Sequential Monitoring of Clinical Trials with Weighted Logrank Test in the Presence of Random Delayed Treatment...

The standard logrank test may lose statistical power substantially when the underlying proportional hazards (PH) assumption is violated. Among non-PH patterns, delayed treatment effects are very commonly anticipated and actually observed not only in cancer immunotherapies and their related combinations with other therapeutic agents, but also in numerous situations across multiple therapeutic areas. A frequently considered scenario is that the PH pattern does not emerge until a certain period of time has elapsed. Based on the generalized piecewise weighted (GPW) logrank test, which is the asymptotically most powerful weighted logrank test detecting random delayed effects, we developed and evaluated a group sequential framework for maximum duration trials based on this test. A variance based procedure for the determination of the sequence of information fractions is proposed. Simulation studies are performed comparing various types of design and handling of information fractions. The procedure can control type I error rate in this group sequential design framework. Power gain of the GPW logrank test is demonstrated for the non-PH scenarios with delayed treatment effects. These results underscore the importance of considering GPW type of logrank test with appropriate design strategies when such delayed effect patterns are expected. Moreover, we have highlighted the economic advantage of sequential monitoring, providing early decision opportunities to accelerate drug development.