ETHICAL CONDUCT OF CLINICAL RESEARCH INVOLVING CHILDREN
Marilyn J. Field and Richard E. Behrman, Editors
THE NATIONAL ACADEMIES PRESS
Washington, D.C.
www.nap.edu
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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. N01-OD-4-2139, TO #115 between the National Academy of Sciences and the National Institute of Child Health and Development and also the U.S. Food and Drug Administration. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the view of the organizations or agencies that provided support for this project.
Library of Congress Cataloging-in-Publication Data
Ethical conduct of clinical research involving children / Marilyn J. Field and Richard E. Behrman, editors ; Committee on Clinical Research Involving Children, Board on Health Sciences Policy, Institute of Medicine of the National Academies.
p. ; cm.
Includes bibliographical references and index.
ISBN 0-309-09181-0 (hardcover)
1. Pediatrics—Research—Moral and ethical aspects. 2. Human experimentation in medicine.
[DNLM: 1. Biomedical Research—ethics—Child. 2. Human Experimentation. 3. Research Subjects. W 20.5 E838 2004] I. Field, Marilyn J. (Marilyn Jane) II. Behrman, Richard E., 1931- III. Institute of Medicine (U.S.). Committee on Clinical Research Involving Children.
RJ85.E85 2004
174.2′8—dc22
2004008514
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COMMITTEE ON CLINICAL RESEARCH INVOLVING CHILDREN
Richard E. Behrman (Chair), Executive Chair,
Education Steering Committee, Federation of Pediatric Organizations, and
Clinical Professor of Pediatrics,
University of California, San Francisco, and George Washington University, Washington, D.C.
Arthur L. Beaudet, Henry & Emma Meyer Professor and Chair,
Department of Molecular & Human Genetics, Baylor College of Medicine
Russell W. Chesney, Le Bonheur Professor and Chair,
Department of Pediatrics, Le Bonheur Children’s Hospital and the University of Tennessee;
Co-director,
Center for Pediatric Pharmacokinetics and Therapeutics, University of Tennessee, Memphis
Francis Sessions Cole III, Park J. White M.D. Professor and Vice Chair,
Department of Pediatrics, and
Professor of Cell Biology and Physiology,
Washington University School of Medicine, and
Director,
Division of Newborn Medicine, St. Louis Children’s Hospital
Deborah L. Dokken, Family Health Care Advocate,
Consultant in Family-Centered Care
Celia B. Fisher, Marie Ward Doty University Chair, Director
Center for Ethics Education, and
Professor of Psychology,
Fordham University
Angela R. Holder, Professor of the Practice of Medical Ethics,
Center for the Study of Medical Ethics and Humanities, Duke University Medical Center
Loretta M. Kopelman, Professor and Chair,
Department of Medical Humanities, Brody School of Medicine, East Carolina University
Susan Z. Kornetsky, Director,
Clinical Research Compliance, Department of Clinical Investigation, Children’s Hospital Boston
Robert M. Nelson, Associate Professor of Anesthesia & Pediatrics,
University of Pennsylvania School of Medicine and The Children’s Hospital of Philadelphia
David G. Poplack, Elise C. Young Professor of Pediatric Oncology and Head,
Hematology/Oncology Section, Department of Pediatrics, Baylor College of Medicine, and
Director,
Texas Children’s Cancer Center, Houston, Texas
Bonnie W. Ramsey, Director,
Cystic Fibrosis Therapeutics Development Network Coordinating Center, Children’s Hospital Regional Medical Center, and
Professor of Pediatrics,
University of Washington School of Medicine
Diane Scott-Jones, Professor of Psychology,
Boston College
Stephen P. Spielberg, Dean,
Dartmouth Medical School,
Vice President for Health Affairs,
Dartmouth College,
Professor of Pediatrics and of Pharmacology and Toxicology,
Dartmouth College
Expert Advisor
ALAN R. FLEISCHMAN, Senior Vice President,
The New York Academy of Medicine
Liaisons to Institute of Medicine and National Research Council Boards
Board on Health Sciences Policy:
DANIEL R. MASYS, Director,
Human Research Protections Program, and
Professor of Medicine,
School of Medicine, University of California, San Diego
Board on Children, Youth, and Families:
ELENA O. NIGHTINGALE,
Scholar-in-Residence, Institute of Medicine
National Cancer Policy Board:
SUSAN L. WEINER, President,
The Children’s Cause, Inc.
Committee Consultants
AMY T. CAMPBELL, Senior Instructor,
Department of Psychiatry and Division of Medical Humanities, University of Rochester Medical Center
ERIC D. KODISH, Director,
Rainbow Center for Pediatric Ethics, Rainbow Babies and Children’s Hospital
MYRA BLUEBOND-LANGNER, Distinguished Professor of Anthropology,
Rutgers University and
Director,
Rutgers University Center for Children and Childhood Studies
Study Staff
MARILYN J. FIELD, Study Director
MARGARET A. MCCOY, Research Assistant
PERRY J. LUKSIN, Senior Project Assistant
Board on Health Sciences Policy Staff
ANDREW POPE, Director,
Board on Health Sciences Policy
TROY PRINCE, Board Assistant
Contents
BOXES, FIGURES, AND TABLES
Boxes
S.1 |
Summary of Categories of Research Involving Children That Are Approvable Under Subpart D of 45 CFR 46, |
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S.2 |
Questions Parents May Want to Ask When Considering Their Children’s Participation in Clinical Research, |
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S.3 |
Key Responsibilities of Investigators for the Ethical Conduct of Clinical Research Involving Infants, Children, and Adolescents, |
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S.4 |
Key Ethical and Legal Responsibilities of IRBs and Research Institutions Involved with Clinical Research That Includes Infants, Children, and Adolescents, |
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1.1 |
Ethical Principles for Human Research Identified in the Belmont Report, |
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1.2 |
Summary of Discussion of Pediatric Research in the 1950s, |
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3.1 |
General Criteria That Research Must Meet to Be Approved Under Federal Regulations, |
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3.2 |
Definitions in Subpart D That Have Also Been Adopted by the FDA, |
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3.3 |
Research Involving Children That DHHS Is Permitted to Conduct or Support, |
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3.4 |
General Responsibilities of Data and Safety Monitoring Boards and Data Monitoring Committees, |
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4.1 |
Determinations Related to Research Risks and Potential Benefits Required by Regulation for Federally Supported, Conducted, or Regulated Research Involving Children, |
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4.2 |
Guidelines for Considering Risk and Risk Minimization in Research That Includes Children, |
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5.1 |
Selected Regulatory Provisions for Informed Consent That Also Apply Generally to Parental Permission for a Child’s Participation in Research, |
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5.2 |
Questions Parents May Want to Ask When Considering Their Child’s Participation in Clinical Research, |
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5.3 |
Questions and Information for Investigators Seeking Waiver of Parental Permission for Adolescent’s Participation in Research, |
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7.1 |
Potential Data for a Federal Database on the System for Protecting Adult and Child Participants in Research, |
7.2 |
Examples of What Might Be Included in a Quality Assurance Database Related to Studies Involving Infants, Children, and Adolescents, |
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8.1 |
Key Responsibilities of Investigators for the Ethical Conduct of Clinical Research Involving Infants, Children, and Adolescents, |
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8.2 |
Key Ethical and Legal Responsibilities of IRBs and Research Institutions Involved with Clinical Research That Includes Infants, Children, and Adolescents, |
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8.3 |
Suggested Elements of IRB and Research Institution Guidance on Clinical Research Involving Infants, Children, and Adolescents, |
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8.4 |
Example of Protocol Checklist for Investigators That Highlights Requirements for IRB Approval of Research Involving Children, |
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8.5 |
Key Responsibilities of Federal Agencies for the Ethical Conduct of Clinical Research Involving Infants, Children, and Adolescents, |
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8.6 |
Examples of Protocols Referred for Review by the Secretary of DHHS Under 45 CFR 46.407, by Year of Referral and Institution, |
Figures
1.1 |
Simplified representation of a system for protecting human research participants (2002, 2003), |
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4.1 |
Algorithm for making assessments of research protocols as required by 45 CFR 46.404-407 and 21 CFR 50.51-54 (2003), |
Tables
4.1 |
Common Research Procedures by Category of Risk (2002), |
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5.1 |
Developmental Differences Influencing a Child’s Participation in Research (1999), |
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8.1 |
Example 1—Variability in IRB Approval of a Multicenter Research Protocol That Includes Children, |
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8.2 |
Example 2—Variability in IRB Approval of a Multicenter Research Protocol That Includes Children, |
B.1 |
State Education-Related Provisions for Research with Children and Adolescents (in School Settings) (2003), |
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B.2 |
Age of Majority (2003), |
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B.3 |
Emancipation Conditions (2003), |
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B.4 |
Mature Minor Provisions (2003), |
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B.5 |
Minor Consent for Certain Conditions/Disorders (2003), |
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B.6 |
Regulation of Research with Children and Adolescents in State Custody: Responses from Child Welfare or Social Services Personnel (2003), |
Preface
Those who care about and for children currently face adilemma. We want children to benefit from the dramatic and accelerating rate of progress in medical care that is fueled by scientific research. At the same time, we do not want to place any children at risk of being harmed by participating in such research, even though their very involvement may be essential to improving the overall medical care of children. We also want to discourage research that is of minimal value. The concern is how best to balance these potentially conflicting objectives. Five important considerations should guide us as we seek to resolve our dilemma.
First, because of the inherent vulnerabilities arising from their immaturity, infants, children, and adolescents need additional protections beyond what is provided to competent adults when they participate in research. This principle underlies all others.
Second, the design of the research required to improve the health and well-being of infants, children, and adolescents must consider their physical, cognitive, emotional, and social development. Similarly, when children of any age become participants in such research, the protections provided must be appropriate to their stages of development.
Third, sharing in the advances in medical care for this vulnerable group includes a special emphasis on protecting them from harm caused by standard medical procedures and treatments based on research with adults when the benefits and risks for children of different ages have not been established through scientific research involving these populations. Except
when it is not feasible or reasonable, research with animals, and adults should precede studies with children to minimize research risks.
Fourth, the system for protecting infants, children, and adolescents involved in research, while ensuring such protection, should not unreasonably impede research that may benefit them. The contribution of rules and regulations to desired outcomes as well as possible unintended negative consequences should be considered.
Finally, all of those responsible for research involving infants, children, and adolescents need to understand the special ethical issues that are relevant to the conduct of such research and the additional protection that must be provided. In certain cases, ethical standards will preclude some otherwise desirable research.
Overall, a satisfactory resolution of our dilemma can be achieved. Children involved in research can be appropriately protected as well as share fairly in the increasing benefits of biomedical science. This report suggests ways to balance sometimes conflicting objectives in ways that will contribute to children’s health and well-being now and in the future.
Richard E. Behrman, M.D., J.D.
Committee Chair
Acknowledgments
The committee and staff are indebted to a number of individuals and organizations for their assistance in the development of this report. The committee learned much through workshops and public meetings it organized to obtain information and perspectives from groups and individuals knowledgeable and concerned about research involving infants, children, and adolescents. Appendix A includes the meeting agendas and participant lists and also cites the organizations that provided written statements to the committee.
Special thanks go to Carolyn Brokowski, Maureen and Joseph Lilly, Joan and Sarah Lippincott, Andrell Vaughn, and Lise Yasui, who were willing to share their experiences with the committee. Consultants Eric Kodish and Myra Bluebond-Langner provided valuable guidance in addition to their presentations to the committee. The committee also appreciates the contributions of Amy Campbell, who prepared the background paper on state policies relevant to children’s participation in research. Mark Green, a Greenwall Foundation Fellow who served as a summer intern, assisted in developing the discussion of pediatric drug research.
A number of people at the Office for Human Research Protections (OHRP), the Food and Drug Administration (FDA), and the National Institute of Child Health and Human Development (NICHD) contributed to this study. Duane Alexander and Gilman Graves at NICHD, which sponsored this study, were unfailingly constructive in their support for the committee’s work. Michael Carome, Leslie Ball, and Kate Gottfried at OHRP provided useful information about the office’s policies, practices,
and databases. David Lepay, Rosemary Roberts, and Susan Cummins at FDA helped the committee understand FDA policies on the protection of human participants in research and also relevant policies involving other aspects of the agency’s mission. In addition, the committee appreciates the information and insights offered by David Wendler and Benjamin Wilfond at the Department of Clinical Bioethics of the National Institutes of Health Clinical Center.
Meetings with researchers and institutional review board members and administrators at the Children’s Hospital of Philadelphia and Children’s National Medical Center (arranged with much appreciated assistance from John Sever) helped provide additional perspective on the practical realities of administering federal and institutional policies to protect child participants in research. Allison Clarke-Stewart and Virginia Allhusen from the University of California, Irvine, generously shared the knowledge and insights into long-term research gained through their Study of Early Child Care and Youth Development. Among the many others who helped the committee clarify issues, find important information, or otherwise complete its work are Laura Rodriguez, Ellen Wright Clayton, Marion Broome, Scott Powers, George Retsch Bogart, Lisya VanHousen, Adam Fried, Suzanne Rivera, Steven Joffe, Rosemary Galvin, Juliette Schlucter, Jane Burns, Judith Argon, Lea Ann Hansen, James Chamberlain, Jackie Moran, and Stacey Berg.
Many within the Institute of Medicine were, as usual, helpful to the study staff. The committee would especially like to thank Jessica Aungst, Natasha Dickson, Judy Estep, Alex Ommaya, Sally Stanfield, Bronwyn Schrecker, and Jennifer Bitticks.
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 Report Review Committee of the National Research Council (NRC). 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. The committee wishes to thank the following individuals for their review of this report:
MARION E. BROOME, University of Alabama at Birmingham
ELLEN WRIGHT CLAYTON, Vanderbilt University
RONALD E. DAHL, University of Pittsburgh Medical Center
REBECCA S. DRESSER, Washington University in St. Louis
ABIGAIL ENGLISH, Center for Adolescent Health & the Law
PAUL L. GELSINGER, Citizens for Responsible Care and Research
PAUL W. GOEBEL, Chesapeake Research Review, Inc.
DALE HAMMERSCHMIDT, University of Minnesota
GREGORY L. KEARNS, Children’s Mercy Hospitals and Clinics, University of Missouri–Kansas City
MICHELE D. KIPKE, University of Southern California and Childrens Hospital Los Angeles
JEFFREY L. PLATT, Mayo Clinic
GREGORY H. REAMAN, Children’s Oncology Group and George Washington University
LISE YASUI, Children’s Oncology Group and New Approaches to Neuroblastoma Therapy Consortium
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 THOMAS F. BOAT, Cincinnati Children’s Hospital Medical Center and University of Cincinnati, and BERNARD LO, University of California, San Francisco. Appointed by the NRC Report Review Committee, 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.