Primary Submission Category: Intercurrent Event
Implementing the principal stratum strategy for intercurrent events with survival outcomes: a tutorial
Authors: Xiaoxiao Zhou, Fan Li,
Presenting Author: Xiaoxiao Zhou*
The International Council for Harmonization (ICH) E9 (R1) addendum introduces the estimand framework to standardize how treatment effects are evaluated. The framework comprises five attributes, including intercurrent events (ICEs) and five strategies to address them. Among these strategies, the principal stratum strategy is the most conceptually and technically challenging because it defines treatment effects on unobserved strata. Its application to survival outcomes is particularly inaccessible to practitioners. This tutorial reviews the methodology and implementation of the estimand framework with the principal stratum strategy to address ICEs with survival outcomes. We illustrate using a clinical trial in oncology and focus on a simple case with binary treatment and a single binary ICE of discontinuation of the assigned treatment. We define the causal effects and review two main methods for estimating
the effects: the mixture model method and the weighting method. For each method, we elaborate the associated assumptions, models, sensitivity analysis, software and provide example R code. We conduct simulation studies that mimic the real study to study the operation characteristics of these methods.