Connecting Instrumental Variable methods for causal inference to the Estimand Framework.

Causal inference methods are gaining increasing prominence in pharmaceutical drug development in light of the recently published addendum on estimands and sensitivity analysis in clinical trials to the E9 guideline of the International Council for Harmonisation. The E9 addendum emphasises the need to account for post-randomization or 'intercurrent' events that can potentially influence the interpretation of a treatment effect estimate at a trial's conclusion. Instrumental Variables (IV) methods have been used extensively in economics, epidemiology, and academic clinical studies for 'causal inference,' but less so in the pharmaceutical industry setting until now. In this tutorial article we review the basic tools for causal inference, including graphical diagrams and potential outcomes, as well as several conceptual frameworks that an IV analysis can sit within. We discuss in detail how to map these approaches to the Treatment Policy, Principal Stratum and Hypothetical 'estimand strategies' introduced in the E9 addendum, and provide details of their implementation using standard regression models. Specific attention is given to discussing the assumptions each estimation strategy relies on in order to be consistent, the extent to which they can be empirically tested and sensitivity analyses in which specific assumptions can be relaxed. We finish by applying the methods described to simulated data closely matching two recent pharmaceutical trials to further motivate and clarify the ideas.