A Comparison of Methods for Treatment Selection in Seamless Phase II/III Design

Seamless phase II/III design aims to integrate a phase II trial for treatment selection and a phase III confirmatory trial. It offers valuable flexibility through mid-trial modifications, potentially optimizing resource utilization and reducing patient burden. In the first stage, multiple experimental treatments are evaluated to select promising ones, which enter the second stage for the confirmatory analysis against the control using data from both stages. Proper statistical methods are needed for the final analysis to control the overall Type I error rate at a prespecified level, regardless of the treatment selection rule used at the interim analysis. In this article, we provide a comprehensive evaluation of four classes of statistical approaches in the literature, which use different ways to integrate combination functions (or conditional error functions) and multiple testing methods (including Bonferroni, Simes, and Dunnett adjustments). Extensive simulation studies are performed to evaluate both the Type I error control and power. In addition, we illustrate the practical implementation of these approaches in real clinical trial settings.