Pragmatic clinical trials (PCTs) differ from traditional randomized controlled trials (RCTs) largely in terms of their purpose. Traditional RCTs can be thought of as explanatory or mechanistic experiments that attempt to minimize potential confounding and ensure a high degree of internal validity. The goal is to determine whether the experimental condition is efficacious when it is the only condition that differs between cases and controls.

PCTs, on the other hand, are often conducted to evaluate whether a therapy or other intervention is effective in the real-world conditions of its proposed use. The ultimate goal of PCTs is to improve practice and policy. Califf and Sugarman (2015) proposed the following definition of a PCT conducted in a healthcare context:

[A trial that is] designed for the primary purpose of informing decision-makers regarding the comparative balance of benefits, burdens and risks of a biomedical or behavioral health intervention at the individual or population level.

Each kind of trial has strengths and weaknesses. Strictly controlled explanatory RCTs seek to maximize internal validity but may not be generalizable outside controlled settings, because the conditions of the study (including the study population) are not representative of the typical settings in which patients receive care. They also often require substantial expense and supportive infrastructure and oversight. PCTs, on the other hand, are more likely to maximize external validity and generalizability and may cost less to perform than traditional RCTs, especially when they can capitalize on existing data sources such as electronic health records. However, less restrictive criteria, a lesser degree of fidelity to the intervention, and a lesser degree of monitoring or compliance result in data that are "messier" or less complete, and may also be more subject to changes in healthcare delivery mechanisms. These considerations may need to be addressed through specialized analytical approaches and possibly larger sample sizes.

Few clinical trials are entirely explanatory or pragmatic; trials exist on a continuum where any given trial contains elements of both in different proportions. The PRECIS-2 system offers a way of thinking about and visualizing explanatory and pragmatic aspects of clinical trial design.

More information and tools for assessing PCT designs for feasibility can be found in the Assessing Feasibility chapter of the Living Textbook.

Can Traditional RCTs Be Pragmatic?

Many traditional RCTs are optimized for their explanatory power. In other words, they are designed to detect differences in the effects of an intervention on particular prespecified parameters. The populations enrolled in such trials are typically highly selected to exclude conditions that could affect the study endpoints and obscure treatment differences. While RCTs often have a high degree of internal validity, they may be less generalizable to unselected patient populations in which many individuals have comorbid conditions that would lead them to be excluded from participation in the trial. For example, it is relatively common for patients with cardiovascular conditions to also have chronic kidney disease, but the latter condition is an exclusion criterion in many cardiovascular RCTs.

Large Simple Trials

Because traditional RCTs may lack generalizability, are designed to maximize explanatory power, and often require extensive and expensive infrastructure to ensure compliance with complex study protocols, they generally do not conform to the "pragmatic" paradigm. However, although the "pragmatic" terminology is relatively recent, the basic ideas have been implemented for some time in community-based and school-based studies and in clinical research under the rubric of "large simple trials." Large simple trials use simplified protocols that focus on collecting only the data that are immediately relevant to the prespecified endpoints; they also typically feature relatively nonrestrictive eligibility criteria.