Testing for subgroup treatment effect consistency in the Cox model

Abstract

An overall treatment effect in a clinical trial may inadequately represent particular patient subgroups, creating uncertainty about whether a population-level efficacy conclusion can legitimately be transferred to them. Conventional interaction tests only investigate whether subgroup-specific treatment effects are exactly equal or not, but cannot detect whether the differences are small enough to be clinically negligible. We develop a formal framework for assessing subgroup treatment effect consistency for time-to-event outcomes within the Cox proportional hazards model. Consistency is formulated as an equivalence problem based on the (weighted) treatment-by-subgroup interaction coefficient. We consider detecting consistency between two complementary subgroups and consistency of subgroup-specific treatment effects with the overall treatment effect. For each setting, we develop a conventional two one-sided tests procedure (TOST) and a new test motivated by optimal equivalence testing for normally distributed parameters. We prove the asymptotic validity of all procedures and show empirically that the new tests are more powerful than their TOST counterparts. Finally, we apply the new methodology to a case study motivated by the CANTOS cardiovascular outcomes trial.