Treatment Effect Quantification for Time-to-event Endpoints -- Estimands, Analysis Strategies, and beyond
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A draft addendum to ICH E9 has been released for public consultation in August 2017. The addendum focuses on two topics particularly relevant for randomized confirmatory clinical trials: estimands and sensitivity analyses. The need to amend ICH E9 grew out of the realization of a lack of alignment between the objectives of a clinical trial stated in the protocol and the accompanying quantification of the "treatment effect" reported in a regulatory submission. We embed time-to-event endpoints in the estimand framework and discuss how the four estimand attributes described in the addendum apply to time-to-event endpoints. We review examples that illustrate heterogeneity in variable definitions for such endpoints and discuss the implications of this heterogeneity on trial results and planning of future trials. In a first case study we illustrate how an intercurrent event can necessitate a different estimand strategy depending on the indication the trial is run in. In a second example, we discuss for a large randomized clinical trial how the analyses for the primary and secondary endpoints as well as the sensitivity analyses actually performed in the trial can be seen in the context of the addendum. To the best of our knowledge, this is the first attempt to do so for a trial with a time-to-event endpoint. Recommendations for planning of future trials are then given, hoping that this will provide a contribution to developing a common framework based on the addendum that can applied to protocols, statistical analysis plans, and clinical study reports in the future.
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