Tsong Yi, Wang Sue Jane, Hung H M James, Cui Lu
Quantitative Methods and Research Staff, OB/CDER/FDA, Rockville, Maryland 20857, USA.
J Biopharm Stat. 2003 Feb;13(1):29-41. doi: 10.1081/BIP-120017724.
In practice, "noninferiority" active-controlled trials have been designed for three different objectives: establishing evidence of efficacy over placebo, preserving a specific percentage of the effect size of the active control, or demonstrating the test treatment is "not much inferior" to the active control. All three objectives can be represented by the same set of statistical hypotheses with the parameters defined differently. The various designs and statistical analysis procedures for active-controlled trials proposed in the literature can be group into two basic types: the historical-controlled trial approach and the cross-study comparison approach. These approaches require some unverifiable constancy assumptions. Under the constancy assumptions, the cross-study comparison uses the estimate effect of active-control treatment as the unbiased estimate of the active/placebo difference in the current noninferiority trial. A normalized Z-statistic is used to test the hypotheses. On the other hand, the historical controlled trial approach uses a conservative confidence limit as if it were a constant to replace the active/placebo difference in the current trial. The two approaches may lead to consistent conclusions only when the constancy assumptions can be supported by a large number of historical studies giving a consistent active-control treatment effect over placebo and that the active-control effect does not change over time.
在实践中，“非劣效性”活性对照试验被设计用于三个不同目标：确立优于安慰剂的疗效证据、保留活性对照效应大小的特定百分比，或证明试验治疗“不比活性对照差太多”。所有这三个目标都可以用同一组统计假设来表示，只是参数定义不同。文献中提出的活性对照试验的各种设计和统计分析程序可分为两种基本类型：历史对照试验方法和跨研究比较方法。这些方法需要一些无法验证的恒定性假设。在恒定性假设下，跨研究比较将活性对照治疗的估计效应用作当前非劣效性试验中活性/安慰剂差异的无偏估计。使用标准化Z统计量来检验假设。另一方面，历史对照试验方法使用一个保守的置信限，就好像它是一个常数，来替代当前试验中的活性/安慰剂差异。只有当恒定性假设能够得到大量历史研究的支持，这些研究给出了一致的活性对照治疗优于安慰剂的效果，并且活性对照效果不随时间变化时，这两种方法才可能得出一致的结论。
