Abstract Per FDA guidance, method comparability should be established if an anti-drug antibody (ADA) assay is run by two or more independent laboratories during a study. Genentech, Inc. is evaluating an immunogenicity risk-based comparability approach consisting of both technical and clinical aspects. Technical comparability of the relative sensitivity (RS) is assessed using the Two One-Sided T-tests (TOST) statistical analysis which evaluates if the difference (in absolute value) of the RS means of the two laboratories is less than a pre-specified level of comparability, the practically significant difference (PSD). Clinical comparability is based on the molecule’s immunogenicity risk. A basic and in-depth assessment for low and high-risk molecules are used, respectively. An alternative strategy for molecules with limited incurred sample availability is to be used. In the basic assessment, samples are either unfortified or fortified with surrogate ADA positive control at method appropriate concentrations in a representative biological matrix. Acceptable comparability requires in both methods i) at least 80% of the unfortified samples screen and confirm negative, ii) at least 90% of the low concentration samples screen and confirm positive; and iii) 100% of the high concentration samples screen and confirm positive. The in-depth assessment uses at least 100 incurred samples from 30 or more ADA-positive and ADA-negative patients. The results are evaluated using a 2 by 2-confusion matrix and Cohen’s Kappa score where 1 indicates perfect agreement. Acceptable comparability requires a Cohen’s Kappa score of greater than 0.40. This strategy allows for a robust technical and clinical method comparability assessment. Graphical Abstract

R. J. Elliott

T. Pourmohamad

Y. Webb-Vargas

W. Yan

I. Nijem

P. Siguenza

Y. Song

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AAPS Journal is the official journal of the American Association of Pharmaceutical Scientists (AAPS), publishing novel and significant findings across various fields of pharmaceutical science that impact human and veterinary therapeutics. The main topics include: drug design and discovery, pharmaceutical biotechnology, biopharmaceuticals, formulation and drug delivery, metabolism and transport, pharmacokinetics, pharmacodynamics, translational research, clinical evaluation and therapeutic outcomes, and regulatory science. We invite submissions of the following article types: original research articles, reviews and mini-reviews, white papers, commentaries and editorials, conference reports, brief/technical reports and rapid communications, regulatory guidelines, tutorials, and pharmaceutical science protocols. Additionally, AAPS Journal publishes themed issues organized by guest editors, focusing on specific areas of current interest in our field.

AAPS Journal 是美国药物科学家协会 (AAPS) 的官方期刊，发表影响人类和兽医治疗的药物科学各个领域的新颖而重要的发现。主要涵盖以下主题：药物设计与发现、制药生物技术、生物制药、制剂与药物递送、代谢与运输、药代动力学、药效学、转化研究、临床评估与治疗结果以及监管科学。我们欢迎以下类型的文章提交：原创研究文章、评论与小型评论、白皮书、评论与社论、会议报告、简要/技术报告与快速通信、监管说明、教程及药物科学协议。此外，AAPS Journal 还发布由客座编辑组织的主题，重点关注我们领域当前感兴趣的特定领域。

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医学, 药学	3

Bioanalytical Method Comparison Strategy for Clinical Anti-drug Antibody Immunoassays

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PHARMACOLOGY & PHARMACY	1