Betensky R A
Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
Stat Med. 1997 Feb 28;16(4):465-77. doi: 10.1002/(sici)1097-0258(19970228)16:4<465::aid-sim384>3.0.co;2-r.
For ethical and efficiency concerns one often wishes to design a clinical trial to stop early if there is a strong treatment effect or if there is strong evidence of no treatment effect. There is a large literature to address the design of sequential trials for detecting treatment differences. There has been less attention paid to the design of trials for detecting lack of a treatment difference and most of the designs proposed have been ad hoc modifications of the traditional designs. In the context of fixed sample tests, various authors have proposed basing the decision to stop in favour of the null hypothesis, H0, on conditional power calculations for the end of the trial given the current data. Here I extend this procedure to the popular sequential designs: the O'Brien-Fleming test and the repeated significance test. I derive explicit boundaries for monitoring the test statistic useful for visualizing the impact of the parameters on the operating characteristics of the tests and thus for the design of the tests. Also, they facilitate the use of boundary crossing methods for approximations of power. I derive appropriate boundaries retrospectively for two clinical trials: one that concluded with no treatment difference (AIDS Clinical Trials Group protocol 118) and one that stopped early for positive effect (Beta-Blocker Heart Attack Trial). Finally, I compare the procedures based on the different upper boundaries and assess the impact of allowing for early stopping in favour of H0 in numerical examples.
出于伦理和效率方面的考虑，人们常常希望设计一项临床试验，以便在存在显著治疗效果或有充分证据表明无治疗效果时提前终止。有大量文献探讨了用于检测治疗差异的序贯试验设计。然而，对于检测无治疗差异的试验设计关注较少，并且大多数提出的设计都是对传统设计的临时修改。在固定样本检验的背景下，许多作者提议根据给定当前数据的试验结束时的条件检验效能计算，做出支持原假设H0的停止决策。在此，我将此方法扩展到常用的序贯设计：奥布赖恩 - 弗莱明检验和重复显著性检验。我推导出了用于监测检验统计量的明确边界，这有助于直观展示参数对检验操作特征的影响，从而用于检验设计。此外，它们便于使用边界交叉方法来近似检验效能。我回顾性地为两项临床试验推导出了合适的边界：一项试验得出无治疗差异的结论（艾滋病临床试验组方案118），另一项试验因积极效果而提前终止（β受体阻滞剂心肌梗死试验）。最后，我在数值示例中比较了基于不同上限边界的方法，并评估了支持原假设H0而允许提前终止的影响。
