Rational Therapeutics for Infants and Children
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
NATIONAL ACADEMY PRESS
NATIONAL ACADEMY PRESS
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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.
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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,
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
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.
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)
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
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.
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.
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
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
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.