Tell me what you want, what you really really want: Estimands in observational pharmacoepidemiologic comparative effectiveness and safety studies

Abstract

AbstractPurposeIdeally, the objectives of a pharmacoepidemiologic comparative effectiveness or safety study should dictate its design and data analysis. This paper discusses how defining an estimand is instrumental to this process.MethodsWe applied the ICH‐E9 (Statistical Principles for Clinical Trials) R1 addendum on estimands – which originally focused on randomized trials – to three examples of observational pharmacoepidemiologic comparative effectiveness and safety studies. Five key elements specify the estimand: the population, contrasted treatments, endpoint, intercurrent events, and population‐level summary measure.ResultsDifferent estimands were defined for case studies representing three types of pharmacological treatments: (1) single‐dose treatments using a case study about the effect of influenza vaccination versus no vaccination on mortality risk in an adult population of ≥60 years of age; (2) sustained‐treatments using a case study about the effect of dipeptidyl peptidase 4 inhibitor versus glucagon‐like peptide‐1 agonist on hypoglycemia risk in treatment of uncontrolled diabetes; and (3) as needed treatments using a case study on the effect of nitroglycerin spray as‐needed versus no nitroglycerin on syncope risk in treatment of stabile angina pectoris.ConclusionsThe case studies illustrated that a seemingly clear research question can still be open to multiple interpretations. Defining an estimand ensures that the study targets a treatment effect that aligns with the treatment decision the study aims to inform. Estimand definitions further help to inform choices regarding study design and data‐analysis and clarify how to interpret study findings.