ReviewJournal of general internal medicine2019
Use of Mortality as an Endpoint in Noninferiority Trials May Lead to Ethically Problematic Conclusions.
Review in Journal of general internal medicine, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers, 1 of them a synthesis that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
5 citing papers in PubMed, 1 synthesis or guideline pooled it, 9 citations in OpenAlex.
- Testing for non-inferior mortality: a systematic review of non-inferiority margin sizes and trial characteristics.BMJ open · 2021Pooled it
- How can non-inferiority studies with mortality end points be ethically justified?Journal of medical ethics · 2026Article
- Appropriate design and reporting of superiority, equivalence and non-inferiority clinical trials incorporating a benefit-risk assessment: the BRAINS study including expert workshop.Health technology assessment (Winchester, England) · 2023Article
- Review
- Letter About: Use of Mortality as an Endpoint in Noninferiority Trials May Lead to Ethically Problematic Conclusions.Journal of general internal medicine · 2020Article
Corrections and comments
- Commented on by
Authors and funding
3 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
Indexed as
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What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.