Control of Unconditional Type I Error in Clinical Trials With External Control Borrowing-A Two-Stage Adaptive Design Perspective.

Patient enrollment can be a substantial burden in rare disease trials. One potential approach is to incorporate external control (EC) into concurrent randomized trials, or EC borrowing, to reduce such burden. Extensive research has been conducted to explore statistical methodologies. As in all designs, type I error control is essential. Conditional type I error rate has been used in the literature as the de facto metrics for type I error rate. However, research has shown that controlling the conditional type I error rate at the alpha level will disallow EC borrowing. Therefore, EC borrowing is practically at an impasse. Kopp-Schneider et al. concluded that a more appropriate metrics for type I error is necessary. We show that a trial with EC borrowing can be considered as a two-stage adaptive design. With this perspective, we propose to define type I error as the weighted averages of conditional type I error rate in trials with EC borrowing. Dynamic borrowing methods for controlling type I error are proposed.