Kleber Troy J, Sherry Alexander D, Arifin Andrew J, Kupferman Gabrielle S, Kouzy Ramez, Abi Jaoude Joseph, Lin Timothy A, Beck Esther J, Miller Avital M, Passy Adina H, McCaw Zachary R, Msaouel Pavlos, Ludmir Ethan B
Department of Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States.
Division of Radiation Oncology, London Health Sciences Centre/Western University, London, Canada.
J Natl Cancer Inst. 2025 May 1;117(5):898-906. doi: 10.1093/jnci/djae318.
Noninferiority and equivalence trials evaluate whether an experimental therapy's effect on the primary endpoint is contained within an acceptable margin compared with standard of care. The reliability and impact of this conclusion, however, is largely dependent on the justification for this design, the choice of margin, and the analysis population used.
A meta-epidemiological study was performed of phase 3 randomized noninferiority and equivalence oncologic trials registered at ClinicalTrials.gov. Data were extracted from each trial's registration page and primary manuscript.
We identified 65 noninferiority and 10 equivalence trials that collectively enrolled 61 632 patients. Of these, 61 (81%) trials demonstrated noninferiority or equivalence. A total of 65 (87%) trials were justified in the use of a noninferiority or equivalence design either because of an inherent advantage (53 trials), a statistically significant quality-of-life improvement (6 trials), or a statistically significant toxicity improvement (6 trials) of the interventional treatment relative to the control arm. Additionally, 69 (92.0%) trials reported a prespecified noninferiority or equivalence margin of which only 23 (33.3%) provided justification for this margin based on prior literature. For trials with time-to-event primary endpoints, the median noninferiority margin was a hazard ratio of 1.22 (range = 1.08-1.52). Investigators reported a per-protocol analysis for the primary endpoint in only 28 (37%) trials.
Although most published noninferiority and equivalence trials have clear justification for their design, few provide rationale for the chosen margin or report a per-protocol analysis. These findings underscore the need for rigorous standards in trial design and reporting.
非劣效性试验和等效性试验旨在评估与标准治疗相比，实验性治疗对主要终点的影响是否在可接受范围内。然而，这一结论的可靠性和影响力很大程度上取决于该设计的合理性、界值的选择以及所使用的分析人群。
对在ClinicalTrials.gov注册的3期随机非劣效性和等效性肿瘤试验进行了一项元流行病学研究。数据从每个试验的注册页面和主要手稿中提取。
我们确定了65项非劣效性试验和10项等效性试验，共纳入61632例患者。其中，61项（81%）试验显示出非劣效性或等效性。共有65项（87%）试验采用非劣效性或等效性设计是合理的，原因包括干预性治疗相对于对照臂具有固有优势（53项试验）、生活质量有统计学意义的改善（6项试验）或毒性有统计学意义的改善（6项试验）。此外，69项（92.0%）试验报告了预先设定的非劣效性或等效性界值，其中只有23项（33.3%）根据先前文献为该界值提供了依据。对于具有事件发生时间主要终点的试验，非劣效性界值的中位数为风险比1.22（范围=1.08-1.52）。研究者仅在28项（37%）试验中报告了针对主要终点的符合方案分析（即按方案分析）。
尽管大多数已发表的非劣效性和等效性试验对其设计有明确的合理性依据，但很少有试验为所选界值提供理由或报告符合方案分析。这些发现强调了在试验设计和报告中需要严格标准。
