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Date: March 25, 2004
Contacts: Vanee Vines, Media Relations Officer
Megan Petty, Media Relations Assistant
Office of News and Public Information
202-334-2138; e-mail <>


Policy-Makers and Researchers Should Improve Standards for,
Evaluation of Clinical Research Involving Children

WASHINGTON -- Federal rules to protect children from risky or unethical clinical research should be extended to cover all pediatric research in the public and private sectors, says a new report from the Institute of Medicine of the National Academies. Currently, the rules apply primarily to studies that are supported by the U.S. Department of Health and Human Services or regulated by the Food and Drug Administration. Some research institutions voluntarily apply them to their studies.

The report also says that the government should offer better guidance – and in more accessible formats – to clinical researchers and institutional review boards (IRBs) to help them interpret the federal rules, which are more restrictive for children than adults. In turn, IRBs – which are responsible for approving human research – should be more thorough and explicit in judging whether research involving children meets the highest ethical and scientific standards. On the whole, as clinical research has grown in scope and complexity, implementing human-research protection policies consistently and effectively has become more challenging.

"Involving more children in clinical research today will benefit the health and well-being of countless children in the future, but unlike most adults, children usually lack the legal right and the intellectual and emotional maturity to consent to research participation on their own behalf," said committee chair Richard E. Behrman, executive chair of the Pediatric Education Steering Committee of the Federation of Pediatric Organizations, Palo Alto, Calif., and clinical professor of pediatrics at both the University of California, San Francisco, and George Washington University, Washington, D.C. "Their vulnerability demands additional protections beyond those provided to mentally competent adults."

The Growth of Research Involving Children

Congress, the National Institutes of Health, and FDA have taken steps in recent years to expand pediatric research, especially studies that test the safety and efficacy of drugs for children. Infants, young children, and adolescents have been called "therapeutic orphans" because drug companies have been reluctant to do tests in these groups after medications have been approved for adults. All too often, physicians have to make the choice of not prescribing particular medications for children, or extrapolating drug doses based on data from studies with adults. However, extrapolation may lead to children getting too much or too little of a drug, or suffering adverse effects not seen with adults, the report says. And extrapolation cannot generate a reliable knowledge base for future clinical care.

The government also has taken steps to more closely review human research in general, and has even temporarily suspended federally funded studies at several leading medical centers after finding deficiencies in their research review programs. Most attention has focused on research involving adults, however. An effective and adequately funded system for protecting all human research participants is essential, but safeguarding child participants requires extra attention and resources, says the report, which the Best Pharmaceuticals for Children Act requested.

A Look at Regulatory Frameworks; Interpreting Risks

HHS published in 1973 the first general regulations on protecting human participants in research, often referred to as the "Common Rule." These regulations require that risks to participants be minimized; risks be outweighed or balanced by anticipated benefits; research participants be equitably recruited; and investigators obtain informed consent from them. Ten years later, HHS published the first regulations specifically governing federally supported or conducted research involving children. These rules define categories of research that may be approved. Under most circumstances, they call for parents or guardians to grant permission before children under age 18 can participate in research. And they say that, when appropriate, researchers should seek from children themselves their agreement to participate in clinical studies. FDA has similar rules for drug studies and other human research that it regulates.

The report says difficulties that researchers encounter when implementing federal regulations usually can be traced to three underlying problems: insufficient guidance about interpretation and implementation of regulations; inadequate attention by scientific investigators and IRBs to special rules for pediatric research; and the intrinsically subjective nature of the criteria for evaluating proposed research, especially criteria concerning the degree of risk.

Categorizing and evaluating risks are among the most challenging tasks for reviewers of studies involving children, the report notes. The committee was asked to consider the regulatory definition of "minimal risk" in the context of such studies. Fewer restrictions are placed on pediatric research that involves minimal risk. In general, federal policies say the term means that the probability and magnitude of harm or discomfort anticipated in research are not greater than what people ordinarily encounter in their daily lives or during routine physical or psychological examinations and tests.

In weighing possible harm from pediatric research protocols, reviewers should compare potential research risks with those commonly encountered by healthy, average children, the committee concluded. It is not acceptable for research to expose children to higher levels of risk simply because they are already imperiled by illness, unsafe neighborhoods, or other aspects of their daily lives.

IRBs should make explicit determinations about each regulatory criterion required for the approval of research protocols involving children, and document those decisions, the report adds. To assist review boards and investigators, HHS's Office for Human Research Protections (OHRP) should use the committee's report to develop clearer guidance and examples.

Understanding and Agreeing to Participation

Obtaining informed permission from parents is a critical protection for children involved in research. Scientific evidence is limited regarding the age at which children can meaningfully take part in discussions and decisions about their own participation in research. But children as young as 7 can understand basic information about what will happen in a study, the report says. The process for seeking consent from older adolescents should be very similar to that for adults.

HHS policies allow parental permission to be waived when it is not a reasonable requirement to protect children – for example, in cases of neglect or abuse – and when other safeguards are provided. FDA should change its rules to allow parental waivers, and its rules should be consistent with the policy on HHS-supported research, the committee said. In the vast majority of cases, however, it is best for parents to be involved in decision-making

Discussions with parents and, when appropriate, children should allow sufficient time for questions and explanations of research protocols, the report emphasizes. In addition, IRBs should adopt explicit written policies on payments for research participation. It is appropriate to reimburse families for expenses related to research, such as parking fees at research facilities, and to give tokens of appreciation. But it is never acceptable to offer higher payments for enrolling children in more risky research. To broaden access to research participation among all socioeconomic groups, investigators also should consider scheduling research visits so that the hours do not interfere with parents' job or family responsibilities.

Regulatory Compliance and Quality Improvement

A dearth of information about pediatric research and protection programs for research involving children makes it difficult to adequately describe how well federal regulations are working, and impedes efforts to improve policies and practices, the report says. HHS should develop and carry out a plan for collecting and reporting data on pediatric research and its oversight. Plus, local and national professional organizations and research institutions should voluntarily promote quality-improvement efforts in the design, review, and conduct of clinical research.

IRBs that review protocols for pediatric clinical studies should include at least three members with expertise in children's health care and research, psychosocial dimensions of child health, and pediatric research ethics – or the boards should bring in people with this knowledge, the committee said. And IRBs should educate reviewers and investigators about their ethical and legal obligations to protect child participants in research. Educational materials and policy guidance should be easy to find and understand.

Federal officials should play key roles in improvement efforts. OHRP, FDA, NIH, and other relevant agencies should provide review boards and investigators with comprehensive, consistent, and easily accessible documents that explain how to interpret and apply federal regulations, the report says. Likewise, federal agencies should cooperate in the continued development of education programs for researchers, IRBs, pediatric academic societies, and other groups at all levels.

The report was sponsored by the U.S. Department of Health and Human Services. The Institute of Medicine is a private, nonprofit institution that provides health policy advice under a congressional charter granted to the National Academy of Sciences. A committee roster follows.

Pre-publication copies of The Ethical Conduct of Clinical Research Involving Children are available from the National Academies Press; tel. 202-334-3313 or 1-800-624-6242 or on the Internet at The cost of the report is $57.00 (prepaid) plus shipping charges of $4.50 for the first copy and $.95 for each additional copy. Reporters may obtain a copy from the Office of News and Public Information (contacts listed above).

[ This news release and the report are available at ]

Board on Health Sciences Policy

Committee on Clinical Research Involving Children

Richard E. Behrman, J.D., M.D. (chair)
Clinical Professor of Pediatrics
University of California, San Francisco, and George Washington University, and
Education Steering Committee
Federation of Pediatric Organizations
Palo Alto, Calif.

Arthur L. Beaudet, M.D.
Henry and Emma Meyer Professor and Chair
Department of Molecular and Human Genetics
Baylor College of Medicine

Russell W. Chesney, M.D.
Le Bonheur Professor and Chair
Department of Pediatrics
Le Bonheur Children's Hospital, and
Center for Pediatric Pharmacokinetics and Therapeutics
University of Tennessee

Francis Sessions Cole III, M.D.
Vice Chair and Park J. White M.D. Professor of Pediatrics, and
Professor of Cell Biology and Physiology
Washington University School of Medicine
St. Louis

Deborah L. Dokken, M.P.A.
Family Health Care Advocate and Consultant
Washington, D.C.

Celia B. Fisher, Ph.D.
Director, Center for Ethics Education,
Marie Ward Doty University Chair and
Professor of Psychology
Fordham University
Bronx, N.Y.

Angela R. Holder, J.D., LL.M.
Professor of the Practice of Medical
Center for the Study of Medical Ethics and Humanities
Duke University Medical Center
Durham, N.C.

Loretta M. Kopelman, Ph.D.
Chair and Professor
Department of Medical Humanities
Brody School of Medicine
East Carolina University
Greenville, N.C.

Susan Z. Kornetsky, M.P.H., C.I.P.
Director, Clinical Research Compliance
Department of Clinical Investigation
Children's Hospital Boston

Robert M. Nelson, M.D., Ph.D.
Associate Professor of Anesthesia and Pediatrics
University of Pennsylvania and
Children's Hospital of Philadelphia

David G. Poplak, M.D.
Elise C. Young Professor of Pediatric Oncology and Head of Hematology/Oncology
Department of Pediatrics
Baylor College of Medicine, and
Cancer Center
Texas Children's Hospital

Bonnie W. Ramsey, M.D.
Director, Cystic Fibrosis Therapeutics Development Network Coordinating Center
Children's Hospital Regional Medical Center, and
Professor of Pediatrics
School of Medicine
University of Washington

Diane Scott-Jones, Ph.D.
Professor of Psychology
Boston College
Chestnut Hill, Mass. Stephen P. Spielberg, M.D., Ph.D.
Vice President of Health Affairs and Professor of Pediatrics and of Pharmacology and Toxicology
Dartmouth College, and
Dartmouth Medical School
Hanover, N.H.


Marilyn J. Field, Ph.D.
Study Director