The estimands framework: a primer on the ICH E9(R1) addendum

Abstract

Estimands can be used in studies of healthcare interventions to clarify the interpretation of treatment effects. The addendum to the ICH E9 harmonised guideline on statistical principles for clinical trials (ICH E9(R1)) describes a framework for using estimands as part of a study. This paper provides an overview of the estimands framework, as outlined in the addendum, with the aim of explaining why estimands are beneficial; clarifying the terminology being used; and providing practical guidance on using estimands to decide the appropriate study design, data collection, and estimation methods. This article illustrates how to use the estimands framework by applying it to an ongoing trial in emergency bowel surgery. Estimands can be a useful way of clarifying the exact research question being evaluated in a study, both to avoid misinterpretation and to ensure that study methods are aligned to the overall study objectives.

Fig 1

Different strategies regarding intercurrent events. In this example, a randomised trial compares intervention with control to understand how outcomes differ at month 2. However, one participant stops treatment before month 2 (ie, an intercurrent event). The figure shows what happens to this participant under each intercurrent event strategy. Under a composite strategy, investigators have decided to assign a score of 0 to any participant who experienced an intercurrent event. Under a while-on-treatment strategy, because the participant experienced an intercurrent event before month 2, their month 1 score of 3 is used in place of their month 2 score. Under a hypothetical strategy, the participant’s outcome that would have occurred had they continued treatment at month 2 is used (here, it is a value of 9); but in practice, this value will not be known and so must be estimated. M=month