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
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 organizations 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
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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.
“Knowing is not enough; we must apply.
Willing is not enough; we must do.”
—Goethe
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OF THE NATIONAL ACADEMIES
Advising the Nation. Improving Health.
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Advisers to the Nation on Science, Engineering and Medicine
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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
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
Acknowledgments
In 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 pharmaceutical 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 patience 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 consulted with many others at FDA in the process, and we appreciate those
who helped them answer our questions. Lisa Mathis and Julia Dunne at FDA also assisted staff in understanding additional aspects of FDA activities related to pediatric drug studies. At the American Academy of Pediatrics, 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.
Reviewers
This 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 confidential 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
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. Appointed 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 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.
Preface
Children, in general, are healthier than their adult counterparts, particularly as adults reach the fifth decade of life and beyond. However, 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. population than adults, so drugs are often designed for adults and initially tested and approved for use in adult populations. Clinicians, however, often begin 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 incentivize 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
the safety and efficacy of drugs in children following the adoption of these policies and their implementation by the Food and Drug Administration (FDA). It reflects the work of an IOM committee, representing a wide range of relevant expertise, that worked diligently for more than a year to collect data on pediatric studies conducted under BPCA and PREA and to assess those data. The members of the committee engaged in lively debates and, in the end, came to conclusions that we believe will contribute to understanding and improving these policies and the pediatric studies prompted by them. For much of its work, the committee primarily relied on documents that were either posted on the FDA website (mostly documents issued after September 27, 2007) or supplied over a period of months by FDA after redaction (mostly documents issued earlier, before Congress required that they be made public).
Committee members pored through hundreds of pages of written requests and FDA clinical and other reviews to extract pertinent information. Thus, unlike many IOM committees, members both created and analyzed the data necessary to reach important conclusions. Also, unlike many other IOM committees, our committee was not asked to make recommendations, with one exception related to recently enacted policies to provide incentives for pediatric studies of biologics. The report was therefore constructed to transmit the conclusions of the committee’s assessments of studies under BPCA and PREA, as well as conclusions from these assessments that might form the basis for future steps by FDA and Congress to build on the strengths and correct some of the shortcomings of these policies or their application.
The committee assessed the data from a spectrum of perspectives: pediatric, psychiatric, pharmacologic, ethical, legal, health policy, and consumer. The committee was assisted in this effort by a number of consultants and contributors to the task of assembling data for this review and sharing fresh insights. Importantly, the committee would like to recognize and express appreciation for the tireless leadership of our committee study director, Marilyn Field, and for the contributions of her staff colleagues, Claire Giammaria and Robin Parsell. It was their efforts that allowed the committee to evaluate and come to conclusions based on an enormous array of data. Above all, the committee hopes that its efforts will encourage ongoing scientifically and ethically sound study of drugs and biologics, particularly for children who are not yet advantaged by therapies demonstrated to be safe and effective for their medical conditions.
Thomas F. Boat, Chair
Committee on Pediatric Studies Conducted Under BPCA and PREA
Contents
Evolution of Policies to Promote Pediatric Studies of Drugs and Biologics
2 CHILDREN’S GROWTH AND DEVELOPMENT AND PEDIATRIC DRUG STUDIES
Developmental Pharmacology and Pharmacogenomics
Tailoring Pediatric Research to Developmental Variability
Short-Term Studies and Long-Term Concerns
3 POLICY FRAMEWORK FOR BPCA AND PREA
Basic Regulatory Framework for Drug Development, Approval, and Surveillance
4 ETHICAL ISSUES IN PEDIATRIC DRUG STUDIES
Regulatory Requirements for Protection of Human Research Participants
FDA Organizational Resources to Support Ethical Standards in Pediatric Research
Ethical Issues in Studies Conducted Under BPCA and PREA
5 SAFETY AND EFFICACY ASSESSMENTS IN STUDIES CONDUCTED UNDER BPCA AND PREA
Sources of Information About Safety and Efficacy Results in Pediatric Drug Studies
Assessing and Monitoring Safety in Pediatric Drug Studies: Selected Issues
Assessing and Reporting Efficacy in Pediatric Drug Studies: Selected Issues
6 BPCA, PREA, AND DRUG STUDIES WITH NEONATES
Medication Testing and Medication Use with Neonates
Drug Studies with Neonates Conducted Under BPCA and PREA
BPCA, NIH, and Studies with Neonates
7 OUTCOMES OF WRITTEN REQUESTS, REQUIREMENTS, STUDIES, AND LABELING CHANGES
Written Requests and PREA Requirements
Pediatric Drug Studies and FDA Reviews
Pediatric Studies and Changes in Labeling
8 PEDIATRIC STUDIES OF BIOLOGICS
Ensuring Pediatric Studies of Biologics
APPENDIXES
A Study Activities, Methods, and Public Meetings
B Dissemination of Information from Pediatric Studies Conducted Under BPCA and PREA
D Biologics Studied and Not Studied in Children
E Written Requests for Studies of Pediatric Hypertension: Longitudinal Changes in FDA Specifications
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Boxes, Figures, and Tables
BOXES
1-1 Knowledge Contributed by Pediatric Drug Studies Conducted Under BPCA and PREA
3-1 Basic Elements of a Written Request
4-1 Determinations of Research Risks and Potential Benefits Required by FDA Regulations
4-2 Categories of Clinical Research Involving Children That Are Approvable Under 21 CFR 50
5-1 CDER Template for Clinical Reviews (2010)
5-2 Safety Review Section of CDER Clinical Review Template (2010)
5-4 Efficacy Review Section of CDER Clinical Review Template
5-5 Examples of Efficacy Endpoints in Pediatric Studies
6-1 Examples of Labeling Changes with Information Based on BPCA-or PREA-Related Neonatal Studies
6-2 Current Labeling of PPIs: References to Neonates and Infants
6-3 Criteria for Selecting Drugs for Priority Investigation in Newborns
7-1 Major Amendments to Written Requests for Pediatric Studies of Drugs for Treatment of Migraine
7-4 Examples of Informative Labeling Changes
7-5 Concerns About Clarity of Labeling Changes
8-1 Examples of Products with PREA Waivers or Orphan Designation Exemptions for Which Pediatric Studies Are Listed at ClinicalTrials.gov
8-2 Products with No Indication of Pediatric Studies in Labeling, FDA Approval Letters, or Clinical Trials Registry (ClinicalTrials.gov)
FIGURES
5-1 Use of extrapolation to support pediatric efficacy claims
B-1 Preferred sources of new dosing information
E-1 Trial design options for pediatric hypertension trials provided for by FDA written requests
TABLES
1-1 Historical Data on Drugs Without Adequate Labeling for Pediatric Use
3-1 Underlying Patent or Exclusivity Incentives That Can Be Extended with Pediatric Exclusivity
3-3 Selected Public Information Requirements of BPCA and PREA Through 2007 Reauthorization
5-3 Use of Extrapolation in IOM Sample of BPCA and PREA Labeling Changes
6-1 Therapeutics Commonly Used in Neonatal Intensive Care
6-2 Labeling Changes for Drugs for Treatment of HIV Infection from Studies That Included Neonates
7-1 Progress of Pediatric Studies Deferred Under PREA, 2007 to 2010
8-1 Summary Information on Biologics Studied in Children
B-2 Sources for Prescribing Information for Clinicians
B-3 Recent Pediatric Labeling Changes Identified by FDA and Comparison to Commonly Used Resources
C-1 Plasma-Derived Therapeutic Proteins
C-2 Therapeutic Monoclonal Antibodies and Fusion Proteins
C-3 Additional Therapeutic Recombinant Human Proteins
D-2 Pediatric Trials Registered at ClinicalTrials.gov for Biologics Initially Approved by FDA Between January 1, 1997, and December 31, 2010
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 |
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 |
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NIH |
National Institutes of Health |
|
NME |
new molecular entity |
|
NRC |
National Research Council |
|
PAC |
Pediatric Advisory Committee |
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PASI 75 |
75 percent or greater improvement from baseline in the psoriasis area and severity index |
|
PD |
pharmacodynamics |
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PDCO |
European Union Pediatric Committee |
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PDR |
Physicians’ Desk Reference |
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PeRC |
Pediatric Review Committee |
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PHS |
Public Health Service |
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PIP |
pediatric investigation plan |
|
PK |
pharmacokinetics |
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PPI |
proton pump inhibitor |
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PREA |
Pediatric Research Equity Act |
SC |
subcutaneous |
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TNF |
tumor necrosis factor |
|
UKHCDO |
United Kingdom Hemophilia Center Doctors’ Organization |
|
UNC |
University of North Carolina |
|
WHO |
World Health Organization |
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