Beyond the Randomized Clinical Trial

Abstract

Randomized clinical trials (RCTs) are familiar to most clinicians involved in the care of patients with cardiovascular disease. RCTs are the uncontested “gold standard” for establishing causation between a therapy and outcomes for a compelling reason: A large randomized experiment is the only study design that can guarantee that control and intervention subjects are similar in all the known and unknown attributes that influence outcomes.1 In general, RCTs use a rigorous experimental design with the primary goal of understanding the “average” overall benefit and risk of using a standardized therapy in a selected group of patients.2 When well conducted, RCTs have internal validity, and a therapy that is found to have a net biological benefit is considered efficacious.3 Establishing the efficacy of new therapies is critical for advancing medical knowledge. Yet even when an RCT demonstrates substantial net benefit for a specific therapy, its optimal role in routine clinical practice can remain unclear. Concerns frequently relate to how well the therapy may perform in different clinical settings and in broader patient populations than those studied in traditional RCTs. In addition, it is often unclear how therapies are best applied within the larger environment of the healthcare delivery system where costs and availability become issues for patients and clinicians. These concepts, which refer to the external validity of a clinical trial,3 become important as new therapies are applied in real-world settings and are a key focus area for many studies in health services and outcomes research. In contrast to efficacy studies like traditional RCTs, effectiveness studies often require a broader range of methodological tools, which can include both experimental and nonexperimental study designs. In the present article, we review reasons why evidence from traditional RCTs must generally be supplemented by evidence from effectiveness studies to inform best …