International Cooperation, Convergence and Harmonization of Pharmaceutical Regulations: A Global Perspective

International Cooperation, Convergence, and Harmonization of Pharmaceutical Regulations

A Global Perspective

Dr. Pierre-Louis Lezotre, MS, PhD

To contact the Author: Lezotre_pierre_louis@yahoo.fr

Table of Contents

Cover image

Title page

Copyright

Dedication

Preface

About the Author

Foreword by Professor Stuart Walker

Introduction

Part I. State of Play and Review of Major Cooperation Initiatives

Abstract

I-1) Global Initiatives

I-2) Regional Initiatives

I-3) Bilateral Initiatives

I-4) Other Cooperation Initiatives

I-5) Conclusion

Part II. Value and Influencing Factors of the Cooperation, Convergence, and Harmonization in the Pharmaceutical Sector

Abstract

II-1) Value of the Cooperation, Convergence, and Harmonization in the Pharmaceutical Domain

II-2) Critical Parameters and Influencing Factors for Cooperation, Convergence, and Harmonization

Part III. Recommendations to Support the Next Phase of International Cooperation, Convergence, and Harmonization in the Pharmaceutical Domain

Abstract

III-1) Overview and Key Principles of the Proposed Global Pharmaceutical System

III-2) Recommendations

Conclusion

Acronyms and Abbreviations

List of Figures, Tables and Plates

Figures

Tables

Color Plates

List of References

Index

Color Plates

Copyright

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First published 2014

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Dedication

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

- 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.

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).

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 lectureships 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-Pacific Region, 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.

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. 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 medicines registered varies widely from country to country in the Southern African Development 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. Regulatory 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 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 integrating 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.

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).

aThe terms pharmaceutical product, medicine, medicinal product, and drug are interchangeable in this book.

bThe 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.

cFor example, in the United States (US), the tragic incident with the 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.

dAcknowledging 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.

eThe 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.

Part I

State of Play and Review of Major Cooperation Initiatives

Abstract

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, to make activities more efficient and to allow the focussing of limited resources on higher-risk areas of concern. This increased cooperation between worldwide regulators has necessitated proactive deliberate efforts towards convergence/harmonisation of regulation, practices and requirements to eliminate or reduce differences.

Cooperation and harmonisation of standards in the pharmaceutical domain are already a reality and have become increasingly important during recent decades, with a high level of commitment to these activities by all stakeholders. The worldwide Drug Regulatory Authorities (DRAs) have been working to end an isolationist attitude that cannot resolve current worldwide issues and challenges caused by an ever increasing globalisation. As a result, many cooperation and harmonisation initiatives have been established at the bilateral, regional and global levels as a response to the changing geo-economic-political situation.

The spectrum of collaboration varies from simple informal technical cooperation to full integration of systems and regulations. Indeed, all these initiatives can be very different in scope (some are part of a broader harmonisation initiative), level of harmonisation (depending on the political support/commitment), organisation (well-structured versus simple discussion) or advancement (established process vs. pilot projects), but they all work towards convergence of requirements and/or practices. All these multiple worldwide cooperation and harmonisation programmes have evolved rapidly over the past decades.

This book section provides the current status of this complex and broad phenomenon of cooperation, convergence and harmonisation in the pharmaceutical sector. It reviews all major global, regional and bilateral cooperation initiatives.

Keywords

Regulation; Medicine; Cooperation; Convergence; Harmonisation; Agreement; International; Regional; Bilateral; Network; Pharmaceutical; Standard; Requirement; Best Practice; European Union; WHO; ICH; ASEAN; PANDRH; SADC; GCC; APEC

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.

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 identifiable levels of harmonization (Figure 1).

FIGURE 1 Levels of Harmonization. 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 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 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 nomination of the Executive Board), supervises the financial policies of the organization, and reviews and approves the proposed budget.

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 Authorities [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.

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 Caribbean 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].

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. According 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 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 Pharmaceuticals). 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

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