The tyranny of non-inferiority trials

Opportunities to decrease the toxicity and cost of approved treatment regimens with lower dose, less frequent, or shorter duration alternative regimens have been limited by the perception that alternatives must be non-inferior to approved regimens. Non-inferiority trials are large and expensive to d...

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Bibliographic Details
Published in:The lancet oncology Vol. 25; no. 10; pp. e520 - e525
Main Authors: Tannock, Ian F, Buyse, Marc, De Backer, Mickael, Earl, Helena, Goldstein, Daniel A, Ratain, Mark J, Saltz, Leonard B, Sonke, Gabe S, Strohbehn, Garth W
Format: Journal Article
Language:English
Published: England Elsevier Ltd 01.10.2024
Elsevier Limited
Subjects:
Adjuvants
Cancer therapies
Chemotherapy
Clinical trials
Clinical Trials as Topic
Cost-Benefit Analysis
Drug dosages
Equivalence Trials as Topic
FDA approval
Hematology, Oncology, and Palliative Medicine
Humans
Meta-analysis
Neoplasms - drug therapy
Patient-centered care
Pharmaceutical industry
Research Design
Schedules
Toxicity
United States > US
ISSN:1470-2045, 1474-5488, 1474-5488
Online Access:Get full text
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Summary:Opportunities to decrease the toxicity and cost of approved treatment regimens with lower dose, less frequent, or shorter duration alternative regimens have been limited by the perception that alternatives must be non-inferior to approved regimens. Non-inferiority trials are large and expensive to do, because they must show statistically that the alternative and approved therapies differ in a single outcome, by a margin far smaller than that required to demonstrate superiority. Non-inferiority's flaws are manifest: it ignores variability expected to occur with repeated evaluation of the approved therapy, fails to recognise that a trial of similar design will be labelled as superiority or non-inferiority depending on whether it is done prior to or after initial registration of the approved treatment, and relegates endpoints such as toxicity and cost. For example, while a less toxic and less costly regimen of 3 months duration would typically be required to demonstrate efficacy that is non-inferior to that of a standard regimen of 6 months to displace it, the longer duration therapy has no such obligation to prove its superiority. This situation is the tyranny of the non-inferiority trial: its statistics perpetuate less cost-effective regimens, which are not patient-centred, even when less intensive therapies confer survival benefits nearly identical to those of the standard, by placing a disproportionately large burden of proof on the alternative. This approach is illogical. We propose that the designation of trials as superiority or non-inferiority be abandoned, and that randomised, controlled trials should henceforth be described simply as “comparative”.
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ISSN:1470-2045
1474-5488
1474-5488
DOI:10.1016/S1470-2045(24)00218-3