A meta-epidemiological analysis of post-hoc comparisons and primary endpoint interpretability among randomized...

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.

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.

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.

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.