Core concepts in pharmacoepidemiology: Confounding by indication and the role of active comparators

Confounding by indication poses a significant threat to the validity of nonexperimental studies assessing effectiveness and safety of medical interventions. While no different from other forms of confounding in theory, confounding by indication often requires specific methods to address the bias it creates in addition to common epidemiological adjustment or restriction methods. Clinical indication influencing treatment prescription is patient-specific and complex, making it challenging to measure within nonexperimental research. Restriction of the study population to patients with the indication for treatment would effectively mitigate confounding by indication and bring about comparability between exposure and comparator populations with respect to probability of the exposure. Active comparators are often an effective practical solution to restrict the study population in this manner when indication cannot be measured accurately. This article discusses various forms of confounding by indication, the utility of active comparators for nonexperimental studies of treatment effects, and the active comparator, new user (ACNU) study design to implicitly condition on indication. Considerations for selecting active comparators and conducting an ACNU study design are discussed to enable increased adoption of these methods, improve quality of nonexperimental studies, and ultimately strengthen our evidence base for intended and unintended treatment effects in relevant target populations.