Shen Meiyu, Dong Xiaoyu, Tsong Yi
a Office of Biostatistics , /Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration , Silver Spring , Maryland , USA.
J Biopharm Stat. 2015;25(2):269-79. doi: 10.1080/10543406.2014.979196.
The cut point of the immunogenicity screening assay is the level of response of the immunogenicity screening assay at or above which a sample is defined to be positive and below which it is defined to be negative. The Food and Drug Administration Guidance for Industry on Assay Development for Immunogenicity Testing of Therapeutic recommends the cut point to be an upper 95 percentile of the negative control patients. In this article, we assume that the assay data are a random sample from a normal distribution. The sample normal percentile is a point estimate with a variability that decreases with the increase of sample size. Therefore, the sample percentile does not assure at least 5% false-positive rate (FPR) with a high confidence level (e.g., 90%) when the sample size is not sufficiently enough. With this concern, we propose to use a lower confidence limit for a percentile as the cut point instead. We have conducted an extensive literature review on the estimation of the statistical cut point and compare several selected methods for the immunogenicity screening assay cut-point determination in terms of bias, the coverage probability, and FPR. The selected methods evaluated for the immunogenicity screening assay cut-point determination are sample normal percentile, the exact lower confidence limit of a normal percentile (Chakraborti and Li, 2007) and the approximate lower confidence limit of a normal percentile. It is shown that the actual coverage probability for the lower confidence limit of a normal percentile using approximate normal method is much larger than the required confidence level with a small number of assays conducted in practice. We recommend using the exact lower confidence limit of a normal percentile for cut-point determination.
免疫原性筛选试验的切点是免疫原性筛选试验的反应水平，在该水平及以上，样本被定义为阳性，在该水平以下，样本被定义为阴性。美国食品药品监督管理局（Food and Drug Administration）发布的《治疗性药物免疫原性测试的分析方法开发行业指南》建议切点为阴性对照患者的第95百分位数上限。在本文中，我们假设分析数据是来自正态分布的随机样本。样本正态百分位数是一个点估计值，其变异性随样本量的增加而减小。因此，当样本量不足时，样本百分位数不能在高置信水平（如90%）下确保至少5%的假阳性率（FPR）。出于这一考虑，我们建议使用百分位数的较低置信限作为切点。我们对统计切点的估计进行了广泛的文献综述，并从偏差、覆盖概率和FPR等方面比较了几种用于免疫原性筛选试验切点确定的选定方法。为免疫原性筛选试验切点确定评估的选定方法包括样本正态百分位数、正态百分位数的精确较低置信限（Chakraborti和Li，2007）以及正态百分位数的近似较低置信限。结果表明，在实际进行的少量试验中，使用近似正态方法得到的正态百分位数较低置信限的实际覆盖概率远大于所需的置信水平。我们建议使用正态百分位数的精确较低置信限来确定切点。
