Invited commentary on Pearl and principal stratification.

Pearl (2011) posed the question of whether confinement of clinical trial analyses involving post-randomization variables to the principal stratum "framework" of Frangakis and Rubin (2002) unduly restricts the scientific questions that can be asked. Frangakis and Rubin illustrated their proposal through examples involving compliance, mediation, and surrogacy. Here the utility of the principal stratum framework, and the potential outcomes formulation from which it derives, are considered for these topics in the specific setting of the Women's Health Initiative randomized, placebo controlled trials of postmenopausal hormone therapy. It is argued that the essential issues related to study reliability and causal interpretation involve the avoidance of context-specific biases that are typically not closely related to whether or not treatment effects have a representation in terms of potential outcomes contrasts. Also, while the questions posed within principal strata may be of interest, some key questions in the hormone therapy setting would not be addressed if restricted to contrasts within principal strata.