Nanopharm Ltd, an Aptar Pharma Company, Cavendish House, Hazell Drive, Newport, NP10 8FY, UK.
AAPS J. 2020 Oct 26;22(6):139. doi: 10.1208/s12248-020-00520-6.
This study used statistical simulations to investigate the performance of the population bioequivalence test applied to image-based particle size measurements (such as morphologically directed Raman spectroscopy) and methods for designing in vitro bioequivalence trials using prior information. Simulations of in vitro population bioequivalence trials were conducted across a range of representative D (number-weighted median particle diameter from a log-normal particle size distribution) and span (which is defined as [Formula: see text] where D and D are the number-weighted 90th and 10th percentiles in particle diameters sampled from a log-normal particle size distribution) values respectively. The performance of the population bioequivalence test in the simulations was driven by an interplay between overall test variability and the widening or narrowing of the bioequivalence region due to variance terms in the test statistic definition. These findings were dependent upon differences in the variability of D and span and may generalise to a wider range of in vitro metrics. Trial design optimisation using power and assurance approaches followed patterns consistent with these findings. As more novel scientific methods are applied to the development of complex generic drug products, the procedures outlined in this study may be used at the inception stage of future in vitro bioequivalence trials to reduce the risk of conducting costly trials with low probabilities of success.
本研究采用统计模拟方法，探讨了基于图像的粒度测量（如形态导向的拉曼光谱）的群体生物等效性检验方法的性能，以及使用先验信息设计体外生物等效性试验的方法。在一系列具有代表性的 D（对数正态粒度分布的数重中值粒径）和跨度（定义为[公式：见正文]，其中 D 和 D 是对数正态粒度分布中采样的粒径的数重 90%和 10%分位数）值范围内，进行了体外群体生物等效性试验的模拟。模拟中，群体生物等效性检验的性能受到总体检验变异性和由于检验统计定义中的方差项导致的生物等效性区域变宽或变窄的相互作用的驱动。这些发现取决于 D 和跨度的变异性差异，并且可能推广到更广泛的体外指标范围。使用功效和保证方法进行的试验设计优化遵循与这些发现一致的模式。随着更多新的科学方法应用于复杂仿制药产品的开发，本研究中概述的程序可在未来体外生物等效性试验的初始阶段使用，以降低进行成功率低的昂贵试验的风险。
