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In a preference clinical trial (PCT), two or more health-care interventions are compared among several groups of patients, at least some of whom have purposefully chosen the intervention to be administered to them. This stands in contrast to the randomized, controlled clinical trial (RCT), where patients are randomly assigned to receive one of the available test interventions. This article argues that when comparing two interventions, A and B, when blinding (or masking) the interventions is difficult or impossible and at least some of the potential participants prefer one or the other of the interventions, then the use of a PCT merits consideration. PCTs can be designed in several different ways, and the selection should be driven by the clinical question posed. PCTs also fall towards the pragmatic endpoint of the explanatory/pragmatic clinical trial continuum, suggesting that they may more favorably influence clinical decision-making in real-world contexts. Researchers often want to know not what is the best treatment irrespective of choice and compliance, but whether an intervention can work for the patients who choose it. If we want to answer the latter question, we must let patients choose.