SAFE AND
EFFECTIVE
MEDICINES
FOR CHILDREN

Pediatric Studies Conducted Under the Best Pharmaceuticals
for Children Act and the Pediatric Research Equity Act

Committee on Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA)

Board on Health Sciences Policy

Marilyn J. Field and Thomas F. Boat, Editors

INSTITUTE OF MEDICINE
OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS
Washington, D.C.
www.nap.edu



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SAFE AND EFFECTIVE MEDICINES FOR CHILDREN Pediatric Studies Conducted Under the Best Pharmaceuticals f or Children Act and the Pediatric Research Equity Act Committee on Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA) Board on Health Sciences Policy Marilyn J. Field and Thomas F. Boat, Editors

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THE NATIONAL ACADEMIES PRESS • 500 Fifth Street, NW • Washington, DC 20001 NOTICE: The project that is the subject of this report 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. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance. This study was supported by Contract No. DHHS-8598, TO #16, between the National Academy of Sciences and the Food and Drug Administration, U.S. Department of Health and Human Services. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the views of the organiza- tions or agencies that provided support for the project. International Standard Book Number-13: 978-0-309-22549-6 International Standard Book Number-10: 0-309-22549-3 Additional copies of this report 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. For more information about the Institute of Medicine, visit the IOM home page at: www. iom.edu. Copyright 2012 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). 2012. Safe and effective medicines for children: Pediatric studies conducted under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, 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 Acad- emy has a mandate that requires it to advise the federal government 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 en- gineers. 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 engineer- ing programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Charles M. Vest is presi- dent 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 Insti- tute 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 Sci- ences 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 providing services to the government, the public, and the scientific and engineering communities. The Coun- cil 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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COMMITTEE ON PEDIATRIC STUDIES CONDUCTED UNDER BPCA AND PREA THOMAS F. BOAT (Chair), Vice President for Health Affairs, Christian R. Holmes Professor and Dean of the College of Medicine, University of Cincinnati, Ohio PETER C. ADAMSON, Professor of Pediatrics and Pharmacology at the University of Pennsylvania School of Medicine, Chief of the Division of Clinical Pharmacology and Therapeutics at The Children’s Hospital of Philadelphia, and Director of Clinical and Translational Research at The Children’s Hospital of Philadelphia Research Institute RICHARD E. BEHRMAN, Consultant, Santa Barbara, California F. SESSIONS COLE III, Park J. White, M.D., Professor of Pediatrics, Professor of Cell Biology and Physiology, Washington University School of Medicine, and Chief Medical Officer, St. Louis Children’s Hospital, Missouri BRIAN FELDMAN, Professor of Pediatrics, Medicine, and Health Policy, Management and Evaluation and Professor of the Dalla Lana School of Public Health, University of Toronto, Canada PAT FURLONG, Founding President and Chief Executive Officer of Parent Project Muscular Dystrophy, Middletown, Ohio ERIC KODISH, Director of the Center for Ethics, Humanities and Spiritual Care at Cleveland Clinic, and F. J. O’Neill Professor and Chair of Bioethics and Professor of Pediatrics, Lerner College of Medicine of Case Western Reserve University, Ohio JENNIFER LI, Professor of Pediatrics (Cardiology), Professor of Medicine (Cardiology), Director of Pediatric Clinical Research, Duke Clinical Research Institute; Core Director of Pediatrics, Duke Translational Medicine Institute; and Division Chief, Pediatric Cardiology, Duke University Health System, Durham, North Carolina CHRISTINA M. MARKUS, Partner and Deputy Practice Leader, FDA & Life Sciences Group, King and Spalding LLP, Washington, DC MILAP C. NAHATA, Division Chairman and Professor, College of Pharmacy, and Professor of Pediatrics and Internal Medicine, College of Medicine of the Ohio State University, Columbus MARK A. RIDDLE, Professor of Psychiatry and Pediatrics and Director of the Children’s Interventions Research Program in Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland JOSEPH W. ST. GEME III, James B. Duke Professor and Chair of Pediatrics and Professor of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina v

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ROBERT WARD, Professor of Pediatrics and Medical Director of Pediatric Pharmacology, University of Utah, Salt Lake City Committee Consultants and Background Paper Authors CHARLES J. COTÉ, Professor of Anaesthesia, Harvard Medical School, Cambridge, Massachusetts LARA ELLINGER, Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago MICHAEL GABAY, Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago ANDREW HERSHEY, Department of Neurology, Children’s Hospital Medical Center, Cincinnati, Ohio MATTHEW M. LAUGHON, Department of Pediatrics, University of North Carolina at Chapel Hill THE LEWIN GROUP, Falls Church, Virginia P. BRIAN SMITH, Duke University Medical Center and Duke Clinical Research Institute, Durham, North Carolina JOAN M. STACHNIK, Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago IOM Staff MARILYN J. FIELD, Senior Program Officer CLAIRE F. GIAMMARIA, Research Associate ROBIN E. PARSELL, Senior Program Assistant ANDREW M. POPE, Director, Board on Health Sciences Policy vi

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Acknowledgments I n preparing this report, the committee and project staff benefited greatly from the assistance and expertise of many individuals and groups. Important information and insights came from three public meetings that the committee organized to collect information and perspectives from officials from the Food and Drug Administration (FDA) and the National Institutes of Health and individuals from organizations representing phar- maceutical and biotechnology companies, pediatricians, researchers, and patient and family advocates. A number of speakers at these meetings, including Anne Zajicek, Natella Y. Rakhmanina, Samuel Maldonado, and Ronald Portman, also shared their knowledge at other times during the course of the study. Appendix A includes the agendas of the public meetings. The committee appreciates the contributions of the authors of the background papers and analyses that appear as Appendixes B, C, and D. We likewise appreciate the analyses conducted by staff of The Lewin Group (including Nancy Walczak, Ian Glen, and Cynthia Schuster) and their pa- tience in discussing the details of these analyses, which changed extensively over the course of the project. Consultants Andrew Hershey and Charles Coté assisted with the analysis of studies and labeling changes involving migraine and anesthetic products. At the College of Pharmacy, University of Illinois at Chicago, Amy LoDolce was very helpful in initiating the work on what became Appendix D of this report. Robert Nelson, our project officer at FDA, and his colleague, Catherine Lee, provided information and clarification on a seemingly endless number of questions about FDA policies, procedures, and documents. They con- sulted with many others at FDA in the process, and we appreciate those vii

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viii ACKNOWLEDGMENTS who helped them answer our questions. Lisa Mathis and Julia Dunne at FDA also assisted staff in understanding additional aspects of FDA activi- ties related to pediatric drug studies. At the American Academy of Pedi- atrics, Tamar Haro and Mark Del Monte provided helpful background information. We also appreciate the work of copyeditor Michael Hayes and Debra Gilliam, Chanda Chay, and John Bowers at Caset Associates. Within the National Academies, we acknowledge the assistance of Adam Berger, Laura Harbold, Donna Randall, Vilija Teel, and Sarah Ziegenhorn, among many others.

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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 reports as sound as possible and to ensure that the report meets institutional standards for objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confiden- tial to protect the integrity of the deliberative process. We wish to thank the following individuals for their review of this report: Jon S. Abramson, Wake Forest University School of Medicine Marilee C. Allen, Johns Hopkins University School of Medicine Daniel Benjamin, Duke Clinical Research Center Susan S. Ellenberg, University of Pennsylvania School of Medicine Chris Feudtner, Children’s Hospital of Philadelphia Henry G. Grabowski, Duke University Sean Hennessy, University of Pennsylvania School of Medicine Raphael Hirsch, University of Pittsburgh School of Medicine Steven Joffe, Dana-Farber Cancer Institute Michael Katz, March of Dimes Foundation Michael Labson, Covington & Burling LLP Fernando D. Martinez, Arizona Health Sciences Center Josef Neu, University of Florida Arthur W. Nienhuis, St. Jude Children’s Research Hospital ix

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x REVIEWERS Alastair J. Wood, Symphony Capital LLC Kathryn C. Zoon, National Institute of Allergy and Infectious Diseases Although the reviewers listed above have provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations, nor did they see the final draft of the report before its release. The review of this report was overseen by Ellen Wright Clayton, Vanderbilt University, and Charles E. Phelps, University of Rochester. Ap- pointed by the National Research Council and the Institute of Medicine, these individuals were responsible for making certain that an independent examination of this report was carried out in accordance with the institu- tional 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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Preface C hildren, in general, are healthier than their adult counterparts, par- ticularly as adults reach the fifth decade of life and beyond. How- ever, children do have multiple acute illnesses each year, and a substantial number of children, often estimated to be 20 percent or more, are burdened with chronic health disorders, some of them disabling or life threatening. Medical attention, including evidence-based prescription of drugs or biologics, is vital for their well-being. In addition, children constitute a smaller percentage of the U.S. popula- tion than adults, so drugs are often designed for adults and initially tested and approved for use in adult populations. Clinicians, however, often be- gin to use these drugs—as is legal—with children without guidance from well-controlled clinical studies. Over time it has become apparent that pharmacologically, as well as in many other ways, children are not “small adults.” In the 1980s and 1990s, policy makers, pediatricians, and others increasingly recognized the need to study the efficacy and safety of drugs in children. Key responses to that recognition—different policies that incentiv- ize or require studies of drugs in children—are the focus of this report. The Best Pharmaceuticals for Children Act (BPCA) provides incentives for drug studies in children, and the Pediatric Research Equity Act (PREA) requires such studies in certain situations. Since the late 1990s, these policies (and their predecessors) have improved the availability of reliable information, which should, in turn, improve the appropriate use of therapeutic agents for children in clinical practice. This Institute of Medicine (IOM) report, which was called for by Congress, documents improvements in the availability of evidence about xi

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xiv CONTENTS Public Access to Information, 84 Conclusions, 86 4 ETHICAL ISSUES IN PEDIATRIC DRUG STUDIES 89 Regulatory Requirements for Protection of Human Research Participants, 90 FDA Organizational Resources to Support Ethical Standards in Pediatric Research, 96 Ethical Issues in Studies Conducted Under BPCA and PREA, 99 Conclusions, 108 5 SAFETY AND EFFICACY ASSESSMENTS IN STUDIES CONDUCTED UNDER BPCA AND PREA 111 Sources of Information About Safety and Efficacy Results in Pediatric Drug Studies, 112 Assessing and Monitoring Safety in Pediatric Drug Studies: Selected Issues, 114 Assessing and Reporting Efficacy in Pediatric Drug Studies: Selected Issues, 127 Conclusions, 139 6 BPCA, PREA, AND DRUG STUDIES WITH NEONATES 141 Medication Testing and Medication Use with Neonates, 142 Drug Studies with Neonates Conducted Under BPCA and PREA, 146 BPCA, NIH, and Studies with Neonates, 163 Conclusions, 165 Addendum: Labeling Changes Based on Neonate Studies Requested Under BPCA or Required Under PREA, July1998 Through December 2010, 168 7 OUTCOMES OF WRITTEN REQUESTS, REQUIREMENTS, STUDIES, AND LABELING CHANGES 177 Written Requests and PREA Requirements, 180 Pediatric Drug Studies and FDA Reviews, 193 Pediatric Studies and Changes in Labeling, 197 Conclusions, 203 8 PEDIATRIC STUDIES OF BIOLOGICS 207 Ensuring Pediatric Studies of Biologics, 208 Identifying Biologics Not Studied with Children, 215 Conclusions, 228

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xv CONTENTS REFERENCES 231 APPENDIXES A Study Activities, Methods, and Public Meetings 261 B Dissemination of Information from Pediatric Studies Conducted Under BPCA and PREA 271 C Biologics in Pediatrics 285 D Biologics Studied and Not Studied in Children 321 E Written Requests for Studies of Pediatric Hypertension: Longitudinal Changes in FDA Specifications 381 F Committee and Staff Biographies 387 INDEX 395

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Boxes, Figures, and Tables BOXES 1-1 Knowledge Contributed by Pediatric Drug Studies Conducted Under BPCA and PREA, 22 1-2 Types of Clinical Trials, 38 3-1 Basic Elements of a Written Request, 75 4-1 Determinations of Research Risks and Potential Benefits Required by FDA Regulations, 91 4-2 Categories of Clinical Research Involving Children That Are Approvable Under 21 CFR 50, 94 5-1 CDER Template for Clinical Reviews (2010), 113 5-2 Safety Review Section of CDER Clinical Review Template (2010), 116 5-3 Examples of Products with Different Safety Profiles for Children and Adults Identified in FDA Clinical Reviews, 120 5-4 Efficacy Review Section of CDER Clinical Review Template, 129 5-5 Examples of Efficacy Endpoints in Pediatric Studies, 132 6-1 Examples of Labeling Changes with Information Based on BPCA- or PREA-Related Neonatal Studies, 154 6-2 Current Labeling of PPIs: References to Neonates and Infants, 162 xvii

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xviii BOXES, FIGURES, AND TABLES 6-3 Criteria for Selecting Drugs for Priority Investigation in Newborns, 165 7-1 Major Amendments to Written Requests for Pediatric Studies of Drugs for Treatment of Migraine, 184 7-2 Elements in Written Requests That Could Limit the Potential of Studies to Yield Useful Information, 186 7-3 Aspects of Studies as Planned or Executed That May Have Limited the Usefulness of Information Submitted, 198 7-4 Examples of Informative Labeling Changes, 200 7-5 Concerns About Clarity of Labeling Changes, 202 8-1 Examples of Products with PREA Waivers or Orphan Designation Exemptions for Which Pediatric Studies Are Listed at ClinicalTrials.gov, 222 8-2 Products with No Indication of Pediatric Studies in Labeling, FDA Approval Letters, or Clinical Trials Registry (ClinicalTrials.gov), 224 FIGURES 5-1 Use of extrapolation to support pediatric efficacy claims, 135 7-1 Changes in drug labeling associated with BPCA, PREA (including the Pediatric Rule), or both, July 1998 through October 2011, 178 7-2 Number of written requests (WR) issued and number of grants of exclusivity, by year, July 1998 through September 2011, 182 B-1 Preferred sources of new dosing information, 275 C-1 Structures of nitroglycerin (C3H5N3O9), a conventional drug, and alteplase, a recombinant form of human tissue plasminogen activator, 287 E-1 Trial design options for pediatric hypertension trials provided for by FDA written requests, 383 TABLES 1-1 Historical Data on Drugs Without Adequate Labeling for Pediatric Use, 20

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xix BOXES, FIGURES, AND TABLES 3-1 Underlying Patent or Exclusivity Incentives That Can Be Extended with Pediatric Exclusivity, 72 3-2 Reasons for Waiver of Pediatric Assessment Requirements Authorized Under PREA with Examples from Recent NDA or BLA Approvals, 80 3-3 Selected Public Information Requirements of BPCA and PREA Through 2007 Reauthorization, 85 5-1 Summary of PAC Recommendations or Actions from the Safety Review 1 Year After a Labeling Change Resulting from a Study Conducted Under BPCA or PREA, June 1, 2003, to June 30, 2011, 126 5-2 FDA Analysis of Use of Extrapolation of Efficacy from Adult to Pediatric Population, Studies Conducted Under BPCA, 1998 to 2009, 137 5-3 Use of Extrapolation in IOM Sample of BPCA and PREA Labeling Changes, 138 6-1 Therapeutics Commonly Used in Neonatal Intensive Care, 145 6-2 Labeling Changes for Drugs for Treatment of HIV Infection from Studies That Included Neonates, 157 6-3 Written Requests for Neonatal Drug Studies Referred by FDA to NIH, by Patent Status and Study Status, 164 ADDENDUM Labeling Changes Based on Neonate Studies Requested Under BPCA or Required Under PREA, July 1998 Through December 2010, 168 7-1 Progress of Pediatric Studies Deferred Under PREA, 2007 to 2010, 192 7-2 Types of Pediatric Studies for Labeling Changes Conducted Under BPCA and PREA Between September 27, 2007, and June 30, 2011, 195 8-1 Summary Information on Biologics Studied in Children, 221 B-1 Infant Dosing Compared with Adult Dosing of Commonly Used Antimicrobials for Bloodstream Infections, 273 B-2 Sources for Prescribing Information for Clinicians, 277 B-3 Recent Pediatric Labeling Changes Identified by FDA and Comparison to Commonly Used Resources, 281

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xx BOXES, FIGURES, AND TABLES C-1 Plasma-Derived Therapeutic Proteins, 288 C-2 Therapeutic Monoclonal Antibodies and Fusion Proteins, 289 C-3 Additional Therapeutic Recombinant Human Proteins, 291 D-1 Labeling Information on Pediatric Uses, Studies, and Certain Safety Warnings for Biologics Initially Approved by FDA Between January 1, 1997, and December 31, 2010, 325 D-2 Pediatric Trials Registered at ClinicalTrials.gov for Biologics Initially Approved by FDA Between January 1, 1997, and December 31, 2010, 359

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Abbreviations and Acronyms AAP American Academy of Pediatrics ACR American College of Rheumatology ADHD attention deficit hyperactivity disorder AERS Adverse Event Reporting System AHA American Heart Association AHRQ Agency for Healthcare Research and Quality BLA Biologics License Application BPCA Best Pharmaceuticals for Children Act BPCIA Biologics Price Competition and Innovation Act CBER Center for Biologics Evaluation and Research CDC Centers for Disease Control and Prevention CDER Center for Drug Evaluation and Research CDRH Center for Devices and Radiological Health CNS central nervous system COG Children’s Oncology Group CYP cytochrome P450 DESI Drug Efficacy Study Implementation DMC data monitoring committee DSI Division of Scientific Investigations of the Center for Drug Evaluation and Research EMA European Medicines Agency xxi

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xxii ABBREVIATIONS AND ACRONYMS EU European Union FDA Food and Drug Administration FDAAA Food and Drug Administration Amendments Act of 2007 FDAMA Food and Drug Administration Modernization and Accountability Act of 1997 FDC Act Federal Food, Drug, and Cosmetic Act of 1938 FEV1 forced expiratory volume in 1 second FOIA Freedom of Information Act GCP good clinical practice GERD gastroesophageal reflux disease HHS U.S. Department of Health and Human Services IBD inflammatory bowel disease IGIV immune globulin intravenous IM intramuscular IND Investigational New Drug IOM Institute of Medicine IRB institutional review board IV intravenous JIA juvenile idiopathic arthritis NDA New Drug Application NICHD National Institute of Child Health and Human Development NIH National Institutes of Health NME new molecular entity NRC National Research Council PAC Pediatric Advisory Committee PASI 75 75 percent or greater improvement from baseline in the psoriasis area and severity index PD pharmacodynamics PDCO European Union Pediatric Committee PDR Physicians’ Desk Reference PeRC Pediatric Review Committee PHS Public Health Service PIP pediatric investigation plan PK pharmacokinetics PPI proton pump inhibitor PREA Pediatric Research Equity Act

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xxiii ABBREVIATIONS AND ACRONYMS SC subcutaneous TNF tumor necrosis factor UKHCDO United Kingdom Hemophilia Center Doctors’ Organization UNC University of North Carolina WHO World Health Organization

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