Vol.:(0123456789) 1 3 Therapeutic Innovation & Regulatory Science https://doi.org/10.1007/s43441-020-00214-3 ORIGINAL RESEARCH Ethical Considerations for Pediatric Placebo‑Controlled Trials: FDA Outcomes and Perspectives Jeremiah D. Momper 1  · Dionna J. Green 2  · Kyunghun Park 3  · Gilbert J. Burckart 3  · Donna L. Snyder 4 Received: 13 May 2020 / Accepted: 24 August 2020 © The Drug Information Association, Inc 2020 Abstract Background Placebo-controlled trials are the most rigorous method of evaluating the safety and efcacy 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 beneft (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 identifed 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 efective 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. Keywords Pediatrics · Drug development · Placebo · Risk analysis · Clinical trials Abbreviations BPCA Best Pharmaceuticals for Children Act PREA Pediatric Research Equity Act Introduction The type of control utilized in a clinical trial afects the inferences that can be drawn from the trial and the degree to which bias in study conduct and analysis can be minimized [1]. Placebo-controlled trials are the most rigorous method of evaluating the safety and efcacy of an investigational treatment. Participants randomized to a placebo group are not always untreated; in many placebo-controlled trials, the investigational treatment and placebo are each added to a standard background therapy (i.e., add-on studies). Placebo-controlled trials ofer several advantages, including (i) measurement of absolute efcacy and safety, (ii) increased efficiency enabling a reduced sample size, (iii) ability to Disclaimer The opinions expressed in this article are those of the authors and should not be interpreted as the position of the US Food and Drug Administration. * Donna L. Snyder Donna.Snyder@fda.hhs.gov 1 Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA 2 Ofce of Pediatric Therapeutics, Ofce of the Commissioner, U.S. Food and Drug Administration, Silver Spring, MD, USA 3 Ofce of Clinical Pharmacology, Ofce of Translational Sciences, Silver Spring, MD, USA 4 Ofce of Pediatric Therapeutics, Ofce of the Commissioner, U.S. Food and Drug Administration, 10903 New Hampshire Avenue, White Oak Building 32 Room 5152, Silver Spring, MD 20993, USA