Chowdhury Shrabanti, Tiwari Ram C, Ghosh Samiran
a Center of Molecular Medicine and Genetics , Wayne State University , Detroit , MI , USA.
b Division of Biostatistics , CDRH, FDA , Silver Spring , MD , USA.
J Biopharm Stat. 2019;29(3):425-445. doi: 10.1080/10543406.2019.1572616. Epub 2019 Feb 11.
For an existing established drug regimen, active control trials are defacto standard due to ethical reason as well as for clinical equipoise. However, when superiority claim of a new drug against the active control is unlikely to be successful, researchers often address the issue in terms of noninferiority (NI), provided the experimental drug demonstrates the evidence of other benefits beyond efficacy. Such trials aim to demonstrate that an experimental treatment is non-inferior to an existing comparator by not more than a pre-specified margin. The issue of choosing such a margin is complex. In this article, two-arm NI trials with binary outcomes are considered when margin is defined in terms of relative risk or odds ratio. A Frequentist test based on proposed NI margin is developed first. Since two-arm NI trials without placebo arm are dependent upon historical information, in order to make accurate and meaningful interpretation of their results, a Bayesian approach is developed next. Bayesian approach is flexible to incorporate the available information from the historical trial. The operating characteristics of the proposed methods are studied in terms of power and sample size for varying design factors. A clinical trial data is reanalyzed to study the properties of the proposed approach.
对于现有的既定药物治疗方案，由于伦理原因以及临床 equipoise，活性对照试验实际上是标准做法。然而，当一种新药相对于活性对照的优效性声明不太可能成功时，研究人员通常会从非劣效性（NI）的角度来解决这个问题，前提是实验药物除了疗效之外还能证明有其他益处。此类试验旨在证明一种实验性治疗不比现有对照差超过预先指定的界值。选择这样一个界值的问题很复杂。在本文中，当界值根据相对风险或比值比来定义时，考虑具有二元结局的双臂 NI 试验。首先开发了一种基于提议的 NI 界值的频率学派检验。由于没有安慰剂组的双臂 NI 试验依赖于历史信息，为了对其结果进行准确且有意义的解释，接下来开发了一种贝叶斯方法。贝叶斯方法在纳入来自历史试验的可用信息方面具有灵活性。针对不同的设计因素，从检验效能和样本量的角度研究了所提方法的操作特征。重新分析了一个临床试验数据以研究所提方法的特性。
