Prospect of Direct Benefit in Pediatric Trials: Practical Challenges and Potential Solutions

Abstract

Clinical research in pediatric patients is necessary to develop safe and effective medicines for children. US Food and Drug Administration (FDA) human subject protection regulations (21 Code of Federal Regulations 50, subpart D) require that, with limited exceptions, research in children that exceeds a defined level of risk must offer a prospect of direct benefit to the individual child that is sufficient to justify those risks. Growing attention to the merits of initiating pediatric clinical trials earlier in the drug and biological product development process has led the FDA to look more closely at the meaning of the regulatory term prospect of direct benefit. In collaboration with the FDA, the Duke-Margolis Center for Health Policy convened a workshop with leading experts in the fields of biomedical ethics, pediatric clinical research, and pediatric product development, as well as patient representatives, to discuss the FDA’s approach to characterizing prospect of direct benefit in the context of scientific advances in product development. Workshop topics included the extrapolation of adult efficacy data to children, use of nonclinical models of disease, use of modeling and simulation to support pediatric dosing, and reliance on biomarkers and surrogate end points in clinical research. Discussion from the workshop is provided herein to communicate the challenges that investigators, industry sponsors, regulators, and institutional review boards face when evaluating pediatric research and to outline several approaches to maximize prospect of direct benefit, minimize unnecessary risks and burden, and facilitate timely access to safe and effective medicines for children.

Enrollment of Pediatric Patients in COVID-19 Interventional Trials

“…Nonetheless, there is growing recognition of the merits and feasibility of initiating pediatric trials earlier. Recent methodologic advancements in pediatric extrapolation, pharmacokinetic and pharmacodynamic modeling, and adaptive trial designs, can be applied to support earlier initiation of pediatric trials . As part of planning efforts for future public health responses, appropriate trial designs should be identified to prioritize earlier and broader inclusion of children in clinical trials to ensure timely access to therapies.…”

Anakinra Pilot – a clinical trial to demonstrate safety, feasibility and pharmacokinetics of interleukin 1 receptor antagonist in preterm infants

“…We considered dose selection a crucial element of this trial, both for safety reasons but also to ensure prospect of direct benefit to participants. Broadly accepted ethical standards for clinical research in children require potential for direct benefit if participation leads to more than minimal risk ( 37 ), and thus Phase 1 dose-finding and pharmacokinetic ‘ADME’ (absorption, distribution, metabolism and elimination) studies are not considered appropriate. Moreover, whilst in the range of auto-immune and auto-inflammatory conditions, for which anakinra is indicated, dose is titrated to clinical response, no such clinical measure for titration exists for the indication of early-life inflammation in premature infants.…”

Opportunities and challenges of pharmacovigilance in special populations: a narrative review of the literature

“…37 38 In addition, the FDA human subject protection regulations clearly stipulate that pediatric clinical trials can only be conducted when the benefits outweigh the risks, or there is sufficient evidence to prove that the risks are reasonable and provide the prospect of direct benefit to children. 35 Due to the paucity of evidence regarding drugs intended for use in children the many differences between children and adults, it is difficult to define this 'direct benefit'. A workshop convened in 2019 by the FDA in collaboration with the Duke-Margolis Center for Health Policy produced expert journals.sagepub.com/home/taw Volume 14…”