The Estimand Framework Applied to Time-to-event Endpoints

Abstract

A draft addendum to ICH E9 has been released for public consultation in August 2017. It 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. While the estimand framework has been developed broadly with different clinical trial settings and endpoints in mind, the examples discussed in publications, at scientific meetings, and in the draft addendum have largely focused on symptomatic studies and continuous, longitudinal endpoints. We embed time-to-event endpoints in the estimand framework and discuss how the four estimand attributes described in the draft addendum apply to time-to-event endpoints. We illustrate how the estimand framework can bring more alignment, clarity and transparency to currently used endpoints and methods, e.g. progression-free survival or treatment switching. The role of censoring of time-to-event endpoints is discussed in the estimand context. In a first case study on progression-free survival in lymphoma, we illustrate how an intercurrent event, new-anti lymphoma therapy, can necessitate a different estimand strategy depending on the indication the trial is run in. In a second case study we outline how the analyses for the primary and secondary endpoints as well as the sensitivity analyses actually performed in a large randomized clinical trial can be seen in the context of the draft addendum. We conclude with recommendations for planning of future trials, hoping that this will provide a contribution to developing a common framework based on the draft addendum that can applied to protocols, statistical analysis plans, and clinical study reports in the future.

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Location
Frankfurt, Germany