  Pragmatic randomized trials are designed to provide evidence for clinical
decision-making rather than regulatory approval. Common features of these
trials include the inclusion of heterogeneous or diverse patient populations in
a wide range of care settings, the use of active treatment strategies as
comparators, unblinded treatment assignment, and the study of long-term,
clinically relevant outcomes. These features can greatly increase the
usefulness of the trial results for patients, clinicians, and other
stakeholders. However, these features also introduce an increased risk of
non-adherence, which reduces the value of the intention-to-treat effect as a
patient-centered measure of causal effect. In these settings, the per-protocol
effect provides useful complementary information for decision making.
Unfortunately, there is little guidance for valid estimation of the
per-protocol effect. Here, we present our full guidelines for analyses of
pragmatic trials that will result in more informative causal inferences for
both the intention-to-treat effect and the per-protocol effect.
