Determining the Appropriateness of Including Children in Clinical Research: Title and subTitle BreakHow Thick Is the Ice?

There are multiple reasons to mandate the inclusion of children in clinical research, yet concomitant ethical tensions related to this research must be satisfied. In simple terms, for medical practice to be based on sound evidence, and for all children to receive optimal medical care, research that includes children is vital.^{1 - 3} However, as a group, children are inherently vulnerable in several respects and the ethical justification for this research rests on thin ice. Consequently, there must be careful scientific and ethical sanction before moving forward with proposed research with children.

Three pillars support the rights and interests of all persons enrolled in clinical research, including investigators and sponsors, institutional review boards (IRBs), and informed consent by participants. Investigators and sponsors are responsible for designing and conducting ethically sound research.⁴ Institutional review boards are charged with oversight of research through prospective and continuing review to ensure that the risks to participants are minimized and that these risks are reasonable relative to any potential benefits to the participants and the knowledge to be gained. Additionally, IRBs are expected to ensure that the selection of participants is appropriate and provisions for obtaining informed consent are in place.⁵ Informed consent helps to meet the ethical obligation of respecting individuals who are potential participants and authorizes their participation in research.⁶

These pillars are important for all research; however, when reviewing and conducting research with children, the processes of review and informed consent must be modified. In particular, IRBs are required by US federal regulations to make careful assessments of risk and potential benefits of research before approving it.⁷ Certain research that poses more than a minor increase over minimal risk without offsetting benefit is not approvable. In addition, these determinations of risks and benefits shape the contours of the consent process for research. In general, to meet the ethical mandate of respecting persons, parental permission and assent of children provides a substitute for informed consent because most children are not capable of providing valid informed consent. Nonetheless, from an ethical perspective this approach is arguably incomplete because the very act of providing permission is not the same as when research participants themselves authorize participation in research through informed consent.

In this issue of THE JOURNAL, 2 groups of investigators report results from their studies on the ethical oversight of research involving children. These empirical studies help to assess how well the specific approaches used to evaluate and protect children in research are working.

Shah and colleagues⁸ presented a series of hypothetical research vignettes to IRB chairpersons and asked them to categorize the risks involved if the research participant was a healthy 11-year-old. The authors found marked variability in the risk determinations, which could either subject children to undue risk or prevent appropriate research from going forward. It is important to note that the respondents were the chairs of the IRBs who may not have had any special expertise in pediatrics and the determination of risk categories was based on their independent assessments rather than the group process, which is assumed in IRB review. By federal regulation, full IRB review must consist of deliberation about proposed research at a convened meeting among a diverse group of individuals.⁵ Similarly, the decisions made about risk were based on hypothetical vignettes, not actual research protocols.

Despite these departures from the realities of IRB review, the variability documented is consistent with other observations⁹ and warrants attention. Whether the variability observed will persist in the wake of a series of interventions, such as new educational requirements for those involved in clinical research,¹⁰ certification of IRB professionals,¹¹ and the accreditation of human research participant protection programs,^{12 - 13} is unclear. However, variability in IRB review is not necessarily bad, provided the decisions of individual IRBs are ethically acceptable and these decisions do not create unmanageable conditions for research conducted at different sites that occur under the purview of different IRBs. The authors suggest that to inform and improve their work, IRBs need guidance on applying the federal rules for research participation and data relating to the true risks of medical procedures and the risks encountered in daily life. It is reasonable to hypothesize that this information could enhance IRB deliberations.

In the second article, Kodish and colleagues¹⁴ investigated how randomization was explained to parents whose children were candidates for enrollment in pediatric leukemia treatment trials. These investigators audiotaped and observed the consent conference at which parents were asked to enroll their child in a clinical trial. Within 48 hours of the consent conference, a parent was interviewed to ascertain his or her understanding of treatment assignment by randomization.

The investigators report that they did not observe or audio record an explanation of randomization in 17% of the consent conferences. It is possible that randomization was explained at some other point during the complex and emotionally arduous process of diagnosis, referral, recruitment, and evaluation for a clinical trial. However, failure to provide a straightforward description of randomization when securing the parents' permission for trial enrollment, even if it would be redundant to do so, is surprising. After all, random assignment is a central feature that distinguishes clinical trial participation from routine clinical care.

Beyond the issue of disclosure, the parents' ultimate understanding of the meaning of randomization is important. The authors report that "50% of the parents interviewed did not understand randomization." More accurately, however, based on the methods used by the investigators, 50% of the parents did not seem to understand that their child's treatment would be selected by random assignment. From the standpoint of providing parental permission, this finding is much more powerful. Paradoxically, disclosure did not correlate with understanding, suggesting how complicated the consent process for this type of research can be.

The authors offer the possibility that the parents may hold a "therapeutic misconception," erroneously believing that the research aspects of a trial (such as random assignment) are being performed with therapeutic intent.¹⁵ Although therapeutic misconception may account for the investigators' observations, other findings, such as 18% of parents not knowing they could refuse participation and 20% not knowing they could withdraw their child from the research at any time, suggest the need not only for more explicit disclosure but also explicit assessment of understanding when obtaining permission for participation in clinical research. The possibility of a therapeutic misconception is not an excuse for the lack of explicit explanation during the consent process. Although clinical trials in pediatric oncology typically enjoy higher rates of patient participation than that found in adult oncology trials,¹⁶ it is critical that such participation reflect the realities of clinical research, including the fact that treatment is randomly assigned.

Other results reported by Kodish et al¹⁴ warrant careful follow-up and evaluation. Of particular concern is that parents of lower socioeconomic status were less likely to understand the meaning of random assignment compared with parents of higher socioeconomic status. In addition, having a nurse present at the consent conferences correlated with better understanding of randomization.

A comprehensive report of the Institute of Medicine on the system used to protect research participants noted that "The absence of sufficient data regarding human research activities significantly impedes the thorough examination of system performance."¹⁷ The data reported in these 2 articles published in this issue of THE JOURNAL^{8 ,14} are a welcome addition to the ongoing discourse concerning the ethics of research. It would be fortuitous if these data could be incorporated by the Institute of Medicine Committee on Clinical Research Involving Children as it meets its charge to address some of the unanswered conceptual and policy questions regarding this research.¹⁸ At minimum, these data provide an important foundation for needed discussion and deliberation regarding the efficacy of the current system to protect children as research participants and are useful for measuring the thickness of the ice on which the ethical justification for this research rests. After all, discussions based on data offer a substantial improvement compared with those based solely on personal, even if expert, experience.

Despite the limitations of their descriptive data, the authors of these 2 articles^{8 ,14} offer some reasonable recommendations for improving clinical research. These recommendations would have even more utility if they were subjected to rigorous testing, preferably with randomization when ethically permissible to do so. As in clinical medicine and in investigations of other important questions in informed consent,¹⁹ it is important to "raise the bar" on what evidence is acceptable to determine the most effective approaches.²⁰

The time is ripe for evidence-based ethics. Similar to evidence-based medicine, an evidence-based ethics would emphasize the importance of data in informing discussions and decision-making about the ethical issues inherent to clinical medicine and research. Moreover, data derived by using more rigorous methods would be privileged in these venues. Of course, such data alone are not capable of making ethical choices but they can go a long way toward informing them. Such informed choices promise to establish a more solid foundation on which research with human participants may proceed.