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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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