Use of Mortality as an Endpoint in Noninferiority Trials May Lead to Ethically Problematic Conclusions
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.
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.
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.
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%.
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.
KEY WORDSnoninferiority trials medical ethics clinical trials outcomes measures
Contributions made to the following manuscript by the listed authors include conception and design: AH, RW, and SA; analysis and interpretation of data: AH and SA; and drafting and editing of the manuscript: AH, RW, and SA.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they do not have a conflict of interest.
- 10.von Birgelen C, Sen H, Lam MK, et al. Third-generation zotarolimus-eluting and everolimus-eluting stents in all-comer patients requiring a percutaneous coronary intervention (DUTCH PEERS): a randomised, single-blind, multicentre, non-inferiority trial. Lancet. 2014;383(9915):413–423.CrossRefGoogle Scholar
- 11.Pilgrim T, Heg D, Roffi M, et al. Ultrathin strut biodegradable polymer sirolimus-eluting stent versus durable polymer everolimus-eluting stent for percutaneous coronary revascularisation (BIOSCIENCE): a randomised, single-blind, non-inferiority trial. Lancet. 2014;384(9960):2111–2122.CrossRefGoogle Scholar
- 13.Raungaard B, Jensen LO, Tilsted HH, et al. Zotarolimus-eluting durable-polymer-coated stent versus a biolimus-eluting biodegradable-polymer-coated stent in unselected patients undergoing percutaneous coronary intervention (SORT OUT VI): a randomised non-inferiority trial. Lancet. 2015;385(9977):1527–1535.CrossRefGoogle Scholar
- 24.Christiansen EH, Jensen LO, Thayssen P, et al. Biolimus-eluting biodegradable polymer-coated stent versus durable polymer-coated sirolimus-eluting stent in unselected patients receiving percutaneous coronary intervention (SORT OUT V): a randomised non-inferiority trial. Lancet. 2013;381(9867):661–669.CrossRefGoogle Scholar
- 38.Mulvenna P, Nankivell M, Barton R, et al. Dexamethasone and supportive care with or without whole brain radiotherapy in treating patients with non-small cell lung cancer with brain metastases unsuitable for resection or stereotactic radiotherapy (QUARTZ): results from a phase 3, non-inferiority, randomised trial. Lancet. 2016;388(10055):2004–2014.CrossRefGoogle Scholar