Addressing the Barriers to Pediatric Drug Development: Workshop Summary (2008)

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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 

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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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  

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 

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 



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 

 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. 

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 

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