Correlation of screening and confirmatory results in tiered immunogenicity testing by solution-phase bridging assays

Kubiak, Robert; Zhang, Lanju; Zhang, Jianchun; Zhu, Yuan; Lee, Nancy; Weichold, Frank F.; Yang, Harry; Abraham, Varghese; Akufongwe, P. F.; Hewitt, Lisa A.; Robinson, Susan; Liu, Weiyi; Liu, Xu; Patnaik, Mun Mun; Spitz, Susan; Wu, Yuling; Roskos, Lorin

doi:10.1016/j.jpba.2012.10.027

Cited by 23 publications

(12 citation statements)

References 18 publications

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“…This could be caused by conservative outlier exclusion during determination of assay cut points [71] and failure to differentiate between analytical and biological variability [72]. The use of non-orthogonal confirmatory assays can also contribute to excessive false positives [73,74].…”

Section: Immunogenicity Assays For Biosimilar Programsmentioning

confidence: 99%

2020 White Paper on Recent Issues in Bioanalysis: Vaccine Assay Validation, qPCR Assay Validation, QC for CAR-T Flow Cytometry, NAb Assay Harmonization and ELISpot Validation ( Part 3 –Recommendations on Immunogenicity Assay Strategies, NAb Assays, Biosimilars and FDA/EMA Immunogenicity Guidance/Guideline, Gene & Cell Therapy and Vaccine Assays)

et al. 2021

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The 14th edition of the Workshop on Recent Issues in Bioanalysis (14th WRIB) was held virtually on June 15-29, 2020 with an attendance of over 1000 representatives from pharmaceutical/biopharmaceutical companies, biotechnology companies, contract research organizations, and regulatory agencies worldwide. The 14th WRIB included three Main Workshops, seven Specialized Workshops that together spanned 11 days in order to allow exhaustive and thorough coverage of all major issues in bioanalysis, biomarkers, immunogenicity, gene therapy and vaccine. Moreover, a comprehensive vaccine assays track; an enhanced cytometry track and updated Industry/Regulators consensus on BMV of biotherapeutics by LCMS were special features in 2020. As in previous years, this year's WRIB continued to gather a wide diversity of international industry opinion leaders and regulatory authority experts working on both small and large molecules to facilitate sharing and discussions focused on improving quality, increasing regulatory compliance and achieving scientific excellence on bioanalytical issues. This 2020 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop and is aimed to provide the Global Bioanalytical Community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2020 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 3) covers the recommendations on Vaccine, Gene/Cell Therapy, NAb Harmonization and Immunogenicity). Part 1 (Innovation in Small Molecules, Hybrid LBA/LCMS & Regulated Bioanalysis), Part 2A (BAV, PK LBA, Flow Cytometry Validation and Cytometry Innovation) and Part 2B (Regulatory Input) are published in volume 13 of Bioanalysis, issues 4 and 5 (2020), respectively.

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Section: Immunogenicity Assays For Biosimilar Programsmentioning

confidence: 99%

2020 White Paper on Recent Issues in Bioanalysis: Vaccine Assay Validation, qPCR Assay Validation, QC for CAR-T Flow Cytometry, NAb Assay Harmonization and ELISpot Validation ( Part 3 –Recommendations on Immunogenicity Assay Strategies, NAb Assays, Biosimilars and FDA/EMA Immunogenicity Guidance/Guideline, Gene & Cell Therapy and Vaccine Assays)

et al. 2021

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“…Statistical procedures, particularly the outlier analysis, recommended for CP determination tend to reduce biological variability and may result in cut points that are very low and do not represent the entire population. It is expected that tiered testing should reduce the number of false positives; however, due to correlation of the screening and confirmatory responses, the tiered assays with low CP may generate a significant number of false positives [78]. It was agreed that it may be appropriate to evaluate setting up CP rules in the future to better differentiate the true positive samples, particularly for ultrasensitive assays.…”

Section: Issues In Cut Point Determination and Ada Assay Drug Tolerance And Sensitivitymentioning

confidence: 99%

“…To determine the SSCP for monoclonal antibodies using a small sample size with few or no repeats, one approach discussed was Rosner's multiple-outlier test for outlier identification. Also used were non-normal Bayesian hierarchical models (e.g., Johnson SU or skew-t) to separate biological and analytical variation, and then estimate the CP as a conservative low bound on a quantile of the posterior predictive distribution of future signals [78,82]. Although statistical methods for cut-point calculations have been discussed in several statistical and white papers in the last decade, less pronounced emphasis has been given to outlier detection approaches as a key component of cut-point determination.…”

Section: Issues With Dynamic Nab Biosimilar Cut Points and Outliersmentioning

confidence: 99%

2018 White Paper on Recent Issues in Bioanalysis: Focus on Flow Cytometry, Gene Therapy, Cut Points and Key Clarifications on Bav (Part 3 – Lba/Cell-Based Assays: Immunogenicity, Biomarkers and Pk Assays)

et al. 2018

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The remaining list of author names, affiliations and Regulatory Agencies Disclaimer can be found at the end of the articleThe 2018 12 th Workshop on Recent Issues in Bioanalysis took place in Philadelphia, PA, USA on April 9-13, 2018 with an attendance of over 900 representatives from pharmaceutical/biopharmaceutical companies, biotechnology companies, contract research organizations and regulatory agencies worldwide. WRIB was once again a 5-day full immersion in bioanalysis, biomarkers and immunogenicity. As usual, it was specifically designed to facilitate sharing, reviewing, discussing and agreeing on approaches to address the most current issues of interest including both small-and large-molecule bioanalysis involving LCMS, hybrid LBA/LCMS and LBA/cell-based assays approaches. This 2018 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2018 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 3) covers the recommendations for large molecule bioanalysis, biomarkers and immunogenicity using LBA and cell-based assays. Part 1 (LCMS for small molecules, peptides, oligonucleotides and small molecule biomarkers) and Part 2 (hybrid LBA/LCMS for biotherapeutics and regulatory agencies' inputs) are published in volume 10 of Bioanalysis, issues 22 and 23 (2018), respectively.

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“…As expected, screening cut points established using reagents stored in PBS (and containing aggregates) were much higher than those obtained with reagents stored in HSB (little or no aggregation) with the difference being approximately 4-fold for disease A population and almost 15-fold for disease B population. It should be noted that all cut point values were obtained after removal of statistical outliers following the customary procedures detailed in [ 15 , 16 ]. The elevated screening cut point values obtained with the PBS reagent preparations were caused by broadening of signal distributions in both disease A and disease B populations.…”

Section: Resultsmentioning

confidence: 99%

“…Confirmatory assay percent inhibition values were calculated as % Inhibition = 100% [1 − (Response in the presence of drug)/(Response in the absence of drug)]. The screening and confirmatory cut points were obtained with the respective false positive rates set to 5% and 1% using statistical methods described in detail elsewhere [ 15 , 16 ].…”

Section: Methodsmentioning

confidence: 99%

Storage Conditions of Conjugated Reagents Can Impact Results of Immunogenicity Assays

Kubiak¹,

Lee²,

Zhu³

et al. 2016

Journal of Immunology Research

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Consistent performance of anti-drug antibody (ADA) assays through all stages of clinical development is critical for the assessment of immunogenicity and interpretation of PK, PD, safety, and efficacy. The electrochemiluminescent assays commonly employed for ADA measurement use drug conjugated with ruthenium and biotin to bind ADA in samples. Here we report an association between high nonspecific ADA responses in certain drug-naïve individuals and the storage buffer of the conjugated reagents used in a monoclonal antibody ADA assay. Ruthenylated reagents stored in phosphate-buffered saline (PBS) buffer had increased levels of aggregate and produced variable and high baseline responses in some subjects. Reagents stored in a histidine-sucrose buffer (HSB) had lower aggregate levels and produced low sample responses. In contrast to PBS, conjugated reagents formulated in HSB remained low in aggregate content and in sample response variability after 5 freeze/thaw cycles. A reagent monitoring control (RMC) serum was prepared for the real-time evaluation of conjugated reagent quality. Using appropriate buffers for storage of conjugated reagents together with RMCs capable of monitoring of reagent aggregation status can help ensure consistent, long-term performance of ADA methods.

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Correlation of screening and confirmatory results in tiered immunogenicity testing by solution-phase bridging assays

Cited by 23 publications

References 18 publications

2018 White Paper on Recent Issues in Bioanalysis: Focus on Flow Cytometry, Gene Therapy, Cut Points and Key Clarifications on Bav (Part 3 – Lba/Cell-Based Assays: Immunogenicity, Biomarkers and Pk Assays)

Storage Conditions of Conjugated Reagents Can Impact Results of Immunogenicity Assays

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