Research with children raises ethical questions

Risk, informed consent top list

In recent years, changes in federal law and guidelines on federally funded research have encouraged the inclusion of children as research subjects in clinical drug trials.

Passage of the 1997 Food and Drug Administration Modernization Act (FDAMA) granted pharmaceutical companies a six-month extension of patent exclusivity for drugs tested in children. And in 1998, the U.S. Food and Drug Administration (FDA) and the National Institutes of Health (NIH) changed their policy guidelines for research grant applications to state that children "must be included in all human subjects research conducted or supported by the NIH unless there are scientific and ethical reasons not to include them."

Both measures were designed to ensure that children with life-threatening medical conditions had access to experimental drugs that might help them — and that children would not be prescribed drugs that had not been specifically tested and deemed safe for pediatric populations.

The result of the changes, however, has been a dramatic increase in the number of clinical trials in children. But, some critics say, there still are many unanswered ethical questions about the appropriate way to include children as research subjects and whether the inherent risks outweigh the potential benefits.

"Determining the ethics of a child research protocol requires attention to specific elements, in addition to the general rules for human research," wrote Benedetto Vitiello, MD, chief of the Child and Adolescent Treatment and Preventive Intervention Branch of the NIH, in a recent issue of the journal Psychopharmacology.1 "Currently, few empirical data are available to guide investigators, families, and ethics committees in the interpretation and application of the ethical principles to the reality of specific research protocols."

The challenges are particularly acute for researchers undertaking trials of psychotropic medications in children, Vitiello tells Clinical Trials Administrator.

Diagnostic criteria for many behavioral disorders are not clearly defined for pediatric patients, making it very difficult to determine which children have a true potential for benefit from trial participation. And many of the drugs to be tested present significant risks of toxicity, side effects, and possibly permanent alterations in brain chemistry.

Investigators and coordinators conducting psychopharmacological research in children must proceed cautiously, he warns.

Federal regulations concerning children

In addition to satisfying all of the ethical requirements for human research in general, research in children must also fall into one of the approvable categories outlined in subpart D (Additional Department of Health and Human Services Protections for Children Involved as Subjects in Research) of part 46 (Protection of Human Subjects) of the Title 45 Code of Federal Regulations.

The categories are as follows:

• Research with prospect of direct benefit — The study presents the probability of direct benefit to the child participant. For example, a child suffering from a condition for which the study drug offers potential for treatment. Note: The risk-benefit ratio must be favorable to the child subject in order to be approvable under this category of research. The risks posed by participation in the trial cannot outweigh other risks the child might ordinarily face either in daily life or in other, accepted, treatment protocols for his or her condition.

• Research without potential for direct benefit, but which presents only a "minor risk" to the participant — Studies aimed at studying mechanisms of action of drugs, pharmacokinetics, or metabolism do not typically offer a direct benefit to research participants. But these studies can be approvable in children as long as their participation does not expose them to "risk of harm not greater than ordinarily encountered in daily life, or during routine physical or psychological examinations or tests."

• Research without potential for direct benefit, but which presents only a "minor increase over minimal risk" — This category of research is only approvable if it: a) presents "experiences to the subjects that are commensurate with those inherent in their actual or expected medical, dental, psychological, social, or educational situations; or b) the study has the "potential to generate new knowledge" considered of "vital importance" for understanding or treating the subject’s disorder or condition.

The inherent problem with these categories is that there are no concrete definitions available for the terms "direct benefit," "minor risk," and "minimal increase over minor risk," says Vitiello.

That determination has been left up to institutional review boards, which have frequently come up with vastly different interpretations of the regulations.

"The regulations contain very good general statements, but they are just general statements," Vitiello says. "One needs to apply them to a particular project that is being reviewed by an IRB. But the IRBs sometimes disagree and have different interpretations."

For example, some IRBs would not approve a placebo-controlled clinical drug trial in children because of the potential for an individual child subject to be randomized to the placebo group and thus not end up having a potential for direct benefit, he notes.

However, many IRBs would consider the overall potential for direct benefit to some subjects, even though a portion would be given only placebos.

"Most IRBs would interpret it as there is potential for direct benefit because some children are being randomized to active treatment," Vitiello says. "It is not that there must be a certainty of benefit, but there must be a prospect of benefit. That is what the regulation requires."

It is appropriate to allow individual IRBs leeway in determining concepts such as "potential benefit" and "minor risk" on a study-by-study basis, he notes.

"The risk may change from setting to setting. For instance, in a very specialized hospital, a procedure might be considered routine and that IRB would deem it minimal risk, but at a hospital where they don’t do that procedure in high volume and they don’t have a lot of skill in doing it, it would become a greater risk," Vitiello explains. "So it is very difficult to have general guidelines that can apply to all settings throughout all the possible scenarios. It requires a lot of interpretation; that is why IRBs have a very important task in trying to make sense using these general principles."

Questionable studies

Some consumer advocates argue, however, that IRBs are inherently biased in favor of allowing research at their institutions — too willing to minimize or rationalize the potential for harm that some protocols pose to child subjects.

In the current research climate, IRBs across the country have approved "high-risk, high-impact" experiments even when those protocols lacked ethical or scientific justification, says Vera Sharav, president of the watchdog group Alliance for Human Research Protection.

Sharav published an article in a recent issue of the American Journal of Bioethics criticizing the recent trends in pediatric research.2

"As currently constituted, IRBs cannot claim to be independent," Sharav says. "IRBs are compromised by an inherent conflict of interest and their decisions bear this out. IRBs are not protecting human subjects who have no voice in the research approval process; they are protecting their institution."

As an example, Sharav cites a study by Pine and colleagues, published in 1997 in the Archives of General Psychiatry,3 that detailed a fenfluramine challenge experiment performed on 34 African-American and Hispanic boys, ages 6 to 11. The child subjects were drawn from a larger study involving 126 brothers who were deemed at risk of following in the footsteps of older brothers who were incarcerated juvenile delinquents.

The investigators stated that there was evidence of a correlation between reduced serotonin activity and aggressive behavior, and hypothesized that by measuring the boys biochemical responses to fenfluramine, a drug thought to be effective in treating some behavioral and personality disorders, they would be able to replicate earlier findings and find a predictive biological marker predisposing the children to violence.

The children were required to follow a special diet for four days, fast for 18 hours prior to the administration of the drug, and then had an IV catheter inserted in their arm, which remained in place for more than five hours, during which time blood was drawn.

The researchers were able to justify the risks and discomfort the children would bear by stating: "Research on the relationship between adverse rearing and serotonin may enhance understandings of the association between serotonin and aggression across development."

The parents of the subjects also were paid $125, and the children received $25 gift certificates to a toy store, Sharav notes.

The drug fenfluramine, she notes, carries the risk of neurotoxicity and heart valve damage.

Although federal regulations prohibit the use of children in research involving "greater than minimal risk" if there is no potential direct benefit to them, four prominent institutional review boards approved this experiment — though there was no potential for direct benefit — the subjects were exposed to a drug known to cause heart-valve damage, and the results of the study were not thought to yield information of great importance to treat a condition the subjects had, Sharav emphasizes.

Researchers argued that the boys were appropriate subjects for participation in a risk-bearing research protocol because they were considered by some to be at risk for exhibiting antisocial behavior in the future.

Even when pediatric drug trials of psychotropic medications are targeted at children with a diagnosed medical condition, the mechanisms to protect the rights of children seem hard to discern, Sharav says.

In November 2000, the National Institutes of Mental Health sponsored the multisite Preschool ADHD Treatment Study (PATS), to test the safety and short-term effects of the drug Ritalin in children ages 3 to 5 years.2

Though the study’s lead investigator admitted that ADHD is not a "well-defined" disorder in such a young age group, the government-sponsored study will recruit 312 3-year-old children into a study in which they will be given increasingly larger doses of Ritalin in order to test their tolerance of the drug.

The investigators cannot possibly provide any scientific evidence to validate an abnormal medical condition in the children being recruited, Sharav says. Yet, they will be given a drug that has the potential to permanently alter the functioning of their brain and central nervous system.

Children are not capable of understanding the risks and benefits of the projects they are asked to participate in, and, at any rate, cannot legally consent to participate. Parents, who can give consent for their children are often not privy to all of the scientific data available — and not available — to support a thoughtful decision on the part of their child.

An independent body dedicated to overseeing all research involving children, and whose makeup includes community representatives, is the only way to ensure that the rights of children are protected, Sharav argues.

What can be done

Without question, more efforts need to be made to improve protections for children involved in research. And some research protocols do expose children to dangers that cannot be completely known or guessed at, currently, says Vitiello.

But, he argues, halting controlled trials of psychotropic medications will mean that these drugs will continue to be prescribed for young children without any available data on the drugs’ safety or efficacy in those populations, he says.

"If research conducted in adults could adequately inform the pediatric use of psychotropics, there would be no need for direct experimentation in children," he says. "Unfortunately, experience has painfully taught us that this is not the case. Developmental differences between children and adults have important implications for pharmacological effects. Even though adult data are relevant to pediatric psychopharmacology, research directly in children is necessary for safe and effective use."

To better protect children, Vitiello says that more research needs to be done on how to improve informed consent procedures in pediatric trials.

"I think it is quite important because in the last few years there has been a lot of attention to providing medical information to the family, and to the child, but also to the family particularly because they make the decision ultimately," he says. "But we don’t have enough information to know whether this effort is really successful or not. Consent forms are becoming really thick and detailed, with many pages and they provide a lot of details. The question is, do people actually understand, and read, and appreciate that information. We are trying to follow up with families who have gone through that process to find out how much they understood."

More information is needed about how IRBs consider and evaluate pediatric research protocols and how they determine their definitions of "minimal risk" and "minor increase over minimal," he adds.

It’s important also for IRBs and data safety monitoring boards to take a full role in monitoring trials, Vitiello says.

Careful monitoring procedures for research subjects, with prompt rescue procedures (identification and treatment of children who deteriorate during the study) can substantially decrease the risk of participation and improve risk-benefit ratios, he states.

Clinical trial investigators and coordinators should also take the added step of developing good assent protocols to ensure that children are willing to participate. Though they cannot legally consent to participate — their parents or guardians must make that decision — children can and should give their assent, an explicit agreement to participate.

Written assent forms, with language appropriate to the child’s developmental stage are used in parallel to parental consent forms, Vitiello says. Assent should be an explicit, affirmative agreement to participate and not just the absence of an objection.

Conversely, if, during the course of a study, a child expresses a desire to stop participating, that decision should be respected.


1. Vitiello B. Ethical considerations in psychopharmacological research involving children and adolescents. Psychopharmacology 2003; 171:86-91.

2. Sharav VH. Children in clinical research: A conflict of moral values. Am J Bioethics 2003; 3:InFocus. Accessed on-line at:

3. Pine DS, Coplan JD, Wasserman GA, et al. Neuroendocrine response to fenfluramine challenge in boys. Arch Gen Psychiatr 1997; 54:839-846.