Pragmatic clinical trials (PCTs) differ from "traditional" randomized controlled trials (RCTs) largely in terms of their overall 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; their ultimate goal is "to improve practice and policy." Califf and Sugarman (2015) propose the following “common sense” definition for a PCT when 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 study (including the study population) are not representative of more typical patient-treatment settings. 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 the electronic health record (EHR). However, less restrictive criteria, a lesser degree of fidelity to intervention, and a lesser degree of monitoring/compliance results in data that are "messier" or less complete, and may also be more subject to changes in the healthcare delivery mechanisms. These considerations may need to be addressed through specialized analytical approaches and possibly larger sample sizes.

Importantly, very few trials are entirely explanatory or pragmatic, but exist on a continuum where any given trial contains elements of both in different proportions. The PRECIS-2 system provides one way of thinking about and visualizing explanatory and pragmatic aspects of clinical trial design.

Additional detailed information and checklists for assessing pragmatic trial designs for feasibility can be found in the Assessing Feasibility section of this resource.

Can Traditional RCTs Be Pragmatic?

Many traditional randomized trials are optimized for their explanatory power. That is, they are designed to detect differences in the effect of an intervention on particular prespecified parameters. The populations enrolled in such trials are typically highly selected in order to exclude conditions that could affect the study endpoints and obscure measurements of treatment differences. As noted in the previous section, while RCTs often have a high degree of internal validity, they may be less generalizable to unselected patient populations where many individuals will have the kinds of comorbid conditions that often result in being excluded from participation in RCTs. For example: it is relatively common for patients with cardiovascular conditions to also suffer from chronic kidney disease, but the latter condition often constitutes an exclusion criterion for 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- and school-based studies and also under the rubric of the "large simple trial" (LST). LSTs typically incorporate extremely simplified protocols that focus on collecting only data that are immediately relevant to the prespecified endpoints; they also typically feature relatively nonrestrictive eligibility criteria.