance database and the EudraCT database, and supports a range of scientific committees and the coordination group for MRPs and Decentralized Procedures [152].

The criteria for the approval of medicines and other technical topics have been extensively harmonized within the EU. Many technical and regulatory guidelines have been released in all areas (quality, nonclinical, and clinical). There has been a specific focus in recent years to improve the European pharmacovigilance system, to simplify the variation system, to harmonize the requirements for clinical trials, and to implement an advanced therapies regulation. The establishment of the European Pharmacopoeia has also been very important to ensure standardization of specifications and quality of medicines in the EU.

All these measures and actions described above have led to improved marketing authorization procedures, the harmonization of data protection in the EU, better access to medicines for children, orphan drug development, clinical trials, and a new regulatory framework for advanced therapies. Lifecycle management of products has also been improved (i.e., the revised legislation on variations to reduce the administrative burden by streamlining the circumstances obliging industry to file applications). The next review of the European system will be noteworthy because it will evaluate if new measures (developed following the last review in 2000) improved the system and produced real dividends in terms of cost efficiencies through economy of scale (via the reduction of the administrative burden where this did not have public health implications). hhh Sixty initial applications for human and veterinary medicines in 2000 to 100 initial applications for human medicines only in 2011. 104 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

It is also worth mentioning that this European system is solid enough to stand the challenges of new therapeutics. The current structure, forum, and processes allow “proactive” harmonization. Indeed, most of the harmonization initiatives are created to discuss existing disharmonies on specific topics. At the beginning, the European harmonization effort, related to pharmaceutical regulation, was focused on disharmonies between countries. Today, even if disharmonies do still exist on some specific subjects, many topics have been successfully harmonized. The processes and structures that have formed over the years now allow the system to cover new subjects for which no national regulations and requirements have been developed yet. Developing this new regulation at the EU level automatically creates harmonized requirements (this can be called “proactive harmonization”).

For example: ▸ Between 2004 and 2007, the EMA established the EMA/CHMP Think-Tank Group on Innovative Drug Development, which identified the needs for new regulations and standards for emerging science and issues in the development of medicines (e.g., biomarkers, new statistical methods, clinical study designs, RMPs, advanced therapies, emerging treatments, etc.) [153]. This group, which included EMA staff and members of the CHMP and its working parties, generated recommendations on how the EMA should tackle these new emerging topics not covered by the existing national, regional, or global regulations and standards. ▸ EMA Innovation Task Force (ITF): In order to provide support for medicine innovation in the EU, the EMA established an internal horizontal cross-sectorial group to focus on emerging therapies and technologies. The ITF brings together competences from the areas of quality, safety, efficacy, pharmacovigilance, scientific advice, orphan drugs, and good practices compliance, as well as legal and regulatory affairs. One of the objectives of the ITF is to address the impact of emerging therapies and technologies on current scientific and regulatory requirements. Its scope also encompasses areas for which there are no established scientific, legal, and regulatory experience. One of their tasks is to identify areas for legal, regulatory, and technical guidance preparation and proposals for consideration by the EMA Committees and working parties, and to contribute to relevant EC initiatives and legislation [154].

The EU today is recognized as a major player in the international harmonization of pharmaceutical regulations. It has developed privileged relationships and initiated cooperation projects with other countries outside the European Community (major developed countries and emerging markets). For example, the EMA cooperates with many of the world’s largest regulatory bodies outside the EUiii in areas such as inspections, safety of medicines, and exchange of information on issues of mutual concern. The establishment of the International and European Cooperation Sector, formed in February 2012 and responsible for the development, coordination, and implementation of the Agency’s international strategy and activities (including confidentiality arrangements with countries outside the EU), demonstrates the EMA commitment iii Such as the US Food and Drug Administration (US FDA), Health Canada, the Ministry of Health, Labour and Welfare (MHLW) and the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan, Swissmedic, the Australian Therapeutic Goods Association (TGA), and the Ministries of Health and of Agriculture and Forestry in New Zealand. INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 105 to international cooperation [155]. Also, collaboration has been initiated with China, India, and Russia on pharmaceuticals, and it is partnering with international organizations (i.e., ICH, WHO, and PIC/S). This work should continue and also be extended. It is indeed important to support the development of globally harmonized standards and requirements in order to ensure fair competition with other parts of the world for the development of medicines and to avoid delay in the availability of essential medicines for European patients. Ensuring against falsified medicines, resolution of pandemic issues, product development in emerging markets, and reliability of clinical data produced outside Europe are good examples where international cooperation is necessary to ensure adequate protection of public health in Europe.

I-2.1.6.2) Challenges and Outstanding Issues in Harmonizing European Pharmaceutical Regulation In spite of all the above-mentioned major progress and regular improvement of legislation by the European Commission, there is still room to improve the EU pharmaceutical system. On the regulatory side, issues dealing with the implementation and interpretation of Com- munity legislation by Member States continue to create obstacles to the free movement of medicines. Stakeholders continue to raise concerns regarding market fragmentation linked to disparities in national pricing and reimbursement schemes (despite the adoption of Direc- tive 89/105/EEC in the early days of the European pharmaceutical system), unnecessary regulatory burdens caused by divergences in the implementation of Community legislation (e.g., clinical trials requirements), and a lack of commercial interest in national markets that are economically less attractive. European patients still suffer from inequalities in the availability and affordability of medicines. This situation could worsen and create significant inequalities between patients in accessing medicines if it is not resolved. Additionally, Europe has been losing ground when it comes to innovation and competitiveness in the pharmaceutical market.

In its communication of December 10, 2008 [156], the EC recognized that further harmonization is necessary to resolve shortcomings in the EU pharmaceutical market in furthering increased globalization of this sector. To improve this issue, the EC confirmed its objective to continue to progress towards a single and sustainable pharmaceuticals market [157].

To further support and improve the public health in Europe and free movement of medicines within the community, and to maintain its competitiveness, the EU needs further harmonization in several areas, such as:

▸ Price and Reimbursement: Different national pricing and reimbursement systems still coexist,jjj leading to market fragmentation, parallel trade, disparities in prices, and time-to-market delays. Recently, Health Technology Assessment (HTA) bodies have been gaining a greater influence on the access to jjj National Health Technology Assessment (HTA) bodies provide recommendations on the medicines and other health interventions that can be paid for or reimbursed by the healthcare system in a particular Member State. Examples include la Commission de la Transparence in France, het College voor zorgverzekeringen (CVZ) in the Netherlands, Tandvårds- och läkemedelsförmånsverket (TLV) in Sweden, and the National Institute for Health and Clinical Excellence (NICE) in the United Kingdom. 106 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS novel medicines by patients, mainly due to increased pressure to cut healthcare budgets. In certain countries, medicines are not made available due to administrative requirements and poor economic rewards. A lack of transparency and harmonization with regard to pricing, reimbursement, and relative effectiveness remains a challenge [158].

In contrast to the benefit–risk assessment carried out by regulators, national HTA bodies compare the “relative effectiveness” of medicines and take their financial cost into account. This post-marketing national HTA evaluation can lead to national differences due to different country needs. The addition of different requests (i.e., different type of studies) from regulators and HTA bodies can also delay availability of new products.

To resolve this major issue, the European Network for Health Technology Assessment (EUnetHTA) was established to support effective collaboration between national HTAs. Also, the EC gave the political mandate to the EMA to begin interacting with HTA bodies when it published the conclusions of the Pharmaceutical Forum in October 2008.kkk Since then, the EMA has begun to collaborate with national HTA bodies and with EUnetHTA [159]. This interaction focuses on centralized approved products and aims to facilitate communication between EMA and HTA bodies early in a medicine’s development and throughout the medicine’s lifecycle.

As mentioned above, the harmonization of price and reimbursement evaluation is critical in supporting a European pharmaceutical market. However, it will be a very difficult and long process to implement due to political and budgetary aspects and differences in pharmaceutical markets and healthcare budgets existing between Member States.

▸ Clinical Trials: The European Clinical Trials Directive (Directive 2001/20/EC) has been an important and necessary step in the harmonization of European pharmaceutical regulation. The principles defined in the Declaration of Helsinki (in 1964) and the ICH GCP E6 guideline (in 1996) allowed some harmonization of clinical practices and protection of clinical patients. But, before this Directive came into force, the rules for performing clinical trials (i.e., regulatory procedures and requirements) varied significantly in the European Community as they were based on differing regulatory approaches in the Member States. This new legislation promoted harmonization of clinical trial practices allowing important improvements related to the protection of patients (i.e., safety and ethical concerns) and reliability of data, and facilitated the exchange of information between DRAs.

However, despite this progress, important negative effects of this new legislation have been reported (e.g., the increase in bureaucracy and administrative costs). The number of clinical trials carried out in the EU has fallen by 15% in recent years, while administrative kkk The Pharmaceutical Forum was set up in 2005 by the European Commission as a three-year process in order to find relevant solutions to public health considerations regarding pharmaceuticals, while ensuring the competitiveness of the industry and the sustainability of national health care systems. More specifically, this forum analyzed three key themes: information to patients on pharmaceuticals, pricing and reimbursement policy, and relative effectiveness. INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 107 costs and delays have doubled [160]. It is still labor intensive and costly to duplicate largely identical administrative procedures for multinational clinical trials. Addition- ally, sponsors spend a great deal of time retrieving the relevant national information and requirements and preparing customized applications without added value for the patient and the regulators (the core scientific information is the same, but the format and administrative information and forms differ). It is indeed a problem for a large pharmaceutical company, as it usually requires additional dedicated departments with the necessary resources to track differences in national requirements and follow the many parallel procedures. But it is even more problematic for SMEs or academic sponsors for whom these costs can reach prohibitive levels.

This multiplication of parallel procedures also has an important impact on the DRAs. Indeed, available resources are used in multiple assessments of the same core information in different Member States, which clearly delays the start of clinical studies. It is important to note that this duplication of assessments does not necessarily increase the quality of the assessment, as the necessary specific expertise might not always be readily available in all the Member States concerned. This is a nonefficient use of national resources without added value for the patients or science.

This implementation problem is partly due to the legal framework that has been chosen for harmonization in this area. As with all Directives, the Clinical Trials Directive had to be transposed in national laws. Unfortunately, in this case, the objectives of the directive were transposed into divergent national legislations, somewhat missing the harmonization goal and making multinational trials difficult to perform.

In its 2009 consultation paper [161], the EC proposed options to improve the situation. One of the best options is to continue with the harmonization process. This would mean creating a real European system of authorization for clinical trials to avoid duplication of assessment. It would avoid the inconsistent assessment conclusions and requests, encourage appropriate use of resources and expertise (for both the sponsors and DRAs), and ensure common implementation of the principles laid down in the Clinical Trials Directive.

The VHP initiative seems to be a good first step. It allows for a better implementation of the EU Clinical Trials Directive principles and further harmonizes the conduct of clinical trials in Europe. However, this procedure cannot be considered as the ultimate solution because it does not resolve all issues [162]. More specifically: • There are still parallel CTA assessments by multiple DRAs. • There are still major differences between countries regarding the time it takes to issue approval. • This is a voluntary cooperation and there are differences in the level of interest and responsiveness between countries. • The current procedure does not remove specific national requirements or differences between national assessments (this is a cooperation effort, not a harmonization of requirements). • This process does not accelerate the First Patient Enrolled (FPE) in Europe. 108 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

To resolve these outstanding issues, the current VHP procedure should be revised to become a real MRP where the assessment will be conducted by only one reference Member State. The content of the dossier should also be fully harmonized between countries.

The establishment of a Centralized Procedure through a new Regulation (which will deliver a Pan-EU approval) would also be very helpful for certain types of products that require specific expertise not available in all EU countries (e.g., advanced therapies), for orphan drugs, and/or for pediatric medicines. This centralized process for CTA would be a good bridge between the EMA Scientific Advice process and the Centralized registration procedure.

The system for registration of clinical trials would then mimic the system already in place for the registration of medicinal products with a combination of three types of procedures: • Centralized Procedure for specific products such as biotechnology and advanced therapies • Mutual Recognition Procedure for other multinational clinical trials • National Procedure for a clinical trial involving only one Member State

This reorganization of the system and procedures, supported by the EC [163] and most of the shareholders involved in clinical trials [164], would utilize the current structures and expertise in Europe, would build on the experience acquired with the registration process, and would facilitate patient access to clinical trials and to new technology within the community. It would allow the necessary flexibility and different levels of review for interventional trials (e.g., a small national study with a well-known entity does not need the same type of evaluation, organization, and bureaucracy as a Phase 1 study with a new fusion protein or a large multinational Phase 3 study). Measures should be put in place to ensure that such reorganization would allow this flexibility and avoid any further increase of delay and administrative costs and burdens. For example, “recognition” of other assessments should be the focus, and “nonrecognition” should be limited to major issues (that should be clearly defined). These “nonrecognitions” of assessment by another country should be rare to avoid regular arbitration or appeals that would further delay the start of the clinical studies. Selection of Reference Member States (RMS) should also be defined because many parameters are involved in such selection (i.e., expertise, resources, balanced workload between countries, etc.). Finally, this new cooperative system should not result in the simple addition of national requirements, but a harmonized scientific assessment that would be implemented equally in all Member States.

This next step in the harmonization of a clinical trial in Europe would certainly be beneficial for patients, sponsors of clinical trials (pharmaceutical companies, but also small entities or academic centers), and DRAs. Some of the above proposals have already been recommended by the European Commission [165]. The recent adoption of a “Proposal for a Regulation of the European Parliament and of the Council on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC” [166] by the Commission represents an important step in the improvement of the current system. However, this process will take time to implement, and national interests will need to be overcome. INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 109

Finally, the assessments of Ethics Committees also need to be reviewed and improved. The Clinical Trials Directive is based on the concept of one Ethics Committee opinion per Member State concerned. However, several Member States maintain a decentralized system where the single Ethics Committee opinion is based on the opinion of several local committees. As a consequence, in the EU there are approximately 1,900 Ethics Committees involved in the assessment of clinical trials [167]. Also, better harmonization of responsibilities between DRAs and Ethics Committees must happen across Europe [168]. It is agreed that ethical issues fall within the responsibility of Member States. However, current practices need to be reviewed in order to smoothly integrate an improved harmonized system and to protect European clinical trials subjects.

▸ Compassionate Use: Compassionate use (making critical medicinal products not yet approved available either on a named-patient basis or to cohorts of patients) is a topic that has not yet been harmonized in Europe. Despite some coordination at the European level (defined by Article 83 of Regulation (EC) No 726/2004 and the EMA Guideline) [169], compassionate use programs remain the responsibility of Member States and are governed by individual Member States’ legislation. Today, these national programs differ from country to country. The EMA/CHMP can provide recommendations to Member States, but they are optional and are only implemented by Member States that wish to use them. They do not replace the national rules and do not create any legal framework in Europe [170].

These programs are important to make new therapies available to patients as soon as possible. They should be handled on a European basis in order to ensure that every European person, wherever their location, has the equal right to access these new medicines at the same time. Today, this difference in access within Europe is clearly contrary to the overall European objective to ensure that all patients within the Community have the same access to the same quality products throughout Europe. Of course, the harmonization of these requirements and procedures should be carefully implemented to avoid the creation of delays compared to the current situation.

▸ Pharmacovigilance: The EU pharmacovigilance system demonstrates that cooperation and harmonization of regulations and practices in Europe is beneficial to patients. Indeed, merging the EU national pharmacovigilance systems into one network increases the quantity of data/reports/ information, which facilitates the early detection of possible safety signals, and therefore the monitoring of product safety. Unfortunately, the Mediator issue in France has shown that the EU pharmacovigilance system needs to be improved to be fully functional. This topic has been one priority of the European network. The ongoing implementation of the new legislation by the EMA and the Member States will be critical.

▸ Mutual Recognition and Decentralized Procedures: Although the Mutual Recognition and Decentralized Procedures have improved over time, challenges still exist, and the principle of these procedures (i.e., recognition of another country’s assessment) is not always respected. In both these procedures, Member States can 110 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS only refuse to recognize other countries’ assessments if they feel that this recognition could have a “potential serious risk to public health.” Unfortunately, this reason for disagreement is vague enough to allow flexibility for Member States. In 2006, a guideline was released [171] to further clarify how this risk should be defined. However, some national DRAs continue to have a broad interpretation of “potential serious risk to public health,” and trigger EMA arbitrations for grounds that do not fall under this specific category [172,173].

In addition to the specific issues discussed above, more general challenges can also impact the harmonization of European pharmaceutical regulation. Although these general considerations are not specific to the pharmaceutical sector, they can influence the establishment and implementation of pharmaceutical regulation. Therefore, they need to be understood and integrated when developing implementation plans and timelines: • The diversity of expertise, resources, and level of development between Member States remains an important challenge (increased with each new enlargement of the EU) when developing a harmonized pharmaceutical regulation. In 2005, for example, the number of referrals to the CMDh was relatively high, reflecting the different positions of Mem- ber States. After several years, the percentage of procedures that had been referred to the CMDh had decreased. In 2011, only 1.5% of MRP and 1.3% of Decentralized Procedures had been referred to the CMDh [174]. This decrease is certainly the result of harmonization between Member States thanks to the increase of collaboration and exchange of information and experiences over the years. However, CMDh statistics also show that there is still a big discrepancy regarding the selection of an RMS for MRP and Decentral- ized Procedures. Some countries (like the United Kingdom or Germany) coordinated more than 250 procedures in 2011 while others (like Luxembourg or Cyprus) have never been used as an RMS [175]. This major difference in workload between countries demonstrates a big gap in work sharing and certainly highlights differences in national DRAs’ expertise and resources and pharmaceutical companies’ interests for each national market. • One of the complexities and difficulties of the EU system is the division of activities undertaken at the national level (e.g., clinical trial responsibility, scientific advice handling, etc.) and at the EU level (e.g., equal scientific advice handling, assessment of pediatric investigational plans, etc.). This requires many communications and infrastructures between the EU and national players. • External economic or political factors could also influence the harmonization of European pharmaceutical regulation. For example, the modification of European borders via new enlargement of the EU (even if the EU leaders have agreed to mark a pause for now, discussion on the accession of countries such as Turkey, Ice- land, and Serbia are still ongoing). Additionally, the possible creation of a “Medi- terranean Union” desired by past French President Sarkozy could also impact the scope and timelines of the next steps of harmonization and integration. Finally, it will be important to see if and how the two new functions created by the Treaty of Lisbon (President of the EU Council and High Representative of the Union for Foreign Affairs and Security Policy) will benefit the EU. The first important dossiers after the creation of these two functions (global financial crisis, global security, and INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 111

support to Greece) have indeed still been handled by the political leaders of major Member States (i.e., France and Germany). I-2.1.6.3) Lessons Learned from the European Experience It is clear that the European system is integrally linked to its own history. This model cannot fully fit every harmonization initiative in the world because every situation and need is different. However, it is worth reviewing the lessons learned from this 50 plus years old initiative. This first Regional Harmonization Initiative (RHI) overcame a lot of challenges, and has since developed into a strong regional harmonized pharmaceutical regulation and system. This success demonstrates that an organized cooperation and harmonization can facilitate the development of high standards and practices.

More specifically, the European initiative clearly demonstrates that a structured stepwise approach is necessary: ▸ First, it is necessary to set up major principles (Directive 65/65/EEC). ▸ Second, it is critical to provide specific detailed requirements and to further detail the agreed principles (Directives 75/318/EEC, 75/319/EEC, etc.). ▸ Third, a structured and organized system is needed to implement the principles and requirements. Technical bodies need to be established to control medicines and manage the establishment of common procedures (especially centralized types). In Europe, it was key that the national DRAs provide expertise and resources to European bodies not only to ensure appropriate availability of resources, but also to ensure full adhesion of the countries into the system and adequate communication between all players of the system (national and European). ▸ When all the basic principles and a system are in place, additional more specific requirements can be discussed so that the system can take into account particular needs (i.e., specific requirements for specific products, population, etc.) in order to have a more coherent system. ▸ Finally, it very important to monitor the system and regularly review the extent to which this system and measures support the harmonization goals and meet the predefined objectives. Evolution of the environmental impact (i.e., globalization, change of membership, change of political commitment, and need for new requirements due to emerging problems, etc.) also has to be taken into consideration, and the regulation and system needs to be carefully adjusted to ensure its longevity.

Another lesson learned from Europe is the importance of cooperation. To be successful and ensure effective functioning of this system, cooperation between the different entities of the system (EMA, HMA, National DRAs, EC) has been, and remains, critical. Even if the European pharmaceutical system is complex, it is well organized. The provision by the Member States of high-quality scientific resources for the evaluation and supervision of medicines is a critical factor for the success of the EU system. Indeed, scientific excellence (as a result of EU-wide pooling of expertise and data) has been a key strength. In this respect, it should be stressed once again that such excellent progress has been highly dependent on close collaboration between the EMA and the national DRAs within the context of the EU regulatory network, and in particular on the 112 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS valuable input of high-quality specialist expertise provided by the Member States. This provision of national resources, coordinated by the EMA, is one of the features of the EU regulatory network.

This success also relies on political support for this European harmonization initiative in order to support the creation of the single market. Without this political commitment (and therefore associated funds and resources), it would have certainly been much more difficult and taken more time to create this system. It is recognized that other harmonization initiatives in the world are certainly suffering from the lack of such political commitment, especially when such harmonization is not driven by the willingness to create a single market (i.e., integration model).

Finally, the EU has also clearly demonstrated that better organization at the regional level is extremely critical to ensuring the success of global harmonization and cooperation. Even if all regions are not working towards integration like Europe, this example of better coordination and representation should be followed and discussed in other regions of the world. Indeed, this example demonstrates that a well-organized and coordinated regional structure is beneficial to all stakeholders [176]: ▸ Individual countries via better representation and better access to international activities/agreements/decisions through regional structure (this is especially true for small countries with less expertise and resources). Individual countries also benefit from the infrastructure (i.e., databases or training programs) and good practices developed at the regional level. ▸ Regions because they allow better representation of interests (Europe has more power than a combination of small countries’ voices, and has an impressive network of experts). ▸ International cooperation and harmonization initiatives because they facilitate communication by reducing the number of contacts and seats at the international level (but provide a structure for dissemination of information). For example, having all EU countries represented at ICH would not be possible.

This regional coordination is very important for the future of global initiatives (such as ICH or WHO projects), but it is even more important in the management of a worldwide health crisis (e.g., pandemic influenza). This European coordination system should be implemented in other regions of the world because the coordination of rapid and efficient communication of information and actions during such a crisis helps the overall coordination of the situation. For example, in the recent case of pandemic influenza, it was critical to have central coordination (not only global, but regional). The EMA (using its “crisis management plan”) allowed Europe to respond rapidly and efficiently to the challenges of an outbreak of pandemic influenza by: ▸ The fast-track review of vaccines (using its best experts) ▸ Monitoring the safety of centrally authorized pandemic-influenza vaccines and antivi- ral medicines ▸ Liaising and coordinating activities with critical partners, including the EC, EU Member States, other European Agencies (such as the European Centre for Disease Prevention and Control), and international partners (such as WHO and regulatory bodies of non- EU countries) to ensure timely exchange of information and coordination of activities relating to the pandemic INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 113

▸ Coordinating the communication of relevant information to the public, healthcare professionals, and the media

All of these activities would be less efficient if performed by each individual country.

I-2.2) The Pan-American Network for Drug Regulatory Harmonization Political and economic development in the Pan-American region has resulted in interest in regional economic integration. Several subregional integration groups have emerged in this area since the 1970s. Harmonization of pharmaceutical regulations and technical standards is a component of this economic integration, but the degree of progress in this area varies a lot from one subregion to another (and even from one country to another). In light of these various economic integration initiatives, the need became evident for an entity in which the different countries of the region could share experiences and expertise.

The Pan-American Network for Drug Regulatory Harmonization (PANDRH) was created in November 1999. This is a regional initiative established to promote drug regulatory harmonization throughout the Pan-American region within the framework of national and subr egional health policies. This continental forum is not a supranational entity, and its decisions represent recommendations to be assimilated into the subregional integration initiatives. The mission of this network is “to promote the harmonization of pharmaceutical regulation covering aspects of quality, safety, efficacy and rational use of pharmaceutical products, the strengthening of National Regulatory Authorities (NRA) capacity within the Region of the Americas based on the right of the population to access quality medicines, recognizing advances in science and technology and within the context of national and sub-regional realities” [177].

The objective of this initiative is to facilitate regional harmonization of medicinal drug requirements and guidelines for specific regulatory issues. This objective is achieved by adopting recommendations for implementation at national and regional levels, and also by supporting the development of training on specific important topics.

However, this initiative also has broader objectives such as: ▸ Promoting and maintaining a constructive dialogue among DRAs, the pharmaceutical industry, and other sectors ▸ Strengthening the DRAs of the region ▸ Encouraging convergence of drug regulatory systems in the Pan-American region ▸ Facilitating technical cooperation among countries in collaboration with subregional integration groups.

Since 2003, PANDRH has been a member of the ICH Global Cooperation Group (GCG). This membership broadens PANDRH’s role because this regional harmonization initiative is now also involved in global harmonization. PANDRH provides a way to disseminate recommendations on drug regulatory harmonization of global initiatives. It also ensures that 114 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS regional specificities and challenges will be considered when new global recommendations are discussed.

I-2.2.1) Membership PANDRH includes representatives from: ▸ DRAs of all Pan American Health Organization (PAHO) Member States ▸ Regional pharmaceutical industry associations: Latin American Association of Phar- maceutical Industry (ALIFAR) and Latin American Federation of the Pharmaceutical Industry (FIFARMA). ▸ Academia ▸ Consumer groups and professional associations

It also includes representatives from the five subregional trade integration groups within the Americas (Plate 2) that are themselves multinational cooperation initiatives but are working on a broader integration with emphasis on political and/or financial interest:

▸ The Andean Community is a Community established in 1969 (by the Cartagena Agree- ment) that currently regroups four countries (Bolivia, Colombia, Ecuador, and Peru). Chile and Venezuela have also been part of this initiative in the past and some others countries are observers. These countries decided voluntarily to join together for the purpose of achieving more rapid, better-balanced, and more autonomous development through Andean, South American, and Latin American integration. They also created a free trade area (including the four current members plus Venezuela). This integration initiative is broad and regroups several areas, one of them being health. The integration of health is governed by the Andean Health Body, which coordinates the actions aimed at improving the healthcare of member countries. It gives priority to cooperative mechanisms that promote the development of subregional supranational systems and methodologies. These actions are also coordinated with the other subregional, regional, and international organizations.

▸ CARICOM, the Caribbean Community, was created in July 1973 (by the signature of the Treaty of Chaguaramas) following the decision in 1972 by the Commonwealth Caribbean leaders to transform the Caribbean Free Trade Association (CARIFTA) into a common market. This treaty was then revised in July 2001 to further the integration process and transition from a common market into a single market and economy. The community currently has 15 Member States (Antigua and Barbuda, The Baha- mas, Barbados, Belize, Dominica, Grenada, Guyana, Haiti, Jamaica, Montserrat, Saint Lucia, St. Kitts and Nevis, St. Vincent and the Grenadines, Suriname, and Trinidad and Tobago) and five Associate members (Anguilla, Bermuda, British Virgin Islands, Cay- man Islands, and Turks and Caicos Islands). Integration in the area of health is coordinated by the Council for Human and Social Development (COHSOD). CARICOM has been very active in increasing cooperation in the domain of health and harmonization of pharmaceutical regulations. The Nassau declaration in July 2001, the Carib- bean Co-operation in Health (CCH) initiative, and the launch of the Caribbean Health INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 115

and Development Commission in September 2003 are examples of this commitment. Discussions include many topics such as the development of a pharmaceutical policy model, the evaluation of medicinal products, and a surveillance network.

▸ SICA (The Central American Integration System) is the institutional framework of subregional integration in Central America. This is the latest step of a long integration process in the region. It was created in December 1991 (by the signing of the Teguci- galpa Protocol) by the States of Belize, Costa Rica, El Salvador, Guatemala, Honduras, Nicaragua, and Panama. This initiative also involves the Dominican Republic as an associated State and some regional and extra-regional observers (Mexico, Chile, Brazil, China, Spain, and Germany). The headquarters of the General Secretariat is located in El Salvador. The first objective of this integration process in Central America was to transform the area into a region of Peace, Liberty, Democracy, and Development, based firmly on the respect, tutelage, and promotion of human rights (following a history of political crisis, conflict, and dictatorial rule in the region). Health topics are covered by the Executive Secretariat of the Council of Ministers of Health in Central America (SE- COMISCA). Several projects are under discussion in this subregion, such as the basis for quality assurance of drugs and a pharmacovigilance system.

▸ MERCOSUR (the “Common Market of the South”) was created in 1991 (by the signature of the Treaty of Asuncion) and encompasses five Latin American countries (Argentina, Brazil, Paraguay [which is currently suspended], Uruguay, and V enezuela). The purpose of this agreement was to set up a common market and eliminate trade barriers among the signatory parties. MERCOSUR has been involved in several health projects (such as implementation of GMPs with training and joint inspections and development of programs on vaccine regulation and control) to promote cooperation between its members and harmonization of specific pharmaceutical regulations in this subregion. To date, there is no mutual recognition system.

▸ NAFTA (North American Free Trade Agreement) was implemented in January 1994 to remove most barriers to trade and investment among the US, Canada, and Mexico. The objective of this agreement was to establish procedures to facilitate trade and investment on the North American continent. This trade liberalization had some positive impact and created one of the largest trade blocs in the world, but some downsides have also been reported by economists (who have shown that NAFTA has not been able to produce an economic convergence). NAFTA has had a minor impact on the harmonization of pharmaceutical regulations in the region and has not been able to resolve the problem of parallel import of pharmaceutical products between Canada and the US.

I-2.2.2) Structure One of the major components of this initiative is the Pan-American Conferences on Drug Regulatory Harmonization held every two to three years. These conferences are the highest instance of the PANDRH Network. They serve to define priority areas for harmonization and to endorse standards, guidelines, and other recommendations, including norms 116 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS and procedures and Steering Committee membership. They also provide a forum for discussing issues of common interest in drug regulation. Participants include all interested parties such as the DRAs of all PAHO Member States, representatives of the regional pharmaceutical industry associations, academia, consumer groups, professional associations, and representatives from the five subregional trade integration groups within the Americas.

The 1st PANDRH Conference took place in November 1997 (in Washington, DC, US). PAN- DRH was then officially created during the 2nd PANDRH Conference in November 1999 (also in Washington, DC). Following these first two conferences, subsequent conferences took place to review ongoing activities of the Working Groups.

PANDRH mimics the ICH structure. It is organized around three major bodies:

▸ The Steering Committee (SC), which ensures operational management of this initiative between conferences, is composed of: • Seven members from five national DRAs (one from each of the subregional economic groups) and two industry representatives (FIFARMA and ALIFAR) • Seven alternate members from five different national DRAs (one from each of the subregional economic groups) and two industry representatives (FIFARMA and LIFAR) • Regulators from other countries (not represented on the SC), representatives from nongovernmental organizations (NGOs) recognized by PAHO/WHO, and other stakeholders invited by the SC who may also participate in SC meetings as observers Members of the committee serve for a period of four years, with staggered rotation to maintain continuity. The SC meets at least twice every year. Its primary role is (1) to establish the agenda for the biennial Pan-American conferences, and (2) to follow up on conference recommendations by establishing and monitoring the progress of Working Groups. The responsibility of this group is to promote progress between conferences through the coordination, promotion, facilitation, and monitoring of the harmonization activities.

▸ The Technical Working Groups are specifically formed to work on topics and areas identified for harmonization. The members are experts in their specific subject matter. A Working Group may include the following categories of members:

• Main Members that represent the national DRA of a country in each of the five subregional blocs, the regional Industry Associations ALIFAR and FIFARMA, and those designated by the Secretariat • Alternate Members designated to attend the meetings instead of the principal members • Observers from any country generally nominated by a participating national DRA (the observers do not retain voting rights) • Expert resources (as needed) to support a specific activity of the group (expert resources do not have voting rights) INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 117

The national DRAs of countries not represented in the Working Group can designate focal points to follow the activity of the group. Each Working Group has a coordinator (and an alternate) who chairs and coordinates the meetings, leads the development of documents, and reports periodically to the SC on the progress of the group. In general, the first task of a new Working Group is to conduct a survey to identify the differences in regulatory requirements among countries in order to prepare a work plan. Then, the group reviews international and regional and/or national recommendations and guidelines and prepares a harmonized proposal. When the harmonized standard is developed, the Working Group is in charge of designing training and helping in implementation of this standard by assisting countries in the dissemination and education concerning this new rule. Technical Working Groups meet in conjunction with SC meetings or separately (determined by a work plan and resources).

▸ A Secretariat, provided by PAHO, supports the initiative technically and administratively. It monitors the PANDRH website, serves as a focal point for the coordination and dissemination of information, coordinates activities arising from recommendations of the conferences and SC, and acts as liaison and a representative of the Network in global and interregional harmonization organizations (ICDRAs, ICH, etc.)

I-2.2.3) History As in other regions of the world, there is a need to promote harmonization of pharmaceutical regulations to facilitate the availability of safe, effective, and good-quality products and thereby protect public health. PAHO initiated communication among the different members of the pharmaceutical sector in the Americas in order to facilitate communication among the different subregional blocs (and also the countries not already covered by these blocs) and organize regional harmonization.

The first Pan-American conference took place in November 1997 (in Washington, DC, US). This conference was considered the first step towards the establishment of PANDRH. During this first conference, the scope and the term “harmonization” were defined (as the search for common ground within the framework of recognized standards, taking into account the existence of different political, health, and legislative realities among the countries of the Region). The structure and financial support of PANDRH were also discussed at this first conference. However, PANDRH was officially created during the 2nd Conference (November 1999 in Washington, DC) following a consultation in Caracas, Venezuela in January 1999, and also several ad hoc discussions and meetings (Meeting of Americas’ Regulators in Washington, DC in November 1997, Regional Working Group on Bioequivalence in Caracas in January 1999, and Regional Working Group on GCP in Buenos Aires in May 1999). During this second conference, the mission statement and objectives of the SC were agreed upon.

This initiative was then officially recognized by the 42nd Directing Council of the PAHO in September 2000. Resolution CD42.R11, which was approved during this Council, provided 118 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS strong support from Ministers of Health of the Member States in the region to PANDRH and to the process of drug regulatory harmonization.

During PANDRH Conference V (in Buenos Aires in November 2008), the regulations governing PANDRH (mission, structures, and procedures) that were originally created during the 2nd Conference were slightly modified to incorporate lessons learned during its first few years of establishment [178].

I-2.2.4) Harmonization and Cooperation Process Harmonization proposals are developed by the Technical Working Groups. These groups primarily use WHO documents as the basis for developing regional guidelines. Other international guidelines including ICH and selected regional (e.g., EU, American subregional) or national technical documents are also used as the basis for harmonization proposals and as reference materials.

After a Working Group has agreed on a draft harmonized document, it is posted on the website for external comment. Comments are reviewed by the Working Group to prepare the final version of the document that will be presented for adoption by the Conferences through the SC. Conclusions and recommendations of the Conferences are to be adopted by consensus (if consensus cannot be reached, the different points of view have to be recorded).

During its seventh meeting (in June 2006 in Washington, DC, US), the SC established a system of phases and stages for its harmonization process. This system, which mimics the ICH process, is composed of five phases, with each having substages: ▸ Phase 1: Development of Draft • Stage 1: Draft proposal (Draft 1; by one or more members of the Working Group [WG]) • Stage 2: Discussion of the proposal by the WG members and selected professionals • Stage 3: Approval of the proposal (Draft 2) by members of the WG ▸ Phase 2: Draft for Public Opinion • Stage 1: Web page consultation • Stage 2: Consolidation of comments (Draft 3) ▸ Phase 3: Preparation of Final Draft • Stage 1: Comments review by the WG • Stage 2: Preparation of Final Draft ▸ Phase 4: Approval (or Nonapproval) by the PANDRH Conference • Stage 1: Review and endorsement by the SC for presentation at the next Conference (the only authority that can adopt the proposal) • Stage 2: Decision of the Conference: approval and modification or adoption; the document can be sent to the WG for additional consideration ▸ Phase 5: Implementation of Proposal • Stage 1: Dissemination of the approved proposal at the national or subregional level (by DRA, by selected members, or at WG activities) • Stage 2: Document discussion and guidelines at the national level with the participation of interested entities INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 119

• Stage 3: Adoption of the proposal at the national and/or subregional level (recognition)

Final technical documents are intended for use at the national level (through the subregional integration groups), but this implementation is at the discretion of each country. Members of the SC are responsible for monitoring implementation in their subregion. PANDRH is also discussing strategies to follow up the implementation of its recommendations at the national and subregional levels. In addition to the biennial Pan American Conferences on Drug Regu- latory Harmonization that allow for communication and exchange, PANDRH is also committed to training all interested parties (including regulators and industry). Such training covers major topics such as GMP inspection, GCP, GLP, bioequivalence, etc.

I-2.2.5) Harmonization and Cooperation Projects The initial priorities that the PANDRH defined during the first conference were GMP (to facilitate the implementation of GMP in the region and ultimately to develop mechanisms for mutual recognition of inspection), bioequivalence, and GCP. Additional topics were then added, each of these considered critical in the development of the network and in the protection of public health in all concerned countries.

Currently, there are 13 areas of priority that have been selected by PANDRH (for which Work- ing Groups have been established): ▸ Good Manufacturing Practices ▸ Bioequivalence ▸ Good Clinical Practices ▸ Medical Plants ▸ Pharmacopoeia ▸ Medicines Classification ▸ Combat Counterfeit Medicines ▸ Pharmacovigilance ▸ Medicines Registration ▸ Good Laboratory Practices ▸ Medicines Promotion ▸ Vaccines ▸ Biotechnological Products

Several recommendations developed so far are based on WHO recommendations. For example, WHO Report 32 was the basis for the discussion on GMPs, and the WHO and ICH guidelines were used to build consensus on GCPs.

Most of the selected topics are technical and have been chosen in order to ensure the quality, safety, and efficacy of the products approved, and that these products are adequately promoted and maintained. The work on drug classification is also key to ensuring a common language and facilitating subsequent harmonization discussions. Combat against drug counterfeiting has also been selected, as this is a major issue in this region directly affecting 120 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS public health in all countries and requiring a multidisciplinary, multi-sectorial, and cross- border perspective. Finally, the activity on drug registration is a broader project, and is very important for ensuring implementation of PANDRH recommendations and for reaching full harmonization of pharmaceutical regulations. This is critical in ultimately developing a collaborative regional or subregional registration process and system and sharing of expertise and resources between countries. This group drafted a proposed list of harmonized requirements for drug registration in the Americas [179].

The current list of selected topics above will certainly be amended in the future if new emerging topics (creating potential health public issues in several countries of the region) need to be discussed and resolved at a regional level. For example, the Working Group on Biotechnological Products has been established following a roundtable session of the 5th PANDRH Conference. This roundtable session was organized to discuss biotechnological products (and also the specific issue of biosimilars). Biosimilars present a clear risk for the patient (if they are not well controlled), but also a major opportunity for increased access to cheaper essential medicines (if they are well regulated). These biotechnological/biologic products have unique technical challenges that require technical and specific expertise. PANDRH will have to work on this topic collaboratively with WHO, which has already released recommendations on this topic.

I-2.2.6) Conclusion PANDRH’s scope of harmonization and cooperation includes technical guidelines, regulatory processes, and the strengthening of national DRAs through harmonization of processes and standards to improve and assure drug quality. By adopting its recommendations and standards, countries in this region can clearly improve the quality of their regulatory system and provide access to quality, safe, and effective drugs.

Moreover, PANDRH plays an important role in the global harmonization of pharmaceutical regulations. It is an important link between global organizations/forums and the regions. Through its involvement in the ICH GCG, it increases: ▸ The integration of the regional challenges/priorities/vision in the development of international standards ▸ The implementation of such international standards in the region

This regional initiative is one of the most difficult to operate because it includes very different regulatory systems and structures (from the most developed system such as the US FDA to the most undeveloped countries in the world). This initiative also has to take into account the existence of very different political, health, and legislative realities among the countries that correspond to very different priorities, interests, and resources. This reality creates difficulties in the management of projects and the establishment of consensus [180]. However, this disadvantage also provides opportunities and benefits as the most developed DRAs can help to mentor the less developed ones. INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 121

Recognizing preexisting asymmetries in the region, PANDRH has become a forum to discuss common issues on drug regulation and share knowledge and expertise. Not all the countries are involved in actually developing the proposals, but all of them participate in the decision of adopting them via the conferences. By promoting the collaboration of experts from different countries/subregions, and also from both the public sector (authorities and academia) and private sector (industry), PANDRH has developed quality recommendations (frequently based on WHO or other international reports and recommendations).

It must be noted that PANDRH is clearly dependent on PAHO/WHO. Without this support and investment, PANDRH would certainly not be viable. Indeed, this financial, technical, and administrative support from PAHO/WHO, which represents an important recognition (both in and outside the region), is critical for the following reasons: ▸ As for all such multinational initiatives, one of the challenges of PANDRH is funding. PANDRH’s budget is primarily supported by PAHO, but additional funds also come from governments, the pharmaceutical industry, international organizations, and registration fees from training courses. ▸ Resources from involved countries are limited. PAHO, by providing a Secretariat, has structured this initiative and allows the practical development of the harmonization projects. ▸ WHO provides critical technical help for the preparation of PANDRH recommendations. Most PANDRH guidelines and documents are indeed based on WHO reports.

The 6th Conference of PANDRH, held in July 2011 (which included over 300 participants from 26 countries), focused its discussions on the theme “Strengthening National Health Regulatory Authorities.” Several working groups presented the conclusions of their work and their recommendations and actions. The topics also addressed during this Conference included the role of PANDRH as coordinator of international cooperation, PAHO’s recognition of national regulatory reference authorities (ANMAT–Argentina, ANVISA–Brazil, INVIMA–Colombia, and CECMED–Cuba), implementation of the PANDRH guidelines in the subregions, and innovative activities of the national DRAs in surveillance or in treatment compliance. This conference concluded with the approval of a strategic orientations document. The main recommendations were aimed at developing more effective cooperation among countries to guarantee, inter alia, the adoption and implementation of the different technical documents produced.

The major challenges for the future (what PANDRH will be assessed on) is the implementation of both its own and ICH’s recommendations. This will determine if this initiative delivers on its promises and if the countries that form this initiative are committed to this harmonization. Because DRAs of all countries in the region participate in the conferences, it is expected that recommendations and guidelines will be adopted and implemented by the individual countries and incorporated in the discussion at subregional economic groups. However, it may not always be so straightforward/automatic, and the implementation of its recommendations may become one of the major challenges of this regional initiative because its members have no obligation to implement harmonized standards. 122 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

The decision to develop a 2013–2020 PANDRH strategic plan to guide future development of the network, and ensure flexibility, scientific rigor, and representation of all stakeholders in the network [181], will certainly strengthen this initiative.

I-2.3) The Gulf Cooperation Council The Gulf Cooperation Council (GCC), also known as the Cooperation Council for the Arab States of the Gulf (CCASG) is a political and economic union. Established in 1981, this trade bloc comprises six Arab states of the Arab Gulf. It represents one of the wealthiest country groupings in the world due to its extensive oil and gas reserves. Its population is approximately 42 million and its gross domestic product (GDP) is estimated at approximately US $917 billion [182].

The GCC has been active in political affairs outside its territory. Due to the instability of the Middle East region, the GCC has been heavily involved in diplomatic discussions to solve the different conflicts and problems of the region (i.e., Iraq/Iran war, Iraqi invasion of Kuwait, Iraqi situation after the breakdown of the former regime, Israeli/Palestinian war, etc.). The objectives are to avoid the expansion of war and eliminate violence and terrorism in the region in order to support regional development and modernization.

In order to achieve unity, the GCC promotes the coordination, integration, and interconnection between its Member States in various fields. One of the first objectives of the GCC is to formulate similar regulations in different areas, including health. Cooperation and coordination in health are under the responsibility of the Council of the GCC Health Ministers (CHM). Under its oversight, the Gulf Central Committee for Drug Registration (GCC-DR) was established to provide Gulf States with safe and effective medicines at a reasonable cost. This committee works towards this objective by promoting cooperation and harmonization among Member States. This initiative covers prescription, nonprescription, generics, and biologics.

On the international side, the GCC represents the region at the ICH Global Cooperation Group (GCG).

I-2.3.1) Membership The current GCC members are six Arab states of the Arab Gulf (Plate 3): Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, and the United Arab Emirates (UAE). Iran and Iraq are currently excluded although both nations have a coastline on the Persian Gulf.

Yemen is currently not part of the union. This country is, however, involved in some GCC initiatives (i.e., activities related to the health sector) in view of a future accession. For example, Yemen is a member of the Council of the GCC Health Ministers (CHM).

I-2.3.2) Structure The Supreme Council is the highest authority of the GCC and is formed by the heads of the Member States. Presidency of the GCC Supreme Council rotates, and it convenes annually INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 123 in a regular session, though additional extraordinary sessions may also be scheduled. This Supreme Council is supported by the Ministerial Council, composed of the Ministers of Foreign Affairs of Member States or other ministers acting on their behalf. The Ministerial Council proposes policies, lays out recommendations, and coordinates existing activities in all fields. Resolutions adopted by other ministerial committees are referred to the Ministerial Council, which in turn refers relevant matters to the Supreme Council for approval.

The CHM is the highest regional level of authority in the area of health. It consists of Health Ministers from each of the GCC Member States (plus Yemen, though presently not a member). It meets for two to three days twice a year, and these meetings are open to all regulators from the GCC Member States and Yemen. WHO (via its Regional Office for the Eastern Mediterranean, EMRO) also attends as an observer. The CHM is supported by an Executive Board to whom an Executive Office General Director reports. The Executive Office is located in Riyadh, Saudi Arabia.

At the working level, a GCC-DR was established to oversee the different activities in the pharmaceutical sector. The Steering Committee of the GCC-DR is composed of two members from each of the Member States (including Yemen), and meets at least four times per year. The membership is limited to government agencies or DRAs. The Executive Office also appoints two of its affiliates as advisors (nonvoting members) to the Steering Committee. This committee is responsible for the registration of the pharmaceutical companies and their products as well as for the preparation of technical regulations and guidelines.

To develop a new guideline, the GCC-DR Steering Committee uses the resources of the Mem- ber States by assigning the drafting of the specific guideline to either a single Member State or several Member States. Technical working groups can also be set up to help in developing the guideline.

Within the Executive Office, a permanent GCC-DR Secretariat was also created to support the organization. The role of this Secretariat is to facilitate the harmonization activities through administration, coordination, and communication. It is also responsible for receiving and reviewing registration files for completeness and for preparing Steering Committee meeting agendas.

I-2.3.3) History The GCC was created on May 25, 1981, and its unified economic agreement was signed by its Member States on November 11, 1981 in Riyadh, Saudi Arabia. The primary objective was to achieve “coordination, integration and interconnection between Member States in all fields in order to achieve unity between them” [183]. This integration plan was developed in detail during the first 20 years following the establishment of the GCC.

On December 31, 2001, the GCC Supreme Council adopted, during its 22nd Session in Muscat, Oman, a revised economic agreement that accelerated this integration. This revised agreement enhanced and strengthened economic ties and increased harmonization among Member States. 124 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

In Chapter II, the agreement defined specific areas that needed to be harmonized in order to support the GCC common market, health being one of these areas. Article 12 also promotes joint projects and adoption of integrated policies between Member States.

Having finally completed all requirements, the GCC common market was declared in Decem- ber 2007 and came into force as of January 2008. This launch of the common market removed barriers to cross-country investment and service trade.

GCC cooperation in the health sector began in the mid-1970s when the GCC health ministers held informal meetings such as the one held in Geneva (May 16, 1975) during the general assembly of WHO. Such cooperation was then formalized with the establishment of the Conference of the Health Ministers of the Arab Countries in the Gulf, which held its first meeting in February 1976. Since 1991, it has been called CHM. As mentioned previously, under the CHM, the GCC- DR was established in 1999 to provide the Gulf States with safe and effective medicines.

I-2.3.4) Harmonization and Cooperation Process The scope of the GCC-DR’s harmonization and cooperation efforts in the pharmaceutical sector covers technical guidelines and regulatory processes. This includes the registration of pharmaceutical companies and products as well as good manufacturing practice (GMP) inspection.

Under the oversight of the CHM, the GCC-DR Steering Committee is responsible for the selection and prioritization of topics, the assignment of the development of guidelines and policies, and the subsequent review and approval of the resulting recommendations.

When a new topic is selected for harmonization, the GCC-DR Steering Committee assigns the development of the guideline/policy to either a single Member State or several Member States, and a technical working group is then established. The membership of this working group is at the discretion of the assigned Member State(s). It may include regulatory, industry, and academic experts. Technical working groups meet regularly (independently of the Steer- ing Committee meetings). An annual meeting is also held with both the Steering Committee and relevant invited experts to discuss policy and regulations.

ICH guidelines are often used as reference material when developing GCC-DR guidelines. Other international guidelines (including WHO recommendations), available national technical documents, and guidelines from other regions (e.g., EU) are also used.

Once developed by a working group, the draft guideline is posted on the GCC and the Saudi Food & Drug Authority (SFDA) websites (http://www.sgh.org.sa and http://www.sfda.gov.sa/ en/Pages/default.aspx). They are also circulated to all Member States for comment. At the end of the consultation period, the working group reviews all comments received, finalizes the document, and proposes its adoption by the GCC-DR Steering Committee. Following its adoption, the General Director of the Executive Office submits the guideline to the CHM for final approval.

GCC-DR Steering Committee members are responsible for monitoring the implementation of the adopted guidelines in their countries. Each country reports whether it encounters any INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 125 problems in implementing the guidelines during an annual meeting where the GCC-DR activities are evaluated.

Standard practices and operating procedures have been developed to govern all steps of the harmonization process (i.e., selection and prioritization of topics, solicitation of comments, approval/ implementation of guidelines and responsibilities of the different bodies, as well as funding). Additional procedures also cover the process in place for the registration of products and companies. The GCC-DR is financed by Member States (using established quotas of contributions) and by registration fees. The status of its activities is communicated through its website, and also through presentations at national and international meetings, workshops, and conferences.

Although the Executive Office organizes GMP training, there is currently no official structured training program within this initiative. Each Member State is responsible for providing training to their regulators.

I-2.3.5) Harmonization and Cooperation Projects The GCC-DR has initiated work on several general topics related to the development and registration of all medicinal products (GMP and GMP inspection, bioequivalence studies, stability, good laboratory practice [GLP], and clinical trials). The group also decided to harmonize practices on post-marketing activities via the development of guidelines on post-marketing surveillance (covering the counterfeiting problem) and pharmacovigilance. Finally, recommendations on specific types of products (biosimilars, sera and anti-venom, vaccines, and blood products) are also under discussion.

The guidelines listed above are at different stages of development (under discussion, drafting in progress, approved, or implemented). They are all based on ICH, WHO, US FDA, and/or EMA recommendations.

In addition to these guidelines, the GCC-DR also established a common central procedure for the registration of both the pharmaceutical companies and the pharmaceutical products. The establishment of a common system of registration and control of medicines was discussed at the first meeting of the CHM in 1976. This subject was a recurrent topic of discussion until actual implementation of this procedure in 2001. Since its implementation, the registration of both medicines and pharmaceutical companies has slowly transitioned from the national to the GCC registration procedure as shown in the Table 6.

Table 6: Evolution of the Number of Products and Companies Approved Nationally vs. Centrally in Saudi Arabia

SFDA/National Registration Centralized Registration

Year No. of drugs No. of companies No. of drugs No. of companies

2008 364 22 87 31 2009 245 22 100 54 126 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

Under this procedure, dossiers (including fees) are submitted to the GCC-DR Secretar- iat. Each country reviews the dossiers and forwards its recommendations to the GCC- DR Steering Committee. The committee’s resolutions are adopted by the majority of the attendant members’ votes (four countries is the minimum that must be represented). GMP inspection and analysis of samples by the accredited laboratories are also part of this central procedure. After the central approval, each country must adopt this central approval nationally.

As mentioned above, the GCC-DR is responsible for GMP inspections, but also for the approval of quality control laboratories and for the review of technical and post-marketing surveillance reports. All these central activities increase the harmonization and integration of the pharmaceutical sector.

I-2.3.6) Conclusion Since its creation and the signing of its initial unified economic agreement in 1981, the GCC has cooperated in many different fields (i.e., political, military, security, legal, economic, environment, and health) and developed common policies in support of achieving full integration. This integration goal was reemphasized in 2001 when the GCC Supreme Council adopted a revised Economic Agreement. In January 2008, the launch of the GCC common market marked an important step in the GCC’s integration.

In the health sector, cooperation began earlier. Before the signature of the unified economic agreement in 1981, the Health Ministers had decided to cooperate in the area of health. Since the initial discussions by the Health Ministers, many objectives have been fulfilled. The development of common guidelines, cooperation in the domain of GMPs, and the establishment of a central registration procedure for companies and products are certainly the major achievements from this group.

The unified purchase of drugs (i.e., common tenders concept) is also one of the most important achievements of the CHM. It has ensured the purchasing of high-quality registered products from registered companies (national or international) for a more affordable price as it increased the amount of products purchased. But it has also ensured the use of the same products by all Member States, which is indeed an important step in the integration process and the creation of the common market. This cooperation allows the member countries to implement common drug policies and adopt an efficient drug quality surveillance reporting system to monitor the efficacy and safety of the registered drugs [184].

Recognizing all the above achievements, and despite clear increases in cooperation, the GCC has, however, not yet fully achieved its goal of unity in the pharmaceutical sector. Indeed, this group has selected an integration model that will require stronger ties between countries. For example, the central registration procedure still involves national reviews and is longer than the national registration [185]. Moreover, approvals delivered via this central procedure still have to be adopted by each member country. This integration process INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 127 is not as advanced as in Europe, where there is a rapporteur that conducts the review of the application on behalf of the group and where the EC approves drugs on behalf of all European countries.

Harmonization of the regulation (via both regional integration and international cooperation) is critical for this region for the following two reasons: ▸ First, this region is highly dependent on medicines developed and manufactured in other countries and regions. Even if pharmaceutical companies (both international and regional) are increasing their investment in the Middle East region, this region is still primarily an import-oriented market. All GCC countries share the same characteristic of being high importers of pharmaceutical products. More than 70% and 80% of pharmaceuticals consumed in Oman and Saudi Arabia, respectively, are imported [186]. It is critical for the region to ensure that products from other countries have been developed and manufactured following acceptable standards and requirements. ▸ Second, we have seen that most of the GCC-DR recommendations and guidelines are based on other international work (i.e., ICH, WHO, etc.). The GCC is therefore dependent on the resources and expertise of these international organizations to develop its own state-of-the-art requirements and standards.

The next step in the integration process of the GCC region will certainly be a better and bigger sharing of resources and expertise. The challenges of this next step will be the development of an organization and infrastructure to support such evolution. Today, the regulatory expertise in the different countries is varied, with Saudi Arabia being the leader in the region. This country represents the biggest pharmaceutical market of the region, with approximately 65% of the pharmaceutical sales of the GCC [187], and its regulatory system is recognized as the most developed of the region. In 2010, the regulatory agency in Saudi Arabia, the SFDA, employed 150 people in its drug sector with approximately 50 reviewers, compared to less than 10 in most of the other GCC countries. The ongoing development of a common and central system needs to ensure that the less developed countries of the regions will benefit from this cooperation without impacting the more developed countries in this sector. Another challenge for this group, like for all other harmonization initiatives, is the implementation of the agreed-upon standards. The GCC needs to work on measures, including the development of a structured training program, to facilitate the implementation and follow-up of recommendations.

I-2.4) Southern African Development Community Today, the Southern African Development Community (SADC) is comprised of 15 Southern Africa States, and its headquarters are located in Gaborone, Botswana.

Each of the SADC Member States is at varied stages of socio-economic development, but are predominantly underdeveloped. Its aggregated gross domestic product (GDP) is approximately US $457 billion, with South Africa representing a significant portion of this amount. 128 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

Its estimated total population is approximately 250 million [188], with an average population growth rate of 2.2% and an average fertility rate of 4.9 births per woman of childbearing age. Approximately 50% of this population lacks sustainable access to affordable and quality essential medicines. The average life expectancy is 39.7 years (the lowest in the world) [189].

The SADC objectives (listed in Article 5 of the SADC Treaty) support regional integration and increased economic, social, and political cooperation in order to promote peace and security, economic growth, well being of the population, and protection of the environment and natural resources of the region. To achieve this major and broad objective, the SADC has launched projects and defined specific actions (e.g., harmonization of policies and creation of appropriate institutions and mechanisms).

Additionally, the SADC has had major milestones, such as the formation of the SADC Free Trade Area (FTA) in 2008, and set future goals, including the establishment of the common market by 2015 and the creation of a single currency by 2018. The first achievement related to the formation of the SADC FTA took place on August 17, 2008 at Sandton, South Africa during the 28th Summit of SADC heads of state and government.

Acknowledging that regional cooperation was critical to addressing the health problems of the region, the SADC decided to include health in its program of action. The need for harmonization of registration and control of medicines was further justified in 1999 when the disparities of legal systems and levels of development affected the implementation of a regional bulk purchasing initiative (involving five medicines used to treat tuberculosis) [190].

The SADC health program was developed taking into account global and regional health dec- larations and targets. To enhance this regional health integration within a legally enforceable framework, a protocol on health matters was developed.

SADC also has access to the international network because it is part of the ICH Global Cooperation Group (GCG).

I-2.4.1) Membership The present members of SADC (Plate 4) are Angola, Botswana, the Democratic Republic of Congo, Lesotho, Madagascar, Malawi, Mauritius, Mozambique, Namibia, Seychelles, South Africa, Swaziland, United Republic of Tanzania, Zambia, and Zimbabwe.

I-2.4.2) Structure The Summit, comprising all the heads and/or governments of SADC Member States, is the highest regional authority and therefore the supreme policymaking institution of SADC. It is responsible for the overall direction and control of the community. Its structure and functions are enumerated in Article 10 of the SADC treaty. The Summit usually meets in the Member State holding the deputy chairpersonship of SADC at the time (additional meetings can also be held if necessary). INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 129

The main objective of the Organ on Politics, Defense and Security, under the oversight of the Summit, is to promote peace and security in the region. The structure, operations, and functions of the Organ are regulated by the protocol on politics, defense, and security cooperation, which was approved and signed by the Summit at its meeting in August 2001 in Blantyre, Malawi.

The chair of the Summit and of the Organ is on a rotating basis. Every year, the Summit elects new chairpersons and deputy chairpersons for the SADC and for the SADC Organ on Poli- tics, Defense and Security Cooperation. The chairperson of the Organ cannot simultaneously hold the position of chair of the Summit.

The Summit is also supported by the Council of Ministers, including ministers (usually ministers of foreign affairs) from each Member State. Among other functions listed under Article 11 of the Treaty, the council oversees the functioning and development of SADC and ensures that policies are properly implemented. The Council is supported by: ▸ The Integrated Committee of Ministers, which oversees the activities of the core areas of integration defined by the Regional Indicative Strategic Development Plan (RISDP). It consists of at least two ministers from each Member State. The SADC Ministers of Health form one of its subcommittees. ▸ The Standing Committee of Officials, a technical advisory committee to the Coun- cil, includes one permanent/principal secretary or an official of equivalent rank from each Member State (preferably from a ministry responsible for economic planning or finance). Its function, listed under Article 13 of the treaty, is to process documentation to the Council.

Since 1999, the SADC leadership has been based on the Troika system, which includes the chair, incoming chair, and the outgoing chair of SADC (other Member States may be co-opted into the Troika if necessary). The Troika represents the Summit between annual meetings and makes quick decisions on behalf of SADC that are ordinarily made during the Summit meetings. This system allows the organization to execute tasks and implement decisions expeditiously. It also allows the provision of policy direction to SADC programs and operations between regular SADC meetings. This Troika system is applied at the Summit level, but is also applicable for the Organ on Politics, Defense and Secu- rity, the Council, the Integrated Committee of Ministers, and the Standing Committee of Officials.

To support the SADC activities, a central Secretariat was formed. This body is defined as the principal executive institution of SADC responsible for the coordination of the harmonization of policies and strategies to accelerate regional integration. It is responsible for the management of SADC meetings, and financial and general administration. It is also involved in strategic planning, management of SADC programs, and the implementation of decisions of SADC policy organs and institutions. Health (including combating illicit drugs), science, and technology have been clustered with other areas under the directorate of Social and Human Development and Special Programmes (SHD&SP). 130 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

Finally, to complete the SADC central institutions, a Tribunal was established in 1992 by Article 9 of the SADC treaty as another one of the institutions of SADC. The Summit, pursuant to Article 4(4) of the Protocol on Tribunal appointed the members of the Tribunal during its Summit held in Gaborone, Botswana on August 18, 2005. The inauguration of the Tribunal and the swearing in of the members took place on November 18, 2005 in Windhoek, Namibia.

One of the characteristics of the SADC is its emphasis on a decentralized institutional arrangement (Figure 2). Following previous negative experiences and failures in regional discussions, the founder states agreed that Member States should be the principal players in the formulation and implementation of policy decisions. Therefore in addition to the central SADC institutions, SADC National Committees were established by the SADC treaty. These SADC institutions at the national level are present in each Member State and include key stakeholders from government, the private sector, and civil society. Their functions are (1) to provide national feedback and input in regional strategy and planning, and (2) to ensure the proper implementation of these agreed-upon regional strategies, protocols, and programs at the national level.

FIGURE 2: SADC Policy and Executive Structures.

Source: SADC website (http://www.sadc.int/), accessed on May 7, 2012. INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 131

I-2.4.3) History This Southern African Union was created in 1980 by nine founding Member States (Angola, Botswana, Lesotho, Malawi, Mozambique, Swaziland, United Republic of Tanzania, Zambia, and Zimbabwe) with the adoption of the Lusaka Declaration on April 1, 1980 in Lusaka, Zambia. At that time, this alliance was called the Southern African Development Coordina- tion Conference, and its main objective was to coordinate development projects in order to lessen economic dependence on South Africa, then under apartheid. The formation of this alliance was the culmination of a long process of consultations begun in the 1970s when it became clear to the leaders of the founder countries that the improvement of living standards would require regional cooperation. This cooperation was directed initially towards the political liberation of the region. Following the decolonization and the political independence of Southern African countries, and acknowledging the poverty and economic problems of the region, the leaders of these countries saw the promotion of economic and social development through cooperation/integration as the next logical step.

On August 17, 1992 (in Windhoek, Namibia), a new declaration and treaty was signed during the Summit of Heads of State and Government. Article 2 of the treaty gave a legal basis to the organization and promoted it from a coordinating conference into a development community. The SADC was then established to spearhead economic integration of Southern Africa. This strengthening of the integration process in Southern Africa was aligned with the overall African continental efforts to promote closer economic relations (as defined in the treaty signed in 1991 to establish the African Economic Community).

In March 2001, SADC country Heads of State and Governments met in Windhoek, Namibia. During this extraordinary Summit, many important decisions were made that triggered an amendment to the SADC treaty. First, the Summit decided to restructure SADC institutions and to establish SADC national committees in order to facilitate the implementation of a more coherent and better-coordinated strategy. The extraordinary Summit also approved the preparation of the RISDP by the secretariat. The purpose of this 15-year plan (which was adopted in August 2003 and launched in March 2004) was clearly to deepen regional integration by providing SADC Member States with a consistent and comprehensive program of long-term economic and social policies. This plan reemphasizes the major objectives of the organization, reviews the socio-economic indicators and challenges of the region, and analyzes all the important domains for the integration process (including health). It also provides objectives and specific targets for priority intervention areas, and specifies plans and timeframes for implementation and monitoring of its important measures. For example, in the health domain, the plan proposes to coordinate, harmonize, and monitor the implementation of regional policies and to standardize the qualification and accreditation systems.

The cooperation in the health domain started in 1997 with the development of the SADC health program. Three key policy documents were important in the implementation of this SADC health program: ▸ The RISDP described above ▸ The SADC Protocol on Health signed on August 18, 1999 at Maputo (see section below) 132 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

▸ The Health Policy Framework [191] that was developed by the SADC Health Ministers and approved by the SADC Council of Ministers in Grand-Baie, Mauritius in September 2000

I-2.4.4) Harmonization and Cooperation Process As defined in Article 22 of the SADC Treaty, protocols were established in each area of cooperation. These protocols spell out the objectives and scope of, and institutional mechanisms for, cooperation and integration. Each protocol (which is approved by the Summit and is registered with the secretariat of the United Nations Organization and the Commission of the African Union) is binding for the Member States that are party to the protocol. More than 20 protocols have been developed in all domains of integration. The protocol on health [192] covers all aspects related to health (from the control of major communicable and noncommunicable diseases to the health laboratory service and institutional mechanisms). Article 29 states that Member States should cooperate in the harmonization of procedures for pharmaceuticals, quality assurance, and registration, and also in the production, procurement, and distribution of affordable essential drugs. The implementation plan of this protocol (which further defines and prioritizes the actions to facilitate implementation of the protocol) fixes the integration of regional regulatory processes and the establishment of a mutual recognition as a 2011–2015 past, present, and future milestone [193].

In line with the SADC Health Protocol, a pharmaceutical program was developed to address issues related to the access to quality medicines in all Member States. This program was approved in June 2004. This SADC pharmaceutical harmonization initiative and cooperative activities include the development of technical guidelines and policies relating to the registration and control of medicines across the SADC Member States. The initiative aims to improve the quality, safety, and efficacy of medicines circulating within the region, and to establish and maintain a regional shared network system for DRAs. The ICH and WHO guidelines, as well as other guidelines, form the basis as reference materials for the development of regional guidelines, with agreement on the adoption of international guidelines whenever possible. Potential topics for harmonization are identified at the level of the subcommittee of Ministers of Health, often with the input of senior ministerial health officials and MRA forum experts. The process of harmonization is initiated through the SADC Secretariat, which prepares and submits for decision an agenda to the Ministers of Health.

Within this context, the SADC Pharmaceutical Business Plan was released in June 2007. This 2007–2013 plan identified priority areas, objectives, and major activities that needed to be implemented both at regional and national levels to improve access to quality and affordable essential medicines (including African traditional medicines). For example, strengthening regulatory capacity (and ensuring that fully functional DRAs are in place with an adequate enforcement infrastructure) and facilitation of the trade in pharmaceuticals within the regions were key strategies developed in the plan. The monitoring and ongoing evaluation of this plan (its implementation was estimated at US $16 million) was also described (see Figure 3, which explains the relationship between the different players INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 133

FIGURE 3: Different Players in the Harmonization of the Pharmaceutical Regulation within the SADC Region.

Summit for Heads of State and Government

Council of Ministers

Sectoral Committee of Joint Ministers of Health and Ministers Responsible for HIV and AIDS

Joint Senior Officials for Health and HIV and AIDS

Regional Level Directorate for Social, Human Development and Special Programmes

Regional specialized technical Stakeholders (e.g., professional subcommittees associations, research institutions, etc.)

SADC National SADC National Contact Point Committee

National Level National Health SADC Health Committee Contact Point

Relationships: *Functional *Reporting Source: Update from the SADC Pharmaceutical Business Plan released in June 2007. 134 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS of the plan). Under the oversight of the Ministers of Health, a group of designated senior officials monitored the implementation of the plan via the establishment of technical subcommittees or task teams. This group of senior officials (from the health departments of each Member State) was also supported by the Secretariat. The sector of the Secretariat responsible for supporting the operations of the pharmaceutical harmonization initiative takes place under the directorate of the SHD&SP.

National Health Ministries also play a significant role (by coordinating and leading the implementation of programs at the national level), and report on progress through their SADC National Committees. Finally, other stakeholders (e.g., professional associations, research institutions, DRAs, etc.) are also involved and requested to provide expertise and feedback on specific actions of the plan.

In 2004, the Medicines Regulatory Forum was created as a technical subcommittee to promote the harmonization and enhancement of the pharmaceutical regulations in the region. This standalone committee is made of the heads of the national regulatory bodies.

I-2.4.5) Harmonization and Cooperation Projects The SADC has released guidelines on several topics. These guidelines regulate the following general areas: ▸ The conduct of clinical trials: these guidelines provide a framework (information to be submitted, review process, etc.) and refer to the entire ICH GCP (this is not a replacement or subimplementation of the ICH GCP). ▸ Registration of medicines: “Guidelines for Submitting Applications for Registration of a Medicine” were released in 2007. An application form is also available. ▸ Good manufacturing practices. ▸ Pharmacovigilance (only basic rules are provided). ▸ Advertising. ▸ Recalls. ▸ Registration of nutritional supplements, vaccines, and traditional medicines. ▸ Bioavailability and bioequivalence. ▸ Stability studies. ▸ Import/export (with an emphasize on GMP).

Most of the above guidelines are based on, or cross-reference, ICH and WHO guidelines and recommendations. These international bodies provide much of the technical assistance to SADC initiatives. When they exist, national rules and requirements are also used (e.g., the GCP requirements from South Africa).

Guidelines have also been developed to cover the following topics that are of specific interest for the region: ▸ Pharmaceutical wholesale ▸ HIV vaccine clinical trials ▸ Donations of pharmaceutical products INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 135

It should be noted that the SADC efforts in the pharmaceutical area include African traditional medicines. These products are an important part of the healthcare environment of these countries. One of the cooperation projects is to establish a regional databank of traditional medicines and medicinal plants, and to develop regional policies and legal frameworks for the practice of these traditional medicines.

Finally, SADC is trying to establish a joint procurement system and to harmonize standard treatment guidelines/lists among countries. These two actions will facilitate the use of the same medicines within the region and therefore allow further harmonization of the pharmaceutical environment.

I-2.4.6) Conclusion Since its inception in April 1980, SADC has demonstrated that regional cooperation and integration is possible and useful for Southern Africa. One of the foremost achievements of SADC has been to put in place a regional program (the SADC Programme of Action) with numerous projects covering cooperation in various economic sectors. The formation of the SADC FTA on August 17, 2008 was an important first step in this ongoing integration process.

The overall and ultimate goal of SADC is integration by 2020; this is a very ambitious plan. Presently, the level of cooperation varies for each area. In some areas, this cooperation only aims to coordinate national activities and policies. In others, the cooperation goes towards real integration. For example, on foreign policy, the main objective is coordination and cooperation, but in terms of trade and economic policy, a tighter coordination is in progress with a view to one day establishing a common market with common regulatory institutions.

In the health and pharmaceutical domain, many harmonization projects have been established despite challenges. Indeed, as recognized in the SADC pharmaceutical business plan, the region has many weaknesses, such as weak regulatory systems (leading to many unregistered products), lack of adequate capacity and trained personnel, outdated medicine and intellectual property laws, and noncompliance to GMP (leading to inadequate availability of medicines and poor and inconsistent quality of these medicines in some Member States). Even if there is a political will, it is very difficult for the authorities of this region to resolve this situation as they are confronted by two major problems: ▸ The management of major diseases (such as HIV/AIDS, tuberculosis, malaria, etc.) ▸ The lack of adequate resources and finances to support all health initiatives

The combination of the two above problems, common to all developing countries, slows down the development of other health activities. All the efforts and resources in the domain of health are rightfully dedicated to the prevention and treatment of the major public health concerns. Activities such as the development of adequate regulatory function and framework or the development and harmonization of pharmaceutical requirements are therefore negatively impacted. Even if all SADC Member States have national medicine policies, legislation, and regulation in place, some of these policies have been draft documents for many years (up to 15 years). A number of the laws date back from the 1960s (some even to the 1930s). It is clear 136 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS that such policies and legislation need revisions to include recent developments and meet current standards in public health and medicines. Such revisions and updates would help the implementation of the SADC harmonized recommendations and guidelines.

However, despite the numerous weaknesses and problems that the region faces, the SADC was able to promote cooperation between Member States in order to improve access to quality medicines. There have been several major accomplishments in the development and harmonization of pharmaceutical requirements, such as the development of pharmaceutical guidelines for the registration and control of medicines, the establishment of the pharmaceutical business plan, and the establishment of the “Medicines Regulatory Forum.”

Moreover, the SADC has now analyzed (with its pharmaceutical business plan) the weaknesses, opportunities, and overall priorities in the pharmaceutical domain (i.e., regulation and control of medicines). The road map includes the assessment and strengthening of DRAs (work performed in collaboration with the WHO), combat against the spread of counterfeit medicines, the development of regional training programs, and the establishment of accredited quality control (QC) laboratories.

To support this road map and other areas of harmonization, the structure of the SADC institution will certainly have to be modified (as done in the past). In order to be successful, SADC will also need to continue to work with external organizations. Support and technical assistance from ICH and WHO will continue to be critical. But, communication and cooperation with other groups and regions (e.g., the New Partnership for Africa's Development [NEPAD]) will also be necessary to coordinate the efforts on the entire continent and share the available resources, financial support, and expertise. This is especially important because some SADC members are also part of other African subregional initiatives.

Finally, the next important phase for SADC is the implementation of the agreed-upon standards, recommendations, and plans (e.g., How will the proposed actions to “strengthen national DRA capacity to implement harmonized SADC guidelines” be managed?). Imple- mentation is a challenge for all harmonization initiatives. This is especially true for this region due to all the weaknesses carried by these countries and the lack of resources and finances. However, the lack of appropriate regulations in some countries may paradoxically become an opportunity; the coordination of the development of the regulation (based on the WHO and ICH recommendations) can be viewed as an a priori harmonization. Moreover, it is interesting to note that the SADC structure presents a specificity not found in other harmonization initiatives. In addition to the standard centralized bodies (i.e., Summit, Council of Ministers, Committee of Senior Officials, Central Secretariat, etc.), the SADC has established National Committees. These national SADC contact points could become critical for this implementation phase. This unusual model may also be useful for other worldwide initiatives.

I-2.5) Association of Southeast Asian Nations The Association of Southeast Asian Nations (ASEAN), established in 1967, has very broad objectives. The aims and purposes of the Association, stated in its Declaration, include: INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 137

▸ The acceleration of economic growth, social progress, and cultural development in the region through joint endeavors in the spirit of equality and partnership in order to strengthen the foundation for a prosperous and peaceful community of Southeast Asian Nations ▸ To promote regional peace and stability through abiding respect for justice and the rule of law in the relationship among countries in the region ▸ To promote active collaboration and mutual assistance on matters of common interest in the economic, social, cultural, technical, scientific, and administrative fields ▸ To provide assistance to each other in the form of training and research facilities in the educational, professional, technical, and administrative spheres ▸ To maintain close and beneficial cooperation with existing international and regional organizations with similar aims and purposes, and explore all avenues for even closer cooperation among them

The ASEAN region has a population of approximately 590 million, a total area of 4.5 million square kilometers, a combined gross domestic product (GDP) of US $1,500 billion, and a total trade of about US $1,500 billion [194]. Its estimated annual pharmaceutical imports and exports is US $9.5 billion [195].

Among the three pillars of the ASEAN Community (Political-Security, Economic, and Socio- Cultural) agreed upon by the ASEAN Leaders in the Declaration of ASEAN Concord II (signed on October 7, 2003 in Bali, Indonesia), the establishment of a single market by 2020 is an important goal. Its objective is to allow the creation of a stable and prosperous ASEAN economic region in which there is a free flow of goods, services, and investments in order to reduce poverty and socio-economic disparities. At the 12th ASEAN Summit in January 2007, the Leaders affirmed their strong commitment to accelerate the establishment of an ASEAN Economic Community (AEC) by 2015 and signed the Cebu Declaration on the Acceleration of the Establishment of an ASEAN Community by 2015.

In 1992, in moving towards this ultimate goal, ASEAN launched the ASEAN Free Trade Area (AFTA) and defined priorities (e.g., healthcare) where regional integration should be accelerated. One of the basic criteria to support AFTA, and ultimately a single market, is the harmonization of standards and regulations.

Therefore, recognizing the importance of the harmonization of standards to facilitate and liberalize trade and investment in the region, ASEAN has established the ASEAN Consultative Committee on Standards and Quality (ACCSQ) to harmonize national standards with international standards and implement mutual recognition arrangements on conformity assessment to achieve its end goal of “One Standard, One Test, Accepted Everywhere.”

The ACCSQ monitors the harmonization of standards and regulations in many different areas (i.e., pharmaceutical products, but also cosmetics, medical devices, food, electrical and electronic equipment, automotive products, wood-based products, etc.). Harmonization in the pharmaceutical area is coordinated by the Pharmaceutical Product Working Group (PPWG). The objective of this group is to harmonize the technical procedures and requirements 138 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS applicable to the ASEAN pharmaceutical industry in the region, taking into account other regional and international developments on pharmaceuticals.

Since 2003, ASEAN has been a member of the ICH Global Cooperation Group (GCG). This membership helps ASEAN to become an important component in the global harmonization process, as it constitutes a way to disseminate the ICH recommendations on drug regulatory harmonization. It also ensures that ASEAN specificities and challenges will be considered when new global recommendations are discussed.

I-2.5.1) Membership The current Member States of ASEAN (Plate 5) are Indonesia, Malaysia, Philippines, Singa- pore, Thailand, Brunei Darussalam, Vietnam, Laos, Myanmar, and Cambodia.

The PPWG includes representatives from the DRA of each of the ASEAN Member States. The ASEAN Secretariat and the industry (at both national and regional levels) are also represented. For example the ASEAN Pharmaceutical Research Industry Association (APRIA), established in August 2006, represents a number of pharmaceutical associations from the ASEAN countries.

I-2.5.2) Structure The highest decision-making body of ASEAN is the meeting of the ASEAN Heads of State and Government (the ASEAN Summit) that is convened annually. Additional ministerial meetings are also held regularly.

Committees of senior officials, technical working groups, and task forces have been created to support the ASEAN Summit and Ministerial meetings and conduct the agreed ASEAN activities.

The ACCSQ was established to coordinate the harmonization of national standards with international standards. This committee reports to the ASEAN Senior Economic Official Meeting (SEOM) that is under the supervision of the ASEAN Economic Ministers (AEM).

The PPWG, under the supervision of the ACCSQ, was created to coordinate the harmonization activities related to the pharmaceutical area. The scope of activities of the PPWG includes the following: ▸ Exchange information on the existing pharmaceutical requirements and regulations implemented by each ASEAN member country. ▸ Review and prepare comparative studies of the requirements and regulations. ▸ Review the harmonized procedures and regulatory systems currently implemented in others regions in order to develop harmonized standards, regulations, and procedures for the region.

For each specific topic selected for harmonization, the PPWG sets up ad hoc committees and assigns one of the Member States as the project leader. Membership of the Ad Hoc Committee is on a voluntary basis. INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 139

The core members of the PPWG are the chair and co-chair, representatives from the DRAs from each ASEAN Member State, a representative from the ASEAN Secretariat, as well as representatives from pharmaceutical industry associations. Delegates from additional Mem- ber States can also participate in PPWG meetings as observers. In addition, ACCSQ members and invited experts may attend the annual PPWG meeting. The Ad Hoc Committee meets prior to the PPWG meetings. Additionally, the PPWG operates through self-sponsorship (i.e., each Member State is responsible for its own funding for traveling or hosting meetings). WHO has also contributed to the process in the past.

PPWG activities are supported by the ASEAN Secretariat, which was established on Feburary 24, 1976 to coordinate the ASEAN branches and to implement ASEAN projects and activities. In 1992, the mandate of the ASEAN Secretary-General was enlarged to initiate, advise, coordinate, and implement the agreed-upon ASEAN activities.

Finally, it should be noted that another working group, the ASEAN Working Group on Pharmaceuticals Development (AWGPD) (under the supervision of the ASEAN Health Ministers Meetings), also participates in the regional harmonization of pharmaceutical regulations through its activities on traditional medicines, good manufacturing practices (GMPs), good clinical practices (GCPs), counterfeiting drugs, and pharmacovigilance [196].

I-2.5.3) History ASEAN was officially established with the signature of its declaration (the Bangkok Decla- ration) on August 8, 1967 in Bangkok, Thailand by the five original Member Countries (i.e., Indonesia, Malaysia, Philippines, Singapore, and Thailand). Brunei Darussalam joined on January 7, 1984, Vietnam on July 28, 1995, Laos and Myanmar on July 23, 1997, and Cambodia on April 30, 1999.

The ACCSQ was formed in 1992 to facilitate and complement the AFTA. Efforts towards specific harmonization of pharmaceutical regulations have been initiated by the ACCSQ since 1992. The Pharmaceutical Product Working Group was then established in September 1999 in Kuala Lumpur, Malaysia following a decision by the ACCSQ during its 13th meeting (March 1999 in Manila). During its inaugural meeting during September 6–7, 1999, the PPWG formulated its terms of reference and set up a work plan (i.e., goals, strategy, activities, expected output, and status). Subsequent meetings focused on the status review of ongoing harmonization activities, and discussion and adoptions of final recommendations.

The ASEAN also decided to develop relationships with other countries. They developed “bilateral agreements” with a number of countries (Canada, India, the US, the Russian Federation, Pakistan, etc.), other regions (Europe, GCC, SADC, Andean Group, Mercosur), and international organizations (United Nations, UNESCO). But one of the most important developments was the creation of the “ASEAN Plus Three” cooperation to promote the East Asia region. This cooperation began in December 1997 with the convening of an informal summit among ASEAN leaders and their counterparts from East Asia, namely China, 140 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

Japan, and the Republic of Korea. It was then formalized in 1999 with the issuance of a joint statement on East Asia cooperation at the 3rd ASEAN Plus Three summit in Manila, Philippines. The ASEAN Plus Three leaders expressed confidence in further strengthening and deepening East Asia cooperation at various levels and areas, particularly in economic, social, political, and other fields. Public health and harmonization of standards are topics under discussion among others. Several bilateral economic arrangements have already been signed, and may be the basis for the possible establishment of an East Asia free trade area in the future [197].

In November 2007, two important documents were ratified: ▸ First, the ASEAN charter which spells out the principles to which all 10 Member States adhere to was signed. This legal framework, which entered into force on December 15, 2008, serves as a firm foundation in formulating the ASEAN community by pr oviding legal status and an institutional framework for ASEAN. It also codifies ASEAN norms, rules, and values, sets clear targets for ASEAN, and presents accountability and compliance. ▸ Second, the ASEAN leaders also signed the Declaration on the ASEAN Economic Com- munity (AEC) blueprint that provides the elimination of forms of nontariff measures and market access limitations in order to transform ASEAN into a single market.

I-2.5.4) Harmonization and Cooperation Process The draft guidelines developed by the Ad Hoc Committees are reviewed, discussed, and then adopted, by consensus, during the PPWG meeting. These standards are then endorsed by the ACCSQ. The PPWG harmonization process includes the following steps: ▸ Exchange and review of information on existing pharmaceutical requirements and regulations of the Member States. ▸ Compare the requirements and regulations to identify key areas for harmonization. ▸ Create an Ad Hoc Committee (and assignment of a lead country) to prepare the draft “harmonized product,” which most of the time is based on guidelines or recommendations already available (in one of the ASEAN countries, internationally, or in another regions). ▸ Circulate the draft to all Member States for comments. ▸ Consolidate comments into the revised draft. ▸ Discuss and adopt (by consensus agreement) the draft by the PPWG. ▸ Endorsement of the document and recommendation by the ACCSQ. ▸ Dissemination of the adopted documents (via the ASEAN website or seminars/ meetings). ▸ Compulsory implementation of the recommendation by the Member States.

In order to organize, coordinate, and monitor the implementation of the agreed-upon recommendations and guidelines, the PPWG set up a specific Task Force and working group to INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 141 focus on a Mutual Recognition Arrangement (MRA) and implementation. They developed a standard operating procedure (SOP) and plan of action. They also assessed the status of the implementation of requirements (i.e., adoption into the national systems) in order to develop appropriate training (to government and industry) to increase understanding of the ASEAN guidelines and fill the gaps among the Member States.

I-2.5.5) Harmonization and Cooperation Projects The first project of the ASEAN PPWG was to compare the existing product registration requirements for pharmaceuticals of ASEAN member countries in order to help define key areas for harmonization. This report was finalized in 1999.

Following this assessment, the group developed the ASEAN Common Technical Require- ments (ACTRs) for pharmaceutical product registration in the ASEAN region. These requirements are sometimes based on the existing national requirements, WHO guidelines and recommendations from other regions (e.g. the ASEAN guidelines for “The Conduct of Bio- availability and Bioequivalence Studies” were created from the EMA/CPMP Note for Guid- ance). But most of the ASEAN ACTRs have been developed via the adoption or modification of the ICH guidelines. They cover all the quality, nonclinical, and clinical aspects already developed by ICH. Labeling requirements, administrative data (i.e., Certificate of Pharma- ceutical Product (CPP), Letter of Authorization, Application Forms, etc.), and the glossary have also been discussed. The final ACTRs were endorsed by the ACCSQ at its 21st meeting (in March 2003). Guidelines to ACTR (e.g., Process Validation and Stability) have also been developed.

The group also developed an ASEAN Common Technical Dossier (ACTD) for pharmaceutical product registration. Like the ICH CTD, this initiative reduces the time and resources needed to compile applications for registration in different countries. Regulatory reviews and communication with the applicant is also facilitated by a standard document of common elements. This ACTD is based on the ICH CTD, but is organized into four parts only (the overview and summaries are included at the beginning of the relevant Parts I, II, and III instead of being grouped under a separate section as in Module 2 of the ICH CTD): ▸ Part I: Table of Contents, Administrative Data, and Product Information ▸ Part II: Quality Document ▸ Part III: Nonclinical Document ▸ Part IV: Clinical Document

A different country has coordinated each part of the ACTD, with Thailand being the lead country for the overall project. The final ACTD was endorsed by the ACCSQ at its 21st meeting (in March 2003). Since then, its implementation has been dictated by different national timelines.

Activities have also been conducted in the area of GMPs. On April 10, 2009, the ASEAN Eco- nomic Ministers (at the 14th ASEAN Summit and related summits in Pattaya, Thailand) signed 142 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS the ASEAN MRA for GMP inspection of manufacturers of medicines. This arrangement establishes the mutual recognition of GMP certifications and/or inspection reports (issued by inspection bodies) that will be used as the basis for regulatory actions such as granting of licenses and supporting post-marketing assessment of conformity of these products.

The PPWG also worked on a bioavailability/bioequivalence study reporting format and a post-market alert system. The objective of the ASEAN post-marketing alert system is to share information relating to defective or unsafe medicines, and also cosmetics, health supplements, and traditional medicines. This pilot project was launched in April 2005 and then adopted by the PPWG in February 2006.

I-2.5.6) Conclusion The two major accomplishments of the PPWG are the ACTD and the ATCRs. The ACTD is the common format for marketing authorization application dossiers, while the ATCRs are the set of written materials intended to guide applicants to prepare application dossiers in a manner that is consistent with the expectations of all ASEAN DRAs. A series of guidelines for the implementation of the ATCRs is being finalized.

Most of the ASEAN recommendations strictly follow the ICH guidelines and recommendations. Indeed, ASEAN is a good example of the influence of the ICH outside the ICH regions and of the integration and implementation of ICH standards outside ICH frontiers.

Beyond these harmonized technical aspects of the pharmaceutical product registration that need to continue, the ultimate goal of the ASEAN PPWG is clearly to implement a system where countries fully cooperate in enhancing mutual regulatory capacities and resources. With the ongoing challenges posed by the globalized economy, and in particular the huge economic growth of China and India, which may have specific impacts on the region, this association of countries is clearly committed to full integration (with the goal to establish an ASEAN economic community by 2015) and moving towards the European community model. The ultimate steps in the pharmaceutical harmonization process will certainly be the development of ASEAN pharmaceutical directives, the development of a Pan-ASEAN registration process (with a centralized procedure), and the establishment of an ASEAN regulatory agency. But the full implementation of this supranational system will take time. It will only be possible when the ASEAN has developed common legislation and structure (i.e., commission, parliament, etc.), as in Europe. The harmonization of pharmaceutical regulations can, however, continue before such an organization is in place. The next logical step is the creation of an MRA procedure. Indeed, this type of procedure is not binding for the countries (and therefore does not require common legislation) and requests only a “facilitator body” and not a supranational evaluation agency. This procedure would be similar to the old “multi-state” procedure that Europe established in 1975 as a first step towards the creation of the system that we know today.

ASEAN is also committed to increased relations with external partners. The creation of the ASEAN Plus Three cooperation may indeed promote the harmonization of pharmaceutical INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 143 regulations in the much broader Asia region. Outside the region, ASEAN and its PPWG clearly want to increase relationships and cooperation with other regional organizations, and also international bodies (i.e., UN, WHO, ICH). This development, which is outside its current framework, could indeed strengthen this initiative by increasing its exposure on an international basis, therefore allowing this organization to play a pivotal role in the international community.

I-2.6) Asia-Pacific Economic Cooperation The Asia-Pacific Economic Cooperation (APEC) is a forum, established in 1989, to facilitate economic growth, cooperation, trade, and investment in the Asia-Pacific region. This region accounts for approximately 40% of the world’s population, approximately 54% of world gross domestic product (GDP), and about 44% of world trade [198].

APEC operates on the basis of nonbinding commitments and open dialogue. Indeed, unlike the World Trade Organization (WTO) or other multilateral trade bodies, APEC participants have no treaty obligations. Decisions made within APEC are reached by consensus, and commitments are undertaken on a voluntary basis. APEC members report progress towards achieving free and open trade, and investment goals through individual and collective action plans.

Since its creation, this intergovernmental grouping has worked to reduce tariffs and other trade barriers across the Asia-Pacific region in order to liberalize trade and investment and facilitate business within the region. APEC also works to create an environment for the safe and efficient movement of goods, services, and people across borders in the region through policy alignment and economic and technical cooperation.

To support its “Three Pillars” (i.e., Trade and Investment Liberalization, Business Facilitation, and Economic and Technical Cooperation), APEC has been active in a broad range of more than 50 topics (from fisheries, agriculture, and tourism to terrorism, finance, and intellectual property). This broad range of topics, under which hundreds of specific projects have been developed, reflects the complex factors and issues related to economic development, growth, and the pursuit of open trade and investment for a region. Several of these topics can influence the health and pharmaceutical sector (such as Intellectual Property or Science and Tech- nology), but two specifically focus on this area: ▸ The Health topic, managed by the “Health Working Group,” focuses mainly on the prevention and management of infectious diseases (naturally occurring or due to bioterrorism) in the region. This working group is not involved in the discussion related to pharmaceutical regulation. ▸ The Life Sciences topic, managed by the Life Sciences Innovation Forum (LSIF), addresses key challenges in the health and pharmaceutical sector in order to create the right policy environment for life sciences innovation. The harmonization of standards and the regional and international cooperation are two of the tools used to achieve the objectives.

As a member of the ICH Global Cooperation Group (GCG) since 2003, APEC LSIF promotes the implementation of the ICH guidelines through its workshops. It also keeps ICH informed on the status of the different ongoing initiatives in the region. 144 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

I.2.6.1) Membership APEC has 21 member economies from the broad Asia-Pacific region, which spans four con- tinents (Plate 6): Australia, Brunei Darussalam, Canada, Chile, People’s Republic of China, Hong Kong, Indonesia, Japan, Republic of Korea, Malaysia, Mexico, New Zealand, Papua New Guinea, Peru, the Republic of the Philippines, the Russian Federation, Singapore, Chi- nese Taipei, Thailand, the United States, and Vietnam.

The 21 members of APEC recognize that strong economies and harmonization initiatives are not built by governments alone, but by partnerships between government and its key stakeholders, including industry, academia, research institutions, and interest groups within the community. Therefore, APEC actively involves these key stakeholders in the work of the forum. At the working level, representatives from the private sector are invited to join many APEC working and expert groups. This process provides an important opportunity for industry to provide direct input into APEC’s ongoing work.

APEC has official observers, the Association of Southeast Asian Nations (ASEAN) Secre- tariat being one of them. These observers participate in APEC meetings and have full access to documents and information.

I-2.6.2) Structure APEC operates as a cooperative, multilateral economic, and trade forum.

APEC policy direction is provided by APEC Leaders from the member economies. Ministe- rial meetings and the APEC Business Advisory Council support the APEC Leaders by issuing recommendations. The directions provided by APEC Economic Leaders are captured in action-oriented work programs to support APEC’s goals.

APEC’s working level activities and projects are guided by APEC Senior Officials and undertaken by four core committees: ▸ Committee on Trade and Investment ▸ Steering Committee on Economic and Technical Cooperation ▸ Economic Committee ▸ Budget and Management Committee

Subcommittees, Expert Groups, Working Groups, and Task Forces carry out the activities led by these four core committees. These Groups are made up of experts from each APEC Mem- ber Economy, and work in specific sectors as directed by APEC Economic Leaders, Ministers, and Senior Officials. The Health Working Group is under the supervision of the Steering Committee on Economic and Technical Cooperation.

The Life Sciences Innovation Forum (LSIF), under the Committee on Trade and Investment, is a tripartite forum involving representatives from government and academia, and also from industry. It brings together scientific, health, trade, economic, and financial considerations to create the right policy environment for life sciences innovation. INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 145

All the APEC activities are supported by the APEC Secretariat, which is based in Singapore and operates as the core support mechanism for the APEC process. It provides coordination, technical, and advisory support, as well as information management, communication, and public outreach services.

I-2.6.3) History The idea of APEC as a cooperative to enhance economic growth and prosperity, and to strengthen the Asia-Pacific community, was first publicly mentioned by the former Prime Minister of Australia (Bob Hawke) during a speech in Seoul, South Korea in January 1989. Later that year, 12 Asia-Pacific economies met in Canberra, Australia to establish APEC. The founding members were Australia, Brunei Darussalam, Canada, Indonesia, Japan, South Korea, Malaysia, New Zealand, the Philippines, Singapore, Thailand, and the US. Hong Kong, China, and Chinese Taipei joined in 1991. Mexico and Papua New Guinea followed in 1993. Chile acceded in 1994. And in 1998, Peru, Russia, and Vietnam joined, taking the full membership up to 21.

Between 1989 and 1992, APEC met as an informal senior official and had a ministerial level dialogue. In 1993, former US President Bill Clinton established the practice of an annual APEC Economic Leaders’ Meeting.

In November 1994, APEC’s vision was reiterated by APEC Economic Leaders during their meeting in Bogor, Indonesia. During this meeting, the Economic Leaders adopted what are referred to as the “Bogor Goals.” These goals of “free and open trade and investment in Asia-Pacific no later than 2020” were based on a recognition of the growing interdependence of the economically diverse region, which comprises developed, newly industrializing, and developing economies. Due to the heterogeneity of the region, it was agreed that the pace of implementation would take into account differing levels of economic development among APEC economies.

In 1995, a framework for meeting the Bogor Goals (referred to as “the Osaka Action Agenda”) was adopted. This action plan focused on three key areas: ▸ Trade and Investment Liberalization ▸ Business Facilitation ▸ Economic and Technical Cooperation

Following this first action plan, several other plans have been adopted over the years to support the implementation of the Bogor Goals. Specific topics (such as climate change and severe acute respiratory syndrome [SARS]) were also discussed.

The Life Sciences Innovation Forum (LSIF) was launched in Los Cabos, Mexico, and its first meeting was held in Thailand in August 2003. It has since become the leading initiative on health and the pharmaceutical sector for APEC.

In October 2003, APEC established the Health Task Force (renamed the Health Working Group in 2007) to address health-related threats in the region (i.e., HIV/AIDS, SARS, avian 146 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS and H1N1 influenza, and bioterrorism). The directives for this specific activity were laid out in the 2003 APEC Leaders’ Statement on Health Security.

In the 2008 Leaders’ declaration that followed the 16th APEC Economic Leaders’ meeting, during November 2008 in Lima, Peru, a new commitment to Asia-Pacific development was agreed upon. Recognizing the global financial crisis as one of the most serious economic challenges ever faced, the leaders highlighted the importance of reducing the gap between developed and developing members. This meeting included discussions related to regional economic challenges (implementing a structural reform and food supply and price), the social dimension of globalization, the enhancement of human security in the region, and the problem of climate change.

The LSIF and the Health Working Group held their first joint meeting in March 2011 in Washington, DC, US to explore possible areas of cooperation. This meeting followed the 2010 recommendations of the APEC Senior Official endorsing a new Terms of Reference for the Steering Committee on Economic and Technical Cooperation. It was then agreed that the role and operations of the Health Working Group would be reviewed with a view to merge, disband, or reorient this body.

I-2.6.4) Harmonization and Cooperation Process The LSIF leads the activities related to the regulatory convergence in the pharmaceutical area within the Asia-Pacific region.

Both APEC and the LSIF have recognized the benefits of convergence related to the pharmaceutical standards within the region. To achieve this goal, these two groups rely on other regional and global harmonization initiatives. Indeed, the LSIF is working towards the adoption and implementation of existing harmonized international guidance and regulatory best practices. It also provides the ability to access funds to advance projects. Unlike ASEAN, the objective is not to proactively develop specific regional harmonized guidance. This practice is in line with the overall APEC goals to facilitate cooperation and trade in the region, and to operate on the basis of nonbinding commitments and open dialogue. As already mentioned, APEC has no treaty obligations required of its participants, and there is no plan for integration (unlike ASEAN, which follows an integration model like Europe). Recognizing this specific context, the objective of LSIF is “regulatory convergence” with gradual alignment over time between member economies. The distinction with “regulatory harmonization” is that “regulatory convergence” does not typically involve or require active harmonization of regulations that would be unrealistic within the APEC environment.

The objectives and priorities of the LSIF, listed in its strategic plan approved by the APEC ministers in 2004, are very broad. This plan includes recommendations on four different sectors: Research, Development, Manufacturing and Marketing, and Health Services. The goal was to develop recommendations that would contribute to a more efficient, effective, and coordinated policy approach to support innovation and health in the region. These recommendations have applications in many different areas (legal, finance, scientific, regulatory, infrastructures, etc.). INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 147

One of the recommendations from this strategic plan follows: “harmonization of standards for life sciences products and services and mechanisms for collaboration and exchange of information among economies were recognized as critical elements” [199]. The principle was to review policies, standards, and regulatory mechanisms against international best practices in order to move towards regional convergence. The objective was also to achieve close collaboration and to facilitate the use of international standards and global best practices through collaboration with outside bodies such as the ICH GCG.

The LSIF has been very active in sponsoring a series of workshops on anti-counterfeiting, ICH quality guidance, clinical trials, and good clinical practice (GCP) inspection. However, it has been recognized that the LSIF has not been used to its full potential to promote regulatory convergence and cooperation compared to some other RHIs [200]. What was missing was the engagement of regulators and the appropriate industry people in this equation, together with the lack of a more focused strategic framework and multiyear plan for medical products.

In 2008/2009, acknowledging the lack of strategic and effective approaches, the LSIF decided to react and strengthen its organization: ▸ In June 2009, the LSIF took an important step towards harmonization by establishing, in Seoul, South Korea, the APEC Harmonization Center (AHC). This followed a proposal from South Korea in August 2008 (at the APEC LSIF VI in Lima, Peru) that was endorsed by the APEC leaders in November 2008 in a Joint Ministerial Statement. As an LSIF organization, this center has its own structure (including a Director, a Secretariat, and an Advisory Board of LSIF Experts), and also its own website (www.apec-ahc.org). This organization includes representatives from government, industry, and academia. Its mandate is to provide a platform to address and solve priority concerns of APEC members on regulatory convergence. Following the establishment of the AHC, several workshops took place. In general, they focused on the regional regulatory convergence, but also discussed specific problems such as multiregional clinical trials and the biosimilar concept. The purpose of these workshops is to allow government, regulators, academics, and the pharmaceutical companies to discuss and exchange information and views on the harmonization of standards. Funding and support from the AHC has allowed for the delivery of more than a dozen workshops since June 2009. ▸ In addition to the AHC, APEC also decided to establish a Regulatory Harmoniza- tion Steering Committee (RHSC) within the LSIF structure to strategically coordinate regulatory convergence in the region. The RHSC brought together senior officials from regulatory authorities and representatives from industry coalitions. This committee provides leadership and direction on regulatory priorities. During its inaugural meeting in Seoul, South Korea in June 2009, the RHSC discussed and finalized its Terms of Reference and started to identify priority projects. Since then, the RHSC has initiated several projects and developed a Strategic Framework on Regu- latory Convergence of Medical Products by 2020 to coordinate activities [201].

Since the creation of the APEC AHC and RHSC, considerable progress has been made with the design, development, and implementation of a more strategic, coordinated, and sustainable 148 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS approach. This includes the Strategic Framework and the creation of priority work areas (PWAs), each of which is associated with a roadmap that defines an overall strategy to achieve the ultimate goal of greater regulatory convergence by 2020 in the area of medical products. Each project or activity undertaken must now support the roadmap and in turn move APEC closer to the 2020 goal. This is a better-structured organization that moves away from individual, uncoordinated activities and workshops to a more directed, coordinated approach with parties and individuals that are in a position to effect change and commit resources.

The workshops, organized and funded by the AHC and led by the RHSC membership, are now tied to a directed roadmap and strategic framework representing the collective efforts and commitment of many economies. These workshops served as a diagnostic of issues, challenges, and opportunities associated with a particular area of focus, with recommendations coming back to the RHSC for consideration. All workshops are championed by the regulators of various APEC economies (for example, the US for medical product quality and supply chain integrity, Korea for biotechnological products and pharmacovigilance, Singapore for cellular- and tissue-based therapies, Chinese Taipei for good review practices and combination products, and Thailand for GCP inspections).

Finally, this organization is partnering with other regional and international players in an effort to promote synergy and more effective use of resources. A good example here is the supply chain roadmap. This is a global issue and requires a global, coordinated approach. The RHSC roadmap is being implemented through the direction of an oversight committee that includes the WHO, EMA, EDQM, and the DRA of Nigeria. In doing so, APEC takes account of and complements like initiatives, and can serve as a catalyst to global action.

I-2.6.5) Harmonization and Cooperation Projects Up to now, the APEC did not proactively develop guidance or harmonized standards and requirements. The objective is to promote convergence via the dissemination of international harmonized information and recommendations (i.e., ICH guidelines). To achieve these goals, the group has developed and funded several projects.

In 2008, the LSIF released an “Enablers of Investment Checklist,” a voluntary guidance tool for member economies to assess and improve their innovative life sciences sector investment opportunities. One of the six principles covered by the checklist is “Efficient and Internationally Harmonized Regulatory Systems.” Under this principle, the LSIF pr omoted the development and implementation of focused efforts on harmonization towards international standards through recognized international organizations (i.e., ICH). Moreover, to support this objective, the LSIF also proposed development of the following: ▸ A regulatory framework (transparent, predictable, and science-based) that allows for the quick introduction of new innovative products ▸ An efficient clinical trial regulatory system focused on safety, efficacy, and ethical standards ▸ An adequate number and level of training programs for regulatory personnel ▸ The publication of proposed regulations for stakeholder comments (which should be taken into account) INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 149

▸ Laws providing for stakeholder consultation throughout the regulatory drafting and review process ▸ Participation in international joint clinical trials

Performance metrics have also been defined to assess the implementation of the recommendations. Finally, some of the other principles on this checklist also support cooperation and convergence as they assess the resources, exchange programs, intellectual property rights, and interagency coordination of life science policy and regulation.

In addition to the “Enablers of Investment Checklist,” LSIF has also developed projects focusing on specific topics of interest, such as:

▸ Clinical Trials: The area of clinical trials was selected as one of the LSIF priorities in its strategic plan. Assessment and improvement of the clinical trial system and regulation in each country has also been recommended in the LSIF “Enablers of Investment Checklist.” The goal was to put in place an effective regulation infrastructure (by harmonizing regulatory practices and policies according to international best practices and standards). This activity includes work on regulatory process and framework (incorporating interagency review of new policies, guidances, and regulations), implementation and promotion of good clinical practices (GCPs)/good manufacturing practices (GMPs), protection and enforcement of intellectual property, establishment of clinical trials registries, and implementation of ICH recommendations. To implement this goal and strengthen the DRAs’ capacity to harmonize practices, a first workshop on “Review of Drug Development in Clinical Trials” was held in March 2008. Several additional workshops concerning clinical trials and GCP (including clinical research inspection) have since been set up on this subject. The first workshop organized by the AHC in 2009 focused on the opportunities and challenges of multiregional clinical trials. Each of the workshops serves to refine recommendations and showcase the China–Japan–Korea Tripartite Research Initiative that is exploring possible ethnic differences between the three countries. As a result of workshops, two roadmaps have been developed: one for GCP inspection (under the leadership of Thailand), and one for multiregional clinical trials (under the leadership of Japan) [202]. The focus will address gaps and needs not addressed by any other institution or regulatory authority to date.

▸ Counterfeit Medicines: Another area of interest for LSIF has been the increase in counterfeit medicines in the region. A series of seminars and workshops have been organized since January 2008 to examine ways to combat this problem. The LSIF has also developed an Anti-counterfeit Medical Product Action Plan. The objective of this plan is to share best practices in the detection and prevention of counterfeits to both DRAs and industry professionals, and organize systems to reduce the threat and occurrence of counterfeit medicines.

▸ Quality Measures: Effort has been made in the quality area. Workshops on the ICH Quality Guidelines have been organized by the LSIF in collaboration with the ICH GCG. These workshops promoted the understanding and implementation of these 150 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

ICH guidelines. Under the leadership of the US FDA, a GMP & Supply Chain roadmap has also been prepared [202].

▸ Safe Medications: LSIF has also promoted safe medicines. Following a proposal from the US and China, a two-day workshop was organized on “Drug Safety and Detection Technology” on September 27–28, 2011 in Beijing, China. This workshop provided a platform to share information and contribute to a publication on the appropriate use of detection and prevention technologies for drug safety and quality by APEC members. The discussions further supported the implementation of the LSIF Anti-Counterfeit Action Plan.

▸ Biotechnology Products and Biosimilars: One of the most recent and important LSIF topics of interest is the development of biotechnology products and biosimilars. A roadmap to promote convergence of regulatory pathways for biotechnology products is under discussion [203–1]. Moreover, the development of biosimilars can bring new hope for patients (on a global basis, but especially for poor countries) because they allow cheaper access to essential medicines. However, at the same time, their development can become a danger and a risk to public health if they are not well regulated. Regulatory discussions and actions on this topic have increased in the past several years (both in developed and developing countries) and have involved many organizations, including WHO. The second AHC workshop (hosted in Seoul, South Korea in Septem- ber 2009) was focused on the topic of biosimilars in order to allow participants from different environments to exchange views and discuss the current status of biosimilar development. The biosimilar workshop in April 2012 involved 50 international participants and 350 domestic participants [203–2].

Finally, it is important to note that APEC also promotes capacity building for its members. This objective is met through the organization of workshops, training courses, and seminars that enable people, businesses, and government departments to improve their skills and knowledge [204].

I-2.6.6) Conclusion The primary focus of APEC is clearly the economy, and its objectives center on the facilitation of trade and business between member economies (with no integration plan). The Asia- Pacific region has consistently been one of the most economically dynamic regions in the world. Since the establishment of APEC in 1989, the total amount of trade has grown significantly [205]. APEC’s work under its three main pillars of activity has helped drive this economic growth. In 2010, APEC conducted an assessment to determine what progress has been made against the Bogor Goals of free and open trade and investment. The results were positive, showing that member economies have taken concerted action and progressed in a wide array of economic, trade, investment, and social areas. Average tariffs in the region have been reduced from about 17% in 1989 to approximately 5.8% in 2010. Nontariff barriers have also been reduced thanks to APEC’s work on trade facilitation. This progress by APEC towards the Bogor Goals contributed to a more than five-fold increase in members’ total trade (goods and services) between 1989 and 2010 (from US $3.1 trillion to US $16.8 trillion). Finally, INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 151 these activities contributed to real benefits for people across the entire Asia-Pacific region. Over the span of 10 years, from 1999 to 2009, poverty was reduced by 35% (poverty levels are measured by calculating the population living on less than US $2 a day) [206].

APEC represents a large region and approximately 40% of the world’s population. This is obviously an advantage in facing the challenge of globalization. However, this size and magnitude can also be a disadvantage in terms of management. Indeed, this region is very heterogeneous with countries at the two extremes of the development spectrum (i.e., very developed and very undeveloped countries). Due to this disadvantage and the heterogeneity of this large region, it is difficult to adopt a treaty and to impose obligations on these members. For this reason, APEC operates on the basis of nonbinding commitments where each country has the choice to implement the decisions. The implementation of economic measures (i.e., reduction of taxes and trade barriers to increase trade between members) is possible since it can quickly benefit all members. However, the lack of a treaty or obligations on members can sometimes be more challenging for more drastic long-term reforms (i.e., the harmonization of standards), as member economies have different priorities. The diversity of the APEC region means that member economies will gradually move closer together in requirements and approaches, but not everyone will implement the measures at the same time. Capacity and local realities must be taken into account.

Though technical cooperation is part of APEC’s objectives (i.e., APEC is very involved on specific topics such as climate change), it is the second priority behind economic development. The health topic, managed by the Health Working Group and the Life Science Innovation Forum, has clearly been funded because this topic has an impact on the economy. As stated on the APEC website, “Life sciences innovation is critical to growth and socio-economic development as healthy people produce healthy economies. Efficient and effective delivery of patient focused products and services can improve a population’s longevity, wellness, productivity and economic potential” [207].

However, even if the above challenges are important, very positive outcomes have to be noted in terms of regulatory convergence in the pharmaceutical area. Indeed, this organization supports convergence via the funding of projects and workshops. LSIF was able to focus its effort on projects that impact all member economies (developed or developing), such as the coordination of multicountry clinical trials, the implementation of GCPs, the quality of medicines, the counterfeit medicines problem, and the emergence of biosimilars. LSIF also creates a forum that allows exchange of information between very different countries and between all the players (regulators, industry, and academia). This communication and dissemination of harmonized standards is very important, and is as essential as the development of the standards itself.

In 2008/2009, acknowledging a lack of strategic coordination, APEC and LSIF decided to better organize the activities. First, they established the AHC to facilitate the exchange of information and the creation of a network. Second, they created the RHSC to strategically coordinate regional convergence. Since this revision of LSIF’s structure and the creation of these two supporting bodies, significant progress has been made and APEC has since declared that further 152 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS harmonization to “achieve convergence on regulatory approval procedures” is targeted for 2020 [208]. To support this goal, many important projects have been initiated on critical topics, such as product quality and supply chain integrity [209], good review practices [210], GCP inspection [211], pharmacovigilance [212], biotechnology products [213], etc. All these changes and projects today represent great promise for this region, and the tools to be developed could also support global cooperation and convergence. The challenge is now to implement the plan and to continue to coordinate the projects in order to achieve the desired objectives. The recent establishment of the RHSC Regulatory Network (including DRAs not currently part of the RHSC) will certainly support the implementation of agreed-upon measures.

I-3) BILATERAL INITIATIVES

I-3.1 Different Types of Bilateral Cooperation Many different types of bilateral cooperation have been established over the years.lll It would be difficult to list and discuss them all as several dozen exist. However, all these types of bilateral cooperation and agreements can be grouped into three categories based on their scope and objectives: ▸ Cooperation between Two Developed Countries: The objective of such cooperation is to exchange good practices and harmonize standards to avoid duplication of efforts (e.g., for orphan drugs). For example, the EU and the US developed a privileged relationship and the exchange of officials and staff between US FDA and EU Authorities allow for a closer collaboration, exchange, and therefore better understanding of each other. ▸ Cooperation between One Developed Country and One Developing Country: This type of cooperation focuses on training, mentoring, and support from the developed country to the developing country. The objective is indeed to build expertise and capacity in the developing country based on the experience of the developed country. For example, the US FDA has established several agreements with developing countries (e.g., Brazil, Mexico, South Africa, Taiwan, etc.) ▸ Cooperation between Two Developing Countries: By pooling experience and resources, two countries can better tackle issues of common interest. This type of cooperation allows for better allocation of sparse resources, and also increases interest for pharmaceutical companies (two small markets with different requirements would be less attractive to industry). For example, Brazil has cooperation projects with Cuba, Dominican Republic, Mozambique, and several other countries [214,215].

One of the most advanced bilateral collaborations is between Australia and New Zealand. It represents a good example of a bilateral cooperation and harmonization model working towards a full integration of systems. Indeed, after several years of convergence and harmonization, Australia and New Zealand agreed to establish a joint Australia New Zealand lll Bilateral cooperation can involve two countries, but it can also mean the collaboration of a regional entity with another party. For example, the European Union has been collaborating with Australia, Canada, the US, and Japan, but also with the GCC group. INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 153

Therapeutic Products Agency (ANZTPA). This new Agency will ultimately replace Austra- lia’s Therapeutic Goods Administration (TGA) and the New Zealand Medicines and Medical Devices Safety Authority (Medsafe). During the first meeting of the ANZTPA Implementa- tion Ministerial Council (Melbourne, January 28, 2012), Ministers from both countries agreed on key elements to establish the joint Trans-Tasman Agency, and also how the joint regulatory scheme will be organized over a five-year period [216–1]. Since then, the framework of the ANZTPA is under discussion [216–2].

This cooperation/harmonization initiative was begun with the objective of sharing expertise and resources in order to provide health benefits for consumers by creating a world-class scheme. It is also expected that this single approval process for both countries will increase efficiency, improve the standards of medicines produced in the two countries, reduce regulatory costs for industry, and facilitate further economic integration [217].

This initiative is a great example of successful bilateral harmonization and cooperation, and emphasizes the importance of a staged approach for this type of project. It also shows that such ultimate integration of systems is challenging. Indeed, the agreement for a joint regulatory scheme was first reached in 2003, but this project was not able to proceed because New Zealand was unable to pass enabling legislation. Negotiations between the countries were also suspended in July 2007 [218].

The increased collaboration between Europe and the US in the pharmaceutical domain is another interesting example of bilateral cooperation. Though this cooperation does not follow an integration model, it is a well-developed bilateral initiative. It is a stepwise and structured program that is interesting as it provides a clear example of what such bilateral collaboration can achieve in a nonintegration process, and also outlines its limitations. It also provides examples of the measures and organization necessary to support such bilateral work.

I-3.2) Bilateral Cooperation between the European Union and the United States of America The European Union (EU) and the United States of America (US), in addition to their collaboration within the scope of multilateral frameworks such as the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), have also established strong regulatory and scientific bilateral cooperation in the pharmaceutical sector. This bilateral cooperation promotes public health, safer trade of products, and harmonization of regulations.

Over the years, the scope of this transatlantic collaboration has increased, and today represents a good example of what bilateral cooperation can achieve.

I-3.2.1) Membership This collaboration mainly involves the European Commission (EC), the European Medicines Agency (EMA) and the United States Food and Drug Administration (US FDA). However, 154 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS it is important to note that the US FDA also maintains an active relationship with national DRAs throughout Europe.

Confidentiality arrangements with the US have been signed at the European level (EC and EMA) and also at the national level with Austria, Belgium, Denmark, France, Germany, Ire- land, Italy, the Netherlands, Sweden, and the United Kingdom. This is particularly important for collaboration in the area of inspections. It also allows the US FDA to exchange information on products not approved via the Centralized Procedure (this exchange is done through the relevant Reference Member States [RMSs]).

I-3.2.2) Structure The leaders of the EU and the US agreed on a framework for advancing transatlantic economic integration and established the Transatlantic Economic Council (TEC) to oversee the efforts outlined in the framework, with the goal of accelerating progress and guiding work between EU–US Summits. The US FDA, EC, and EMA have reported under the TEC umbrella for several areas of EU–US pharmaceutical cooperation, such as: ▸ Inspections ▸ Biomarkers ▸ Product-specific risk management activities ▸ Parallel scientific advice ▸ Biosimilars ▸ Development of medicinal products for children/pediatric use ▸ Advanced therapy medicinal products ▸ Safety reporting from clinical trials

Moreover, confidentiality agreements have been established to create a framework allowing the exchange of confidential information between the EU and the US FDA as part of their regulatory and scientific processes. They include information on advanced drafts of legislation and regulatory guidance documents, as well as nonpublic information related to ensuring the quality, safety, and efficacy of medicinal products for human (and veterinary) use. An implementation plan has also been agreed upon between all parties to allow for a successful exchange of information and documents between the EU and the US FDA in accordance with the terms of the confidentiality agreements. The objective of this implementation plan was to describe the processes by which each party will under- take information and document exchange as envisioned by the confidentiality agreements. Also, to facilitate this transatlantic pharmaceutical cooperation, the US FDA and the EMA have established “liaison officials.” These liaison officials remain employed by their home organizations, but their physical location in the partner agency is designed to facilitate collaboration. Their role is to facilitate regulatory and scientific cooperation between the US FDA and the EMA, and to coordinate information exchange. They also increase awareness of interaction opportunities with the EMA and the US FDA, and potential new areas of common interest [219,220]. INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 155

I-3.2.3) History Since 1989, regular EU–US FDA bilateral meetings have taken place [221]. In May 1998, the European Community and the US signed a Mutual Recognition Agreement (MRA) that applied to, among other technical sectors, pharmaceutical good manufacturing practices (GMPs) [222]. However, this MRA is not operational.

In 2003, the scope of this bilateral cooperation intensified with the establishment of confidentiality arrangements between the parties. These agreements signed on September 12, 2003 were then extended on September 15, 2005. In September 2010, these confidentiality agreements were extended again, and are now in effect for an indefinite period without the need for further renewal. These two 2010 official statements of authority and confidentiality commitment [223,224] restate the agreement to pursue in-depth collaboration and exchange of confidential nonpublic information between the US FDA and the EMA. It is interesting to note that these statements reiterate that the shared information includes confidential commercial or trade secret information (the US FDA is required by current legislation to ask pharmaceutical companies before sharing trade secret information with counterpart DRAs).

At the EU–US Summit on April 30, 2007, further momentum was given to regulatory collaboration with the signature of the Framework for Advancing Transatlantic Economic Inte- gration between the European Union and the United States of America by EC President José Manuel Barroso, German Chancellor Angela Merkel, and US President George W. Bush. This document called for more effective, systematic, and transparent regulatory cooperation, and the removal of unnecessary differences between regulations. It also specifically requested the promotion of “administrative simplification in the application of regulation of medicinal products.”

I-3.2.4) Harmonization and Cooperation Process The objective of this bilateral process is more towards cooperation than harmonization per se. Exchange of information between the parties allows for a better understanding of each other’s systems and requirements, and therefore builds confidence and recognition facilitating convergence. This EU–US cooperation also tries to avoid future disharmony by upstream regulatory cooperation on new medicines legislation [225].

The exchange of information and practices are well structured and occur on a regular basis, but the exchange can also be done on an ad hoc basis if necessary. ▸ Regular Exchange: The EMA and US FDA exchange a list of specific information on applications (both pre-authorization of new molecules and post-authorization of marketing products), including decisions made for such applications on a quarterly basis. They also exchange other information such as a list of Good Clinical Practice (GCP) inspections or pharmacovigilance topics (either product- or nonproduct-related issues). 156 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

▸ Ad Hoc Exchange: In addition to the exchange of new drafts of final legislation or guidelines (prior to publication), the EU and US FDA also exchange information relating to scientific advice, difficulties in relation to the evaluation of applications, and urgent drug safety issues and other issues impacting public health. These types of information are exchanged prior to their release into the public domain.

Meetings or workshops on regulatory issues of mutual concern are also organized on an ad hoc basis.

Finally, the EMA and the US FDA publish an annual report summarizing their interactions under the confidentiality arrangements. These arrangements also provide for annual meetings between the US FDA, the EMA, and the EC to monitor the operation of activities within the scope of the agreed-upon implementation plans. However, it should be noted that the sharing of product-related information is limited to medicinal products evaluated or authorized in accordance with the EU Centralized Procedure, as well as medicinal products authorized at the national level by the EU Member States, which are subject to arbitration or referral in accordance with European Community procedures [226].

I-3.2.5) Harmonization and Cooperation Projects Initiatives related to general topics are reported below. In addition to these initiatives, cooperation has also been established in certain specific scientific areas or for a specific type of product (i.e., oncology, pharmacogenomics, nanotechnology, Advanced Therapy Medicinal Products [ATMP], blood products, and vaccines). I-3.2.5.1) Transatlantic Administrative Simplification Project Under the auspices of the Transatlantic Economic Council, on November 28, 2007 the EC hosted the “Transatlantic Administrative Simplification Workshop” in Brussels, Belgium, which was co-chaired by the EC and the US FDA and organized in collaboration with the EMA and the Heads of the EU National Medicines Agencies (HMA). The key objective was to identify opportunities for administrative simplification through transatlantic cooperation in the removal of unnecessary burdens of administrative practices and guidelines. This would allow more human and fiscal resources to be focused on greater innovation and efficiency in the development of quality products. It was agreed that this project should not require change to legislation, and of course, the simplifications should maintain or increase current levels of public health protection.

As a follow up to the Transatlantic Administrative Simplification Workshop, a “Medicines Regulation Transatlantic Administrative Simplification Action Plan” was published in June 2008, outlining administrative simplification projects to be taken forward. This document promoted further cooperation and pilot collaboration programs in major areas such as inspections, biomarkers, counterfeit medicines, risk management (content and format), scientific advices, biosimilars, pediatrics, and advanced therapies. INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 157

During the annual EC/EMA–US FDA bilateral meeting in September 2010, it was agreed that the majority of projects in the original plan had been successfully completed and that most of the pilot projects had been extended and became “standard” cooperation [227]. Ongo- ing developments and new initiatives in transatlantic administrative simplification are now included in the annual reports on interactions between the US FDA and the EMA.

I-3.2.5.2) Collaboration on Inspections Several projects have been initiated to increase collaboration on GMP and GCP inspections. Ad hoc exchanges on specific products, quality defects, product shortages, and on draft guidelines also took place.

▸ GMP Inspections: Several pilot projects were first initiated in the context of the Transatlantic Administrative Simplification Workshop deliverables. An initial project (established in cooperation with the European Directorate for the Quality of Medicine and the Australian Therapeutic Goods Agency) was conducted between December 2008 and December 2010 and related to GMP inspections of Active Pharmaceutical Ingredients (API) manufacturers [228]. The project’s objective was to determine whether greater international collaboration and information sharing could help to better distribute inspection capacity, thus allowing more sites to be monitored and reducing unnecessary duplication.

The second project, related to finished products, allowed EU–US FDA joint inspections and was aimed at developing ways of working together on joint inspections of routinely scheduled sites in the territory of the US or EU, to reduce duplicate inspections and the resulting burden on both the pharmaceutical industry and the DRAs.

This pilot phase, conducted under confidentiality agreements, allowed the development of new tools for work sharing and the exchange of information in order to share inspection reports and to organize joint inspections. Increased transparency and visibility of inspections performed by participating authorities allowed a successful collaboration between authorities on manufacturing sites of common interest. It also increased the number of inspections performed that were of value to more than one authority. This pilot phase confirmed that such collaboration in the area of GMP inspections led to a reduction in duplicate inspections, more efficient use of combined inspectional resources, and wider global inspectional coverage. Following the successful conclusion of the pilot, it was agreed to maintain the cooperation established [229].

In December 2011, the US FDA and the EMA decided to further enhance their GMP inspection cooperation by moving from confidence building to reliance upon [230]. This initiative, launched in January 2012, allows the EMA and the US FDA to share inspections of manufacturing sites in each other's territories. This important step follows the positive experience acquired through the pilot joint inspection programs and other information sharing projects that have occurred over several years. This strategy allows some inspections on each other’s territories to be deferred or waived completely based on a number of considerations and on a risk-based approach [231]. This strategy is applicable to GMP inspections related to 158 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS manufacturing sites located in the US and the European Economic Area (EEA), mainly focusing on routine post-authorization and surveillance inspections as a first step [232]. The result of this arrangement could free up inspection resources that would then become available for inspections to other regions.

Ongoing EMA–US FDA joint inspection pilot projects will continue according to the agreed- upon procedures [233,234] as it remains important to maintain mutual confidence and build further mutual understanding of GMP inspection approaches. Some successful pilot programs will also be expanded to new partners such as the ongoing collaboration on GMP inspections of active substance manufacturers [235].

▸ GCP Inspections: Due to the increased globalization of pharmaceutical product clinical development, and based on previous positive experiences in the GMP field, the EMA and US FDA agreed to launch a pilot EMA–US FDA GCP initiative. The objective of this GCP initiative, conducted between September 2009 and March 2011, was to reinforce and systematize periodic information exchanges on GCP-related activities between the US FDA and EMA. These included the exchange of GCP inspection plans to improve inspection coverage, the exchange of information on applications to help identify candidates for collaborative inspections, and the exchange of inspection outcomes and reports (both negative and positive) and their potential impact. Conduct of collaborative GCP inspections and the sharing of information on interpretation of GCP (such as draft guidelines or policies) were also part of this project.

The pilot initiative has been very productive. A considerable amount of information has been exchanged on many products [236], and this communication (which included 23 teleconferences and four face-to-face meetings) has facilitated improvements in the inspection coverage and decision-making processes of the agencies. The 13 collaborative inspections conducted under the initiative have contributed greatly to each agency’s understanding of the other’s inspection procedures. They have also led to the identification of potential improvements to these procedures. Both agencies have learned several general lessons during the process [237].

In addition, exchanges of views on interpretation of GCP documents have also been organized. During the pilot initiative, the EMA and the US FDA have shared different pieces of GCP-related guidance documents, position papers, and policies in order to harmonize the agencies’ understanding of GCP and to standardize the requirements for industry wherever convergence would be beneficial for the clinical research process.

At the end of the program, both parties considered this pilot initiative very successful and agreed to continue this collaboration, incorporating lessons learned with the broader aim of moving from “confidence building” to the mutual acceptance of inspectional findings. The agencies will also expand the scope of the initiative to sites outside the US and EU [238]. INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 159

I-3.2.5.3) Interactions on Pharmacovigilance/Safety Issues Although not defined as a cluster, interactions in the area of safety continue to play an important part in the ongoing collaboration between the US FDA and the EMA.

Such interaction is organized through the different channels listed below [239]: ▸ Videoconferences take place on a bimonthly basis and include product-related issues and issues related to risk management. Usually five to six products are discussed at these teleconferences. ▸ Regular informal teleconferences in order to exchange information on emerging safety and strategic issues. ▸ EMA shares the Early Notification System on a monthly basis and the US FDA sends advance notice of publication of its quarterly update reports on potential safety signals. ▸ Joint projects have also been established, such as the collaborative project on the Progres- sive Multifocal Leukoencephalopathy Research Agenda to stimulate research into this important safety issue that affects some biological agents.

I-3.2.5.4) Parallel Scientific Advice The objective of this program is to allow interaction between the EMA and the US FDA assessors and sponsors during product development. This dialogue between the two agencies’ assessors and sponsors on scientific issues [240] aims to optimize product development and avoid both unnecessary testing replication and unnecessary diverse testing methodologies.

Such a procedure can be valuable for products developed for indications for which development guidelines do not exist, or if guidelines do exist, the EMA’s and the US FDA’s recommendations differ significantly. Experts from the EMA and the US FDA exchange views and discuss draft responses to questions from the applicants on their clinical development programs or on new biomarkers.

General principles for this voluntary parallel scientific advice were published in 2009 by the EMA and the US FDA [241]. It is important to understand that this is a parallel procedure, and unfortunately, not joint advice. The goals of the EMA and US FDA are primarily to share information and perspectives, rather than specific harmonization of study or regulatory requirements (although they recognize that harmonization is a beneficial outcome). After this procedure, the two agencies conduct their individual regulatory decision-making process regarding drug development issues and marketing applications. Each agency provides independent advice to the sponsor regarding questions posed according to their own usual procedures and timelines. The advice of each agency may therefore still differ after the joint discussion. However, in many cases, these discussions between regulators achieved a high degree of alignment and helped industry move closer to a global development plan [242].

In 2010, following a rather slow acceptance in previous years (due to hesitation from industries to use this procedure that does not commit the two agencies to issue common advice), the EMA and the US FDA discussed seven new parallel scientific advice procedures. WHO 160 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS experts were involved in two of these procedures, due to the therapeutic area covered by the request. In addition to the formal parallel scientific advice exchanges between the US FDA and the EMA, ad hoc informal scientific advice teleconferences between the agencies took place for five products in 2010 [243].

I-3.2.5.5) Clusters “Clusters” or specific areas of mutual interest have been identified, and a more structured working relationship has been established. These clusters (i.e., oncology, pediatrics, orphan medicines, pharmacogenomics, blood products, biosimilars, and vaccines) facilitate the exchange of information through teleconferences relating to applications for marketing authorization and extensions of indications, including risk management plans [244].

The latest cluster established, with a focus on biosimilars [245], significantly increased cooperation between the agencies. The recent announcement from the EMA stating that the agency will now accept data from reference product batches sourced outside the EU for biosimilar product applications [246] will certainly boost the EU–US cooperation in this domain and the global development of biosimilar products. This decision follows the US FDA proposal to also accept comparative data referencing a product that is not approved in the US [247].

I-3.2.5.6) Collaboration on Orphan Drug Development The EU–US FDA collaboration on orphan drug development has been important. Discussions between the EMA and the US FDA usually include sharing of information on applications submitted in order to approach and discuss criteria for designation. A common application form has been designed and agreed to so that sponsors can apply for orphan designation (of the same medicinal product for the same use) in both jurisdictions using this common form, facilitating the exchange of information. Since 2010, discussions have also included analysis of different opinions.

On February 26, 2010, the US FDA and the EMA announced that they had agreed to accept the submission of a single annual reportmmm from sponsors of orphan products designated for both the US and the EU [248]. Each regulatory body continues to conduct their own review of the annual report to assure the information meets their own requirements. The use of one single report benefits both the sponsor and the two regulatory agencies. The sponsors benefit from the elimination of duplication of efforts to develop two separate reports, and the regulators can better identify and share information throughout the development process of an orphan product.

I-3.2.5.7) Pediatrics Collaboration in pediatrics is governed by the principles agreed to in 2007 [249]. This framework includes information exchange (product-specific and general issues) and invitation of the other party to relevant pediatrics meetings. The two main objectives are (1) to avoid exposing mmm These reports provide information on the status of the development of orphan medical products, including a review and status of ongoing clinical studies, a description of the investigation plan for the coming year, any anticipated or current problems in the process, difficulties in testing, and any potential changes that may impact the product’s designation as an orphan product. INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 161 children to unnecessary trials, and (2) to facilitate the development of global pediatric development plans that are based on scientific grounds and that are compatible for both agencies.

In practice, the cluster on pediatrics organizes monthly teleconferences between the EMA’s pediatric team and the US FDA during which Pediatric Investigational Plans (PIPs) are discussed in detail and information between the two agencies is exchanged. In addition, more general questions have also been addressed, such as extrapolation, choice of endpoints, and patient/parent reported outcomes. From September 2009 until September 2010, 42 products and four general topics were discussed [250]. Since the end of 2009, US FDA representatives have been able to participate in certain EMA PDCO discussions and vice versa. The EMA has also provided the US FDA access to its internal database that includes scientific details on all PIPs.

I-3.2.5.8) Parallel Evaluation of “Quality by Design” Aspects of Applications Several guidelines have been developed at the ICH level (ICH Q8, Q9, Q10) in order to facilitate the implementation of “Quality by Design.” Taking into account the global perspective of pharmaceutical manufacturing, the EMA and US FDA agreed that it would be beneficial if at this early stage of implementation assessors from the US and EU could exchange their views on the implementation of ICH concepts and relevant regulatory requirements using actual applications.

A three-year pilot program, operating under the US–EU Confidentiality Arrangements, started in April 2011. This program allowed parallel evaluation of “Quality by Design” aspects of applications submitted to the EMA and the US FDA at the same time [251–1]. On August 20, 2013, the EMA and US FDA published the lessons learned and Q&A resulting from the first parallel assessment. Both agencies found the pilot program extremely useful to share knowledge, facilitate a consistent implementation of the ICH guidelines, and harmonize regulatory decisions to the greatest extent possible [251–2].

I-3.2.6) Conclusion The bilateral collaboration between the EU and the US has been extremely productive, and today it is recognized as a very successful initiative. Its scope has increased over the years, from the basic exchange of information and harmonization of format to close collaboration and discussion of divergent positions. The liaison placement in each organization has also been an important decision to facilitate such cooperation. This increase in interaction, in a relatively short period of time, has been driven in part by reaction to crises and in part by proactive measures to enhance EMA–US FDA communication and collaboration [252]. The establishment of the Transatlantic Administrative Simplification project in 2007 has also been beneficial as it initiated several pilot projects that further demonstrated the need for, and benefits of, such collaboration.

In general, activities in all the clusters have increased over time, and there has been an overall increase in the number of ad hoc requests for teleconferences on specific products and topics. Following a significant increase between 2008 and 2009, the total number of monthly US FDA and EMA interactions (i.e., teleconferences, document exchanges, etc.) now averages about 55 per month, excluding document exchanges relating to cluster and pilot activities. 162 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

Significant achievements have also been made in several critical areas for public health such as orphan medicinal products (with the agreement on a single annual report), drug development (with the establishment of the parallel scientific advice procedure and collaboration on pediatric development), GCP and GMP inspections (with several successful pilot projects that increased collaboration), and safety of products (with close collaboration and regular exchange of safety information, risk management, and safety alerts). Exchange of draft regulation (before release in the public domain) has also facilitated harmonization of practices and exchange of opinions. Finally, tools for more effective tracking have also been developed. All these achievements confirm that collaborations between countries have a positive impact on public health. It is particularly evident in certain areas such as orphan drug development (for diseases affecting a small population) or the exchange of information relating to urgent drug safety issues (to better assess and understand risks).

It is also important to note that this successful collaboration allows not only for the convergence of practices, but more importantly, this exchange of information and communication builds confidence in each other’s systems, practices, and evaluations, allowing for a sharing of activities in certain areas. This is already the case in the area of inspection. In December 2011, EMA spokesperson Monika Benstetter stated that “each agency is now relying on its partner for drug manufacturing facility inspection data.” [253]

The success of this transatlantic cooperation is partly due to the fact that it has been well structured and organized over the years. The establishment of clusters and then the creation of the liaison officials’ positionsnnn strengthen regulatory cooperation between the agencies. These decisions have been extremely beneficial from the perspective of education and timely communication. A large number of staff visits and exchanges also took place, and there is now more routine involvement in the scientific work of both agencies. The US FDA representatives take part as observers in Committee for Medicinal Products for Human Use (CHMP) discussions, and the EMA representatives are provided with access to webcasts of US FDA Advisory Committees.

However, other parameters such as those listed below have also been critical for this success, and clearly demonstrate their importance of this type of cooperation and harmonization initiative: ▸ First, it is clear that the political commitment to increased cooperation has been important. Indeed, closer collaboration was evident after the signing of the “Framework for Advancing Transatlantic Economic Integration between the European Union and the United States of America” in 2007 by EC President José Manuel Barroso, German Chan- cellor Angela Merkel, and US President George W. Bush. ▸ Second, the establishment of confidentiality agreements, which since 2010 are effective for an indefinite period, allow both parties to exchange inspection reports or other nonpublic product-related information. This was critical in the establishment of collaboration as this communication on specific practical cases allowed the parties to nnn Since 2009, the FDA has seconded a permanent representative to the EMA’s office in London. Since early 2010, the EMA has seconded a representative to the FDA’s offices. INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 163

discuss the similarities and differences of opinion when assessing product applications and documentation. Although necessary, sharing only public information (i.e., new regulations and guidelines) does not provide this opportunity. ▸ Third, this bilateral collaboration benefited from the fact that both parties had the same level of maturity and development of their systems and regulations, and similar public health needs and challenges (even if they were not always identical). ▸ Lastly, the step-by-step approach established has been helpful because it provided clear priorities (with the clusters), allowed progressive exchange of information (from ad hoc requests to regular teleconference and nonpublic product information exchange), and time for each party to evaluate the partner agency’s system and practices (with several specific pilot projects and visits/exchange of staff). Although it took some time and a lot of effort, these different steps were beneficial as they facilitated transparency and confidence building. This clear understanding of similarities and differences of practices is a prerequisite to foster a culture of convergence of each agency’s assessments and evaluations.

To conclude, this bilateral collaboration is now very developed and has moved from confidence building and exchange of information, to recognition of each other’s information and data for decision making. Its success so far supports the continuation of this collaboration and even its extension, as confidence in each other’s system continues to increase. Although it is recognized that each party will remain ultimately responsible for public health in their territories, closer cooperation and convergence are obviously possible in many domains. Finally, it would be beneficial to continue to expand successful projects to additional partners (as has been the case for GMP inspections of active substance manufacturers [254]) in order to foster greater international collaboration and information sharing.

I-4) OTHER COOPERATION INITIATIVES

In addition to the bilateral, regional, and global regulatory initiatives described in previous sections, other technical and scientific harmonization projects have also been initiated. Although these projects do not enter in the scope of this research (as they do not specifically relate to regulatory harmonization), it is important to mention them, as the standards they develop are often used by the regulatory harmonization initiatives.

The following organizations and projectsooo have indeed supported the harmonization of standards in the pharmaceutical domain:

▸ The Pharmacopoeial Discussion Group (PDG) involves (since 1989) the European Pharmacopoeia (EP), the Japanese Pharmacopoeia (JP), and the US Pharmacopeia (USP) to harmonize pharmacopoeial standards (i.e., excipient monographs and selected general chapters). It works in collaboration with ICH, and WHO became an observer in May 2001. ooo This list of organizations/projects below is provided as an example and does not represent an exhaustive list. 164 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

▸ The International Organization for Standardization (ISO) is the world’s largest developer and publisher of international standards (with a network of the national standards institutes of 163 countries and a central secretariat in Geneva, Switzerland). This is a nongovernmental organization that today has more than 19,000 international standards and other types of normative documents covering many technical areas.

▸ The Pharmaceutical Inspection Co-operation Scheme (PIC/S) facilitates (since 1995)ppp cooperation and networking in the field of good manufacturing practice (GMP) in order to lead the international development, implementation, and maintenance of harmonized GMP standards and quality systems of inspectorates in the field of medicinal products. The PIC/S activities include the development and promotion of harmonized GMP standards and guidance documents, the training of inspectors, and the assessment of inspectorates. This initiative currently includes more than 40 worldwide pharmaceutical inspection authorities.

▸ The Council for International Organizations of Medical Sciences (CIOMS) is an international, nongovernmental, nonprofit organization that was established jointly by WHO and the United Nations Educational, Scientific and Cultural Organization (UNESCO) in 1949. It includes over 55 international, national, and associate member organizations representing many of the biomedical disciplines, national academies of sciences, and medical research councils. One of the objectives of CIOMS is to facilitate and promote international activities in the field of biomedical sciences, and its activities include programs on drug development and international nomenclature of diseases.

▸ The World Medical Association (WMA) is an international organization founded in 1947 to represent physicians. Today, it includes 100 National Medical Associations, and its goal is to achieve consensus on the highest international standards of medical ethics and professional competence. The Declaration of Helsinki (developed in 1964) is the WMA’s best-known policy statement.

Finally, other groups of experts have also worked and released recommendations on specific topics related to the harmonization of pharmaceutical regulations (e.g., the PhRMA’s [Pharmaceutical Research and Manufacturers of America] Simultaneous Global Devel- opment project [255] or the nonprofit TransCelerate BioPharma project [256]). All these projects contribute to the global convergence and harmonization of pharmaceutical regulations.

I-5) CONCLUSION

Many harmonization initiatives have been established over the past several decades because regulators understand that cooperation can help in resolving the new challenges brought on by globalization. Understanding the importance and advantages of cooperation and ppp The Pharmaceutical Inspection Convention (PIC) had been operating since 1970. INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 165 harmonization in supporting their mandate to promote and protect public health, many countries and regions have strongly enhanced their collaboration with other countries bilaterally and multilaterally at the regional and global levels.

The globalization of the pharmaceutical market has highlighted several problems that have been associated with data generated from foreign countries and with imported products. For example, in 2008, deaths associated with heparin imported from China into the US was due to contamination of its pharmaceutical ingredients at a Chinese plant, and in Panama, the diethylene glycol found in cold and fever medicine killed many people [257–259]. These problems have been a wake-up call, and they further increased the recognition of benefits to be derived from leveraging the activities and resources of foreign counterpart DRAs [260].

For example, the US has strongly increased their international collaboration in the pharmaceutical domain. US legislators decided that such international cooperation and harmonization activities are an integral part of the US FDA’s mission. Indeed, the Food and Drug Administration Modernization Act of 1997 stated that one of the missions of the FDA is to “participate through appropriate processes with representatives of other countries to reduce the burden of regulation, harmonize regulatory requirements, and achieve appropriate reciprocal arrangements” [261]. Since then, the US FDA’s international work has grown expo- nentially, especially over the past decade, to respond and adapt to the new global society [262]. It has increased communicationqqq and developed regulatory cooperation with other countries (bilaterally and multilaterally). The US FDA’s role in harmonization and multilateral relations is to coordinate and collaborate on activities with various international organizations (i.e., WHO, ICH, PANDRH, and APEC) and individual countries on international standards and harmonization of regulatory requirements. In pursuit of appropriate international collaboration, the US FDA utilizes a wide variety of International Arrangements, including “Confidentiality Commitments”rrr and “Memoranda of Understanding and other Cooperative Arrangements.”sss

The EMA is one of the US FDA’s closest regulatory partners. The US FDA maintains an active, robust bilateral relationship with Europe (i.e., EMA and the European Commission [EC]), along with national DRAs throughout Europe. The increase of US cooperation with China is another focus of the US FDA’s international cooperation.ttt Due to the increase of US trade

qqq Communication is conducted via conferences, symposia, or workshops, and also annual meetings with counterpart DRAs. rrr These Confidentiality Commitments have been developed with all other major worldwide DRAs and WHO to facilitate information sharing. sss Memoranda of Understanding and other Cooperative Arrangements have been signed with many other worldwide DRAs regarding cooperation on several topics including GMPs. ttt In his budget proposal for FY 2013, the US President supported this approach by adding $10 million to the US FDA’s budget base. 166 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS with China,uuu the US FDA must increase its capacity for inspecting and analyzing Chinese products before they are shipped to the US. In order to accomplish this, the US FDA established an office in Beijing, China in November 2008 and employed 14 people (with additional employee hiring planned in the following years [263]). It has allowed for solid relationships with Chinese regulators and exporters, and has trained more than 1,600 manufacturers and regulators on US safety standards in two years [264]. Finally, there has been increasing recognition within the US FDA of the need to strengthen regulatory capacity and provide technical and scientific expertise to developing countries to ensure that products exported to the US meet US FDA standards and adequate levels of patient protection. Many cooperative initiatives have been established to meet this goal [265].

This increased US FDA commitment to global cooperation is expected to continue, as confirmed in the 2011 special report released by the US FDA Commissioner, Dr. Margaret A. Hamburg [266]. Indeed, this report strongly supports substantial and fundamental changes to the US FDA operating model to further expand its global activities and to transform the US FDA “from a domestic agency operating in a globalized world to a truly global agency fully prepared for a regulatory environment in which product safety and quality knows no borders.” Another report, released on April 23, 2012, further details the activities and strategy the US FDA is using to support this transformation [267]. To manage all these international programs, a new US FDA Directorate (Office of Global Regulatory Operations and Policy) was created in July 2011. Under this Directorate, the US FDA’s Office of International Programs serves as the agency’s focal point for all international matters and is responsible for maxi- mizing the impact of the US FDA’s global interactions. Additional US FDA reorganizations were also announced in 2012 to further respond to drug industry globalization [268]. Also, in addition to China, the US FDA now has staff stationed permanently in India (New Delhi and Mumbai), Belgium (EU Office, Brussels), the UK (EMA, London), Italy (Parma), Costa Rica (Latin America Office, San Jose), Chile (Santiago), Mexico (Mexico City), South Africa (Pretoria), and Jordan (Amman). These foreign offices, which will continue to expand, are a key part of the US FDA’s new global strategy to focus on building relationships with regulators in other countries. Working through these partnerships, the US FDA aims to develop an information network through which regulators worldwide can also share knowledge about criminal enterprises, as well as leveraging the knowledge and resources of trusted counterpart agencies. This expanded international presence also allows for greater access for US FDA inspections and for building regulatory capacity in countries where such assistance is needed.

Japan is another country that has over the years significantly increased its global cooperation with other DRAs and has actively promoted international harmonization of standards. Japan is a founding member of the ICH, and continues to actively contribute to this global multilateral initiative. It has also been involved with regional harmonization activities (i.e., the APEC initiative). More recently, it has also developed several bilateral collaborations with uuu From October 1, 2006 to September 30, 2011, the total number of shipments of US FDA-regulated products from China increased from approximately 1.3 million to 2.1 million. Of the 2.1 million entry lines arriving in 2011, 30% were drugs and devices, and 12% were human food products (“FDA Fact Sheet: Increasing FDA Capacity in China,” FDA website [http://www.fda.gov/default.htm]; accessed on May 12, 2012). INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 167 other countries and regions, including the US, EU, Australia, Canada, Singapore, and China. These bilateral collaborations are based on confidential agreementsvvv and include information sharing. Proactive exchange of staff has also been agreed upon with some DRAs (Phar- maceuticals and Medical Devices Agency [PMDA] International Liaison Officers have been located at the EMA [269] and in Washington, DC to facilitate cooperation with the EU and the US [270]). Japan’s PMDA has also developed privileged relationships with China and South Korea following the pandemic influenza crisis [271,272]. Since 2007, this tripartite initiative has specifically cooperated on clinical research and promoted regional clinical trials [273,274].

In February 2009, the Advisory Council approved the PMDA International Strategic Plan as a framework for its international activities [275]. This plan outlined the strategies for bilateral, regional, and global cooperation, and established an internal office in charge of international affairs. In line with this International Strategic Plan, further goals (to be attained by 2020) were published in November 2011 [276–1]. Finally, a Roadmap for the PMDA International Vision was released in April 2013. In this roadmap, the PMDA defines more specific actions to support its international vision [276–2].

The primary objective of this increase in international collaboration was to urgently resolve the “drug lag”www that has impacted the Japanese pharmaceutical market in the past (2.4 years in 2006). Many measures have been taken to improve the clinical testing environment (including the promotion of global clinical trials) and expedite drug approval decisions (via, among other measures, the increase of collaboration with the other worldwide DRAs). A global, simultaneous drug development approach has also been strongly recommended. Many actions, including release of guidelines, have been taken to facilitate such global development [277].

In addition to the US and Japan, other major DRAs of developed countries (such as Health Canada and the Australian TGA) also recognized the important added value of global cooperation and therefore increased their involvement in international activities. The EU, based on its prior experience of harmonization and cooperation from the establishment of its own system, has also developed external bilateral and multilateral collaborations and is today an important international partner.

Although these diverse, coexisting, bilateral, regional, and global initiatives create complexity, it is important to note that they are complementary. Global harmonization does not preclude having regional harmonization and regional harmonization does not preclude bilateral agreements. In fact these three levels of harmonization and cooperation bring about different added value:

▸ Bilateral agreements allow for a bigger exchange of information, including product- specific data, through confidential agreements and the development of privileged relationships (and trust) between regulators as they allow for assessment of one another’s

vvv In the case of China, a cooperative agreement has been established. www Drug lag is defined as the difference of availability of new medicines between the US and Japan. 168 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

systems and practices.xxx These assessments are indeed critical for confidence building and can ultimately support the signing of agreements, allowing for recognition of inspection or the exchange of nonpublic information (e.g., EU/US collaboration and confidentiality agreements). Bilateral collaboration also helps strengthen relationships, which would be more difficult in the context of a multilateral initiative, and facilitates training and mentoring activities between developed and developing countries.

▸ Regional harmonization allows for the harmonization of policies between countries that are usually closer in term of systems, cultures, and levels of development. It is indeed easier to harmonize closed systems and policies between countries of similar culture and environment (for example, it is more difficult to harmonize systems and policies between Asia and North America because they have very different medical practices and cultures). This level is essential for global harmonization because it provides a structure. Achieving global harmonization without a supporting regional organization structure is impossible. This regional level allows for inclusion of regional realities and difficulties in global discussions, and eases the diffusion and implementation of the global recommendations.

▸ Global harmonization is the highest level of harmonization. Compared to regional harmonization, the global harmonization initiative is not driven by economic objectives; the goal is not to create a free trade area or a single market, but to develop global consensus and standards in order to allow the world’s population to have access to medicine and innovative therapies.

To conclude, these bilateral, regional, and global cooperative activities have been beneficial as they supported the harmonization of requirements globally and therefore facilitated the availability of safe and efficacious medicines, critical in promoting global public health, on a worldwide basis. Many topics and standards have already been partly or fully harmonized at a bilateral, regional, or global level. For example, most of the requirements regarding the conduct of nonclinical studies, and also the GMP and good clinical practice (GCP) principles, have been agreed on, allowing for joint inspection projects. A common format of application has been developed, and many technical aspects have been harmonized through the ICH’s work. Col- laboration has also been increasing in resolving major topics requiring global interaction, such as orphan drug evaluationyyy and development of medicines for the pediatric population.zzz Confidence and trust have been built between developed countries through pilot projects, but xxx For example, bilateral collaboration allows two countries to assess their respective inspection systems or systems to control critical information (such as trade secrets). Such assessments of each other systems could be possible in the case of multilateral collaboration, but would be more complex. yyy Because only a small number of the population is affected by these life-threatening diseases or serious conditions, it is critical to have global requirements in order to facilitate global clinical studies. Moreover, the pharmaceutical industry has been reluctant to invest in the research and development of medicinal products to treat these conditions. The development of global requirements allows quick access to the global market and therefore allows a better return on investment. zzz It is critical that countries cooperate in this area to avoid exposing children to unnecessary trials. INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 169 also through the location of official liaisons in other DRAs to facilitate collaboration. This has been positive, and this new type of interaction is very promising as it increases relationships and allows for the better exchange of experiences and information.aaaa The establishment of liaisons in other countries also allows more proactive measures and risk analysis in the area of quality systems and inspections [278]. Exchanges of information between DRAs have also dramatically increased. This regular communication between regulators facilitates evaluation of risk (e.g., via exchange of safety alerts) and assessment of new medicines. Finally, systems have been put in place to help developing countries (e.g., CPP scheme, prequalification of medicines, Article 58 of European Regulation (EC) No 726/2004, etc.).

However, without underestimating all these important positive outcomes, it is clear that differences still exist and that further efforts will be required to support this ongoing harmonization process. There are still differences between countries in terms of standards and strategies to assess compliance against standards. The conduct of global clinical studies continues to present many challenges (i.e., related to registration, conduct of the studies, and also the use of data), and there are still several clinical trial registries and databases in use. The safety of medicines has been one of the main focuses of DRAs in the past due to major problems and events, but there has not been a real effort toward worldwide harmonization regarding risk-mitigation strategies. Additionally, new standards continue to be developed by different bodies (i.e., ICH vs. regional organizations) in parallel that not only duplicate efforts, but also create disharmony (e.g., biosimilars requirements had first been developed by individual countries and also by WHO). There is also a significant difference in the level of implementation of harmonized standards (i.e., the ICH recommendations/guidelines) between countries, and the CTD format has still not been implemented in all countries. It has also been reported that differences between developed and developing countries has in fact continued to increase in the past several years due to the increased complexity of technologies associated with the development of new therapies. Even between two close partners like the US and EU, which have developed a privileged partnership and strong cooperation, there are still important differences in standards. For example, the US is still requiring two placebo-controlled studies to determine efficacy of a new medicine, while the EU is more interested in comparative studies using an active comparator. This difference is due to different legal requirements and scientific opinions regarding the value of such comparative data [279]. This situation may change in the future with the growing interest in the US for “comparative effectiveness” promoted by the Obama administration.

Finally, this complex worldwide harmonization context (with increased communication and exchange of experience, information, and good practices) requires good communication and coordination between all these ongoing initiatives. Even if such communication was initiated by WHO and ICH (with the GCG group), further improvement would still be needed. This enhanced coordination of international cooperation would indeed be beneficial, as it would provide the necessary transparency regarding the focus and responsibility of each initiative (i.e., development of standards, coordination of implementation of recommendations, etc.). aaaa Exchange of information and best practices has been one of the most important outcomes of the EU/US bilateral collaboration. 170 INTERNATIONAL COOPERATION, CONVERGENCE, AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

It would also facilitate the appropriate use of resources and expertise, and therefore avoid duplication of efforts or conflicting recommendations and actions. Overlapping membership between the initiativesbbbb may not be fully efficient, and can create confusion and duplication of work.

Although the increased coordination of these diverse initiatives would be beneficial, it will certainly be challenging. It will need to be thoroughly structured and implemented, and it will also be critical that the coordinated body is a recognized and experienced entity, with appropriate mandate and power.

bbbb The US, Canada, and some LATAM countries are part of the PANDRH initiative and also the APEC initiative. P A R T II Value and Influencing Factors of the Cooperation, Convergence, and Harmonization in the Pharmaceutical Sector

Following the review of all major harmonization initiatives in the pharmaceutical sector (see Part I), two questions need to be answered before any action can be recommended: ▸ Do the ongoing and past harmonization initiatives have (or have they had) value, and if so, would further harmonization be possible and would it be beneficial? ▸ What are the important lessons from the past, and the ongoing harmonization initiatives that should be considered for planning the next steps?

II-1) VALUE OF THE COOPERATION, CONVERGENCE, AND HARMONIZATION IN THE PHARMACEUTICAL DOMAIN

Differences in regulations between countries have been a problem in many areas (i.e., mobile phones, electrical equipment, etc.). In past decades, these differences were more problematic, but today it is common to travel and to buy and sell items on the Internet between people living throughout the world. To support this globalization of economic and social expectations, the harmonization of standards and regulations is necessary in many areas. Therefore, competent authorities began to collaborate, most of the time under the United Nations (UN) organization, to exchange information and to harmonize their regulations. These collaborations have been successful in certain domains (e.g., international air navigation), while challenging in others (e.g., climate change).

International Cooperation, Copyright © 2014 Pierre-Louis Lezotre. Convergence and Harmonization of Pharmaceutical Regulations 171 Published by Elsevier Inc. All rights reserved. 172 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

Cooperation and harmonization of standards in the pharmaceutical domain are already a reality, and have in fact been increasingly important in the past several decades (see Part I). This harmonization seems natural and logical in the current environment of increased globalization imposed by the current geo-economic-political situation. However, even though this is a reality, it is important to analyze whether all stakeholders benefit from this increased cooperation and harmonization in order to recommend future actions or potential improvements.

II-1.1) Value for Patients and Global Public Health Even though there are differences between developed and developing countries or between regions, diseases go beyond borders and are present worldwide. It therefore seems logical that the development and manufacture of medicines against these diseases should be based on the same global standards, independent of where the sites of manufacture are or the clinical studies occur.

The harmonization of standards and cooperation between countries are beneficial to patients and global public health in several ways:

▸ Increase of Worldwide Access to Medicines: Pharmaceutical access is defined as the timely availability of quality medicines to those patients who need them. The unavailability of some medicines poses a real threat to public health and welfare. Many interrelated factors (i.e., availability of financial resources, government policies, infrastructure conditions, private and public sector insurance programs, appropriate use, supply management, manufacturing capacity, research and development decisions, etc.) determine the level of access. It is clear that the level of harmonization of pharmaceutical regulations and cooperation (regionally or globally) also influences pharmaceutical access in both developed and developing countries. These activities increase the availability of high-quality, safe, and effective medicines worldwide, and promote better access to a larger worldwide population. For example, the “drug lag” in Japan (i.e., delay of availability of new medicines vs. the US) has been partly attributed to specific local requirements requested by Japanese regulators. The same analysis partly attributed the recent reduction of this “drug lag” (from 2.4 years in 2006 to 1.1 years in 2010) to the implementation of PMDA measures to increase global cooperation [280]. By promoting the conduct of multinational clinical trials that meet international standards, the harmonization of regulation also facilitates faster access to innovative and quality medicines for worldwide patients. Indeed, harmonization of rules (i.e., implementation of ICH Good Clinical Practices [GCP]) and the introduction of a “mature” regulatory system (i.e., consistent and transparent) increase the interest of the global pharmaceutical industry in performing multinational studies, and therefore increase access to drugs in development for patients from these countries.

▸ Promotion of the Development and Implementation of High Standards: Collaboration facilitates dissemination, recognition, and adoption of best practices. Moreover, if the creation/harmonization of an international standard follows an INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 173

appropriate and rigorous process (i.e., based on scientifically driven discussions), the quality, robustness, and relevance of such standards will increase as it integrates different expertise, experiences, and points of view from the best worldwide experts in the field. This will ultimately benefit the patients who will have the assurance that their medicines have been developed and manufactured according to the highest standards. In certain domains, there are a limited number of experts worldwide (e.g., new technologies or specific diseases), therefore it is critical to gather these international experts together to develop high-quality standards.

▸ Reduction of Unnecessary Testing in Animals and Humans: The reduction of unnecessary testing in animals and humans should always be a priority for ethical reasons. The amount of human and animal experimentation is reduced when companies only have to produce one set of data for all regions.

▸ Promotion of Innovation and Development of Medicines for Unmet Medical Needs: One could question if the increase in harmonization of standards can decrease innovation and delay availability of a drug in certain markets. For example, it could be argued that if today Country A requires a one-year study to support the r egistration of a new product in a specific indication, while Country B requires only six months, the harmonization of requirements could potentially delay the availability of this product in Country B by six months. However, although there is indeed a risk of delay, which may in fact be beneficial for the patient if the harmonization discussions conclude that the risk/benefit assessment is more relevant at 12 months, harmonization and cooperation activities are in fact contributing to pharmaceutical innovation by promoting predictable and consistent requirements [281] and reducing regulatory uncertainty. Reducing the risk for industry (by releasing clear and harmonized technical guidelines and accepting foreign data), and increasing return on investment (by increasing global marketing opportunities), these harmonization activities stimulate investment in research and development (R&D). Moreover, the elimination of redundancy and duplication of work and testing to satisfy different requirements frees up resources for R&D. Finally, MedDRA and other harmonization of terminologies facilitate and increase communication between experts, which in turn increases cooperation and innovation. Harmonization of regulations and requirements can also make development of certain types of products financially viable for industry. These development projects would indeed not be funded if different worldwide requirements needed different programs or clinical studies to support global registration. For example, before ICH recommendations on how to demonstrate comparability of biotechnological/biological products subject to changes in their manufacturing process [282], regional disparities created economic problems (i.e., wasted inventories, shelf-life, several parallel manufacturing processes) or implementation delays for industry, which discouraged process upgrades and improvements. Finally, it is also important to note that harmonization of requirements is critical for the development and availability of orphan drugs that treat life-threatening conditions and rare diseases because it allows multinational clinical studies and obviates 174 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

the development challenges due to the limited number of patients. The success of the European Union (EU) orphan drug regulation demonstrated how harmonization and cooperation can improve public health and increase availability of these types of medicines. Prior to this European legislation, a number of Member States had adopted specific measures to increase knowledge on rare diseases, but these initiatives did not lead to any significant progress in research on rare diseases. Follow- ing the implementation of EU Regulation (EC) No 141/2000, the number of orphan medicinal products authorized significantly increased. During the first five years of the implementation, 458 applications for orphan designation were submitted, resulting in 268 products being designated, relating to over 200 different rare conditions [283].

▸ Contribution to the Control of Medicine Quality: The harmonization of technical quality standards (e.g., Good Manufacturing Practices [GMP] domain) contributes to ensure that medicines, most of the time developed, manufactured, and tested in different countries, are of good quality. Moreover, falsified medicines are a major threat to public health and safety. As falsi- fications become more sophisticated, the risk that falsified medicines reach patients in undeveloped (as well as developed) countries increases every year. This calls for a comprehensive strategy at the international level. International cooperation already exists through the International Medical Products Anti-Counterfeiting Taskforce (IMPACT) [284] created by WHO in 2006. International cooperation and harmonization of regulatory actions are critical to ensure success against falsified medicines.

▸ Contribution to the Evaluation and Monitoring of the Safety of Medicines: The establishment of a global collaboration framework and the harmonization of reporting (i.e., formats and processes) enhance the safety of products. It allows exchange of information and rapid communications between worldwide DRAs regarding new product safety problems via agreed-upon common tools (e.g., Electronic Individual Case Safety Reports, Periodic Safety Update Report [PSUR], and Development Safety Update Report [DSUR]). This is critical to better monitor the safety of medicines, and has a direct benefit for patients. Such cooperation also allows pooling of information from different sources, regions, and countries. This increase of the quantity of safety information facilitates the early detection of possible safety signals and therefore improves the monitoring of product safety. Pharmacovigilance would be even more effective if it was supported by a truly effective “global” system. Pharmaceutical companies already have global departments that assess the safety profile of a product based on safety reporting from different parts of the world where the product is registered and marketed. True harmonization of practices and cooperation between worldwide DRAs is also necessary to have a real safety profile of the product (especially for an orphan drug where the patient population is limited).

▸ Support to Developing Countries: Global cooperation and harmonization of standards support and assist achievement of the UN Millennium Development Goals INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 175

(MDGs) as discussed in Part I-1.1. These activities improve health in developing regions by increasing access to safe and effective medicines of good quality. This is accomplished by strengthening the technical and administrative capacity via collaboration and the sharing of resources and expertise [285]. Technical and administrative assistance from the international community (i.e., ICH, WHO, or major DRAs) are indeed critical in supporting the development and enhancement of regulation in certain regions (e.g., Africa). This assistance (i.e., training, development of high quality standards, and technology transfer) helps developing countries to establish a mature regulatory system. It provides mentoring opportunities where more experienced DRAs from developed countries can share knowledge and experience with less advanced DRAs from developing countries. Without the help from international organizations, these countries/regions would not have the resources, expertise, or time to discuss, assess, and regulate new topics (i.e., biosimilars, gene therapies, etc.). If they apply “standard” rules to these types of state-of-the-art products and therapy, the patients may be exposed to risk. Harmonization and cooperation also facilitate the economic development of low- income countries because they increase the attractiveness of their local facilities for the manufacture of medicines and the conduct of clinical studies. A 2010 Industry Survey [286] showed that better cooperation between African countries (to reduce country-specific requirements) would promote access to new medicines, encourage more companies to register medicines in Africa, and ensure a continuous supply of medicines. Indeed, specific country requirements increase the cost of medicines to African countries, and in some cases contribute to the discontinuation of medical sup- plies to these countries. Finally, until recently, the focus of DRAs from developing countries was to exercise a regulatory oversight on products that were licensed and used in developed countries. However, some new products (i.e., new vaccines) are now being developed for use in the developing world, and sometimes exclusively in these markets. More clinical trials are being conducted in countries with weak regulatory systems, who are therefore confronted with new challenges which they are not in a position to address (i.e., assessing clinical trial applications and marketing applications not yet assessed by a developed country) [287]. Several initiatives, such as the WHO prequalification of products, the WHO regulatory pathways initiative, the WHO Initiative for Vaccine Research, or the EMA Scientific Opinion via the “Article 58” procedure, have already been established. International cooperation between WHO, developed countries, and developing countries is critical in this situation.

All the above benefits of harmonization and cooperation to patients and global public health are even more apparent if one reviews the public health risks that the lack of harmonization would generate. For example, in the absence of the ICH process, the DRAs of the three ICH regions may have continued to diverge in their practice and may have requested further local/regional focus and repetition in drug development activities. This increase of development time and efforts would have surely delayed the availability 176 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS of key medicines to patients. Moreover, if there were no cooperation and harmonization, certain developing countries would not be able to develop and implement functioning regulatory systems and pharmaceutical regulation on their own. This lack of pharmaceutical control would alleviate unethical activities that would ultimately impact global public health with: ▸ Increased production and importation of substandard/counterfeit medicines [288] ▸ Conduct of unethical clinical trials ▸ Corruption ▸ Distribution of unregistered medicines ▸ Irrational prescribing practice ▸ Irrational dispensing practice

The case of biosimilar products also demonstrates how the lack of harmonized requirements (or lack of implementation of harmonized standards) can impact public health. Although these products have recently been an important global health topic of discussion and many countries prepared appropriate requirements over the past several years, other countries have not yet developed specific regulations (or not yet integrated the WHO recommendations) to cover the risk associated with the approval and use of these specific products. Due to the lack of appropriate regulation related to this specific type of product (and sometimes without having any regulations for biologics at all), these countries (i.e., Argentina) evaluate and approve these “biosimilar” products using the same requirements as those for standard generics. They do not take into consideration the specific risks associated with biosimilar products [289] not present in the case of standard generic (e.g., immunogenic- ity). In some countries, the need for less expensive medicines may also link to the approval of subpotent biological/biosimilar products. This lack of implementation of international requirements and standards has an obvious risk for patients and public health.

II-1.2) Value for Regulators DRAs have the mandate to protect and enhance the health of their population by facilitating access to medicines of public health importance without compromising on quality, safety, and efficacy. However, as international markets expand and pharmaceutical companies operate more and more globally, the task of regulators to assess compliance with legislation and monitor the safety and quality of medicines becomes increasingly difficult and resource intensive. In addition, cuts in government budgets in recent years oblige the DRAs to rethink processes and utilization of resources. This is obviously a difficult exercise because they need to manage new challenges (i.e., increased globalization but also sophisticated products, new technologies, increased communication through the Internet, counterfeiting, etc.) with less budget and resources. In this context, maintaining the capacity and expertise to meet their obligations becomes a problem. As rightly stated by the Heads of Government of the Caribbean Community in the Nassau Declaration on Health in July 2001, “while the resources and absorptive capacity of no one single institution, country or nation are sufficient to reverse the negative trend, the evidence of ‘best practices’ and technological breakthroughs, the international, regional and national mechanisms and frameworks … provide hope of what can be achieved through a collective response” [290]. INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 177

Cooperation with other countries seems indeed the only alternative to manage the situation and to address the specific challenges associated with the globalization of the development, manufacture, and distribution of medicines. This is not a choice anymore if these countries want to provide people with more effective and safer medicines more quickly [291]. Therefore, cooperation has been intensified at different levels and the networking of institutions in developing and developed countries is an important element in building regulatory capacity and trust. Development of common standards for scientific evaluation and inspection also facilitates regulatory communication and information sharing. Of course, each country will remain responsible for the final decision (e.g., to approve/suspend a drug), but exchange of evaluation/information (e.g., safety alerts) is a “must” and not a “nice to have” anymore. Worldwide DRAs are required to harmonize their activities with the international community. Numerous Memorandum of Agreements (MoA) or Memorandum of Understanding (MoU) have been put in place between DRAs to allow legal exchange of information.

However, even if this has been imposed on them, most regulators now agree that domestic and international measures complement each other, and therefore domestic and international operations should be carried out seamlessly with the understanding that they are inseparable in nature [292]. For example, the new international focus of the US FDA and the reorganization of its inspectional resources (i.e., the opening of overseas offices) helped to enforce compliance, and it is now easier for the US FDA to control and inspect these foreign manufacturing sites [293]. The ICH process also demonstrated that harmonization brings value and benefits to DRAs because it improves consistency, efficiency, and transparency of review, which in turn facilitates information sharing among regulators and ultimately promotes faster access to life-saving treatments to patients on a worldwide basis [294].

Moreover, harmonization and cooperation also allow regulators to learn from each other’s experiences, to leverage international expertise, and to keep up with international best practices and standards. For example, the decision by the EMA and US FDA to collaborate on biosimilar products will certainly help the US FDA to catch up with Europe in its development of the regulation of these products. Indeed, Europe has already gathered a lot of experience in this area (the first biosimilar product was approved in Europe in 2006), while the US has just recently passed their law on biosimilars. In Europe the regulatory framework for biosimilars is largely established, with both general guidelines and product- specific guidelines (e.g., human insulin, somatropin, erythropoietins, interferon-alpha, low- molecular-weight heparins, and monoclonal antibodies) having been put in place by the EMA. The EMA is also currently working on draft guidelines for a number of other product class-specific guidelines, including interferon-beta and follicle-stimulation hormone. The US, on the other hand, is lagging behind the EU because the legal pathway (Biologics Price Competition and Innovation [BPCI] Act) was only signed into law on March 23, 2010 by US President Barack Obama [295].

DRAs from developing countries also benefit from the experience, expertise, and resources from other countries. Regulators from these developing countries also see the value in coop- erating with both developed and developing countries [296]. For instance, the cooperation 178 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS project between Brazil and Mozambique demonstrates that cooperation and harmonization between developing countries can be very beneficial [297].

Finally, harmonization also decreases the duplication of activities and therefore facilitates work sharing and optimization of DRAs’ time and resources. It can help manage DRAs’ workloads more efficiently (critical due to the increase of complex and voluminous data to review in a resource-constrained environment), and ultimately improve overall regulatory performance. It is also a way to resolve some of the resource limitations and budget constraints in developing countries. However, although important, resource saving should not be the only objective to ensure success of cooperation. Even if it is expected that cooperation and harmonization can increase efficiency in the long term, such activities can in fact require more work at the beginning. Harmonization and cooperation can deliver much more than resource saving (e.g., better informed decisions, increased protection of public health, and facilitated availability of medicines in developing countries).

Even if the vast majority of worldwide regulators and national DRAs fully support and recognize the value of harmonization and cooperation, some resistance may sometimes arise. This sporadic resistance from some regulators and national authorities to increase cooperation and harmonization is inherent to the relative fear of losing “power” and sovereignty. These concerns need to be kept in mind when establishing new harmonization projects or collaboration as it could raise implementation challenges, even if this threat is not fully realized. Indeed, even if cooperation obviously implies recognition of other evaluations and expertise, regional or global cooperation does not replace national judgment/decisions and harmonization does not automatically mean a loss of national sovereignty or autonomy. It depends on the model selected (i.e., integration vs. cooperation) and the stage of the harmonization process. Collaborative mechanisms (i.e., joint assessments or inspections) does not imply common decision making. Close collaboration can occur even if a registration decision itself stays in the hands of sovereign nations. The European system also demonstrates that, even in a case of integration where Member States relinquished part of their sovereignty in favor of the Community and delegated some of their decision-making powers to shared institutions and supranational bodies, national DRAs remained crucial for the pharmaceutical network. For example, experts and regulators involved in harmonization activities come from national DRAs (i.e., EMA is a network of experts who are made available by the national DRAs of all EU Member States).

Regional and global collaboration does not replace national DRAs. This is an evolution of regulators’ activities and responsibilities. National DRAs will still be responsible for managing specific countries’ health needs and establishing public health priorities. Even if a global medicines evaluation system were established, national DRAs would remain the ultimate decision-making bodies. However, everyone can learn something from others! To fulfill their mandate to promote and protect public health in the current global environment, each DRA needs to ask itself the following questions: ▸ What are the strengths of counterpart DRAs? ▸ How do we leverage each other competencies and expertise? INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 179

II-1.3) Value for Industry The cost of drug development increased considerably in the past decade due to more advanced and expensive technology and new requirements. Today, the average cost of bringing a new medicine to market is US $1.3 billion [298], it takes approximately 12 years (from the first toxicity dose to the first launch), and it has a success rate of 5% [299]. The combination of this strong increase in research and development (R&D) costs and the decrease of new molecular entity (NME) approvals has significantly impacted R&D productivity. Moreover, reduction in prices and reimbursement of medicines by worldwide governments (due to health budget restrictions), combined with low sales growth, has placed additional pressure on profit mar- gins for pharmaceutical companies [300]. The only solution for innovative companies to keep up with this decrease of R&D productivity and to improve their return on investment is to market new medicines globally with minimal additional costs required to satisfy the regulatory requirements of different countries.

However, although entering global markets has significant advantages and facilitates return on investment, pharmaceutical companies face challenges in marketing their products in different countries/regions with diverse regulatory requirements and practices. These different, and sometimes conflicting or contradictory, requirements make this global effort difficult, time consuming, and costly. Pharmaceutical companies must integrate the challenge of com- plying with these disparate international requirements and regulatory systems. This means expending resources to develop knowledge on local specificities and markets that translate to operational complexity and additional costs and time. Resources that could best be used for increasing R&D productivity are often used to meet different regulatory requirements that may add little to the evaluation of the risk–benefit of new therapies. More importantly, these specific local requirements delay the availability of new medicines for the population of these countries.

It is of course essential to establish a sufficient body of clinical and scientific evidence to ensure that newly introduced innovative medicines are safe and effective. This work is needed whatever the cost and resources it requires. However, some of the existing local regulatory requirements that necessitate repetition of work already conducted are viewed as impeding the ability to rapidly bring innovative medicines to address unmet medical needs. Indeed, this regulatory variability across multiple countries brings an extreme complexity to development activities and ultimately impedes, rather than facilitates, patient access to meaningful, new, evidence-based medicines [301]. On the contrary, consistency and scientific quality of recommendations from DRAs (e.g., for study design) ease the development of new medicines and reduce the risk.

The ICH process demonstrated that harmonization brings value and benefits to pharmaceutical industries as it enables industry to reduce development times by removing the duplication of studies that was previously required to gain global market approval for a new medicine. This directly affects the bottom line through reduced development times and resources (that can be allocated to new additional development projects). This harmonization of standards also facilitates organization of companies and intracompany globalization [302]. 180 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

Harmonization of quality specifications and analytical tests between countries would also mean an important cost savings for industry. It would reduce the need for several tests and batch releases of the same product batch. Moreover, some countries require in-country testing of each lot marketed in their territory (these analytical tests are performed by a government laboratory or a third-party laboratory contracted by the DRAs). If all countries had the same specifications and tests, and agreed to accept analytical results from other countries, in-country testing would not need to be repeated in several countries. This elimination of duplication of testing would obviously reduce the cost, time, and resources associated with multiple lot releases and in-country testing. This is also important for in vivo assays, to reduce unnecessary use of animals.

Harmonization of requirements also facilitates the development of new markets that are currently not profitable for global companies due to the cost of specific requirements. However, it is important to ensure that global standards are appropriately implemented in each region/ country to avoid disadvantaging local drug manufacturers/industries. The implementation of global standards should not create a barrier to local companies and facilitate big global industry. It is therefore important to balance the necessary implementation of scientific global standards to support/improve public health in all countries while addressing the needs of each country. Overregulating the pharmaceutical market in low-income countries could indeed impact the local economy.

Some industry representatives may at first be opposed to the harmonization of regulation for several reasons. The first concern from industry is the unnecessary increase of requirements that harmonization and cooperation could generate. This is a legitimate concern because an easy way to harmonize a topic between countries is to combine all current requirements from different countries (i.e., if one country requests Study A and another country requests Study B for the registration of new medicines, a quick solution would be to ask for both Studies A and B). To avoid this unreasonable duplication of requirements (which would be against one of the main objectives of harmonization: to reduce duplication of activities), the harmonization process needs to be considered carefully. This harmonization needs to be based on scientific evidence and evaluation to allow for the development of high standards. This is not a quick compromise or addition of requirements, but a common requirement established following a thorough evaluation of the situation. Of course, the basis of this common scientific evaluation needs to take into account the existing worldwide requirements. The ICH process is an excellent example of how scientific-driven evaluation can produce common high-quality standards.

Second, one could argue that these new global requirements could reduce flexibility and a creative “development program.” They are also concerned that harmonization may impact regulator and sponsor interaction during the development of medicines and that certain regulators may apply these new harmonized rules to everyone without discerning the specificity of each product/program. Although these concerns need to be kept in mind when organizing and implementing the next steps of global harmonization and cooperation, they seem to be not fully relevant for the following reasons: INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 181

▸ For nonemerging topics: Pharmaceutical companies prefer to avoid surprises. The worst situation for a company is the unknown and its associated risks. Therefore, the two major benefits of harmonization (i.e., allowing for a global development plan supporting global registration and decreasing the unknown and its risks) outweigh the potential flexibility of having diverse requirements. Moreover, if there is a good scientific reason not to follow a guideline/recommendation, the company will always have the opportunity to discuss this deviation to general rules via scientific meetings during development.

▸ For new emerging topics and therapies: Regulator and innovative companies’ interactions during development will always be necessary. Development of a new class of compound or the first products to treat a new indication or disease will always need this type of interaction and sometimes a creative development program. Even if a proactive discussion is put in place between DRAs for new emerging topics, the role of this discussion will be to agree on terminology, endpoint, etc. The relevance and importance of the dialogue between the regulators and the first company developing such medicines will still be critical.

Finally, some industry resistance may also come from the fear of creating a global system that would deliver a common global decision that, in the case of a negative outcome, would mean refusal in all countries worldwide. However, it is important to remember that a global system would not mean a global marketing authorization. Unlike the European integrated system, a global system could provide a concerted/shared evaluation of data, but not a common decision regarding risk/benefit assessment. Following the shared evaluation of technical data (or recognition of the assessment from another country), each national DRA would remain the decision-making body. Each country would conduct their individual regulatory decision-making process regarding the risk/benefit evaluation following their own procedures and requirements. Each DRA would provide an independent decision, which could therefore still differ. This national decision-making process would also happen if a global mutual recognition procedure were to be established.

II-1.4) Would Further Cooperation and Harmonization Be Possible and Beneficial? As presented in Part I, a substantial amount has already been done to harmonize pharmaceutical regulations. Many harmonization initiatives (i.e., bilateral, regional, and global) have already been established. The combination of this proactive collaboration with the natural convergence of issues and priorities on a worldwide basis (due to the globalization of trade and development/manufacture of pharmaceutical products) led to the convergence of requirements. However, there is still divergence between countries on many topics. More can be done to continue to protect and promote global public health (e.g., further harmonization and support for international clinical studies, better proactive support for the development of global standards related to emerging issues and new technologies, closer cooperation between DRAs, etc.). Moreover, the lack of international coordination of all harmonization initiatives is a problem. All of these ongoing initiatives remain segregated. ICH (via the GCG) 182 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS and WHO initiated a type of coordination, but these efforts only promote good communication between the different players to share experiences and information on projects. Although such communication between global and regional initiatives is of course important, it is not sufficient. There is clearly a lack of leadership in the coordination of these initiatives and duplication of efforts. More proactive management of international actions needs to be established, and a global strategy (which would define clear objectives and responsibilities) needs to be agreed on. All current participants of the harmonization (at national, regional, and global levels) are critical, but the management of all these ongoing activities would certainly decrease duplication and would be more efficient and productive.

There is also an urgent need to increase access to priority essential medicines by reducing the time it takes for beneficial therapies to reach patients in need in developing countries/ regions (such as Africa). However, lack of appropriate resources is a major and common problem in these countries (most of these countries have weak or nonexistent independent DRAs with experienced experts and reviewers). Harmonization of pharmaceutical regulations and cooperation at regional and international levels is an important element of the solution. Shar- ing resources between countries and use of international expertise (i.e., ICH) can resolve the problem if this cooperation is well structured and if the political support and legal framework are available in addition to funding. Moreover, the harmonization of regional regulation will develop new and bigger pharmaceutical market opportunities that will interest pharmaceutical manufacturers and therefore the development of medicinal products for the entire region. These opportunities would not be developed if each country has different standards and requirements for the registration of such products. Pharmaceutical companies usually focus their efforts first on major developed countries (i.e., the US and EU), as they are the major markets and the regulatory approval processes are more developed and transparent in these countries. They seek first approval for a new product in these regions even if the product is largely needed in developing countries. This practice can delay the entry of a new medicine in a developing country by 10 to 15 years. For example, for rotavirus infection, where the majority of between 352,000 and 592,000 children who die annually of its effects live in the developing world, this could mean thousands of deaths before medication is available [303]. The first rotavirus vaccine was initially available in the US where rotavirus is not as large of a health issue compared to developing countries, where a substantial number of children die due to this virus and where there is less access to medical treatments.

The vast majority of stakeholders support this continued harmonization effort and consider cooperation as the only solution to tackling the new challenges brought by the increased globalization of the pharmaceutical sector. Drug development and manufacture is indeed more and more global, therefore harmonization is more important than ever. In certain instances (e.g., regional integration process), harmonization and cooperation are critical, as divergences in national product standards often act as a barrier to trade and impede the creation of a free trade area or a single market.

The need for further cooperation and harmonization in the pharmaceutical sector (i.e., information exchange, joint assessments, and inspections) to reduce duplication has been clearly highlighted by worldwide regulators during the 14th International Conference of DRAs [304]. Major INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 183

DRAs have also recognized the need to substantially change their operating models and to increase their global partnerships in order to address the challenges of the future [305]. Industry representatives have also strongly emphasized on numerous occasions that they support these activities and would welcome further worldwide harmonization of requirements.

Some resistance has, however, been raised, and these opponents to harmonization have criticized the significant costs, effort, resources, and time that such initiatives require. A 2005 article [306] even challenged the benefit of such projects. It argued that international harmonization is driven by industry and that there have been examples of less stringent requirements for drug approval at the international level than at the national level. Although additional efforts are necessary, the examples listed in this article are not fully representative of the overall situation. This negative position against harmonization is not shared by the majority of stakeholders, and numerous regulators have strongly repeated their support of international cooperation and harmonization. These criticisms against harmonization and cooperation will certainly fade away if global harmonization is developed in a coordinated and transparent fashion involving all stakeholders. However, it is important to take these concerns into account and continue to make sure that ICH and other international standards are developed based on appropriate and relevant scientific facts and discussions. Each harmonization project needs to be carefully evaluated in order to ensure that new proposed harmonized standards can be implemented and will bring benefit to global public health. The harmonization process demands money and many resources, so it cannot only be an intellectual exercise. The ultimate goal is not the harmonization of the technical requirements and processes themselves, but the improvement of public health and the increased timely access to quality, safe, and effective drugs on a worldwide basis. The harmonization process should clearly maintain or increase current levels of public health protection. In any case, it should not create “lower” standards. Also, harmonization and development of global standards should not imply reduction of medical alternatives. Although not beneficial for the entire population, certain traditional medicines can be valuable for certain subpopulations, regions, or countries. The global system therefore needs to allow for flexibility to develop these medicines and not restrict the choice to one global therapy.

If the harmonization process continues at the same pace as during recent decades, a global system of assessment and control of medicines (at least for specific products such as orphan drugs) will certainly be established as it presents advantages for all stakeholders. The mul- tiplicity of registration procedures, and sometimes standards/requirements, obliged the pharmaceutical companies to set up priorities regarding worldwide submission plans. This can affect the availability of medicines in some small markets or countries. The establishment of a worldwide registration procedure, using international harmonized requirements, would be the only way to make sure that new therapies are available at the same time in both major and small markets. By improving the transparency, predictability, and efficiency of regulatory processes, the global system would also contribute to reducing unnecessary regulatory burden and promoting industry compliance. It would also facilitate the communication and coordination of pharmaceutical activities for emerging diseases and crisis management. 184 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

Today, this ultimate step of harmonization and cooperation seems far away and very difficult to implement. However, the European pharmaceutical regulatory system was also considered impossible to implement in 1939, but its success, in a relatively short period of time, demonstrated it was indeed possible! Although the European integration model cannot be applied to establish a global system, it demonstrates that the many challenges and resistance against harmonization/cooperation can be overcome if appropriate decisions are taken. More specifically, the European experience demonstrated that: ▸ Cooperation between (and even integration of) countries with different economic and societal/cultural environments and pharmaceutical markets is possible. ▸ Legal enforcement of harmonization (i.e., the creation of a mandatory implementation of harmonized topics) facilitates and accelerates harmonization. ▸ Political support is essential to achieve major harmonization objectives. ▸ Implementation of ICH guidelines in countries with less-developed regulatory systems is possible (e.g., EU enlargement to the Eastern European countries in 2004). ▸ Regional cooperation facilitates global harmonization and implementation of ICH guidelines. ▸ Partnership between central bodies (i.e., EMA, European Pharmacopoeia [EP], EU control laboratory network) and national DRAs is possible as long as roles and responsibilities are clearly defined. ▸ Countries can recognize the assessment performed by one rapporteur or another country (i.e., inspection or assessment of an application) if they agree on the standards used for evaluation.

Of course, implementing a global system may be more difficult than establishing the Euro- pean system as there is no integration objective and therefore no economic/political pressures to create a single market, as was the case in Europe. However, it is possible if there is a political commitment. Scientists, regulators, and pharmaceutical companies have already shown, via their cooperation through ICH, WHO, and regional and bilateral collaborations, that they are ready for the next phase of harmonization.

Harmonization is a long process and the establishment of a global system will take time. The establishment of this global system can only be foreseen as a long-term stepwise project. It will require a lot of effort and commitment to progressively plan, organize, and implement several measures (at national, regional, and global levels) that will gradually structure international cooperation. Continuous political support will be crucial through the entire process. The politics should help in defining the scope and objectives of the cooperation, but the harmonization process should be left to technical and scientific experts. Without political support and a well-defined, science-driven, stepwise plan focused on public health, the establishment of a global system will remain elusive.

To ensure ultimate success, this harmonization process needs to evolve and take into consideration the economic, political, and other parameters (discussed in Part II-2). Indeed, these measures need to integrate the current political and economic context. Any short-term uto- pian measure or action that would not fulfill the current political and economic interests (e.g., developing a global supranational system that would give global approvals via a centralized INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 185 procedure without consulting the national or regional DRAs) would be unrealistic, unreasonable, and therefore not viable. Long-term major changes will only be possible when organization is in place and based on the (geo)political evolution, as was the case in Europe.

Also, to be successful and beneficial for everyone, the new global system needs to be customized and take into account the specific and varying needs of all countries. Countries are indeed very different in terms of medical practice, legal obligations, level of development, etc. This diversity has to be taken into account when developing the global system. More- over, it is important that this evaluation and the proposed improvements take into account the different regulatory capacity of all countries. Some countries do not have the expertise and resources to ensure that high standards are met. Is it therefore necessary to impose a costly investment to implement all global harmonized guidelines in all countries? The answer to this question is complex. Of course, certain global standards (e.g., GMP or GCP) need to be implemented similarly in all countries for ethical reasons, and also because medicines and data produced in one country will be used on a worldwide basis. However, it is not fair and/or practical to impose all new “high-level requirements” on developing countries. The cost of implementation can be too high for some requirements that may not be critical in a developing country as these requirements may require state-of-the-art science, equipment, expertise, and resources not available in these developing countries. A balance should therefore be found between the necessary implementation of high standards that not only support public health, but also the realities of developing countries. Increasing the requirements without benefit to public health could have major negative impact on the economy and development of these countries. Introducing high standards for all medicines without differentiation could lead to the failure of providing treatments for neglected diseases in developing countries [307]. The development and commercialization of these treatments are only interesting for small companies in developing countries (not multinational companies). Because they are relatively unprofitable for major pharmaceutical companies, R&D efforts aimed at new treatments for certain tropical diseases, as well as the availability of existing products, have decreased. If small pharmaceutical companies interested in developing and commercializing these medicines are limited by the need to comply to general high global standards (developed by ICH for all new medicines without distinction), such treatments will no longer be available. Therefore, careful evaluation of the benefit and potential negative impact of any new harmonization initiatives (especially global initiatives) needs to be conducted and mechanisms need to be in place to allow appropriate flexibility in the treatment of certain diseases.

In summary, the thorough evaluation of the current system outlined in previous sections makes it evident that harmonization of pharmaceutical regulations offers many direct benefits to both DRAs and the pharmaceutical industry, with beneficial impact for the protection of public health. Key benefits include better monitoring of medicines; preventing duplication of clinical trials in humans and minimizing the use of animal testing without compromising safety and effectiveness; streamlining the regulatory assessment process for new drug applications; allowing more informed decisions; and reducing development times and resources for drug development. However, although previous and ongoing harmonization and cooperation initiatives have already been beneficial, major improvements are still possible and 186 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS would clearly provide many advantages to all stakeholders. It would help developing countries by providing expertise, experience, and support, but it would also help developed countries by ensuring better control of the medicines used in their countries that were developed and manufactured outside their own borders. Today, a population’s health suffers or benefits not just from its own domestic regulatory environment, but also from decisions made outside the country. All the positive initiatives and dedication seen in recent decades at the national, regional, and global levels need to be leveraged so that this collective knowledge and these resources continue to improve global public health.

The establishment of a coordinated global pharmaceutical system would have a significant added value on the promotion and protection of global public health. The recommendations presented in Part III have been developed with the following questions in mind: What is the best structure and process for this global pharmaceutical system, and how can this framework/network be realistically implemented?

II-2) CRITICAL PARAMETERS AND INFLUENCING FACTORS FOR COOPERATION, CONVERGENCE, AND HARMONIZATION

Following the review of the status of all ongoing initiatives (Part I), we concluded that further harmonization would be beneficial for all stakeholders (Part II-1.4). However, to effectively discuss how to organize these next steps of harmonization, it is critical to first analyze the lessons of the past and the ongoing harmonization initiatives to understand what the critical parameters of harmonization and its influencing factors are. This analysis is essential to ensure success of the next necessary steps.

II-2.1) Critical Parameters for Cooperation, Convergence, and Harmonization II-2.1.1) Regulatory Capacity (i.e., Resources, Expertise, Infrastructure) A pharmaceutical regulatory system, supported by relevant legislation, is an essential component of a functioning healthcare scheme. This regulatory system includes, at the very least, the necessary legislation and regulations, and an authority that controls all pharmaceutical products through pre-marketing evaluation, marketing authorization, and post-marketing surveillance. It should also include an inspectorate, access to a medicine quality control laboratory, enforcement mechanisms, and safety monitoring [308].

Implementation of medicine policies has improved over the years [309], but there are still important problems. The level of effectiveness of national regulations varies widely across countries, as regulatory capacity is very different from one country to another. Some have mature, well-developed, and well-resourced systems, while others have weak or no regulatory system at all. For various reasons, many DRAs do not have the full capacity to perform all regulatory functions. In some countries, the inclusion of the regulatory functions as a department of the Ministry of Health also creates some challenges [310,311]. INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 187

As presented in Figure 4, there are important differences in regulatory capacity among all the WHO Member States [312].

FIGURE 4: Differences in Regulatory Capacity Globally.

20% 50%

30%

Developed Variable Limited

Source: Overview on medicines regulation: regulatory cooperation and harmonization in the focus, Presentation from Dr. Sam- vel Azatyan (WHO) at the WHO/UNICEF Technical Briefing Seminar on Essential Medicines Policies, 31 October – 4 Novem- ber 2011, WHO Headquarters, Geneva, Switzerland.

Even in a given region, regulatory capacity can vary. For example, Figure 5 shows that in Africa, among 46 WHO Member States, there are major differences.

FIGURE 5: Differences in Regulatory Capacity in the African Region.

33%

24%

39%

Developed Moderate Basic Limited

Also, personnel resources of DRAs vary from one or two people in small countries [313] to thousands of people in developed countries. For example, the US FDA employs approximately 15,000 people, with approximately 4,500 dedicated to the assessment and control of biologics and drugs [314,315].

This worldwide variation needs to be taken into consideration when discussing the organization of international harmonization and cooperation because harmonization projects require 188 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS time, money, resources, and expertise. Without regulatory capacity, it is indeed difficult for a country to be involved in harmonization initiatives. Moreover, due to these resource constraints, the requirements developed and successfully implemented in one country may not be equally successful in another.

Many governments do not seem to recognize the potential benefits of a strong medicine regulatory system, and do not make the necessary political and financial commitments to secure one [316]. However, in many instances, the issue is not a lack of political support, but a lack of appropriate mechanisms capable of translating the high degree of political commitment into concrete programs of community building and integration. In other words, the politicians are willing to initiate the activities, but they do not have the resources and infrastructure to support this ambition. Indeed, a lot of countries do not have the resources, capacity, and expertise to implement such a functioning regulatory system [317]. Their main challenges are the following: ▸ Costs associated with the development of a regulatory system, participation in harmonization, and implementation of agreed-upon common standards ▸ Limited human and financial resources and institutional capacity ▸ Lack of effective legislation ▸ Lack of technical expertise and a trained staff ▸ Lack of supportive environment (i.e., no policy framework and no legislation) and quality management systems

For example, according to Dr. José Luis Di Fabio (of the Area of Technology, Health Care and Research, Pan American Health Organization [PAHO]/WHO), 65% of the countries in the Americas have a regulatory authority, but most do not have the capacity to evaluate and regulate products [318]. The challenge in these countries is to develop the expertise and systems in order to raise the level of regulation and confidence and therefore allow recognition of this specific authority and system. Mutual recognition is indeed based on the confidence in all countries’ DRAs. This is why PAHO/WHO developed the “qualification procedure” for authorities.

Also, an assessment of medicines regulatory systems in 26 Sub-Saharan African countries over a period of eight years showed that, although structures for medicine regulation existed in all countries assessed (and the main regulatory functions were addressed), in practice, the measures were often inadequate and did not form a coherent regulatory system. Common weaknesses included a fragmented legal basis in need of consolidation, weak management structure and processes, and a severe lack of staff and resources. On the whole, countries did not have the capacity to control the quality, safety, and efficacy of the medicines circulating in their markets or passing through their territories [319].

This capacity issue is amplified by the fact that the sparse healthcare resources in these developing countries need to also manage other major public health issues. Most of the countries recognize the value of harmonization and cooperation (especially for developing countries), but the shortage of resources requires prioritization. Presently, harmonization is one of the priorities for developed countries (e.g., the EU or US are both involved in many global, regional, and bilateral initiatives), but it is not the first priority for less-developed countries. Their focus regarding the public health sector is, rightly, the prevention and control INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 189 of certain emerging/resurging infectious and communicable diseases such as dengue, chol- era, tuberculosis, Severe Acute Respiratory Syndrome (SARS), avian influenza, and typhoid fever, along with the prevention and control of HIV/AIDS. They also need to ensure access to quality essential medicines and low-priced generic products; in addition, the fight against substandard and counterfeit medicines is a growing issue.

In conclusion, it is evident that building regulatory capacity in developing countries is critical to allowing them to benefit from global harmonization, which in turn would benefit global public health. This support, with appropriate funding and resources, needs to be customized to their realities and needs. Complex systems and regulations from developed countries are not an appropriate response. The first focus should be to establish national and/or regional DRAs with appropriate powers in order to control the pharmaceutical market. Even with limited resources, this national or regional contact is necessary to liaise with other countries and develop a strategy and system based on a country’s individual needs. Many resources are available (e.g., via the WHO programs) to establish a pharmaceutical system and regulations appropriate to the level of development of the country [320]. To address the current issues in developing countries, it is also evident that national capacity building needs to be supported by regional and global cooperation and coordination.

II-2.1.2) Communication Effective communication enhances cooperation, which in turn facilitates harmonization, especially for some cultures.

One of the initial steps of any harmonization initiative is to identify the main contacts (with the appropriate decision-making powers) from each party and build a strong communication channel between the identified parties. Understanding each other’s needs and challenges facilitates the building of trust and confidence in each other. This establishment of relationships between parties is key to a successful collaboration, as it will define the communication style throughout the entire process.

Good communication is key during all steps of the harmonization process, from initiation to implementation of the harmonized rules. But building strong communication based on mutual understanding and trust takes time, and many parameters can influence it (i.e., culture, distance between partners, fluency in English, etc.). Development and training of regulators on cultural differences and foreign languages (especially English) is obviously an important prerequisite to collaboration. For example, one of the first measures that the PMDA put in place to increase its international activities was to strengthen its foreign language training and daily educational activities in order to help relevant staff members improve their foreign language skills [321]. In addition, PMDA has also made efforts to improve and expand the English version of its website to provide the latest information in English [322].

Communication also involves the “human” factor. This human interaction should not be underestimated because good relationships and understanding of each other’s differences can facilitate the discussions/exchange and vice versa [323]. Indeed, harmonization does 190 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS not only require infrastructure and resources, it requires willingness from the different players to communicate and exchange successfully. For example, during my research, regulators reported that some regulators from the US FDA or Health Canada have sometimes had more information and updates on activities happening in Europe than some small national Euro- pean DRAs due to their close and regular communication with the EMA or certain national DRAs. Of course, as already mentioned in the previous section, Europe is a great example of harmonization. But even in this region that is mostly harmonized and integrated in terms of pharmaceutical regulation, there is some miscommunication occurring.

Changes in international trade and data protection [324,325], brought on by increased globalization, must also be considered. More specifically, the protection of commercially confidential informationa is an important issue because it impacts the communication and exchange of information between countries. It is obvious that it is important that DRAs exchange the maximum amount of information to achieve effective communication. Today, however, pharmaceutical companies and manufacturers provide different levels of information and data to different countries due to the risk associated with the dissemination of trade secrets. There is a concern that if major DRAs share information with “developing” DRAs, a leak could occur and proprietary/confidential information could become publicly available (e.g., proprietary information on a brand could be available to generic companies in developing countries). Consequently, most of the agreements between DRAs exclude the exchange of trade secret information and proprietary information and data (i.e., under these agreements the DRAs cannot exchange proprietary information/data on specific products). Regulators believe that these limitations have an important impact on cooperation as they limit communication and the exchange of information with other DRAs. This limitation would become even more problematic if a global framework for the evaluation of medicines (i.e., a EU Mutual Recognition Procedure [MRP]-type procedure) was established.

Pharmaceutical companies are already evaluating the pros and cons to registering a product in certain countries, especially where there is no (or limited) data exclusivity legislation in place, even if there are patent laws, because such laws are not always respected [326]. In this case, the harmonization of regulation between countries will obviously not be beneficial because medicines will not be registered and, therefore, available globally. To respond to this situation, several countries (including China and India) have started to issue “compulsory licenses” for local generic makers to produce drugs that are still within the patent life [327]. This amendment of legislation will certainly increase the concerns of pharmaceutical companies regarding trade secret information. In the case of China, the legislation amendment permits domestic firms that receive the licenses to be able to apply for permission to export

a There is no unique and exhaustive legal interpretation of the concept of “commercially confidential information.” A 2007 EMA document (titled “Principles to Be Applied for the Deletion of Commercially Confidential Information for the Disclosure of EMEA Documents,” EMEA/45422/2006) considers that this information relates to either intellectual property “know-how” and trade secrets (such as formulae and processes) or commercial confidences (such as development plans). INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 191 their versions of the patented drugs for “reasons of public health,” which can cover a broad range of situations.

This problem of communication of trade secrets and confidential information therefore needs to be taken into consideration when developing global harmonization, worldwide cooperation mechanisms, and communication channels. Appropriate measures should be in place to balance the needs of developing countries to have access to essential medicines, but at the same time to avoid dissemination of confidential data that could impact innovation.

Finally, good communication between parties requires appropriate mechanisms and tools:

▸ Firstly, it is important before discussing harmonization to have a glossary to ensure that all parties use the same “language” because the different regulations impose conflicting definitions/terminology (e.g., definition of a medicinal, biotechnological, or biological product). The development of internationally recognized nomenclatures and classifications have been an important part of ICH and WHO work, and many tools have been developed (CTD, MedDRA, INN, ICD, ICF, ICHI, ATC, DDD, etc.). Moreover, the product classifications and/or nomenclatures need to be harmonized (especially in the case of an integration model) to facilitate communication and exchange of information between different national DRAs. Different brand/proprietary names of the same product in different countries can be confusing. Different nonproprietary names are a bigger problem. This issue has been partly resolved with the creation of the INN by the WHO. Indeed, before INN, the differences in nonproprietary names around the world were an issue (e.g., paracetamol vs. acetaminophen). These different names were given by different national bodies using different naming conventions. Today, INN is the worldwide standard for names. Unfortunately, in the US a USAN name is still a requirement (most other countries accept an INN-approved name). Moreover, USAN still has a different naming convention than the INN. Even if most of the new products have the same USAN and INN name, these different naming conventions can create some issues when a company wants to register a new name globally, creating conflicting feedback and positions that can take years to resolve.

▸ Secondly, harmonized and common training is very important between reviewers from different countries. This part of harmonization was recognized in Europe very early on in the process [328]. It facilitates the implementation of harmonized, high-quality performance standards, increases consistency in review/inspection, and decreases the discrepancies in the implementation of these standards.

▸ Thirdly, telecommunication and informatics infrastructures are important to ensure efficient communication. Appropriate communication tools supporting rapid and easy communication between parties (especially in the case of safety issues) need to be in place. In some countries, this communication (and exchange of information) is sometimes difficult due to the lack of infrastructure (e.g., computers). This lack of infrastructure has some impact on communication (i.e., connection to a safety/PhV database or clinical trial application). Basic communication tools such as communicating via e-mails or access to the Internet can still cause serious problems. 192 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS II-2.1.3) Definition of Clear Goals and Appropriate Planning Harmonization is a long and stepwise process that requires huge effort and focus!

All successful harmonization arrangements to date (i.e., ICH, EU, etc.) have taken a significant amount of time to develop. They required numerous meetings, technical discussions, and complex negotiations to resolve scientific differences and/or legal issues. If the process had moved too fast, people may have been concerned about certain issues (e.g., losing their independence), and the success of the project may have been impacted. Trust and acceptance needs time, as evidenced by the establishment of relationships and cooperation between the ICH and non-ICH regions. The GCG was created in 1999, and it took almost 10 years for the GCG/ICH to create real partnerships with the Regional Harmonization Initiatives (RHIs). This time was necessary to get to know one another and to understand each other’s needs and challenges in order to establish the high level of trust, understanding, and respect necessary before setting up practical actions for the implementation of ICH guidelines in non-ICH regions (via training, shared meetings, etc.).

The most prevalent reasons for failure of alliance and cooperation projects are related to the lack of upfront clear specific goals and appropriate planning and structure (i.e., underestima- tion of time and the skills required) [329]. To be efficient and avoid any confusion, it is therefore important to clearly determine up front the scope and objective of the initiative. This alleviates future discussion and allows the focus to be on actions. It is also critical to establish a plan, with intermediate goals, in order to remain focused on the ultimate objectives. For example, ICH has worked since its creation towards harmonization of technical topics, while the EU developed a structure and system for harmonizing the laws and regulation of its member countries to promote both public health and the free circulation of pharmaceuticals within the European trade areas. Though these two organizations both work towards regulatory harmonization, they are very different as they have very different objectives.

True harmonization is much more than common documentation and standards. The objective is to have similar or collaborative approaches to medicine registration that ultimately allows for mutual recognition and/or centralized registration (if desired) in the long term. But this is a long process and it requires effective communication and collaboration (e.g., information sharing and working jointly) to understand similarities and differences and to build trust. The reality of resources and efforts needs to be taken into account when establishing this plan. Therefore, project planning and management is key.

Major steps can be distinguished as follows: ▸ A general exchange aimed at enhancing collaboration and mutual understanding. ▸ The formulation of a framework agreement as the formal basis to start the harmonization process. ▸ The development of harmonized nomenclatures and procedures. ▸ The adoption of harmonized product and qualification standards. ▸ The mutual recognition of the harmonized standards. ▸ Compliance to apply consistent practices in selected areas. ▸ Maintenance and update of a harmonized topic: Harmonization of the regulation is not a one-time activity. Science is not static, so harmonization of the technical INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 193

requirements should not be static. Processes need to be put in place to ensure that when the fundamentals, assumptions, and science evolve, the agreement will be reassessed (and changed if necessary) to avoid countries evolving on their own.

Although the above sequence seems simple, in practice the tasks are tedious, and often initiate challenges that require systematic and thorough resolutions.

The African Medicines Registration Harmonization (AMRH) Initiative determined typical key milestones and timeframes for its regional medicines registration harmonization projects. This model, presented below in Figure 6, can be generalized to any other worldwide harmonization project (i.e., international, regional, or subregional). Although each harmonization initiative can differ in its specific content and duration (due to the baseline level of harmonization and other legal, cultural, and political factors), the concept and process is always the same. This process takes time and the coordination of communication and the predetermination of a structured plan and process is critical.

FIGURE 6: Model of Typical Key Milestones and Timeframes for Harmonization Projects.

Source: “African Medicines Registration Harmonization (AMRH) Initiative: Summary, Status and Future Plans,” NEPAD and WHO, November 2009. 194 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

II-2.1.4) Organization and Structure The review of ongoing harmonization initiatives in Part I showed that there are different models of cooperation based on the scope and objectives of the project. They can range from a simple technical collaboration to full harmonization and integration of systems and regulations. Depending on the model, different options can be selected to enhance regulatory cooperation, each of these options requiring a different degree of collaboration and time to impact [329].

All successful organizations have an appropriate structure to coordinate efforts (ICH, WHO, and Europe are good examples). Harmonization is an intense process that requires dedicated resources and infrastructure to be successful. Responsibilities, duties, and functions need to be defined and distributed appropriately between the bodies.

At the very least, a harmonization initiative needs to be supported by: ▸ An oversight committee (called a “Steering Committee” or “Governance Commit- tee”): The role of this committee is to set up priorities, coordinate actions and projects, and monitor those activities to ensure appropriate development towards predefined goals. ▸ A secretariat: The role of the secretariat is to support the administrative work and to provide project management. Transparency of the process requires publication of an agenda and meeting minutes, and dissemination of harmonized standards and decisions, etc.

Communication is also critical between the national institutions and regional or international initiatives. A designated contact needs to be established between national activities and regional/international discussions to avoid duplication of effort or even conflicting decisions. This contact is essential to (1) feed the regional and international discussion with specificities/challenges/etc. from the country; and (2) ensure good implementation of agreed-upon harmonized standards.

Finally, the structure and organization of harmonization initiatives also needs to evolve as the program evolves. A specific structure may be ideal for certain phases of harmonization/cooperation but not relevant for others. An early initiative needs a limited relationship at a high level, and the involvement of a finite number of people. However, the integration phase requires more stable and defined institutions. For example, SADC’s structure evolved over time. It started as a “Coordinating Conference” (with limited institutions and focused on coordination of national actions) before becoming a “Development Community” (with defined institutions and a focus on integration). To support this evolution, SADC’s structure changed over time, and is regularly evaluated to ensure that it adequately supports the initial objectives.

II-2.1.5) Implementation and Monitoring After reaching agreement, the harmonized rules and standards need to be implemented, a key phase of any harmonization initiative. However, this ultimate step is not simple, and disharmony could still exist if the agreement is not adopted consistently in all regions. INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 195

Implementation of harmonized standards/requirements by each country can be more difficult than creating them. The results of such efforts depend on the willingness and commitment of all stakeholders. Many factors can affect the actual implementation of a standard, and therefore the overall harmonization process: ▸ The lack of resources, expertise, systems, or the organization necessary for the implementation. ▸ Inaccurate translation of a rule or technical recommendation. ▸ A different understanding of the rules due to cultural differences. ▸ The need for major modification of legislation not supported by the political system or legislators. ▸ A lack of pragmatism/practicality (i.e., if the rule is too vague, unclear, too theoretical, or leaves too much flexibility to the parties). For example, the texts relative to the arbitration process in Europe allow a country to refer a matter to the EMA/CHMP in case of disagreement during an MRP/Decentralized Procedure only if there is a potential risk to public health. However, this notion of public health risk is vague and has allowed countries to abuse this clause to trigger this procedure for any disagreement with the Reference Member State (RMS) evaluation.

All these factors can indeed impede the implementation phase or create diverse interpretations of recommendations/guidelines by the different parties (which is not the objective of a harmonization process). Diverse interpretation of a rule can lead to worsening of the situation and require additional efforts from industry to comply with a new standard.

There are many examples of harmonization initiatives that did not deliver the expected value due to misinterpretation of the rules/standards. For example, ICH has developed Guideline E5 to standardize the evaluation of ethnic factors and therefore avoid duplication of clinical studies. While industry and regulatory authorities have agreed that this guideline represents the best available model for developing clinical evidence of the safety and efficacy of new therapies across different ethnicities, its implementation has been problematic. Within the ICH countries, the challenges tend to be caused by ambiguities and lack of direction as to the sufficiency of data that would allow for extrapolation of findings to the new region. In emerging markets (i.e., non-ICH countries), the adoption, adaptation, and implementation of the principles outlined in ICH E5 are more problematic and tend to be much more systemic. For example, many of the emerging markets simply require that a bridging study always be performed [330].

To avoid these implementation problems, the strategy of implementation needs to be planned early. Goals and plans need to be agreed upon up front (before the harmonization process starts), and this ultimate goal needs to be kept in mind throughout the harmonization process. The plan needs to evaluate the benefit of the project (e.g., with regards to public health), but also assess its potential impact (on legislation and current rules) to anticipate potential limitations in its implementation. A great common standard will never be used if its implementation requires an expertise, a legal framework, an appropriate system, and/or resources not available in the countries/regions involved. In the case of harmonization of technical standards (i.e., ICH), the preparation of a successful implementation begins with the selection 196 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS of the topics for harmonization. Technical guidelines must be value-added and able to be implemented (it should not remain a theoretical exercise). To facilitate implementation, it is also critical to build a scientific consensus among all stakeholders (consultation needs to happen early).

Several actions can facilitate the implementation phase:

▸ Adequate budget and time needs to be allocated to this last step of harmonization. For example, the Korean Ministry of Health invested in training, facilities, operation systems, etc., between $0.5 to $1 million/center/year for five years in nine clinical centers to support the implementation of GCP [331].

▸ Appropriate coordination and structure need to be established to support proper implementation. The success of ICH has been possible through effective and consistent guideline implementation (e.g., with the creation of IWG). Also, the SADC has implemented “National Committees” that are present in each Member State. This model is very interesting and may help other worldwide initiatives to implement the agreed-upon common rules. It creates a contact point at a more local level and therefore improves understanding, monitoring, and support for the implementation.

▸ Direct adoption of standards without regional/local “adaptation” needs to be favored. Sometimes a rule cannot be implemented in a country without modifications (e.g., due to a lack of resources/expertise). Some non-ICH regions/countries have been adopting and implementing the exact ICH guidelines. However, others have been adapting some ICH guidelines. These adaptations can clearly create some harmonization compli- cations. It is therefore crucial to involve all regions early in the discussion to evaluate difficulties of future implementation. During the harmonization process, the working group needs to evaluate if the guidelines will not be applicable to certain regions/countries (or will require a certain level of adaptation).

▸ Legislative texts or agreements need to be quickly followed by detailed guidelines, standard operating procedures (SOPs), manuals, and/or questions and answers (Q&As), etc. These documents, clarifying the rules, reduce the risk of misinterpretation and/or conflicting interpretations of rules and agreements.

▸ Transparency and appropriate communication needs to occur throughout the process involving all stakeholders early on (i.e., regulators, but also those affected by regulation such as industry, the public, etc.) to avoid major surprises at the time of implementation. The process should ensure the issuance of notice of a proposed regulation with a sufficient consultation period to [332]: • Allow all stakeholders to have access to the draft proposals and to submit comments. • Adequately consider and analyze those comments. • Respond to significant points and explain the rationale for revisions when adopting the final regulation. INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 197

Openness and transparency in the preparation and application of regulations are also fundamental to ensure public confidence. Allowing people to review/comment and participate in the preparation of the harmonized rules and standards will clearly reduce surprises and help with implementation. In addition to promoting transparency, relevant consultation with all parties ensures that all perspectives on the issue have been considered, highlights alternative approaches and enhances awareness (which facilitates implementation and encourages compliance). ▸ Training needs to be organized because implementation is indeed much more important than publishing guidelines. The promotion of common understanding and training are key. All stakeholders need to become familiar with the new rules. Regulators and industry need to be trained, but also any other party affected by the rules (i.e., investigators, ethics committees, etc., in the case of GCP, for example) ▸ Implementation of new requirements needs to be monitored and corrective measures need to be taken if necessary. It is indeed crucial to ensure that everyone implement the rules and standards correctly, but also that all stakeholders continue to have a good understanding of the rules over time, especially when there are new versions and modifications of the rules.

PhRMA and the US FDA developed a simple methodology to assess the implementation, application, and utilization of ICH guidelines. This methodology, presented in Figure 7, defines six steps (Topic Selection, Dissemination, Publication, Training, Implementation, and Management) and can be applied to any harmonization of technical standards. For each step, relevant processes and actions are defined.

FIGURE 7: Implementation Process Flow.

ssecorP Implementation Step snoitcA

Good guideline topic Guideline must be value- selection Topic Selection added and ‘implementable’

Use multiple avenues Formal communication (Journals, Websites, process Dissemination Meetings)

Active distribution (using Distributed to Targeted local regulatory Publication Stakeholder and discussed procedures) at relevant meetings

Educating appropriate ‘ Early, often, all; within and users (Regulators and Training across organizations Industry)

Integrated process-address Putting guideline ‘theory’ Implementation questions/issues; Need into ‘practice’ appropriate resources

Active monitoring Feedback to Steering of utilization Management Committee (for potential corrective actions)

Source: Presentation on Strategy of Implementation by CAPT Justina A. Molzon at the IV Pan American Conference on Drug Regulatory Harmonization, Dominican Republic, March 2005. 198 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

This methodology is an important tool to provide adequate assessment of implementation and resolution of potential problems that may occur during this implementation. The analysis also demonstrates that processes and systems need to be in place and resources allocated to ensure adequate implementation of agreed-upon standards.

II-2.1.6) Involvement of All Stakeholders There are many individuals or organizations that are dependent on or are affected by the final product or output of a harmonization or cooperation project (i.e., national DRAs, regional and global bodies, industry, academia, patients, etc.). The early identification and involvement of all these stakeholders in the process increases the chance of success. Of course, involvement of stakeholders is tailored to meet the circumstances. Some stakeholders may be more crucial (i.e., DRAs) and therefore more involved (or involved at an earlier stage) than others, but this has to be clearly defined to avoid confusion. Roles and responsibilities of each stakeholderb need to be determined early and decision makers identified. Insufficient involvement and ineffective communication with stakeholders can lead to project failure. Involvement of the inappropriate stakeholders in a project may also reduce the value of the harmonization and may lead to criticism in the end.

Keeping all stakeholders informed and/or involved throughout the process has several practical advantages. First, it is important to take into consideration the different needs and challenges of all stakeholders when developing the objectives and scope of a harmonization project. This helps define practical and realistic goals. Second, keeping all stakeholders informed throughout the project builds trust and support in the process and decreases the risk of surprises at a late stage. Third, engaging stakeholders in the process through good management of their expectations develops their active interest and commitment to the project. This ensures that all parties will be actively engaged and ensures smooth implementation of harmonized standards.

It is also obvious that the degree of involvement and interaction between different stakeholders with varied backgrounds, experiences, and expertise leads to better standards that are more likely to be adopted and implemented. Also, in some countries, there is a lack of centralization and coordination of activities. In these countries, local authorities are not always closely collaborating with federal bodies, especially in the case of inspections [333]. It is therefore important to make sure that all the players in a system are involved and aware (not only the central DRAs) to ensure good implementation of common standards.

Today, there are cooperation and harmonization initiatives that involve only regulators (e.g., EMA, WHO–ICDRA) versus other initiatives that involve many players such as academic representatives and industry (e.g., ICH, APEC). Involvement of public interest groups (i.e., patient associations) is also very important to increase transparency and combat corruption in certain countries. b Several methods allow clear and early definition of roles and responsibilities, such as the RACI model that defines who is “Responsible,” “Accountable,” “Consulted,” or “Informed.” INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 199

The ICH process is a good example of a harmonization initiative that understood early on that its activities necessitated the involvement of different stakeholders. The success of this unique initiative that includes both regulators and industry representatives has shown that the implementation of agreed-upon standards is indeed facilitated if both industry and DRAs share responsibility for decisions or actions. Moreover, the inclusion of observers from non- ICH regions and then RHIs and some individual DRAs (of countries which are a source of Active Pharmaceutical Ingredients [APIs], medicinal products, or clinical data for the ICH regions) also promote and facilitate the implementation of ICH standards. The same goals (developing and implementing harmonized standards and guidelines) would certainly be much more difficult to meet if this process had been managed by the DRAs of the three ICH regions only.

Finally, it is interesting to note that in the past decade many foundations and philanthropic organizations (i.e., the Bill and Melinda Gates Foundation, the Clinton Foundation, etc.) have been associated with harmonization work, especially in Africa. These new participants should continue to be further involved in collaboration initiatives as they bring additional resources and financial support. However, this growing complexity in the institutional landscape for global health, characterized by more partnerships, foundations, financial instruments, and bilateral and multilateral agencies that influence global health policy making, need to be coordinated. The challenge is to manage complexity and seek creative solutions that promote convergence around common goals. There are also opportunities to improve collaboration and use innovation at the national and international levels to fight inequities and to continue progress for better health [334].

II-2.1.7) Voluntary Cooperation versus Legal Commitment Enforcement of harmonized standards and compliance to these standards are an important part of a harmonization initiative.

Today, most of the current harmonization processes are done on a voluntary basis (ICH, PAN- DRH, APEC, etc.). However, legal enforcement of harmonization (i.e., creating a mandatory implementation of a harmonized topic) facilitates and accelerates harmonization. The Euro- pean experience has shown that having a legal basis for a cooperation initiative allows deeper harmonization and quicker implementation of common rules.

Of course it is more difficult to establish legal obligations in a nonintegration initiative. However, even in this situation, legal enforcement is possible if appropriate agreements are signed. MRAs can indeed be signed by one or more parties to mutually recognize or accept some or all aspects of each other’s requirements. Several examples demonstrated that the signature of such legal texts (especially when these agreements are comprehensive, technical, and easily implementable) promote further harmonization or cooperation. For instance, the signature of the Framework for Advancing Transatlantic Economic Integration between the European Union and the United States of America in 2007 by EC President José Manuel Barroso, German Chancellor Angela Merkel, and US President George W. Bush accelerated regulatory collaboration between the EU and US. Also, the implementation of the SADC pharmaceutical cooperation program was facilitated by the signature of the health protocol 200 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS because this supportive legal text (defined in the SADC Treaty) was binding for the SADC Member States. Its Article 29 requires the Member States to cooperate in the harmonization of procedures of pharmaceuticals, quality assurance, and registration, and also in the production, procurement, and distribution of affordable essential drugs.

II-2.2) Factors Influencing Cooperation, Convergence, and Harmonization in the Pharmaceutical Domain Intrinsic parameters reviewed in Part II-2.1 are very important to ensure success of a cooperation initiative. However, we will see in this section that other factors can also drastically influence the harmonization projects (including scientific debate on technical requirements). It is therefore important to take them into account when establishing cooperation and harmonization projects.

II-2.2.1) Globalization Globalization is the primary factor that has accelerated and influenced convergence and harmonization of pharmaceutical regulations in past years.

Globalization is a fact of the 21st century. It brings many opportunities (e.g., access to new culture more easily) but also many challenges. The emergence of worldwide health threats such as the increasing number of counterfeit medicines or pandemic influenza (that can spread globally in a few days [335]) cannot be controlled at the local level. Also, the impact of the Internet on global access to information and markets has introduced significant new challenges and questions on the relevance of current regulatory systems. Borders count for very little in the light of these challenges.

Moreover, the globalization of the general economy (with increased travel of people and exchange of goods, finance, and information around the globe) and the modification of economic powers forced pharmaceutical companies to revise their strategy, processes, and management approach [336], which in turn triggered the globalization of the pharmaceutical market (i.e., development, manufacture, and distribution activities). This fundamental change in the global economic landscape requires countries to change their regulatory approaches to promote and protect the health of their population. For example, 24 million shipments of US FDA-regulated products were imported into the US in 2011 from 228 foreign jurisdictions. This represents a four-fold increase over past decade [337]. This trade activity should continue to increase as the most important consequences of the pressure to reduce costs and increase productivity will continue to move manufacturing activities to new locations, looking to global supply chains to reduce costs.c Just as cost pressures will only become more severe over time, companies will indeed continue the movement of manufacturing and production activities to lower-cost countries for the foreseeable future [338]. It is expected that eventually the growth in imported US FDA-regulated products will outpace the growth of US domestic production. According to some estimates, imports of US FDA-regulated c For example, the cost of formulation of an Active Pharmaceutical Ingredient (API) can range from 15% to 40% less to produce in India as compared with the US. INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 201 products may triple by 2015 compared to 2007, corresponding to a 15% annual growth rate. Companies will not only be producing more products abroad, but these products will follow complex paths through multistep supply chains [339]. Today, it is not uncommon that raw materials, intermediates, excipients, and finished dosage forms are all manufactured in different countries.

Similarly, clinical studies are increasingly being conducted on a multiregional, if not global, basis [340]. About one quarter of all clinical trials in the EU are also performed in the third world [341], and approximately 60% of patients enrolled in pivotal trials included in Euro- pean Marketing Authorization Applications (MAAs) come from outside Europe [342]. Also, the number of US Investigational New Drugs (INDs) and applications for marketing approval supported by foreign clinical trials has increased in recent years [343]. Even if North Amer- ica and Europe have been the leading destinations in terms of trial numbers, a continuing shift towards other regions is expected [344,345]. Developing countries are increasingly more involved in these global studies [346]. Of the 149,672 studies listed on the US registry of clinical trials, a significant number have sites outside the US. Plate 7 shows the locations of these studies in 185 different countries (from all regions of the world).

In addition to the financial incentives, the developing countries offer a large pool of patients and the possibility of finding untreated or “naive” patients more easily.d Finally, many countries have been developing or enhancing their regulations (a majority of the time based on ICH recommendations) to attract clinical research and improve credibility of data and reported results [347,348]. For example, in Korea, the Korean Good Clinical Practice (KGCP) was established in December 1987, but has only been enforced since October 1995. In 2000, the KGCP was revised to harmonize with the ICH E6 guidance. Moreover, many other improvements have been implemented since 2000. All these improvements have translated to a significant increase of clinical trials (domestic and multinational) approved and conducted in Korea (from 31domestic studies in 1999 to 229 domestic plus 210 multinational studies in 2010 [349]).

Both India and China are the current leading destinations for pharmaceutical companies as they offer a number of advantages, most notably the lower cost of skilled labor. India in particular trains six times the number of chemists annually compared to the US, and companies can access this talent for 10% of the cost for the same in America. In total, estimates indicate that bulk manufacturing in India can reduce costs for US and EU companies by 30% to 40% [350]. Thanks to these major advantages, the Indian pharmaceutical industry has already established itself as a key player in the manufacturing arena, with almost half of the active pharmaceutical ingredients worldwide being produced there. Finished products, especially generics, are also very likely to come from countries with rapidly expanding pharmaceutical manufacturing, such as India [351]. Finally, the service industry from drug discovery to clinical development, data management, and statistical analysis, has also seen exponential growth with investment from practically all major global pharmaceutical companies [352]. India’s Phase 3 trials are growing seven times faster than the global average [353], supported d A naive patient is a patient that has never been administered the investigational medicines. 202 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS by the attractiveness of its over 1 billion people, 15,000 hospitals, 900,000 hospital beds, and 700,000 physicians [354].

However, India’s attractiveness is today not only related to the fact that it is a location for cost-effective pharmaceutical product manufacturing and development. It has become a key market for finished products because the Indian middle class (estimated to be about 30% of the total population, making it more than 300 million, equivalent to the total US population) is now experiencing increased incidences of indications traditionally considered diseases of the West (e.g., hypertension, cardiovascular diseases, allergies, central nervous system diseases, etc.) and has the economic means to afford expensive Western therapies. Its growing economy, combined with the important regulatory changes in India over the past several years [355] and its desire to harmonize its regulation with ICH majors and other worldwide authorities, will certainly continue to position India as one of the new key countries for pharmaceutical companies [356]. Finally, it is also important to note that the presence of Indian generic firms in developed markets have quickly increased over the past several years [357].

The pharmaceutical market in China has already expanded over the past several decades with important investments from international companies [358,359]. From its 2003 ranking of ninth place, it represented the fifth largest pharmaceutical market in the world in 2008, and it is expected to continue to increase. It was also listed as the 13th country involved in clinical trials in 2009 (which represents an important increase compared to 2005 when it was listed as 29th) [360]. Also, Chinese pharmaceutical invention patent applications went from approximately 1,000 in 1999 to more than 9,000 in 2006 [361]. More cooperation is expected between the Chinese State Food & Drug Administration (SFDA) and foreign regulators with the international background and experience of the newly nominated SFDA Chief [362]. This will certainly continue to increase the influence of China on the global pharmaceutical market.

In addition to the impact of India and China on healthcare of developed countries, the low price of the medicines manufactured in these countries also impacts the public health of developing countries. The small developing countries are overly dependent on these low- price imported drugs. For example, about 85% of the generic antiretroviral products used in the SADC region are imported from India (and 15% are manufactured within the SADC region) [363]. With the global financial crisis affecting health budgets, it is expected that other countries will also increase their relationship with these emerging countries to reduce the prices of their imported medicines currently sourced from developed countries [364].

Finally, the increase of exchange between population/countries has created new needs and therefore new risks. For example, the growing demand for foreign traditional medicines in the Western environment is associated with new specific risks [365].

To summarize, globalization of the pharmaceutical market brings many opportunities to enhance global public health by forcing worldwide authorities to work together, but it also raises many specific concerns. The movement of clinical research to developing countries INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 203 presents particular challenges, such as safeguarding the integrity of data, ensuring that equivalent ethical standards are met, the threat of double standards, and the need to have confidence in local regulatory and supervisory arrangements [366,367]. Acknowledging that the inspectional resources of the US FDA can inspect only 1% to 2% of clinical trial sites [368], it is clear that such challenges cannot be resolved by an increase of inspections.

Another area of growing concern relates to the increased manufacturing of products in developing countries, and in particular the potential for substandard material to enter the supply chain [369]. Several problems have indeed been associated with data generated from foreign countries or with imported products. It is therefore critical to ensure that products manufactured in foreign countries and data from clinical research conducted in third-world countries comply with international standards. Considering the huge number of foreign manufacturing sites or global studies, no DRA can adequately keep pace with the pressures of globalization alone. It is indeed impossible for them to rely on their own inspectional resources. For example, even the US FDA, which is the biggest DRA in the world with a total annual budget of approximately US $4.5 billion [370,371] and an Office of Regulatory Affairs [372] of approximately 5,000 employees [373], does not have the resources to inspect all foreign drug establishments. It has been estimated that at current rates it would take an estimated nine years for the US FDA to inspect every high-priority pharmaceutical facility just once [374].

In this context, the most effective way (and certainly the only way) to resolve these concerns brought on by globalization is to increase cooperation between DRAs and harmonization of standards between countries.

II-2.2.2) Evolution of the Communication between Worldwide Authorities Communication between worldwide DRAs has increased tremendously over the last decade. Globalization has indeed encouraged regulators to work and communicate outside their country and region to fulfill their mission of public health protection, and DRAs have increasingly recognized the value of supporting their internal programs through international collaboration.

As explained in Part II-1, this increased communication and harmonization over the past several years has ultimately been beneficial for all players in the pharmaceutical sector (e.g., patients, regulators, and industry).

Initially, exchanges between worldwide DRAs were focused on major public health concerns (i.e., primarily safety issues) with approved products or with issues related to the development of new and innovative products. These communications were generally handled at a high level by the DRAs, did not occur frequently, and followed a formal/official process. With the implementation of specific Memorandums of Understanding (MoUs) between agencies, communication has improved considerably between major worldwide authorities (e.g., US FDA, EMA, Health Canada, MHLW, TGA, and AMSM [formerly AFSSAPS]), and this has expanded both formal and informal communication at many levels of the DRAs (including 204 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS scientific and reviewer staff). In Europe, more open exchanges between national regulatory agencies were fostered through the formation of the EMA in 1995. Additionally, while they are not DRAs as such, bodies such as ICH and WHO have served as an international forum for the establishment of common regulatory principles as well as important international networking opportunities for regulatory scientists. Through these different levels of interaction, professional relationships and trust has been developed over time between key regulatory scientists and their respective agencies. Today, as a result, more regular formal and informal communications occur between worldwide DRAs and their respective staffs on many different topics. These topics include major concerns, but also other subjects related to specific products or their testing, registration, or post-marketing activities for all types of products. This type of interaction is now becoming integrated in the day-to-day activities of many of the major worldwide DRAs.

As an example, I have been involved in meetings with different worldwide DRAs for approximately 15 years. During that time, none of the agencies I have met indicated that they were exchanging information or communicated with other worldwide DRAs on the topics covered during our meetings (I acknowledge that they may have had these discussions without informing me). However, for the first time, during a Sponsor and Agency meeting in Sep- tember 2009 with one of the major worldwide regulatory agencies, an Agency representative formally asked for authorization to communicate and exchange information with his counterpart from other major worldwide DRAs that were also involved with the topic covered during the meeting. Note that the subject of the meeting related to a manufacturing/testing change and not the development of a new or innovative product. This example clearly shows the evolution in the way of thinking concerning international cooperation, and the increase of communication and exchange between worldwide DRAs.

In addition to the natural but slow evolution of the communication between worldwide regulators described above, recent major events that required global coordination of public health and regulatory actions have tended to accelerate this evolution, such as: ▸ After the terrorist attack on the World Trade Center on September 11, 2001, and the subsequent US anthrax attacks and “copycat” bioterrorist pranks in Europe and North America, several major worldwide public health and regulatory authorities coordinated their actions against the perceived bioterrorist threats. ▸ In 2002/2003, the SARS crisis also required a worldwide coordination of efforts to limit the propagation of the virus and its consequences, which was greatly aided by the WHO network with the support of national public health and regulatory agencies. ▸ Between 2003 and 2005, an increased scientific and public awareness of the pandemic potential of H5N1 drove numerous exchanges between worldwide public health and regulatory authorities to deal with that potential threat. ▸ More recently, in 2009 the H1N1 outbreak resulted in one of the most urgent and widely coordinated international responses to a pandemic in recent decades. The global propagation of the virus again required globally coordinated actions and communication between worldwide DRAs. However, compared to previous crises, these actions and communications were not limited to the national management of the crises and the coordination and management of safety measures. For the first INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 205

time on such an urgent and large scale, several worldwide DRAs (including the US FDA, EMA, national European DRAs, Health Canada, TGA, MHLW, and China’s SFDA) communicated in general terms with regard to the development of vaccines, discussed issues with international potency standards and testing, and exchanged updates on when products might come to the market and the status of clinical trials related to these vaccines. Note that product-specific trade secret information was specifically excluded from these multilateral discussions due to the lack of legal framework (however, such information may have been discussed during separate bilateral and/or trilateral discussions between DRAs that have specific MOUs and/ or confidentiality agreements in place [375–377]). This multilateral activity was coordinated through WHO [378] and supported by the national agencies involved. The purpose of these important exchanges was to support national and international emergency preparedness and response, and individual jurisdictions proceeded with manufacturing and regulatory paths that they felt were most appropriate to their respective national needs. While different vaccine choices were made in various countries in the time leading up to the H1N1 pandemic with regard to the use of vaccine adjuvants, one result of international regulatory collaboration subsequent to the pandemic was the effort to develop international guidance through WHO on the use of vaccine adjuvants.

Even though cooperation has increased over the past decade, it is clear that the level of, and participation in, worldwide harmonization and cooperation is different for each country. Har- monization and cooperation is a long, step-by-step process requiring many prerequisites. The willingness of worldwide authorities to exchange and cooperate with their peers depends on the following factors: ▸ Memorandum of Understanding (MoU) signed with other countries ▸ National laws and regulations ▸ General level of comfort based on cultural history and previous experiences in cooperation (e.g., an EU regulatory representative would have had more experience with regulatory exchanges with comparable external DRAs than a US FDA representative, due to the former’s experience operating within the EU regulatory system) ▸ Individual behaviors (this is still important, but with enhanced international cooperation increasingly becoming an objective in key agencies, the culture in agencies is changing)

To conclude, it is obvious that communication between worldwide agencies will continue to increase. This continued evolution seems inevitable, and most of the players agree that such communication has been beneficial to public health in our increasingly global environment. Moreover, the above examples demonstrate that the rapid and extensive coordination that was achieved with the H1N1 outbreak and the more sustained efforts to develop international guidance through bodies such as ICH and WHO clearly illustrate the large- scale change that is taking place in international regulation. These types of technical and regulatory international cooperation are beneficial for everybody (especially the patients), and do not alter the ultimate responsibility of each country to render a decision for a specific product. 206 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

The H1N1 case demonstrated that while initial differences in opinion with regard to the risk/ benefit evaluation for adjuvanted H1N1 vaccines resulted in different choices with respect to the use of these products at the time, collaboration in this area has driven the development of an international guidance on adjuvants.

II-2.2.3) Political Decisions and Commitments Political stability is a prerequisite for the establishment of a developed pharmaceutical system. It is obvious that developing countries during war will have difficulties in developing and implementing appropriate regulations and structure to control their pharmaceutical market. These countries have other priorities and cannot devote adequate resources to the pharmaceutical sector and the harmonization initiatives such as ICH. For example, the Southern African Development Coordination Conference was created to focus on political liberation of the region and to lessen economic dependence on the then apartheid South Africa. It was only with the achievement of political independence by SADC Member States [379] and the end of the South African apartheid regime in 1994 that this organization became a “Development Community” (SADC). Economic integration (and all efforts towards harmonization) could then really begin in Southern Africa.

In some countries, corruption and conflict of interest can also weigh against harmonization and globalization of the pharmaceutical market. For example, it is expected that the recent major political changes in several Arab countries will ultimately have an impact on the pharmaceutical regulations and systems of these countries.

However, political stability in a country is not sufficient to adequately support the development of a pharmaceutical system. It is well established that no national DRAs will be successful in implementing pharmaceutical regulation if they do not have full and continuing government support [380]. To perform effectively, DRAs must have the necessary political support, legal power, human and financial resources, and independence in decision making [381].

Many events have demonstrated the critical influence of politics on the establishment of pharmaceutical regulations, including: ▸ The mediator event in France that triggered political decisions that significantly changed the French pharmaceutical regulations and system [382,383]. ▸ The delay in the availability of biosimilars in the US, compared to many other countries, is due to a lack of political decision. In this case, the long political debate and multiple delays in passing laws delayed the registration of such products in the US for many years. It is important to note that this delay also delayed the harmonization of the requirements on a global basis as the lack of US framework prevented any global discussion on this subject. ▸ One important strategic change in the US was the approval of embryonic stem cell research that followed the election of President Barack Obama. Such research was forbidden under President George W. Bush’s administration. It was authorized INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 207

three days after the start of President Obama’s administration, with the US FDA approval of a Phase 1 human study conducted by Geron Corporation to test the safety of a treatment derived from embryonic stem cells for patients with spinal cord damage [384].

Political decisions and commitments are also vital for the harmonization of regulations between countries.

Most of the harmonization initiatives started with political decisions. For example: ▸ European harmonization is a direct consequence of the political decision to establish the European Union. ▸ The establishment of WHO and its pharmaceutical programs was a political agreement between countries. ▸ The foundation for advanced technical and regulatory cooperation and harmonization between the EU and US came from the signature of the Framework for Advancing Transatlantic Economic Integration between the European Union and the United States of America by Commission President José Manuel Barroso, German Chancellor Angela Merkel, and US President George W. Bush (at the EU–US Summit on April 30, 2007).

This political support is also critical for the entire harmonization process, including the implementation of recommendations. It needs to define appropriate priorities, to devote appropriate resources, and to support the project administratively and financially. Har- monization is indeed not free. Even if it is believed that more efficient use of resources will reduce costs for the long term, cooperation and harmonization efforts require investments (i.e., time, resources, and budgets for communication and travel). A recurring theme in all harmonization initiatives is the enormous pressure on resources at every level. The creation of the European pharmaceutical system is a good example. The audit of this system in 2000 by Cameron McKenna and Andersen Consulting [385] has clearly shown this important need for resources. Authorities noted the scarcity of expert assessment resources and suitably qualified people for the large number of working groups and other demands that the pharmaceutical systems made of national DRAs. Even if the purpose of the creation of the EMA and the new regulatory procedures was to use resources more efficiently, in reality, pan-European regulation has seen no real dividends in terms of cost efficiencies through economy of scale. On the contrary, the political pressure for the involvement of a national authority in every policy and assessment activity that may affect its market and citizens, coupled with the increased complexity of the process of regulation, has increased the administrative burden of European regulation as well as its sophistication. One CPMP member expressed the view that the centralized system in the EU was capable of providing the best regulatory assessment in the world because it encouraged networking of experts across Member States, but it was admitted that the system was also very expensive to run as a result. National authorities were under significant resource pressure and the relative funding of the centralized system by the Community and indirectly by national agencies was an increasing cause for concern in some Member States. 208 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

Political support is always necessary and a driver of the harmonization, but it can have different objectives: ▸ Economic reasons: to create a free trade area or a single market with other countries. ▸ Increase communication with other countries: to cope with increased globalization of the pharmaceutical environment and enhance public health. ▸ Geopolitical reasons: developed countries support global harmonization to facilitate capacity building and control of the pharmaceutical market in developing countries. This support also benefits developed countries because it allows better control of products/data from these countries.

In Europe, the implementation of pediatric regulation is a good example of how political decisions can influence the regulation and harmonization/cooperation between countries to enhance public health. Prior to the introduction of the European Commission proposal (Sep- tember 29, 2004), there were no adequate national measures to support the development of high-quality and adequate medicines for children. More than 50% of the medicines used to treat children had not been tested and were not authorized for that use [386]. Following a political decision, the EU regulation created these requirements and obligations. Following the implementation of this text on January 26, 2007, pharmaceutical companies started to invest in pediatric development and included this new component in their strategy. In 2009, the EMA received applications for Pediatric Investigation Plans (PIP) relating to 364 clinical indications.

However, although political support is clearly important, it is not automatic and easy to achieve.

Firstly, the priorities of ministers of health depend on the health issues in that country. In the developing countries where there is an important problem of HIV/AIDS (especially when this public health problem is coupled with an important poverty issue), health resources will be rightly dedicated to the prevention and management of this disease versus the harmonization of the pharmaceutical regulation with other countries and regions.

Secondly, national/regional protectionism can also delay or limit harmonization efforts. In this case, the lack of political commitment, sometimes exacerbated by lobbies (that benefit from loose regulation and lack of global harmonization), is a response to two political considerations:

▸ Loss of sovereignty: Any harmonization process raises questions about sovereignty as harmonization of standards implies a certain loss of control for the countries involved. It is obvious that the influence of politics is even more important in the case of MRAs or integration models. These models of harmonization raise practical and obvious concerns regarding loss of sovereignty. Resistance to relinquishing power can result in a clear obstacle to harmonization and cooperation. The joint Australia New Zealand Therapeutic Products Agency (ANZTPA) project is a good example where politics (and also economic factors) can interfere with harmonization [387]. INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 209

▸ Industrial competitiveness: Some countries may see harmonization of regulation and cooperation with other countries as a concern for competitive advantage and want to protect the competitiveness of their own industry. For example, regulation on advanced therapy is one topic on which most developed countries in the world should fully collaborate because this is a new, important, and promising topic without historical differences that may be difficult to harmonize. However, due to the huge potential for industry, each country or region needs to balance cooperation/harmonization with competitiveness/stimulation of its own industry regarding new technologies. For example, in 2007, the EU institutions agreed on a Regulation on advanced therapies (Regulation (EC) No 1394/2007), designed to ensure the free movement of advanced therapy products within Europe, to facilitate access to the EU market, and to foster the competitiveness of European companies in the field. Indeed, the lack of an EU-wide regulatory framework for advanced therapy in the past led to divergent national approaches which hindered patients’ access to products, hampered the growth of this emerging industry, and ultimately affected EU competitiveness in a key biotechnology area [388]. This regulation has special incentives for small- and medium-sized enterprises.

To conclude, political support is clearly a key element to ensure a successful harmonization process. Therefore, a harmonization plan should evaluate, a priori, the potential political implications of the proposed projects to mitigate any negative impact and ensure appropriate support.

II-2.2.4) Economy There is an important interdependence between economy and public health in general. Unfor tunately, a bad economy can impact public health as demonstrated by the recent cuts in worldwide governmental health budgets due to the worldwide financial crisis. However, the opposite is also true. There is also a positive relationship between economic growth and improvement of public health. Studies have shown that the level of economy and public health of a country are indeed linked [389]. It seems obvious that when economies get richer, a greater proportion of diseases is treated and more sophisticated treatments are employed.e,f This improvement in public health in a specific country does not only benefit the patients who can enjoy the additional years of life without disability, but also benefits the country/community as a whole by e There are several US studies that estimated the value of a year of life at approximately US $150,000, acknowledging that there are a lot of different numbers in the literature and that this value varies of course in the time period and is different in other countries (Murphy and Topel 2003; Norhaus 2003). f History has clearly demonstrated this relationship. During bad economic times (such as the financial crisis in 2008/2009), there is a decrease in start-up companies, which are mainly financed by venture capital (see 2009 BIO paper on “The Ongoing Financial Markets Crisis and Lack of Access to Capital Threatens America’s Biotechnology Industry and the Development of Innovative New Therapies for Patients”). Moreover, analysis has shown that R&D expenditure falls during recessions (see “Stress in the life sciences innovation model: Impact of the Global Financial Crisis, “presented by Bruce Rasmussen during the APEC Life Sciences Innovation Forum in Singapore on August 4, 2009). This decrease in start-up companies and R&D expenditure has an obvious impact on innovation and research/development of new therapies. 210 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS decreasing the burden due to bad public health. Indeed, a combination of early death and an increase in disability in a younger active population (as quantified by the “disability adjusted life years lost” by the economists) has a clear impact on the economy of the country as it influences the increase/decrease of treatment costs, labor force, productivity, and hence the gross domestic product (GDP). For example, estimated losses in national income from heart disease, stroke, and diabetes in 2005 were US $18 billion in China, US $11 billion in the Russian Federa- tion, US $9 billion in India, and US $43 billion in Brazil. These losses accumulate over time. It is estimated that, between 2005 and 2015, China will have lost US $558 billion in national income due to heart disease, stroke, and diabetes alone [390].

The relationship between economy and harmonization of pharmaceutical regulations is also important, but more complex.

First, economic decisions can influence harmonization initiatives, positively or negatively. Most of the regional initiatives related to the harmonization of pharmaceutical regulations are indeed a positive consequence of an intergovernmental decision to set up a trade bloc (e.g., Europe, GCC, ASEAN, MERCOSUR). The creation of these trade blocs requires a reduction of barriers to trade in all sectors (including the pharmaceutical sector) and the establishment of common requirements/standards. Depending on the level of economic integration, trade blocs can fall into different categories, such as preferential trading areas, free trade areas, customs unions, common markets, and economic and monetary unions. Of course, the higher the economic integration, the deeper the harmonization. However, economic considerations can also negatively impact harmonization efforts. Although globalization has created new opportunities, major pharmaceutical companies are still focusing their efforts of development to meet the needs of developed countries because these countries continue to represent an important part of their revenue [391]. World sales of pharmaceuticals are indeed highly skewed toward the developed world markets. Developing countries account for more than 80% of the world’s population, but they are responsible for only about 10% of global sales [392]. Companies therefore have no incentive to include developing countries and establish a global development plan if such a global plan would delay registration in Europe or the US.

Second, decisions in the pharmaceutical domain can also impact employment and the general economy. The pharmaceutical sector has experienced some important structural changes over the years (due mainly to technological innovations, increasingly stringent regulatory requirements, and globalization of activities) that have affected markets and increased the costs and risks of development of new products. Today, this sector is highly regulated and is very complex as it involves a large variety of players (i.e., multinational major pharmaceutical firms, but also start-up companies, a lot of contractors, and other research organizations such as universities, public and private research centers, financial institutions, DRAs, governments, health care systems, consumers, physicians, etc.). Many parameters can influence the competitiveness of this industry [393], including changes in regulation or integration/harmonization activities. However, the pharmaceutical market is clearly a “strategic” sector for all countries/regions in the world because it is large, high growth, high revenue, and globalized. For example, in Europe, the pharmaceutical sector employs more than 634,000 people and accounts for more than 17% of the EU R&D INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 211 expenditure [394]. Therefore, actions in the pharmaceutical sector always have the dual objectives of safeguarding public health (by providing people with safe and effective medicines) while creating a business environment that stimulates research, boosts innovation, and supports the competitiveness of industry. This has to be kept in mind when working on harmonization initiatives to understand the resistance from some governments (especially global harmonization where the different regions have to consider this dual objective). For example, it is commonly agreed that the establishment of Europe and the creation of supranational legislation in view of harmonization of practice and requirements was one of the factors (in addition to the increased globalization of the sector and other challenges) that impacted the competitiveness of Europe compared to the US and Asia. The implementation and interpretation of Community legislation by Member States created obstacles to the free movement of medicines. Overburdening requirements also affected competitiveness, especially for small- and medium-sized enterprises [395].

In summary, economic parameters and their potential consequences need to be considered when discussing harmonization activities. Of course, they should not be the major or unique factors, but they need to be considered along with other parameters because they may support or limit the harmonization process. If a harmonization project impacts the economy too much (by impacting the attractiveness and competitiveness of a country or region), there is a good chance that it will be difficult to implement as demonstrated by the introduction of the Euro- pean Clinical Trials Directive. Notwithstanding the added value of this legislation, it has been recognized that this Directive has increased bureaucracy and the costs of clinical trials conducted in Europe [396], which in turn greatly reduced European competitiveness in the field of clinical research (especially in the context of globalization of these activities with emerging investigation sites in Eastern Europe and in the Asia-Pacific region). This was one of the reasons that convinced the European Commission to launch the “Impact on Clinical Research of European Legislation (ICREL) project to help determine the most relevant pathways for improvement of this new legislation. The legislative and regulatory framework is indeed one of the major determinants for the attractiveness of a given region for clinical research. This sector is critical to promoting public health, but is also crucial for the economy as it employs people and represents a substantial amount of money invested. It is, for example, a source of employment and of revenue for investigational sites and many subcontractors.

II-2.2.5) Differences in Cultures and Traditions Cultural differences and diverse traditions have influenced the establishment of national regulations, requirements, and systems. For example, the importance and recognition of physicians and other stakeholders are different in each culture [397]. In addition, some products are sometimes used by a limited number of countries (i.e., the venotonic products primarily used in France or traditional therapies in certain countries). This difference of environment and the specific needs of local markets continue to require appropriate and specific local regulation and organization.

Cultural and traditional differences can also limit harmonization efforts on topics of common interest. For example, during the first meeting of the Pediatric Medicines Regulators’ Network in February 2010, participants observed that it may not be possible to reach a global 212 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS consensus as to the ethics of clinical studies in children because opinions include cultural aspects. For example, current guidelines differ as to: ▸ Whether children should be included in research studies ▸ Whether research in children is beneficial to the participants themselves ▸ Whether healthy children may be subjected to clinical studies, and if so, under what circumstances ▸ The definition of the ages of “children” Cooperation is still relevant to understanding differences and agreeing on technical topics (i.e., of clinical trials, terminology, etc.), but harmonization of ethical standards may not be possible due to these cultural differences [398].

Historical differences on how reviewers evaluate data and drug applications can also impact cooperation. For example, some review the summaries of information provided by the company first (this is the case in Europe, which used to require expert reports, now replaced by the CTD overviews). Others prefer starting with source data (e.g., the US). This type of historical difference needs to be taken into account when developing common Good Review Practices (GRevPs).

Finally, awareness of cultural differences is important in communication and should not be underestimated, as communication is critical to achieve cooperation and harmonization (see Part II-2.1.2). Communication codes (verbal and nonverbal) between French, Dutch, Ital- ians, Americans, Japanese, Batswanans, Kuwaitis, or Brazilians are very different. It is therefore critical that people involved with harmonization and cooperation initiatives understand such differences to avoid problems of communication. Many courses and training on cultural differences are available. They are important tools to initiate and maintain respectful and strong relationships with counterparts.

The establishment of the EU (bringing together Member States with major historical, social, and cultural differences and 23 official languages) demonstrated that these differences can be overcome if there is a political commitment. However, it is important to keep these differences in mind when working on harmonization/cooperation initiatives to avoid communication problems and to understand approaches, systems, methods, and the interests of other parties.

II-2.2.6) Ethnic Factors Ethnic factors are characteristics related to race or large populations grouped according to common traits and customs. This definition gives ethnicity, by virtue of its cultural as well as genetic implications, a broader meaning than racial. Ethnic factors may be classified as either intrinsic or extrinsic [399]:

▸ Intrinsic ethnic factors are factors that help to define and identify a subpopulation and may influence the ability to extrapolate clinical data between regions (e.g., genetic polymorphism, lean body mass, body composition, organ dysfunction, etc.).

▸ Extrinsic ethnic factors are factors associated with the environment and culture in which a person resides (e.g., diet, use of tobacco and alcohol, exposure to pollution and sunshine, socio-economic status, compliance with prescribed medications, etc.). They tend to be less dependent on genetics and more socially, culturally, and behaviorally determined. INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 213

Ethnic factors can limit global development of medicines and require duplication of clinical studies. These factors can indeed affect the medication’s safety, efficacy, dosage, and dose regimen, but also raise specific risks for a certain population [400].

Until now, DRAs have managed this risk by requesting that all, or much of, the foreign clinical data in support of registration be duplicated in a new population, and/or that bridging studies be performed to extrapolate data from another population.

The ICH E5 guideline [401] is an important tool to help characterize the influence of ethnic factors in order to facilitate extrapolation of data to different populations and therefore minimize the need for duplication of clinical studies. The recent increased cooperation between China, Korea, and Japan in the clinical domain is based on their ethnic similarities (genetic, but also cultural) [402].

Evaluation of the impact of ethnic factors on treatment effect is important to support global development and facilitate international clinical studies, but this evaluation is also key due to the changing demographics in most of the developed countries. For example, the US population is becoming increasingly ethnically and racially diverse. The Caucasian population is growing more slowly than other groups, but Caucasians continue to account for the majority of trial participants. The US FDA has expressed concern regarding the extrapolation of the results to others subgroups [403].

II-2.2.7) Differences in Medical Practices Differences in medical practices and therapeutic approaches exist between countries and regions of the world. These differences (defined as extrinsic ethnic factors by ICH [401]) may be due to several reasons, including education, cultural/traditional differences, level of development of each country, specific and genetic diseases, etc. Different diets, importance of physical therapies, and environmental/climatic conditions also need to be considered.

These differences in medical practices can limit harmonization and complicate the design of global clinical studies: ▸ Choice of comparator products (due to different therapeutic arsenals and/or standard therapies in each country/region, but also due to confusion generated by different names of medicines) ▸ Selection of endpoint ▸ Definition of disease and clinical relevance and significance of results ▸ Monitoring of underlying illnesses ▸ Evaluation and limitation of concomitant therapies

It is interesting to see that ICH efficacy guidelines are not therapeutic class specific even when: ▸ There are, in some therapeutic classes, individual drug evaluation guidelines among the three regions. ▸ Differences between guidelines can result in obstacles to the mutual use and acceptance of clinical data. 214 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

At the ICH Steering Committee meeting in September 1998, it was agreed that this should be adopted as a new area of work for ICH, with the first such guideline being undertaken as a “pilot study” to assess the feasibility of extending work in this area. It was agreed to develop the first therapeutic class-specific guideline for anti-hypertensive drugs (E12). However, this pilot work showed how differences in medical practices can impact the global development of medicines. It was finally agreed that this document should be considered an “ICH Princi- ple Document” rather than an “ICH Guideline” because there were differences in the requirements of the three regions that could not be harmonized (i.e., the need for studies comparing the new medicine with current standard therapy and the specific requirements regarding co-administration with other anti-hypertensives). No other guideline for clinical evaluation of specific therapeutic categories has been developed since this E12 document.

II-2.2.8) Difference in Legislation, Statutes, and Systems While worldwide DRAs generally share similar scientific concerns, differences between legislations and regulatory systems/frameworks can present important obstacles to harmonization. Some countries have an independent agency (e.g., FDA in the US, Health Canada in Canada), some have semi-independent institutes, some have a multinational/supranational agency (EMA in Europe), and some do not have an independent agency (i.e., the system is driven by the Ministry of Health [MoH]). The difference in statutes of each DRA, when they exist, can sometimes impact the objectives of cooperation with their counterparts. In some countries, certain aspects of the pharmaceutical sector are governed by national laws, and other aspects are governed by state or provincial laws. This decentralization of roles and responsibilities provides another level of complexity for harmonization [404]. Although there has been significant progress during the last several decades, with strong participation and motivation of regulators, overcoming these obstacles will ultimately require unprecedented levels of international cooperation and profound modifications of legislations.

Most of the legislative texts have been voted in by national/regional legislators following major public health issues. Even if the legislators reacted to the same issues (e.g., the thalidomide problem in 1961), different actions have been taken and different fundamental laws have been passed in each country. This different legislative environment can impact harmonization efforts. For example, one of the reasons (among many others) for the delay of registration and use of biosimilar products in the US compared to other developed countries was the lack of a legal basis for such products (because most of the biologics were approved under the Public Health Service Act and not under the Federal Food, Drug and Cosmetic Act, which has allowed generic products since the Hatch–Waxman Amendment in 1984) [405]. Until US legislators defined this legal basis, it was impossible to have US regulation for this type of product and therefore harmonization of requirements with other countries.

The different status/legislation of borderline products in the world is another example dem- onstrating how legislation can complicate harmonization between countries. Some products can be considered “medicines” in certain countries and “medical devices” in other countries (e.g., products for dry eyes). Discussing the harmonization of regulations becomes difficult in INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 215 this case because these products fall within different regulatory frameworks and also within the scope of different harmonization initiatives.

Finally, the legislative context also impacts the communication and exchange of information between DRAs. Indeed, some countries passed legislative texts to protect trade secrets and commercial information (e.g., the Uniform Trade Secrets Act in the US). Although government needs to protect sensitive information, these restrictions may impact/complicate harmonization and cooperation between countries [406].

The impact of differences in legislations (and the time and effort to overcome these differences and to change legislations) is well known and has already restricted or impacted certain harmonization initiatives. For example, the Transatlantic Administrative Simplification project between the EU and US (see Part I-3.2.5) was limited to actions that would not require changes in legislation. Also, one of the major issues of concern to PANDRH members is the recognition that serious limitations exist in some subregions, such as Central America, where no legal framework exists to authorize and implement the commitments made by technical groups [407].

Any new harmonization initiative needs to take this factor into account. It is important to avoid the need for legislation changes and to work within the current legislation boundaries to avoid delays. Regulation can be passed or revised more rapidly and simply. If a harmonization project requires legislative changes (in the case of an integration project or major harmonization efforts), this delay needs to be clearly factored in the plan since passing a new or revised law may require a lengthy process [408].

II-2.2.9) The Fourth Hurdle In the past, three criteria were used to assess a new medicine and evaluate the risk/benefit ratio: quality, safety, and efficacy. A fourth hurdle has become more and more important in the last decade: the evaluation of the cost effectiveness of the medicine. In other words, it is not sufficient to demonstrate that a new drug is of high quality, safe, and efficacious, but it also has to have benefits over existing therapies. This new hurdle is obviously one of the consequences of the decrease of healthcare budgets worldwide. Escalating healthcare costs and the need to balance budgets have led payers in many jurisdictions to become more restric- tive in their decisions to reimburse new expensive health technologies. These considerations mean that coverage has become a major roadblock for new medicines. Even if DRAs and payers have distinct roles and information needs, winning regulatory approval is of little use to industry or patients when the medicine is not reimbursed, as access to high-priced medicines will effectively be precluded for most patients. This new hurdle has led to a number of important consequences on the development of new products [409].

The increased importance of this new criteria (entirely based on national pharmaceutical needs and strategy) and the increased communication between DRAs and Health Technol- ogy Assessment (HTA) (e.g., as is the case in Europe [410]) will also influence the regulatory environment of new medicines [411]. This is an important change of environment that could impact the ongoing global harmonization of the regulation. For example, until now, the need 216 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS to evaluate new medicines against existing therapies has been supported in Europe, but not by US regulators/legislators. Although this concept of comparative effectiveness has not yet become a new criterion to register a drug in the US, the change in US legislation will certainly harmonize the EU and US positions on this topic [412].

II-2.3) Conclusion All the parameters and factors discussed above are critical to consider because they can influence the success of a harmonization/cooperation initiative. A good idea is not sufficient. All harmonization initiatives need to take these parameters into consideration to ensure success. Even the establishment of an appealing harmonization project, supported by all stakeholders, needs to integrate these factors and associated challenges.

The European harmonization of the rules for performing clinical trials is an excellent example to demonstrate that: ▸ All influencing factors and potential problems of implementation need to be taken into consideration very early (before the rule comes into effect). ▸ The choice of the legal framework for harmonization is critical. ▸ It is important to avoid any possible interpretation of the rules (rules and the implementation process should be as clear as possible). ▸ The implementation of harmonized rules is at least as important as the rules themselves. ▸ Monitoring of the implementation is required.

The harmonization of clinical trial requirements is one of the most critical harmonization topics for the development of new medicinal products. Ironically, the initial implementation of harmonized European requirements has been very difficult. Although the EU Clinical Trials Directive was an important step and everyone initially welcomed it (as it created a certain level of harmonization), it has been one of the most criticized pieces of the Euro- pean legislation on medicines. As this harmonization has not been sufficiently far-reaching, its implementation has been very difficult and has led to an undesired increase of clinical trial complexity. The fact that the clinical trials legislation was established as a Directive (requiring transposition of its principles into national legislation) partly explains the problem. Because most of the EU countries already had their own legislation and practice before the adoption of the Directive, their interpretation of the Directive and the changes brought to the national legislation were highly dependent on this preexisting framework. As a result, the harmonization target was missed and these differences in interpretation of the modalities for the agreed-upon principles led to even higher complexity levels (especially for multinational clinical trials). Today, a sponsor of a clinical trial needs to have very detailed knowledge about every country’s national requirements for the clinical trial authorizations and has to integrate the different requirements to the protocol and the Investigational Medicinal Product Dossier (IMPD) resulting from parallel submission in multinational trials.

To better understand this problem of implementation, the European Commission launched a retrospective comparative study to measure and analyze the direct and indi- rect impact of the Clinical Trials Directive (and its related guidelines) on all categories of INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 217 clinical research and on the different stakeholders. This project, called Impact on Clinical Research of European Legislation (ICREL), compared the mean differences for several parameters between 2003 (i.e., prior to the entry into force of the Clinical Trials Directive) and 2007.

According to the ICREL report [413]: ▸ There has been an indisputable increase in the administrative burden for DRAs (this is reflected by an increase in workforces and related costs, which is paralleled by a rise in fees). ▸ Performing a clinical trial has become considerably more difficult and costly. Staff needs in pharmaceutical companies for administrative work for submitting a request for authorization of a clinical trial has doubled compared to the circumstances prior to the entry into force of the Clinical Trials Directive. ▸ The timelines for the overall protocol and substantial amendment approval process were extended by approximately 30%.

In this report, some recommendations were also proposed, such as: ▸ Using a risk-based approach to regulation would result in a substantial reduction in workload and cost for both the Sponsor and DRAs, particularly for academic institutions that run a number of low-risk studies using marketed drugs. Not all clinical studies require the same level of requirements. ▸ Simplifying the Clinical Trial Authorization (CTA) process by the competent authorities through a single CTA for multinational trials would reduce duplication of efforts and also save time, costs, and expertise. ▸ Further harmonizing practices in ethics committee requirements.

Based on this ICREL report, the European Commission released a public consultation paper in October 2009 [414] that highlighted five key issues to be addressed: ▸ Multiple and divergent assessments of clinical trials: While the Clinical Trials Directive sets out common rules (that ensure harmonization of the concepts), experience shows that these requirements are applied very differently by the respective Member States, and conflicting points are brought up by the DRAs of these Member States. ▸ Inconsistent implementation of the Clinical Trials Directive (e.g., definition of a substantial amendment). ▸ The regulatory framework is not always adapted to the practical requirements. ▸ Adaptation to peculiarities in trial participants and trial design. ▸ Ensuring compliance with Good Clinical Practices in clinical trials performed in third- world countries. This is critical because about 25% of all clinical trials performed in the EU also involve at least one third-world country and 65% of all data/patients submitted in pivotal clinical studies in the framework of an application for an EU-wide marketing authorization are generated in third-world countries.

These key issues highlighted by the European Commission were shared by sponsors and other stakeholders involved in the conduct of clinical trials in Europe [415]. They confirmed that, although concepts promoted in these new texts were good and improved the situation 218 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

(e.g., improvement of data reliability and increase of communication and cooperation), they did not achieve their aim. They stressed that it was very common to receive divergent assessments from Member States (certainly due to differences in culture, clinical practice, and health systems). They agreed that the new system created additional administrative costs/burdens and reduced the competitiveness of Europe on a global scale without improving the safety and rights of subjects. Moreover, it could affect the development of new and innovative treatments because clinical trials are sponsored not only by large multinational pharmaceutical companies, but also by small, local pharmaceutical companies or research organizations with limited resources.

The new revision of the EU legislation [416], based on an evaluation of failure that involved all stakeholders, will hopefully resolve most of the challenges in order to finally meet the predefined objective.

Learning from this EU case and recognizing the importance of the numerous and complex factors that can influence the outcomes of a harmonization/cooperation initiative, it seems important to follow a simple step-by-step approach when developing a harmonization initiative in order to integrate and better control all the parameters. Those steps are as follows: ▸ Step 1: Create an oversight committee with relevant decision-making power from each party. This committee will then need to meet on a regular basis to monitor progress of the initiative. ▸ Step 2: Define objectives and agree on clear and realistic goals.g ▸ Step 3: Put in place an appropriate structure and organization to support projects (i.e., secretariat, working parties, etc.). This structure needs to involve all relevant stakeholders, and at a minimum, continuous updates need to be provided. ▸ Step 4: Set up a plan to achieve intermediate goals and ultimate objectives. The plan needs to incorporate appropriate and realistic timelines and also define roles and responsibilities. The value of each funded project (i.e., development of a specific harmonized standard) needs to be evaluated by assessing its benefit against the current situation, the budget and resources available, the development, implementation, and maintenance it will require, and the potential implementation challenges. ▸ Step 5: Develop harmonized rules and standards. All stakeholders need to have the opportunity to review and comment on rules before they come into effect. ▸ Step 6: Implement new harmonized rules and standards. ▸ Step 7: Monitor implementation and use of each harmonized rule and standard and evaluate if this implementation achieves predefined goals and supports the ultimate objective. ▸ Step 8: Maintain and revise rules when needed.

g Each goal needs to be Specific, Measurable, Attainable, Relevant, and Timely (also known as the “SMART” criteria). INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 219

Of course, this basic approach is only a starting point that needs to be customized to the specific situation, context, and objectives. Each project needs to be thoroughly detailed, but following this simple step-by-step approach provides a structured and logical process to integrate all critical parameters for success and limit the influence of external factors. It also gives time to partners for communication and the establishment of relationships, and ensures that political leaders are in agreement with the objectives, plan, and investment (i.e., resources, budget, etc.). P A R T III Recommendations to Support the Next Phase of International Cooperation, Convergence, and Harmonization in the Pharmaceutical Domain

As discussed throughout this document, globalization has fundamentally changed the pharmaceutical environment and created unique regulatory challenges for governments and regulators [417,418]. The future of medicine regulation lies in successful collaboration and networking [419]. Regulators support the idea that they need to operate more as a functional network rather than as individual players [420]. In order to be efficient, this increased cooperation needs to be structured and coordinated. A global functioning and effective system for the evaluation and control of medicines, based on current resources and structure, needs to be designed. This new global system also needs to be supported by an overarching strategy with a common vision and mission. Roles, responsibilities, and accountabilities need to be clarified (i.e., who develops the standards, who disseminates these standards, etc.), and governance and decision-making bodies need to be agreed upon. Finally, processes need to be established and supported by the appropriate information technology (IT) tools and infrastructure.

The establishment of this structured global pharmaceutical system represents a new step in a process that has evolved throughout the years: ▸ Step 1: Development of national regulations and standards ▸ Step 2: Cooperation between countries and harmonization of certain standards (i.e., bilateral, regional, and global)

International Cooperation, Copyright © 2014 Pierre-Louis Lezotre. Convergence and Harmonization of Pharmaceutical Regulations 221 Published by Elsevier Inc. All rights reserved. 222 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

▸ Step 3: Coordination of harmonization initiatives and further continued harmonization of standards ▸ Step 4: Coordinated action on a global basis based on systems and communications

Presently, the development of the global pharmaceutical regulation is at Step 2. As discussed in Part II-1.4, more benefits could be achieved by the further coordination of ongoing activities (Step 3). This solid coordination of all initiatives is necessary to progress to the ultimate goal (Step 4), which would allow the efficient use of resources and would better protect international public health. The creation of a global functioning safety framework or the establishment of an international procedure for the registration of medicines and for the evaluation and control of clinical studies cannot be possible without first achieving the formation of a structured system. This was demonstrated with the European construction, which went through the same type of stepwise process on a regional level. This regional pharmaceutical system, currently in Step 4, promotes better decision making based on good assessment and a better-informed decision.

It is important to note that Step 4 does not require integration and can therefore be applied globally. Technical evaluation can be coordinated globally, but each country can keep its own decision-making process. Today, this ultimate goal is possible due to the cooperation undertaken over the past several decades and the incredible level of harmonization achieved so far. Twenty years ago this next phase of collaboration, which represents the only alternative to meet present-day needs and challenges, would have been impossible. The relationship built between all global stakeholders and the numerous harmonization and cooperation projects developed over the years are the foundations of the future global system. In addition, all the tools created to facilitate global communication and exchange of information will support the next phases of cooperation.

Of course, beginning this new phase of global cooperation and harmonization in the pharmaceutical sector will require major additional efforts at national, regional, and global levels. However, at the same time, this challenging goal represents an incredible and exciting opportunity! It brings about the possibilities for resolving outstanding difficulties in developing countries to further support pharmaceutical innovation and to better promote and protect global public health. This increased collaboration also supports the United Nations Millen- nium Development Goals.a

a The United Nations Millennium Development Goals (MDGs) are eight international goals that UN Member States (and international organizations) have agreed to achieve. They are derived from the United Nations Millennium Declaration, signed in September 2000, which endorsed a framework for development and committed world leaders to combat poverty, hunger, disease, illiteracy, environmental degradation, and discrimination against women. These MDGs are interdependent, and several relate either directly or indirectly to health. WHO is therefore very involved in this process and works with countries to achieve the health-related MDGs. INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 223 III-1) OVERVIEW AND KEY PRINCIPLES OF THE PROPOSED GLOBAL PHARMACEUTICAL SYSTEM

The proposed global pharmaceutical system is a structured scheme (Plate 8) developed to better coordinate the different ongoing initiatives. The following questions were considered when developing this system: ▸ What is the best use of available resources to reduce workload and achieve effectiveness? ▸ What is the best way to share regulatory information on a worldwide basis and how should this information be shared, and by whom? How can available tools be used to facilitate information exchange? ▸ How can procedures be streamlined and processes improved on a worldwide basis? ▸ How can expert knowledge be used to better promote global public health? ▸ How can resources be directed to essential functions in developing countries? ▸ How can bilateral, regional, and global initiatives be structured to improve the system, and what should be the role of each level? ▸ What should be the role of each player (i.e., ICH, WHO, national bodies, regional bodies, etc.)?

This structured system represents a new strategic approach to the global registration and control of medicines, allowing leverage of experience from each stakeholder and more efficient use of available resources and expertise. This proposal incorporates learning from past and ongoing harmonization and cooperation initiatives (analyzed in Part I). In addition, it proposes improvements and further development of the current framework, but utilizes, as much as possible, the current structures, tools, and networks that were already successfully developed. The proposal was designed to enhance the value of harmonization and cooperation to all stakeholders, and to respond to the increased demand for further harmonization and cooperation.

The establishment of this proposed global system (with increased WHO leadership) to coordinate global cooperation in the domain of product registration is aligned with the Interna- tional Conference of Drug Regulatory Authorities (ICDRA) recommendations. Indeed, the first recommendation of the 12th ICDRA was to improve access to medicines using new regulatory pathways. More specifically, it was recommended that [421–1]: ▸ Countries should make use of new regulatory pathways provided by highly evolved regulatory agencies in order to avoid duplication of effort and to enable optimal use of limited resources. ▸ In cooperation with well-resourced regulatory agencies, WHO should assist Mem- ber States in providing training on the best use of regulatory information on product approvals available in the public domain. ▸ WHO should continue its efforts to prequalify products. ▸ WHO should assist national regulatory agencies in developing innovative approaches to improve access to safe and effective essential medicines of quality that address public health needs. 224 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

These principles were reemphasized during the 15th ICDRA that took place in Tallinn, Esto- nia, in October 2012. During this 15th conference, new targeted recommendations were indeed focused on the continuity and improvement of networking, collaboration, and cooperation [421–2]. Innovative global movements were encouraged to enhance international regulatory collaboration to yield tangible results beyond what has been achieved to date and took into account the capacity of medicines regulatory authorities.

Part III-2 presents and details the necessary measures and actions that need to be developed and implemented to establish this proposed global pharmaceutical system.

Critical parameters for harmonization and external influencing factors (discussed in Part II-2) have been considered when developing these recommendations to facilitate the implementation of the proposed measures and actions.

The vision of this new collaborative effort is to protect and promote international public health by leveraging global experience, structure, resources, and expertise. Its mission is to facilitate international cooperation to assure worldwide access to innovative, safe, and effective medicines.

This proposed system is based on the following principles: ▸ Better coordination of all ongoing harmonization and cooperation initiatives by one unique coordinating body. ▸ Establishment of an international body to proactively develop and maintain high global technical standards. ▸ Design a global system that can benefit all countries. ▸ Continuous support for capacity building in developing countries. ▸ Importance of regional and bilateral communication. ▸ The decision-making process needs to remain national (or regional in the case of regional integration). ▸ Involvement of all stakeholders. ▸ Balance the need for national procedures and the necessary implementation of global processes.

III-1.1) Better Coordination of All Ongoing Harmonization and Cooperation Initiatives by One Unique Coordinating Body Global harmonization of pharmaceutical regulations cannot be directed as a central unique program. To be successful, the new global system needs to incorporate all ongoing harmonization initiatives (i.e., at the national, regional, and global levels) and to combine bilateral, regional, and global projects in an overarching strategy. The idea is not to “reinvent the wheel,” but to leverage all the current efforts by better coordinating and structuring the ongoing work in order to move to the next level of global cooperation and harmonization of pharmaceutical regulations. INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 225

Over the past several decades, many harmonization initiatives have been established at national, subregional, regional, and global levels. Each of them has its own individual objective, str ucture, and process, but they all move towards the same goal: promotion of public health in the most resource-efficient manner with a better informed, transparent, and consistent decision-making process. This process based on good scientific expertise and judgment facilitates the access of patients to new safe and effective medicines. While the growing promi- nence of health in international affairs is welcome, and the increasing international interest for developing collaboration and harmonizing technical standards is beneficial (see Part II-1), the multiplication of these independent projects can sometimes become confusing and counterproductive. If all these efforts are not well coordinated, the duplication of work and new standards will continue to be a problem and the harmonization objective will not be achieved [422].

Moreover, all these bilateral, regional, and global initiatives have evolved and grown over time. Today, they involve the same players and have become interdependent. Countries are involved in global cooperation (e.g., EMA and US FDA collaboration with WHO to support developing countries), bilateral cooperation (e.g., the EU/US bilateral cooperation for inspections has been extended to other countries), and regional initiatives.

Bilateral cooperation influences regional and global harmonization, and regional activities have implications beyond their region and play an important role in building global harmonization [423]. Better coordination is therefore required to avoid duplication of effort (e.g., between regional and global initiatives), and therefore better use of resources and expertise.

Several valuable attempts have been made by WHO and the ICH to increase communication between harmonization initiatives. However, with the increased number of projects worldwide, it is now time to facilitate communication between independent initiatives as well as to coordinate them. There is a need to promote greater coherence and to provide an opportunity for a more inclusive dialogue between the many different players that are involved. This new phase of harmonization and collaboration will bring efficiency in the harmonization process, and significantly improve the global pharmaceutical environment.

At present, there is no single platform that allows interaction between governments, global health organizations, partnerships, regional organizations, multilateral and bilateral agencies, philanthropic foundations, private sector organizations, and other relevant stakeholders. Through its role as the directing and coordinating authority for international health work, WHO can provide such a platform [424]. WHO represents a unique link between global, regional, and local levels, and therefore provides the best option to coordinate all international pharmaceutical initiatives.

The need for a “strong WHO to lead global efforts to improve health” was further emphasized by Dr. Margaret Chan, Director-General of WHO, in November 2011 [425]. Indeed, stronger leadership from WHO would promote greater coherence in the actions of multiple health partners to maximize their impact. 226 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

III-1.2) Establishment of an International Body to Proactively Develop and Maintain High Global Technical Standards Most harmonization initiatives have been established to explore existing disharmonies on specific topics. Continuous harmonization of existing requirements among countries is essential. However, harmonization and cooperation can provide much more than harmonization of current national or regional divergences. The ultimate objective, to benefit public health, is to put in place mechanisms to prevent disharmony. If new emerging issues were proactively treated at a global level (i.e., creation of an international agreement for each new specific problem, issue, and topic prior to each region and country creating its own regulations and guidelines), the new agreed-upon global standards would automatically be identical in all regions and countries. This process can be called “proactive harmonization.” The importance of such global cooperation for the development of new regulations and standards for emerging science and issues in the development of medicines (i.e., biomarkers, new statistical methods and clinical study designs, risk management plans, advanced therapies and emerging treatments, etc.) has been highlighted by the evaluation performed between 2004 and 2007 by the EMA/CHMP think-tank group on innovative drug development [426].

This next step in global harmonization demands resources, organization, and political support. This proactive global approach also requires a new mode of operation to globally monitor emerging scientific issues and develop “consensus principles” arising from scientific discussions of new data and understanding. As Mr. Thomas Lönngren (former EMA Execu- tive Director) highlighted during the ICH6 conference in Osaka, Japan in November 2003, new technologies have an impact on established systems. Classic scientific evaluation needs to be complemented by public policy considerations (i.e., risk perception and risk management, and also societal, economic, traditional, ethical, and environmental factors). Moreover, regulatory requirements must reflect scientific progress and not just define scientific pathways, because the focus at this stage of the science should be on understanding the consequences of new therapies and not just the development of guidelines. So the focus and objectives and the structure of the discussion have to be customized to this early discussion on new technologies; it cannot be the same as that for already-defined and regulated topics.

The discussion on modification of the requirements for Phase I studies following the TGN1412/ TeGenero trial issue [427,428] is an obvious example of work that should have occurred at the global level. It is indeed clear that even though this incident occurred in the United Kingdom (UK), it is a critical topic that impacts all development of new therapies wherever the clinical studies are performed. So, why was a UK Expert Scientific Group [429] initiated instead of an international workshop? Did the UK authorities have to show that they were actively doing something, or is it because there was no international structure available for this type of discussion?

This example, among others, demonstrates how a real coordinated global system could better support and protect global public health. The benefit of such cooperation would not only be the establishment of sound scientific standards by the best international experts, but also the reduction of duplication of efforts. Indeed, to be successful for the long term, all the efforts of harmonization need to be coupled with measures that support “proactive harmonization” to INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 227 avoid new differences in opinion regarding new emerging topics. The primary objective is to coordinate the discussion and to provide a forum for members to exchange scientific and regulatory information on these emerging issues and to provide a mechanism for communication and resolution of potential differences in opinion. In addition to the harmonization of differences, efforts should be made to collaboratively develop new standards and requirements. All these measures and mechanisms will ensure that the situation will improve significantly.

Moreover, new requirements and standards for new technologies need to be addressed on a global rather than a national basis. Recent innovations in biomedical science and the potential to use these to develop advanced breakthrough therapies have not yet delivered on their promise of better health. This new era brought many new challenges and forced DRAs to revisit their processes and approaches [430]. New requirements, standards, and processes are required for these new types of therapies. This challenge is also an incredible opportunity to develop new common global standards and mechanisms to better work together to avoid future disharmonies.

The ICH forum seems the best body to lead this effort and to facilitate the exchange of expertise, data, and experience on emerging scientific subjects. This objective is not a utopia, and is obviously something that is difficult to implement. Several modifications of the ICH process will be required to incorporate this new responsibility (see Recommendation 3 under Part III-2) because the current organization does not support this proactive work. Although “proactive harmonization” has been a continued objective of ICH, it has also been one of its biggest struggles. As stated in the ICH statement following ICH5 in November 2000, ICH had the intention to implement this idea of prevention of disharmony in new scientific areas via the dialogue between the different parties. However, even if ICH has had limited success on this front (e.g., ICH Guidelines E15 [431] and E16 [432]), this goal has been very difficult to implement (e.g., gene therapy).

The mission of DRAs is to protect the public health by assuring the safety, efficacy, and security of medicines. However, DRAs are also responsible for advancing public health by helping to speed up innovation that makes medicines more effective and safe. The development of common standards will not affect competition between the regions and should not be used as an economic barrier. These new global standards will clearly support the development of new therapies. If ICH is reorganized to include this new responsibility of proactively developing new common standards, it will become a truly international body in charge of developing and maintaining global technical pharmaceutical standards.

III-1.3) Design a Global System That Can Benefit All Countries It is critical that a global system is conceived to meet the needs and regulatory capacity of both developed and developing countries.

Presently, developed and developing countries have very different needs in terms of medicines and healthcare. In 2003, the average non-ICH citizen had less than a 5% probability of being treated with any drug approved by ICH standards [433]. Today this percentage may have slightly increased, but there is still a fundamental discrepancy between countries and regions. The first priority of developing countries is to provide access to essential medicines 228 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS of good quality for priority health problems (i.e., malaria, tuberculosis [TB], HIV/AIDS). For these countries, the first focus of cooperation should therefore be to ensure the quality of products on the market and fight against substandard medicines manufactured under non- GMP conditions. On the contrary, authorities from developed countries that already have essential basic medicines available focus their energy on speeding up innovation and facilitating the development of new innovative products (e.g., gene therapies). However, it is also true that lifestyles in developing countries are increasingly reflecting those in developed countries, with high and increasing incidences of smoking, diabetes, and cardiovascular and respiratory diseases. Therefore, the focus of development of new medicines against major conditions and diseases for developed and developing countries are becoming more similar.

The major difference between developed and developing countries in the pharmaceutical sector resides in regulatory capacity. All developed countries have fully operational pharmaceutical regulations and systems to ensure the quality, efficacy, and safety of medicines, even if their systems and procedures slightly differ. However, developing countries have very limited or no regulation and systems. The reality is that many low-income countries cannot ensure the safety, efficacy, and quality of medicines in their markets due to a lack of expertise, resources (i.e., staffing and financial), standards, systems, and training [434].

The involvement of each country in the global pharmaceutical system will depend on the maturity of its regulatory system:

▸ Developed countries with advanced regulatory systems can provide expertise and resources. These countries, which could become “reference countries” (see Recommen- dation 4 under Part III-2), actively participate in ICH discussions and the development of international standards and guidelines.

▸ Developing countries with minimal resources and systems in place do not have the resources and expertise to actively participate in the development of new standards and guidelines, but they do have the skills and experience to manage their own decision- making processes. Some of these countries can use international standards and guidelines in their evaluations, but do not have the resources and expertise to participate in their development. Others can evaluate the risk–benefit ratio of a new medicine based on the assessment report of another country. These countries are also able to provide feedback on needs and challenges to Regional Harmonization Initiatives (RHIs) to represent them in global discussions. They can also review and comment on the new rules through their RHIs.

▸ Developing countries with no functioning regulatory system are not able to make scientific evaluations or decisions. They rely entirely on other countries’ expertise and international community programs. However, it is important to note that it is better that these countries utilize the expertise of other countries rather than developing an improper system due to inappropriate resources, structure, and expertise. There are two scenarios to support these countries: • The country recognizes the approval from other countries via the WHO Certificate of Pharmaceutical Product (CPP) certification scheme when the product is approved in another country (see Recommendation 5.2 under Part III-2). INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 229

• The country uses the expertise of another country or WHO for the evaluation of a new product specific for developing countries (not needed in developed countries; see Recommendation 5.3 under Part III-2).

Regulatory models and systems are not importable, and they should be in harmony with the resources available and the environment of each country. A national regulatory system needs to reflect the level of development of a relevant country’s pharmaceutical sector. In developing countries with sparse resources and limited infrastructure, it is unrealistic to develop a system based on those of developed countries. In these countries, priorities should be defined and implemented and should depend on available resources and realistic objectives.

Harmonization of regulation between countries with different systems and political and social priorities is possible. The coexistence of the three levels of involvement listed above in the global pharmaceutical system is acceptable as long as they are structured and well coordinated. Not all countries need to participate in the development of guidelines (that would be impossible to manage anyway due to the number of players). The ideal would be to use the resources, expertise, and resources from developed countries in order to support worldwide public health.

Considering these major differences in the level of development between countries, the global system needs to be designed to help developing countries deal with the technical complexities and capacity challenges they are facing, without impacting the advanced technical exchange and cooperation between developed countries. The structure and organization needs to be able to cover the different needs that exist between the countries. The different levels of cooperation (i.e., bilateral, regional, and global) can facilitate this dual objective. Also, separate projects can be established, some involving only developed countries, and others involving all countries or only developing countries, but all these activities need to be integrated in the overall global framework and strategy.

III-1.4) Continuous Support for Capacity Building in Developing Countries Assistance to developing countries is an important objective of the global pharmaceutical system.

A cross-regional comparison of the regulatory environment in emerging markets of the Asia- Pacific, the Middle East, Africa, and Latin America [435] concluded that “Notwithstanding the apparent differences and diversity between the regions, the regulatory aspirations, barriers, problems and priorities, related to the review and availability of new medicines, are essentially similar.” An overarching strategy to support these countries is therefore possible, even if some customization of measures is necessary to integrate specific needs in some regions.

Strengthening regulatory capacity in the developing world can reap significant benefits for the health and quality of life of individuals and communities in those countries. In these developing countries (which represent 4.8 billion people [436]), harmonization and cooperation are important to support public health, and should be kept in mind when developing global harmonization. Indeed, the lack of resources can be compensated to some extent 230 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS by effective cooperation and information sharing at the bilateral, regional, and global levels. However, it is also important to reemphasize that strengthening regulatory capacity in developing countries will not only be beneficial for these countries, but also for developed countries [437,438]. This gives the ability to DRAs from developed countries to fulfill their mission to better monitor and ensure the safety of the supply chain for medicines that enter their countries from other parts of the world [439]. The growing demand for foreign traditional medicines in the Western world, associated with new specific risks, is a good example of developing countries needing to support developed countries as they have the technical expertise of these types of medicines not available in developed countries [440].

Also, it is critical to support the development of emerging countries in the field of pharmaceuticals because these markets will continue to grow. An HSBC report entitled “The World in 2050” [441] concludes that many of the world’s current top economic powers will continue to decline and be replaced by fast-rising emerging markets. According to this report, 19 of the world’s 30 top economies will be emerging countries by 2050, with China becoming No. 1 (ahead of the US at No. 2), India No. 3, Brazil No. 7, and Mexico No. 8 (ahead of France at No. 9).

During a WHO consultation meeting which involved many developed and developing countries [442], it was recognized that: ▸ Development of an approach towards a grading system for performance of core regulatory functions to be performed with minimum resources needs to be established for developing countries. ▸ Critical mass is needed to reduce the extent of unregulated market and potential public health risks. ▸ It is essential to stimulate and initiate collaboration (and share information, resources, and expertise) between various developing countries. This includes facilitating joint assessments between regulators through subregional approaches. ▸ Internationally accepted guidelines should be employed, but adapted to suit local needs and circumstances if needed. ▸ Cooperation with well-established regulatory authorities should be better established, especially for complex applications (e.g., biotechnology products). ▸ The Certificate of Pharmaceutical Product (CPP) process needs improvement. Although CPP is perceived as a positive element in the drug regulation and marketing authorization process of developing countries, there are currently limitations and challenges. ▸ Involvement and coordination of WHO in all activities and at national, regional, and global levels is critical. ▸ The WHO prequalification process is judged as an important tool, but it cannot replace the national registration procedure.

One of the major recommendations of this meeting was that WHO should support bilateral and regional harmonization initiatives (e.g., ASEAN, GCC, SADC, PANDRH) to promote more efficient application of limited resources without creating expensive systems or structures. There should be support for harmonization and development of common technical requirements, subject to the condition that the countries participate in the development of those requirements. INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 231

III-1.5) Importance of Regional and Bilateral Communication The three levels of communication and harmonization (i.e., bilateral, regional, and global) are very complementary (see Conclusion of Part I). The establishment of the global system cannot be successful without appropriate regional and bilateral collaboration. This regional and bilateral communication is indeed very important because it allows for better exchange of information and deeper collaboration between partners.

Bilateral collaboration allows partners to share experiences and gain an understanding of each other’s regulatory systems. This evaluation of similarities or differences of practices is critical to supporting global cooperation activities. Moreover, bilateral cooperation between mature DRAs and developing countries is critical as it is the best way to implement training and to share expertise and experience to support capacity building in developing countries.

Regional collaboration is a critical link between countries and global activities as it not only represents countries in global discussions, but also relays outcomes of the global discussions to other countries. It is also important to note that the development of regional cooperation and harmonization is critical for developing regions as these activities create a larger market for the pharmaceutical industries. Small national markets are less attractive for industry and sometimes this results in lack of research and development of medicines for diseases of public health importance as the selection of these products is driven largely by market demand. As a result, medicines for some diseases and health conditions critical for certain regions and countries are neglected because no viable market exists. On the contrary, a larger regional market, with harmonization of requirements, is attractive for industry. For example, a large regional Southern African Development Community (SADC) market for the pharmaceutical industries, estimated in 2000 at US $2.5–3 billion [443], creates increased opportunities compared to a nonharmonized national market. The development of this viable regional pharmaceutical market would not only have critical impact on the availability of essential quality medicines and therefore public health of the region, but also on the economic growth of the region (i.e., creation of job opportunities).

Bilateral collaboration, or collaboration between a limited numbers of partners, is also a perfect model to try practical pilot projects as it is easy to put projects in place when there are a limited number of participants. After the pilot project is well developed and improved if necessary, it can then be expanded to include additional partners and become a more global project. The 2008–2010 pilot project established between the EMA, the US FDA, and Australia’s Therapeutic Goods Administration (TGA), relating to GMP inspections of Active Pharma- ceutical Ingredients (API) manufacturers [444] that was then expanded to additional partners [445], is a perfect example. First and foremost, this pilot project demonstrated that such collaboration is highly beneficial, and secondly allowed the three agencies to learn lessons, therefore improving the program before expanding it to additional partners (i.e., other countries and WHO). The refined terms of reference and procedures [446] can therefore include learning from the limited pilot project to more effectively foster greater international collaboration and information sharing in this area. 232 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

III-1.6) The Decision-Making Process Needs to Remain National (or Regional in the Case of Regional Integration) Acknowledging the reality of inadequate and sometimes nonexistent regulatory capacity in many developing countries, regulation of medicines in these countries often relies on the approval or opinions emitted by DRAs of developed countries. This “delegation” of the assessment and sometimes approval of medicines is the only option available for these countries. Without this external help, no control would be enforced.

This support needs to continue for less developed countries to ensure access to essential medicines for their population. However, this support needs to be coupled with a long-term plan to implement a decision-making process as well as post-marketing surveillance in the country because delegation of the decision-making process can carry some concerns. The risk/benefit balance is highly dependent upon the healthcare system and situation of each individual country (i.e., the public health situation and alternative therapies available in each country). Therefore, decisions based on this balance cannot be fully delegated to another country that has a different level of development and needs [447].

The rotavirus vaccine is a good example that demonstrates that the final risk/benefit decision to approve a new medicine needs to be performed on a country-by-country basis, or regionally when supranational legal rules exist (e.g., in Europe), and not be delegated to a third party. The first rotavirus vaccine (RotaShield from Wyeth) was pulled from the market in 1999 less than one year after its introduction due to reports of bowel blockage or intussus- ceptions. Following this withdrawal, GlaxoSmithKline (GSK) made an unusual decision for a pharmaceutical company: to first license their product, the rotavirus vaccine named Rotarix, in Mexico and other Latin American countries. Only after its approval in Mexico in July 2004 did GSK submit an application in Europe (in December 2004), and then three years later, in the US (in June 2007). This decision was driven by the fact that the risk/benefit ratio of this same product (with the same intrinsic properties and quality) was different in developing versus developed countries: ▸ In the US and most other developed countries, contracting rotavirus infection is unlikely to be fatal due to the availability of treatment for gastroenteritis and rehydration therapies. Therefore the potential risk to develop bowel blockage due to the product is a serious concern. ▸ However, in a less developed country without access to treatment for gastroenteritis and rehydration therapies, an infected child with rotavirus is more likely to die [448]. In that context, the risk of a bowel obstruction, which took RotaShield off the market, seems a small price to pay to save thousands of lives. For example, this product would save a substantial number of lives in India (where 6% of the deaths of children under five years of age are due to rotavirus) before seeing the first bowel obstruction event (the risk for this event is less than 1 in 10,000) [449].

A new regulatory cooperation needs to be established between developed and developing countries. The technical assessment of a product can be delegated, but the ultimate decision should be made in view of the specifics of each country. The acceptance of expertise is INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 233 not equal to the acceptance of a decision. As much as possible, depending on resources and expertise available, developing countries should use the expertise of reference countries but conduct a sovereign and independent decision-making process according to their national situation and needs [450].

When a country has very limited resources, the goal should be to focus these scarce resources on: ▸ Analyzing the conclusions of the technical assessment from another body (i.e., DRAs from developed countries, a regional body, or WHO) using the CPP scheme, and reviewing the risk/benefit balance in view of the specific public health situation ▸ Developing post-marketing surveillance ▸ Controlling and enforcing global requirements in their market, rather than losing time and resources developing their own requirements

The international community needs to support this effort by: ▸ Developing relevant and technical standards and requirements ▸ Supporting capacity building via financial aid and training ▸ Providing help to perform the technical assessment, leaving the ultimate decision to the country (e.g., approval of a new medicine)

III-1.7) Involvement of All Stakeholders Only effective collaboration between all stakeholders can ensure successful outcomes. The initiatives that are based on cooperation between regulatory authorities, academia, and industry (i.e., ICH, APEC LSIF, etc.) have shown that presently it is working very well as it takes into account all aspects of the problems. Of course, there are different levels of interaction, and each stakeholder has different responsibilities. Not all decisions should be collegial. It is obvious that the authorities responsible for public health need to remain the ultimate decision makers for new legislation and regulation or approval of new medicines. However, the development of new technical standards benefit from the cooperation between all stakeholders.

One key element for success is the collaboration between the public and private sectors (i.e., regulatory authorities and industry). Although authorities remain the ultimate decision makers, the pharmaceutical industries must adopt and implement the requirements to guarantee and improve the quality, efficacy, and safety of products. It is therefore important to involve industry in the development of new standards to ensure smooth implementation. This has been a key parameter for the success of ICH, and has also been important for other projects and organizations (e.g., PANDRH). Indeed, the ICH process has achieved success because it is based on scientific consensus developed between industry and regulatory experts who share responsibility for the implementation of the ICH harmonized guidelines and recommendations. This success clearly demonstrates that these two major parties need to partner to be successful. Early partnership between authorities and industry, if well organized and controlled (to avoid corruption, bribery, or any other unlawful and unethical influence), ensures that the outcome of the harmonization follows national and regional legislation and can be implemented successfully. 234 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

Other players also need to be involved in this harmonization process to help develop and disseminate information: ▸ Academia can provide scientific expertise in the development of standards. ▸ Patients and consumers, as users of the medicines, are also key stakeholders. Their level of involvement with DRAs has increased steadily over the years and they are now involved in certain regulatory discussions and recommendations (e.g., the EMA). Patient and consumer protection organizations can indeed bring additional and different points of view if they are members of scientific committees and management boards. For example, they can respond to specific requests from the scientific committees, working parties, or scientific advisory groups, especially regarding evaluation of an unmet medical need [451]. ▸ Healthcare professionals also need to be involved in the pharmaceutical network as their work is critical in the implementation of certain regulation and harmonization initiatives (i.e., improvement of information on medicines, pharmacovigilance activities, etc.). ▸ Foundations and philanthropic organizations, such as the Bill & Melinda Gates Foun- dation (B&MGF) or the William J. Clinton Foundation, have been associated with harmonization work over the past decade, especially in Africa. Players like these need to be involved in the implementation of the new system as they can support capacity building.

Transparency during the process is very important to ensure that all stakeholders are involved and represented. It is important to ensure that every party is aware and can share potential challenges before a new rule and standard is implemented. This involvement of all stakeholders must happen not only at the global level (e.g., ICH), but also at the regional level. Regional harmonization initiatives need to ensure that all players are involved, or at the least informed. For example, it is important that PANDRH continues to involve national industry associations, via the inclusion of the Latin American Association of Pharmaceutical Industry (ALIFAR) and the Latin American Federation of the Pharmaceutical Industry (FIFARMA), in order to ensure that everyone will disseminate the information and be actively involved in the harmonization process. If the harmonization became an authoritarian implementation of global requirements without explanation and regional/local support, the implementation would be more difficult, and resistance and delays could be expected.

III-1.8) Balance the Need for National Procedures and the Necessary Implementation of Global Processes As already noted, the global pharmaceutical system does not replace the current systems or procedures. Therefore, it needs to be integrated into the current processes and practices of DRAs.

Not all measures need to be centralized and not all medicines or clinical studies need to be registered globally. National or regional procedures are still necessary for most products, and flexibility needs to remain for purely national or regional needs.

Moreover, it is essential to maintain production capacity in developing countries, and some flexibility in implementing global standards, because small companies from these countries INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 235 develop and commercialize less expensive medicines (i.e., generics). These local smaller companies also have developed treatments for neglected diseases that are commercially unprofitable for the larger global pharmaceutical companies. Although it is important that even small pharmaceutical companies comply with basic principles and basic technical requirements, global harmonization should not create unaffordable costs that small companies would not be able to finance [452]. Unfortunately, this may limit the availability of cheaper generic products or treatments for neglected diseases in these countries. Finally, it is very important to ensure that the global harmonization of pharmaceutical regulations and the increase of pharmaceutical standards will not impact the humanitarian distribution of essential medicines in low-income countries [453].

It is a difficult balance that needs to be found between the necessity to have high standards for the development of new medicines, the ability of small companies in the developing world to cope with the increased costs of these standard improvements, and the assurance that a cheaper generic will not be exported (legally or illegally) to developed countries, impacting the research and development of new medicines.

III-2) RECOMMENDATIONS

As discussed in Part II-1, harmonization has important benefits for all stakeholders. A lot of work has already been done and continues to be developed. Following the assessment of current harmonization initiatives, the challenges faced, and the successes and the factors influencing these initiatives, there are a number of measures and actions that would certainly facilitate the implementation of the global pharmaceutical system presented in Part III-1. All these proposed measures and improvements are working towards better protection and promotion of public health by allowing better and faster worldwide access to safe, efficacious, and quality medicines.

Some of the recommendations below (or part of them) have already been independently discussed or proposed by other authors or groups, but have unfortunately not been implemented yet or have only been partially implemented. Reviewing these measures together, in the context of the proposed global system, shows the value of each of the recommendations.

All of the following recommended measures and actions are realistic and possible. It is of course recognized that while some of the recommended improvements may have already started or will be relatively easy to implement, some other recommendations that call for more drastic changes will certainly be more challenging and difficult to implement. These drastic changes, that will require more structural and legal changes, will necessitate strong political support and intense efforts by all stakeholders.

All of these recommendations could be classified in different ways (i.e., short-term vs. long-term projects, structural vs. technical measures, bilateral vs. regional vs. global initiatives, etc.). However, this has not been done on purpose. It is important not to grade 236 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS or order these measures because all of them are important to establish an effective global pharmaceutical system. Some minor, short-term, and easy-to-implement actions or decisions may be essential for the subsequent implementation of major changes. None of these recommended measures can indeed support, on their own, significant improvement in harmonization and cooperation in the pharmaceutical sector. However, the addition of these complementary recommended measures at the national, regional, and global levels could support the establishment of a structured global pharmaceutical system and promote better convergence/harmonization that would ultimately better protect and promote global public health.

The proposed measures and actions can be implemented at different rates and follow different timelines (i.e., short, medium, and long term). Implementation of all of them in a coordinated fashion would be beneficial considering the interdependencies of many of these measures. A detailed plan, with intermediate goals, will need to be established and tailored to the available resources and political support.

III-2.1) Recommendation 1: Establish WHO as the Coordinator of the New Global Pharmaceutical System As previously discussed, coordination of all current harmonization efforts is essential.

WHO is the best candidate for this coordinating role, and has the legitimacy to manage the global pharmaceutical system. This increased responsibility in the coordination of medicines will further fulfill its global mandate “to act as the directing and co-ordinating authority on international health work” [454]. Moreover, Article 72 of its constitutionb offers the opportunity to further develop its leading and coordinating role in the access of medicines on a worldwide basis. According to this article, ICH could become a WHO committee, and all cooperation and harmonization initiatives could be legally coordinated by WHO.

Moreover, its unique role and position allow WHO to develop privileged relationships with regional and national authorities. Today, the work of WHO is a great combination of actions at country, regional, and global levels. It therefore has the structure, expertise, and experience to coordinate the development and implementation of the harmonization of pharmaceutical regulations at all three levels. This decentralized and coordinated structure, which represents an important network of world leaders in public health, will be very beneficial in the implementation of the global pharmaceutical system. Its experience and expertise on the worldwide coordination of projects, as proven by the number of projects performed or still ongoing, and not only related to disease prevention and control, but also implementation of health b Article 72 of the World Health Organization Constitution allows the Organization to “take over from any other international organization or agency whose purpose and activities lie within the field of competence of the Organization such functions, resources and obligations as may be conferred upon the Organization by international agreement or by mutually acceptable arrangements entered into between the competent authorities of the respective organizations.” INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 237 systems [455], is also valuable. Many projects (i.e., International Nonproprietary Names [INN], ICDRA, etc.) have already facilitated cooperation and harmonization in the pharmaceutical domain (see Part I-1.1). The PANDRH initiative, established and coordinated by the Pan American Health Organization (PAHO), is also a good example. This involvement of WHO in the regional harmonization of the Americas has several advantages: ▸ It supports the initiative technically and administratively. ▸ It monitors the PANDRH website. ▸ It serves as a focal point for the coordination and dissemination of information. ▸ It coordinates activities arising from recommendations of the conferences and Steering Committee. ▸ It acts as liaison and representative of the Network in global and interregional harmonization organizations (i.e., ICDRA, ICH, etc.).

WHO coordination would also ensure that every country benefits from harmonization. Today there are many developing countries not represented in the discussion, either directly at the global level (i.e., ICH) or via RHIs (especially countries in Africa and the Middle East). WHO coordination would ensure the widest possible dissemination and availability of information and guidance. It would also serve as the important meeting point between developed and developing countries because in some countries WHO can sometimes be considered the local system supporting public health and medicine regulation. WHO has developed several regulations for countries that do not have the expertise and resources for this activity. For example, in 1998, WHO developed a manual for DRAs to help regulate generic products [456]. It has also published other regulations to help developing countries establish their pharmaceutical regulation (e.g., biologics). All these actions position WHO as the unique organization to (1) build a pharmaceutical system and regulation in developing countries, and (2) harmonize the regulation and standards in all of these countries. Moreover, the International Health Regulations (IHR) [457] are evidence that an international legal instrument, binding on all WHO member countries across the globe,c can be developed to help the international community prevent and respond to public health risks that have the potential to cross borders and threaten people worldwide. Indeed, it demonstrates that further integrated global cooperation in the area of health, with the WHO being in the center of this cooperation to coordinate this effort, is possible and beneficial [458,459].

This type of legal instrument could indeed be implemented and used in the domain of pharmaceutical regulation. A legal instrument could set up the procedures by which each country would agree to: ▸ Develop basic pharmaceutical regulation and capacities to monitor the pharmaceutical market. c Under the WHO Constitution, all WHO Member States were automatically bound by the new IHR because they did not affirmatively opt out within a limited time period; only a small number made reservations. Although the IHR does not include an enforcement mechanism per se for states that fail to comply with its provisions, the potential consequences of noncompliance are themselves a powerful compliance tool. 238 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

▸ Inform WHO, and therefore other countries, of new important risk and benefit data on products. ▸ Collaborate with other countries on technical domains and evaluations and new emerging science and issues.

This need for WHO to further cooperate with regional harmonization initiatives and organizations has been recognized in its Medicines Strategy [460]. Further WHO involvement and coordination was also clearly requested by worldwide regulators during the 14th Interna- tional Conference of Drug Regulatory Authorities in December 2010. This included the consideration of establishing an advisory network for clinical trial and GCP-related issues, and the establishment of a scheme for the exchange of complete medicine assessment reports (complementary to public assessment reports) between DRAs. This scheme would better support abridged authorization procedures based on the authorization granted by other DRAs [461].

This proposed enhanced coordination of WHO requires appropriate support. WHO was not able to adequately play its role of coordinator between ICH and non-ICH regions as was initially planned. Moving forward, appropriate resources and focus should be available to ensure active management, engagement, and coordination of international activities under an overarching global strategy. Without appropriate support, this proposed WHO coordination would remain a theoretical reorganization of global activities that would not add value.

The ongoing internal WHO reform will certainly facilitate the development of WHO as a coordinator of the global pharmaceutical system. Indeed, without underestimating its value, it has been recognized that the evolution of WHO’s work, and the increasing number of players in global health, necessitate changes in the way WHO is governed so that it can continue to carry out its mandate as the directing and coordinating authority on international health work [462]. The fundamental objectives for the ongoing internal reforms, endorsed in May 2011 by the 64th World Health Assembly, are “to foster a more strategic and disci- plined approach to priority setting, to enhance the oversight of the programmatic and financial aspects of the WHO, and to improve the efficiency and inclusivity of intergovernmental consensus building, by strengthening the methods of work of the governing bodies. The main objective of reforming WHO’s role in global health governance is to increase the level of engagement with other stakeholders who influence global health policy and to capitalize more effectively on WHO’s leadership position to bring about greater coherence among the many actors involved in global health.”

Of course, this is a general reform of WHO not specifically targeted to its roles in the pharmaceutical domain. However, some of these proposed changes are relevant for harmonization and cooperation in the pharmaceutical domain: ▸ Better coordination of activities, not only internal WHO activities, but also activities with external partners at the global, regional, and national levels ▸ Increased global–regional linkage ▸ Better coordination of international work with other partners and initiatives through a range of coalitions and alliances, partnerships, and through some form of framework or INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 239

code of conduct (without undermining its intergovernmental nature or opening itself to influence by those with vested interests) ▸ Enhanced support for Member States’ participation with a greater exchange of information through electronic and other means.

III-2.2) Recommendation 2: Establish an International Medicines Agency This new International Medicines Agency could be a branch of WHO that would coordinate the global pharmaceutical system and manage the day-to-day business in line with WHO strategy. One of its objectives would be to enhance and better structure communication between worldwide DRAs from both developed and developing countries, and put in place systems and tools to facilitate this collaboration. It would also represent WHO in international discussions and conferences related to harmonization and cooperation in the pharmaceutical sector.

The International Medicines Agency should be based on the EMA model. It should be an administrative body that would utilize a network of national experts. It would also work closely with the WHO’s Department of EMP and ICH, and would use all other appropriate WHO programs and structure (other global departments, but also regional and local offices) to fulfill its responsibilities and exchange information with worldwide DRAs.

This new Agency would also coordinate certain new programs proposed in this section: ▸ The international procedure for the evaluation of new medicines (see Recommenda- tion 12) ▸ The control of global clinical studies (see Recommendation 9) ▸ The safety framework (see Recommendation 8)

Other long-term projects could also be developed by this International Medicines Agency, such as: ▸ Establishment of a scientific advice procedure for products that will be registered through the international procedure. ▸ Establishment of a global designation procedure for orphan medicines, with harmonized criteria. As a first step, the EU/US bilateral collaboration on orphan drugs, and especially the agreement to accept the submission of a single annual report from sponsors of orphan products [463], could be extended to all countries having such an annual reporting requirement. This single global annual report would be easy to implement on a global basis because each regulatory body could continue to conduct their own review of the report to assure the information meets their own requirements. However, this global reporting would decrease the resources needed from the sponsor to prepare separate reports and would help regulators better identify and share information throughout the development process of an orphan product. These two outcomes are critical to support the development of orphan drugs since: • They are mainly developed by small companies with limited resources. • Their development needs to be coordinated globally to be efficient, due to the limited pools of patients and exposure. 240 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

This Agency would be the primary point of contact for the countries and regions for all these procedures and activities. It would be responsible for the coordination of actions, evaluations, and the dissemination of information (i.e., assessment and inspections reports, etc.).

Appropriate IT projects (e.g., databases, quick and secure communication systems, quality and knowledge management systems, etc.) would need to be developed to support international activities and facilitate the rapid exchange of information and documents (e.g., CPPs, assessment and inspection reports, etc.) and joint activities. Indeed, a pilot collaboration project in inspection has shown that innovative tools, databases, and systems are needed to facilitate real-time exchange of information. Without such tools and support, cooperation is less efficient [464]. In addition, this electronic platform would need to protect the exchange of confidential and sensitive information between regulators.

It is important to establish a clear mandate to define the roles and responsibilities of this new Agency. A detailed strategic plan would need to be created to define short-, medium- and long-term objectives. Based on its mandate and strategic plan, a detailed analysis should be conducted to evaluate the staff and financial support that would be required. Governance and reporting structures would also need to be defined.

It may be appropriate to initially limit the responsibilities and scope of this new Agency to specific products such as orphan medicines or medicines for major unmet medical needs. At the end of this pilot phase, a review of the operation of the new system would be conducted. The goal of this audit would be to review the extent to which the results achieved have met the objectives. After this review and the implementation of necessary improvements, the mandate and scope of the Agency could be increased.

III-2.3) Recommendation 3: Further Strengthen and Enhance ICH to Become a Viable International Body Proactively Developing and Maintaining Global Technical Standards The ICH process remains a key component in the global harmonization of pharmaceutical regulations. Since its launch in 1990, this process has clearly proven its utility and has had a positive impact on the development of pharmaceutical products. Much success has already been achieved that goes beyond the three original ICH regions and original goals. This initiative contributed to the enhancement of global public health by preventing unnecessary duplication of development work without compromising the regulatory obligations of quality, safety, and effectiveness. This has been achieved through the harmonization of technical requirements for the registration of medicines and the development of many critical tools that facilitated global regulatory communication. This harmonization has been relatively quick considering the level of disharmony that existed. It is now a mature harmonization process and all stakeholders recognize its value [465–467]. These activities towards harmonization of technical standards and requirements obviously need to continue to support the next steps of international cooperation. It is also essential that ICH, in collaboration with other organizations if necessary, continue to harmonize dictionaries and terminologies (e.g., standards for INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 241 the identification of medicines [468]) and tools to strengthen and ease communication. The success of the Common Technical Document (CTD) format or ICH’s Medical Dictionary for Regulatory Activities (MedDRA) has demonstrated that harmonization of language (i.e., format of dossier, dictionaries, etc.) is essential to cooperation [469]. Without common language, exchange of information and different points of view is more difficult.

One of the key benefits of ICH has been to create, for the first time, a structured forum that allows international experts from both DRAs and the pharmaceutical industry to share their experience and set up high scientific-driven standards. Also, mechanisms have been established to facilitate dialogue and collaboration between ICH and non-ICH regions. These efforts obviously need to continue, and it will be critical to utilize this well-established and recognized forum to support the next steps of global harmonization and cooperation. How- ever, the pharmaceutical market and regulatory environment have changed drastically over the past decade. Although ICH has evolved over the years, new expansion and focus are necessary to meet current and future needs. Several improvements can be recommended to strengthen ICH and prepare it for the next stage of harmonization.

III-2.3.1) ICH Needs to Become a Truly International Body While the success of ICH is beyond any doubt and everyone acknowledges the huge participation of ICH in the current status of harmonization, it is important to recognize that the major harmonization challenges are now significantly different from those 20 years ago when ICH was created. In the past, the vast majority of those new substances and products were developed in Western Europe, Japan, and the US. It was therefore relevant to limit the scope of ICH to these three regions in order to facilitate the coordination of activities. How- ever, research and manufacture of new products is not confined to these three ICH regions any longer. As discussed in Part II-2.2.1, non-ICH regions are now an integral part of drug development. New emerging countries are more and more involved and are playing significant roles in this area: ▸ Clinical trials have expanded into regions including Asia, Eastern Europe, Central and South America, the Gulf countries, and Africa. Many clinical trials have been conducted on a multinational basis. ▸ Non-ICH countries are becoming major suppliers of Active Pharmaceutical Ingredients (APIs).

Moreover, non-ICH regions include some of the most dynamic and rapidly changing pharmaceutical markets. Some of these regions have recently upgraded their regulatory systems to promote the development of innovative and better-quality products. For example, China was the first country to approve a gene therapy product [470]. That reality needs to be taken into account and measures need to be taken to ensure that the worldwide development and manufacturing of medicines comply with ICH standards because these medicines will be distributed globally.

ICH understood early on that communication would be necessary between ICH and non-ICH regions in order to be successful and to respond to the increased globalization of drug development and manufacture. It has therefore extended its activities beyond ICH regions to facilitate 242 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS implementation of ICH standards in non-ICH regions. Over the years, different actions have been put in place to facilitate the exchange between ICH and non-ICH parties, including: ▸ Inclusion of non-ICH Observers at the Steering Committee ▸ Creation of the Global Cooperation Group (GCG) ▸ Extension of GCG membership to RHIs and then the DRAs of individual countries ▸ Creation of the Regulatory Forum ▸ Invitation of RHIs to the Steering Committee and Working Group (WG)

ICH’s GCG has been a key element of its success because it increased awareness of ICH’s work and supported implementation of ICH standards outside the ICH regions (via training and seminars). However, all these measures are no longer sufficient to respond to the increasing importance of non-ICH regions in the pharmaceutical sector. Despite these important adjustments over the years, the current structure and management of ICH, solely governed by the three ICH regions, has become obsolete, as it no longer represents the current condition of the pharmaceutical market. Criticisms have been made regarding the current management of ICH [471]. The lack of representation of developing countries on the ICH Steering Committee has also been criticized [472]. The ICH Steering Committee itself has recognized that ICH has to develop new operating principles to better include non-ICH organizations and regions and leverage ICH efforts [473].

ICH needs to become a truly international body versus a multinational initiative producing standards used beyond its borders. Non-ICH regions need to be better integrated into the ICH process. Also, incorporation of the challenges of emerging countries has to be done earlier in the process to facilitate implementation of the ICH standards in these regions. To do so, a more drastic modification of the ICH organization is necessary. Selection of topics for harmonization and development of standards needs to consider worldwide needs and challenges, and this should not be only directed by the three ICH regions.

Therefore, membership of ICH needs to change so that all regions are represented. Of course, the ICH Steering Committee cannot include representatives from all countries in the world, but the extension of this committee to non-ICH members is necessary. The ICH Steering Com- mittee membership should therefore be revised to include:

▸ A representative from each of the RHIs currently represented at the GCG: This inclusion should be conditioned to the willingness of these RHIs to promote implementation of all ICH standards in their territory. Although most of these RHIs cannot legally force their DRAs to apply such standards, there should be active engagement to work towards this goal. Procedures should also be developed to evaluate future adhesion of additional RHIs that would apply, or to manage possible future changes in regional representation (Do we need multiple RHIs to represent several subregional of Africa or only one regional representation of the entire continent?). This adhesion will have to be evaluated on a case-by-case basis, taking into account the involvement of the candidate RHI on pharmaceutical harmonization, what region and area this RHI represents, and its willingness to facilitate implementation of ICH standards by its members.

▸ A representative from the DRAs of some individual countries: Criteria for inclusion of individual countries in addition to the RHIs need to be carefully defined. INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 243

The value of these inclusions has to be seriously evaluated on a case-by-case basis to keep the ICH organization manageable. Also, these DRAs should commit to follow the ICH recommendations, as is already the case for the current ICH regulatory members (i.e., EC/EMEA, US FDA, and MHLW). Two different scenarios are possible: • DRAs from major developed countries already involved in global harmonization and currently implementing ICH standards (i.e., Australia or Canada) • DRAs from emerging countries playing a significant role in the development and manufacture of medicines, and not sufficiently represented by current RHIs.

An alternative to this proposed structure would be to reduce ICH membership to major developed countries (i.e., EU, Japan, US, and also Canada and Australia) and WHO. WHO would then become the coordinator of ICH activities in the developing regions. Although, this option would have certain benefits (it would reduce the number of participants and involved countries with the same level of expertise, but it would also allow representation of countries not currently part of an RHI), past experience has shown that it would be difficult to implement. Since its establishment, WHO has been participating in the ICH Steering Committee as an Observer to play this role of global coordinator and to be the link with non-ICH regions. Unfortunately, this important task has been difficult to implement. Moreover, this alternative structure would not leverage all the collaboration and networking that have been built by ICH over the years. RHIs have been very involved and committed to GCG activities. Therefore, these regional representatives seem the most appropriate and effective way to link global ICH activities and local markets in order to ensure: ▸ Appropriate integration of regional and national needs and challenges in ICH work ▸ Global awareness and implementation of ICH standards

Of course, WHO could supplement the RHIs’ work by increasing awareness of ICH work to all its members and incorporating ICH standards in WHO recommendations and guidelines.

It is important to note that this revised membership would ensure that global pharmaceutical companies would still be represented by the three current industry ICH members (i.e., JPMA, EFPIA, and PhRMA), and that smaller companies from emerging countries would be represented by RHI representatives because most of these regional initiatives include industry representation.

Finally, to manage the increased number of ICH members and the different capacities and expertise between current and new members, other organizational changes would be necessary: ▸ First, the decision-making process (e.g., for the development or revision of guidelines) should be reviewed and revised if necessary to accommodate the increased number of participants and avoid unnecessary bureaucracy and administrative burden. ▸ Second, although all newly defined ICH members would have access to all ICH work and therefore the ICH working parties, their participation in all activities should not be mandatory. It is important that all newly defined ICH members have the opportunity 244 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

to review ICH documents (i.e., plans, draft guidelines, etc.) before they move to the next step of development. However, active participation of all ICH members in the development of guidelines is not necessary, and may in fact impede the productivity and focus of the WG and complicate its management. Moreover, some RHIs or individual DRAs may not have the resources and/or expertise to support all scientific discussions. Mem- bership of each WG should therefore be thoroughly evaluated at the beginning, taking the following parameters into consideration: • The number of WG members should be limited to the minimum to facilitate their work. Each participant needs to have a significant background and expertise on the topic to harmonize. • Each WG should include appropriate representation from both DRAs and industry. • Third parties (e.g., pharmacopoeial authorities, generic industry associations, representatives of the nonprescription pharmaceutical industry, etc.) could be invited to some WG discussions if necessary on an ad hoc basis. • Although not actively engaged in the development of standards, all ICH members should have the opportunity to review the draft document before it moves to the next step of development. For example, the organization of regional mini-symposia by the RHIs during Step 2 of technical guidelines would allow for early feedback to be received from regions. • Clear and detailed meeting minutes of each WG discussion should be issued and sent to the ICH members not actively involved so that all ICH members can provide feedback to the WG coordinator if necessary. • Capacity limitation in certain developing countries should not impact the scientific discussions or limit the development of high state-of-the-art standards. Common standards need to be based on scientific discussions and data. There should be no compromise on safety and quality to ease the harmonization. Capacity limitation in certain developing countries should be managed by other measures (see Recom- mendation 5), not by establishing substandards. ▸ Third, the use of teleconferencing or any other present day electronic communication tools should be encouraged. Face-to-face meetings should be limited to key discussions.

This fundamental structural change would ensure better international representation and would transform ICH into a truly international body. Early and more active participation of all concerned parties would facilitate implementation of ICH standards on a global basis. The ongoing ICH reform [92–4] is an important step towards this necessary evolution of ICH.

III-2.3.2) ICH Needs to Better Monitor Implementation of ICH Standards on a Worldwide Basis One of the challenges for the future expanded ICH process will be to ensure implementation of its standards. With the proposed structural changes and increased scope of the initiatives described above, measures need to be in place to ensure that all ICH standards will be implemented in both developed countries (as was the case in Europe, Japan, and the US), but also in new ICH members that do not always have the same resources and expertise. Without appropriate global implementation and maintenance of its standards, the new extended ICH will not be successful. INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 245

First, it is necessary to ensure that emerging countries will have sufficient support. This technical and regulatory support can be provided via appropriate training to the DRAs and seminars with local industries. These regional training events have already been organized in the past. They should become a standard part of the ICH process for each new guideline and standard. The inclusion of representatives from RHIs and DRAs from individual countries in the WGs will increase the number of potential trainers. As has been done in the past, RHIs should be responsible for organizing seminars and training in their regions with support from ICH experts and WG coordinators. Support to the appropriate regional training should be an important responsibility of each WG and ICH expert, who should be expected to travel to each region to discuss, explain, and teach the new guidelines.

Because GCG has been in charge of coordination of international training in the past, it makes sense that this group continues to be involved. The overall global coordination role of the GCG (i.e., the relationship between ICH and non-ICH regions) will not continue to be relevant as all regions will be directly represented at the Steering Committee. The mandate of the GCG should therefore be reviewed to focus on the global coordination of implementation of ICH standards. This will include the following three main activities: ▸ Support RHIs in facilitating dissemination of standards globally. This will be a role of support because RHIs will now be the primary and direct link between the Steering Committee and the countries. ▸ Assess all national or regional requests (i.e., training, seminars, or any other projects supporting implementation) and coordinate the appropriate availability of trainers and expertise from the relevant WG. ▸ Establish a system and procedures to monitor the implementation and continued appropriate use of the new or revised guidelines and standards.

The GCG will be responsible for updating the Steering Committee and the WG on the status of implementation and to advise on appropriate measures if the implementation or use of guidelines and standards are not satisfactory. Monitoring reports from the GCG will also help ICH to maintain the guidelines and standards and to decide when revisions or updates are necessary. Of course, ICH guidelines must also be revised when science or practices evolve.

Second, it is important to ensure that ICH guidelines and standards are implemented globally without modification or adaptation. These regional and national adaptations should be an exception and be justified because they can impede the effort of harmonization and require duplication of development work. Even a slight difference in adapting certain guidelines (e.g., GCP) can sometimes create important obstacles and become an impediment to global development (e.g., for the performance of multinational clinical trials in the case of GCP). Ultimately, this impacts access to drugs in development and clinical studies for patients of certain countries.

If there is a major implementation challenge anticipated in a region, which may require adaptation of the rules, this challenge should be discussed early on within the WG to evaluate appropriate solutions. It is indeed counterproductive if a harmonized standard is then 246 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS adapted nationally. For example, it is peculiar that ASEAN has developed its own CTD as the ASEAN CTD is clearly based on the ICH CTD. So why did the ASEAN CTD not just implement the ICH CTD? In general, ASEAN follows the ICH work and recommendations very strictly when developing ASEAN Common Technical Requirements (ACTRs), and ASEAN recommendations often refer to ICH. This is indeed a good example of implementation of ICH recommendations and guidelines by a non-ICH region. But for the ASEAN Common Technical Dossier (ACTD), ASEAN did not keep the ICH CTD Module 2, and has included the documents of the Module 2 (i.e., Quality Overall Summary, Summaries and Overviews) in the quality, nonclinical, and clinical sections. According to ASEAN’s Pharmaceutical Prod- uct Working Group (PPWG) members, the ACTD was developed based on the ICH CTD, but also took into consideration practices among the ASEAN countries. It was felt that the format for the ACTD was more structured and helped with the flow of the evaluation. These differences and disharmonies, only based on preferences and not on legal or scientific problems, are not a big adaptation, but they still necessitate unnecessary reformatting of applications for registration in the ASEAN regions, which delays the registration of the medicines.

This ACTD example shows the difference between: ▸ “Being part of the harmonization process”: The EU, US, and Japan adopted the CTD without modification of the format, although some specifics exist such as the inclusion of the Integrated Summary of Safety (ISS)/Integrated Summary of Efficacy (ISE) in the US. ▸ “Being free to integrate and adopt the ICH guidelines in totality or to modify them before adoption” (e.g., as ASEAN did for the ICH guideline).

With the proposed organizational changes of ICH, this type of adaptation should hopefully not happen in the future because RHIs will be active members of the ICH Steering Committee and WGs and not only observers via the ICH GCG. More proactive communication, transparency, and exchange within the WGs should decrease the need for adaptation of guidelines post-adoption. The Regulatory Forum is also a great tool to convince worldwide regulators to use these global ICH standards and to resolve implementation issues [474].

Sometimes adaptations of rules are not intentional and it is a matter of language and translation, culture, and interpretation. The only way to minimize this misinterpretation is to involve all parties early in the process to make sure everyone understands the objective of the harmonization. It is also critical to make sure that the harmonized guideline is as clear as possible, leaving no room for ambiguity. Although critical, this is sometimes difficult. For example, although the ICH M3 work [475] is a good example that demonstrates the importance of the ICH harmonization process and its positive impact on the minimization of the use of animal resources during development, it also clearly shows the difficulty in developing scientific consensus. ICH recognized in the revised M3(R2) guideline (Section 18) that although this document represents an important step forward in the harmonization of nonclinical requirements, there remain some further important issues yet to be resolved (i.e., the duration of repeated dose toxicity studies, the remaining difference on the inclusion of women of childbearing potential in clinical studies, and the estimation of the first dose in humans). INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 247

III-2.3.3) ICH Needs to Become More Proactive in the Development of New Standards As mentioned in Part III-1, the establishment of a global system requires a new way of working. A proactive harmonization approach needs to be implemented to enhance the benefit of global cooperation. ICH has a key role to play to support this new approach. The proactive development of high-quality, state-of-the-art standards for new emerging topics would be an “a priori harmonization” because it would develop common standards to avoid future disharmony.

ICH has been focusing on the harmonization of current disharmonies between countries and regions. This activity is important and needs to continue. However, this well-established and functioning forum that includes respected international experts should now also be utilized to discuss new emerging topics that are not yet regulated or for which no standard exists. ICH needs now to become more proactive in new emerging topics and lead global proactive collaboration that will support innovation. It should become a body that allows for the exchange and consensus of new concepts and approaches, before national or regional guidelines and recommendations are issued. This is an important area of improvement to position ICH as the central point for the development and maintenance of all international technical and regulatory standards.

This early scientific discussion and development of standards would benefit global public health. For example, the EU/US FDA collaboration on biomarkers (e.g., development and joint qualification), initiated under the Transatlantic Administrative Simplification project, supports the acceleration of pharmaceutical product development. Also, the US FDA and EMA established a cluster on advanced therapies [476]. This bilateral initiative on these two emerging scientific topics is positive, but this work would be even more effective if it were done under a global scope. Indeed, it would not only rejoin all worldwide experts in these new domains, but also proactively harmonize the terminology and develop common standards and regulations for new technologies.

Early on, the ICH Steering Committee recognized the value in preventing future disharmony through early collaboration and exchange of information on newly emerging issues, originat- ing in one of the regions [477]. The ICH E15 [478] and E16 [479] guidelines are good examples of how ICH could support innovation via the development of common terminology and standards in new emerging areas. Unfortunately, there have not been many other accomplishments to that end, and ICH remains reactive more than proactive in facilitating the agreement of global rules and standards.

The discontinuation of activities towards the development of a new multidisciplinary guideline (Guideline M6) on gene therapies for lack of resources demonstrated the previous non- commitment of ICH to “proactive harmonization.” The lack of leadership in the discussion of requirements for Phase I studies following the TGN1412/TeGenero trial issue (see Part III-1.2) or proactive enhancement of the M3 guideline are other examples of ICH’s lack of proactivity. It is indeed interesting to see that the ICH M3 discussion related to explanatory clinical studies started after the release of regional guidelines. 248 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

Both the US FDA and EU had already released their own guidelines on this new concept, whereas Japan did not yet have a guideline on this subject. The US guideline, titled “Explor- atory IND Studies,” was released as a draft in April 2005 and then as final guidance for industry in January 2006. In Europe, the CHMP began to discuss this topic in 2002 and then released a position paper in January 2003 titled “Position paper on non-clinical safety studies to support clinical trials with a single microdose,” which has since been revised. In March 2006, the CHMP also released for consultation a concept paper that proposed the development of a CHMP guideline on “the non-clinical requirements to support early phase 1 clinical trials with pharmaceutical compounds.” Many years after the start of discussions and activities by the US FDA and the CHMP on this topic, ICH acknowledged, in the Final M3(R2) Concept Paper endorsed on September 20, 2006, that these regional initiatives presented some level of disharmony. ICH also tried in the revised M3(R2) guideline to harmonize the technical requirements for these exploratory clinical studies. As previously mentioned, the a posterior harmonization of scientific requirements is a long process involving a lot of discussions and interactions. So, why did the M3 group not try to reach consensus on this new approach and revise the M3 guideline earlier to include this new emerging microdose approach? Why did they wait for the release of regional recommendations to harmonize the differences between the EU and US positions instead of trying to reach a worldwide consensus up front before regional authorities took a position and released guidance? This would have prevented the duplication of work and discussion by the US FDA, CHMP, and ICH and the release of specific regional recommendations that have now created confusion about requirements.

This lack of proactivity may be related to different factors (i.e., structure, lack of resources, no commitment from regions to raise the issue to ICH when encountering a new emerging issue, etc.). All these potential causes should be evaluated to propose appropriate solutions. It would certainly be beneficial to establish an ICH reflection group to assess options on how to tackle new emerging scientific and development issues as the EMA did in 2004 with the EMA/CHMP think-tank group on innovative drug development. Regular meetings (e.g., on an annual basis) should then be organized to evaluate evolution of science and technology to determine if work is needed in a new emerging area.

In any case, the basic philosophy on how to resolve an emerging problem in the health and pharmaceutical area should change. Resolution of such problems is in the best interest of all countries. Development of national or regional standards is still possible to cover regional specific regulations, but every effort should be made to ensure that “global” topics related to the development and marketing of pharmaceutical products are first assessed globally. They should be evaluated for (1) their international impact, and (2) to determine if it is possible to have a common global view and position on these topics. Development of solutions carried out at the global level would naturally have to suit national needs without duplicating efforts.

As previously stated, ICH is the most appropriate body to evaluate if a problem or the development of a new standard would have a global impact. However, to be successful, ICH needs to be supported by the active involvement of WHO, RHIs, and national authorities. WHO, and national and regional authorities should defer new areas and emerging concepts to ICH for international discussion. When an emerging problem arises, the national and regional INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 249 authorities should first check at which level this problem can best (or must) be resolved instead of first developing national rules, regulations, and standards (i.e., the microdose case). Again, the priority should be focused on the international level. Only if the international level is not relevant or possible should the new regulation be developed at the regional and national level.

To support this evaluation, specific criteria should be useful in evaluating at which level a problem should be discussed and solved. There are three primary criteria that authorities of a specific country or region should use to examine a new problem: ▸ Is the problem only present at the national or regional level? ▸ Could the problem (or its resolution) affect other countries in the future? ▸ Would a global cooperation of the topic bring a better solution or facilitate resolution?

A clear and simple process should be in place to allow any stakeholder (i.e., national DRAs, pharmaceutical companies, academia, etc.) to submit a request to ICH for evaluation of new topics or standards or to forward information on a problem that requires discussion on a regional and global basis. The report template should include the following sections: ▸ Problem to be addressed and the urgency of the resolution ▸ Background information, problem analysis, and clarification on why the problem needs to be resolved at the regional and global bases ▸ Proposed potential options that could be adopted at the regional or global level

This change of the process (i.e., to evaluate if a standard needs to be developed globally by ICH before starting parallel national or regional activities) would certainly: ▸ Fully support global harmonization and cooperation in the pharmaceutical sector ▸ Ensure availability of high-quality standards on a worldwide basis ▸ Allow countries to obtain early access to standards on new emerging topics, especially those that do not have the resources and expertise to develop their own standards.

Finally, this global approach would drastically decrease the resources needed for the development of technical standards and allow for better allocation of these resources. Most of the influential and well-known national and regional experts that are involved in the preparation of national and regional recommendations are also part of the ICH discussions. Focusing on an international recommendation via ICH, versus preparing national and regional recommendations and then harmonizing these recommendations, seems more logical and a more efficient use of resources.

The definition of a new proactive approach recently announced by the ICH Steering Commit- tee [97–2] will hopefully improve the situation.

III-2.3.4) Legal Basis With the proposed organizational changes, ICH will become a viable international body. It is therefore logical to connect it with WHO so that it has a greater international visibility. This official integration of ICH under WHO, which is fully aligned with WHO functions and 250 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS objectives,d would not only increase worldwide visibility of ICH, but also further motivate WHO to fully support the development of global standards through ICH. It would be a strong political commitment to global harmonization and cooperation in the pharmaceutical sector.

Currently, ICH is an independent joint initiative, which has no real legal basis (no treaty or constitution has been signed). This is a project that has only been agreed upon between the three ICH regions. Until now, ICH has not imposed its views on any country or regions and does not have the legal basis to do so, but it does attempt to facilitate the understanding and use of ICH standards and recommendations. Compliance is voluntary for the non-ICH regions, and even for the ICH regions, ICH guidelines and recommendations do not have the force of law [480]. This absence of legal enforcement has not impeded ICH’s success. Until now, commitment from both DRAs and industry from the three ICH regions was sufficient to increase mutual understanding and confidence for cooperation and implementation of harmonized standards and guidelines. Although not legally binding on DRAs or industry, ICH recommendations are often treated as absolute requirements. Moreover, although ICH is not able to initiate international standards and guidelines for medicines (only WHO has this authority), some ICH countries have also implemented its recommendations, either partially or entirely.

The next stage of harmonization and the global extension of ICH will however require more visibility and further political commitments from all countries in the world: ▸ “Proactive” cooperation on new technologies in order to allow up-front harmonization will demand political support. Regulatory bodies will first need to discuss with international peers before releasing individual requirements. ▸ It may be difficult to obtain the same level of commitment from the new ICH members due to limited resources or expertise.

The extension of ICH and the implementation of its guidelines in all countries in the world can be facilitated if ICH operates within the auspices of WHO. This could be done if ICH became a new WHO committee in accordance with the WHO Constitution [481].

As a specialized Agency of the United Nations (UN), WHO operates under the general powers of the UN and the authority provided by its own constitution. Although its conventions and agreements are not automatically legally binding to its memberse and do not create automatic legal obligation on its Member States, WHO has more authority than ICH for the adoption and implementation of international standards [482]. In addition to the possibility to adopt conventions or agreements, WHO also has the authority to adopt regulations on several topics, including “standards with respect to the safety, purity and potency of biological, pharmaceutical and similar products moving in international commerce” [483]. Finally, WHO can make recommendations to its members [484], and each country has the obligation to report annually on the action taken with respect to recommendations d Article 2(u) of the WHO Constitution states that the Organization shall “develop, establish and promote international standards with respect to food, biological, pharmaceutical and similar products” e According to the WHO Constitution Articles 19 and 20, conventions and agreements adopted by WHO need to be ratified or turn into law by each country in accordance with its constitutional processes. INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 251 made to it by the organization and also with respect to conventions, agreements, and regulations [485].

In addition to providing a better legal status to ICH and better integration of its work in the global system, the inclusion of ICH within the WHO organization would also negate criticisms that have been raised against ICH [482], such as: ▸ ICH is governed by only three major regions, and developing countries have minimal say in the development of ICH standards. ▸ It can be perceived that major pharmaceutical companies are driving these activities to facilitate their global expansion and increase their revenues.

Political representatives have officially criticized ICH because it was not established under WHO [486].

Finally, even if ICH was born from discussions at the WHO ICDRAs meeting in 1989, the low level of involvement of WHO since the creation of ICH has been a continuous criticism. It would be beneficial to realign ICH standards and WHO recommendations and to better structure and harmonize the development of international standards. The increased coordination and integration of ICH standards in WHO recommendations would certainly increase clarity and therefore ensure adherence of all countries to ICH standards. Also, the global discussions occurring in specific global forums within the WHO organization can provide information to ICH for the development and revision of technical guidelines. The development and revision of guidelines to incorporate pediatric special needs is an example of where the discussion occurring within the WHO network (e.g., the Pediatric medicines Regulators’ Network [PmRN]) can help ICH succeed [487].

III-2.3.5) Conclusion The development and maintenance of standards on a worldwide basis versus having each country and region developing their own obviously have many advantages, such as: ▸ Avoiding duplication of work and discussions ▸ Allowing for the involvement of the best international experts in the field ▸ Removing certain activities from DRAs so that they can focus on other tasks (i.e., evaluation and control of medicines against these common worldwide standards). ▸ Allowing for global development and acceleration of availability of medicines globally

The success of the ICH initiative has resulted in considerable interest from outside the three ICH regions. This interest and collaboration between current ICH and non-ICH regions will certainly help in advancing ICH to this new recommended phase. If this proposed radical reorganization and extension is successfully achieved, ICH will definitely become a key element of the global pharmaceutical system and the central point for the development and maintenance of all international technical and regulatory standards.

Some aspects of Recommendation 3 are in the scope of the ongoing ICH reform [92–4] that was officially announced during the finalization of this book. This critical reform will hopefully resolve most of the current limitations of ICH discussed in this document. 252 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS III-2.4) Recommendation 4: Identify and Qualify “Reference Countries/ DRAs” Today some DRAs are assuming the role of reference authorities (e.g., deliverance of CPPs, training support, etc.) without having been evaluated to confirm if they can perform this function. Developing countries, which do not have the resources and expertise to assess the documentation on their own, rely on the documentation received from partner authorities to make decisions.

Due to the importance and critical role of these reference DRAs for the registration of new medicines in developing countries, it seems urgent to confirm which DRAs can perform this role of reference for other countries. Moreover, several programs proposed in this section will also require appropriate support from reference DRAs (e.g., the international procedure for registration of medicines). Before implementation of these new procedures and programs, appropriate qualification of reference countries and DRAs is necessary to ensure that such organizations have appropriate expertise, resources, and systems to accurately support the global pharmaceutical system.

With the CPP scheme, WHO started to define the requirement of a “reference DRA,” but further efforts are necessary in this area [488].

A certification program (based on International Organization for Standardization [ISO] standards and coordinated by WHO) should be established and clear and auditable criteria and parameters should be defined. Audits should be performed by WHO or by independent parties.

Several areas will need to be evaluated to make sure that a given DRA can become a “Refer- ence DRA,” including: ▸ The governance and efficiency of the structure ▸ The control and maintenance of systems and databases that are in place ▸ The quality system and the appropriate use of good practices ▸ The transparency of the decision-making processes ▸ The policies relating to resolving conflicts of interest ▸ The control of confidential information and trade secrets ▸ The appropriateness of processes and technical standards ▸ The training and expertise of staff ▸ The hiring system ▸ The ethical principles ▸ The relevant national legislation (i.e., patent law, data exclusivity, etc.)

PAHO has already developed such a program for regional reference authorities (i.e., Level 4) [489]. This should be used as an example to evaluate reference authorities in other regions, but also to designate International Reference Countries and DRAs.

III-2.5) Recommendation 5: Strengthen Assistance to Developing Countries to Better Integrate Them in the Global Pharmaceutical System The development of health systems is critical to ensure availability of medicinal products in developing countries. This is a prerequisite for the implementation of pharmaceutical INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 253 regulations and international harmonized standards [490]. According to the WHO framework for health systems, a well-functioning health system ensures equitable access to medical products, vaccines, and technologies of assured quality, safety, efficacy, and cost-effectiveness (especially those that are essential), and their scientifically sound and cost-effective use [491].

To achieve these objectives, many actions are needed, including implementation of national policies, standards, guidelines, and regulations that support policy. Many international guidelines have already been implemented, but each country needs to validate, monitor, promote, and support implementation of these international norms and standards to promote quality medicines, vaccines, and technologies, and ethical, evidence-based policy options and advocacy. They also need to monitor the quality and safety of medicines [490].

Of course, the health system of developing countries does not need to be as sophisticated as those of the developed countries. This would not be realistic, due to a lack of resources and expertise, or even necessary. However, their health system should at a minimum ensure the implementation of agreed-upon international norms, the adequate monitoring of medicinal products on their national market, and the establishment of national specific policies (i.e., distribution, cost, etc.). All these actions need to be supported by the international community as they require funds, resources, and expertise. The limited resources in these countries should be focused on areas that cannot be delegated to other countries or international organizations.

Several projects have already been funded to promote the establishment of adequate health systems in developing countries (e.g., WHO support of the Health System Strengthening activities within Global Fund proposals). Additionally, specific procedures have been established by WHO and developed countries to support registration of medicines in developing countries (e.g., CPP scheme, WHO prequalification of medicines, Article 58 of the European Regulation (EC) No 726/2004, etc.). Some developed countries have already included this development cooperation in their legal texts. For example, the European Treaty of Lisbon introduced for the first time a specific legal basis for development cooperation and humanitarian aid [492].

It is essential that the worldwide community continue to support developing countries to facilitate their integration into the global pharmaceutical system. Appropriate funds should also be available. This support should be customized to each country’s needs and focus on two priorities: ▸ The development of appropriate health systems ▸ Strengthening the current framework to provide adequate technical assistance to these countries

Several improvements can be recommended to increase assistance to developing countries.

III-2.5.1) Continue to Build Regulatory Capacity in Developing Countries and Train Staff on Critical and Focused Core Functions Regulatory capacity is characterized as the ability of national regulatory authorities (i.e., DRAs or Ministries of Health [MoHs]) to perform their core functions to ensure the availability 254 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS of high-quality and safe medicines. Regulatory capacity is needed for registration of new medicines, but also for post-marketing activities and surveillance of products after marketing authorizations are issued. Mechanisms to develop effective post-marketing surveillance need to be incorporated into any regulatory system.

Appropriate systems and structures must be in place to ensure effective medicine regulation. It is obvious that weak regulatory frameworks and lack of enforcement can lead to various problems (i.e., regulatory delays and backlogs, lack of specific timelines, lack of regulatory tools and guidelines, lack of requirements, and lack of access to appropriate technology) that ultimately limit access to medicines. Moreover, norms and standards set by WHO or other organizations to safeguard public health have little impact if countries lack the capacity to regulate and enforce compliance of these standards [493].

However, in many countries, drug regulatory procedures are still largely ineffective due to chronic shortages of human and technical resources. Authorities in developing countries are resource constrained in terms of staffing, standards, systems, and training. Staffing seems to be the key challenge, but sound and consistent standards, and the existence and effective implementation of laws, regulations, guidelines are also necessary for ensuring medicines that meet set standards are available in the country. For various reasons, many regulatory authorities do not have the full capacity to make a complete assessment of the application for registration of medicines, and have to rely on the assessment of other regulatory authorities.

Capacity building is an important part of the WHO mandate. Many projects have been initiated in this area [494]. For example, WHO has been working with certain countries to support their commitment to build and improve national regulatory capacity by assessing their regulatory system to identify gaps and develop strategies for improvement [495].

Setting up pharmaceutical regulations and systems in a developing country needs to follow a stepwise approach by addressing the most important items first. It is important that national authorities with limited resources concentrate on actions that provide major added value regarding public health. For instance, in resource-constrained countries, setting up an adequate pharmaceutical distribution system may be urgently necessary, but pharmaceutical registration can wait for several years because evaluation of medicines can be delegated to other trusted reference countries (e.g., EMA based on the Article 58 of European Regulation (EC) No 726/2004) or WHO (i.e., the prequalification process). However, the control of the national market and its distribution cannot be delegated.

Indeed, the development and implementation of regulations for medicine registration is costly and labor intensive. Therefore, establishing a medicine registration system is generally not justified until a country has developed regulations in other pharmaceutical sectors. One of the first priorities of developing countries is to develop a complete register of what is on sale in its market (i.e., product name, INN name, manufacturer information, country of origin, formulation, etc.) to allow the national authority to evaluate information from other countries and WHO about problems with a particular medicine and take appropriate measures. As a country’s INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 255 economic development improves and more resources become available, priorities may change. The DRA can start evaluating new medicines before they are placed on its market by relying on evaluations and decisions from other countries with well-developed DRAs and systems, using the WHO CPP scheme (focusing first on easy evaluations such as second-line products and generics) [496]. This is a first step to developing expertise and training reviewers. These reviewers can be either employees of the DRA or from an academic institution or hospital. The latter rather than a DRA employee seems a better choice from the start because it allows for the best experts in the field and reduces costs, as these independent experts are paid only for their reviews. In either case, policy and control needs to be in place to avoid any conflict of interests.

Three development stages can be identified: ▸ Those countries with very limited resources and no registration system in place (only a register listing the products available on the market) ▸ Those countries with some resources (but no strong expertise) and a minimal authorization procedure based on the CPP scheme ▸ Those countries with resources, expertise, and the capability to implement a full registration procedure

Assistance obviously needs to be customized to the countries’ needs and level of development. An evaluation needs to be performed country by country to analyze which regulatory functions can be performed by a given country, and which should be pooled subregionally or globally. It should also be evaluated under which circumstances decisions made elsewhere should be considered and what decision models should be chosen. Different models for decision making can be implemented based on resources, capacity, expertise, and the needs of each country: full review, abridged review, and verification [497]. WHO should develop standard regulatory and registration packages based on these three models. The structure, resources, competences, and other requirements necessary for the different approaches would need to be defined. In certain countries there is a need to first create a regulatory environment, with independently thinking personnel with technical, ethical, and legal training before discussing harmonization and cooperation. Training of regulators is an important part of the capacity building program. Mechanisms to train and develop DRA personnel need to be adequately addressed.

Bilateral cooperation is an optimal tactic to implement a training plan because regulators from developing countries can be trained by mature and well-established DRAs. For example, the EMA trains reviewers from other countries [498]. In addition, Health Canada and the US FDA can also provide training [499]. This training can also be coordinated through ICH (see Recommendation 3).

The goal of a capacity building program is to help each country progress to the next level of development. To achieve this goal, a customized and stepwise plan needs to be in place for each country. Transparency and communication are also important.

Though it will take time, development of an effective regulatory system is possible. It should be kept in mind that all developed countries have also been through an “emerging market” phase before establishing a strong and effective system. 256 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

III-2.5.2) Improve the Certification Scheme on the Quality of Pharmaceutical Products (CPP Scheme) Established by WHO The WHO certification scheme that established the Certificate of Pharmaceutical Product (CPP) process is recognized as a positive element in support of drug regulation and a marketing authorization system for developing countries. It established a process to help support developing countries. WHO should continue to coordinate this scheme and promote its use on a worldwide basis. However, there are limitations and challenges associated with the current process that should be resolved. Additionally, the responsibilities and regulatory capacity of importing and exporting countries should be further clarified and controlled.

First and most importantly, it is critical to control the “reference regulatory authorities” (or “certifying authorities”) because the system is based on their reliability and depends on their regulatory capacity, experience, and expertise. WHO has defined the obligations that certifying authorities need to fulfill in order to be able to deliver a certificate, but each Member State assumes the responsibility to determine, through a process of self-evaluation, whether it satis- fies these prerequisites [500]. The scheme contains no provision, under any circumstance, for external inspection or assessment, either of a competent national authority or of a manufacturing facility. Many questions remain, such as the frequency or quality of the inspections. This is obviously a weakness of the system. As further discussed in Recommendation 4, WHO should investigate criteria and mechanisms for evaluation of technical standards, expertise, and quality systems of these “reference regulatory authorities,” and consider an accreditation, certification, or recognition process based on ISO standards [501]. Moreover, some developing countries require the CPP to be issued by the authorities of the “country of origin” (i.e., location of the manufacturing site). However, in today’s environment, the manufacturing site may not be in a country where the DRA carried out the primary review of the application. It seems more appropriate that the CPP is issued by a certified “Reference DRA.”

Secondly, the verification of the authenticity of the certificate by the developing countries is not clear. Leaving the flexibility to developing countries on how to use the CPP scheme, based on their capacity, is important. However, responsibilities of the importing countries should be better defined and a global mechanism should be established to assist in the verification of CPPs. To resolve this problem, further cooperation and harmonization of standards between reference countries and developing countries is important. WHO should be more involved in the process and should better implement and coordinate a global process. For example, a global database (or exchange of CPP between countries via an electronic system/notification) would certainly be more efficient and secure than issuing paper certificates. This would also replace the lengthy process of legalization by embassies or consulates.

Finally, even though WHO created models, there are variations in the format and content of certificates, and sometimes the certificate is prepared by manufacturers for endorsement by authorities. The format and the content should be further harmonized and revised to include appropriate and critical technical information essential for developing countries. For this purpose, the issue of confidentiality between countries should be addressed to INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 257 allow the sharing of important information such as assessment reports and inspection reports (see Recommendation 10).

III-2.5.3) Improve and Better Organize Regulatory and Technical Support from Mature DRAs (Newly Defined as “Reference DRAs”) and WHO to Less Developed Countries Further efforts are necessary to improve the availability of life-saving medicines in a timely manner to patients in developing countries and to ensure that the medicines are of high quality and efficacious. These efforts are important for both medicines intended for global distribution and also medicines specifically designed for developing countries:

▸ Medicines developed for all markets: As previously discussed, many harmonization and cooperation initiatives have been established. But a new global approach is needed for the medicines that are developed for both developed and developing countries because their access is almost always delayed in developing countries. Moreover, the evaluation of potential differences between populations (based on the ICH E5 guideline) is not always performed because major DRAs focus on the registration of new medicines for their own territory and population. This creates a potential public health issue because many countries approve medicines on the basis that they have been licensed and used, for example, in the US or Europe. For the countries that base their assessment on approvals granted by other countries, it is important to implement and institutionalize a consistent and effective process, and define the content of the technical regulatory package, to validate the regulatory decisions made by other DRAs. The use of scientific reports prepared by experts in other national authorities does not necessarily mean that decisions made by the other authorities are automatically adopted. When a well-prepared scientific report is available, a small national authority may be in a position to make its own decision in light of local circumstances. The WHO Blue Book provides a decision tree on how developing countries should evaluate reports from an exporting country’s regulatory authorities [502].

▸ Medicines specifically developed for developing countries: Procedures have been created by WHO and major DRAs to support developing countries in their evaluation and control of medicines (e.g., the WHO Prequalification Program, the US FDA tentative approval process for antiretroviral medicines, or Article 58 of EU Regulation [EC] No 726/2004 [503]). These are important steps, but additional efforts are necessary [504,505]. These initiatives could also provide further support to capacity building of developing countries through partnerships, or scientific and technical assistance [506].

The establishment of the proposed global pharmaceutical system and the associated measures recommended throughout this section represent a new approach to technical support for developing countries. This new global approach will require strong political commitment because it will necessitate major modifications of the current regulatory systems and practices and also the development of a new or improved regulatory pathway by major developed 258 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

DRAs. It will also require better organization and coordination of the current harmonization initiatives, both regional and global.

III-2.6) Recommendation 6: Support Acceleration of Regional Harmonization and Cooperation and Better Coordinate These Activities within and between Regions Regional harmonization and cooperation is a critical piece of the puzzle. This level represents the backbone of the proposed global system as it allows input from the region on global activities and facilitates dissemination and implementation of global standards throughout the world. Without this link between national reality and global development of standards, global harmonization will remain a theoretical exercise that will be difficult to implement. For example, without strong regional representation, the proposed new extended ICH organization would be difficult to manage because it would necessitate multiplication of national representations. Also, the regional level is critical to the WHO structure. Without its regional offices, this global agency would have difficulties coordinating its activities on a worldwide basis, building capacity in developing countries, and providing appropriate support and training to regions based on their needs and challenges.

The increase in regional harmonization and cooperation will not only benefit global harmonization, but in certain regions it will also help to reduce the burden on countries that cannot appropriately regulate their pharmaceutical market due to limited resources or expertise. Helping the less developed countries of a region will also benefit the entire region because it will ultimately facilitate the limitation of drug counterfeiting or increase the quality of medicines moving throughout the entire region. By sharing this responsibility, resources will be better utilized and public health will be more protected.

The 14th International Conference of Drug Regulatory Authorities reaffirmed the importance of regional harmonization efforts that are already ongoing in different parts of the world in various forms and models. It was also recognized that WHO could further support these collaborative initiatives by providing technical assistance where capacity building is needed. WHO is also in a unique position to facilitate networking and information exchange among regulators [507]. Additionally, the recent increase of worldwide interest in harmonization also necessitates an urgent reevaluation of the regional representation and cooperation. Indeed, the ICH GCG increased the awareness of non-ICH countries and contributed to the global expansion of the harmonization of pharmaceutical regulations. This success may now create a “boomerang effect.” Individual countries not represented by the current RHIs have joined the discussions. This model has limits because the increasing numbers of individual countries impact the management of activities. Better involvement of the regions in the global discussion is the only alternative. The objective is to ensure that all countries are represented at the regional and global levels, and that they have access to this global network without impacting the focus of global discussions with too many participants.

It is important to note that the proposed acceleration of regional cooperation, although critical and urgent, should be done methodically. Drawing lines between countries to identify INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 259 simple regions without considering the current regional and subregional initiatives and also the current geopolitical situation and discussions would be foolish and impossible to implement. Instead, this review should focus on actions that would better support and leverage the current projects driven by the current harmonization and cooperation initiatives and similarities between countries. Geography is important when defining regions, but culture, economy, language, history, religion, and past and ongoing conflicts also need to be considered. When all these parameters have been taken into account, it is sometimes difficult to define borders, as demonstrated by certain ongoing debates (e.g., in Europe determining if Turkey is part of Europe or the Middle East).

Moreover, acceleration of regional cooperation does not always mean integration. Although integration would certainly be the best option for developing territories, all regions are different and each of them has its own challenges and needs. Therefore, the European integration model may not be the right model in other regions. Additionally, the choice of the model of harmonization is much broader than pharmaceutical harmonization as it involves political and economic considerations and decisions. Finally, differences in the levels of development between countries have to be considered. Although the more developed countries of a given region can help less developed countries in regulatory capacity building, rights of smaller countries have to be respected. For example, in the sub-Saharan Africa grouping, South Africa may be seen as the “leading agency” in that region, and therefore has the potential to have undue influence on regional decision making. This is also the case with Saudi Arabia in the Middle East.

It is therefore essential to perform a thorough evaluation region by region. Responsible people in charge of the regional pharmaceutical harmonization have to set up a cooperation framework that best fits the situation. This is a difficult task. For example, in some regions, better organization and coordination of multiple subregional initiatives with one regional coordinator between subregionsf would certainly be beneficial. In other regions, more integration, with the creation of a regional agency, may be the solution. The development and delimitation of regions also need to balance the benefit of having a limited number of larger regions (and therefore facilitating coordination) and the advantage of having smaller and more homogeneous and integrated blocs to facilitate integration and implementation of standards.

The following sections provide an evaluation of certain regions that may benefit from stronger regional cooperation and/or representation. Specific attention has been paid to Africa, for which regional cooperation seems critical to resolve its many challenges.

III-2.6.1) Africa Africa remains the world’s poorest and most underdeveloped continent. African countries face many health, but also social, development, economic, trade, education, diplomatic, defense, security, and political challenges. However, as expressed by the Ugandan President, f WHO can play this role of coordination in some regions through its regional offices. This is already the case in America where the Pan American Health Organization (PAHO) supports the PANDRH initiative. 260 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

Yoweri Museveni, on October 22, 2008 for the launch of the African Free Trade Zone: “The greatest enemy of Africa, the greatest source of weakness has been disunity and a low level of political and economic integration.”

Regional cooperation, and harmonization of standards and environment, is clearly needed in Africa as some of its challenges cannot be resolved effectively by individual countries. Both internal players and external observers agree with this observation and recognize the need for (and relevance of) harmonization, cooperation, and collaboration [508]. The question is, how should such cooperation be structured and coordinated to be successful and help individual countries and the African population?

III-2.6.1.1) Complex Environment and Many Specific Challenges Impacting Regional Cooperation Today, the regional cooperation environment in Africa is very complex and the true implementation of an African community, if possible, will take many years. The different sub-regions present major differences in culture, religion, language, and level of development. For example, the Maghreb countries and some Eastern African countries are more similar to the Middle East countries than to the central or southern African countries. Moreover, tension and wars within and between countries has made regional cooperation difficult. Instead, this environment facilitated the establishment of numerous subregional cooperation initiatives (with different internal capabilities and implementation success): ▸ Southern African Development Community (SADC) ▸ Community of Sahel-Saharan States (CEN-SAD) ▸ Common Market for Eastern and Southern Africa (COMESA) ▸ East African Community (EAC) ▸ Economic Community of Central African States (ECCAS/CEEAC) ▸ Economic Community of West African States (ECOWAS) ▸ West African Economic and Monetary Union (or UEMOA from its name in French, “Union Economique et Monetaire Ouest Africaine”) ▸ Intergovernmental Authority on Development (IGAD) ▸ Arab Maghreb Union (AMU) ▸ Economic Community of the Great Lakes Countries (CEPGL) ▸ Liptako-Gourma Authority (LGA) ▸ Mano River Union (MRU)

These existing subregional cooperation initiatives are primarily involved in economic cooperation, but some are also involved in other areas such as politics and the military. Healthcare is also covered most of the time with success. Some of these blocs also launched specific discussions on the harmonization of pharmaceutical regulations (e.g., SADC, CEN-SAD, COMESA, EAC, UEMOA).

On July 9, 2002, the African Union (AU) was launched as a successor to the Organization of African Unity (OAU) to promote the unity and solidarity of its 53 African states and INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 261 act as a collective voice for the entire African continent.g The objectives of this Union are to: ▸ Accelerate the political and socioeconomic integration of the continent. ▸ Promote and defend African common positions on issues of interest to the continent and its people. ▸ Achieve peace and security in Africa. ▸ Promote democratic institutions, good governance, and human rights.

This Union has both political and administrative bodies. The Assembly, made up of all the heads of state or governments of Member States of the AU, is the highest decision-making entity. Its headquarters are based in Addis Ababa, Ethiopia. The establishment of an AU military troop to conduct peacekeeping missions in many internal conflicts has been one of the first achievements of the Union. The Union has adopted important programs (e.g., the New Partnership for Africa's Development [NEPAD]), establishing norms at the continental level to combat corruption and to support democracy and development. In the domain of health, the African Ministers of Health meet regularly in conferences and have sponsored some initiatives such as the development of the Africa Health Strategy: 2007–2015 and the Pharmaceutical Manufacturing Plan for Africa. This Pharmaceutical Manufacturing Plan promotes the development of local production of essential medicines and recognizes the need for African countries to strengthen their medicine regulatory systems by pooling their resources. Discussions on the regional harmonization of pharmaceutical regulations were recently coordinated by NEPAD, in collaboration with WHO, through the African Medicines Regulatory Harmonization (AMRH) initiative. The aim is to coordinate activities within and across Regional Economic Communities (RECs), and to ensure consistencies in the REC harmonization initiatives. This program has been very active since its creation in February 2009 (see below), but one of the challenges is that the RECs are not at the same level of development.

In addition to the subregional blocs and the establishment of the AU, there are additional layers of cooperation: ▸ Cooperation between subregional groups also exists. For example, on October 22, 2008, SADC agreed with the COMESA and the EAC to form the African Free Trade Zone [509]. The leaders of the three trading blocs agreed to create a single free trade zone consisting of 26 countries from Egypt to South Africa with a gross domestic product (GDP) of an estimated US $624 billion. The objective of this new agreement is to end problems arising from the fact that several of the member countries belong to multiple subregional groups. It is a new step in African organization, as it will certainly decrease competition and duplication between subregional initiatives and increase efficiency in African discussions and cooperation. It will certainly also strengthen African power in international negotiations. However, this new additional cooperation layer, between the AU and the subregional groups (that will continue to exist), also adds some complexity to the management and coordination of the overall African region. g Except for Morocco, which has special status since it officially left the OAU in 1984. 262 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

▸ Some African countries are also part of other groups beyond the African continent (i.e., the Arab League and the Indian Ocean Commission [IOC]).

Due to the lack of resources and the political instability in the region, implementation has been the biggest challenge for all the regional or subregional cooperation initiatives listed above. Moreover, the lack of coordination of these multiple coexisting initiatives has created complexity, confusion, and challenges. All the subregional blocs should form the “pillars” of the AU, but in practice, the AU does not coordinate all subregional initiatives (some of them are not even officially recognized by the AU). Consequently, these initiatives have overlapping memberships (e.g., UEMOA is a union between some of the members of ECOWAS) that have sometimes led to conflicting and overlapping agreements. Today, 75% of African countries belong to two or more RECs [510]. To resolve this problem and accelerate the economic and political development of the African continent, it is agreed that cooperation is needed. However, there are different views on how this cooperation should be implemented. One of the key debates in relation to the achievement of greater continental integration is the priority that should be given to the integration of the continent as a unit unto itself versus the integration of the existing subregions. In other words, is it better to focus on the ultimate goal of regional integration versus focusing first on the more realistic integration of subregional groups as the basis for future African integration?

III-2.6.1.2) Status of Regional Harmonization in the Pharmaceutical Sector All the challenges described above, coupled with the regional geo-political situation, do not encourage regional cooperation in the health and pharmaceutical domains. Several examples show the difficulties the AU has in implementing harmonization: ▸ The Africa Health Strategy: 2007–2015 plan provides only general guidelines and an “inspirational framework” that countries or subregional blocs may use. To be efficient, this first step needs to be followed by a more practical involvement of the AU in order to better coordinate cooperation between countries and subregional blocs. ▸ In many African countries, the lack of harmonized technical requirements and capacity for medicine registration jeopardizes timely access to essential medicines [511]. For example, Tenofovir Disoproxil Fumarate (TDF) has been registered since October 2001 in the US and since February 2002 in Europe, and is commonly prescribed in developed countries as part of a first-line antiretroviral therapy to treat HIV/AIDS. How- ever, according to Médecins Sans Frontières, by February 2006, more than four years after TDF had become available to patients in the US, registration had been applied for in only 11 of 54 African countries. These disparities are mainly due to the lack of harmonization of requirements in Africa that complicate the registration (i.e., meeting each country’s individual requirements takes time and imposes unnecessary delays) [512]. ▸ Due to the lack of resources and expertise, national authorities cannot fulfill their obligation to regulate the pharmaceutical market, and therefore fewer quality medicines are available in Africa and prices are higher (compared to developed countries). This lack of access to essential medicines contributes to the significant disparities in health and life expectancy between low-income African countries and high-income countries. INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 263

Lack of harmonized technical requirements and capacity for medicine registration continues to jeopardize timely access to quality, safe, efficacious, and affordable essential medicines in Africa [508]. However, despite the numerous challenges and difficulties, progress has been made towards the harmonization of pharmaceutical regulations. Subregional blocs and WHO have developed projects. More recently, NEPAD (supported by the Pan-African Parliament [513]) and WHO have started to coordinate this harmonization regionally. This initiative follows a REC-based approach by focusing on the coordination of REC projects. Following the release of an important WHO concept paper in 2008 that laid down the principles and objectives of harmonization [514], NEPAD organized a workshop in Johannesburg, South Africa held on February 24-26, 2009 (in collaboration with WHO and charitable foundations). During this meeting, all the players, including representatives from 40 national DRAs and nine representatives from subregional blocs, agreed that harmonization of pharmaceutical regulations would improve access to quality medicines. They also reviewed the ongoing subregional efforts and discussed the challenges and next steps of such harmonization. The agreed-upon strategic approach consists of (1) mobilizing financial and technical resources for harmonization projects developed and coordinated by the subregional groups, and (2) facilitating the communication between these subregional groups. The aim is to support African countries in overcoming current challenges and constraints by building effective medicine registration through regional harmonization and capacity building.

The funded projects need to support the overall objective to strengthen national and regional regulatory capacity and to promote a common framework via the implementation of: ▸ A Common Technical Document (CTD) ▸ Harmonized technical requirements ▸ Common procedures for the registration of essential medicines

To support and manage this initiative and follow the progress of these projects (both proposed and funded), a consortium (including NEPAD and the Pan-African Parliament, WHO, the Bill & Melinda Gates Foundation (B&MGF), the UK Department for Interna- tional Development (DFID), the Clinton Health Access Initiative (CHAI), and the World Bank) has been created.

NEPAD in collaboration with the consortium’s partners has also spearheaded and coordinated the African Medicines Regulatory Harmonization (AMRH) initiative through the regional economic communities and countries [515].

Since the initiation of this regional coordination by NEPAD, through its AMRH program, several projects have been designed by RECs. The first harmonization project, led by the EAC, was launched in March 2012 [516]. This first project is extremely important as it will further demonstrate the value of harmonization and also highlight the challenges and provide lessons to be shared with other RECs.

The establishment of the new AMRH Programme Advisory Committee in March 2012 was also an important milestone that supported further coordinated and strategic 264 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS harmonization actions. Finally, AMRH has given support to other important projects, such as: ▸ The development of a framework for harmonization in the North and Northeastern African region. ▸ The organization of an AMRH stakeholders consultation meeting in March 2012: this meeting, attended by 117 participants, provided a forum for sharing experiences, challenges, lessons learned, and best practices, but also allowed reflection and development of a unified consensus moving forward [508]. ▸ Communication with all stakeholders to define a long-term strategy to resolve regulatory capacity limitation in Africa through coordination of training, establishment of Regulatory Centers of Excellence, and engagement of academic institutions [517]. ▸ The development of a law model and framework for medicine regulation and harmonization in Africa to assist RECs and/or countries in their endeavor to enact or review their regional and/or national laws and serve as a reference [518].

III-2.6.1.3) Recommendations for the Next Phase of Regional Cooperation NEPAD, through its AMRH program, has been active over the past several years and has initiated harmonization and collaboration among African subregions. To improve access to quality medicines for the African population, it is now critical to continue to sponsor a continental project directed towards three objectives:

▸ Further develop the coordination of the multiple subregional harmonization initiatives. This coordination will rationalize the actions and funding, and the use of scarce resources and expertise. It will also allow communication within the entire African community in order to develop trust among all countries that will then support the next steps of harmonization. The AU is important to ensure that there is no duplication of work and that each regional initiative is not reinventing the wheel. NEPAD is not in competition with the RECs, rather it serves as a complement. NEPAD is a platform that allows communication and work between RECs. The establishment of the AMRH Programme Advisory Committee will certainly enhance this coordination [519].

▸ Extend harmonization and cooperation beyond the simple coordination of the subregional initiatives. The establishment of a single African Drug Agency that would pool resources available across national DRAs and RECs (following the EU EMA model) is very important for Africa [520,521], and should be the next objective. As a first step and pilot project, this regional Agency could focus on the evaluation and control of essential medicines. Post-marketing surveillance could also be coordinated by this Agency. This increased integration will certainly be difficult to obtain, but it would allow a better use of resources and expertise. Each participating Member State would have the opportunity to participate in this central Agency (e.g., evaluation of dossiers, inspections, etc.) according to their available resources and expertise. Today, the lack of resources, expertise, and structure does not allow the African continent to provide adequate review and control of medicines. Having an African central system that would assess drug applications would remove many burdens from the less developed countries that could then focus their energy on the final risk/benefit INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 265

decision (if national capacity allows it) and control of their pharmaceutical market (i.e., counterfeiting, etc.). Moreover, in the countries with no resources, regional cooperation is critical to keep the evaluation and registration of new medicines at the “local” level in order to better respond to local needs and challenges. The African Agency would be more aware of the African public health situation than the US FDA or EMA, and would be able to analyze the risk/benefit ratio and decide which products were needed for the African population. Finally, if there were a unique list of approved products in Africa, this would aid in controlling the parallel and illegal pharmaceutical market. As in Europe, this regional system should utilize current existing national and RECs structures and resources.

▸ Coordinate African participation in the international discussions. Presently, the African countries are not well represented in the global discussion due to the lack of resources and expertise. It is important to ensure that all African countries benefit from global harmonization and cooperation (i.e., the ICH work). Today, the SADC and the EAC, which both represent only a minor portion of the African countries, are the only African representation at ICH. The AU as a whole, through the NEPAD/AMRH initiative, should be part of the ICH process. Having one regional contact would surely facilitate the exchange of information, the communication of African challenges and specificities, and the dissemination of international harmonized recommendations. Certainly, it would also help NEPAD/AMRH increase its visibility as a regional contact.

To be successful, the African continent cooperation project needs to involve all players (i.e., national DRAs, RECs, and the AU). Ultimately, the AU should be the leader and coordinator of these harmonization activities. However, the involvement of WHO, at least in the first steps of the project (i.e., the establishment of the harmonization system and processes), is critical. In the framework of its mandates, WHO is well recognized as an international nonpartisan entity. It has gained a lot of experience in the management and organization of such harmonization processes (e.g., the WHO regional office for the Americas provides the secretariat of the PANDRH initiative). Moreover, WHO has established a good network of experts, institutions, and foundations that could be helpful for the development of this harmonization. Finally, WHO (via its international resources, regional office for Africa, and country offices in African Member States) can provide technical support and training to strengthen national regulatory authorities’ capacities and ensure implementation and follow-up of agreed-upon actions. The consortium that has been established seems the most appropriate entity to coordinate the first steps of the harmonization as it brings together political, technical, and donor organizations that are key to the success of this project. It is also a great opportunity for capacity building and training for the AU in view of its future responsibilities (i.e., building an African medicine system).

To conclude, the establishment of multiple blocs shows a strong political desire and commitment to cooperate with other African countries. Moreover, establishment of the AU offers hope for greater cooperation and peace between the continent’s many countries. However, it is difficult to imagine that a fully politically functioning AU will be implemented soon. This continent has its own cultural and historical specificities and challenges for which a model 266 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS like the European community may not be entirely possible or appropriate, at least in the short term. Over the years, multiple subregional initiatives have been established and are today part of the African environment. They are very different and at various stages of cooperation; some are moving towards integration while others are focusing on targeted cooperation. Considering this complex environment and the implementation challenges, the first priority should be to continue to coordinate all the efforts in the health domain, both regional and subregional, without waiting for the implementation of a full and stable economic and political AU. Even though cooperation has many challenges, it should remain a primary focus in Africa, as it is certainly the only way for this region to resolve its numerous problems. This is especially true in the health domain where the lack of resources, expertise, and structure is very important. The majority of African countries have limited to no regulatory capacity [522]. The time it takes to register medicines in Africa ranges from 2 months to 36 months on average, depending on the country [523]. The critical problem of access to essential medicines that are safe and of good quality can only be resolved via: ▸ Cooperation between countries and blocs (which implies harmonization of the requirements) to share expertise and scarce resources and avoid duplication of efforts ▸ Support from international organizations (i.e., ICH or WHO).

The development and extension of the current WHO/NEPAD harmonization initiative would of course benefit African patients, as it will increase access to less expensive, quality medicines. Also, it will benefit national DRAs by providing additional resources and expertise, and the pharmaceutical industry by increasing harmonized standards and transparency.

Africa is the world’s second-largest and second-most populous continent, following Asia. With approximately one billion people [524], it represents an important potential market for pharmaceutical industries (even though it remains the world’s poorest continent), if this market can be coordinated. Harmonization of the standards and requirements for the registration of products in Africa will certainly have an impact on the development choices made by the pharmaceutical industry because it will decrease the development costs and time to market, but most importantly will increase transparency and predictability of registration of medicines in the region. Increasing the attractiveness of Africa will also increase the competition between pharmaceutical companies and therefore decrease the cost of essential medicines.

III-2.6.2) Asia Many countries in Asia participate in ICH discussions and WHO initiatives. This achieves some level of convergence and consistency between countries. However, despite the level of interest and participation in these forums, the level of convergence is not homogeneous across all countries in Asia, partly due to the different levels of socioeconomic development in each country. Today, the harmonization of pharmaceutical regulations within Asia is only partial, and its participation in ICH discussions is not organized to represent all Asian countries. INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 267

Asia is a large region, and can be broadly divided into three subregions:h ▸ The Indian subcontinent, which that includes India, Pakistan, Nepal, Sri-Lanka, and Bangladesh ▸ North Asia, including China, Hong-Kong, Taiwan, and Korea ▸ Southeast Asia (SEA), including Indonesia, Malaysia, Philippines, Singapore, Thai- land, Brunei Darussalam, Vietnam, Laos, Myanmar, and Cambodia

Presently, there is no harmonization activity for the entire Asian region as a whole. Today, the majority of harmonization activities occur in the Southeast Asia subregion.

In 1967, within Southeast Asia, ASEAN was established to achieve some degree of common economic, social, and cultural objectives, and to promote regional peace and stability. To achieve these broad objectives, several projects have been funded; one of them was the harmonization of pharmaceutical regulations. Coordinated by the PPWG, this specific harmonization initiative has been very active and has released several harmonized guidelines, which are essentially adopted from, or based on, ICH guidelines. It should be noted that the countries of this subregion are at different stages of implementation and that full harmonization is not expected to happen in the near future. For now, harmonization does not lead to a centralized procedure. Instead, each country conducts its own evaluations and decides on whether an approval should be granted for each product. However, though many additional efforts would be necessary to achieve full integration, this initiative is progressing towards a European model and supports the overall ASEAN objective to achieve a single market by 2015/2020. Finally, ASEAN, as a member of the ICH GCG since 2003, is involved in the global harmonization of pharmaceutical regulations.

Within the two other Asian subregions, some individual countries have tried to implement ICH or WHO recommendations. However, there have been no (or minimal) harmonization efforts between countries in these two subregions. The primary collaboration has been between China and Korea. The political situation (e.g., tension between China and Taiwan, and tension between India and Pakistan) and different levels of socioeconomic development may explain the lack of harmonization and cooperation among countries in these two subregions. Moreover, China and India may eclipse the other countries in their respective subregion by becoming increasingly more important globally. China and India now represent an important source for active pharmaceutical ingredients, medicinal products, and/or clinical data (see Part II-2.2.1), and for this reason have been invited to join the ICH GCG. But these two countries have joined the ICH activities individually, and do not represent the other countries from their respective subregions.

However, it should be noted that, although it does not involve all countries, a new ASEAN Plus Three collaboration has been initiated by ASEAN to promote the East Asia subregion. This cooperation includes ASEAN, China, the Republic of Korea, and Japan. This is a first step towards better regional harmonization. h Japan is being considered as an entity on itself since it is already involved in global harmonization discussions (i.e., it is a founder country of ICH). 268 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

In summary, the level of harmonization is not homogeneous across all of Asia. There is currently no regional initiative to harmonize pharmaceutical regulations across the entire region. The majority of harmonization activities occur in the region of Southeast Asia. While there are some efforts by individual countries in the Indian subcontinent and North Asia regions to implement ICH or WHO recommendations, harmonization among the countries in each of these two subregions is minimal at best. More importantly, there is no structure in place to represent all of the Asian countries at ICH; currently only ASEAN, China, and India are represented.

Further actions should therefore be undertaken to increase cooperation within the region, or at least within the Indian subcontinent and East Asia subregions. This would not only simplify the regulatory environment and therefore increase availability of new medicines in Asia, but also improve representation of all Asian countries in international discussions.

III-2.6.3) Middle East Without underestimating the benefit of the GCC harmonization process, the representation of the entire Middle East region in the international pharmaceutical harmonization discussion is one of the key challenges for the future. The GCC has been very active, and its involvement is critical. However, this organization is only a subregional initiative that currently represents seven countries (including Yemen). It does not involve all countries of the region. Even if it is difficult to precisely define the Middle East region, as several definitions exist (e.g., some refer to a broader territory including Turkey and North African countries such as Algeria, Morocco, and Tunisia), this region is clearly not limited to the GCC countries. Major regional players in the pharmaceutical sector (i.e., Egypt and Lebanon) are not part of the GCC. The organization of the Middle East region, with a regional coordinator to coordinate all the efforts in the region, needs to be discussed and evaluated.

Of course, tensions and conflicts in the region make it difficult to appoint a single representative for the entire region. Many regional trade agreements have been signed and regional integration initiatives have been established, but all of them have made only limited progress, except GAFTA [525]. However, the existing broad union, the League of Arab States (which groups more than 20 Middle East and North African Arab states), may be more representative of the entire region than GCC, and should be represented in the global discussion. The WHO Regional Office for the Eastern Mediterranean could also be involved, and could provide support following the model of the PAHO, which supports the PANDRH initiative.

It is interesting to note that some projects working towards harmonization of pharmaceutical standards and regulation between Arab countries have been initiated. The Arab Union of the Manufacturers of Pharmaceuticals and Medical Appliances (AUPAM) has been leading this effort. For example, the ICH CTD was recommended as the format for drug registration in the Arab world [526,527]. This is obviously a first step in harmonizing pharmaceutical regulations in this region, and efforts are progressing in the right direction.

However, even if Arab countries have many similarities (i.e., culture, religion, language, etc.), the League of Arab States is still in the initial stage regarding harmonization of pharmaceutical INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 269 regulations. There are many challenges facing Arab regulatory harmonization. The establishment of an Arab Drug Agency and an Arabian registration procedure for all the Arab countries seems difficult to implement today [528]. To achieve this ultimate goal, the first harmonization effort should be supported further by political representatives, and additional focused projects should be funded. Also, due to the overlap of membership between the League of Arab States and the African Union, it makes sense to further develop relationships between NEPAD/AMRH and the League of Arab States for the harmonization of pharmaceutical regulations. This will certainly help both organizations to strengthen their efforts in this domain.

III-2.7) Recommendation 7: Continue to Harmonize Good Manufacturing Practices (GMP), Good Laboratory Practices (GLP), and Good Clinical Practices (GCP) Globally to Support Increased Cooperation on Inspections Good Manufacturing Practices (GMP), Good Laboratory Practices (GLP), and Good Clinical Practices (GCP) have been increasingly harmonized over the years. They have been harmonized regionally (e.g., Europe, ASEAN), but also globally, by several organizations (e.g., ICH, WHO, Pharmaceutical Inspection Co-operation Scheme [PIC/S]). Several bilateral Mutual Recognition Agreements (MRAs) have also been signed to recognize each other’s good practices and sometimes to accept each other’s GMP certificates [529,530].

Moreover, new emerging countries have also started to implement good practices using global recommendations. For example, in 2010, a new GMP regulation was released by China’s State FDA to harmonize it with global standards. This regulation is almost identical to the ICH Q7 guideline and EU GMP Annex 1 [531]. Since 1999, GCP has been implemented in China and is also consistent with ICH guidelines [532]. The Indian GCP regulation is also similar to the ICH GCP and includes elements of WHO, the US FDA, and the EU GCP [533].

Today, however, despite these important improvements to harmonize good practices, there is not one single set of international GMP, GLP, or GCP used globally because the proposed harmonized recommendations have not been rigorously implemented on a worldwide basis [534]. Even if in principle the different texts have the same goals, there are some differences between national or regional regulations, some being subtle, and some more pronounced. For example, there are different GLP regulations that companies need to follow when they conduct nonclinical studies [535–537]. Also, not only do the WHO GMP and ICH GMP have differences, but the GMP regulations of the EU, US, and Japan still differ in many aspects, even if they are all based on the ICH GMP. Finally, although worldwide GCP frameworks are based on ICH E6, each country tends to deviate slightly from it in one form or another.

The increasing globalization of development, manufacturing, and distribution of medicines calls for a full harmonization of GMP, GLP, and GCP.

Major pharmaceutical companies and contract research organizations (CROs) operating globally currently manage the situation by preparing internal standard operating procedures (SOPs) or manuals that combine the requirements of the different texts, but having one set of international GMP, GLP, and GCP would certainly increase clarity and compliance. Moreover, 270 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS if regulators and inspectors agreed on one set of global GMP, GLP, and GCP, it would facilitate cooperation in the review of applications and inspections.

Many demands are placed on the inspector departments of DRAs. For example, the majority of DRAs are obliged by law to have systems in place to verify the GMP status of medicine manufacturers. Most mature DRAs ensure that the manufacturers in their territory are subject to routine GMP inspections. However, different approaches are taken to supervise the manufacture of medicines outside a national territory, and to supervise and inspect active pharmaceutical ingredients (API). A number of countries have MRAs or memoranda of understanding (MOUs) with other countries that allow them to rely on results from inspections performed by other countries. However, these MRAs or MOUs are often limited in scope, and subject to certain restrictions. Since the adoption of the ICH guideline on Quality Risk Management in 2005, the application of risk-based approaches to the planning of inspections has increased in importance, and there is increasing interest in additional international collaboration.

A retrospective analysis of inspection data from the EMA, US FDA, EDQM, and TGA confirmed that many inspected sites are of shared interest, and that there is a tendency of the participating regulators to perform duplicate inspections [538]. With increased globalization, it is increasingly evident that sharing of resources by authorities is necessary and in the best interest of public health. For example, sponsors often submit the same clinical trials in support of Marketing Authorization Applications (MAAs) in all countries. Subjects participating in the pivotal clinical trials in these applications are often recruited in several countries. Worldwide regulators and inspectors must verify that clinical trials, both in their own territories and in other regions of the world, have been conducted in an ethical manner, have been carried out in accordance with the investigational plan, and have data that have been correctly reported. The increasing globalization of large-scale and complex clinical trials, coupled with limited inspection resources, dramatically limits the range of trials and clinical investigators who can be inspected for GCP compliance. If regulators can work in a collaborative and synergistic manner in carrying out GCP inspections and implement information exchanges, then inspection-related resources can be used more efficiently, and inspection coverage can be increased. Moreover, rationalization of the use of global inspection resources, by sharing information and avoiding the unnecessary duplication of inspection work, would also provide some relief to manufacturers, who direct substantial resources to host multiple inspections [539].

The positive experience of collaboration between the EU and US in the inspection area has shown the potential resource efficiencies to be gained if authorities rely on each other’s inspection outcomes [540]. Several pilot studies have been established. For example, the nine joint API GMP inspections conducted under a pilot programi (five in India, one in Croatia, one in Mexico, one in Japan, and one in China), the exchange of information on 642 sites, and the review of close to 100 inspection reports, have helped to build up confidence between the participants, and have facilitated better use of EU and US FDA combined inspection resources [541,542]. The EU and US GCP joint inspection initiative has also been extremely successful i This pilot program has been established in cooperation with the European Directorate for the Quality of Medicine and the Australian Therapeutic Goods Agency. INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 271 and has improved inspection coverage. It has also shown that each agency’s inspection procedures are more similar than different [543]. This EU/US example should be used to develop collaboration with other worldwide DRAs. Increased collaboration on inspections should indeed result in more effective use of resources and a higher safety level for products from third-world countries. In the case of collaboration between two mature DRAs like the EU/US FDA case, exchange of best practices and better use of resources to cover an increased number of inspected sites (collectively) is an obvious advantage. Duplicate inspections can sometimes be justified (e.g., if there are different scopes), but most of the time there should be no reason to perform duplicate inspection.

Following the success of the pilot projects, DRAs have already decided to consolidate and extend their international partnerships in the areas of GMP and GCP inspections, and also pharmacovigilance inspections. These collaborations include development and improvement of tools, agreements, and networks [544]. However, to be successful, this initiative needs to be followed by other countries.

In a perfect world, each country would control the compliance to standards for all activities occurring in its territory and exchange its findings with other countries where the product is sold or data is used to avoid the duplication of inspections. Unfortunately, not all countries have the resources and expertise to implement functioning and efficient national inspection systems. Regulatory harmonization with third-world countries regarding GMP inspection is often difficult to achieve due to the fact that each party needs to have full confidence that the certification process of the other party can completely satisfy its own regulatory requirements. This confidence can only be established with countries that have compatible procedures and a comparable level of technical development and requirements. Bilateral collaboration and signature of MRAs are the best way to achieve this comparison of systems between two parties. Some MRAs include a transitional period to allow time to perform this evaluation for confidence building [545]. Collaboration between mature DRAs and inspectors from developing countries is therefore important to support capacity building and training in less developed countries. Several developing countries have established good practices [546]. This effort needs to be strengthened on a worldwide basis and the full harmonization of GMP, GLP, and GCP would facilitate capacity building and training.

Several measures could be implemented to support developing countries in this area: ▸ The establishment of reference DRAs (see Recommendation 4) would be beneficial in the area of inspection to clarify which countries have appropriate resources, policies, and expertise to perform quality inspections. These would help developing countries decide which certificates from counterpart DRAs can be accepted and which countries can provide appropriate training and support for capacity building. ▸ The inspections in developing countries could be performed by a team of experts from several entities (i.e., WHO, national DRAs, and/or an inspector from a reference DRA). The value of this collaborative procedure for joint inspections has already been demonstrated with the WHO Prequalification Program [547], and especially the 2010 project of the East African Community (EAC) [548]. This model should be replicated in other regions, especially for assessing selected technically complex, high-priority products. 272 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

Finally, the concept of an EU Qualified Person (QP) should be generalized to better manage the complexity of a global drug supply chain and support global cooperation in inspections. This QP ensures that each batch has been manufactured according to GMP principles and released according to approved specifications, regardless of the location of the manufacturer. This approach could also be applicable in other areas such as clinical trials and compliance to GCP.

III-2.8) Recommendation 8: Develop a More Consolidated Global Safety Framework Today, medicines are distributed globally. The risk associated with the administration of these medicines is the same in all countries (except in exceptional cases where a safety problem is associated with a specific group presenting particular risks due to intrinsic or extrinsic ethnic factors). It is therefore logical that the collection of safety information, evaluation of the risk, and the measures to mitigate this risk are done on a global basis.

Globally, safety monitoring and risk mitigation have been an increased area of focus over the past decade. Today, all worldwide DRAs agree that safety is an important aspect of the evaluation and lifecycle management of medicines. Unfortunately, safety measure and mitigation strategies vary between countries. Further cooperation and harmonization of requirements in this area is therefore recommended because: ▸ Collection of data globally (following common procedures and format) in one unique location will increase knowledge on the products and therefore better safety monitoring and signal detection. It would provide different insights from different exposure groups. ▸ The risk should be minimized for everyone taking medicines, both in developed and developing countries. ▸ The duplication of safety evaluations and a mitigation plan may complicate the implementation of appropriate measures.

DRAs should work closely on this topic and harmonize their approach for drug safety monitoring and risk evaluation. Pharmaceutical companies suffer from different requests from different agencies at different times for the same/similar issues of a product. Due to nonharmonized drug safety regulations, the many duplicated efforts that are needed to deal with the bureaucracies do not enhance drug safety, but rather translate into a redundant investment of industry resources and increased costs of healthcare on a global basis. Several initiatives have been established to further harmonize requirements (i.e., ICH guidelines, PhRMA discussions related to the harmonization of worldwide databases, etc.), but further cooperation is required.

III-2.8.1) Develop a Global Safety Database Pharmacovigilance (PhV) is defined as the science and activities relating to the detection, assessment, understanding, and prevention of adverse effects or any other drug-related problem [549]. The aims of PhV are to enhance patient care and patient safety in relation to the use INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 273 of medicines and to support public health programs by providing reliable, balanced information for the effective assessment of the risk–benefit profile of medicines.

Different safety databases have been created by developed countries (e.g., EU Eudra- Vigilance, FDA Adverse Event Reporting System [FAERS], etc.) to facilitate this activity. WHO also established a PhV program in response to the thalidomide disaster in 1961. WHO Headquarters is responsible for policy issues, while the operational responsibility rests with the WHO Collaborating Center for International Drug Monitoring (the Uppsala Monitoring Centre [UMC]) based in Uppsala, Sweden. In 1971, this program developed an international database for monitoring adverse reactions to drugs using information derived from Member States: the VigiBase™. A common reporting form was developed, agreed-upon guidelines for entering information formulated, common terminologies and classifications prepared, and compatible systems for transmitting, storing and retrieving, and disseminating data were created. This program for international drug monitoring provides a forum for WHO Member States to collaborate in PhV. However, today, this database is a duplication of the national/regional PhV databases. It does not represent a unique global database (pharmaceutical companies still report data to the multiple national and regional databases).

Merging all these different databases into one single global database (which could be an improved version of the current WHO VigiBase™) would not only reduce duplication of efforts from both industry and regulators, but it would be beneficial to better control the safety of products (currently different databases contain different data). It would facilitate communication and exchange of safety information between DRAs. This increased pool of global data would also facilitate early detection of potential safety signals.

The development of this common global safety database should be relatively easy because most current databases use the same dictionary (MedDRA) and follow the same standards (ICH M2 standards). However, one of the difficulties in setting up a global database is that sometimes certain product formulations or strengths vary between countries and regions. These differences need to be considered when developing the global database to avoid error in interpretation of information and data.

WHO also established a system of “Drug Alerts.” Rapid Drug Alerts are issued by WHO whenever a serious problem in the safety of any medicinal product arises. Focal points from different departments within WHO constitute the Alert Committee. On receiving information on a “potential” alert, a rapid ad hoc meeting of the Alert Committee is arranged to validate the information from its source and to verify its authenticity, to check for any causal relationship that might have been established, and to assess the extent of distribution of the product, etc. If the material warrants rapid and worldwide distribution, a Drug Alert is composed and mailed to DRAs and nominated national information officers in the Member States. It is obvious that such an international communication system coupled with a single global safety database (that would include all the safety information collected globally) would improve signal detection and ultimately the control of safety of medicines globally. 274 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

III-2.8.2) Harmonize Strategies on Risk Management to Facilitate Compliance and Risk Mitigation All worldwide DRAs have significantly improved their strategies to minimize the risks associated with medicines and to allow early risk detection. Unfortunately, even if the objective is the same, DRAs have developed different strategies. For example, the EU authorities ask for the risk assessment (i.e., Risk Management Plan [RMP]), and part of this plan is the risk mitigation measures, while the US FDA does not ask for the risk assessment, but requests risk mitigation measures (i.e., Risk Evaluation and Mitigation Strategy [REMS]) if there is a risk. Moreover, in the EU, RMPs are required for all new medicines,j and the RMP format is well defined, while in the US, RMPs are not required in all submissions. In fact, the US FDA assesses the risk, and if there is a significant risk that can be mitigated, a REMS is requested. Today, only 25 REMS have been developed.

It is acknowledged that, because of differences in indication and healthcare systems, target populations may be different across the world and risk minimization needs to be tailored to regional specifics. In addition, differences in disease prevalence and severity, for example, may mean that the benefits of a medicinal product may also vary between regions. However, even if a product has a different RMP for each region, several elements can be common to all [550].

Terminology, formats, and requirements of a risk management plan should be agreed upon. The move to a modular format (e.g., the new modular structure for EU risk management plans) would facilitate submission to different regulatory authorities and certainly facilitate global cooperation. This would facilitate the implementation of measures, efficiency of risk management plans, and their monitoring. It would also facilitate risk communication and a common risk/benefit assessment [551].

III-2.9) Recommendation 9: Facilitate the Development and Control of International Clinical Studies International clinical studies are increasingly the basis for regulatory approval of new medicines. While such globalization of clinical trials presents tremendous opportunities, they are not without challenges [552]. Many unique issues need to be addressed to allow data generated from one region to be readily available and usable in another region. Furthermore, the diversity of patients and medical practice patterns open a host of questions on how to interpret trial results and their applicability to both the broad and the specific trial populations. There are also many regulatory differences within and between regions that can have an impact on the conduct and design of such multi-state clinical trials.

Many discussions occurred at the bilateral, regional, and global levels in order to facilitate the development of international clinical studies as it prevents the unnecessary duplication of studies, accelerates and increases efficiency and cost-effectiveness of drug development, and facilitates global registration [553]. In the past few years, Japan has specifically supported this idea because it would certainly resolve the delay of availability of new j In the EU, every new application needs to assess the risk, and if there is a risk, the measures to decrease this risk need to be developed. INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 275 medicines in their country [554,555]. Many DRAs already recognize that sponsors may choose to conduct multinational clinical studies. They also accept foreign clinical study results in support of marketing applications. For example, the US FDA amended its regulations in 2008 regarding the acceptance of foreign clinical studies not conducted under an Investigational New Drug (IND) application as support for an IND or a New Drug Appli- cation (NDA), Abbreviated New Drug Application (ANDA), or Biologics License Applica- tion (BLA) [556].

The experience with the European Clinical Trials Directive has shown the benefits of conducting multi-state clinical trials. Global clinical research helps to respond to global questions about the safety and efficacy of medicinal products and treatment. Research in third-world is needed, so that specific situations can be taken into consideration. More- over, international clinical research allows capacity building and the sharing of knowledge and its application [557]. More importantly, these studies allow patients from developing countries to have access to some of the latest medicines. Finally, these international studies are also critical for the pharmaceutical industry to increase patient pools (especially naive patients), support global development of medicines, and reduce the costs of development.

The increase in conduct of international clinical studies will also eliminate the need to perform specific clinical studies in some countries that recently required clinical experience in their territory (i.e., China, Russia, etc.) to support registration of new medicines. These new requests are based on scientific concerns (i.e., evaluation of ethnic factors on treatment effect) or more political and economic reasons.

However, globalization of clinical research has specific challenges that need to be resolved [558]. Certain basic principles need to be enforced when conducting international clinical studies, such as: ▸ The fundamental ethical rules need to be respected in all countries and investigation sites wherever the study is conducted. ▸ The conduct of clinical trials in other countries should not impact the quality and integrity of the results. ▸ The potential impact of ethnic factors on the treatment effect should be evaluated to facilitate interpretability of data and generalization of results. ▸ DRAs should ensure regulatory oversight of clinical studies performed in their territory.

In recent years, intellectual property protection, enforcement of fundamental ethical rules, and improvement of regulatory oversight have been strengthened in many emerging markets, but efforts are still needed. There remain many challenges linked to the design, planning, and conduct of global clinical studies [559], such as: ▸ Longer clinical trial start-up times due partially to different approval times of Clinical Trial Applications (CTA) (from 1 to 9+ months) ▸ The existence of different local regulations, requirements, and processes ▸ The uncertainty of GCP compliance in some countries ▸ Lack of transparency and predictability in certain DRAs’ processes 276 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

▸ Lack of sufficient resources in certain DRAs ▸ Differences in medical practices (e.g., the consequence of the choice of endpoints and comparators) ▸ Ambiguous and different interpretations of the ICH E5 guidelines on ethnicity assessment

To overcome outstanding challenges, the promotion of international clinical studies with investigator sites in all regions of the world requires the enforcement of ethical, regulatory, and scientific standards in all countries. Moreover, the promotion of international studies needs to be coupled with an increased effort to resolve current concerns in developing countries [560], especially related to ethical treatment of participants and the integrity of data [561]. Efforts regarding the harmonization of standards need to continue and regulators need to further cooperate to enforce international ethical and scientific rules.

The conduct and control of international clinical studies will certainly be facilitated by some of the general recommended measures discussed in other sections (i.e., increase of support for regulatory and technical capacity building in developing countries, increase of appropriate training, increase of transparency and communication between DRAs, development of a global consolidated global safety framework, etc.). However, additional specific measures are also necessary to better promote, coordinate, and control international clinical studies.

III-2.9.1) Ethical Principles Need to Be Enforced Globally Ethical principles are universal and not negotiable. Any disregard of the rules that protect clinical trial participants is unacceptable regardless of where the clinical trial is performed. Regulators need to take action if clinical trials performed in other countries exploit a particular vulnerability of their population.

International rules for protection of clinical trial participants are in place. These internationally agreed-upon documents laying out universally applicable principles independently of where the clinical trial has been performed include: ▸ The Nuremberg Code of 1947 on medical experiments [562] ▸ The Declaration of Helsinki on Ethical Principles for Medical Research Involving Human Subjects from the World Medical Association [563] ▸ The Convention on Human Rights and Biomedicine (Oviedo Convention) from the Council of Europe [564] ▸ The International Ethical Guidelines for Biomedical Research Involving Human Sub- jects from the Council for International Organizations of Medical Sciences (CIOMS) [565] ▸ The Guideline on Good Clinical Practice from ICH [566]

Everyone agrees with these general principles. However, the challenge is the practical application, and even more importantly, supervision and enforcement of those principles. This is especially true because many clinical trials are now conducted in low- and INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 277 middle-income countries. Developing countries have specific challenges for implementing standards. For example, the implementation of a true informed consent concept in India is difficult due to a high illiteracy rate, variety of languages, and paternalistic traditions that complicate the investigator–patient relationship [567]. Critics have also said that lesser- paid doctors in these countries may feel pressured to admit ineligible patients to meet their enrollment goals or to collect questionable data to satisfy the sponsors. In other cases, ineligible patients may have been recruited because it was the only possibility for them to receive treatment.

The ethical issue related to the conduct of international clinical trials has been discussed in several reports, such as: ▸ The study report on clinical trials in developing countries commissioned by the Euro- pean Parliament [568] ▸ The report “Ethics for Drug Testing in Low and Middle Income Countries – Consider- ations for European Market Authorizations” [569] ▸ The report “Ethical Concerns in Clinical Trials in India: An Investigation” from the Cen- tre for Studies in Ethics and Rights [570] ▸ The report and recommendations of the US National Bioethics Advisory Commission [571]

All stakeholders need to be actively involved in the enforcement of these ethical principles. First, the sponsor of the studies needs to thoroughly evaluate the potential clinical sites before starting the study (i.e., the quality of the study team, compliance to standards, responsiveness, control of confidential data, etc.). It should also ensure (through training, appropriate monitoring, and relevant audits) that its employees or partners follow the relevant international ethical rules in all countries where the study is performed. Second, the authorities of all countries hosting clinical sites need to establish relevant regulatory systems and procedures to oversee such studies. Third, DRAs of developed countries involved in the studies need to create mechanisms to control data generated in third-world countries. This involvement of developed countries in the conduct of clinical trials in developing countries (e.g., via inspection) is indeed important because it helps implement ethical standards in these countries [572,573]. Moreover, developed countries also support the implementation of global standards by requesting that foreign studies supporting marketing applications comply with international standards. For example, the US FDA amended its regulations on April 28, 2008 regarding the acceptance of foreign clinical studies not conducted under an IND as support for an IND or a new marketing application. The final rule (which is codified at 21 CFR 312.120, and which took effect on October 27, 2008) requires that such studies be conducted in accordance with GCP, including review and approval by an independent ethics committee and informed consent from subjects. The GCP requirements in the final rule encompass both ethical and data integrity standards for clinical studies. This requirement is intended not only to help ensure the quality and integrity of the resulting data, but also to promote the protection of human subjects enrolled in foreign clinical studies [574]. In April 2012, the EMA also released practical guidance to ensure that clinical trials submitted in an EU Marketing Authorization Application (MAA) meet the required ethical and GCP standards no matter where in the world they have been conducted [575]. 278 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

If all these controls are in place, the promotion of international clinical studies will not only accelerate the development of global programs and the access of new medicines globally, but also support the development of developing countries.

III-2.9.2) Continue to Harmonize Clinical Standards Harmonization is critically important in the area of clinical trials because they are very often performed in more than one country, the results may be used in marketing applications for medicines throughout the world, and an investigational product may have been produced in a different country from that of the clinical trial.

There should not be different standards (i.e., scientific or ethical) applied at different sites of an international study, regardless of the regulatory system in each county. For example, if a study is submitted to the US FDA, the same standards should be applied to US sites as to sites from other regions. In addition to the necessity of continuing to implement harmonized ICH GCP throughout the world, DRAs should continue to harmonize standards in the clinical arena.

Designing a global study today that meets all worldwide requirements is not easy. Differ- ences in medical practices and registration requirements (i.e., the need for comparative data against standard therapy) complicate this task. It is sometimes difficult to choose a comparator, select an endpoint, or define rules for concomitant therapies. The ICH work on the E12 guideline [576] demonstrated that these factors are difficult to overcome.

Further harmonization on the medical approaches to specific major diseases and the development of a therapeutic class-specific guideline should continue (within the ICH framework and medical forums). This is critical to support the global development of medicines and facilitate the conduct of international clinical studies.

III-2.9.3) Better Integrate the Evaluation of the Potential Impact of Ethnic Factors on Treatment Effect during Medicine Development Although ethnic differences among populations may cause differences in a medicine’s safety, efficacy, dosage, or dose regimen, many medicines have comparable characteristics and effects across regions. Requirements for extensive duplication of clinical evaluation for every compound can delay the availability of new therapies and unnecessarily waste medicine development resources [577]. It is therefore important to have a thorough evaluation of ethnic factors during the development of medicines instead of automatically repeating clinical studies to assess safety and efficacy in each population. This calls for changes in the basic philosophy of global medicine development.

Any candidate medicines for global development should systematically be characterized as ethnically sensitive or insensitive as early as possible during the development so that the risk/benefit assessment can be conducted for different populations. The ICH E5 guidelines [577] provide a method to assess the influence of these ethnic factors during development. If sensitive, it will be important to fully evaluate the influence of ethnic factors (both intrinsic INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 279 and extrinsic) upon the medicine’s effect (i.e., efficacy and safety). This type of evaluation is critical to: ▸ Understand potential opportunities and risks for certain populations. ▸ Support exchange of information (and a conclusion of an evaluation) between DRAs, and to ultimately support a central evaluation. ▸ Help each country in their ultimate risk/benefit analysis and decision.

Today, the evaluation of ethnic factors, as per ICH E5, is not always performed. When it is performed and submitted, this evaluation is not always sufficient to avoid the duplication of the clinical studies [578].

The early evaluation of the potential impact of ethnic factors on treatment effect would also facilitate the development of Phase 3 international clinical studies. An early knowledge of the differences (or lack of differences) of treatment effect on a diverse population would increase the understanding of the molecule and help better design clinical studies. The promotion of Phase 3 international clinical studies, in which diverse populations would be represented, would then facilitate further evaluation of ethnic factors on treatment effect [579]. This is critical in order to support global development, and also allow better evaluation of the data for all subgroups of the population in a given country [580]. Although it would require some statistical adjustment to incorporate the heterogeneity of the sample size, the results from these international studies would include different ethnic and racial populations that would not be well represented if the study was performed in a single country, even if these different ethnic groups were represented in the country. Having such information at the time of registration would be valuable for all worldwide DRAs because most developed countries are observing the continuing diversification of their demographics [581].

III-2.9.4) Facilitate Registration of Multi-State Clinical Studies It is critical to ensure that the conduct of international clinical studies does not delay the development of new medicines by increasing the time to obtain worldwide approvals to begin such studies or by increasing the enrollment period. If the promotion of international clinical studies delays development, it will obviously not be a positive advancement for many worldwide patients as it delays the availability of new medicines. Moreover, there will be no incentives for pharmaceutical companies because it will delay the approval of new medicines in major markets (i.e., the US and EU) that still represent an important part of their revenues. For example, what would be the value for a pharmaceutical company to delay the US approval for six months in order to include developing countries in an international Phase 3 clinical study?

Today, pharmaceutical companies face many challenges when they want to conduct international clinical studies due to diverse regulatory requirements and registration procedures. They must register the study through disparate regulatory systems. It also requires that all DRAs involved agree on the protocol (i.e., endpoints, scales, placebo vs. no placebo, primary time point, etc.). This means multiple parallel communications with several DRAs and also expending resources to develop knowledge on local specificities and procedures. These specific local 280 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS procedures translate to operational complexity and additional time and ultimate delays in the start of the studies. Moreover, resources that could best be used for increasing R&D productivity are often used to meet these different regulatory administrative requirements.

It is, of course, essential that DRAs thoroughly evaluate clinical and scientific documents to ensure that the proposed clinical study does not present a risk for patients. This work is needed, whatever the cost and resources it requires. However, the repetition of local procedures and evaluations does not increase the added value of this assessment. It is more important to ensure that the reviewers have the appropriate expertise and experience to assess the documentation. The regulatory variability and multiplication of procedures across multiple countries brings an extreme complexity in order to register the study without providing benefit for the patients. Systems and mechanisms are therefore needed to avoid the multiplication of procedures and evaluations that delay the study start. It seems more efficient to have one well-structured evaluation, performed by an expert, rather than the addition of evaluations, sometimes performed in countries that do not have the expertise to conduct such an evaluation.

There have been proposals for establishing a grouping of countries to oversee the conduct of clinical trials at the regional level in countries that do not have the mechanism or capability to do so [582]. This measure would certainly facilitate and accelerate the start of multi-state clinical studies. The African Vaccine Regulatory Forum (AVAREF) [583] has already demonstrated the value of such cooperation.

Moreover, an international registration of clinical studies should also be established for certain types of studies (e.g., for studies on orphan diseases). The newly established International Medicines Agency could coordinate this international procedure using the same model of the international procedure for registration of medicines (see Recommendation 12). The Euro- pean Voluntary Harmonization Procedure (VHP) could also be used as a model. Although this procedure has some disadvantages and therefore needs improvement [584], it provides a model that combines a common evaluation while keeping the ultimate decision to approve the study at the national level.

This new international collaborative procedure would be beneficial for developing countries that do not have the resources or expertise for this type of evaluation. This increased transparency and collaboration would also facilitate surveillance and monitoring of clinical studies in third-world countries and therefore ultimately facilitate the recognition of data.

III-2.9.5) Further Consolidate All Clinical Trials Registries and Databases into One Global Registry The registration of all interventional trials is a scientific, ethical, and moral responsibility. The Declaration of Helsinki states that “Every clinical trial must be registered in a publicly accessible database before recruitment of the first subject.” Most worldwide authorities implemented this requirement by launching their own databases. Today, several databases exist in the world (e.g., the US ClinicalTrial.gov website, the European Clinical Trials Register, etc.) to make information on clinical trials publicly accessible. INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 281

However, information and results of clinical trials are not always easily available everywhere in the world despite the existence of these several registries. When available, information can be different from one registry to another depending upon the nomenclature of each registry. Indeed, clinical trials usually involve participants from more than one institution, and often more than one country. As each country has its own requirements for clinical trials research conducted within its borders, it is possible that single trials could be included on more than one registry, and hence appear on more than one registry database. A further complication is that the data appearing on each registry database about a single trial may differ (e.g., the trial title, the trial reference number, or the countries of recruitment may have been entered differently, or one record may be more up-to-date than another).

In 2005, WHO launched the International Clinical Trials Registry Platform (ICTRP) to provide a means to link international registries together, provide a single point of access to clinical trials information, and make it possible to clearly identify trials and make it easier for patients, families, patient groups, and others to access the information. This initiative clearly improved transparency and global access to clinical trials data by all stakeholders. Moreover, this initiative created a forum to harmonize the format and criteria to report not only information, but also processes. For example, the establishment of a Universal Trial Number (UTN) facilitates the unambiguous identification of clinical trials even though it may have multiple registration records.

Now that the ICTRP has achieved its goals to link existing international registries, a second step in the development of this platform should be initiated. This platform should now be further developed and used as a truly global registry instead of a central repository for other international registries. In other words, information from sponsors and national authorities should be directly included on this new global registry, which would be used as the only source of worldwide clinical trials information and data. This database could be divided into two parts, based on the European model (e.g., the European Clinical Trials Register website gives public access to a subset of the EudraCT database information reserved for regulatory agencies [585]), as follows: ▸ One part with confidential information and scientific details reserved for DRAs ▸ One part with a subset of the information that would be publicly available

The creation of a truly global registry beyond the WHO initial goal to link current worldwide registriesk would meet current objectives and also avoid duplication of work, decrease discrepancies and mistakes (because a unique source would be used worldwide), and facilitate access to, and exchange of, information. It would also be easier to check compliance of data, and finally, would further support developing countries and regions.

k Resolution WHA 58.34 called on the global scientific community, international partners, the private sector, civil society, and other relevant stakeholders to “establish a voluntary platform to link clinical trial registers in order to ensure a single point of access and the unambiguous identification of trials with a view to enhancing access to information by patients, families, patient groups, and others.” 282 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

Although this platform is already in place, this modification of its scope would certainly face several challenges and require additional work up front, such as: ▸ Translation of information into several languages to allow access to everyone. As a first step, information on a given clinical trial should be available in English and any official languages used in the countries involved in this specific study (this is already the case with the current organization and situation). ▸ Further discussions with all current WHO Primary Registries should occur to make sure that additional requirements from these worldwide databases are included in the data set. The data set of this new global registry will certainly be more detailed than the current WHO ICTRP data set. ▸ This new global registry would require resources (structured at a global level, but also at the regional level) and a process.

In summary, despite challenges that will certainly need to be addressed, the consolidation of all clinical trial information in one controlled database accessible to everyone would facilitate the exchange of information and data. It would also improve research transparency, decrease duplication of work in the long term, allow identification of gaps in research, increase collaborations between researchers, and as a result, ultimately strengthen the validity and value of the scientific evidence base. Physicians, researchers, and patients would be better informed regarding alternatives, and therefore better able to make more informed decisions.

III-2.10) Recommendation 10: Initiate Discussions to Better Exchange and Control Confidential Information and Trade Secrets in the Current Globalized Environment One of the limitations in the communication between worldwide DRAs is the general restriction on the exchange of trade secret information (or companies’ proprietary confidential information) in most of the MOUs between regulators. Even between DRAs that have signed confidentiality agreements, it remains a limitation [586]. This is of course not the case between national DRAs as part of an integration process such as in Europe. This problem needs to be resolved in order to support the next step of harmonization and communication (especially related to the exchange of positions, conclusions on product evaluations, and inspection reports) and allow worldwide DRAs to fulfill their mission to protect public health. Some regulators have even publicly stated that it is critical that trade secret laws are changed to allow them to share manufacturing information with other regulators [587].

Today, authorities can work within this legal limitation of an MOU by obtaining a sponsor’s agreement to exchange quality information with other major DRAs. While this can be time- consuming and likely reduces the level of information exchange that could be mutually beneficial to industry and regulators alike, it is still a useful approach. For DRAs that are choosing to work more collaboratively on an international level, they report that a key motivation for doing so is to work towards harmonized global product specifications. When DRAs share their product insights and regulatory experience and work collaboratively between institutions and the sponsor, the regulatory burden on the sponsor to meet several distinct national requirements can be reduced (see Recommendation 13 on product release). This can also INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 283 lead to a reduction in the error rate associated with the need to satisfy different regulatory requirements for the same product in different markets, and can free up resources to focus on product quality and development.

There are, of course, other pressures that necessitate the sharing of quality information. Under specific situations, major DRAs may exchange quality information in the absence of a sponsor’s authorization if an urgent safety issue is involved. Note that such exchanges only occur between specific DRAs under an MOU, which ensures that equivalent controls on trade secret information are in place. In these situations, it is considered an intuitional obligation under an MOU to share the necessary quality information, even in the absence of sponsor authorization, if it is felt that patient safety is at risk. Because internationally based pharmaceutical manufacturers typically have SOPs in place that require them to notify all DRAs where their product is licensed of product safety issues, typically information sharing to regulators is initiated by the sponsor. In the situation where a DRA is the source of the critical information, sponsors have understood the institution’s obligation to communicate with other lead DRAs.

However, globally this problem is more complex and should not be left open to individual resolution on a case-by-case basis. It is critical that these exchanges of confidential and proprietary information are legally protected in order to avoid the diffusion of such critical data to the general public. The current status quo, where sensitive information is only exchanged between developed countries, may not continue to be relevant to protect sensitive information in the current globalized environment. The 2001 World Trade Organization (WTO) Decla- ration on the TRIPS Agreement [588] and Public Health (also known as the Doha Declaration [589]) clarified that: ▸ Intellectual property protection is important for the development of new medicines. ▸ Trade-related aspects of intellectual property rights, however, should not prevent WTO members from taking measures to protect public health.

The Doha Declaration also reaffirmed the commitment of developed countries to support developing countries by providing incentives to their enterprises and institutions to promote and encourage technology transfer to developing countries.

Therefore, the right balance needs to be found and appropriate measures need to be established to facilitate the exchange of information between DRAs without impacting the development of new medicines. More specifically, these exchanges of sensitive information should be allowed, but limited to specific types of information (and levels of information) within a defined legal framework and between DRAs that have appropriate legislation in place. DRAs need to have confidence that the other party is able to control critical information before exchanging such types of data. In this case, bilateral collaboration is important in order to allow DRAs to assess each other and build confidence in each other’s system to control critical information. A certification process would also be useful (see Recommendation 4).

All these measures are critical to avoid the following dissemination of confidential information or trade secrets via less regulated countries: pharmaceutical company → Reference DRAs → 284 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS authorities of less regulated countries → public/competitors/generic companies. The diffusion of such information through the above route would have major impacts on pharmaceutical innovation.

It is also important to note that similar problems may also exist even though sensitive information is protected by patents. If the national legal system does not enforce such patent protection, the innovator may lose the benefit of its invention.

Finally, another tool to support innovation (and ensure that there is a fair balance between return on investment and market access to competition) is also to harmonize and enforce legislation on data protection.

III-2.11) Recommendation 11: Advance Regulatory Science and Develop International Good Regulatory/Review Practices to Harmonize the Review Processes The concept of “regulatory science” is relatively new, and, as yet, there is no widely accepted definition of the term. However, from the perspective of many science-based medicine regulators, regulatory science is the science of developing new tools, standards, models, and approaches to assessing the efficacy, safety, manufacturing quality, and performance of medical products, in the service of public health [590–593].

This is a broad concept that involves a wide range of disciplines, including clinical, epidemio- logic, manufacturing, and statistics, as well as informatics and analytic systems. These tools can help regulators review and renew knowledge about medical products during all parts of their lifecycles, as they inform about the fundamentals of risk/benefit assessment, management, and communication.

Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) also defines regulatory science as “the science to adjust the achievements of science and technology with a view to make use of them for people and society in the most desirable way, by making exact prediction, assessment, and judgment based on evidence.” This science of harmonization based on data aims to show an ideal direction and way of thinking based on certain facts, data, and results, to develop various arguments, and to integrate them in a certain direction. One of the important principles is that reproducibility by a third person is ensured [594,595]. This concept needs to be further developed to facilitate collaboration in the assessment of new medicines. Advance- ments in this area are indeed key to increasing harmonization and cooperation between regulators, but also support capacity building in developing countries. These activities will also become critical to support the implementation of international registration of medicines or clinical studies (see Recommendations 9.4 and 12) that will require standardization of the reviews (i.e., how the applications and their data are assessed) and assessment reports (i.e., how the findings and conclusions are summarized by the reviewers).

Most of the opinions of worldwide DRAs are based on balancing the desired effects or “benefits” of a medicine against its undesired effects or “risks.” For example, an authority can INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 285 recommend the authorization of a medicine whose benefits are judged to be greater than its risks. In contrast, a medicine whose risks outweigh its benefits cannot be recommended for marketing. The risk and benefit balance is generally considered the most difficult part of the assessment process, even for experienced assessors. Indeed, weighing the benefits and risks of a medicine is a complex process because it involves the evaluation of a large amount of data. In addition, there is always some uncertainty about the actual benefits and risks of a medicine, because they can only be determined by evaluating the information that is available at a given point in time.

A review of practices and processes in several EU DRAs has shown that there were no common definitions on the concepts of benefits and risks and no formal guidance on the process of their balancing [596]. Interviewees, between regulatory agencies and within the same agency, expressed divergent views on the meaning of benefits and risks, and how they are weighed. Notably, especially with regard to risks, there was a great variance of responses. In practice, evaluating and balancing benefits and risks for a medicinal product is an intui- tive and implicit process based on expert judgment. In all six agencies there was no mention of the use of a validated and structured process for assessing benefits and risks, but most of the interviewees acknowledged the need for a more systematic approach and the value it can add.

The development of Good Regulatory Practices (GRPs) is an important component of regulatory science. These harmonized tools to conduct various regulatory activities allow standardization of practices, increased transparency, and informed decision-making processes. WHO defined in its “Blue Book” the elements and principles of GRPs [597]. This standardization of practices is especially important to assess regulatory applications.

Good Review Practices (GRevPs) can be defined as “review standards (i.e., standard operating procedures and templates) and related initiatives (i.e., reviewer manuals and training programs) designed to ensure the timeliness, predictability, consistency, and high quality of reviews and review reports” [598]. Standardization of the evaluation of medicines facilitates recognition of each other’s assessments (i.e., between divisions of the same DRAs or between DRAs). One basic principle is to ensure that the review report is prepared such that others can easily understand the scientific facts and problems identified in the evaluation report. This transparency is essential to facilitate cooperation [599]. It is indeed important to organize the evaluation report and to structure the evaluation of data so that conclusions can be easily understood by others.

Currently, the development and implementation of GRPs/GRevPs is possible through the development of harmonized requirements and a common submission format (i.e., CTD), which greatly influenced the regulatory review processes and allowed better consistency and transparency [600,601].

Several DRAs, from developed and developing countries, have already invested in regulatory science and developed GRPs [602,603]. ICH has also worked on GRevPs [604,605]. Finally, regional harmonization initiatives such as the APEC LSIF also developed such 286 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS types of good practices because their implementation, combined with adoption of common, science-based standards and guidelines, is essential to promote regulatory cooperation [606,607].

While this increased interest in better structure in review processes is a good evolution, the multiplication of national and regional good practices are not the best way to efficiently support cooperation. The review practices are sometimes different between countries due to historical and cultural habits. All these initiatives should be coordinated and GRPs should be harmonized. It would indeed be better to have one set of international GRPs that would include the best current practices from worldwide regulators. WHO should be involved in this process to further develop the Medicines Regulatory Package for developing countries.

During the 14th International Conference of Drug Regulatory Authorities in December 2010, worldwide regulators recommended that WHO work with national DRAs to “define recommended elements of model product assessment reports, including benefit–risk considerations” [608].

However, before developing international GRPs, it is necessary to assess the systems and processes of individual DRAs against a set of agreed-upon indicators. This benchmarking of practices among worldwide regulators will be a good opportunity to identify strengths and best practices and any opportunities for improvement. Of course, this benchmarking of practices needs to take into account the level of development and resources of each country and regional specificities.

In Europe, the Benchmarking of European Medicines Agencies (BEMA) program has been established by the Heads of Medicines Agencies to assess the systems and processes in individual DRAs against a set of indicators in four areas (i.e., management systems, assessment of marketing authorization applications, pharmacovigilance activities, and inspection services) [609]. This BEMA program could be used as a model for the establishment of a global evaluation and ultimately the development of international GRPs. WHO has also established valuable projects to review regulatory systems. Other interesting tools have also been developed such as the scorecards to assess the quality of a regulatory submission and its review [610]. All these available evaluation programs and tools should be used to develop international GRPs. Also, in order to facilitate the development of future best practices and harmonize the way the new regulation is developed (to facilitate exchange and transparency), the authorities should follow a standard defined process. The Regula- tory Impact Statement (RIS) defined by ASEAN [611] provides the key elements of this structured process: ▸ Define the problem. ▸ Set objectives. ▸ Assess feasible options. ▸ Analyze the impacts arising from these options. ▸ Consult stakeholders (and other regions if necessary). ▸ Finalize the regulation. INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 287

▸ Monitor the implementation (including consideration of appropriate enforcement mechanisms and/or training) and success of the new regulation.

Training is indeed critical in the implementation of good practices, especially in the case of international practices, because many factors could influence their implementation (see Part II-2.2). Shared training, which would involve regulators from different worldwide DRAs, would be a good opportunity to avoid different interpretations and therefore different imple- mentations of recommendations. It would also be a great opportunity to continue to build relationships between reviewers.

It is important to note that the implementation of international GRPs and GRevPs does not mean that the decisions of different DRAs will be automatically the same because weight and importance of risk and benefit parameters varies among DRAs and governments [612,613]. However, even if variations in the acceptability of risk among regulators can, for example, explain a divergence of decisions to approve a new product, it does not eliminate the added value of a common scientific assessment. Conclusions regarding the quality, safety, and efficacy of a product should be the same worldwide because it is based on available scientific evidence (or lack of data that creates uncertainties surrounding a new medicine).l Therefore, common risk/benefit assessment standards and methodologies can be developed and agreed upon on a worldwide basis [614,615].

Several initiatives have been launched to evaluate several qualitative or quantitative approaches for balancing benefits and risks in decision making about medicines [616], and to provide methodologies for a more detailed justification of risk/benefit assessments done by the agencies [617]. Matrixes, grids, and other visualization tools for the evaluation of risk/ benefit of new medicines have been, or are being, developed by certain DRAs or consortia [618]. Efforts in this area need to continue because the development of a formal framework, with appropriate templates and incorporation of both qualitative and quantitative assessments, allowing risk/benefit assessment of new medicines, is essential for increased cooperation between regulators, and also promotes transparency and predictability. This important change of approach to risk/benefit assessment, from implicit to explicit value judgments, would allow better description of the risks and benefits (in new marketing authorization applications and assessment reports), and therefore better articulation and understanding of the risk/benefit decisions [619].

The Unified Methodologies for Benefit–Risk Assessment (UMBRA) initiative, established by the Centre for Innovation in Regulatory Science (CIRS) and involving both regulators and industry, provides a platform for the coordinated development of benefit–risk assessment methodologies that could be used internationally [620]. This promising initiative, based on the lessons learned from the various projects in this domain, has already developed common elements of an overarching, internationally accepted, standardized risk/benefit framework [621] (Figure 8). l This is, for example, different for the HTA assessment, which includes price/reimbursement evaluation dependent upon political choices and the healthcare budget in each country. 288 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

FIGURE 8: The UMBRA Eight-Step Benefit–Risk Framework.

Source: CIRS Website (http://cirsci.org/), accessed in September 2012.

III-2.12) Recommendation 12: Establish an International Procedure for the Evaluation of Medicines The establishment of an international procedure would represent an incredible step forward in global pharmaceutical cooperation. This ultimate level of collaboration between DRAs not only represents the best solution for the efficient management of global DRA resources, but it is a wonderful opportunity to better utilize international experience and expertise, to improve the evaluation of new innovative medicines, and to ensure that the best international experts are involved in this review.

The idea to institute a real international procedure for the evaluation of new medicines is not new. However, the complexity related to its implementation, requiring important political support and appropriate systems and organization between countries, so far has prevented its accomplishment. This important increase of collaboration between DRAs also requires prerequisite activities (i.e., harmonization of technical requirements, building of trust, and development of appropriate communication between DRAs).

Although this new phase of coordination will still require strong political support and the creation of solid and appropriate organization to coordinate the evaluation (see INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 289

Recommendation 2), it is today conceivable. Thanks to ICH work and other bilateral, regional, and global cooperation, many technical requirements have been harmonized over the past few decades.

Moreover, numerous collaborative projects between developed countries have built trust and mutual understanding on each other’s policies, practices, and systems. Technical collaboration between reviewers or inspectors has already been established bilaterally or multilaterally (e.g., EU/US collaboration on orphan drugs, EU/US parallel scientific advice procedure, EU/ US/Australia collaboration on GMP inspections, etc.). Also, all the tools that were created to facilitate global communication and the exchange of information (e.g., creation of a common dossier format, a common medical dictionary, relevant tools to exchange information easily, etc.) will facilitate the implementation and management of this new international procedure. Finally, these prior cooperation projects advanced awareness of the importance of developing best practices that are critical for the implementation of the international procedure (see Recommendation 11).

It is important to note that the establishment of an international procedure does not require integration. Technical evaluation can be coordinated globally, but each country can keep its own decision-making process according to its own legislation. This is in no way a loss of sovereignty, but a sharing of expertise and resources to the advantage of all parties.

Examples of international technical evaluation of drugs on behalf of Member States already exist, but have been restricted to special products as follows: ▸ WHO provides technical expertise to the United Nations on the subject of drugs of abuse under the United Nations Single Convention on Narcotic Drugs (1961) and the United Nations Convention on Psychotropic Substances (1971). In this specific case, WHO undertakes medical and scientific evaluations of the dependence- producing properties of substances to enable the United Nations Commission on Narcotic Drugs to make decisions on their control status [622]. Since 1949, through its Expert Committee on Drug Dependence, WHO has reviewed more than 400 substances. ▸ The WHO Prequalification Program (see Part I-1.1.5.11) is also an excellent example of a cooperative framework for evaluation and inspection activities. This program has been established to support developing countries and is focusing on essential medicinal products (mainly on the quality aspect). However, this procedure shows that global collaboration in this domain is possible and beneficial to accelerate the access of medicines on a worldwide basis.

Europe has also successfully implemented procedures for the registration of medicines on a regional level. Of course, the European integration model cannot be applied as such on a global basis, but some principles can be utilized to establish an international procedure for the evaluation of medicines. Although the European decentralized procedure represents the best example for the international procedure, because it leaves the final decision to the Member States, the evaluation model of the centralized procedure (which includes experts from EU Member States) is also an interesting model for the international evaluation of new medicines. 290 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

Acknowledging that the objective of the international procedure is not to support the creation of a single/common market, it is critical to separate the technical evaluation of applications and the decision-making process. Technical evaluation can be coordinated, but the decision- making process needs to remain the responsibility of each country. The proposed international procedure is therefore based on the following principles: ▸ The applicant selects the countries concerned (the list of countries would be part of the application form) and submits the application in all selected countries. ▸ Evaluation of technical data can be performed by one reference country or a group of experts from all reference countries. These two options have their own advantages and disadvantages: • Option 1 (Evaluation performed by one reference country): This option would follow the example of the European decentralized procedure where a “reference country” (selected from the list of reference countries, see Recommendation 4) would assess the application. Although this option is obviously the easiest to implement, it may not be the one producing the best outcome. The problem of reassess- ment of data by the “concerned” countries previously noted with the European MRP would certainly limit the benefit of the procedure. • Option 2 (Evaluation performed by a group of experts from all reference countries): This international team of expert reviewers would include a representative appointed by the DRA from each “reference country.” Each of these representatives would, of course, use its national experts (or regional expert in the case of Europe) to perform the evaluation. This centralization of the evaluation would be beneficial because it would leverage international expertise and experience, would increase collaboration between reference countries, and would ensure that the review of applications were performed by the best worldwide experts in the field. This collegial review would be centralized, but each country would then follow its own decision-making process based on the assessment report. If additional studies and data were necessary for a local purpose (i.e., if there is a potential effect of ethnic factors on the medication’s safety, efficacy, dosage, and dose regimen, if stability data are necessary for different climatic zones, etc.), the reasons would have to be justified and clearly explained. These local requests should remain the exception. ▸ The objective of the evaluation is to review technical data according to GRevPs (see Recommendation 11). Findings are then reported in a detailed and structured way (a standard report format needs to be designed) to highlight the risks and benefits of the new medicines. ▸ Following this coordinated evaluation and the release of the assessment report, each concerned country involved in the procedure uses the report to evaluate the risks and benefits of the new medicines.

Of course, not all medicines need to be evaluated through this new international procedure. It should be specifically applicable to new innovative treatments that require a high level of expertise that is not available in all countries (e.g., gene therapy). This international procedure could also be used for medicines intended for the treatment of certain specific diseases that are common to developed and developing countries (e.g., HIV/AIDS), or urgent treatments INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 291 and vaccines required in the case of a pandemic crisis (e.g., H1N1). All other medicines would continue to be registered via current national or regional procedures.

This international procedure would of course also be beneficial for orphan medicines that treat life-threatening conditions and rare diseases because the implementation of a global program is essential to obviate the development challenges due to the limited number of patients. Moreover, the development of these orphan medicines is often done by small pharmaceutical companies that do not have the resources or budget to register their products through all the national procedures worldwide. This international procedure would facilitate the global availability of these medicines. The success of the EU orphan medicine regulation and registration system demonstrated how harmonization and cooperation can improve public health and increase availability of these types of medicines [623].

The establishment of this proposed procedure is obviously a long-term project that will require a strong political commitment. A pilot phase should first be established to evaluate the value of this procedure before its potential extension to include other medicines. This pilot phase would be restricted to specific products to further evaluate the system and to propose improvements of the procedure. For example, during the pilot phase, the procedure could be only opened to orphan medicines.m This category of products, which would specifically benefit from a common/single worldwide assessment of the benefits and risks, represents an important pool of candidates for the pilot phase [624].

It is important to note that, although this international procedure will be driven by the expertise coming from developed countries, it will also accelerate registration of new medicines in developing countries. Indeed, after the evaluation of the application, the assessment report would be available for countries with limited resources and expertise. Every country where the application has been filed will be able to use this assessment report to approve (or not) the new medicines. The CPP scheme (improved as proposed in Recommendation 5.2) will also continue to be available to support developing countries.

Due to the involvement of both developed and developing countries in this international procedure, and the current lack of legal framework to protect sensitive information (see Recom- mendation 10), the exchange of confidential data and trade secrets between DRAs needs to be carefully addressed. Appropriate measures need to be implemented to balance the needs of developing countries to have access to the international procedure, but at the same time to avoid dissemination of confidential data that could impact innovation: ▸ First, experts and reviewers from the reference countries need to have access to the same information and data and to be able to communicate and exchange on all aspects of the application. To resolve the current legal restriction on the exchange and communication of confidential nonpublic information and trade secrets, several actions are required: m During the pilot phase, orphan designation would need to be obtained from each of the reference countries involved in the procedure. However, collaboration should be initiated to harmonize the criteria for designation and establish a global designation procedure. 292 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

• DRAs from reference countries need to establish confidential agreements and commitments (i.e., the official statements of authority and confidentiality commitment signed between the US FDA and EMA [625,626]). • The exact same application, including the same level of data, needs to be submitted by the applicant in all reference countries selected and a statement certifying it is the case needs to be included in the application form. • The applicant needs to explicitly allow communication between experts from all the reference countries. The following statement could be included in the application form: “It is hereby confirmed that the applicant consent and authorize the Drug Reg- ulatory Authorities of the reference countries involved in this procedure to exchange and communicate on all information included in this application.” ▸ Second, exchange of confidential information and trade secrets should be limited to countries that have established data exclusivity legislation and strong patent laws [627]. Only “reference countries” that have had their systems and policies (to control confidential information and trade secrets) evaluated (see Recommendation 4) would receive such critical information. Moreover, they would only be able to communicate with other reference countries that had the same evaluation of their systems and policies. Two different applications would therefore be developed by the company: • A full application including all the details on the manufacturing process and quality information, which would be sent to the reference countries • An abridged application with limited details on the manufacturing process that would not incorporate any trade secret information (that would be sent to all other countries not designated as reference countries) It should be noted that pharmaceutical companies are already customizing the level of information to the countries. They produce a full application for developed countries and an “International Registration File” (with fewer details) for developing countries. ▸ Third, the format and level of detail included in the assessment report needs to be carefully evaluated because numerous countries will use this report. Commercial information and trade secrets should be removed from the assessment report, as is the case presently for the European or Australian public assessment reports.

Without the implementation of these measures, it is unlikely that pharmaceutical companies will use this international procedure.

III-2.13) Recommendation 13: Encourage Harmonization of Analytical Tests and Release Specifications of Products Registered Globally and Promote Recognition of Lot Release Results between Countries Requesting In-Country Testing Harmonization of release specifications and analytical tests is always beneficial because it reduces duplication of testing and potential errors in conducting multiple analytical tests with multiple specifications. Appropriate justification of selected methods and specifications is more useful than the multiplication of tests. INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 293

Moreover, several countries in the world request in-country retesting of each lot of medicines marketed in their territory if the lot has not been manufactured in the country. These multiple lot releases do not improve the quality of medicines or the control of medicine quality. How- ever, the elimination of this duplication of testing would be beneficial. First, it would reduce the unnecessary use of animals (in the case of in vivo assays). Second, it would reduce cost, time, and resources (of both government laboratories and pharmaceutical companies) associated with multiple lot releases and in-country testing.

To achieve this objective, several actions are needed: ▸ Harmonization of analytical tests (i.e., harmonization of pharmacopoeias). ▸ Harmonization among DRAs of release specifications and analytical tests when a new medicine is registered. ▸ Agreement from DRAs to accept analytical results from other countries when another reference government laboratory in the world has already performed in-country testing. This confidential exchange of information and results on official batch release could follow the model of the Official Control Authority Batch Release (OCABR) network established by the EDQM [628].

It is worth noting that this recommendation, although beneficial, may be difficult to implement in certain countries. In-country testing involves national laboratories and therefore produces activities in the country. The reduction of this in-country testing would eliminate this source of the national economy and employment.

III-2.14) Recommendation 14: Increase Cooperation in the Battle against Counterfeit and Substandard Products Counterfeit [629] and substandard [630] products represent an important problem for the global pharmaceutical network and a serious threat to global health. The WHO estimates that 10% of all drugs worldwide are counterfeited [631]. This problem calls for an urgent comprehensive strategy at all levels [632].

The magnitude of the problem is much greater in developing countries, where low-quality medicines may be the only ones to reach the poor. For example, a survey in Rwanda showed that 20% of hypertensive medicines purchased on the market were of substandard content and 70% were of insufficient stability. Similar results were found for other essential medicines in many other developing countries. In 2009, substandard traditional anti-diabetic medicines in China were found to contain six times the normal dose of glibenclamide and were associated with the deaths of two people and the hospitalization of nine others.

Counterfeiting remains more prevalent in developing countries; however, with international markets opening up to globalization, the problem has extended to all countries. The number of recorded cases of falsified medicines for chronic diseases has also increased in developed countries, for example, through unregulated Internet sales used by patients. Atorvastatin (for the treatment of high cholesterol) was reported in the US in 2007 to contain no active ingredient, and was sold via Internet sites operated outside the US. In 2007, counterfeited olanzapine 294 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

(for treating bipolar disorder and schizophrenia) was detected in the legal supply chain in the UK, and was found to be lacking sufficient active ingredient [633].

Among other measures (i.e., police investigation and legal actions), the harmonization of pharmaceutical regulations and the cooperation between countries help against this phenomenon [634,635]. Many initiatives have already been established in this domain at the national, regional, and global levels. However, despite all these initiatives, this is still an increasing global threat. Better coordination and harmonization of actions would certainly increase efficiency of all these initiatives. The WHO IMPACT program has been critical in coordinating this effort. This program should be continued and intensified. Better global identification and traceability of drugs would also make it more difficult to introduce a counterfeit product into the supply chain. The online Medicine Quality Database, developed under the auspices of the Promoting the Quality of Medicines (PQM) program, is an important tool against this major growing problem [636]. Conclusion

Globalization is a reality of the 21st century, and today, health is a shared responsibility involving equitable access to essential care and a collective defense against transnational threats [637]. The development, manufacture, and distribution of medicines have also been internationalized. For example, nearly 40% of the drugs used in the United States (US) are made elsewhere, and about 80% of active pharmaceutical ingredients (APIs) used in drugs manufactured in the US come from outside its borders (i.e., from more than 150 countries, many with less sophisticated manufacturing and regulatory systems) [638]. This is not only a trend in the US, but it is also the case for most other countries. Among all drugs registered for marketing in Australia, 85% are produced overseas [639]. The same trend is observed for the clinical development of new medicines. Many pivotal clinical studies included in Marketing Authorization Applications (MAAs) are performed worldwide.

This increased globalization has fundamentally changed the environment for regulating medicines and created unique regulatory challenges for regulators [640]. In the current environment, no single Drug Regulatory Authority (DRA), even the US FDA, which is the biggest DRA in the world, can adequately keep pace with the pressures of globalization [641]. The regulatory paradigm has indeed changed from national to international, and not a single regulator today can work successfully in isolation and not have access to the experience, knowledge, and information of other regulators [642]. International pharmaceutical norms and standards are more important than ever before as they serve as global tools whose function is to ensure the safety and quality of medicines. This creates an increasing need for convergence, harmonization, and cooperation. Currently in the world, cooperation with counterpart DRAs is a core element of a modern regulatory system, and no regulatory environment for authorizing and controlling medicinal products can now be considered effective and sustainable if it is developed in isolation [643].

Also, despite the recognition of the right to health in international law and all the global and regional efforts, almost 2 billion people worldwide still lack access to essential medicines. This deprivation causes immense suffering that is avoidable. Improving access to existing medicines could save 10 million lives each year, 4 million of them in Africa and Southeast Asia. Besides deprivation, gross inequities in access to medicines remains the greatest challenge of the world’s present pharmaceutical situation. Average per capita spending on medicines in high-income countries is 100 times higher than in low-income countries, approximately US $400 compared with US $4, respectively. Despite the development of new emerging markets and a change of the global pharmaceutical environment,

International Cooperation, Copyright © 2014 Pierre-Louis Lezotre. Convergence and Harmonization of Pharmaceutical Regulations 295 Published by Elsevier Inc. All rights reserved. 296 INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS

WHO estimates that 15% of the world’s population still consumes over 90% of the world’s pharmaceutical production [644]. There are many factors that can explain this difference in access to medicines between developing and developed countries. The population’s income is obviously one of the major factors, but the level of development of the pharmaceutical system and regulation in a given country is also important. One-third of countries have either no medicine regulatory authority or inadequate capacity to regulate the medicine market. The absence of such systems, regulations, and authority is clearly inconsistent with the right to the highest attainable standard of health. For this reason, one of WHO’s short- term target goals for Africa is to get at least 76% of the continent’s countries to adopt and implement international norms and standards for the quality, safety, and efficacy of essential medicines [645]. To achieve this important goal in Africa, and also in other regions, it is critical that developed countries and the international community help developing countries establish effective, integrated, inclusive health systems, and the appropriate medicine regulatory authorities and regulations.

International cooperation, convergence, and harmonization of pharmaceutical regulations has became the only clear choice to meet the fundamental human right to have access to high-quality, safe, and effective medicines in both developed and developing countries.

Cooperation and harmonization as concepts are straightforward, but in practice, pharmaceutical regulation is highly correlated to medical practice, culture, history, and economy, and therefore the process of harmonization is not an easy task. Many critical parameters need to be integrated (see Part II-2.1), and several influencing factors need to be taken into consideration (see Part II-2.2) to ensure successful implementation.

A substantial amount has already been done to harmonize pharmaceutical regulations and increase cooperation between regulators. Many bilateral, regional, and global initiatives have been established to support this necessary cooperation and harmonization process in the pharmaceutical sector (see Part I). The thorough review of all these initiatives highlights their benefits and clearly calls for continuous support and extension of ongoing efforts (see Part II-1).

However, without underestimating all these important positive efforts and outcomes, it is clear that differences still exist and that further fundamental changes will still be required to support this ongoing harmonization process. The current national regulatory systems are too outdated to meet current needs [646]. The new globalized pharmaceutical environment and increased cooperation require new processes and systems. All stakeholders, including regulators, recognize the need to substantially change the operating models of DRAs to address the challenges of the future. It is obvious that cooperation between countries and the continued development of global standards is critical to support this change, but further fundamental changes are required to control the risks raised by increased globalization. This need for further cooperation and harmonization in the pharmaceutical sector to reduce duplication was clearly highlighted by worldwide regulators during the 14th International Conference of DRAs [647]. Addressing the impact of globalization has also been identified by Europe as one of the key drivers to ensure public health [648]. Recognizing this critical situation, the US FDA INTERNATIONAL COOPERATION, CONVERGENCE AND HARMONIZATION OF PHARMACEUTICAL REGULATIONS 297 has already confirmed its intention to move to the next steps of cooperation and to establish a global coalition of regulators [649].

After five years of research, a thorough evaluation of the current situation and the evolution of convergence, harmonization, and cooperation over the past decades, I am convinced that the establishment of the proposed coordinated global pharmaceutical system (detailed in Part III) is the best realistic alternative to fulfill the objective to establish a global coalition of regulators and to respond to this increased demand for further cooperation and harmonization in the pharmaceutical sector. The overall goal is to provide the information most relevant to each country in order to allow a decision-making process based on its needs, while avoiding requirements for generating country-specific data that does not add value to public health. This framework presents advantages for all stakeholders, and would definitively have significant added value for the promotion and protection of global public health.

It is important to reiterate that the objective of the proposed global pharmaceutical system is not to replace current initiatives and impose a supranational authority on countries. This would be unrealistic and not helpful. The goals are rather to better coordinate and leverage all the positive initiatives and the dedication seen in past decades at the national, regional, and global levels so that the collective knowledge and resources continue to improve global public health. It logically builds on the incredible achievements made so far, and uses as foundations all the numerous harmonization and cooperation projects developed over the years that have built relationships between all global stakeholders and developed tools to support global communication and the exchange of information.

However, even if this proposed system utilizes current resources and systems, it proposes fundamental changes to the way medicines are controlled and authorized. To be successful, the implementation of this global framework will need to be well organized and further discussed with all stakeholders. Involvement of all stakeholders will indeed be critical because the implementation of these changes will need to become a shared responsibility. It will also require political courage and vision. Scientists, regulators, and pharmaceutical companies have already shown, via the multiple collaborations already established, that they are ready for this next logical phase of cooperation and harmonization.

To conclude, although the implementation of this new global pharmaceutical system will require much additional effort and dedication, it is an incredible and very exciting opportunity because it could resolve outstanding difficulties in developing countries, further support pharmaceutical innovation, and better promote and protect global public health. It responds to the current needs of both developed and developing countries. This new strategic global approach, with increased collaboration between countries and better use of global resources, experience, and expertise, also supports the United Nations Millennium Development Goals. Acronyms and Abbreviations

ACCSQ: ASEAN Consultative Committee on Standards and Quality ACP: African, Caribbean, and Pacific Island ACSoMP: WHO’s Advisory Committee on Safety of Medicinal Products ACTD: ASEAN Common Technical Dossier ACTRs: ASEAN Common Technical Requirements ADR: Adverse Drug Reaction AE: Adverse Event AEC: ASEAN Economic Community AEM: ASEAN Economic Ministers AFSSAPS: Agence Française de Sécurité Sanitaire du Médicament et des Produits de Santé AFTA: ASEAN Free Trade Area AHC: APEC Harmonization Center ALIFAR: Latin American Association of Pharmaceutical Industry ANSM: Agence Nationale de Sécurité du Médicament et des Produits de Santé AMRH: African Medicines Registration Harmonization ANZTPA: Australia New Zealand Therapeutic Products Agency APEC: Asia-Pacific Economic Cooperation API: Active Pharmaceutical Ingredient APRIA: ASEAN Pharmaceutical Research Industry Association ASEAN: Association of Southeast Asian Nations ATC/DDD: WHO’s Anatomical Therapeutic Chemical Classification with Defined Daily Doses ATMP: Advanced Therapy Medicinal Products AU: African Union AUPAM: Arab Union of the Manufacturers of Pharmaceuticals and Medical Appliances AVAREF: African Vaccine Regulatory Forum AWGPD: ASEAN Working Group on Pharmaceuticals Development BAN: British Approved Names BEMA: Benchmarking of European Medicines Agencies BLA: Biologics License Application B&MGF: Bill & Melinda Gates Foundation BRN: Blood Regulators Network BWP: EMA’s Biologics Working Party CADREAC: Collaboration Agreement between Drug Regulatory Authorities in European Union Associated Countries CARICOM: Caribbean Community CARIFTA: Caribbean Free Trade Association CAT: EMA’s Committee for Advanced Therapies CBER: US FDA’s Center for Biologics Evaluation and Research CCASG: Cooperation Council for the Arab States of the Gulf CCO: WHO’s Department of Country Focus CCS: WHO’s Country Cooperation Strategy CDER: US FDA’s Center for Drug Evaluation and Research CEN: European Committee for Standardization CEP: Certificate of Suitability of the Monographs of the European Pharmacopoeia CHAI: Clinton Health Access Initiative

299 300 ACRONYMS AND ABBREVIATIONS

CHM: Council of the GCC Health Ministers CHMP: EMA’s Committee for Medicinal Products for Human Use CIOMS: Council for International Organizations of Medical Sciences CIRS: Centre for Innovation in Regulatory Science CMDh: EU’s Co-ordination Group for Mutual Recognition and Decentralized Procedures – Human COHSOD: CARICOM’s Council for Human and Social Development COMP: EMA’s Committee for Orphan Medicinal Products COREPER: Committee of Permanent Representatives CPMP: Committee for Proprietary Medicinal Products CPP: Certificate of Pharmaceutical Product CRO: Contract Research Organization CSI: WHO’s Civil Society Initiative CTA: Clinical Trial Application CTD: Common Technical Document CTFG: Clinical Trials Facilitation Group CVMP: EMA’s Committee for Medicinal Products for Veterinary Use DCF: Dénominations Communes Françaises DCVRN: Developing Countries’ Vaccine Regulators Network DFID: UK’s Department for International Development DG: Directorates-General DoH: Department of Health DRA: Drug Regulatory Authority DRAs: Drug Regulatory Authorities DSUR: Development Safety Update Report EAC: East African Community EC: European Commission ECBS: Expert Committee on Biological Standardization ECSC: European Coal and Steel Community ECSPP: WHO Expert Committee on Specifications for Pharmaceutical Preparations eCTD: Electronic Common Technical Document EDQM: European Directorate for the Quality of Medicines & HealthCare EEA: European Economic Area EEC: European Economic Community EFPIA: European Federation of Pharmaceutical Industries and Associations EFTA: European Free Trade Association EMA: European Medicines Agency EMEA: European Agency for the Evaluation of Medicinal Products EMP: WHO’s Department of Essential Medicines and Health Products EMRO: WHO Regional Office for the Eastern Mediterranean ENCePP: European Network of Centres for Pharmacoepidemiology and Pharmacovigilance EP: European Pharmacopoeia EPSCO: Employment, Social Policy, Health and Consumer Affairs Council ERMS: European Risk Management Strategy ESTRI: Electronic Standards for Transmission of Regulatory Information EU: European Union EUnetHTA: European Network for Health Technology Assessment EURATOM: European Atomic Energy Community EURS: European Review System EUTCT: EU Telematics Controlled Terms EWG: ICH’s Expert Working Group FIFARMA: Latin American Federation of the Pharmaceutical Industry FPE: First Patient Enrolled FTA: Free Trade Area GCC: Gulf Cooperation Council ACRONYMS AND ABBREVIATIONS 301

GCC-DR: Gulf Central Committee for Drug Registration GCG: ICH Global Cooperation Group GCP: Good Clinical Practices GDP: Gross Domestic Product GLP: Good Laboratory Practices GMO: Genetically Modified Organism GMP: Good Manufacturing Practices GTDG: ICH’s Gene Therapy Discussion Group GRevP: Good Review Practices GRP: Good Regulatory Practices GVP: EMA’s Good Pharmacovigilance Practice Guidelines HIV/AIDS: Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome HL7: Health Level 7 HMA: Heads of Medicines Agencies (Europe) HMPC: EMA’s Committee on Herbal Medicinal Products HSS: WHO’s Health Systems and Services HTA: Health Technology Assessment HWO: Head of WHO Office ICD: WHO’s International Classification of Diseases ICDRAs: International Conference of Drug Regulatory Authorities ICF: WHO’s International Classification of Functioning, Disability and Health ICH: International Conference on Harmonization of Technical Requirements for Registration of Pharma- ceuticals for Human Use ICHI: WHO’s International Classification of Health Interventions ICREL: Impact on Clinical Research of European Legislation ICRS: WHO’s International Chemical Reference Substances ICSR: Individual Case Safety Report ICTRP: The WHO International Clinical Trials Registry Platform IDHL: International Digest of Health Legislation IFPMA: International Federation of Pharmaceutical Manufacturers & Associations IGPA: International Generic Pharmaceutical Alliance IHR: International Health Regulations IMPACT: International Medical Products Anti-Counterfeiting Taskforce IMPD: Investigational Medicinal Product Dossier IND: Investigational New Drug INN: International Nonproprietary Names IPA: EU’s Instrument for Pre-accession Assistance IRCH: International Regulatory Cooperation for Herbal Medicines ISE: Integrated Summary of Efficacy ISO: International Organization for Standardization ISS: Integrated Summary of Safety IT: Information Technology ITF: EMA’s Innovation Task Force IWG: Implementation Working Group JAN: Japanese Adopted Names JP: Japanese Pharmacopoeia JPMA: Japan Pharmaceutical Manufacturers Association LSIF: APEC’s Life Sciences Innovation Forum MAA: Marketing Authorization Application MCA: UK’s Medicines Control Agency (now renamed MHRA) MDGs: Millennium Development Goals Medsafe: New Zealand’s Medicines and Medical Devices Safety Authority MedDRA: ICH’s Medical Dictionary for Regulatory Activities MERCOSUR: The “Common Market of the South” 302 ACRONYMS AND ABBREVIATIONS

MHLW: Japan’s Ministry of Health, Labour and Welfare MHRA: UK’s Medicines and Healthcare products Regulatory Agency MoA: Memorandum of Agreement MoH: Ministry of Health MoU: Memorandum of Understanding MRA: Mutual Recognition Agreement (or Arrangement) MRP: Mutual Recognition Procedure MSSO: MedDRA Maintenance and Support Services Organization NAFTA: North American Free Trade Agreement NDA: New Drug Application NEPAD: New Partnership for Africa’s Development NGO: Nongovernmental Organization NIHS: Japan’s National Institute of Health Sciences NME: New Molecular Entity OMCL: EU’s Network of Official Medicines Control Laboratories PAHO: Pan American Health Organization PANDRH: Pan American Network for Drug Regulatory Harmonization PDCO: EMA’s Paediatric Committee PDE: Permitted Daily Exposure PDG: Pharmacopoeial Discussion Group PERF: Pan European Regulatory Forum PhRMA: Pharmaceutical Research and Manufacturers of America PhV: Pharmacovigilance Ph. Int.: International Pharmacopoeia PIC/S: Pharmaceutical Inspection Co-operation Scheme PIP: Pediatric Investigational Plan PMDA: Japan’s Pharmaceuticals and Medical Devices Agency PmRN: Paediatric Medicines Regulators’ Network PPWG: ASEAN’s Pharmaceutical Product Working Group PRAC: EMA’s Pharmacovigilance Risk Assessment Committee PSUR: Periodic Safety Update Reports PWAs: APEC’s Priority Work Areas QC: Quality Control QP: Qualified Person QWP: EMA’s Quality Working Party Q&A: Questions and Answers RECs: Africa’s Regional Economic Communities REMS: Risk Evaluation and Mitigation Strategy RHI: Regional Harmonization Initiative RHSC: LSIF’s Regulatory Harmonization Steering Committee RISDP: SADC’s Regional Indicative Strategic Development Plan RMP: Risk Management Plan RMS: Reference Member State R&D: Research and Development SADC: Southern African Development Community SANCO: EC’s DG “Health and Consumers” SARS: Severe Acute Respiratory Syndrome SBP: Similar Biotherapeutic Product SC: Steering Committee SDO: Standards Development Organization SEOM: ASEAN’s Senior Economic Official Meeting SFDA: Saudi Food & Drug Authority SHD&SP: Social and Human Development and Special Programmes SICA: The Central American Integration System ACRONYMS AND ABBREVIATIONS 303

SMEs: Small- and Medium-Sized Enterprises SMQs: Standardized MedDRA Queries SOP: Standard Operating Procedure STF: Study Tagging File TEC: Transatlantic Economic Council TGA: Australia’s Therapeutic Goods Administration UAE: United Arab Emirates UK: United Kingdom UMBRA: Unified Methodologies for Benefit-Risk Assessment Initiative UN: United Nations UNAIDS: Joint United Nations Programme on HIV/AIDS UNESCO: United Nations Educational, Scientific and Cultural Organization UNICEF: United Nations Children’s Fund US: United States of America USAN: United States Adopted Names US FDA: United States Food and Drug Administration USP: US Pharmacopeia UTN: Universal Trial Number VHP: EU Voluntary Harmonization Procedure WG: Working Group WHA: WHO World Health Assembly WHO: World Health Organization VHP: EU’s Voluntary Harmonization Procedure WIN: Work Instructions WMA: World Medical Association WSMI: World Self-Medication Industry WTO: World Trade Organization XML: Extensible Markup Language List of Figures, Tables and Plates

FIGURES

Figure 1: Levels of Harmonization Figure 2: SADC Policy and Executive Structures Figure 3: Different Players in the Harmonization of the Pharmaceutical Regulation within the SADC Region Figure 4: Differences in Regulatory Capacity Globally Figure 5: Differences in Regulatory Capacity in the African Region Figure 6: Model of Typical Key Milestones and Timeframes for Harmonization Projects Figure 7: Implementation Process Flow Figure 8: The UMBRA Eight-Step Benefit-Risk Framework

TABLES

Table 1: List of ICH Conferences Table 2: Type of ICH Procedures Table 3: ICH M2 Recommendations Table 4: Membership Country and Year of Addition into the EU Table 5: Summary of the Structure of the European Union and Roles/Responsibilities Table 6: Evolution of the Number of Products and Companies Approved Nationally vs. Centrally in Saudi Arabia

COLOR PLATES

Plate 1: Map of the European Union Plate 2: PANDRH Subregional Blocs Plate 3: GCC Members Plate 4: SADC Member States Plate 5: The 10 Countries of ASEAN Plate 6: APEC Member Economies Plate 7: Locations of Studies Registered on ClinicalTrials.gov Plate 8: Pr oposed Global Pharmaceutical System and Network

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Page numbers followed by “f” and “t” indicate figures and tables respectively.

0-9 mutual recognition agreements/arrangements, 8–9 4th Hurdle, 215–216 NAFTA, 115 5th International Conference on Harmonization PANDRH, 114–115, 123–124, 126 (ICH5), 42–43 regulators, 177 14th International Conference of Drug Regulatory WHO, 13, 15–16 Authorities, 258 ALIFAR. See Latin American Association of Pharmaceutical Industry A allergens, 84 abbreviated new drug applications (ANDA), Americas/Pan American Health Organization. 274–275 See Pan American Health Organization academia involvement, 234 AMRH. See African Medicines Registration access considerations, 172, 182 Harmonization ACSoMP. See Advisory Committee on Safety of analytical tests, 180, 292–293 Medicinal Products Anatomical Therapeutic Chemical Classification additional ICH members, 36 with Defined Daily Doses (ATC/DDD), ADR. See adverse drug reactions 18–19 advanced-therapy medicinal products (ATMP), 75, 97 ANDA. See abbreviated new drug applications adverse drug reactions (ADR), 23 Andean community, 114 advertising, 84 animal testing, 173, 180 Advisory Committee on Safety of Medicinal ANZTPA. See Australia New Zealand Therapeutic Products (ACSoMP), 23 Products Agency Africa APEC. See Asia-Pacific Economic Cooperation international body establishment appropriate planning strategies, 192–193 recommendations, 259–266 Arab Union of the Manufacturers of Pharmaceuticals regional cooperation initiatives, 259–266 and Medical Appliances (AUPAM), 268 regulatory capacity critical parameters, 187–188 arbitration, 84 WHO structure, 12. See also Southern African ASEAN. See Association of Southeast Asian Development Community Nations African Medicines Registration Harmonization Asia, 12, 266–268 (AMRH) Asia-Pacific Economic Cooperation (APEC) cooperation initiative, 8, 8f cooperation, 66, 143–152 milestones/timeframes, 193 harmonization, 66, 146–150 proposed global system recommendations, history, 145–146 263–266 Life Sciences Innovation Forum, 143–152 agreements membership, 144 ASEAN, 139–140 networks, 143–152 bilateral cooperation initiatives, 152–163 “Process”, 146–148 CADREAC, 68–69 projects, 148–150 EU, 76–77, 81, 87 regional initiatives, 66, 143–152 European Economic Area, 69, 75–76 structures, 144–145 ICH, 65, 68–69 Assembly. See World Health Assembly Memorandum of Agreements, 177 assistance strengthening, 252–258

331 332 INDEX

Association of Southeast Asian Nations (ASEAN) clusters, 160 agreements, 139–140 communication, 231 cooperation, 65, 136–143 coordination to one unique body, 224–225 harmonization, 65, 140–142 developed countries, 152–163 history, 139–140 developing countries, 152–153 ICH, 138, 142, 245–246, 266–268 EU-US cooperation, 152–163 international body establishment GMP, 155, 157–158 recommendations, 245–246, 266–268 Good Clinical Practices, 158 membership, cooperation regional initiatives, 138 harmonization, 153, 155–161 networks, 136–143 history, 155 “Process”, 140–141 inspection collaboration, 157–158 projects, 141–142 international body establishment regional initiatives, 65, 136–143 recommendations, 224–225, 231 structures, 138–139 medicine evaluation, 289 Working Groups, 137–143 membership, 153–154 ATC/DDD. See Anatomical Therapeutic Chemical networks, 152–163 Classification with Defined Daily Doses orphan medicinal products, 160 ATMP. See advanced-therapy medicinal products parallel scientific advice program, 159–160 audits, 85 pediatric medicines, 160–161 AUPAM. See Arab Union of the Manufacturers of pharmacovigilance, 159 Pharmaceuticals and Medical Appliances “Process”, 155–156 Australia New Zealand Therapeutic Products projects, 156–161 Agency (ANZTPA), 152–153 proposed global system recommendations, authorization: medical products, 94–96 224–225 quality by design, 161 B safety issues, 159 BAN. See British Approved Names structures, 154 Benchmarking of European Medicines Agencies Transatlantic Administrative Simplification (BEMA), 286 Workshop, 156–157 beneficial considerations types, 152–153 cooperation & harmonization, 181–186 US-EU cooperation, 152–163 proposed global system recommendations, Biological Reference Materials, 25–26 227–229 biological standardization, 25–26 Benefit–Risk Assessments, 287, 288f biosimilars, 150, 160 best practices biotechnology products, 150 clinical practices, 73, 119, 158, 217, 269–272 blood, 84 EU cooperation initiatives, 78, 146–148 Blue Book, 30 ICH cooperation initiatives, 40, 54, 61–62 Bogor Goals, 145 international body establishment British Approved Names (BAN), 23 recommendations, 269–272 budget considerations, 215–216 laboratory practices, 73, 269–272 business plans, 132–134 patients and global public health, 172–173 pharmacovigilance, 93 C regulatory practices, 285 CADREAC. See Collaboration Agreement between review practices, 285. See also Good Manufacturing Drug Regulatory Authorities in European Practices. Union Associated Countries Better Medicines for Children, 26–27 Caribbean Community, 114 bilateral cooperation initiatives, 152–163, 167–168 Caribbean Co-operation in Health (CCH), 114 agreements, 152–163 Caribbean Free Trade Association (CARIFTA), 114 INDEX 333

Caribbean Health and Development Commission, international body establishment 114 recommendations, 274–282 CBER. See Center for Biologics Evaluation and standards, 278 Research clinical trial applications (CTA), 98, 107 CCASF. See Cooperation Council for the Arab States clinical trials of the Gulf APEC, 149 CCH. See Caribbean Co-operation in Health databases, 280–282 CCO. See Department of Country Focus EU initiatives, 97–100, 106–109 CCS. See Country Cooperation Strategy registration, 279–282 CDER. See Center for Drug Evaluation and value and influencing factors, 216–219 Research WHO, 19 Center for Biologics Evaluation and Research Clinical Trials Facilitation Group (CTFG), 98 (CBER), 35 clusters: bilateral cooperation initiatives, 160 Center for Drug Evaluation and Research (CDER), CMDh. See Co-ordination Group for Mutual 35 Recognition and Decentralized Procedures – Central American Integration System (SICA), 115 Human Centralized procedures, 84, 86, 94, 108 codifying Directives, 85 Centre for Innovation in Regulatory Science (CIRS), Coding Symbols for a Thesaurus of Adverse 287 Reaction Terms (COSTART), 53 CEP. See Certificates of Suitability of the COHSOD. See Council for Human and Social Monographs of the European Pharmacopoeia Development Certificate of Pharmaceutical Products (CPP) collaboration developing countries, 230 ICH cooperation initiatives, 39–40, 43 medicine evaluation, 291 international body establishment quality, 24–25, 256–257 recommendations, 224–225, 231 WHO, 256, 24, 256–257 WHO supporting bodies, 14–15 Certificates of Suitability of the Monographs of the Collaboration Agreement between Drug European Pharmacopoeia (CEP), 77 Regulatory Authorities in European certification Union Associated Countries (CADREAC) quality considerations, 256–257 procedure, 68–69 reference DRAs, 252 Commission Decisions, 69–70 WHO, 20, 24–25, 256–257. See also Certificate of commitment considerations, 206–209 Pharmaceutical Products Committee for Advanced Therapies (CAT), 75 China, 201–202 Committee on Herbal Medicinal Products (HMPC), CHMP. See Committee for Medicinal Products for 74, 97 Human Use Committee for Medicinal Products for Human Use CIOMS. See Council for International Organizations (CHMP), 73–74, 89 of Medical Sciences Committee for Medicinal Products for Veterinary CIRS. See Centre for Innovation in Regulatory Use (CVMP), 75 Science Committee for Orphan Medicinal Products Civil Society Initiative (CSI), 17 (COMP), 74 classifications: WHO, 18–19 Committee of Permanent Representatives clinical efficacy, 92–93 (COREPER), 70–71 clinical practices: best practice, 73, 119, 158, 217, common market, 80–81 269–272 Common Technical Documents (CTD) clinical studies Africa, 263 ethics, 276–278 ASEAN, 141 ethnic factors, 278–279 EU pharmaceutical regulation, 83 globalization, 201 ICH, 42, 50, 56–59, 245–246 334 INDEX communication Registration of Pharmaceuticals for Human Use, bilateral initiatives, 231 34–64 critical parameters, 189–192, 194 registration technical requirements, 34–64 DRAs, 203–206 WHO, 8–33 harmonization, 189–192, 194 harmonization influencing factors, 203–206 beneficial considerations, 181–186 proposed global system recommendations, 231 CIOMS, 164 worldwide authorities, 203–206 economical integration, 65 COMP. See Committee for Orphan Medicinal global initiatives, 7, 9–64 Products initiatives, 7 compassionate considerations, 109 integration models, 8 competiveness, 209 intergovernmental agreement, 65 compliance considerations, 274 international organizations, 164 Concept Papers, 45–46 Pharmacopoeial Discussion Group, 163 Concertation procedure, 83–84 PIC/S, 164 conferences political considerations, 65 14th International Conference of Drug Regulatory regional initiatives, 64–152, 168 Authorities, 258 WHO, 16–17 ICDRA, 11, 16–18, 41, 221 ICH ICH5, 42–43 global initiatives, 34–64 ICH, 43–44. See also International Conference on value considerations, 175–177, 179, 181–182, 184 Harmonization; Pan-American Conferences influencing factors, 186, 200–216 on Drug initiative review current status, 7–170 Regulatory Harmonization inspections, 157–158, 164 confidential information, 190–191, 282–284 integration models, 8 consensus principles, 42–43, 47, 226 intergovernmental agreement, 65 consumer involvement, 234 international body establishment continuous support, 229–230 recommendations, 226–227 contract research organizations (CRO), international organizations, 164 269–270 ISO, 164 cooperation PANDRH, 113–122 accelerated support, 258–269 Pharmacopoeial Discussion Group, 163 Africa, 259–266 PIC/S, 164 APEC, 66, 143–152 political considerations, 65 ASEAN, 65, 136–143 proposed global system recommendations, beneficial considerations, 181–186 235–294 bilateral initiatives, 152–163, 167–168 regional initiatives CIOMS, 164 Africa, 259–266 coordination considerations, 224–225 APEC, 66, 143–152 critical parameters, 186–200 ASEAN, 65, 136–143 current status, 7–170 European Union, 66–113 definitions, 3–4 GCC, 122–127 EC-ACP-WHO Partnership, 30 harmonization, 64–152, 168 economical integration, 65 PANDRH, 113–122 EU regional initiatives, 66–113 SADC, 127–136 GCC regional initiatives, 122–127 Registration of Pharmaceuticals for Human Use, global initiatives, 223, 7–64 34–64 harmonization, 7, 9–64 registration technical requirements, 34–64 ICH, 34–64 SADC, 127–136 INDEX 335

state of play, 7–170 planning appropriateness, 192–193 value considerations, 171–186 regulator capacity, 186–189 ICH, 175–177, 179, 181–182, 184 resources, 186–189 WHO, 174, 175–177, 179, 181–182, 184 stakeholder involvement, 198–199 WHO structure, 194 global initiatives, 8–33 voluntary cooperation, 199–200 harmonization, 16–17 CRO. See contract research organizations value considerations, 174, 175–177, 179, 181–182, CSI. See Civil Society Initiative 184 CTA. See clinical trial applications WMA, 164 CTD. See Common Technical Documents coordination of global system recommendations, CTFG. See Clinical Trials Facilitation Group 224–225, 236–239 culture differences, 211–212 Co-ordination Group for Mutual Recognition and currency, 81, 128 Decentralized Procedures – Human (CMDh), current status 79 cooperation initiative reviews, 7–170 Coordinators: ICH, 36, 38 harmonization in Africa, 262–264 corporate level structures, 11 ICH achievements, 60–64 COSTART. See Coding Symbols for a Thesaurus of Adverse Reaction Terms D cost considerations, 179, 215–216 daily doses, 18–19 Council of the European Union, 70–71, 88 databases, 272–273, 280–282 Council of the GCC Health Ministers (CHM), 122, data elements and standards, 59–60 124 data protection, 190 Council for Human and Social Development data retrieval and presentation, 54 (COHSOD), 114 DCF. See Dénominations Communes Françaises Council for International Organizations of Medical Decentralized procedures, 86, 95, 109–111 Sciences (CIOMS), 164 decision considerations, 87, 206–209 Council of Ministers, 129 decision-making processes, 232–233 counterfeit medicines, 11, 149, 293–294 Declaration of ASEAN Concord II, 137 Country Cooperation Strategy (CCS): initiatives, 13 defense considerations, 129 Country Focus (CCO), 13–14 defining goals, 192–193 country level structure, 12–14 Dénominations Communes Françaises (DCF), 23 CPP. See Certificate of Pharmaceutical Products Department of Country Focus, 13–14 critical parameters Department of Essential Medicines and Health appropriate planning strategies, 192–193 Products, 11, 17, 20 commitment considerations, 206–209 developed countries communication, 189–192, 194 bilateral cooperation initiatives, 152–163 convergence, 186–200 decision-making processes, 232–233 cooperation, 186–200 international body establishment defining goals, 192–193 recommendations, 228 economy, 200–201 regulatory capacity, 228 expertise, 186–189 developing countries goal defining strategies, 192–193 assistance strengthening, 252–258 harmonization, 186–200 bilateral cooperation initiatives, 152–153 implementation considerations, 194–198 continuous support, 229–230 information communication, 189–192 core functions, 253–255 legal commitment, 199–200 decision-making processes, 232–233 monitoring considerations, 194–198 DRAs, 257–258 organization, 194 health system development, 252–258 336 INDEX developing countries (Continued) regulatory science, 284–287 international body establishment regulatory support, 257–258 recommendations, 228–230, 252–258 risk management/mitigation, 274 product manufacture, 203 technical standards, 227 regulatory capacity, 228–230, 253–255 technical support, 257–258 regulatory support, DRAs, 257–258 trade secrets, 282–284 staff training, 253–255 International Medicines Agency establishment, support, 174–175 239–240 technical support, 257–258 patients and global public health, 172–173 training, 253–255 political decisions and commitments, 206–209 DG. See Directorates-General proprietary confidential information, 282–284 DG SANCO, 73, 99 qualification, 252 Directives, 83–87, 96–100, 106–109, 275 regulator value considerations, 176–179 Directorates-General (DG), 71–72 regulatory science, 284–287 Director-General, 10 regulatory support, 257–258 Discussion Groups, 38, 163 risk management/mitigation, 274 diversity considerations, 66 technical standards, 227 Doha declaration, 283 technical support, 257–258 dosage considerations, 18–19 trade secrets, 282–284 DRA. See Drug Regulatory Authorities WHO, 7, 11, 18, 24–27, 29–31 draft documents, 118, 140 Drug Regulatory systems, 30–31 drug dictionaries, 59–60 MedDRA, 36, 38, 53–55 E Drug Information, 30 East African Community (EAC), 32–33, 260–261 drug registration, 122–123, 125–126 Eastern Mediterranean, 12 Drug Regulatory Authorities (DRA) EC. See European Commission communication, 203–206 economics/economy compliance, 274 Africa, 261, 263 confidential information, 257–258, 282–284 influencing factors, 209–211, 215–216 developing countries, 257–258 integration, 65 EU technical bodies, 76 public health, 209–211 evaluation procedure establishment, 288–292 eCTD. See Electronic Common Technical Documents GMP, 269–270 EDQM. See European Directorate for Quality of ICH, 242–243 Medicines and HealthCare identification, 252 EEA. See European Economic Area information confidentiality, 282–284 EEC. See European Economic Community international body establishment efficacy considerations, 51–52, 92–93 recommendations, 252 EFPIA. See European Federation of Pharmaceutical compliance, 274 Industries and Associations confidential information, 282–284 EFTA. See European Free Trade Association developing countries, regulatory/technical Electronic Common Technical Documents (eCTD), 56 support, 257–258 Electronic Standards for Transmission of Regulatory evaluation procedure establishment, 288–292 Information (ESTRI), 42, 55–57 identification, 252 Electronic Submissions (eSubmissions), 100–101 information confidentiality, 282–284 EMA. See European Medicines Agency International Medicines Agency establishment, EMP. See Essential Medicines and Health Products 239–240 employment, 70–71, 210–211 proprietary confidential information, 282–284 Enablers of Investment Checklist, 148–149 qualification, 252 EP. See European Pharmacopoeia INDEX 337

Essential Medicines and Health Products (EMP), 11, advanced-therapy medicinal products, 75, 97 17, 20 agreements, 76–77, 81, 87 ESTRI. See Electronic Standards for Transmission of best practices, cooperation initiatives, 78, 146–148 Regulatory Information bilateral cooperation initiatives, US, 152–163 ethical factors, 109, 276–278 birth of, 79–82 ethnic factors, 195, 212–213, 278–279 challenges, 105–111 EU. See European Union clinical efficacy, 92–93 EudraCT, 100 clinical trials, 97–100, 106–109 EudraGMP, 101 compassionate use, 109 EudraLex, 89 cooperation initiatives, 66–113 EudraLink, 101 Decentralized procedures, 86, 95, 109–111 EudraNet, 101 Directives, 83–87, 96–100, 106–109 EudraPharm, 101 efficacy, 92–93 EudraVigilance, 101 Electronic Submissions, 100–101 EURATOM. See European Atomic Energy herbal medicinal products, 74, 97 Community history, 66, 79–87 Europe Iceland, 69–70 clinical studies, 275 ICH, 35, 248 harmonization regional initiatives, 65 institutions, 70–72, 71t ICH membership, 35 legislation, 83–90 WHO structure, 12 lessons learned, 111–113 European Atomic Energy Community (EURATOM), Liechtenstein, 69–70 80–81 medical product authorization, 94–96 European Commission (EC), 35, 71–72, 153–163, medicine evaluation, 289 216–219 membership, 67–70 European Directorate for Quality of Medicines and Member States, 66–67, 77–79 HealthCare (EDQM), 20, 72, 76–77 multidisciplinary considerations, 93–94 European Economic Area (EEA) Agreements, 69, Mutual Recognition Procedure, 83–84, 94–95, 75–76 109–111 European Economic Community (EEC), 80–81 networks, 66–113 European Federation of Pharmaceutical Industries non-clinical requirements, 91–92 and Associations (EFPIA), 35 Norway, 69–70 European Free Trade Association (EFTA) States, 69, organizations, 70–79 75–77 orphan medicinal products, 74, 96–97 European Medicines Agency (EMA) outstanding issues, 105–111 clinical efficacy & safety, 92 pediatric medicines, 74–75, 96 EU achievements & successes, 102–105 pharmaceutical regulation, 83–87 EU membership, 68 pharmacovigilance, 73, 75, 92, 109 EU Member States, 77 politics, 207 EU technical bodies, 72 prices, 105–106 EU-US bilateral cooperation initiatives, 153–163 “Process”, 87–90 ICH membership, 35 projects, 90–101 regulator value considerations, 177 quality, 90–91 European Medicines Regulatory Network, 78 regional cooperation initiatives, 66–113 European Parliament, 70, 81–82, 88 regulations, 83–90, 96–100 European Pharmacopoeia (EP), 73, 77, 91 regulatory science, 285–286 European Review Systems (EURS), 101 reimbursements, 105–106 European Union (EU) safety, 92–93 achievements, 102–105 structures, 66, 70–79 338 INDEX

European Union (EU) (Continued) Global Cooperation Group (GCG), 34, 36–40, 242, successes, 102–105 245 technical bodies, 70, 71t, 72–77 global initiatives technical requirements, 90–94 cooperation, 221, 7–64 Telematics Program, 100–101 harmonization, 221, 7, 9–64 US bilateral cooperation initiatives, 152–163 international body establishment value considerations, 177, 184 recommendations, 226–227 EURS. See European Review Systems proposed global system recommendations, EU Telematics Controlled Terms (EUTCT), 101 235–294 evaluations WHO, 8–33 DRAs, 288–292 globalization international procedure establishment, 288–292 clinical studies, 201 patients and global public health, 174 influencing factors, 200–203 EWG. See Expert Working Group global public health value considerations, 172–176 Executive Board Resolutions, 16–17 global regulatory capacities, 187 expert committees, 14, 20 global technical standards, 226–227, 240–251 expert groups, 290 glossary usage considerations, 191 expertise considerations, 186–189 GLP. See Good Laboratory Practices Expert Working Group (EWG), 37, 55 GMP. See Good Manufacturing Practices extrinsic ethnic factors, 212 goal defining strategies, 192–193 Good Clinical Practices (GCP), 73, 119, 158, 217, F 269–272 FDA. See Food and Drug Administration Good Laboratory Practices (GLP), 73, 269–272 FIFARMA. See Latin American Federation of the Good Manufacturing Practices (GMP) Pharmaceutical Industry bilateral cooperation initiatives, 155, 157–158 5th International Conference on Harmonization EU Directives, 84 (ICH5), 42–43 EU regional initiatives, 91 financial incentives, 201 EU technical bodies, 73 Food and Drug Administration (FDA) EU Telematics Program, 101 EU-US cooperation initiatives, 153–163 GCC, 122 ICH, 35, 248 international body establishment implementation considerations, 197 recommendations, 269–272 international clinical studies, 274–275 PANDRH, 119 regulator value considerations, 177 WHO, 20–21, 24–25 Formal ICH procedures, 47–49 Good Pharmacovigilance Practice guidelines (GVP), foundation organization involvement, 234 93 founding members: ICH, 35–36 Good Regulatory Practices (GRP), 285 The 4th Hurdle, 215–216 Good Review Practices (GRevPs), 285 14th International Conference of Drug Regulatory government regulatory capacities, 188 Authorities, 258 GRevPs. See Good Review Practices France, 206 GRP. See Good Regulatory Practices Free Trade Area (FTC), 128, 137, 139 GTDG. See Gene Therapy Discussion Group future challenges: ICH, 62–64 Gulf Cooperation Council (GCC) G cooperation regional initiatives, 122–127 GCC. See Gulf Cooperation Council drug registration, 122–123, 125–126 GCP. See Good Clinical Practices harmonization, 125–126 Gene Therapy Discussion Group (GTDG), 63–64 history, 123–124 genetically modified organisms, 84 international body establishment Germany, 207 recommendations, 268–269 INDEX 339

membership, 122 implementation considerations, 194–198 networks, 122–127 monitoring considerations, 194–198 “Process”, 124–125 tradition differences, 211–212 structures, 122–123 integration models, 8 GVP. See Good Pharmacovigilance Practice guidelines intergovernmental cooperation, 8, 65 international body establishment H recommendations, 226–227 H1N1 outbreak, 204–205 international organizations, 164 H5N1 pandemic potential, 204 legal commitment, 199–200 harmonization monitoring considerations, 194–198 accelerated support, 258–269 organization, 194 analytical tests, 292–293 PANDRH, 66, 113–122 APEC, 66, 146–150 pharmaceutical regulations, 4 ASEAN, 140–142 Pharmacopoeial Discussion Group, 163 beneficial considerations, 181–186 PIC/S, 164 bilateral cooperation initiatives, 153, 155–161 political consideration, 65, 206–209 CIOMS, cooperation, 164 proposed global system recommendations, clinical trials, 216–219 235–294 communication, 189–192, 194 regional initiatives, 64–152, 168, 224–225 cooperation release specifications, 292–293 beneficial considerations, 181–186 SADC, 132–135 CIOMS, 164 scientific intergovernmental cooperation models, 8 economical integration, 65 structure, 194 global initiatives, 7, 9–64 technical cooperation models, 8 initiatives, 7 technical standards, 226–227 integration models, 8 tradition differences, 211–212 intergovernmental agreement, 65 value considerations, 171–186 international organizations, 164 WHO, 174, 175–177, 179, 181–182, 184 ISO, 164 voluntary cooperation, 199–200 Pharmacopoeial Discussion Group, 163 WHO PIC/S, 164 cooperation global initiatives, 8, 16–31 political agreement, 65 value considerations, 174, 175–177, 179, 181–182, political integration, 65 184. See also International Conference on projects, 50–60 Harmonization regional initiatives, 64–152, 168 Heads of Medicines Agencies (HMA), 78, 93 WHO, 16–17 health care professionals involvement, 234 coordination considerations, 224–225 health system development, 252–258 culture differences, critical parameters, 211–212 Health Systems and Services (HSS), 11 current status in Africa, 262–264 Health Technology Assessments (HTA), 105–106 definitions, 4 Health Working Group, 143, 145–146 EC-ACP-WHO Partnership, 30 herbal medicinal products, 74, 97 economical factors, 65, 210 history EU-US bilateral cooperation initiatives, 155–156 APEC, 145–146 GCC, 125–126 ASEAN, 139–140 global initiatives, 223, 7, 9–64 bilateral cooperation initiatives, 155 implementation considerations, 194–198 EU, 66, 79–87 influencing factors, 186–216 EU-US cooperation initiatives, 155 communication, 189–192, 194 GCC, 123–124 culture differences, 211–212 ICH, 41–44 340 INDEX history (Continued) culture differences, 211–212 PANDRH, 117–118 decision considerations, 206–209 SADC, 131–132 economics, 209–211, 215–216 US-EU cooperation initiatives, 155 ethnics, 212–213 WHO, 15–16 The 4th Hurdle, 215–216 HMA. See Heads of Medicines Agencies globalization, 200–203 HMPC. See Committee on Herbal Medicinal Products harmonization, 186, 200–216 homeopathic products, 84 legislation, 214–215 HSS. See Health Systems and Services medical practice differences, 213–214 HTA. See Health Technology Assessments political commitments/decisions, 206–209 human blood, 84 practice differences, 213–214 human interactions, 189–190 statutes, 214–215 human plasma, 84 system considerations, 214–215 human testing, 173 therapeutic differences, 213–214 tradition differences, 211–212 I Informal Expert/Implementation Working Group, 37 ICD. See International Classification of Diseases information communication, 189–192 ICDRA. See International Conference of Drug information confidentiality, 190–191, 282–284 Regulatory Authorities information sharing, 39–40 Iceland, 69–70 infrastructure, 186–189 ICF. See International Classification of Functioning, initiative reviews: cooperation current status, 7–170 Disability and Health IND. See investigational new drugs ICH5. See 5th International Conference on innovation promotion, 173 Harmonization Innovation Task Force (ITF), 104 ICH. See International Conference on Harmonization Innovative Drug Development, 104 ICHI. See International Classification of Health inspections, 157–158, 164, 269–272 Interventions institutions, 70–72, 71t ICREL. See Impact on Clinical Research of European Instrument for Pre-accession Assistance (IPA), 68–69 Legislation integration, 8, 39–40 ICSR. See Individual Case Safety Report intergovernmental cooperation, 8, 65 ICTRP. See International Clinical Trials Registry international body establishment recommendations, Platform 226 IFPMA. See International Federation of accelerated support, 258–269 Pharmaceutical Manufacturers & Associations Africa, 259–266 IHR. See International Health Regulations analytic tests, 292–293 Impact on Clinical Research of European Legislation ASEAN, 245–246, 266–268 (ICREL), 216–217 Asia, 266–268 implementation considerations assistance strengthening, 252–258 harmonization, 194–198 beneficial considerations, 227–229 ICH cooperation global initiatives, 37, 43, 48 best practices, 269–272 Implementation Working Group (IWG), 37 bilateral initiatives, 224–225, 231 India, 201–202 clinical studies, 274–282 Individual Case Safety Report (ICSR), 56 collaboration, 224–225, 231 industrial considerations, 179–181, 190–191, 209 communication importance, 231 influencing factors compliance, 274 budget considerations, 215–216 cooperation, 258–269 communication, 203–206 coordination considerations, 224–225 convergence, 186, 200–216 coordinator establishment, WHO, 236–239 cooperation, 186, 200–216 counterfeiting, 293–294 cost effectiveness, 215–216 CPP scheme, 256–257 INDEX 341

decision-making, 232–233 regulatory science, 284–287 developed countries, 228 regulatory support improvements, DRAs, 257–258 developing countries, 228–230, 252–258 release specifications, 292–293 DRAs, 252 review practice development, 284–287 compliance, 274 risk management/mitigation, 274 confidential information, 282–284 safety frameworks, 272–274 developing countries, 257–258 science-based medicines, 284–287 evaluation procedure establishment, 288–292 specification release, 292–293 identification, 252 stakeholder involvement, 233–234 international body establishment substandard products, 293–294 recommendations, 282–284 technical standards, 226–227, 240–251 International Medicines Agency establishment, technical support, 257–258 239–240 trade secrets, 282–284 proprietary confidential information, 282–284 unique coordinating bodies, 224–225 qualification, 252 WHO, 236–239, 256–257 regulatory support improvements, 257–258 International Chemical Reference Substances (ICRS), regulatory/technical support improvements, 20, 77 257–258 International Classification of Diseases (ICD), 15–16, risk management/mitigation, 274 18–19 technical standards, 227 International Classification of Functioning, technical support, 257–258 Disability and Health (ICF), 18–19 trade secrets, 282–284 International Classification of Health Interventions GCC, 268–269 (ICHI), 18–19 GCP, 269–272 international classifications, 18–19 global technical standards, 226–227 international clinical studies, 274–282 GLP, 269–272 International Clinical Trials Registry Platform GMP, 269–272 (ICTRP), 19, 281 harmonization, 224–225, 258–269 International Conference of Drug Regulatory health system development, 252–258 Authorities (ICDRA), 11, 16–18, 41, 221 ICH, 227, 240–251 International Conference on Harmonization (ICH) identification, DRAs, 252 achievements, 60–64 information confidentiality, 282–284 agreements, 65, 68–69 inspections, 269–272 APEC, 143 international clinical studies, 274–282 ASEAN, 138, 142, 245–246, 266–268 International Medicines Agency, 239–240 best practices, 40, 54, 61–62 key principles, 223–235 birth of, 41–42 lot release result recognition, 292–293 challenges, 62–64 medicine evaluation, 288–292 collaboration, 39–40, 43 Middle East, 268–269 Common Technical Documents, 42, 50, 56–59 national procedure considerations, 234–235 communication, 203–204 overview, 223–235 Concept Papers, 45–46 product specification release, 292–293 conferences, 43–44 proprietary confidential information, 282–284 consensus guidelines, 42–43, 47 qualification, DRAs, 252 cooperation reference authorities, 252 global initiatives, 34–64 reference country identification/qualification, 252 and harmonization projects, 50–60 reference DRAs, 252, 257–258 value considerations, 175–177, 179, 181–182, 184 regional initiatives, 224–225, 231 Coordinators, 36, 38 regulatory capacity, 228–230, 253–255 efficacy, 51–52 regulatory practice development, 284–287 ESTRI, 42, 55–57 342 INDEX

International Conference on Harmonization (ICH) Steering Committee, 36–37, 39–42, 45–46, 50, 57 (Continued) structures, 36–40, 241–244 Expert Working Group, 37, 55 success drivers, 61–62 founding members, 35–36 technical standards establishment, 227, 240–251 future challenges, 62–64 Tripartite Guideline adoption, 48 GCC, 122 UN, 250–251 GCG, 34, 36–40, 242, 245 value considerations, 175–177, 179, 181–182, 184 global cooperation initiatives, 34–64 WHO, 248–251 guidelines, 50–53 Working Groups, 36–37, 46, 55 harmonization value considerations, 175–177, 179, workshops, 43–44 181–182, 184 international cooperation: definitions, 3–4 history, 41–44 International Drug Monitoring, 23 implementation considerations, 195–196 International Federation of Pharmaceutical implementation guidelines, 37, 43, 48 Manufacturers & Associations (IFPMA), 36 industry, 179 International Health Regulations (IHR), 13, 31 information sharing, 39–40 International Medicines Agency, 239–240 integration, 39–40 International Nonproprietary Names, 11, 20, 22–23 international body establishment International Organization for Standardization recommendations, 227, 240–251 (ISO), 164, 252 legal basis of standards establishment, 249–251 International Pharmacopoeia (PH.Int.), 11, 20–22 limitations, 62–64 international procedure establishment, 288–292 maintenance guidelines/procedures, 43, 50 international trade, 190 MedDRA, 36, 38, 53–55 intrinsic ethnic factors, 212 membership, 35–36, 242 investigational new drugs (IND), 274–275 mission, 34 ISO. See International Organization for monitoring standards, 244–246 Standardization multidisciplinary considerations, 51–53 ITF. See Innovation Task Force networks, 34–64 IWG. See Implementation Working Group new harmonization action, 45–46 J PANDRH, 113–114, 120 JAN. See Japanese Adopted Names patients and global public health, 175–176 Japan, 35, 226 proactivity in standard development, 247–249 Japanese Adopted Names (JAN), 23 procedure considerations, 46–50 Japanese Adverse Reaction Terminology “Process”, 44–50 (J-ART), 53 proposed global system recommendations, 227, Japan Pharmaceutical Manufacturers Association 240–251 (JPMA), 35 Q&A Procedures, 49 J-ART. See Japanese Adverse Reaction Terminology quality, 51 JPMA. See Japan Pharmaceutical Manufacturers registration technical requirements, 34–64 Association Regulators Forum, 40 regulator value considerations, 177 K revision procedures, 49–50 key principles of proposed global system, 223–235 RHI, 242 Korean Good Clinical Practice (KGCP), 201 SADC, 128, 134–135 safety, 51 L Secretariat, 36, 38 labeling, 84 standard development proactivity, 247–249 laboratory good practices, 73, 269–272 standard monitoring, 244–246 Latin American Association of Pharmaceutical standards establishment, 249–251 Industry (ALIFAR), 114, 116 INDEX 343

Latin American Federation of the Pharmaceutical EU-US bilateral cooperation initiatives, 153–154 Industry (FIFARMA), 114, 116 GCC, 122 legal considerations ICH, 35–36, 242 ICH standards establishment, 249–251 PANDRH, 114–115 voluntary cooperation, 199–200 SADC, 128 WHO establishment as coordinator, 237 US-EU bilateral cooperation initiatives, 153–154 legislation WHO, 10 communication, 190–191 Member States, 66–67, 77–79, 123, 127–128 critical parameters, 186 Memorandum of Agreements (MoA), 177 definitions, 2 Memorandum of Understanding (MoU), 177 EU, 83–90 MERCOSUR, 115 influencing factors, 214–215 MHLW. See Ministry of Health, Labour and Welfare licenses, 190–191 Middle East, 268–269 Liechtenstein, 69–70 Millennium Development Goals (MDG), 174–175, Life Sciences Innovation Forum (LSIF), 143–152 9–10, 13, 222 lot release result recognition, 292–293 Ministers: SADC, 129 LSIF. See Life Sciences Innovation Forum Ministry of Health, Labour and Welfare (MHLW), 35 mission: ICH, 34 M MoA. See Memorandum of Agreements MAA. See Marketing Authorization Applications model certificates, 20 maintenance guidelines/procedures, 43, 50 monitoring considerations, 174, 194–198, 244–246 manufacturing practices. See Good Manufacturing MoU. See Memorandum of Understanding Practices MRA. See mutual recognition agreements/ Marketing Authorization Applications (MAA), 73 arrangements markets: EU history, 80–81 MRP. See Mutual Recognition Procedures mature DRAs, 257–258 multidisciplinary considerations, 51–53, 93–94 MDG. See Millennium Development Goals multi-state clinical studies, 279–280 Medical Dictionary for Regulatory Activities Multi-State licensing, 83–84 (MedDRA), 36, 38, 53–55 mutual recognition agreements/arrangements medical practice differences, 213–214 (MRA), 8–9 medical product authorization, 94–96 Mutual Recognition Procedures (MRP) medicines EU authorization procedures, 94–95 access considerations, 172 EU Directives, 84 development, ethnic factors, 278–279 EU membership, 68 evaluation procedure establishment, 288–292 EU pharmaceutical regulation, 83 quality, 174 EU regional initiatives, 83–84, 94–95, 109–111 registration systems, 254–255 mutual understandings: ICH, cooperation global regulation definitions, 1–2 initiatives, 39 safety, 174 unmet medical needs, 173 N Medicines Quality Assurance Program, 20 NAFTA. See North American Free Trade Agreement Medicines Regulatory Forum, 134 National Committees, 130, 134 Mediterranean, 12 National Health Ministries, 134 Medium-Term Strategic Plans, 19 national procedure considerations, 234–235 membership NEPAD. See New Partnership for Africa’s APEC, 144 Development ASEAN, 138 networks bilateral cooperation initiatives, 153–154 APEC, 143–152 EU, 67–70 ASEAN, 136–143 344 INDEX

bilateral cooperation initiatives, 152–163 Pan European Regulatory Forum (PERF), EU, 66–113 68–69 EU Telematics Program, 101 parallel scientific advice program, 159–160 GCC, 122–127 parliaments, 70, 81–82, 88 ICH, 34–64 patents, 190–191, 282–284 PANDRH, 113–122 patient considerations, 172–176, 234 SADC, 127–136 PDCO. See Pediatric Committee WHO, 17–19, 26–27. See also Pan-American PDG. See Pharmacopoeial Discussion Group Network for Drug Regulatory Harmonization Pediatric Committee (PDCO), 74–75 new harmonization action, 45–46 pediatric medicines, 26–27, 74–75, 96, 160–161, New Molecular Entities (NME), 179 211–212 New Partnership for Africa’s Development PERF. See Pan European Regulatory Forum (NEPAD), 8, 261, 263–266 Pharmaceutical Committee, 72, 76 New Zealand, 152–153 Pharmaceutical Inspection Co-operation Scheme NME. See New Molecular Entities (PIC/S), 164 nomenclature. See International Nonproprietary pharmaceutical products Names definitions, 1 non-clinical requirements, 91–92 quality assurance, WHO, 19–23 North American Free Trade Agreement quality certification, WHO cooperation global (NAFTA), 115 initiatives, 24–25 Norway, 69–70 safety, WHO cooperation global initiatives, 23 WHO, quality assurance, 19–23 O pharmaceutical regulation definitions, 1–2, 4 Official Medicines Control Laboratories Pharmaceutical Research and Manufacturers of (OMCL), 77 America (PhRMA), 35, 197 organization involvement, 70–79, 194, 234 pharmacopoeia orphan medicinal products, 74, 160, 289, 291 European Pharmacopoeia, 73, 77, 91 Osaka Action Agenda, 145 International Pharmacopoeia, 11, 20–22 oversight committees. See Steering Committees Pharmacopoeial Discussion Group (PDG), 163 P pharmacovigilance Pacific, 12 bilateral cooperation initiatives, 159 PAHO. See Pan American Health Organization EU, cooperation and harmonization regional Pan American Health Organization (PAHO), 12, 114, initiatives, 73, 75, 92, 109 117–118, 188 safety database development, 272–273 Pan-American Network for Drug Regulatory value considerations, 174 Harmonization (PANDRH) Pharmacovigilance Program, 23 agreements, 114–115, 123–124, 126 Pharmacovigilance Risk Assessment Committee cooperation, 113–122 (PRAC), 75 cooperation regional initiatives, 115–116 philanthropic organization involvement, 234 harmonization, 66, 113–122 PH.Int. See International Pharmacopoeia history, 117–118 PhRMA. See Pharmaceutical Research and ICH, 113–114, 120 Manufacturers of America membership, 114–115 PIC/S. See Pharmaceutical Inspection Co-operation networks, 113–122 Scheme “Process”, 118–119 planning appropriateness, 192–193 projects, 119–120 plasma, 84 regional cooperation initiatives, 113–122 policy implementation, 186 structures, 115–117 political considerations WHO, 116, 119–122 agreements, 65 INDEX 345

commitments, 206–209 proprietary confidential information, 282–284 decisions, 206–209 public health, 172–176, 188–189, 209–211 integration, 65 public sector collaborations, 233 medicine evaluation, 291 regulatory capacities, 188 Q SADC, 129 Q&A Procedures: ICH, 49 stability, 206–209 Q3C Guideline, 50 support, 206–209 qualification considerations, 252 unions, 81–82 quality population considerations, 202 APEC, 149 post-authorization regulatory activities, 96 ASEAN, 137 PRAC. See Pharmacovigilance Risk Assessment assurance, 19–23 Committee by design, 161 practice differences, 213–214 certification, 20, 24–25, 256–257 pre-authorization activities, 95 control, 174, 20, 123 prequalification of medicines, 11, 20 CPP scheme, 24–25, 256–257 prequalification programs, 28–29, 32 EU, 90–91 prescriptions, 84 ICH, 51 prices, 105–106 specifications, 180 primary legislation, 87 WHO, 256–257 principles of proposed global system, 223–235 R private sector collaborations, 233 R&D. See Research and Development proactive harmonization, 226 radiopharmaceuticals, 84 proactivity in standard development, 247–249 REC. See Regional Economic Communities procedure considerations recommendations ICH, 46–50 EU initiatives, 88 medicine evaluation establishment, 288–292 international body establishment, 226–227 “Process” WHO as coordinator establishment, 236–239 APEC, 146–148 reference authorities, 252 ASEAN, 140–141 reference country identification/qualification, 252 bilateral cooperation initiatives, 155–156 reference DRAs, 252, 257–258 EU, 87–90 Reference Member States, 68 GCC, 124–125 Regional Economic Communities (REC), 261, 263 ICH, 44–50 Regional Harmonization Initiative (RHI), 111, 242 PANDRH, 118–119 regional initiatives SADC, 132–134 Africa, 259–266 product manufacture, 203 APEC, 66, 143–152 product specification release, 292–293 ASEAN, 65, 136–143 professionals involvement, 234 collaboration, 224–225, 231 projects communication, 231 APEC, 148–150 cooperation ASEAN, 141–142 Africa, 259–266 bilateral cooperation initiatives, 156–161 APEC, 66, 143–152 EU, 90–101 ASEAN, 65, 136–143 PANDRH, 119–120 EU, 66–113 SADC, 134–135 GCC, 122–127 proposed global system recommendations, harmonization, 64–152, 168 235–294. See also international body PANDRH, 113–122 establishment recommendations SADC, 127–136 346 INDEX regional initiatives (Continued) bilateral cooperation initiatives, 159 coordination to one unique body, 224–225 databases, 272–273 decision-making processes, 232–233 EU, 92–93 GCC, 122–127 ICH, 51 harmonization, 64–152, 168, 224–225 international body establishment international body establishment recommendations, 272–274 recommendations, 224–225, 231 patients and global public health, 174 PANDRH, 113–122 WHO cooperation global initiatives, 23 proposed global system recommendations, 224–225 SARS crisis, 204 SADC, 127–136 Schuman Declaration, 80 regional level structures, 12 science-based medicines, 284–287 regional regulatory capacities, 187 scientific intergovernmental cooperation models, 8 registration: clinical trials, 279–282 secondary legislation, 87–88 Registration of Pharmaceuticals for Human Use, 34–64 Secretariat regulations APEC, 145 definitions, 1–2 GCC, 123, 126 EU regional initiatives, 83–90, 96–100 harmonization critical parameters, 194 regulators: value considerations, 176–179 ICH, 36, 38 Regulators Forum, 40 PANDRH structure, 49 regulatory approval guidelines, 20 SADC, 129 regulatory capacity security, 129 continuous support, 229–230 Senior Economic Official Meeting (SEOM), 138 critical parameters, 186–189 SEOM. See Senior Economic Official Meeting developed countries, 228 serums, 84 developing countries, 228–230, 253–255 SICA (The Central American Integration System), 115 international body establishment single currency, 81 recommendations, 228–230, 253–255 single markets, 80–81 Regulatory Consultation and Discussion, 47 solvents, 50 regulatory practice development, 284–287 SOP. See standard operating procedures regulatory science, 284–287 Southeast Asia, 12 regulatory support, 257–258 Southern African Development Community reimbursements, 105–106 (SADC) release specifications, 292–293 cooperation, 127–136 Research and Development (R&D), 179 harmonization, 132–135 residual solvents, 50 history, 131–132 resource considerations, 186–189 ICH, 128, 134–135 review practice development, 284–287 membership, 128 revision procedures, 49–50 networks, 127–136 RHI. See Regional Harmonization Initiative pharmaceutical regulations, 2–3 risk assessments, 75 political decisions and commitments, 206 risk management, 92, 274 “Process”, 132–134 risk mitigation, 274 projects, 134–135 Rotavirus vaccine, 232 proposed global system recommendations, 260 regional initiatives, 127–136 S structures, 128–130, 194 SADC. See Southern African Development sovereignty, 208 Community specification consideration, 20, 292–293 safety stability: politics, 206–209 APEC, 150 staff training, 253–255 INDEX 347 stakeholder involvement, 198–199, 218, 233–234 Sunset Clause, 86 standard development proactivity, 247–249 supporting bodies: WHO, 14–15 standardization, 25–26, 164, 252 Supreme Council, 123–124 standard operating procedures (SOP), 269–270 standards T clinical studies, 278 TDF. See Tenofovir Disoproxil Fumarate ICH, 249–251 technical cooperation, 8, 70, 71t, 72–77 monitoring, 244–246 technical requirements patients and global public health, 174 ASEAN, 141 proposed global system recommendations, 278 EU, 90–94 state of play of cooperation initiative reviews, 7–170 registration considerations, 34–64 statutes, 214–215 technical standards, 226–227, 240–251 Steering Committees technical support, 257–258 APEC, 147 Technical Working Groups, 116–117 electronic communication, 57 Telematics Program, 100–101 GCC, 123 Tenofovir Disoproxil Fumarate (TDF), 262 harmonization critical parameters, 194 term selection considerations, 54 ICH terrorism, 204 Concept Papers, 45–46 testing procedures, 173 cooperation global initiatives, 36–37, 39–42, therapeutic chemical classification, 18–19 45–46, 50, 57 therapeutic differences, 213–214 history, 41–42 toxins, 84 international body establishment trade secrets, 190–191, 282–284 recommendations, 242 traditional medicines, 27–28 standard development proactivity, 247 tradition differences, 211–212 standard monitoring, 245 training, 253–255 PANDRH, 116 Transatlantic Administrative Simplification STF. See Study Tagging Files Workshop, 156–157 structures treatment considerations, 278–279 APEC, 144–145 Treaty of Amsterdam, 82 ASEAN, 138–139 Treaty on European Union, 68, 82 bilateral cooperation initiatives, 154 Treaty from Maastricht, 82 cooperation regional initiatives, 66, 70–79 Treaty of Lisbon, 82 critical parameters, 194 Treaty of Rome, 80–81 EU cooperation initiatives, 66, 70–79 tribunals, 130 EU-US bilateral cooperation initiatives, 154 Tripartite Guideline adoption, 48 GCC, 122–123 U harmonization, 194 UMBRA. See Unified Methodologies for Benefit– ICH, 36–40, 241–244 Risk Assessments PANDRH, 115–117 UN. See United Nations SADC, 128–130, 194 Unified Methodologies for Benefit–Risk US-EU bilateral cooperation initiatives, 154 Assessments (UMBRA), 287, 288f WHO, 10–15 unique coordinating bodies, 224–225 Study Tagging Files (STF), 56 United Nations (UN) Sub-Saharan African countries, 188 Convention on Psychotropic Substances, 289 substandard products, 293–294 ICH, standards establishment, 250–251 success drivers: ICH, 61–62 Millennium Development Goals, 174–175, 9–10, 222 successes: EU, 102–105 prequalification programs, 28–29 Summits, 128, 138, 155 Single Convention on Narcotic Drugs, 289 348 INDEX

United States Adopted Names (USAN), 23 workshops, 43–44 United States (US) World Health Assembly (WHA), 10, 15–17, 22 bilateral cooperation initiatives, 152–163 World Health Organization Adverse Reaction clinical studies, 274–275 Terminology (WHO-ART), 53 EU cooperation initiatives, 152–163 World Health Organization (WHO) ICH membership, 35 Africa, 266, 261, 265 medicine evaluation, 289 agreements, 13, 15–16 politics, 206–207 Better Medicines for Children, 26–27 unmet medical needs: considerations, 173 biological standardization, 25–26 US. See United States certification, 20, 24–25, 256–257 USAN. See United States Adopted Names classifications, 18–19 V clinical trials, 19, 281 collaborating centers, 14–15 vaccines, 84 communication, critical parameters, 203–204 value considerations cooperation access considerations, 172, 182 global initiatives, 8–33 convergence, 171–186 harmonization, 16–17 cooperation, 171–186 value considerations, 175, 175–177, 179, 181–182, ICH, 175–177, 179, 181–182, 184 184 WHO, 175, 175–177, 179, 181–182, 184 coordination to one unique body, 224–225 EU, 177, 184 corporate level structure, 11 global public health & patients, 172–176 counterfeit products, 294 harmonization, 171–186 country level structure, 12–14 ICH, 175–177, 179, 181–182, 184 CPP scheme, 256, 24, 256–257 WHO, 175, 175–177, 179, 181–182, 184 developing countries, 230 ICH, 175–177, 179, 181–182, 184 DRAs, 7, 11, 18, 24–27, 29–31 industry, 179–181 drug dictionaries, 59 patients & global public health, 172–176 Drug Regulatory systems, 30–31 public health & patients, 172–176 establishment as coordinator of new system, regulators, 176–179 236–239 WHO, 175, 175–177, 179, 181–182, 184 expert committees, 14 veterinary products, 75 global initiatives, 8–33 VHP. See Voluntary Harmonization Procedure Good Manufacturing Practices, 20–21, 24–25 voluntary cooperation, 199–200 harmonization Voluntary Harmonization Procedure (VHP), 98, cooperation, 8, 16–31 107, 280 value considerations, 175, 175–177, 179, 181–182, W 184 Western Pacific: WHO structure, cooperation history, 15–16 initiatives, 12 ICDRA, 11, 16–18 WHA. See World Health Assembly ICH WHO. See World Health Organization history, 41 WHO-ART. See World Health Organization Adverse standard development proactivity, 248 Reaction Terminology standards establishment, 248–251 wholesale distribution, 84 ICTRP, 19, 281 WMA. See World Medical Association INN, 11, 22–23 Working Groups international classifications, 18–19 APEC, 143, 145–146 International Health Regulations, 13, 31 ASEAN, 137–143 International Medicines Agency establishment, ICH, 36–37, 46, 55 239–240 INDEX 349

International Pharmacopoeia, 11, 20–22 quality certification, 20, 24–25, 256–257 medicine evaluation, 289 regional level structure, 12 membership, 10 regulatory support, DRAs, 257–258 networks, 17–19, 26–27 safety of pharmaceutical products, 23 PANDRH, 116, 119–122 structures, 10–15 patients and global public health, 175 substandard products, 294 pediatric medicines, 26–27 supporting bodies, 14–15 pharmaceutical product quality assurance, 19–23 technical support, 257–258 pharmaceutical product safety, 23 traditional medicines, 27–28 political decisions and commitments, 207 value considerations, 175, 175–177, 179, prequalification programs, 28–29, 32 181–182, 184 proposed global system recommendations, World Medical Association (WMA), 164 224–225 World War II, 79–80 quality, 256–257 worldwide access considerations, 172 quality assurance, 19–23 worldwide authorities, 203–206 Color Plates

PLATE 1 Map of the European Union.

Source: Europa Website (http://europa.eu/index_en.htm), accessed on August 19, 2013. PLATE 2 PANDRH Subregional Blocs.

Source: Presentation from Dr. James Fitzgerald at the ICH GCG Meeting, Yokohama, June 9, 2009. PLATE 3 GCC Members.

Source: Presentation from Prof. Saleh Bawazir at the ICH GCG Meeting, Cincinnati, OH, US, June 14, 2011. PLATE 4 SADC Member States.

Source: Presentation from Dr. Joseph Mthetwa at the ICH GCG Meeting, Fukuoka, Japan, June 5, 2012. PLATE 5 The 10 Countries of ASEAN.

Source: Presentation from Dr. Yuppadee Javroongrit at the ICH GCG Meeting, Fukuoka Japan, June 5, 2012. PLATE 6 APEC Member Economies.

Source: APEC at a Glance, APEC website (http://www.apec.org/), accessed on August 31, 2013. PLATE 7 Locations of Studies Registered on ClinicalTrials.gov.

Source: ClinicalTrials.gov, accessed on July 30, 2013. PLATE 8 Proposed Global Pharmaceutical System and Network.

GLOBAL

WHO

EMP Internaonal ICH Department Medicines Agency

INN ICD/ICF ICTRP ATC/DDD ICDRAs Ph. Int.

Regional WHO Oﬃces RHIs DEV. Country 1 DEV. Country 2 REF. Country 1 RHI 1 Africa Americas DEV. Country 3 REF. Country 2 RHI 2 DEV. Country 4 REF. Country ... Eastern REF. Country N Europe DEV. Country 5 Med. RHI ... DEV. Country 6

South- RHI N DEV. Country ... East Western Paciﬁc SRHI SRHI Asia SRHI SRHI n DEV. Country N 1 2 3

WHO Local Offices REGIONAL NATIONAL* *: REFerence or DEVeloping Country can also represent a region in case of integraon (i.e., Europe)

: Support for capacity building : Coordinaon of capacity building EMP: Department of Essenal Medicines and Health Products : Request for training and technical support : Implementaon and monitoring of internaonal standards RHI: Regional Harmonisaon Iniave : Feedback on needs and challenges : Bilateral agreements SRHI: Subregional Harmonisaon Iniave : Technical support/experse : Coordinaon of all centralized acons (registraon, clinical studies, safety framework, etc.)