Pediatric and Adult Placebo Response Rates in Placebo‐Controlled Clinical Trials Submitted to the US Food and Drug Administration 2012–2020

Abstract

The use of placebo concurrent control (placebo‐controlled) is the most rigorous method of evaluating the safety and efficacy of investigational treatments. However, the use of a placebo group in pediatric product development can be challenging due to ethical considerations and potential differences in placebo response rates between adults and children. This study reports the US Food and Drug Administration's experience with placebo response rates in the pediatric population. Products studied under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act between 2012 and 2020 were screened. Study characteristics including study type, primary efficacy endpoint(s), placebo response rates for the primary efficacy endpoint(s) and studied age range were collected. A total of 71 drug products used a placebo‐controlled trial. Of these, thirteen products had an identical study design and trial characteristics including the primary efficacy endpoints between pediatric and adult studies. Fifteen products were studied in trials with identical study design but only different primary efficacy endpoints in pediatric and adult populations. Ten products had combined adolescent and adult trials with separate pediatric trials in younger age groups. In each of these cases, the pediatric placebo response was greater, for some trials, and less, for other trials, than the adult placebo response. The pediatric placebo response can vary within an age group for a drug product. Future studies should examine the factors leading to a similarity or dissimilarity in placebo response between pediatric patients and adults.

Extrapolation of Adult Efficacy Data to Pediatric Systemic Lupus Erythematosus: Evaluating Similarities in Exposure–Response

“…However, FDA analyses of pediatric placebo-controlled trials across different therapeutic areas suggests that differences in the placebo response rate between adults and children are most often associated with differences in study designs and end points. 47 Second, despite a higher placebo response, the treatment effect of belimumab was similar between adults and children, with the net change in SRI-4 responders at week 52 (the primary end point) being nearly identical between the pediatric trial and 1 of the 2 adult trials. Additionally, adults and children experienced similar changes in disease activity biomarkers.…”

“…A high placebo response in children has been observed with treatment for other rheumatic diseases in children, 46 and may be 1 reason for clinical trials failing to show a positive drug effect. However, FDA analyses of pediatric placebo‐controlled trials across different therapeutic areas suggests that differences in the placebo response rate between adults and children are most often associated with differences in study designs and end points 47 . Second, despite a higher placebo response, the treatment effect of belimumab was similar between adults and children, with the net change in SRI‐4 responders at week 52 (the primary end point) being nearly identical between the pediatric trial and 1 of the 2 adult trials.…”