Review of Recent Pharmacoepidemiologic Post-Market Safety Studies Through the Lens of the Estimand Framework.

The ICH E9(R1) estimand framework provides a systematic approach to ensure alignment among clinical trial objectives, trial conduct, statistical analyses, and interpretation of results, however, whether it can be readily utilized for the pharmacoepidemiologic safety studies has not been established. We selected articles on drug safety published in the Journal Pharmacoepidemiology and Drug Safety (PDS), during 2020 to investigate whether estimand attributes were well defined in the study design and reporting. We found that among twenty-five articles selected, nineteen were cohort studies and six were nested case-control studies. All studies had well-defined exposure, outcome, target population, and population level summary. The term intercurrent event (ICE) was not mentioned in any of the studies; however, many cohort studies discussed drug discontinuation, treatment modification and terminal events, and strategies to handle them. All studies used methods to control for confounding: propensity score methods or covariate adjustment, or both for cohort studies; matching and covariate adjustment for the nested case-control studies. We conclude that while the estimand framework can serve to add clarity and precision to pharmacoepidemiologic safety studies, more detailed considerations are required for bias assessment to compensate for the lack of randomization and other shortcomings in observational studies. Recent pharmacoepidemiology frameworks, such as Target Trial Emulation, STaRT-RWE, HARPER could be combined with the complementary principals from the estimand framework to help achieve the study objectives.