Abbvie, Inc, North Chicago, Illinois, USA.
B2S Consulting, 6656 Flowstone Way, Indianapolis, Indiana, 46237, USA.
AAPS J. 2017 Sep;19(5):1487-1498. doi: 10.1208/s12248-017-0107-3. Epub 2017 Jul 21.
Today, the assessment of immunogenicity is integral in nonclinical and clinical testing of new biotherapeutics and biosimilars. A key component in the risk-based evaluation of immunogenicity involves the detection and characterization of anti-drug antibodies (ADA). Over the past couple of decades, much progress has been made in standardizing the generalized approach for ADA testing with a three-tiered testing paradigm involving screening, confirmation, and quasi-quantitative titer assessment representing the typical harmonized scheme. Depending on a biotherapeutic's structural attributes, more characterization and testing may be appropriate. Unlike bioanalytical assays used to support the evaluation of pharmacokinetics or toxicokinetics, an important component in immunogenicity testing is the calculation of cut points for the identification (screening), confirmation (specificity), and titer assessment responses in animals and humans. Several key publications have laid an excellent foundation for statistical design and data analysis to determine immunogenicity cut points. Yet, the process for statistical determination of cut points remains a topic of active discussion by investigators who conduct immunogenicity assessments to support biotherapeutic drug development. In recent years, we have refined our statistical approach to address the challenges that have arisen due to the evolution in biotherapeutics and the analytical technologies used for quasi-quantitative detection. Based on this collective experience, we offer a simplified statistical analysis process and flow-scheme for cut point evaluations that should work in a large majority of projects to provide reliable estimates for the screening, confirmatory, and titering cut points.
如今，免疫原性评估是新型生物疗法和生物类似药非临床和临床测试不可或缺的一部分。免疫原性基于风险评估的一个关键组成部分涉及到抗药物抗体 (ADA) 的检测和特征描述。在过去的几十年中，在标准化 ADA 测试的通用方法方面取得了很大进展，采用了涉及筛选、确证和准定量滴度评估的三层测试范例，这代表了典型的协调方案。根据生物疗法的结构属性，可能需要进行更多的特征描述和测试。与用于支持药代动力学或毒代动力学评估的生物分析测定不同，免疫原性测试的一个重要组成部分是计算用于识别（筛选）、确证（特异性）和动物和人类滴度评估反应的切点。有几个关键出版物为确定免疫原性切点的统计设计和数据分析奠定了良好的基础。然而，对于进行免疫原性评估以支持生物疗法药物开发的研究人员来说，确定切点的统计过程仍然是一个活跃的讨论话题。近年来，我们改进了我们的统计方法，以解决由于生物疗法的发展和用于准定量检测的分析技术而出现的挑战。基于这种集体经验，我们提供了简化的统计分析过程和切点评估流程图，该过程和流程图应适用于大多数项目，为筛选、确证和滴度切点提供可靠的估计。
