Most noninferiority trials were not designed to preserve active comparator treatment effects

Abstract

Objectives: To evaluate whether noninferiority trials are designed to adequately preserve the historical treatment effect of their active comparators.

Study design and setting: We reviewed 162 noninferiority trials published in high-impact medical journals. We assessed whether trials were designed to ensure that interventions could only be declared noninferior 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 noninferior 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 noninferiority margin that was too wide (n = 18). In a subset of 61 noninferiority trials which referenced a prior randomized trial or meta-analysis evaluating the active comparator, only 25 (41%) used a noninferiority margin small enough to preserve at least 50% of the active comparator's treatment effect. Overall, 14 of 162 noninferiority trials (9%) would have allowed the intervention to be declared noninferior even if it was worse than either placebo or another historical control.

Conclusion: Most noninferiority trials published in major medical journals could allow erroneous declarations of noninferiority.

Keywords: Clinical trial; Equivalence trial; Noninferiority trials; Randomized controlled trial.