BackgroundNon‐inferiority trials comparing different active drugs are often subject to treatment non‐adherence. Intention‐to‐treat (ITT) and per‐protocol (PP) analyses have been advocated in such studies but are not guaranteed to be unbiased in the presence of differential non‐adherence.MethodsThe REMoxTB trial evaluated two 4‐month experimental regimens compared with a 6‐month control regimen for newly diagnosed drug‐susceptible TB. The primary endpoint was a composite unfavorable outcome of treatment failure or recurrence within 18 months post‐randomization. We conducted a simulation study based on REMoxTB to assess the performance of statistical methods for handling non‐adherence in non‐inferiority trials, including: ITT and PP analyses, adjustment for observed adherence, multiple imputation (MI) of outcomes, inverse‐probability‐of‐treatment weighting (IPTW), and a doubly‐robust (DR) estimator.ResultsWhen non‐adherence differed between trial arms, ITT, and PP analyses often resulted in non‐trivial bias in the estimated treatment effect, which consequently under‐ or over‐inflated the type I error rate. Adjustment for observed adherence led to similar issues, whereas the MI, IPTW and DR approaches were able to correct bias under most non‐adherence scenarios; they could not always eliminate bias entirely in the presence of unobserved confounding. The IPTW and DR methods were generally unbiased and maintained desired type I error rates and statistical power.ConclusionsWhen non‐adherence differs between trial arms, ITT and PP analyses can produce biased estimates of efficacy, potentially leading to the acceptance of inferior treatments or efficacious regimens being missed. IPTW and the DR estimator are relatively straightforward methods to supplement ITT and PP approaches.

中文翻译：

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评估不依从干预措施的非劣效性试验的疗效：意向治疗和符合方案分析是否符合目的？

背景比较不同活性药物的非劣效性试验通常会受到治疗不依从性的影响。此类研究中提倡进行意向治疗 (ITT) 和符合方案 (PP) 分析，但在存在差异性不依从性的情况下，不能保证无偏倚。 方法 REMoxTB 试验评估了两种为期 4 个月的实验方案，与针对新诊断的药物敏感结核病的 6 个月控制方案。主要终点是随机分组后 18 个月内治疗失败或复发的复合不利结果。我们进行了一项基于 REMoxTB 的模拟研究，以评估处理非劣效性试验中不依从性的统计方法的性能，包括：ITT 和 PP 分析、观察到的依从性调整、结果的多重插补 (MI)、逆概率结果当试验组之间的不依从性存在差异时，ITT 和 PP 分析通常会导致估计治疗效果出现重大偏差，从而导致治疗效果不足或过度夸大了 I 类错误率。对观察到的依从性进行调整会导致类似的问题，而 MI、IPTW 和 DR 方法能够纠正大多数非依从性场景下的偏差；在存在未观察到的混杂因素的情况下，他们并不总是能够完全消除偏见。 IPTW 和 DR 方法通常是无偏的，并保持了所需的 I 型错误率和统计功效。结论当试验组之间的不依从性存在差异时，ITT 和 PP 分析可能会产生对疗效的有偏差的估计，可能导致接受较差的治疗或有效的方案被错过。 IPTW 和 DR 估计器是补充 ITT 和 PP 方法的相对简单的方法。