Making Better Drugs for Children with Cancer

Committee on Shortening the Time Line for New Cancer Treatments National Cancer Policy Board

Peter C. Adamson, Susan L. Weiner, Joseph V. Simone, and Hellen Gelband, Editors

INSTITUTE OF MEDICINE AND NATIONAL RESEARCH COUNCIL OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS
Washington, D.C.
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Making Better Drugs for Children with Cancer Making Better Drugs for Children with Cancer Committee on Shortening the Time Line for New Cancer Treatments National Cancer Policy Board Peter C. Adamson, Susan L. Weiner, Joseph V. Simone, and Hellen Gelband, Editors INSTITUTE OF MEDICINE AND NATIONAL RESEARCH COUNCIL OF THE NATIONAL ACADEMIES THE NATIONAL ACADEMIES PRESS Washington, D.C. www.nap.edu

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Making Better Drugs for Children with Cancer THE NATIONAL ACADEMIES PRESS 500 Fifth Street, N.W. 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. NO2-CO-01029 between the National Cancer Institute and the National Academy of Sciences. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the view of the organizations or agencies that provided support for this project. International Standard Book Number 0-309-09608-1 (Book) International Standard Book Number 0-309-54925-6 (PDF) Additional copies of this report are available from the National Academies Press, 500 Fifth Street, N.W., Lockbox 285, Washington, DC 20055; (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area); Internet, http://www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at: www.iom.edu. Copyright 2005 by the National Academy of Sciences. All rights reserved. Printed in the United States of America.

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Making Better Drugs for Children with Cancer THE NATIONAL ACADEMIES Advisers to the Nation on Science, Engineering, and Medicine 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. Wm. 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. Harvey V. Fineberg 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. Wm. A. Wulf are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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Making Better Drugs for Children with Cancer COMMITTEE ON SHORTENING THE TIME LINE FOR NEW CANCER TREATMENTS JOSEPH P. NEWHOUSE (Chair), Professor of Health Policy and Management, Harvard University, Boston, MA PETER C. ADAMSON, Chief, Clinical Pharmacology and Therapeutics, Pediatric Oncology, The Children’s Hospital of Philadelphia, Philadelphia, PA JAMES O. ARMITAGE, Dean, University of Nebraska College of Medicine, Omaha, NE JILL BARGONETTI, Associate Professor, Hunter College Department of Biological Sciences, New York, NY KATHLEEN M. FOLEY, Attending Neurologist, Memorial Sloan-Kettering Cancer Center and Professor of Neurology, Neuroscience & Clinical Pharmacology, Weill Medical College of Cornell University, New York, NY ALAN M. GARBER, Director, Center for Health Policy; and Center for Primary Care and Outcomes Research, Stanford University, Stanford, CA KAREN HERSEY, Senior Intellectual Property Counsel, Massachusetts Institute of Technology, Cambridge, MA CARL MORRIS, Professor of Statistics, Harvard University, Cambridge, MA RICHARD A. RETTIG, Senior Social Scientist, RAND Corporation, Alexandria, VA LOUISE B. RUSSELL, Research Professor of Economics, Institute for Health, Rutgers University, New Brunswick, NJ WILLIAM B. SCHULTZ, Partner, Zuckerman Spaeder LLP, Washington, DC JOSEPH V. SIMONE, Consultant, Simone Consulting, Dunwoody, GA BRUCE W. STILLMAN, Director, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY ELLEN STOVALL, Executive Director, National Coalition for Cancer Survivorship, Silver Spring, MD SUSAN L. WEINER, President, Children’s Cause for Cancer Advocacy, Silver Spring, MD

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Making Better Drugs for Children with Cancer National Cancer Policy Board Liaisons JOHN MENDELSOHN, President, M.D. Anderson Cancer Center, University of Texas, Houston, TX DAVID PARKINSON, Vice-President of Oncology, Amgen, Inc., Thousand Oaks, CA National Cancer Policy Board Staff Hellen Gelband, Study Director Roger C. Herdman, Director, National Cancer Policy Board Anike Johnson, Administrator

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Making Better Drugs for Children with Cancer NATIONAL CANCER POLICY BOARD JOSEPH V. SIMONE (Chair), Simone Consulting, Dunwoody, GA ELLEN STOVALL (Vice-Chair), National Coalition for Cancer Survivorship, Silver Spring, MD BRUCE W. STILLMAN (Vice-Chair), Cold Spring Harbor Laboratory, Cold Spring Harbor, NY JILL BARGONETTI, Hunter College, New York, NY TIMOTHY EBERLEIN, Washington University School of Medicine, St. Louis, MO KATHY GIUSTI, The Multiple Myeloma Research Foundation, New Canaan, CT KAREN HERSEY, Massachusetts Institute of Technology, Cambridge, MA JIMMIE C. HOLLAND, Memorial Sloan-Kettering Cancer Center, New York, NY WILLIAM G. KAELIN, Harvard Medical School, Boston, MA WILLIAM W. McGUIRE, UnitedHealth Group, Minnetonka, MN JOHN MENDELSOHN, M.D. Anderson Cancer Center, Houston, TX KATHLEEN HARDIN MOONEY, University of Utah College of Nursing, Salt Lake City, UT PATRICIA A. NOLAN, Rhode Island Department of Health, Providence, RI DAVID PARKINSON, Amgen, Inc., Thousand Oaks, CA JOHN D. POTTER, Fred Hutchinson Cancer Research Center, Seattle, WA LOUISE B. RUSSELL, Rutgers University, New Brunswick, NJ THOMAS J. SMITH, Medical College of Virginia at Virginia Commonwealth University, Richmond, VA ROBERT C. YOUNG, Fox Chase Cancer Center, Philadelphia, PA

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Making Better Drugs for Children with Cancer 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 NRC’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 report 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: William E. Evans, St. Jude Children’s Research Hospital Michael P. Link, Stanford University School of Medicine Stuart E. Siegel, Childrens Hospital Los Angeles 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 Gilbert Omenn, Harvard Medical School and Leslie Z. Benet, University of California, San Francisco, School of Pharmacy. Appointed by the National Research Council and Institute of Medicine, they were responsible for making certain that an independent examination of this report was carried out in accordance with 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.

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Making Better Drugs for Children with Cancer Acronyms and Abbreviations ALL acute lymphocytic leukemia AML acute myeloid leukemia APL acute promyelocytic leukemia BPCA Best Pharmaceuticals for Children Act BRB Biological Resources Branch CF cystic fibrosis CNS central nervous system COG Children’s Oncology Group CTEP Cancer Therapy Evaluation Program DDG Drug Development Group DES diethylstilbestrol DTP Developmental Therapeutics Program FDA Food and Drug Administration FDAMA Food and Drug Administration Modernization Act GMPs Good Manufacturing Practices HL Hodgkin’s lymphoma

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Making Better Drugs for Children with Cancer IND Investigational New Drug IOM Institute of Medicine MMV Medicines for Malaria Venture NCE new chemical entity NCI National Cancer Institute NHL non-Hodgkin’s lymphoma NIH National Institutes of Health PhRMA Pharmaceutical Research and Manufacturers of America PRB Pharmaceutical Resources Branch RAID Rapid Access to Intervention Development RAND Rapid Access to NCI Discovery Resources R&D research and development

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Making Better Drugs for Children with Cancer Contents     EXECUTIVE SUMMARY,   1      INTRODUCTION,   4      CHILDHOOD CANCERS: BACKGROUND,   5      AGENTS IN USE AND IN TESTING FOR CHILDREN WITH CANCER,   9      THE EXISTING CAPACITY FOR DEVELOPING NEW AGENTS SPECIFICALLY FOR CHILDHOOD CANCERS,   9      Developmental Therapeutics Program,   13      Drug Discovery Resources,   13      Drug Discovery Screening Services,   13      Drug Discovery Databases and Analytical Tools,   16      Access to Discovery Resources: The RAND Program,   16      Drug Development Resources,   16      Access to Drug Development Resources: RAID,   17      Access to Drug Development Resources: NCI Drug Development Group,   18      Clinical Trials: The Children’s Oncology Group,   18      PUTTING THE PIECES TOGETHER,   19      Basic Science,   19      Drug Discovery,   19

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Making Better Drugs for Children with Cancer      Drug Testing,   20      Preclinical Testing,   20      Clinical Trials,   21      What Is Missing?,   21      DELAYS IN TESTING APPROVED AGENTS IN CHILDREN,   24      Starting Pediatric Trials Earlier in the Drug Development Process,   25      Completing Pediatric Clinical Trials More Quickly,   26      THE NEED TO PRIORITIZE AGENTS FOR TESTING IN CHILDREN WITH CANCER,   27      TESTING AND LABELING OF DRUGS FOR PEDIATRIC USE,   28      The Pediatric Rule,   29      The Short-Lived 1994 Pediatric Rule,   29      The 1998 Pediatric Final Rule and the Pediatric Research Equity Act of 2003,   30      Pediatric Subcommittee of the FDA Oncologic Drugs Advisory Committee,   31      The Pediatric Incentive,   31      RECOMMENDATIONS,   34      APPENDIX A,   36      Types of Childhood Cancer,   36      Leukemias,   36      Central Nervous System Tumors and Miscellaneous Intracranial and Intraspinal Neoplasms,   37      Neuroblastoma and Other Sympathetic Nervous System Tumors,   38      Lymphomas and Other Reticuloendothelial Neoplasms,   38      Soft-Tissue Sarcomas,   39      Malignant Bone Tumors,   39      Renal Tumors,   40      Retinoblastoma,   40      Germ Cell, Trophoblastic, and Other Gonadal Neoplasms,   40      REFERENCES,   41