Sensitivity analyses for the principal ignorability assumption using multiple imputation.

Abstract

In the context of clinical trials, there is interest in the treatment effect for subpopulations of patients defined by intercurrent events, namely disease-related events occurring after treatment initiation that affect either the interpretation or the existence of endpoints. With the principal stratum strategy, the ICH E9(R1) guideline introduces a formal framework in drug development for defining treatment effects in such subpopulations. Statistical estimation of the treatment effect can be performed based on the principal ignorability assumption using multiple imputation approaches. Principal ignorability is a conditional independence assumption that cannot be directly verified; therefore, it is crucial to evaluate the robustness of results to deviations from this assumption. As a sensitivity analysis, we propose a joint model that multiply imputes the principal stratum membership and the outcome variable while allowing different levels of violation of the principal ignorability assumption. We illustrate with a simulation study that the joint imputation model-based approaches are superior to naive subpopulation analyses. Motivated by an oncology clinical trial, we implement the sensitivity analysis on a time-to-event outcome to assess the treatment effect in the subpopulation of patients who discontinued due to adverse events using a synthetic dataset. Finally, we explore the potential usage and provide interpretation of such analyses in clinical settings, as well as possible extension of such models in more general cases.