论文标题
三臂非效率试验中扩展的科赫雷梅尔设计的同时置信区间
Simultaneous confidence intervals for an extended Koch-Röhmel design in three-arm non-inferiority trials
论文作者
论文摘要
对于只有不稳定的参考治疗且安慰剂组的使用可以在道德上是合理的,建议进行三臂“金标准”非效率试验。对于此类试验,已经提出了一些研究设计,该设计使用安慰剂组测试“测定敏感性”,即试验复制功效的能力。如果参考在给定试验中失败,则也可以通过无效的实验治疗表明非效率,因此变得无用。在本文中,我们扩展了所谓的Koch-röhmel设计,其中需要进行实验治疗的功效证明,以便合格非效率测试。尽管实验治疗的功效是测定敏感性的指示,但并不能保证参考具有足够的有效效率,可以让非效率索赔有意义。因此,仅当参考文献表现出对安慰剂的优越性,而在实验治疗中表现出优越性的优势,则建议仅当参考表现出优势,而不是安慰剂,而$δ$以这种方式可以证明对参考的历史效果,则选择了$δ$。在本文中,我们通过与兼容的同时置信区间补充其自适应测试来扩展先前的工作。置信区间通常由非效率试验的监管指南提出并建议。我们展示了如何采用不同的方法来同时置信区间,从文献到三臂非效率试验的设置,并在仿真研究中比较这些方法。最后,我们将这些方法应用于真实的临床试验示例。
Three-arm `gold-standard' non-inferiority trials are recommended for indications where only unstable reference treatments are available and the use of a placebo group can be justified ethically. For such trials several study designs have been suggested that use the placebo group for testing 'assay sensitivity', i.e. the ability of the trial to replicate efficacy. Should the reference fail in the given trial, then non-inferiority could also be shown with an ineffective experimental treatment and hence becomes useless. In this paper we extend the so called Koch-Röhmel design where a proof of efficacy for the experimental treatment is required in order to qualify the non-inferiority test. While efficacy of the experimental treatment is an indication for assay sensitivity, it does not guarantee that the reference is sufficient efficient to let the non-inferiority claim be meaningful. It has therefore been suggested to adaptively test non-inferiority only if the reference demonstrates superiority to placebo and otherwise to test $δ$-superiority of the experimental treatment over placebo, where $δ$ is chosen in such a way that it provides proof of non-inferiority with regard to the reference's historical effect. In this paper we extend the previous work by complementing its adaptive test with compatible simultaneous confidence intervals. Confidence intervals are commonly used and suggested by regulatory guidelines for non-inferiority trials. We show how to adopt different approaches to simultaneous confidence intervals from the literature to the setting of three-arm non-inferiority trials and compare these methods in a simulation study. Finally we apply these methods to a real clinical trial example.