Division of Medical Oncology, Princess Margaret Cancer Centre and University of Toronto, Toronto, ON, Canada; Optimal Cancer Care Alliance, Ann Arbor, MI, USA.
IDDI (International Drug Development Institute), Louvain-la-Neuve, Belgium; I-BioStat, Hasselt University, Hasselt, Belgium.
Lancet Oncol. 2024 Oct;25(10):e520-e525. doi: 10.1016/S1470-2045(24)00218-3.
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".
减少已批准治疗方案毒性和成本的机会受到限制，因为人们认为替代方案必须不劣于已批准的方案。非劣效性试验规模大且昂贵，因为它们必须从统计学上表明，替代方案和已批准的疗法在单一结果上存在差异，差异幅度要远小于证明优越性所需的幅度。非劣效性的缺陷显而易见：它忽略了在多次评估已批准疗法时预计会出现的可变性，未能认识到具有类似设计的试验将根据其是在已批准治疗的初始注册之前还是之后进行而被标记为优越性或非劣效性，并且将毒性和成本等终点排除在外。例如，虽然通常需要 3 个月的毒性和成本更低的治疗方案来证明其疗效不劣于 6 个月的标准治疗方案，但该标准疗法没有这样的义务来证明其优越性。这种情况就是非劣效性试验的暴政：其统计数据使成本效益较低的方案得以延续，这些方案不是以患者为中心的，即使较不密集的疗法提供的生存获益几乎与标准疗法相同，因为替代方案承担了不成比例的证明负担。这种方法是不合逻辑的。我们建议放弃将试验指定为优越性或非劣效性，并建议今后将随机对照试验简单地描述为“比较”。
