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Recent events highlight the need to clarify rules and policies for pediatric studies.
The media and the politicians had a field day recently, blasting biomedical researchers for decade-old studies that used foster children as "guinea pigs" to test AIDS drugs. Subsequent review of these programs by local and federal agencies reveals that most investigators followed research rules and ethical standards. But the ready charges of "exploitation" and "shameful" behavior leveled by observers reveal that the public is all too willing to believe the worst of clinical trial sponsors and investigators. These developments also indicate how poorly people understand the challenges involved in conducting clinical studies, especially for children.
Pharmaceutical companies are under pressure to underwrite studies to provide information on appropriate dosing and use of drugs in young patients. Yet, sponsors are subject to attack because such studies often carry risk. The clear need for special protections and precautions when studying drugs in children have generated extensive rules and procedures governing pediatric research. But policies are often unclear, and unanticipated problems can lead to difficulties.
The foster children "scandal" involved efforts to provide AIDS treatment trials for children while also collecting information on appropriate use of new AIDS cocktails for young patients. The researchers generally followed the rules for enrolling youngsters and protecting their rights, which then were based on policies adopted in 1983 by the Department of Health and Human Services (HHS) under Subpart D of the "Common Rule." These allow institutional review boards (IRBs) to approve pediatric studies that adhere to basic requirements for informed consent and oversight so long as the research does not involve "greater than minimal risk" to study participants.
If the risk is more than minimal, the IRB still may approve the study if it determines that the:
HHS also may approve studies that fail to meet these criteria if experts determine that the research addresses a serious problem affecting children's health or welfare and meets basic ethical principles. Because the AIDS trials in question offered sick children access to new antiviral treatments, the physicians organizing these studies believed that participation did provide direct benefits to subjects, despite the risks.
Carrots & Sticks: Two Ways FDA Has Encouraged Ethics
The researchers maintain that it would have been "unconscionable and unjust" to exclude children in foster care from this opportunity for life-saving treatment. They are now thoroughly disheartened at being attacked for what they consider altruistic efforts to obtain critical care for very sick youngsters. The studies included children from conventional families, and did not single out foster children as easily accessible subjects. However, many of the 2000 babies born infected with HIV each year in the early 1990s were poor, minority children and ended up in public and private child welfare agencies, including state foster care programs. The AIDS trials began at a time when scientists were starting to document the efficacy of AIDS drug cocktails for adults, so the National Institutes of Health (NIH) offered support for studies on what treatments could save the lives of young HIV-infected patients.
The point of controversy is who provided consent for foster children that participated in these trials, a question that involves complex legal issues. Children generally require parental consent to participate in clinical research, But in some cases, guardians and other parties may provide consent for children without parents, including those who are "wards of the state." The state laws that govern foster care, however, vary considerably regarding clinical research participation. Some states forbid any involvement, some have no special policies, and some allow participation with oversight by an independent advocate (see sidebar "Policies for Prisoners").
State and federal agencies are reviewing how these studies were conducted, who participated, and whether appropriate consent and oversight policies were followed. Witnesses from HHS and the medical research community testified at a hearing last month before the House Ways and Means Subcommittee on Human Resources, which has been involved with foster care issues. They said that current government policies adequately protect children in medical research, and that drug testing on children is critical to ensure proper care for sick youngsters. Members of the committee seemed to feel that further action was not warranted, but held off final judgment pending the results of investigations by HHS' Office of Human Research Protections (OHRP) and state agencies.
The allegations regarding exploitation of foster children largely ignored extensive efforts to establish and update ethical standards governing pediatric research over the past 30 years. The research community has long recognized that informed consent raises special challenges when children are involved, and that additional safeguards are needed to prevent even the appearance of unethical behavior. Various committees and research ethics boards have addressed these issues, and the growth in pediatric clinical trials over the last decade has reinvigorated these efforts.
Policies for Prisoners
Congress called on the Institute of Medicine (IOM) three years ago to review federal regulations and policies governing pediatric research and issue recommendations for change, particularly regarding informed consent, payment related to children's participation in research, and IRB responsibilities. The resulting report on "Ethical Conduct of Clinical Research Involving Children," published in March 2004, called for more detailed guidance from OHRP and the Food and Drug Administration (FDA) to help IRBs interpret rules governing children.
In particular, the IOM panel recommended clearer definition of "minimal risk," the threshold for requiring increased safeguards and heightened oversight of pediatric studies. One aim is to reduce differences between FDA and HHS policies on topics such as when parental consent might be waived. The IOM report also urged IRBs to include pediatric research experts on their panels when evaluating pediatric study protocols, and to adopt explicit written policies on reimbursement of families with children participating in research. It encouraged all government agencies and private researchers to adopt the Subpart D rules governing children, which have been implemented primarily for studies funded by NIH or that fall under FDA's purview (see sidebar "Carrots & Sticks").
The HHS Secretary's Advisory Committee on Human Research Protections (SACHRP) already was working to update and clarify terminology related to pediatric research, and moved to incorporate the IOM recommendations into its deliberations. One objective is to define more clearly when a child may participate in a study that involves more than minimal risk and offers little direct benefit. This may relate to the age of the child, whether risks are comparable to those encountered in daily life or routine medical care, and whether the study addresses conditions of such "vital importance" to warrant approval of a more risky study protocol.
At the April 2005 SACHRP meeting, the panel approved recommendations of its Part D subcommittee for clarifying a number of issues related to assessing risk in pediatric trials. SACHRP requested that HHS issue further guidance reflecting its analysis of how investigators and IRBs should deal with domestic and foreign studies that involve slightly more than minimal risk.
If a riskier study offers the prospect of direct benefit to subjects, SACHRP proposes that approval depend on whether potential harms are minimal and similar to alternative approaches. When a study offers no prospect of direct benefit but is likely to yield generalizable knowledge about the subject's disorder, an IRB should determine that risks still are fairly low, that interventions won't produce much pain or discomfort, and that the resulting information is of "vital importance" for addressing the disorder.
SACHRP also is encouraging IRBs to seek higher level review by HHS of complex studies that do not easily meet approval criteria. OHRP issued guidance last month on what protocols IRBs should submit to HHS for further review.
Jill Wechsler is the Washington editor of Applied Clinical Trials, (301) 656-4634 firstname.lastname@example.org.