Clinical equipoise (i.e., uncertainty within the expert clinical community) is considered as a prerequisite for a randomized controlled trial (RCT). Indeed, a RCT must start with an “honest null hypothesis”, which indicates controversy in the clinical expert community about the superiority of one of the 2 compared interventions. At the planning stage, randomization may reflect the clinical uncertainty, namely, by the randomization ratio. A 1:1 ratio appears to best fit this state of uncertainty.

We aimed to assess whether the clinical equipoise principle is satisfied in unbalanced RCTs (i.e., with an unequal probability of subjects being allocated to one group than another).

Observational and comparative study between unbalanced and balanced RCTs. We searched the “core clinical journals” of MEDLINE to identify reports of two-parallel–group superiority unbalanced RCTs published between January 2009 and December 2010. For each unbalanced RCT, we identified a maximum of 4 reports (to maximize power) of matched balanced RCTs dealing with the same population. Our primary outcome was the proportion of positive RCTs (i.e., with statistically significant results for the primary outcome [P<0.05], showing greater efficacy with the new treatment than the control treatment).

We selected 46 reports of unbalanced RCTs and 164 of balanced RCTs; 65.2% unbalanced RCTs and 43.9% of balanced RCTs were positive [odds ratio 2.38; 95% confidence interval: 1.23, 4.63]. As compared with balanced RCTs, unbalanced RCTs were more often industry-funded and their control treatments were more often inactive. Adjusting for these latter variables did not modify the results.

This result questions the respect of clinical equipoise in unbalanced RCTs.