Comparison of adaptive seamless Phase 2/3 designs for dose selection in clinical trials with multiple endpoints.

Adaptive seamless Phase 2/3 designs provide possible pathways to expedite drug development by combining dose selection and confirmatory evaluation on the selected dose with the control group in the same trial. Various methods have been developed to demonstrate the potential advantages compared to conventional development plan with separate Phase 2 and 3 trials. More practical and complicated situations occur when we want to achieve the goal of combining dose selection and confirmatory evaluation in clinical trials with multiple endpoints. Examples of multiple endpoints include multiple efficacy endpoints needed in the final stage for regulatory submissions. In this article, a few inferential adaptive seamless Phase 2/3 designs have been proposed which can combine dose selection and confirmatory stage in clinical trials evaluating multiple endpoints, including adaptive graph-based multiple testing procedure, adaptive seamless design with graph-based combination test, and seamless design with rank-based Dunnett-adjusted test. Simulations are conducted to confirm the control of the familywise type I error rate with an illustrated example design and assess the power. These designs can preserve the familywise type I error rate, and adaptive graph-based multiple testing procedure is more powerful than the others.