2021 White Paper on Recent Issues in Bioanalysis: ISR for Biomarkers, Liquid Biopsies, Spectral Cytometry, Inhalation/Oral & Multispecific Biotherapeutics, Accuracy/LLOQ for Flow Cytometry ( Part 2 – Recommendations on Biomarkers/CDx Assays Development & Validation, Cytometry Validation & Innovation, Biotherapeutics PK LBA Regulated Bioanalysis, Critical Reagents & Positive Controls Generation)

Abstract

The 15th edition of the Workshop on Recent Issues in Bioanalysis (15th WRIB) was held on 27 September to 1 October 2021. Even with a last-minute move from in-person to virtual, an overwhelmingly high number of nearly 900 professionals representing pharma and biotech companies, contract research organizations (CROs), and multiple regulatory agencies still eagerly convened to actively discuss the most current topics of interest in bioanalysis. The 15th WRIB included three Main Workshops and seven Specialized Workshops that together spanned 1 week in order to allow exhaustive and thorough coverage of all major issues in bioanalysis, biomarkers, immunogenicity, gene therapy, cell therapy and vaccines. Moreover, in-depth workshops on biomarker assay development and validation (BAV) (focused on clarifying the confusion created by the increased use of the term “context of use” [COU]); mass spectrometry of proteins (therapeutic, biomarker and transgene); state-of-the-art cytometry innovation and validation; and critical reagent and positive control generation were the special features of the 15th edition. This 2021 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 2021 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 2) covers the recommendations on ISR for Biomarkers, Liquid Biopsies, Spectral Cytometry, Inhalation/Oral & Multispecific Biotherapeutics, Accuracy/LLOQ for Flow Cytometry. Part 1A (Endogenous Compounds, Small Molecules, Complex Methods, Regulated Mass Spec of Large Molecules, Small Molecule, PoC), Part 1B (Regulatory Agencies' Inputs on Bioanalysis, Biomarkers, Immunogenicity, Gene & Cell Therapy and Vaccine) and Part 3 (TAb/NAb, Viral Vector CDx, Shedding Assays; CRISPR/Cas9 & CAR-T Immunogenicity; PCR & Vaccine Assay Performance; ADA Assay Comparability & Cut Point Appropriateness) are published in volume 14 of Bioanalysis, issues 9 and 11 (2022), respectively.

The 2022 Lady Estelle Wolfson lectureship on neurofilaments

“…Clinically, it will be important to find out if they are of pathological relevance or only an epiphenomenon? Methodologically, it will be relevant to find out if they interfere with the reliability of the immunoassay by abolishing parallelism (Hersey et al, 2022; Khalil et al, 2018). Tissue specificity.…”

“…This is an important development to move from research use only assays to clinically approved assays. Regarding analytical issues the white paper highlights the need for achieving parallelism (Hersey et al, 2022;Lu et al, 2011) and notes situations where there is a lack of parallelism:…”

“…Another high‐throughput immunoassay has been developed by Siemens Healthineers (Uzgiris et al, 2022). To address these points and downstream effects experts at the interface between pharmacy and regulatory authorities have come together in a very relevant White‐paper (Hersey et al, 2022). This is an important development to move from research use only assays to clinically approved assays.…”

“…This is an important development to move from research use only assays to clinically approved assays. Regarding analytical issues the white paper highlights the need for achieving parallelism (Hersey et al, 2022; Lu et al, 2011) and notes situations where there is a lack of parallelism: Calibrator and analyte are not recognised in the same way which can be the case in presence of aggregates or diversity of antibodies in the endogenous matrix sample Endogenous binding partners interfere A matrix effect …”

“…Assuming appropriate analytical validation recommendations were made for clinical biomarkers as surrogate endpoints of for patient selection/stratification (Hersey et al, 2022): To understand the behaviour of a biomarker in the study population To provide analytical and clinical data for proposing what is the best biomarker for providing a clinical endpoint To engage early with regulatory agencies To carefully and rigorously address the quality control strategy which needs to be sustainable To validate the method pre‐analytically (sample collection and processing), analytically (sensitivity, specificity, precision, stability, accuracy, cutoff point) and clinically (agencies requirements, specific context of use, study risk) …”