Regulating Medicines
in a Globalized World

THE NEED FOR INCREASED RELIANCE AMONG REGULATORS

Alastair J. Wood and Patricia Cuff, Editors

Committee on Mutual Recognition Agreements and Reliance in the
Regulation of Medicines

Board on Global Health

Health and Medicine Division

A Consensus Study Report of

THE NATIONAL ACADEMIES PRESS
Washington, DC
www.nap.edu

THE NATIONAL ACADEMIES PRESS 500 Fifth Street, NW Washington, DC 20001

This activity was supported by a contract between the National Academy of Sciences and the U.S. Food and Drug Administration’s Office of International Programs (HHSP233201400020B). Any opinions, findings, conclusions, or recommendations expressed in this publication do not necessarily reflect the views of any organization or agency that provided support for the project.

International Standard Book Number-13: 978-0-309-49863-0
International Standard Book Number-10: 0-309-49863-5
Digital Object Identifier: https://doi.org/10.17226/25594
Library of Congress Control Number: 2020930367

Additional copies of this publication are available from the National Academies Press, 500 Fifth Street, NW, Keck 360, Washington, DC 20001; (800) 624-6242 or (202) 334-3313; http://www.nap.edu.

Copyright 2020 by the National Academy of Sciences. All rights reserved.

Printed in the United States of America

Suggested citation: National Academies of Sciences, Engineering, and Medicine. 2020. Regulating medicines in a globalized world: The need for increased reliance among regulators. Washington, DC: The National Academies Press. https://doi.org/10.17226/25594.

COMMITTEE ON MUTUAL RECOGNITION AGREEMENTS AND RELIANCE IN THE REGULATION OF MEDICINES

ALASTAIR J. J. WOOD (Chair), Professor of Medicine (Emeritus), Professor of Pharmacology (Emeritus), Vanderbilt University

DAVID W. BEIER, Managing Director, Bay City Capital

THOMAS J. BOLLYKY, Director, Global Health Program, Council on Foreign Relations

KATHERINE C. BOND, Vice President, International Public Policy and Regulatory Affairs, U.S. Pharmacopeia

MARTHA A. BRUMFIELD, President and Chief Executive Officer (Former), Critical Path Institute

DAVID COCKBURN, Head of Manufacturing and Quality Compliance (Retired), European Medicines Agency

ELIZABETH GOLBERG, Senior Fellow (Former), Mossavar-Rahmani Center for Business and Government, Harvard Kennedy School

LAWRENCE O. GOSTIN, Linda D. & Timothy J. O’Neill Professor of Global Health Law, Georgetown University

GAVIN HUNTLEY-FENNER, Human Factors and Safety Consultant, Huntley-Fenner Advisors, Inc.

BARBARA KOREMENOS, Professor, University of Michigan

MURRAY LUMPKIN, Deputy Director, Global Health/Integrated Development, Lead for Global Regulatory Systems Initiatives, Bill & Melinda Gates Foundation

LEMBIT RÄGO, Secretary-General, Council for International Organizations of Medical Sciences

Study Staff

PATRICIA CUFF, Study Director (from April 2019), Senior Program Officer

MONICA WHITLEY, Study Director (until August 2019)

DANIEL FLYNN, Research Associate

INEZ ADAMS, Research Assistant

KELLY CHOI, Senior Program Assistant (from April 2019)

NATALIE LUBIN, Senior Program Assistant (until April 2019)

JULIE PAVLIN, Director, Board on Global Health

Consultant

RONA BRIERE, Editor

This page intentionally left blank.

Reviewers

This Consensus Study Report was reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise. The purpose of this independent review is to provide candid and critical comments that will assist the National Academies of Sciences, Engineering, and Medicine in making each published report as sound as possible and to ensure that it meets the institutional standards for quality, objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process.

The committee thanks the following individuals for their review of this report:

Although the reviewers listed above provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations of this report nor did they see the final draft before its release. The review of this report was overseen by JOSHUA M. SHARFSTEIN, Johns Hopkins Bloomberg School of Public Health, and

WILLIAM M. SAGE, The University of Texas at Austin. They were responsible for making certain that an independent examination of this report was carried out in accordance with the standards of the National Academies and that all review comments were carefully considered. Responsibility for the final content rests entirely with the authoring committee and the National Academies.

Acknowledgments

During the course of this year-long study, the committee invited key participants from different countries to share their insights at open committee meetings and information-gathering sessions. This report would not have been possible without their important contributions. The committee would like to take this opportunity to thank all of those who gave generously of their time, knowledge, experience, and resources (see Appendix D). In particular, the committee would like to thank the Bill & Melinda Gates Foundation, which supported the committee’s information-gathering session in London, and the U.S. Food and Drug Administration for sponsoring this study, with special thanks to Mark Abdoo, Russell Campbell, and Mary Lou Valdez. The committee would be remiss if it did not acknowledge the contributions of the National Academies staff, including administrative assistance from Kelly Choi and Natalie Lubin, research help from Inez Adams and Daniel Flynn, oversight from Julie Pavlin and Monica Whitley, and overall study coordination and direction from Patricia Cuff. Similar appreciation goes to the talented editing staff headed by Rona Briere and supported by Alisa Decatur. It is through the participation of all of these valued stakeholders that the committee presents this study report stemming from the input and efforts of everyone involved.

This page intentionally left blank.

Preface

Globalization is now an integral part of all of our lives. We routinely expect to be able to perform many aspects of our everyday activities regardless of where we are. We step off an international flight in some far-flung destination and expect to instantly use our cell phone, order a ride hailing service, pay for a hotel with our credit card, access our electronic documents held on a distant server, and even withdraw cash from our local bank account while traveling to faraway lands. Just as our lives have been touched by the power of globalization, so, too, has the pharmaceutical industry. Drug development, authorization, and regulatory supervision have become international endeavors, with most medicines now being global commodities.

Drug companies operate in many parts of the world, utilize global supply chains that often include facilities in countries with weaker regulations than those of the United States, perform pivotal trials in multiple countries to support registration submissions in multiple jurisdictions, and subsequently market their medicines throughout most of the world. However, they are then regulated by individual national regulators, each of which requires submissions for review prior to marketing authorization. Each review procedure requires resources on the part of the sponsor and of the regulatory authorities, and often there is little acknowledgment that a similar product review is occurring, sometimes simultaneously, in several other countries. All of these national regulators have the mission of ensuring that drugs authorized for use in their countries are safe, effective, and appropriate for their health care system and their population. The standards for such safety, efficacy, and quality judgments among the major

well-resourced regulators (the U.S. Food and Drug Administration [FDA]; the European Medicines Agency; the Pharmaceuticals and Medical Devices Agency, Japan; Health Canada; the Medicines & Healthcare products Regulatory Agency, UK; Swissmedic; and the Therapeutic Goods Administration, Australia) are well known and similar, if not identical. Although the final judgment on whether to approve a drug for marketing is an important sovereign decision for each national regulator to make, based on what is appropriate and what level of risk tolerance exists in a given society, in some cases much of the work that forms the scientific basis for the authorization decision is quite similar, if not identical, across the various regulators. The result is considerable duplicative and redundant work being performed throughout the world, which benefits neither national nor global public health. For example, having multiple regulators inspecting the same manufacturing site has little value and in fact may compromise public health because the time might better be devoted to inspecting different sites and therefore ensuring the safety of a larger spectrum of manufacturing sites. Clearly if different versions of a product are manufactured by the same company at different sites for different markets, inspections of the different sites are required. Similarly, multiple detailed reviews of exactly the same data by multiple national reviewers are unlikely to improve knowledge of the product or patient outcomes. In this context, the purpose of this FDA-requested study was for an expert committee convened by the National Academies of Sciences, Engineering, and Medicine to consider the role of mutual recognition and other reliance activities among regulators in contributing to enhancing public health.

Through its conversations with various key stakeholders, the committee came to recognize that two very different roles exist for national regulators in relation to reliance activities. First, there is the potential for horizontal reliance activities. These are activities conducted among well-resourced regulators who share similar regulatory and scientific skillsets, as well as regulatory and structural similarities, that can more easily give way to mutual confidence and bidirectional reliance. It was within such reliance activities that committee members saw opportunities for more effective public health protection by improving and expanding the potential for relying on the work of other similar regulatory authorities for making informed decisions.

Additional opportunities for leveraging reliance activities more broadly have the potential to impact public health globally. This was the concept envisioned by members of the committee, who proposed greater access by less-resourced regulators to the regulatory work products (e.g., inspection reports, scientific assessments) of well-resourced regulators. In this way, less-resourced regulators would be better positioned to make informed sovereign regulatory decisions, while using their own finite resources in the

most efficient manner. Reliance in these scenarios might be unidirectional, but at present such reliance often is not possible because of the unwillingness or inability of some national regulators to share unredacted or less-redacted work products. Lack of access to such work products has direct negative impacts on the global health of millions of patients, especially those outside of Europe, North America, and Oceania.

The committee also recognized that as medicines, such as biologicals and biosimilars, become increasingly more complex and as cell-based and genetic therapies become more widespread, only a limited number of national regulators will be able to deploy the full range of skills necessary for comprehensive reviews of such products. Thus, it becomes imperative that reviews of complex medicines be made available to other regulators so they can provide appropriate oversight of these products in their jurisdictions. Addressing these challenges is a high priority for global health, one that requires the attention of both national regulators and legislators to facilitate the ability of others to use the work products of well-resourced regulators.

The committee considered the opportunities that increased reliance activities by regulatory authorities might provide for the national and global public health, but also considered the practical difficulties of implementing such activities. Global regulators have been working diligently in the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use and other fora to develop and agree on harmonized technical standards for the registration of medicines. As with so many of the things we now take for granted that function seamlessly across national frontiers, there are opportunities for improvements in medicines regulation that could enhance global health. However, it is worth emphasizing that the committee did not see this exercise as necessarily being one that would reduce costs, but rather one that could enhance public health by allowing the most efficient deployment of scarce and precious global regulatory resources.

This page intentionally left blank.

Contents

ACRONYMS AND ABBREVIATIONS

SUMMARY

1 INTRODUCTION

Study Context

Charge to the Committee

Study Scope and Approach

Organization of the Report

2 THE JOB OF MEDICINES REGULATORS IN TODAY’S WORLD

Core Functions of Regulators and Regulatory Authorities

Regulators Working Together

Recognition and Reliance

Cooperation and Collaboration Tools of Regulatory Authorities

3 WHAT POLICY MAKERS NEED TO KNOW ABOUT TODAY’S REGULATORY ENVIRONMENT

Overview of Good Practices

Public Health Mandate

Impediments to Regulatory Authority Reliance

Challenges to Reliance Between Regulatory Authorities in a Globalized World

4 STAKEHOLDER VIEWS OF RECOGNITION AND RELIANCE

Views of Stakeholders

Synthesizing the Challenges and Opportunities

5 REMOVING IMPEDIMENTS AND FACILITATING ACTION FOR GREATER RECOGNITION AND RELIANCE AMONG REGULATORY AUTHORITIES

Medicines Regulation in a Globalized World

Improving Public Health Through Better-Designed MRAs

Responding to Evolving Science and Technology

Better Utilization of the EU-US MRA

Facilitating Information Sharing Among International Medicines Regulators

Evaluating Public Health Impacts of Recognition and Reliance Arrangements for Medicines Regulation

6 THE WAY FORWARD

Pharmacovigilance and Post-Market Surveillance

Aggregate Safety Reports

Expanding Mutual Recognition Agreements to Go Beyond Good Manufacturing Practice

Evaluating Public Health Impacts of Recognition and Reliance

Final Thoughts

REFERENCES

APPENDIXES

A Glossary

B Table of Mutual Recognition Agreements

C Table of Global Good Manufacturing Practice (GMP) Reliance Initiatives Based on the International Coalition of Medicines Regulatory Authorities’ Mapping Exercise

D Study Methods

E Committee Member Biographies

Boxes, Figures, and Table

BOXES

1-1 Statement of Task

2-1 World Health Organization (WHO) Definitions of Recognition and Reliance

2-2 Work Sharing: Australia-Canada-Singapore-Switzerland (ACSS) Consortium

2-3 Representative Multilateral, International Cooperative and Collaborative Efforts in Pharmaceutical Regulation

3-1 Batch Release

3-2 Summary of the International API Inspection Program Evaluation

4-1 Impediments to International Communication and Collaboration

4-2 Challenges Within Regulatory Reliance

4-3 Benefits and Perceived Benefits of Reliance in Medicines Approval Decisions

4-4 Benefits of International Communication and Collaboration

4-5 Perceived Benefits of Reliance in Good Manufacturing Practice (GMP) Inspections

4-6 Opportunities Within Reliance for Good Manufacturing Practice (GMP) Inspections, as Well as Other Areas

FIGURES

S-1 Lifecycle of a medicine

S-2 Building confidence and trust from and for greater reliance

1-1 Building confidence and trust from and for greater reliance

2-1 Recognition as a subset of reliance

2-2 Trust components needed for reliance

3-1 The complex drug landscape

3-2 Lifecycle of a medicine

TABLE

3-1 Comparison of MRAs

Acronyms and Abbreviations