Chasing Shadows: How Implausible Assumptions Skew Our Understanding of Causal Estimands

The ICH E9 (R1) addendum on estimands, coupled with recent advancements in causal inference, has prompted a shift toward using model-free treatment effect estimands that are more closely aligned with the underlying scientific question. This represents a departure from traditional, model-dependent approaches where the statistical model often overshadows the inquiry itself. While this shift is a positive development, it has unintentionally led to the prioritization of an estimand's ability to perfectly answer the key scientific question over its practical learnability from data under plausible assumptions. We illustrate this by scrutinizing assumptions in the recent clinical trials literature on principal stratum estimands, demonstrating that some popular assumptions are not only implausible but often inevitably violated. We advocate for a more balanced approach to estimand formulation, one that carefully considers both the scientific relevance and the practical feasibility of estimation under realistic conditions.