Blinded sample size reassessment in non‐inferiority and equivalence trials
Blinded sample size reassessment in non‐inferiority and equivalence trials
复制标题
非劣效性和等效性试验中的盲样样本量重新评估
作者：
T. Friede;M. Kieser
即使在临床试验的设计和实施高度标准化的情况下，观察到的主要结果变量的变异性也可能存在相当大的研究间差异。因此，以固定样本量设计进行研究意味着存在导致样本量过高或过低的相当大的风险。通过应用内部试点研究的设计可以缓解这一困难。在计划阶段进行临时样本量计算后，将招募一部分计划样本，并根据观察到的变异性重新计算样本量。为了符合一些监管指南的要求，重新评估程序只能使用盲法数据。此外，应该量化对 I 类错误率的影响。目前的文献仅针对优效性试验提供了 t 检验情况下实际水平的分析结果。在这些情况下，盲样本大小重新计算不会导致 I 类错误率的膨胀。我们将该方法扩展到具有正态分布结果变量的非劣效性和等效性试验以及根据均值比率和差值制定的假设。令人惊讶的是，与测试优越性的情况相比，我们观察到实际的 I 类错误率高于名义水平。膨胀的程度取决于所需的样本量、内部试点研究的样本量以及标准化等效性或非劣效性裕度。事实证明，对于大多数实际情况，显着性水平的提升可以忽略不计。然而，样本量重新评估的后果必须逐案讨论，并且通常不能通过仅使用盲数据这一事实来反驳对程序实际规模的监管担忧。版权所有 © 2003 约翰·威利父子有限公司
Even in situations where the design and conduct of clinical trials is highly standardized, there may be a considerable between‐study variation in the observed variability of the primary outcome variable. As a consequence, performing a study in a fixed sample size design implies a considerable risk of resulting in a too high or too low sample size. This difficulty can be alleviated by applying a design with internal pilot study. After a provisional sample size calculation in the planning stage, a portion of the planned sample is recruited and the sample size is recalculated on the basis of the observed variability. To comply with the requirement of some regulatory guidelines only blinded data should be used for the reassessment procedure. Furthermore, the effect on the type I error rate should be quantified. The current literature presents analytical results on the actual level in the t‐test situation only for superiority trials. In these situations, blinded sample size recalculation does not lead to an inflation of the type I error rate. We extended the methodology to non‐inferiority and equivalence trials with normally distributed outcome variable and hypotheses formulated in terms of the ratio and difference of means. Surprisingly, in contrast to the case of testing superiority, we observed actual type I error rates above the nominal level. The extent of inflation depends on the required sample size, the sample size of the internal pilot study, and the standardized equivalence or non‐inferiority margin. It turned out that the elevation of the significance level is negligible for most practical situations. Nevertheless, the consequences of sample size reassessment have to be discussed case by case and regulatory concerns with respect to the actual size of the procedure cannot generally be refuted by referring to the fact that only blinded data were used. Copyright © 2003 John Wiley & Sons, Ltd.
影响因子：
2
作者：
Wittes, J;Schabenberger, O;Proschan, M
通讯作者：
Proschan, M