An Exact Procedure for the Evaluation of Reference-Scaled Average Bioequivalence
An Exact Procedure for the Evaluation of Reference-Scaled Average Bioequivalence
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DOI：
10.1208/s12248-016-9873-6
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发表时间：
2016-03-01
期刊：
影响因子：
4.5
通讯作者：
Endrenyi, Laszlo
中科院分区：
文献类型：
--
作者：
Tothfalusi, Laszlo;Endrenyi, Laszlo
参考标度平均生物等效性(RSABE)已被美国食品和药物管理局(FDA)推荐，并以其密切相关的形式被欧洲药品管理局(EMA)用于高可变(HV)和窄治疗指数(NTI)药物产品的生物等效性(BE)测定。FDA建议用近似法评估RSABE。寻求开发一种替代的、数值精确的方法。提出了一种新的评估RSABE的算法，称为Exact。这是基于观察到的RSABE的统计模型服从非中心t分布。对于交叉研究设计和平行分组研究设计，得到了分布参数。对HV和NTI药物的模拟BE研究比较了建议的确切方法与FDA和EMA推荐的方法的功率和消费者风险。准确的方法通常比FDA的方法具有更高的威力。在某些异方差条件下，除部分重复设计外，两种方法的消费者风险均低于标称误差风险。RSABE的估计量是有偏的；模拟证明了Hgees修正的正确性。FDA的方法还有另一个小而有意义的偏见。基于导出的精确解析公式，RSABE的可信区间是一致最强的。在标准情况下，它们的计算只需要一行程序脚本。该算法假定这两种配方的受试者内方差的估计值都是可用的。采用部分重复设计时，每种算法的消费者风险均高于5%。
Reference-scaled average bioequivalence (RSABE) has been recommended by Food and Drug Administration (FDA), and in its closely related form by European Medicines Agency (EMA), for the determination of bioequivalence (BE) of highly variable (HV) and narrow therapeutic index (NTI) drug products. FDA suggested that RSABE be evaluated by an approximating procedure. Development of an alternative, numerically exact approach was sought. A new algorithm, called Exact, was derived for the assessment of RSABE. It is based upon the observation that the statistical model of RSABE follows a noncentral t distribution. The parameters of the distribution were derived for crossover and parallel-group study designs. Simulated BE studies of HV and NTI drugs compared the power and consumer risk of the proposed Exact method with those recommended by FDA and EMA. The Exact method had generally slightly higher power than the FDA approach. The consumer risks of the Exact and FDA procedures were generally below the nominal error risk with both methods except for the partial replicate design under certain heteroscedastic conditions. The estimator of RSABE was biased; simulations demonstrated the appropriateness of Hedges' correction. The FDA approach had another, small but meaningful bias. The confidence intervals of RSABE, based on the derived exact, analytical formulas, are uniformly most powerful. Their computation requires in standard cases only a single-line program script. The algorithm assumes that the estimates of the within-subject variances of both formulations are available. With each algorithm, the consumer risk is higher than 5% when the partial replicate design is applied.