Rational Therapeutics for Infants and Children

Workshop Summary

Sumner Yaffe, M.D., Editor

with the assistance of Ronald W. Estabrook, Peter Bouxsein, Sarah Pitluck, and Jonathan R. Davis

Based on a Workshop of the Roundtable on Research and Development of Drugs, Biologics, and Medical Devices

Division of Health Sciences Policy

INSTITUTE OF MEDICINE


NATIONAL ACADEMY PRESS
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Rational Therapeutics for Infants and Children: Workshop Summary Rational Therapeutics for Infants and Children Workshop Summary Sumner Yaffe, M.D., Editor with the assistance of Ronald W. Estabrook, Peter Bouxsein, Sarah Pitluck, and Jonathan R. DavisBased on a Workshop of the Roundtable on Research and Development of Drugs, Biologics, and Medical Devices Division of Health Sciences Policy INSTITUTE OF MEDICINE NATIONAL ACADEMY PRESS Washington, D.C.

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Rational Therapeutics for Infants and Children: Workshop Summary NATIONAL ACADEMY PRESS 2101 Constitution Avenue, N.W. Washington, D.C. 20418 NOTICE: The project that is the subject of this workshop summary 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 Roundtable responsible for the workshop summary were selected for their special competences and with regard for appropriate balance. Support for this project was provided by the American Medical Association; Baxter International, Inc.; Eli Lilly; the U.S. Food and Drug Administration (Center for Biologics Evaluation and Research, Center for Devices and Radiological Health, and Center for Drug Evaluation and Research); the Health Industry Manufacturers Association; Hoffmann-La Roche; Merck & Co., Inc.; National Institutes of Health (Office of Rare Diseases and National Institute of Child Health and Human Development); Pfizer; and Wyeth-Ayerst. The views presented are those of the authors and are not necessarily those of the funding organizations. This report is based on the proceedings of a workshop that was sponsored by the Roundtable on Research and Development of Drugs, Biologics, and Medical Devices. It is prepared in the form of a workshop summary by and in the name of the editor with the assistance of staff and consultants, as an individually authored document. Sections of the workshop summary not specifically attributed to an individual reflect the views of the editor and not those of the Roundtable on Research and Development of Drugs, Biologics, and Medical Devices. The content of those sections is based on the presentations and the discussions that took place during the workshop. International Standard Book No. 0-309-06937-8 Additional copies of this workshop summary are available for sale from the National Academy Press, 2101 Constitution Avenue, N.W., Box 285, Washington, DC 20055. Call (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area), or visit the NAP’s on-line bookstore at www.nap.edu. For information about the Institute of Medicine, visit the IOM home page at www.iom.edu. The full text of this Workshop Summary is available online at www.nap.edu/readingroom. Copyright 2000 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 image adopted as a logotype by the Institute of Medicine is based on a relief carving from ancient Greece, now held by the Staatliche Museen in Berlin.

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Rational Therapeutics for Infants and Children: Workshop Summary THE NATIONAL ACADEMIES National Academy of Sciences National Academy of Engineering Institute of Medicine National Research Council 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 government on scientific and technical matters. Dr. Bruce M. Alberts 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 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. William A. Wulf 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. Kenneth I. Shine 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 providing 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. Bruce M. Alberts and Dr. William A. Wulf are chairman and vice chairman, respectively, of the National Research Council.

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Rational Therapeutics for Infants and Children: Workshop Summary This page in the original is blank.

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Rational Therapeutics for Infants and Children: Workshop Summary ROUNDTABLE ON RESEARCH AND DEVELOPMENT OF DRUGS, BIOLOGICS, AND MEDICAL DEVICES RONALD W. ESTABROOK (Chair), Virginia Lazenby O'Hara Professor of Biochemistry, University of Texas Southwestern Medical Center, Dallas ARTHUR L. BEAUDET, Investigator, Howard Hughes Medical Institute, and Professor and Chair, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, (through February 1999) LESLIE Z. BENET, Professor and Chair, Department of Biopharmaceutical Sciences, School of Pharmacy, University of California at San Francisco D. BRUCE BURLINGTON, Director, Center for Devices and Radiological Health, U.S. Food and Drug Administration, Rockville, Maryland (through March 1999) ROBERT CALIFF, Director, Duke Clinical Research Institute, Durham, North Carolina MICHAEL D. CLAYMAN, Vice President, Global Regulatory Affairs, Lilly Research Laboratories, Indianapolis, Indiana ADRIAN L. EDWARDS, Private Practice, Internal Medicine/Cardiology, The New York and Presbyterian Hospitals, New York City DAVID W. FEIGAL, Director, Center for Devices and Radiological Health, U.S. Food and Drug Administration, Rockville, Maryland (from June 1999) STEPHEN GROFT, Director, Office of Rare Diseases Research, National Institutes of Health, Bethesda, Maryland ANNE B. JACKSON, American Association of Retired Persons, Washington, D.C. ROBERT I. LEVY, Senior Vice President, Science and Technology, American Home Products, Wyeth-Ayerst Research, Madison, New Jersey MICHAEL R. McGARVEY, Chief Medical Officer, Blue Cross and Blue Shield of New Jersey, Inc., Newark KSHITIJ MOHAN, Corporate Vice President for Research and Technical Services, Baxter Health Care Corporation, Roundlake, Illinois STUART L. NIGHTINGALE, Associate Commissioner, Health Affairs, Food and Drug Administration, Rockville, Maryland PAUL GRANT ROGERS, Partner, Hogan & Hartson, Washington, D.C. DANIEL SECKINGER, Group Vice President, Professional Standards, American Medical Association, Chicago (through December 1997) WHAIJEN SOO, Vice President, Clinical Sciences, Roche Pharmaceuticals, Hoffmann-La Roche, Inc., Nutley, New Jersey REED TUCKSON, Senior Vice President, Professional Standards, American Medical Association, Chicago (from October 1998) JANET WOODCOCK, Director, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Rockville, Maryland

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Rational Therapeutics for Infants and Children: Workshop Summary SUMNER YAFFE, Director, Center for Research for Mothers and Children, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland KATHRYN ZOON, Director, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Rockville, Maryland Liaisons to the Roundtable JAMES S. BENSON, Executive Vice President, Technology and Regulatory Affairs, Health Industry Manufacturers Association, Washington, D.C. C. THOMAS CASKEY, Senior Vice President for Research, Merck & Co., Inc., West Point, Pennsylvania BRIAN J. MALKIN, Associate Director for Patents and Hearings, Office of Health Affairs, U.S. Food and Drug Administration, Rockville, Maryland BERT SPILKELR, Senior Vice President, Scientific and Regulatory Affairs, Pharmaceutical Research and Manufacturers of America, Washington, D.C. Study Staff JONATHAN R. DAVIS, Senior Program Officer PETER BOUXSEIN, Senior Program Officer SARAH PITLUCK, Research Assistant VIVIAN P. NOLAN, Research Associate NICOLE AMADO, Project Assistant (until August 1999) Division Staff ANDREW M. POPE, Division Director ALDEN CHANG, Project Assistant THELMA COX, Project Assistant SETH KELLY, Project Assistant CARLOS GABRIEL, Financial Associate HALLIE WILFERT, Administrative Assistant Consultant KATHI HANNA Copy Editor MICHAEL HAYES

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Rational Therapeutics for Infants and Children: Workshop Summary Reviewers All presenters at the workshop have reviewed and approved their respective sections of this workshop summary for accuracy. In addition, this workshop summary has been reviewed in draft form by independent reviewers 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 Institute of Medicine (IOM) in making the published workshop summary as sound as possible and to ensure that the workshop summary meets institutional standards. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. Although the independent reviewers have provided many constructive comments and suggestions, responsibility for the final content of this workshop summary rests solely with the IOM. The Roundtable and IOM thank the following individuals for their participation in the review process: Cheston M. Berlin, University Professor of Pediatrics and Professor of Pharmacology, Department of Pediatrics, Milton S. Hershey Medical Center, Hershey, Pennsylvania Jeffrey L. Blumer, Professor of Pediatrics and Pharmacology, Case Western Reserve University and Chief, Division of Pediatric Pharmacology and Critical Care, Rainbow Babies and Children's Hospital, Cleveland Sanford N. Cohen, Cape Coral, Florida Ronald N. Hines, Codirector, Birth Defects Research Center, and Professor of Pediatrics and Pharmacology/Toxicology, Department of Pediatrics, Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee Frank L. Hurley, Chief Scientific Officer, Quintiles Transnational Corporation, Arlington, Virginia Gideon Koren, Member, American Board of Medical Toxicology and Fellow Royal College of Physicians and Surgeons Allan M. Korn, Senior Vice President of Clinical Affairs and Chief Medical Officer, Blue Cross and Blue Shield Association, Chicago Allen A. Mitchell, Director, Sloan Epidemiology Unit, Professor of Epidemiology and Pediatrics, Boston University School of Public Health and Medicine, Brookline Robert M. Ward, Professor, Pediatrics and Director, Pediatric Pharmacology Program, Division of Neonatology, University of Utah, Salt Lake City Mel Worth, Scholar-in-Residence, Institute of Medicine, The National Academies, Washington, D.C.

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Overcoming Barriers to Collaborative Research: Report of a Workshop This page in the original is blank.

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Rational Therapeutics for Infants and Children: Workshop Summary Preface The Institute of Medicine's (IOM's) Roundtable on Research and Development of Drugs, Biologics, and Medical Devices evolved from the Forum on Drug Development, which was established in 1986. Sponsor representatives and IOM determined the importance of maintaining a neutral setting for discussions regarding long-term and politically sensitive issues justified the need to revise and enhance past efforts. The new Roundtable is intended to be a mechanism by which a broad group of experts from the public* and private sectors can be convened to conduct a dialogue and exchange information related to the development of drugs, biologics, and medical devices. Members have expertise in clinical medicine, pediatrics, clinical pharmacology, health policy, health insurance, industrial management, and product development; and they represent interests that address all facets of public policy issues. From time to time, the Roundtable requests that a workshop be conducted for the purpose of exploring a specific topic in detail and obtaining the views of additional experts. Summaries of these workshops are prepared and disseminated to make the discussion readily accessible to the members of the Roundtable and other interested parties. Such workshop summaries are intended only to convey the presentations and discussion that took place at the workshop; they do not include any conclusions or recommendations on the part of the Roundtable or any further data or analysis of the issues. *    Representatives of federal agencies serve in an ex officio capacity. An ex officio member of a group is one who is a member automatically by virtue of holding a particular office or membership in another body.

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Rational Therapeutics for Infants and Children: Workshop Summary The first workshop for the Roundtable was held on April 14 and 15, 1998, and was entitled Assuring Data Quality and Validity in Clinical Trials for Regulatory Decision Making. The summary on that workshop is available from IOM. This workshop summary covers the second workshop, which was held on May 24 and 25, 1999, and which was aimed at facilitating the development and proper use of drugs, biologics, and medical devices for infants and children. It explores the scientific underpinnings and clinical needs, as well as the regulatory, legal, and ethical issues, raised by this area of research and development. The environment for pediatric therapeutics has been altered by two important developments. First, the Food and Drug Administration Modernization Act, enacted in 1997, provides incentives to pharmaceutical manufacturers that conduct acceptable studies with children and drugs identified by the U.S. Food and Drug Administration, to be ones for which information on the effects on the pediatric population would be beneficial. Second, in December 1998 the U.S. Food and Drug Administration published a final role that established certain requirements for studies with the pediatric population and drugs that significantly affect infants and children. This workshop addressed many important issues. For example, many questions about the biochemistry of the enzymes involved in drug metabolism remain unanswered, in particular, the variability in the responses of individuals to drugs. The differences in the pharmacodynamics and pharmacogenetics of drug metabolism between children and adults remain undetermined. In addition, the influence of diet on the process of induction of these enzymes during the various stages of development deserves extensive study. Three sets of concerns need to be addressed to advance the development of rational therapeutics for infants and children: What is the scientific basis for differences in the responses to drugs of humans during their life spans, from the time of development in fetuses, infants, and young children through the process of aging? How do the metabolic, immune, and other systems of infants and children function differently at various stages of growth, what are the factors that influence these differences, and do they alter responses to drugs? What data need to be known to determine pediatric drug dosages? Can dosages be extrapolated from data for adults? How can responses to drugs be evaluated ethically in children? This summary on the workshop is organized as topic-by-topic descriptions of the presentations and discussions that occurred during the workshop. Although the proceedings were rich and wide-ranging, this workshop summary does not purport to be a comprehensive or exhaustive exploration of the issues discussed. Nor does it represent a consensus of views or opinions from IOM or the Roundtable. Rather, it summarizes a dialogue among representatives from

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Rational Therapeutics for Infants and Children: Workshop Summary different sectors and their thoughts on what research and what public policy issues may merit further attention. The editor's summary material at the beginning of each section provides some context and overview of the identified presentations. On behalf of the members of the Roundtable, I express my warmest appreciation to the authors of this workshop summary for providing a timely and useful summary of the issues raised and the discussions that occurred. I also want to thank the individuals and organizations that gave valuable time to provide information and insight to the Roundtable through participation in the workshop. Each of the following contributed greatly: Charles H. Ballow, Kaleida Health Millard Fillmore Hospital; Mark Batshaw, George Washington University Medical Center, Children's Research Institute, Children's National Medical Center; Emmett Clemente, Ascent Pediatrics, Inc.; Thierry Cresteil, Centre National de la Recherche Scientifique, Institut Gustave Roussy, Villejuif, France; Sherin U. Devaskar, Magee Women's Hospital, University of Pittsburgh School of Medicine; Susan Ellenberg, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration; David Feigal, Jr., Center for Devices and Radiological Health, U.S. Food and Drug Administration; Jane Henney, U.S. Food and Drug Administration; Ralph Kauffman, Children's Mercy Hospital; Greg Kearns, Division of Pediatric Clinical Pharmacology, Children's Mercy Hospital; Michael Labson, Covington & Burling; Steve Leeder, Children's Mercy Hospital; Murray Lumpkin, Center for Drug Evaluation and Research, U.S. Food and Drug Administration; Michael MeGarvey, Blue Cross and Blue Shield of New Jersey, Inc.; Dianne Murphy, Center for Drug Evaluation and Research, U.S. Food and Drug Administration; Robert M. (Skip) Nelson, Medical College of Wisconsin; David Poplack, Baylor College of Medicine and Texas Children's Cancer Center; Stephen Spielberg, R.W. Johnson Pharmaceutical Research Institute; Stanley J. Szefler, National Jewish Medical and Research Center, University of Colorado Health Sciences Center; Robert Temple, Center for Drug Evaluation and Research, U.S. Food and Drug Administration; John Watchko, Department of Pediatrics, Magee Women's Hospital, University of Pittsburgh School of Medicine; Karen Weiss, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration; and John T. Wilson, Department of Pediatrics, Louisiana State University Medical Center. I also thank the following IOM staff for their valuable contributions in this activity: Vivian Nolan, Nicole Amado, Alden Chang, and Thelma Cox. Consultant and technical writer Kathi Hanna contributed significantly to the writing of many sections of the workshop summary. The extensive commentary and suggestions made by the copy editor, Michael Hayes, are gratefully acknowledged. Finally, the Roundtable and IOM also wish to thank the sponsors that supported this activity. Financial support for this project was provided by the

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Rational Therapeutics for Infants and Children: Workshop Summary American Medical Association, Baxter International Inc., Eli Lilly, U.S. Food and Drug Administration (Center for Biologics Evaluation and Research, Center for Devices and Radiological Health, and Center for Ding Evaluation and Research), the Health Industry Manufacturers Association, Hoffmann-La Roche, Merck & Co., Inc., National Institutes of Health (Office of Rare Diseases and National Institute of Child Health and Human Development), Pfizer, and Wyeth-Ayerst. Sumner Yaffe, M.D. Editor

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Rational Therapeutics for Infants and Children: Workshop Summary Contents     EDITOR'S SUMMARY   1 1   INTRODUCTION   8     Science, Challenges, and Children   8     First Steps   8     New Rule Making   10     Challenges to Studies with Children   11     The Role of FDA   12 2   SIMILARITIES AND DISSIMILARITIES IN PHYSIOLOGY, METABOLISM, AND DISEASE STATES AND RESPONSES TO THERAPY IN CHILDREN AND ADULTS   14     Historical Background   15     Differences Between Children and Adults   16     Differential Responses of Children to Drugs   21     Molecular Basis of Drug Metabolism   23     Gene Expression and Ontogeny of Drug Metabolism   29 3   PHARMACOKINETICS AND PHARMACODYNAMICS IN CHILDREN VERSUS ADULTS   34     Drug Metabolism in Children and Adolescents: Insights from Therapeutic Adventures   35     Ontogeny of P-Glycoprotein, an ATP-Dependent Transmembrane Efflux Pump   41

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Rational Therapeutics for Infants and Children: Workshop Summary     Developmental Aspects of Glucose Transporters   44     Formulation   46     Anti-Infectives   48     Childhood Asthma   50     Pediatric Oncology   58 4   EXTRAPOLATION OF SAFETY AND EFFICACY DATA TO CHILDREN   61     Special Considerations for Evaluating Medical Devices in Infants and Children   62     Defining Surrogate Endpoints and Biomarkers for Drug Action in Trials with Pediatric Subjects   64     Prediction of Long-Term Effects on Postnatal Brain Development   66     Evaluating Biologic Therapeutics in Pediatric Clinical Trials   68 5   RAISING AWARENESS OF REGULATORY, LEGAL, AND ETHICAL ISSUES   71     FDA Perspective on New Regulations   72     Roles of Institutional Review Boards and Data-Monitoring Committees in Clinical Trials   73     Ethics of Drug and Biologic Research in Infants and Children   76     Legal and Regulatory Considerations for the Conduct of Clinical Trials with Pediatric Populations   85     International Development of Drugs for Pediatric Patients: An Industry Perspective   88     Panel Discussion   90 6   CONCLUDING REMARKS   92     REFERENCES   95     APPENDIXES     A   Workshop Agenda   105 B   Biographies   111