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对于具有较高受试者个体间差异的药物进行生物等效性(BE)和生物类似性评价时,使用通常的双单侧检验(TOST)法既十分困难,甚至也不可能;除非不考虑伦理规范,而进行大样本的人体试验。因此,美国食品药品管理局(FDA)和欧盟药品管理局(EMA)等监管机构对高个体差异药品的生物等效性评价分别颁布了替代方法。这2个监管机构的替代方法依据相同的原理,但是关键细节略有不同。FDA建议当受试者个体间差异超过30%时,使用“标化均值生物等效性”(scaled-average BE,SABE)评价;该方式使用已有计算机软件通过线性转换来计算等效性的95%上限;并要求采用第2级标准评价:两产品间相关参数的几何均值之比的点评估(point estimate)在0.80到1.25之间。而EMA则建议采用“带扩展限度的平均生物等效性”(average BE with expanding limits,ABEL)进行高个体差异药品的评价;该方式与SABE方式相关,但可以使用简单的双单侧检验方法进行评估;EMA也要求采用相同的第,2级标准评价,且要求这2个标准仅适用于受试者个体间差异不超过50%的情形。这2个机构采用了不同的监管常数(等效性评价指标)。FDA建议的计算指标会使生物等效限不连续,且所需样本量大,并且在CV=30%附近有很高的I型误差。而EMA的评价指标不会产生这种不连续性,I型误差也很低。总之,EMA的评价方法更好。
The usual two-sided test (TOST) is difficult or even impossible when evaluating the bioequivalence (BE) and bio-similarity of drugs with higher inter-individual differences Ethical norms, and large samples of human trials. As a result, regulators such as the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have separately promulgated alternative approaches to assessing the bioequivalence of highly differentiated drugs. The alternatives for the two regulators follow the same principle, but the key details are slightly different. The FDA recommends using the “scaled-average BE” (SABE) rating when subjects differ more than 30%; this method uses the existing computer software to calculate the equivalent by linear transformation 95% upper limit of sex; and requires the use of Level 2 criteria: Point estimates for the geometric mean ratio of the relevant parameters between the two products range from 0.80 to 1.25. The EMA, however, recommends the use of the “average BE with expanding limits (ABEL)” for the evaluation of highly differentiated drugs; this approach is related to the SABE approach, but a simple double-sided Test methods; EMA also requires the same level 2 and 2 criteria to be evaluated, and requires that these 2 criteria apply only if the individual differences do not exceed 50%. These two agencies have adopted different regulatory constants (equivalent evaluation indicators). The FDA-calculated calculation will result in discontinuities in the bioequivalence limit and a large sample size, with a very high type I error around CV = 30%. The EMA evaluation index will not produce this discontinuity, I type error is very low. In short, EMA’s evaluation method is better.