Evaluating Causal Effects on Time‐to‐Event Outcomes in an RCT in Oncology With Treatment Discontinuation

In clinical trials, patients may discontinue treatments prematurely, breaking the initial randomization. In our motivating study, a randomized controlled trial in oncology, patients assigned the investigational treatment may discontinue it due to adverse events. The ICH E9(R1) Addendum provides guidelines for handling such "intercurrent events." The right strategy to adopt depends on the questions of interest. We propose adopting a principal stratum strategy and decomposing the overall intention-to-treat effect into principal causal effects for groups of patients defined by their potential discontinuation behaviour. We first show how to implement a principal stratum strategy to assess causal effects on a survival outcome in the presence of continuous-time treatment discontinuation, its advantages, and the conclusions that can be drawn. Our strategy allows us to properly handle the time-to-event intermediate variable, which is not defined for patients who would not discontinue, and to account for the fact that the discontinuation time and the primary endpoint are subject to censoring. We employ a flexible model-based Bayesian approach to tackle these complexities, providing easily interpretable results. We apply this Bayesian principal stratification framework to analyze synthetic data of the motivating oncology trial. Supported by a simulation study, we shed light on the role of covariates in this framework. Beyond making structural and parametric assumptions more credible, they lead to more precise inference. Also, they can be used to characterize patients' discontinuation behavior, which could help inform clinical practice and future protocols.