Instrumental variable analysis in randomized trials with non- compliance and observational pharmacoepidemiologic studies

Introduction Instrumental variable (IV) analysis potentially accounts for unmeasured confounding in observational studies, but it can also control for noncompliance in randomized trials. IV analysis requires that the IV is related to treatment status, yet independent of confounders of the treatment-outcome relation. This implies that in pharmacoepidemiologic scenarios where IV analysis is needed the most (because of strong unmeasured confounding), IVs will typically be weakly associated with treatment. Furthermore, IV analysis assumes that the IV affects the outcome only through the treatment under study. A common IV in pharmacoepidemiological studies is the physician prescribing preference, which for the latter assumption implies that physicians only differ in their preference for the treatment under study, but they do not differ with respect to e.g. preferences for concomitant treatments, skills, organization of their practice, etc. Assumptions underlying IV assumptions need thorough evaluation before proceeding with IV analyses. Here, IV analysis is illustrated, its key assumptions are illustrated by a randomized trial with non-compliance, and the utility of IVs for observational pharmacoepidemiologic studies is discussed. Conclusion The validity and applicability of IV analysis in observational pharmacoepidemiologic studies still have to be established, which requires more applications of IV analysis and debate on the likelihood of the assumptions underlying IV analysis.