Discussion
EVENTS, EVENT
Failure to initiate treatment is a common intercurrent event in randomised trials. An mITT approach is frequently used, whereby participants who do not begin treatment are excluded from the analysis; however, it is not clear what estimand is being targeted by such an approach or the assumptions required for unbiasedness. In this article, we show that the mITT estimator which excludes participants who do not begin treatment targets a principal stratum estimand, and is unbiased under the assumption that if a participant experiences the intercurrent event under one treatment condition, they would also experience it under the other conditions.This assumption is likely to be fulfilled in many settings, including most double-blind trials, where the decision to initiate treatment will not be affected by the treatment arm. This assumption may also be plausible in many open-label trials as well; for instance, in FLO-ELA, there is strong justification for expecting cancellation of surgery not to be affected by treatment group. However, these assumptions are not always appropriate, and when they are not, the mITT estimator will be biased. The results in this article can help investigators determine whether an mITT approach is appropriate for their trial. When the underlying assumptions cannot be justified, alternative methods to estimate the principal stratum estimand can be used (see Bowden et al.In addition to determining whether the mITT estimator will be unbiased, investigators also need to decide whether a principal stratum estimand is appropriate to use. This decision will depend on the specific aims of each individual trial; however, we argue that for failure to initiate treatment, a principal stratum strategy often is the most clinically relevant choice. For example, in the FLO-ELA trial, cancellation of surgery renders the participant no longer part of the population of interest (which is participants undergoing emergency laparotomy); hence, a principal stratum approach may be more reflective of the treatment effect in routine clinical practice compared to other strategies, such as treatment policy (which compares two different strategies of fluid delivery during surgery, Despite the appeal of the principal stratum estimand, it has rarely been used in practice.mITT analyses have been criticised on the basis of ambiguity, that is, the term has been used by different researchers to mean different things.Although this article has focused on the intercurrent event ‘failure to initiate treatment’, the results could also apply to other intercurrent events where the assumptions discussed here are likely to be fulfilled. For instance, in trials where mortality is an intercurrent event but the treatments are known to not affect mortality (for instance, in certain palliative care trials), then (if clinically appropriate) the estimator described in 