The distinction between explanatory and pragmatic trials has shaped the trajectory of clinical research for decades. First introduced by Schwartz and Lellouch in 1967, these concepts underscore two distinct yet complementary approaches to evaluating medical interventions. Explanatory trials are designed to determine efficacy under idealized conditions, whereas pragmatic trials assess effectiveness in the complexity of routine clinical practice.
Explanatory trials are most often employed in the early stages of development. They recruit highly selective patient populations, adhere to rigid protocols, and involve intensive monitoring. This methodology ensures maximum internal validity, enabling researchers to establish whether an intervention can work in principle. For instance, many pivotal Phase II trials adopt an explanatory framework to provide proof of concept before advancing to larger studies. However, the controlled nature of these conditions often limits external validity, making it difficult to extrapolate findings to the diversity of real-world healthcare.
Pragmatic trials, by contrast, are designed to answer whether an intervention does work in everyday practice. They employ broad inclusion criteria, allow flexibility in clinical decision-making, and prioritize outcomes of direct relevance to patients and health systems such as hospital admissions, survival, or quality of life. A prominent example is the Salford Lung Study in the United Kingdom, which assessed an asthma and COPD therapy within routine care settings. This design enrolled patients with multiple comorbidities and tested the intervention under normal clinical workflows, thereby enhancing generalizability.
Rather than representing a binary distinction, explanatory and pragmatic features exist along a continuum. The PRECIS-2 tool, developed in 2015, provides a structured means of characterizing trial design across nine domains, including eligibility criteria, follow-up intensity, and outcome relevance. This framework underscores that many studies integrate elements of both approaches, depending on their scientific and regulatory objectives.
For a global CRO such as Tigermed, this distinction carries significant operational relevance. Explanatory trials remain indispensable for regulatory approval, particularly in early-phase development, where safety and efficacy must be established under controlled conditions. At the same time, pragmatic evidence has become increasingly valuable to payers, clinicians, and policymakers, who require data on whether novel therapies provide meaningful benefit across heterogeneous, real-world populations. As healthcare systems worldwide demand evidence that bridge the gap between controlled research and clinical practice, the ability to design and deliver both explanatory and pragmatic trials have become a strategic necessity.
In summary, explanatory trials determine whether a treatment can work, while pragmatic trials evaluate whether it does work in the settings where it matters most across the full spectrum of patients, providers, and healthcare systems. Modern development strategies depend on leveraging both approaches, ensuring that innovation is supported by evidence that is at once scientifically rigorous and clinically meaningful.
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