Objectives: Randomized noncomparative trials (RNCTs) promise reduced accrual requirements vs randomized controlled comparative trials because RNCTs do not enroll a control group and instead compare outcomes to historical controls or prespecified estimates. We hypothesized that RNCTs often suffer from two methodological concerns: (1) lack of interpretability due to group-specific inferences in nonrandomly selected samples and (2) misinterpretation due to unlicensed between-group comparisons lacking prespecification. The purpose of this study was to characterize RNCTs and the incidence of these two methodological concerns.
Study Design And Setting: We queried PubMed and Web of Science on September 14, 2023, to conduct a meta-epidemiological analysis of published RNCTs in any field of medicine. Trial characteristics and the incidence of methodological concerns were manually recorded.
Results: We identified 70 RNCTs published from 2002 to 2023. RNCTs have been increasingly published over time (slope = 0.28, 95% CI 0.17-0.39, P < .001). Sixty trials (60/70, 86%) had a lack of interpretability for the primary endpoint due to group-specific inferences. Unlicensed between-group comparisons were present in 36 trials (36/70, 51%), including in the primary conclusion of 31 trials (31/70, 44%), and were accompanied by significance testing in 20 trials (20/70, 29%). Only five (5/70, 7%) trials were found to have neither of these flaws.
Conclusion: Although RNCTs are increasingly published over time, the primary analysis of nearly all published RNCTs in the medical literature was unsupported by their fundamental underlying methodological assumptions. RNCTs promise group-specific inference, which they are unable to deliver, and undermine the primary advantage of randomization, which is comparative inference. The ongoing use of the RNCT design in lieu of a traditional randomized controlled comparative trial should therefore be reconsidered.
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