Adaptive Clinical Trials in Pediatric Critical Care: A Systematic Review

Abstract

Objectives: This systematic review investigates the use of adaptive designs in randomized controlled trials (RCTs) in pediatric critical care.

Data sources: PICU RCTs, published between 1986 and 2020, stored in the www.PICUtrials.net database and MEDLINE, EMBASE, CENTRAL, and LILACS databases were searched (March 9, 2022) to identify RCTs published in 2021. PICU RCTs using adaptive designs were identified through an automated full-text screening algorithm.

Study selection: All RCTs involving children (< 18 yr old) cared for in a PICU were included. There were no restrictions to disease cohort, intervention, or outcome. Interim monitoring by a Data and Safety Monitoring Board that was not prespecified to change the trial design or implementation of the study was not considered adaptive.

Data extraction: We extracted the type of adaptive design, the justification for the design, and the stopping rule used. Characteristics of the trial were also extracted, and the results summarized through narrative synthesis. Risk of bias was assessed using the Cochrane Risk of Bias Tool 2.

Data synthesis: Sixteen of 528 PICU RCTs (3%) used adaptive designs with two types of adaptations used; group sequential design and sample size reestimation. Of the 11 trials that used a group sequential adaptive design, seven stopped early due to futility and one stopped early due to efficacy. Of the seven trials that performed a sample size reestimation, the estimated sample size decreased in three trials and increased in one trial.

Conclusions: Little evidence of the use of adaptive designs was found, with only 3% of PICU RCTs incorporating an adaptive design and only two types of adaptations used. Identifying the barriers to adoption of more complex adaptive trial designs is needed.