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Global Biomarker Standardization Consortium: CSF Reference Method Sub-group Chairs: Kaj Blennow & Henrik Zetterberg 1 Goal • Quantify concentration of analyte as accurately as possible in the certified reference material to then be used to compare other methods and platforms available – Assumptions - Reference method for AB42 will be independent of antibody - Reference method will be used to measure absolute levels of AB42 in certified reference material (i.e. certified batch of native premortem human CSF) and will be used as standard of truth. - Reference method will be fully validated and compliant with GCP best practice. - Reference method will use universally accepted reference calibrators - Out-of-scope?? - Comparison of correlation of current immunoassay methodologies (Bland-Altman) to “gold standard” reference method - Identifying diagnostic cut-points for individual immunoassays. 2 Methods to evaluate (for pros/cons) • • • • • • • MRM published by Waters et al… Absorbance/HPLC based methods PPD (Randy Jenkins)- Assay from ICAD poster Caprion/Covance Proteome Sciences - “validated” ab42 assay C2N – quant ab42 and “total ab” assay Immunoassay based approaches – MSD, Myriad RBM, INNX/Fujirebio • … • Note: need request validation reports from each. 3 Reference Methods Issues • • • • • • • • • • • • Issue: are we considering what is available today or what may need to get developed Consideration of pre-analytic methods and their impact on the analytical methods Oligomer vs monomer of Ab42 What is the minimum validation required? What is the quality standard? What is overall target goal? FDA clearance or approval, operate in research space only? Resources to achieve the goals? Suggest pull EMA opinions based on BMS submission regarding CSF biomarkers MSD-RUO initially, require more than MSD alone if tied to drug or indication, working on how take to next level, what are clinical study design and samples for a PMA . . .Individual Dx would use the reference method as part of the PMA. Invite DX companies: OCD, Roche to the “table”, CRO have done “validated” Pfizer/ICON, BARC, and Covance Issue: is method/assay validated and available? Where should it be done? What should the universal reference standard be – how will this be decided? Immunoassays see many fragments of AB and tau – which fragments will be measured by the reference method? 4 Terms to be Defined • • • • • • • • • • • • Certified Reference Material Universal Reference Calibrators NIST IFCC IRMM Quality Control Samples Reference method Traceability Validation Primary calibrators Reference calibrators Working calibrators 5 Actions – Nov th 29 2011 • Group to start compiling validation reports for measurement of AB42, T-Tau by MRM mass spec or HPLC. – Holly – C2N, PPD – OMAR – Waters/Millipore – Charlotte – Proteome Sciences – Caprion/Covance - Bob 6