Michael Tsui1, Sunita Rehal2, Vipul Jairath3, Brennan C Kahan4. 1. Schulich School of Medicine and Dentistry, 1151 Richmond St, London, Ontario N6A 5C1, Canada. 2. MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, 90 High Holborn, London WC1V 6LJ, UK. 3. Department of Medicine, University of Western Ontario, 1151 Richmond St, London, Ontario N6A 5C1, Canada; Department of Epidemiology and Biostatistics, University of Western Ontario, 1151 Richmond St, London, Ontario N6A 5C1, Canada. 4. Pragmatic Clinical Trials Unit, Queen Mary University of London, London, E1 2AB UK. Electronic address: b.kahan@qmul.ac.uk.
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.
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.