Use of Mortality as an Endpoint in Noninferiority Trials May Lead to Ethically Problematic Conclusions.

BACKGROUND: Noninferiority trials are becoming more common. Their design often requires investigators to "trade" a secondary benefit for efficacy. Use of mortality as an outcome of interest leads to important ethical conflicts whereby researchers must establish a minimal clinically important difference for mortality, a process which has the potential to result in problematic conclusions.

OBJECTIVE: We sought to investigate the frequency of the use of mortality as an outcome in noninferiority trials, as well as to determine the average pre-specified noninferiority ("delta") values.

DESIGN: We searched MEDLINE for reports of parallel-group randomized controlled noninferiority trials published in five high-impact general medical journals.

MAIN OUTCOME MEASURES: Data abstracted from articles including trial design parameters, results, and interpretation of results based on CONSORT recommendations.

RESULTS: One hundred seventy-three manuscripts reporting 196 noninferiority comparisons were included in our analysis. Of these, over a third (67 trials) used mortality either as their sole endpoint (11 trials) or as part of a composite endpoint (56 trials). Nine trials were consort A, 21 trials consort B, 19 trials consort C, 12 were consort F, 4 consort G, and 2 were consort H. Four analyses showed statistically significant more deaths in the new treatment arm, while meeting consort criteria as "inconclusive" (consort G), (Behringer et al. in Lancet. 385(9976):1418-1427, 2015; Kaul et al. in N Engl J Med. 373(18):1709-1719, 2015; Bwakura-Dangarembizi et al. in N Engl J Med. 370(1):41-53, 2014) and thirteen trials utilizing mortality as an endpoint and had an absolute increase of > 3%, and six had an absolute increase of > 5%.

CONCLUSIONS: The use of mortality as an outcome in noninferiority trials is not rare and scenarios where the new treatment is statistically worse, but a conclusion of noninferiority or inconclusive do occur. We highlight these issues and propose simple steps to reduce the risk of ethically dubious conclusions.