The central tenet of pediatric research ethics is that it should not pose greater than minimal risk (or the risks of daily life) to participants, and, when greater risk cannot be avoided in research, there must be a commensurate potential for direct benefit to pediatric participants or benefit to an identifiable class of children. Only in extraordinary circumstances can children and their parents be asked to take on greater risk with no prospect of direct benefit. Accordingly, the Presidential Commission for the Study of Bioethical Issues (the Bioethics Commission) concluded that, in the context of pediatric medical countermeasure (MCM) research before a bioterrorism attack (i.e., “pre-event” MCM research), studies must generally pose no more than minimal risk. The Bioethics Commission concluded that pre-event pediatric MCM research posing greater than minimal risk can only proceed after national-level review and approval by the Secretary of Health and Human Services (the Secretary).
Although the regulatory provision for national-level review of pediatric research has been in place for more than 30 years, it has been used only 14 times, and experts convened to assist the Secretary in evaluating those protocols have consistently noted uncertainty in applying the regulatory criteria, which, in part, call for compliance with “sound ethical principles” without specifying what these are. The criteria for national-level review provide fundamental baseline protections for those children involved in approved protocols while permitting sufficient flexibility for the Secretary to exercise discretion in reviewing research, allowing her to tailor the review for a given context. This flexibility is important to ensure that essential research can go forward, but it leaves reviewers with few guidelines about what is otherwise a unique form of review.
Recognizing these difficulties, the Bioethics Commission developed a rigorous ethical framework to guide national-level review of pre-event pediatric MCM research. Of note, the Bioethics Commission found certain conditions in the context of pre-event pediatric MCM research merited stricter research limitations than otherwise permitted by the regulatory criteria for national-level review. For pre-event pediatric MCM research, the proposed framework requires that any approved protocol present no greater than a minor increase over minimal risk, despite the absence of a risk limitation for national-level review in other circumstances.
Other considerations outlined by the Bioethics Commission derive from the circumstances requiring national-level review more generally, rather than solely the considerations of MCM-related pediatric research. For instance, the Bioethics Commission concluded that, given that children in research meriting national-level review (i.e. greater than minimal risk with no prospect of direct benefit) participate primarily for the benefit of other children and society more broadly, justice requires that care and compensation be guaranteed for any research-related injury to a child participant. In addition, the Bioethics Commission concluded that equitable and appropriate access to any successfully tested intervention must also be guaranteed prior to the initiation of research.
The ethical framework, laid out below, provides additional specification of national-level review criteria, clarifying, specifying, and emphasizing the three regulatory criteria that govern national-level review. The Bioethics Commission clarified when a protocol offers a “reasonable opportunity” to address a “serious problem” affecting the health and welfare of children, stating that the research ”must present an opportunity to learn about a specific MCM candidate that might be useful in protecting or treating children exposed to a serious threat,” defined by consequences of exposure that are “life-threatening, permanently disabling, debilitating, or similarly grave” from an event that is “relatively likely, as opposed to remote.” The Bioethics Commission also specified a rigorous set of conditions to determine if research would be conducted in accordance with “sound ethical principles.” These conditions limit the degree of risk that may be posed by any protocol, account for essential concerns in research design, establish requirements for post-research distribution, treatment and compensation for research-related injury, and call for community engagement and transparency and accountability. Finally, the Bioethics Commission emphasized that researchers and persons independent of the research must communicate the heightened risks and uncertainties involved in MCM research so parents can provide informed permission and children can provide meaningful and developmentally appropriate assent.
Although the framework was developed to assess pediatric MCM research, it encompasses many of the considerations required for any national-level review. Expert panels might find that it presents useful guidance as they evaluate non-MCM pediatric protocols.