Wu Ying, Zhao Liang, Hou Yan, Li Kang, Zhou Xiaohua
Department of Epidemiology and Biostatistics, Public Health College, Harbin Medical University, Harbin, 150081, Heilongjiang, China.
Stat Med. 2015 Mar 15;34(6):950-65. doi: 10.1002/sim.6392. Epub 2014 Dec 23.
The three-arm clinical trial design, which includes a test treatment, an active reference, and placebo control, is the gold standard for the assessment of non-inferiority. In the presence of non-compliance, one common concern is that an intent-to-treat (ITT) analysis (which is the standard approach to non-inferiority trials), tends to increase the chances of erroneously concluding non-inferiority, suggesting that the per-protocol (PP) analysis may be preferable for non-inferiority trials despite its inherent bias. The objective of this paper was to develop statistical methodology for dealing with non-compliance in three-arm non-inferiority trials for censored, time-to-event data. Changes in treatment were here considered the only form of non-compliance. An approach using a three-arm rank preserving structural failure time model and G-estimation analysis is here presented. Using simulations, the impact of non-compliance on non-inferiority trials was investigated in detail using ITT, PP analyses, and the present proposed method. Results indicate that the proposed method shows good characteristics, and that neither ITT nor PP analyses can always guarantee the validity of the non-inferiority conclusion. A Statistical Analysis System program for the implementation of the proposed test procedure is available from the authors upon request.
三臂临床试验设计包括试验治疗组、活性对照组和安慰剂对照组，是评估非劣效性的金标准。在存在不依从性的情况下，一个常见的问题是意向性分析（ITT，这是非劣效性试验的标准方法）往往会增加错误得出非劣效性结论的可能性，这表明尽管存在固有偏差，但对于非劣效性试验而言，符合方案分析（PP）可能更可取。本文的目的是开发用于处理三臂非劣效性试验中删失的事件发生时间数据的不依从性的统计方法。这里将治疗改变视为不依从性的唯一形式。本文提出了一种使用三臂秩保持结构失效时间模型和G估计分析的方法。通过模拟，使用ITT、PP分析以及本文提出的方法详细研究了不依从性对非劣效性试验的影响。结果表明，所提出的方法具有良好的特性，并且ITT和PP分析都不能始终保证非劣效性结论的有效性。作者可应要求提供用于实施所提出检验程序的统计分析系统程序。
