Estimand framework and intercurrent events handling for clinical trials with time-to-event outcomes

The ICH E9(R1) guideline presents a framework for clinical trials to align planning, design, conduct, analysis, and interpretation (ICH, 2020). The three key steps in the framework are: estimand, estimator, and sensitivity analysis (Mallinckrodt et al., 2020). ICH E9(R1) highlights the importance of dealing with intercurrent events (ICEs), which are defined as: "Events occurring after treatment initiation that affect either the interpretation or the existence of the measurements associated with the clinical question of interest. It is necessary to address intercurrent events when describing the clinical question of interest in order to precisely define the treatment effect that is to be estimated." ICH E9(R1) proposes five strategies for dealing with ICEs in clinical trials with quantitative outcomes and categorical outcomes: treatment policy strategy, hypothetical strategy, composite variable strategy, while-on-treatment strategy, and principal stratum strategy.