ABSTRACT Recently, adaptive seamless phase II/III designs (ASDs) have gained attention because they improve the efficiency of drug development. In an ASD, a phase II trial, which explores the dose–response relationships and identifies treatments for the phase III trial, is combined with a phase III trial, which aims to demonstrate the efficacy and safety of the selected treatment arms in a single trial. This study focused on ASD, which selects treatment groups based on the short–term outcomes observed early in the trial, and involves a confirmatory outcome as the long–term outcome. The method based on the combination test, which considers treatment group selection based on short–term outcomes, tends to be conservative. In other words, it controls the type I error rate more strictly than necessary as the correlation decreases among outcomes in phases II and III. To address this issue, we proposed an adaptive seamless phase II/III randomization test that can appropriately consider the correlation between outcomes based on a randomization distribution, where phase II has a binary outcome and phase III has overall survival. Based on the simulation study, the proposed method improved conservatism owing to the correlation among outcomes and controlled the type I error rate around the nominal level. In addition, the power of this method tended to be higher than that of the method based on the combination test in most scenarios. Overall, the proposed method can increase the probability of trial success compared with conventional phase III designs.
Sato et al. (Sun,) studied this question.