高变异药物生物等效性研究设计的样本量。

Sample sizes for designing bioequivalence studies for highly variable drugs.

机构信息

Semmelweis University, Department of Pharmacodynamics, Budapest, Hungary.

出版信息

J Pharm Pharm Sci. 2012;15(1):73-84. doi: 10.18433/j3z88f.

DOI:10.18433/j3z88f

PMID:22365089

Abstract

PURPOSE

To provide tables of sample sizes which are required, by the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA), for the design of bioequivalence (BE) studies involving highly variable drugs. To elucidate the complicated features of the relationship between sample size and within-subject variation.

METHODS

3- and 4-period studies were simulated with various sample sizes. They were evaluated, at various variations and various true ratios of the two geometric means (GMR), by the approaches of scaled average BE and by average BE with expanding limits. The sample sizes required for yielding 80% and 90% statistical powers were determined.

RESULTS

Because of the complicated regulatory expectations, the features of the required sample sizes are also complicated. When the true GMR = 1.0 then, without additional constraints, the sample size is independent of the intrasubject variation. When the true GMR is increased or decreased from 1.0 then the required sample sizes rise at above but close to 30% variation. An additional regulatory constraint on the point estimate of GMR and a cap on the use of expanding limits further increase the required sample size at high variations. Fewer subjects are required by the FDA than by the EMA procedures.

CONCLUSIONS

The methods proposed by EMA and FDA lower the required sample sizes in comparison with unscaled average BE. However, each additional regulatory requirement (applying the mixed procedure, imposing a constraint on the point estimate of GMR, and using a cap on the application of expanding limits) raises the required number of subjects.

摘要

目的

提供欧洲药品管理局（EMA）和美国食品和药物管理局（FDA）要求的样本量表，用于设计涉及高度变异药物的生物等效性（BE）研究。阐明样本量与个体内变异之间关系的复杂特征。

方法

用各种样本量模拟了 3 期和 4 期研究。通过缩放平均 BE 和扩展限平均 BE 方法，在不同的变异和两个几何均数（GMR）的真实比值下，对它们进行了评估。确定了产生 80%和 90%统计功效所需的样本量。

结果

由于复杂的监管期望，所需样本量的特征也很复杂。当真实 GMR=1.0 时，没有额外的约束，样本量与个体内变异无关。当真实 GMR 从 1.0 增加或减少时，所需的样本量会在 30%以上的变异率上升。对 GMR 的点估计额外的监管限制和对扩展限使用的上限进一步增加了高变异时所需的样本量。与 EMA 程序相比，FDA 需要的受试者更少。