The regulatory framework for considering the fetal effects of new drugs is limited. This is partially due to the fact that pediatric regulations (21 CFR subpart D) do not apply to the fetus, and only US Health and Human Service (HHS) regulations apply to the fetus. The HHS regulation 45 CFR Part 46 Subpart B limits research approvable by an institutional review board to research where the risk to the fetus is minimal unless the research holds out the prospect of a direct benefit to the fetus or the pregnant woman (45 CFR 46.204). Research that does not meet these requirements, but presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health of pregnant women, fetuses, or neonates, may be permitted by the Secretary of the HHS after expert panel consultation and opportunity for public review and comment (45 CFR 46.407). If the product is regulated by the US Food and Drug Administration (FDA), FDA may get involved in the review process. The FDA does however have a Reviewer Guidance on Evaluating the Risks of Drug Exposure in Human Pregnancies from 2005 and this guidance does discuss the intensity of drug exposure. Estimation of that exposure using physiologically based pharmacokinetic (PBPK) modeling has been suggested by some investigators. Given that drug exposure during pregnancy will impact the fetus, a number of new guidances in the last 2 years also address inclusion of pregnant women in clinical drug trials. Therefore, the drug-specific information on fetal pharmacology will increase dramatically in the next decade due to interest in drugs administered in pregnancy and with the assistance of model-informed drug development.
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.
Clinical Trials as Topic/ethics , Pediatrics , Biomedical Research , Child , Humans
Including adolescents in adult clinical trials can play an important role in making innovative new medicines available to children in a timelier fashion. Stakeholders involved in the processes leading to regulatory approval and labeling of new drugs recognize that challenges exist in involving adolescents and older children in clinical trials before the safety and efficacy of these drugs are established for adults. However, it has been possible to design and execute phase 3 trials that combine adults with adolescents which are medically and scientifically sound and ethically justified. Based on this experience and considerations of the medical and scientific, ethical, and operation-related matters, the 2019 Pediatric Innovation Research Forum advocated for the position that adolescents routinely be considered for enrollment in phase 3 clinical trials. The Forum also concluded that exclusion of adolescents in adult pivotal trials occur only when a thorough evaluation of the target disease and the potential benefit and risks of the study intervention supports a delay in their involvement until after completion of clinical trials in adults.
Clinical Trials as Topic , Adolescent , Adult , Child , Humans
BACKGROUND: Placebo-controlled trials are the most rigorous method of evaluating the safety and efficacy of investigational treatments, yet the use of a placebo control in pediatric drug development is challenging and potentially controversial. Regulations provide additional protections for children participating in human subject research and limit the amount of risk to which children may be exposed without benefit (21 CFR 50, subpart D, Additional Safeguards for Children in Clinical Investigations). The objective of this paper is to describe the US Food and Drug Administration (FDA) experience with placebo-controlled trials conducted as part of pediatric drug development programs including compliance with 21 CFR 50, subpart D. METHODS: Pediatric drug development programs conducted under the Best Pharmaceuticals for Children Act (BPCA) or the Pediatric Research Equity Act (PREA) between 2012 and 2018 were reviewed. Trials that utilized a placebo control were identified and trial characteristics and risk mitigation strategies were extracted from publicly available sources. RESULTS: During this time frame, a total of 266 products were studied under pediatric product development initiatives. Of those, 67 products (25%) were studied in 96 individual placebo-controlled trials in pediatric patients. The majority of these studies included approaches to minimize risk to children in the placebo arm, including 49 trials that utilized placebo as an add-on to known effective therapy for the disease and 48 trials that included rescue therapy in the study protocol. CONCLUSIONS: When designed and conducted appropriately, placebo-controlled trials meet requirements under current US federal regulations for the protection of children in research.
Controlled Clinical Trials as Topic , Research Design , Child , Humans , United States , United States Food and Drug Administration
