Group sequential design using restricted mean survival time as the primary endpoint in clinical trials.

Abstract

The proportional hazards (PH) assumption is often violated in clinical trials. If the most commonly used Log-rank test is used for trial design in non-proportional hazard (NPH) cases, it will result in power loss or inflation, and the effect measures hazard ratio will become difficult to interpret. To circumvent the issue caused by the NPH for trial design and to make the effect measures easy to interpret and communicate, two simulation-free methods about restricted mean survival time group sequential (GS-RMST) design are introduced in this study: the independent increment GS-RMST (GS-RMSTi) design and the non-independent increment GS-RMST (GS-RMSTn) design. For the above two designs, the corresponding analytic expression of the variance-covariance matrix, the calculations of the stopping boundaries and sample size are given in the study. Simulation studies show that both designs can achieve the corresponding nominal type I error and nominal power. The GS-RMSTn simulation studies show that the Max-Combo test group sequential design is robust in different NPH scenarios and is suitable for discovering whether there is a treatment effect difference. However, it does not have a corresponding easy-to-interpret effect measure indicating effect difference magnitude. GS-RMST performs well in both PH and NPH scenarios, and it can obtain time-scale effect measures that are easy to understand by both physicians and patients. Examples of both GS-RMST designs are also illustrated.