Table 4.

Recommended use of pragmatic and explanatory trial designs for particular clinical scenarios

	Suggested trial design
Comparative effectiveness research comparing two standard-of-care therapies (eg, anticoagulation strategies)	Pragmatic trial suggested; trial represents minimal additional risk beyond those of routine clinical care
Evaluation of a medication that is already in common clinical use but not approved for the studied indication (off-label), compared with a control (usual care or a placebo)	Pragmatic trial preferred; trial represents minimal additional risk beyond those of routine clinical care
Evaluation of a medication that is approved for another indication but is not approved or already in common clinical use for the studied indication	Explanatory trial preferred; trial represents substantial risks to participants beyond those of routine clinical care and requires traditional informed consent and adverse event monitoring; however, efficiency could be improved by transitioning to a more pragmatic design as safety data become available from early participants, which could be accomplished using pre-planned adaptive trial designs (similar to the seamless phase 2/3 designs used in drug development trials)
Evaluation of a novel, unapproved treatment	Explanatory trial suggested; benefits and risks of treatment are unknown; trial represents substantial risks to participants beyond those of routine clinical care and requires traditional informed consent and adverse event monitoring
Evaluation of a complex or time-intensive intervention that is not in clinical use (eg, a novel mode of ventilation that requires frequent assessments and titration)	Explanatory trial suggested; benefits and risks of treatment are unknown; trial represents substantial risks to participants beyond those of routine clinical care and requires traditional informed consent; intervention fidelity and patient safety require additional resources that are unlikely to be present in routine clinical care