ADDRESSING THE BARRIERS TO PEDIATRIC DRUG DEVELOPMENT

Workshop Summary

Cori Vanchieri, Adrienne Stith Butler, and Andrea Knutsen, 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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Cori Vanchieri, Adrienne Stith Butler, and Andrea Knutsen, Rapporteurs Forum on Drug Discovery, Development, and Translation Board on Health Sciences Policy

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THE NATIONAL ACADEMIES PRESS 500 Fifth Street, N.W. Washington, DC 20001 NOTICE: The project that is the subject of this report was approved by the Gov- erning Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engi- neering, and the Institute of Medicine. Support for this project was provided by the Department of Health and Human Services (Contract Nos. 223-01-2460, HHSP233200600500P, HHSPP23320042509X1, and N01-OD-4-2139); the Department of Veterans Affairs (Contract No. V101(93)P- 2136); Abbott Laboratories; American Diabetes Association; American Society for Microbiology; Amgen, Inc.; Association of American Medical Colleges; Astra- Zeneca Pharmaceuticals; Blue Cross Blue Shield Association; Burroughs Well- come Fund; Doris Duke Charitable Foundation; Eli Lilly and Company; Entelos, Inc.; Genentech; GlaxoSmithKline; Johnson & Johnson; March of Dimes Founda- tion; Merck and Company; Pfizer, Inc.; Schering-Plough Research Institute; and UnitedHealth Foundation. Any opinions, findings, conclusions, or recommenda- tions expressed in this publication are those of the author(s) and do not neces- sarily reflect the view of the organizations or agencies that provided support for this project. International Standard Book Number-13: 978-0-309-10742-6 International Standard Book Number-10: 0-309-10742-3 Additional copies of this report are available from the National Academies Press, 500 Fifth Street, N.W., Lockbox 285, Washington, DC 20055; (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area); Internet, http://www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at: www.iom.edu. Copyright 2008 by the National Academy of Sciences. All rights reserved. Printed in the United States of America Suggested citation: IOM (Institute of Medicine). 2008. Addressing the barriers to pediatric drug development: Workshop summary. Washington, DC: The National Academies Press. 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.

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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 char- ter of the National Academy of Sciences, as a parallel organization of outstand- ing engineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising 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. Charles M. Vest 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. Charles M. Vest are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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FORUM ON DRUG DISCOVERY, DEVELOPMENT, AND TRANSLATION Gail H. Cassell (Co-Chair, 1/1/2005–12/31/2008), Eli Lilly and Company Jeffrey M. Drazen (Co-Chair, 7/1/2008–12/31/2008; Member, 1/1/2005– 6/30/2008), New England Journal of Medicine Edward W. Holmes (Co-Chair, 1/1/2005–6/30/2008; Member, 7/1/2008– 12/31/2008), National University of Singapore Barbara M. Alving (4/10/2008–12/31/2009), National Center for Research Resources Naomi Aronson (1/9/2007–12/31/2008), Blue Cross and Blue Shield Association Hal Barron (8/1/2008–12/31/2008), Genentech, Inc. Leslie Z. Benet (1/1/2005–12/31/2008), University of California, San Francisco Nina Bhardwaj (1/1/2005–9/7/2006), New York University School of Medicine Catherine Bonuccelli (1/9/2007–12/31/2008), AstraZeneca Pharmaceuticals Linda Brady (1/9/2007–12/31/2008), National Institute of Mental Health Robert M. Califf (1/1/2005–12/31/2008), Duke University Medical Center Scott Campbell (1/1/2005–12/31/2008), American Diabetes Association C. Thomas Caskey (1/1/2005–12/31/2008), The University of Texas- Houston Health Science Center Francis D. Chesley, Jr. (1/9/2007–10/25/2007), Agency for Healthcare Research and Quality Mark Clanton (1/1/2005–12/31/2006), National Cancer Institute Peter Corr (1/9/2007–12/31/2008), Celtic Therapeutics James H. Doroshow (7/19/2007–12/31/2008), National Cancer Institute William E. Evans (1/1/2005–12/31/2006), St. Jude Children’s Research Hospital Joseph M. Feczko (1/9/2007–12/31/2008), Pfizer, Inc. Wayne Fenton [Deceased] (1/1/2005–9/3/2006), National Institute of Mental Health Garret A. FitzGerald (1/1/2005–12/31/2008), University of Pennsylvania School of Medicine Elaine K. Gallin (1/1/2005–12/31/2008), The Doris Duke Charitable Foundation Steven K. Galson (1/9/2007–12/31/2008), Office of the Surgeon General v

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Alan M. Garber (1/1/2005–12/31/2007), Stanford University Robert L. Garnick (11/16/2007–2/28/2008), Genentech, Inc. Mikhail Gishizky (1/1/2005–12/31/2008), Entelos, Inc. Stephen Groft (1/1/2005–12/31/2008), National Institutes of Health Carole A. Heilman (1/1/2005–3/13/2006), National Institute of Allergy and Infectious Diseases Peter K. Honig (7/19/2007–12/31/2008), Merck & Co., Inc. Dale Hu (1/1/2005–12/31/2005), Centers for Disease Control and Prevention Richard A. Justman (7/19/2007–12/31/2008), United HealthGroup Michael Katz (1/1/2005–12/31/2008), March of Dimes Foundation William F. Keane (1/1/2005–7/3/2007), Merck & Co., Inc. Chaitan Khosla (1/1/2005–12/31/2006), Stanford University Antonia Kolokathis (1/1/2005–12/31/2005), Pfizer, Inc. Allan M. Korn (1/1/2005–12/31/2006), Blue Cross and Blue Shield Association David Korn (1/1/2005–12/31/2008), Association of American Medical Colleges Ronald L. Krall (1/9/2007–12/31/2008), GlaxoSmithKline Jeffrey M. Leiden (1/1/2005–12/31/2007), Clarus Ventures John M. Leonard (1/9/2007–7/5/2007), Abbott Laboratories Nancy Loving (1/1/2005–6/7/2006), National Coalition for Women with Heart Disease John R. Marler (1/1/2005–12/31/2008), National Institute of Neurological Disorders and Stroke Musa Mayer (1/1/2005–12/31/2008), AdvancedBC.org Mark B. McClellan (4/2/2007–12/31/2008), The Brookings Institution Garry A. Neil (1/1/2005–3/19/2007), Johnson & Johnson Joshua J. Ofman (1/1/2005–12/31/2008), Amgen, Inc. Suzanne R. Pattee (1/1/2005–12/31/2008), Cystic Fibrosis Foundation Cecil B. Pickett (1/1/2005–12/31/2006), Schering-Plough Research Institute Joanne L. Rhoads (1/9/2007–12/31/2008), National Institute of Allergy and Infectious Diseases [Retired] Todd Rich (3/2/2008–12/31/2008), Genentech, Inc. Brian Schuster (1/1/2005–12/31/2006), U.S. Department of Veterans Affairs B. A. Schwetz (1/1/2005–9/30/2007), U.S. Department of Health and Human Services Janet Shoemaker (1/1/2005–12/31/2008), American Society for Microbiology Lana Skirboll (1/9/2007–12/31/2008), National Institutes of Health Nancy S. Sung (1/1/2005–12/31/2008), Burroughs Wellcome Fund vi

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James R. Swartz (1/1/2005–12/31/2005), Stanford University Jorge A. Tavel (7/19/2007–12/31/2008), National Institute of Allergy and Infectious Diseases Reed V. Tuckson (1/1/2005–7/3/2007), UnitedHealth Group Sean Tunis (1/1/2005–12/31/2006), Centers for Medicare & Medicaid Services Janet Woodcock (1/1/2005–12/31/2008), U.S. Food and Drug Administration IOM Stafff Robert B. Giffin (Director, 7/13/2006–present) Alexander K. Ommaya (Director, 1/1/2005–7/7/2006) Adrienne Stith Butler (Senior Program Officer, 12/1/2006–5/31/2007) Sally Robinson (Program Officer, 12/18/2006–present) Heather Begg (Program Associate, 1/1/2005–7/7/2006) Andrea Knutsen (Senior Program Assistant, 10/3/2005–present) Jennifer Rainey (Research Assistant, 1/1/2005–7/7/2006) vii

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Reviewers T his report has been reviewed in draft form by individuals 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 report as sound as possible and to ensure that the report meets institutional standards for objectivity, evidence, and respon- siveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. We wish to thank the following individuals for their review of this report: Marion E. Broome, Indiana University School of Nursing and Nursing Outlook Journal P. Joan Chesney, St. Jude Children’s Research Hospital Thomas G. Dewitt, Cincinnati Children’s Hospital Medical Center William E. Evans, St. Jude Children’s Research Hospital Michael Katz, March of Dimes Birth Defects Foundation John S. March, Department of Psychiatry and Behavioral Science, Duke University Although the reviewers listed above have provided many con- structive comments and suggestions, they did not see the final draft of the report before its release. The review of this report was overseen ix

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x REVIEWERS by Dr. Ralph E. Kauffman, Professor Emeritus, University of Missouri- Kansas City. Appointed by the Institute of Medicine, he was respon- sible for making certain that an independent examination of this report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of this report rests entirely with the authoring committee and the institution.

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Contents Summary 1 1 Introduction 7 Response to Drugs in Various Age Groups, 7 Product Labeling, 8 Organization of This Summary, 9 2 Regulatory Framework 10 Best Pharmaceuticals for Children Act, 12 Pediatric Research Equity Act, 14 Impact of Pediatric Drug Legislation, 16 Discussion, 19 3 Current Challenges in Developing and Prescribing Drugs for Children 20 Barriers to Pediatric Drug Development, 20 Formulations, 26 Dosing, Bioavailability, and Drug Response, 28 4 Models for Enhancing Pediatric Drug Development 29 Vaccine Development in the United States, 29 The European Union’s New Regulatory Approach, 31 The St. Jude’s Model for Pediatric Oncology Drugs, 34 xi

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xii CONTENTS 5 Challenges and Opportunities for the Future 36 Systemic Solutions, 36 Elimination of Economic Barriers, 38 Concluding Thoughts, 39 References 41 Appendixes A Workshop Agenda 43 B Speaker Biographies 46