Table 1 Sources of heterogeneity in pragmatic trials as compared to explanatory trials

Patients and setting of included centres

May try to limit enrolment to academic centres and centres with a more homogeneous patient case mix.

Usually have a large number of selection criteria, some of which may be designed to include a homogeneous group of patients more likely to respond to treatment, adhere to treatment and complete follow-up.

Deliberately include a variety of centres, possibly with a heterogeneous patient case mix.

Usually have fewer selection criteria so as to deliberately include a diversity of patients who will qualify for the treatment in clinical practice.

Intervention and control

Treatments are highly protocolised; enforce strict adherence to the protocol in each arm; co-interventions are not allowed or are limited and specified in detail; blind patients and providers to eliminate performance bias and subjectivity in assessment of outcomes.

Permit some tailoring while keeping core interventions common across all sites and for all participants; do not enforce adherence to protocol; permit co-interventions that would be used in target sites and settings after the intervention is shown to be effective; avoid using placebo; avoid blinding patients or providers.

Outcome

Standardised outcome assessment; use central adjudication; blind outcome assessors to eliminate subjectivity in assessment of outcomes.

Favour objective outcomes, relevant for both patients and physicians; standardisation, adjudication and blinding of outcome assessors should be discouraged except if there is a risk of biasing the trial result.

Regulatory and ethical issues

Requirement for written, informed consent from all participants; vulnerable participants (e.g. patients with co-morbidities or lacking decision-making capacity) commonly excluded.

In some cases, “clinical-style” or integrated consent may be permitted. Vulnerable participants generally included.