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

BackgroundNoninferiority 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.ObjectiveWe 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.DesignWe searched MEDLINE for reports of parallel-group randomized controlled noninferiority trials published in five high-impact general medical journals.Main Outcome MeasuresData abstracted from articles including trial design parameters, results, and interpretation of results based on CONSORT recommendations.ResultsOne 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%.ConclusionsThe 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.