What Makes an Estimand Useful? Guidance on the Choice of Intercurrent Event Strategies

While the use of estimands in randomized trials is increasing, there is little guidance on which intercurrent event strategies should be used. The article by Fleming et al. seeks to address this gap. They argue that strategies such as hypothetical, principal stratum, and while-alive generally cannot be used to reliably inform decision making, and that treatment policy (and composite for mortality) strategies should be used instead. In this Commentary we argue that there are a variety of settings where strategies such as hypothetical, principal stratum, and while-alive can reliably inform decision-making and are preferable to a treatment policy strategy. We provide an alternative approach for selecting intercurrent event strategies, which systematically considers the trade-off between relevance (whether it addresses a useful question) and reliability (the ability to be estimated such that stakeholders can have confidence in the results) of each strategy in order to identify those that can be used to robustly inform decision-making. Our overall conclusion is that there is no single intercurrent event strategy that is appropriate in all settings; all strategies can be beneficial when used in appropriate settings, but harmful when used in inappropriate settings.