This JAMA Guide to Statistics and Methods compares pragmatic randomized controlled trials, which focus on important challenges that patients, physicians, and policy makers face in day-to-day life with explanatory trials that seek to test a hypothesis.
The concept of a “pragmatic” clinical trial was first proposed nearly 50 years ago as a study design philosophy that emphasizes answering questions of most interest to decision makers.1 Decision makers, whether patients, physicians, or policy makers, need to know what they can expect from the available diagnostic or therapeutic options when applied in day-to-day clinical practice. This focus on addressing real-world effectiveness questions influences choices about trial design, patient population, interventions, outcomes, and analysis. Gottenberg et al2 reported the results of a trial designed to answer the question “If a biologic agent for rheumatoid arthritis is no longer effective for an individual patient, should the clinician recommend another drug with the same mechanism of action or switch to a biologic with a different mechanism of action?” Because the authors included some pragmatic elements in the trial design, this study illustrates the issues that clinicians should consider in deciding whether a trial result is likely to apply to their patients.
Why Are Pragmatic Trials Conducted?
Pragmatic trials are intended to help typical clinicians and typical patients make difficult decisions in typical clinical care settings by maximizing the chance that the trial results will apply to patients who are usually seen in practice (external validity). The most important feature of a pragmatic trial is that patients, clinicians, clinical practices, and clinical settings are selected to maximize the applicability of the results to usual practice. Trial procedures and requirements must not inconvenience patients with substantial data collection and should impose a minimum of constraints on usual practice by allowing a choice of medication (within the constraints imposed by the purpose of the study) and dosage, providing the freedom to add cointerventions, and doing nothing to maximize adherence to the study protocol.
The pragmatic trial strategy contrasts with that used for an explanatory trial, the goal of which is to test a hypothesis that the intervention causes a clinical outcome. Explanatory trials seek to maximize the probability that the intervention—and not some other factor—causes the study outcome (internal validity). Explanatory trials seek to give the intervention the best possible chance to succeed by using experts to deliver it, delivering the intervention to patients who are most likely to respond, and administering the intervention in settings that provide expert after-care. Explanatory trials try to prevent any extraneous factors from influencing clinical outcomes, so they exclude patients who might have poor adherence and may intervene to maximize patient and clinician adherence to the study protocol. Explanatory trials are structured to avoid downstream events that could affect study outcomes. If these events occur at different rates ...