An introduction to causal modeling in clinical trials.

PURPOSE: We review and compare two causal modeling approaches that correspond to two major and distinct classes of inference - efficacy and intervention-based inference - in the context of randomized trials with subject noncompliance.
METHODS: We review the definitions of efficacy and intervention-based effects in the clinical trials literature and relate these to two separate and distinct causal modeling approaches: the structural mean modeling (SMM) approach and the principal stratification, instrumental variable approach.
RESULTS: The SMM-based efficacy approach focuses on the effect of actually receiving treatment. In contrast, the principal stratification method addresses the effect of treatment assignment within partially unobserved latent subgroups defined by compliance behavior. While these approaches differ in terms of philosophy, model definitions, and estimation, they estimate the same causal effect under certain assumptions, but estimate very different causal effects when those assumptions are relaxed. We illustrate these results using a randomized psychiatry trial where the focus is physician compliance to the designated protocol and the other examines patient compliance to the designated protocol, both from the same trial. LIMITATIONS: The validity of the models under the instrumental variable, SMM and principal stratification approaches depends on modeling assumptions, some of which may not be verifiable from the observed data and potentially less realistic than the no-confounding assumption made by non-causal approaches.
CONCLUSIONS: This comparison in terms of efficacy versus intervention-based effects in causal modeling parallels the explanatory versus pragmatic approaches in clinical trials research; therefore researchers should weigh carefully when choosing causal modeling methodology based on whether efficacy or intervention-based effects are of interest.