Power With Confounders in Clinical Trials Using External Controls.

When the number of patients is limited in clinical trials for rare diseases and pediatric developments, enrolling sufficient participants for confirmatory randomized clinical trials is difficult. Alternative trial designs using external controls have been proposed: augmented randomized clinical trials (ARCTs) and supplemented single-arm trials (SSATs). In order to assess the favorable situations in which to implement each trial design, we propose to specify the sensitivity analysis for confounding at the planning phase, and call it "pre-sensitivity analysis." In addition, we assessed the probability that the pre-sensitivity analysis would show a treatment effect, which we define as "power with confounders." A simulation was carried out across multiple cases, which considered the number of participants from external control data sources and the randomization ratio in an ARCT. The simulation indicated that allocating relatively more participants to the control arm in an ARCT could be considered when the available historical data are equal to or less than the number of concurrent trial participants. Conversely, when the available historical data are sufficient, allocating more participants to the test arm in an SSAT or ARCT could be considered.