Background Noninferiority (NI) and equivalence trials evaluate whether an experimental therapy’s effect on the primary endpoint (PEP) is contained within an acceptable margin compared to 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. Methods A meta-epidemiological study was performed of phase 3 randomized NI and equivalence oncologic trials registered at ClinicalTrials.gov. Data was extracted from each trial’s registration page and primary manuscript. Results We identified 65 NI and 10 equivalence trials that collectively enrolled 61,632 patients. Sixty-one trials (81%) demonstrated NI or equivalence. Sixty-five trials (87%) were justified in the use of an NI or equivalence design either because of an inherent advantage (53 trials), a significant quality-of-life improvement (6 trials), or a significant toxicity improvement (6 trials) of the interventional treatment relative to the control arm. Sixty-nine trials (92.0%) reported a prespecified NI or equivalence margin, of which only 23 (33.3%) provided justification for this margin based on prior literature. For trials with time-to-event PEPs, the median NI margin was a hazard ratio of 1.22 (range, 1.08-1.52). Investigators reported a per-protocol (PP) analysis for the PEP in only 28 trials (37%). Conclusions Although most published NI and equivalence trials have clear justification for their design, few provide rationale for the chosen margin or report a PP analysis. These findings underscore the need for rigorous standards in trial design and reporting.

中文翻译：

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肿瘤学非劣效性和等效性试验的合理性、边缘值和分析人群：一项荟萃流行病学研究


背景非劣效性 （NI） 和等效性试验评估与标准护理相比，实验性治疗对主要终点 （PEP） 的影响是否包含在可接受的范围内。然而，这一结论的可靠性和影响在很大程度上取决于这种设计的合理性、边际的选择和所使用的分析人群。方法 对 ClinicalTrials.gov 年注册的 3 期随机 NI 和等效肿瘤学试验进行了 meta 流行病学研究。从每项试验的注册页面和原始手稿中提取数据。结果 我们确定了 65 项 NI 和 10 项等效试验，共招募了 61,632 名患者。61 项试验 （81%） 证明 NI 或等效性。65 项试验 （87%） 由于干预治疗相对于对照组的固有优势（53 项试验）、生活质量的显著改善（6 项试验）或毒性显著改善（6 项试验）而证明使用 NI 或等效设计是合理的。69 项试验 （92.0%） 报告了预先指定的 NI 或等效边距，其中只有 23 项 （33.3%） 根据先前的文献提供了该边距的合理性。对于具有事件发生时间 PEP 的试验，中位 NI 边缘的风险比为 1.22 （范围，1.08-1.52）。研究人员报告了仅在 28 项试验 （37%） 中对 PEP 进行符合方案 （PP） 的分析。结论 尽管大多数已发表的 NI 和等效试验都有明确的理由支持其设计，但很少有人为所选的边缘提供理由或报告 PP 分析。这些发现强调了试验设计和报告需要严格的标准。