Table 1.

Design and conduct of pragmatic versus explanatory trials for acute care research

	Explanatory trials	Pragmatic trials
Patient population	Inclusion criteria are tight, often with multiple exclusion criteria, intended to minimise the number of patients needed to detect a treatment effect, including any of the following approaches: •Creating a homogeneous trial population (to minimise statistical noise) •Enrolling patients who are likely to respond to the treatment (predictive enrichment) •Enrolling patients who are likely to experience the primary outcome (prognostic enrichment) •Excluding patients who are expected to have poor adherence to treatment or follow-up •Excluding patients with comorbidities that might lead to poor outcomes through mechanisms other than those targeted by the trial intervention (competing risks) •Excluding patients at high risk of adverse events on the basis of their age or comorbidities	Inclusion criteria are broad, with few exclusions; trial population tends to be larger and more similar to those who receive treatment as part of usual care
Recruitment and enrolment	Screening and enrolment are conducted by a research team, separate from treating clinicians	Screening (identification of trial candidates) and enrolment are conducted by treating clinicians (embedded in routine care)
Delivery of intervention	Intervention is delivered by the research team in a way that differs from delivery in usual care, including the following approaches: •Providing additional study-specific resources (eg, a study physician dedicated solely to ventilator titration for enrolled participants) •Providing substantial levels of trial-specific training on the delivery of the intervention beyond what would be available during future clinical use •Using experts to deliver the intervention (eg, using plastic surgeons in a trial that compares available techniques for repairing lacerations even though this is normally done by emergency medicine physicians in routine care) •Incorporating additional measures to improve adherence to treatment •Incorporating co-interventions into the protocol to minimise variability	Intervention is delivered in the way that it would be delivered as part of usual care outside of a trial (eg, by treating clinicians without any additional trial-specific resources or training)
Follow-up	Follow-up is more intense than would occur in usual care, and can include: •Additional research visits •Follow-up phone calls to increase treatment adherence or measure outcomes •Clinical visits triggered by study outcomes or adverse events in a way that might mitigate their severity	Treatment and follow-up are performed as they would be in usual care with minimal (if any) trial-specific follow-up
Primary outcome	Outcomes might not be relevant to patients (eg, surrogate outcomes, biomarkers, laboratory or radiographic outcomes) or might require testing that would not occur in usual care (adjudication of the primary outcome(s) by a blinded panel of experts, study-specific imaging, biopsies)	Patient-centred outcomes are routinely available from data collected as part of usual care (eg, mortality, intubation, hospital admission)

The considerations presented here are adapted from the PRagmatic Explanatory Continuum Indicator Summary 2 (PRECIS-2) tool,³⁰ which can be used to aid design decisions consistent with the intended purpose of a trial. This validated tool has nine domains—eligibility criteria, recruitment, setting, organisation, flexibility (delivery), flexibility (adherence), follow-up, primary outcome, and primary analysis—scored from 1 (very explanatory) to 5 (very pragmatic) to facilitate design decisions.