Abstract Bioequivalence (BE) trials are sometimes preceded by a pilot relative bioavailability (BA) trial to investigate whether the test formulation is sufficiently similar to the reference. The geometric mean ratio and its confidence bounds provide guidance as to how the BE trial can be appropriately sized to attain sufficient power. The aim of this work is to optimize the sample size of a pilot BA trial in order to minimize the overall sample size for the combination of pilot and pivotal trials. This is done through specification of a gain function associated with any of two possible outcomes of the trial; that is, abandon further development of the test formulation or proceed to a pivotal BE trial. The gain functions will be constructed on the basis of sample size considerations only, because subject numbers are indicative of both the cost and the feasibility of a clinical trial. Using simulations, it is demonstrated that for drugs with high intrasubject variability, the BA trial should be sufficiently sized to avoid erroneous decision making and to control the overall cost. In contrast, when the intrasubject variability of the pharmacokinetic (PK) parameters is low, not conducting the BA trial should be considered. It is concluded that the rather typical practice of conducting small pilot trials is unlikely to be a cost-effective approach.

中文翻译：

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使用贝叶斯决策理论框架优化相对生物利用度试验中的样本量

摘要 生物等效性 (BE) 试验有时会在试验性相对生物利用度 (BA) 试验之前进行，以调查试验制剂是否与参考制剂足够相似。几何平均比及其置信界限为如何适当调整 BE 试验的规模以获得足够的功效提供指导。这项工作的目的是优化试点 BA 试验的样本量，以最小化试点和关键试验组合的总体样本量。这是通过指定与试验的两种可能结果中的任何一种相关的增益函数来完成的；也就是说，放弃测试配方的进一步开发或进行关键的 BE 试验。增益函数将仅基于样本量考虑构建，因为受试者数量表明了临床试验的成本和可行性。使用模拟表明，对于具有高受试者内变异性的药物，BA 试验的规模应该足够大，以避免错误的决策并控制总体成本。相反，当药代动力学 (PK) 参数的受试者内变异性较低时，应考虑不进行 BA 试验。结论是，进行小型试点试验的相当典型的做法不太可能是一种具有成本效益的方法。当药代动力学 (PK) 参数的受试者内变异性较低时，应考虑不进行 BA 试验。结论是，进行小型试点试验的相当典型的做法不太可能是一种具有成本效益的方法。当药代动力学 (PK) 参数的受试者内变异性较低时，应考虑不进行 BA 试验。结论是，进行小型试点试验的相当典型的做法不太可能是一种具有成本效益的方法。