Case Study
Clinical Trials for Children
In whose best interest?

by Denise B. Angst and Joal M. Hill

Children, of course, are not simply miniature adults. They differ intellectually, emotionally, and physiologically. And because their ability to give meaningful consent is not fully developed, children are vulnerable to manipulation.

For that reason, some have argued that our duty to protect the young precludes enrolling them in scientific studies. Others argue, however, that a misguided attempt to protect infants and children may actually subject them to increased risk, since they will receive therapies proven effective only in adults.

Take prescription drugs marketed in the U.S., for instance. Many of these medications are used "off-label" in children. They have not been tested for safety and efficacy on children and have not been approved for use by children.

The argument continues. If children are excluded from clinical trials, effective therapies cannot be developed. This is particularly true when performing research on diseases that cause permanent damage or death prior to adulthood.

Over time, governmental authorities have recognized that special protections for children as a vulnerable population must be balanced with the need to ensure that research results are safe and effective for them. As a result, in 1998 the Food and Drug Administration mandated that children be included in clinical trials when researchers anticipate results will be used in pediatric medicine. That same year, the National Institutes of Health (NIH) ruled that, where scientifically and ethically justifiable, children must be included in all NIH conducted or supported human subject research. Pediatric clinical trials are therefore on the rise.

Yet, even if one endorses inclusion of children in human subjects research, other concerns remain. The "therapeutic misconception"—a mistaken belief that participation in research would not be recommended if the doctor did not think it would directly benefit the individual—may be more common in pediatric than in adult research. There is also debate about whether children should be exposed to high-risk studies with serious side effects if there is little likelihood of direct benefit. An additional quandary concerns the definition of what risk is acceptable for sick versus healthy children. Concerns about informed consent in pediatric research also lack clear consensus. Should the child's assent or dissent play a role in the informed consent process? Whose decision trumps when parents disagree? The following case illustrates some of these issues.

Carol and William Ward's fourteen-year-old daughter has cystic fibrosis (CF). Katie has received excellent care throughout her life, and she has maintained good grades and pursued extracurricular activities. She understands her illness, including the fact that CF patients die in young adulthood. She has every intention, however, of beating the odds with expected improvements in the treatment of CF. The Wards have been very open with Katie about her disease, but until recently never discussed participation in research.

Dr. Berger, Katie's physician, has approached the Wards about enrolling Katie in a clinical trial of a new medication. Today, they met with Dr. Berger's research coordinator, who explained the protocol and carefully went over the consent form, answering their questions and advising the family to take a few days before making a final decision. Katie was present during this meeting, and although she did not say much, she did indicate that she wants to be in the study. "Even if it doesn't help me right now," she said, "it might help other kids."

Carol and William have arranged to speak with Dr. Berger privately because they disagree about what serves Katie's best interests. William would like Katie to be in the study. He was profoundly affected by his cousin's death from CF at age sixteen and is committed to fight Katie's symptoms and find a cure in her lifetime. When Carol reminds him that the consent form plainly states, "direct benefit to participants in this research cannot be guaranteed," William responds, "But Dr. Berger would not have suggested it if he didn't think it would help Katie."

Carol focuses more on Katie's quality of life. She fears that, because of the potentially serious side effects, participation in the study will disrupt the normalcy of Katie's childhood, which she has worked hard to provide. "If Katie were sicker I might consider allowing her to participate," explains Carol, "but I don't want to compromise what health she enjoys without greater certainty that she will benefit." Carol also questions Katie's signature of assent on the consent form, which follows parental signatures. "I think it is wrong to ask a child to make that kind of decision," she says. "It ought to be up to the parents until children are eighteen or older."

Katie's father has unfortunately, albeit understandably, fallen victim to the therapeutic misconception. This misunderstanding is likely when, as in this case, the treating doctor also conducts the research. In his role as Katie's physician, Dr. Berger is indeed concerned with treatments beneficial to her. However, as a researcher he looks for results that are generally true for the study population but not necessarily effective for each participant.

Keeping the process of informed consent for the research separate from discussions about Katie's medical care would help offset the therapeutic misconception. Having the research coordinator conduct the informed consent interview is one way of making the distinction between clinical treatment and research. However, it is also important for Dr. Berger to explicitly convey that he offers participation to all qualifying CF patients and that there is, in fact, no guarantee that Katie will directly benefit.

Obtaining proper consent in this case is complicated by the fact that Katie's parents do not agree about whether she should participate, and there may be additional concerns about the extent to which Katie's desire to take part should influence the ultimate decision. According to the NIH Office of Human Research Protections (OHRP), all research on children under eighteen requires parental permission and a signed consent form. In this case the Wards must both sign that document, because the risk to Katie is more than minimal. When research presents only minimal risk to the child, or if the risk is more than minimal but there is prospect for direct benefit, only one parent's signature is required. High-risk studies with no prospect of direct benefit require special review by OHRP in addition to the usual requirements.

Although parental signatures are required on research consent forms, federal rules clearly state that this constitutes parental permission only, and does not mean that parents are consenting for their children in the same way they would consent for themselves. The rules emphasize the importance of a child's "assent," which is defined as an "affirmative agreement to participate" (45 Code of Federal Regulations 46.402). The fact that Katie wants to participate in the research does not mean that she comprehends what is involved. Therefore, her signature of assent should not be obtained until her understanding has been assessed. Because children are quite variable in their cognitive abilities, this can be a challenge, but certainly a good faith effort should be made to judge Katie's assent by standards appropriate to her age group. Moreover, federal rules clearly state that silence should not be interpreted as assent.

If these facts were different and if the Wards wanted Katie to be in the study but she objected, what should Dr. Berger do? The American Academy of Pediatrics recommends that children's dissent be respected when participation is not essential to their welfare or can be deferred without substantial risk.

Denise B. Angst is director of pediatric research at Lutheran General Children's Hospital. She is a member of the Advocate Health Care Institutional Review Board and the Advocate Systemwide Research Task Force.