Most non-inferiority trials were not designed to preserve active comparator treatment effects

Abstract Objective To evaluate whether non-inferiority trials are designed to adequately preserve the historical treatment effect of their active comparators. Study design and setting We reviewed 162 non-inferiority trials published in high impact medical journals. We assessed whether trials were designed to ensure that interventions could only be declared non-inferior if they preserved at least 50% of the active comparator’s historical treatment effect. Results Only 25 of 162 trials (15%) were designed so that interventions could only be declared non-inferior if they preserved at least 50% of the active comparator’s historical treatment effect. Most trials did not provide evidence that the active comparator was effective (n=101), provided inadequate evidence (n=18), or used a non-inferiority margin that was too wide (n=18). In a subset of 61 non-inferiority trials which referenced a prior randomized trial or meta-analysis evaluating the active comparator, only 25 (41%) used a non-inferiority margin small enough to preserve at least 50% of the active comparator’s treatment effect. Overall, 14 of 162 non-inferiority trials (9%) would have allowed the intervention to be declared non-inferior even if it was worse than either placebo or another historical control. Conclusion Most non-inferiority trials published in major medical journals could allow erroneous declarations of non-inferiority.