Many randomized clinical trials may not be justified: a cross-sectional analysis of the ethics and science of randomized clinical trials.

OBJECTIVE: We have proposed that three scientific criteria are important for the ethical justification of randomized clinical trials (RCTs): (1) they should be designed around a clear hypothesis; (2) uncertainty should exist around that hypothesis; (3) that uncertainty should be as established through a systematic review. We hypothesized that the majority of a sample of recently published RCTs would not explicitly incorporate these criteria, therefore rendering them potentially unjustified on scientific grounds.

STUDY DESIGN AND SETTING: Cross-sectional analysis of all RCTs published in the New England Journal of Medicine and the Journal of the American Medical Association in 2015. Each article and protocol was reviewed for: (1) a clearly stated central hypothesis; (2) references to "equipoise," or "consensus;" (3) some indication of evidentiary uncertainty; (4) a meta-analysis or systematic review surrounding the hypothesis or study question.

RESULTS: We included 208 RCT articles and 199 protocols. Among combined articles and protocols, 76% had a clearly stated hypothesis, 99% referenced some form of uncertainty, and 54% cited a relevant systematic review or meta-analysis. Only 44% of combined texts contained all three scientific criteria. There were few references to "equipoise" (10%) or "consensus" (11%), and those references to equipoise were most often inconsistent with accepted definitions.

CONCLUSION: The majority of RCTs (56%) did not meet the three scientific criteria described previously and therefore may be scientifically and therefore ethically unjustified. We recommend that "equipoise," "clinical equipoise," and "lack of consensus" be abandoned as scientific criteria for RCTs and be replaced by an expectation that RCTs have a clearly stated, meaningful hypothesis around which uncertainty has been established through a systematic review of the literature.