The importance and implications of comparator selection in pharmacoepidemiologic research.

PURPOSE OF REVIEW: Pharmacoepidemiologic studies employing large databases are critical to evaluating the effectiveness and safety of drug exposures in large and diverse populations. Because treatment is not randomized, researchers must select a relevant comparison group for the treatment of interest. The comparator group can consist of individuals initiating: (1) a similarly indicated treatment (active comparator), (2) a treatment used for a different indication (inactive comparator) or (3) no particular treatment (non-initiators). Herein we review recent literature and describe considerations and implications of comparator selection in pharmacoepidemiologic studies. RECENT
FINDINGS: Comparator selection depends on the scientific question and feasibility constraints. Because pharmacoepidemiologic studies rely on the choice to initiate or not initiate a specific treatment, rather than randomization, they are at-risk for confounding related to the comparator choice including: by indication, disease severity and frailty. We describe forms of confounding specific to pharmacoepidemiologic studies and discuss each comparator along with informative examples and a case study. We provide commentary on potential issues relevant to comparator selection in each study, highlighting the importance of understanding the population in whom the treatment is given and how patient characteristics are associated with the outcome.
SUMMARY: Advanced statistical techniques may be insufficient for reducing confounding in observational studies. Evaluating the extent to which comparator selection may mitigate or induce systematic bias is a critical component of pharmacoepidemiologic studies.