Title: Treatment Effect Quantification for Time-to-event Endpoints -- Estimands, Analysis Strategies, and beyond,
Abstract: 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 point out that if the proportional hazards
assumption is not met, the estimand targeted by the most prevalent methods used
to analyze time-to-event endpoints, logrank test and Cox regression, depends on
the censoring distribution. 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. Questions that remain open with
the addendum for time-to-event endpoints and beyond are formulated, and
recommendations for planning of future trials are given. We hope that this will
provide a contribution to developing a common framework based on the final
version of the addendum that can be applied to design, protocols, statistical
analysis plans, and clinical study reports in the future.