What are pragmatic and explanatory trials, and what are their designs and relative advantages?

Pragmatic and Explanatory Trials: Design and Relative Advantages

Pragmatic trials and explanatory trials exist on a continuum, with pragmatic trials designed to evaluate effectiveness in real-world conditions while explanatory trials test efficacy under ideal conditions. 1

Definitions and Core Concepts

• Explanatory trials aim to answer the question: "Can this intervention work under ideal conditions?" These trials test whether an intervention is efficacious in an optimal environment. 1, 2

• Pragmatic trials seek to answer the question: "Does this intervention work under usual conditions?" These trials measure effectiveness in real clinical practice settings. 1, 3

• Most trials are not purely pragmatic or explanatory but fall along a pragmatic-explanatory continuum, with elements of both approaches. 1, 2

Design Characteristics

Explanatory Trial Design

• Employs strict inclusion/exclusion criteria to create a homogeneous study population 3
• Implements rigorous control of variables other than the intervention 3
• Prioritizes internal validity (reliability/accuracy of results) over external validity 3
• Often uses blinding and concealed randomization to neutralize patient preference and other participative factors 4
• Typically conducted in specialized research settings with highly trained staff 2

Pragmatic Trial Design

• Uses few exclusion criteria to maximize generalizability to routine practice 1, 3
• Allows flexibility in intervention interpretation and management decisions 3
• Prioritizes external validity (generalizability of results) while maintaining adequate internal validity 3
• Often incorporates patient preferences and other participative factors that influence real-world effectiveness 4
• May utilize cluster randomization to decrease contamination bias in non-blinded trials 3
• Frequently collects implementation outcomes to study strategies for uptake and sustainability in real-world settings 1

The PRECIS-2 Framework

• The Pragmatic-Explanatory Continuum Indicator Summary (PRECIS-2) uses a 9-domain approach to assess trial design pragmatism: 1, 5

  • Eligibility criteria
  • Recruitment
  • Trial setting
  • Organization (how care delivery is achieved)
  • Flexibility of delivery
  • Flexibility of adherence
  • Follow-up
  • Primary outcome
  • Primary analysis

• Each domain is scored from 1 (very explanatory) to 5 (very pragmatic) to facilitate discussion and ensure trial design aligns with intended use of results 1

Relative Advantages

Advantages of Explanatory Trials

• Maximize internal validity through rigorous control of variables 3
• Provide clear evidence of efficacy under ideal conditions 2
• Reduce confounding factors through randomization and blinding 1
• Balance both measurable and unmeasurable confounders through randomization 1
• Essential for establishing causal relationships between interventions and outcomes 2

Advantages of Pragmatic Trials

• Maximize external validity and generalizability to routine clinical practice 3, 6
• Include broader, more representative patient populations 1
• Account for real-world factors like patient preferences and adherence issues 4
• Provide evidence on relative effectiveness in routine clinical practice 6
• Can be integrated with routine clinical care, potentially reducing research costs 1
• Help bridge the gap between research and practice by producing directly applicable results 6, 2

Common Pitfalls and Challenges

• Pragmatic trials may overly compromise internal validity in pursuit of generalizability 3
• Explanatory trial results often fail to be broadly generalizable to real-world settings 2
• Balancing pragmatic and explanatory elements requires careful consideration of study objectives 5
• Data collection in pragmatic trials must avoid changing routine care to maintain generalizability 6
• Different stakeholders (clinicians, researchers, policymakers) may have different preferences regarding trial design 6

Practical Applications

• Pragmatic trials are particularly valuable for comparative effectiveness research and public health interventions 4
• Explanatory trials are essential for establishing initial efficacy before broader implementation 2
• Large, simple pragmatic trials can be integrated with routine clinical care to bridge evidence gaps 1
• Cluster randomized trials (like REACT and REACT2 trials in IBD) represent pragmatic approaches to comparing treatment algorithms in community practices 1

In conclusion, both pragmatic and explanatory trials serve important but different purposes in advancing medical knowledge. The choice between designs should be guided by the specific research question, with recognition that most trials incorporate elements of both approaches along the pragmatic-explanatory continuum. 1, 2