International Regulatory Harmonization Amid
Globalization of Drug Development

Workshop Summary

Victoria Weisfeld and Tracy A. Lustig, Rapporteurs

Forum on Drug Discovery, Development, and Translation

Board on Health Sciences Policy

INSTITUTE OF MEDICINE
OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS

Washington, D.C.

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Victoria Weisfeld and Tracy A. Lustig, Rapporteurs Forum on Drug Discovery, Development, and Translation Board on Health Sciences Policy

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THE NATIONAL ACADEMIES PRESS  500 Fifth Street, NW  Washington, DC 20001 NOTICE: The workshop that is the subject of this workshop summary was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. This activity was supported by contracts between the National Academy of Sciences and the Department of Health and Human Services (HHSN26300023 [Under Base #HHSN263201200074I] and Contract No. N01-OD-4-2139 TO #276; HHSF22301026T [Under Base #HHSF223200810020I]), AbbVie Inc., American Dia- betes Association, American Society for Microbiology, Amgen Inc., Association of American Medical Colleges, AstraZeneca, Bristol-Myers Squibb, Burroughs Wellcome Fund, Celtic Therapeutics, LLLP, Critical Path Institute, Doris Duke Charitable Foundation, Eli Lilly and Company, FasterCures, Friends of Cancer Research, GlaxoSmithKline, Johnson & Johnson, March of Dimes Foundation, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Pfizer Inc., and Sanofi. The views presented in this publication do not necessarily reflect the views of the organizations or agencies that provided support for the activity. International Standard Book Number-13:  978-0-309-28479-0 International Standard Book Number-10:  0-309-28479-1 Additional copies of this workshop summary are available for sale 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. For more information about the Institute of Medicine, visit the IOM home page at: www.iom.edu. Copyright 2013 by the National Academy of Sciences. All rights reserved. Printed in the United States of America The serpent has been a symbol of long life, healing, and knowledge among almost all cultures and religions since the beginning of recorded history. The serpent adopted as a logotype by the Institute of Medicine is a relief carving from ancient Greece, now held by the Staatliche Museen in Berlin. Suggested citation: IOM (Institute of Medicine). 2013. International Regulatory Harmonization Amid Globalization of Drug Development: Workshop Summary. Wash- ington, DC: The National Academies Press.

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“Knowing is not enough; we must apply. Willing is not enough; we must do.” —Goethe Advising the Nation. Improving Health.

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The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Academy has a mandate that requires it to advise the federal govern- ment on scientific and technical matters. Dr. Ralph J. Cicerone is president of the National Academy of Sciences. The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engineers. It is autonomous in its administration and in the selection of its mem- bers, sharing with the National Academy of Sciences the responsibility for advis- ing the federal government. The National Academy of Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. C. D. Mote, Jr., is president of the National Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Institute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Harvey V. Fineberg is president of the Institute of Medicine. The National Research Council was organized by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy’s purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in pro- viding services to the government, the public, and the scientific and engineering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Ralph J. Cicerone and Dr. C. D. Mote, Jr., are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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PLANNING COMMITTEE For the Workshop ON International Regulatory Harmonization Amid Globalization of Biomedical Research and Medical Product Development1 Thomas J. Bollyky (Co-Chair), Council on Foreign Relations, Washington, DC Steven K. Galson (Co-Chair), Amgen Inc., Thousand Oaks, CA Michael J. Brennan, Aeras, Rockville, MD Raymond Chua, Singapore Health Sciences Authority Hans-Georg Eichler, European Medicines Agency, London, UK James Fitzgerald, Pan American Health Organization, World Health Organization, Washington, DC Lynn D. Hudson, Critical Path Institute, Tucson, AZ Andreas Seiter, World Bank, Washington, DC Alice E. Till, PhRMA, Washington, DC Mary Lou Valdez, Food and Drug Administration, Silver Spring, MD Janet Woodcock, Food and Drug Administration, Rockville, MD IOM Staff Anne B. Claiborne, Forum Director Tracy A. Lustig, Senior Program Officer Rebecca A. English, Associate Program Officer Elizabeth F. C. Tyson, Research Associate Robin Guyse, Senior Program Assistant Andrew M. Pope, Director, Board on Health Sciences Policy 1 Institute of Medicine planning committees are solely responsible for organizing the workshop, identifying topics, and choosing speakers. The responsibility for the published workshop summary rests with the workshop rapporteurs and the institution. v

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FORUM ON DRUG DISCOVERY, DEVELOPMENT, AND TRANSLATION1 Jeffrey M. Drazen (Co-Chair), New England Journal of Medicine, Boston, MA Steven K. Galson (Co-Chair), Amgen Inc., Thousand Oaks, CA Russ Biagio Altman, Stanford University, CA Margaret Anderson, FasterCures, Washington, DC hugh Auchincloss, National Institute of Allergy and Infectious Diseases, Bethesda, MD Christopher P. Austin, National Center for Advancing Translational Sciences, Bethesda, MD Ann C. Bonham, Association of American Medical Colleges, Washington, DC Linda Brady, National Institute of Mental Health, Bethesda, MD Gail H. Cassell, Harvard Medical School (Visiting), Carmel, IN Peter B. Corr, Celtic Therapeutics, LLLP, New York, NY Andrew M. Dahlem, Eli Lilly and Company, Indianapolis, IN James H. Doroshow, National Cancer Institute, Bethesda, MD Gary L. Filerman, Atlas Health Foundation, McLean, VA Mark J. Goldberger, Abbott Pharmaceuticals, Rockville, MD Harry B. Greenberg, Stanford University School of Medicine, CA Peter K. Honig, AstraZeneca, Wilmington, PA Kathy L. Hudson, National Institutes of Health, Bethesda, MD LYNN D. HUDSON, Critical Path Institute, Tucson, AZ S. Claiborne Johnston, University of California, San Francisco Michael Katz, March of Dimes Foundation, White Plains, NY Petra Kaufmann, National Institute of Neurological Disorders and Stroke, Bethesda, MD Jack D. Keene, Duke University Medical Center, Durham, NC Rusty Kelley, Burroughs Wellcome Fund, Research Triangle Park, NC Ronald L. Krall, University of Pennsylvania Center for Bioethics, Steamboat Springs, CO Freda C. Lewis-Hall, Pfizer Inc., New York, NY Carol Mimura, University of California, Berkeley Bernard H. Munos, InnoThink Center for Research in Biomedical Innovation, Indianapolis, IN Elizabeth (Betsy) Myers, Doris Duke Charitable Foundation, New York, NY 1  Institute of Medicine forums and roundtables do not issue, review, or approve individual documents. The responsibility for the published workshop summary rests with the work- shop rapporteurs and the institution. vii

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John J. Orloff, Novartis Pharmaceuticals Corporation, East Hanover, NJ Robert E. Ratner, American Diabetes Association, Alexandria, VA Michael Rosenblatt, Merck & Co., Inc., Whitehouse Station, NJ James S. Shannon, GlaxoSmithKline, Brentford, Middlesex, UK Janet Shoemaker, American Society for Microbiology, Washington, DC Ellen V. Sigal, Friends of Cancer Research, Washington, DC Lana R. Skirboll, Sanofi, Washington, DC Brian L. Strom, University of Pennsylvania Perelman School of Medicine, Philadelphia Janet Tobias, Ikana Media and Mount Sinai School of Medicine, New York, NY Joanne Waldstreicher, Johnson & Johnson, New Brunswick, NJ Janet Woodcock, Food and Drug Administration, Rockville, MD IOM Staff Anne B. Claiborne, Forum Director Rebecca A. English, Associate Program Officer Elizabeth F. C. Tyson, Research Associate Robin Guyse, Senior Program Assistant Andrew M. Pope, Director, Board on Health Sciences Policy viii

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Reviewers This workshop summary has been reviewed in draft form by indi- viduals chosen for their diverse perspectives and technical expertise, in accordance with procedures approved by the National Research Council’s Report Review Committee. The purpose of this independent review is to provide candid and critical comments that will assist the institution in making its published workshop summary as sound as possible and to ensure that the workshop summary meets institutional standards for objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integ- rity of the process. We wish to thank the following individuals for their review of this workshop summary: Tobias Massa, Bristol-Myers Squibb Company John Purves, EPCA Ltd Linda Rosenstock, University of California, Los Angeles Nathalie Strub Wourgaft, Drugs for Neglected Diseases initiative Although the reviewers listed above have provided many construc- tive comments and suggestions, they did not see the final draft of the workshop summary before its release. The review of this workshop sum- mary was overseen by Clyde J. Behney, Institute of Medicine. Appointed by the Institute of Medicine, he was responsible for making certain that an independent examination of this workshop summary was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of this workshop summary rests entirely with the rapporteurs and the institution. ix

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Contents ACRONYMS xv 1 INTRODUCTION 1 Opening Remarks, 4 International Harmonization: An Industry Perspective, 5 International Harmonization: A Regulator’s Perspective, 9 2 Principles and Definitional Considerations 13 The Terminology Landscape and Options for Regulators, 13 Standards Settings in the Context of Regulatory Harmonization, 17 3 Overview of the Current Global Regulatory Landscape 23 ICH, 23 PANDRH, 25 APEC Member Economies, 29 Harmonization Initiatives in Africa, 31 4  Areas of Need for Harmonized Standards and Barriers to Progress in Addressing the Gaps 35 Gaps from the Regulator’s Perspective, 35 Gaps from the Perspective of Nongovernmental Organizations, Foundations, and Product Development Partnerships, 37 Breakout Session Reports, 39 xi

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xii contents 5  Characteristics of Harmonized Regulations and Regulatory Structures 49 Radiation Safety Standards, 49 Reflections on the Experiences of WHO, 52 6  Finding Solutions: Options and Systemic Approaches 57 Legal Framework, 57 Cooperation and Collaboration, 58 Mutual Trust and Recognition, 59 Capacity Building, 60 Business Case, 61 Top-Level Support, 62 Meta-Harmonization, 63 Suggestions for Moving Forward, 64 7 Tactics and Strategies for a Way Forward 67 Key Themes, 67 Suggested Paths Forward, 72 REFERENCES 77 APPENDIXES A Workshop Agenda 79 B Participant Biographies 91

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Boxes 1-1 Statement of Task for the Workshop, 3 1-2 Selected International Harmonization Efforts, 7 5-1 Differing Units of Measurement, 51 6-1 Examples from Other Industries, 65 xiii

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Acronyms AMRH African Medicines Regulatory Harmonization APEC Asia-Pacific Economic Cooperation AU African Union AVAREF African Vaccine Regulatory Forum BMGF Bill & Melinda Gates Foundation CARICOM Caribbean Community CDER Center for Drug Evaluation and Research CHMP Committee for Medicinal Products for Human Use (EMA) CIRS Centre for Innovation in Regulatory Science CMC Chemistry, Manufacturing and Controls C-Path Critical Path Institute DNDi Drugs for Neglected Diseases initiative EAC East African Community EFPIA European Federation of Pharmaceutical Industries and Associations EMA European Medicines Agency EU European Union xv

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xvi ACRONYMS FDA U.S. Food and Drug Administration FDASIA U.S. Food and Drug Administration Safety and Innovation Act GATT General Agreement on Tariffs and Trade GCG Global Cooperation Group (ICH) IAEA International Atomic Energy Agency ICAO International Civil Aviation Organization ICH International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use IOM Institute of Medicine ISO International Organization for Standardization JPMA Japanese Pharmaceutical Manufacturers Association MERCOSUR Mercado Común del Sur (the Southern Common Market, South America) MHLW Ministry of Health, Labor, and Welfare (Japan) MS multiple sclerosis NAFTA North American Free Trade Agreement NDA new drug application NEPAD New Partnership for Africa’s Development NRC U.S. Nuclear Regulatory Commission PAHO Pan American Health Organization PANDRH Pan American Network for Drug Regulatory Harmonization PhRMA Pharmaceutical Research and Manufacturers of America PIC/S Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme PMDA Pharmaceuticals and Medical Devices Agency (Japan) QBD Quality By Design RHSC Regulatory Harmonization Steering Committee (APEC) SICA Sistema de la Integración Centroamericana (the Central American Integration System)

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ACRONYMS xvii TB tuberculosis UN United Nations VXDS Voluntary Exploratory Data Submissions WHO World Health Organization WHO PQ WHO prequalification WHO PQP WHO Prequalification of Medicines Programme WTO World Trade Organization

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