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Thursday, September 13
Thu, Sep 13, 1:15 PM - 2:30 PM
Thurgood Marshall West
Design and Analysis of Clinical Trials in the Presence of Non-Proportional Hazards (PH) Treatment Effect

Design and Analysis of Clinical Trials in the Presence of Non-Proportional Hazards (PH) Treatment Effect (300795)

*Keaven Martin Anderson, Merck Research Laboratories 

Loss of power and clear description of treatment differences are key issues in designing and analyzing a clinical trial where non-proportional hazards is considered likely. A logrank test may be very inefficient and interpretation of the hazard ratio estimated using Cox regression is potentially problematic. The current ICH E9 (R2) addendum would suggest starting with a clinically relevant estimand, e.g., expected life gain. One can then consider designing a trial with most appropriate methods supporting the estimand, e.g., RMST. However, such an approach may be case specific and lack of power under important choices of the alternate hypothesis distribution. On the other hand, here may be a desire to have robust power under such a variety of types of alternative approaches. The non-proportional hazards working group has proposed a combination test based on 4 tests including logrank and 3 weighted logrank tests in order to provide robust power under a variety of alternative hypotheses. These can be specified for primary analysis at the design stage and methods appropriately accounting for combination test correlations are efficient. We examine design and analysis considerations under a delayed or mildly crossing hazards assumption and present a strawman proposal for practitioners.