The path to regulatory qualification of cerebrospinal fluid biomarkers as enrichment tools in clinical trials of patients with early Alzheimer’s disease: For the coalition against major diseases

The exponential growth in patient needs, the tremendous personal and societal burden, the high cost of basic and clinical research, and the enormous investments of pharmaceutical companies to develop new therapies for Alzheimer's disease (AD) remain a big challenge. Despite the identification and proof of clinical utility for cerebrospinal fluid (CSF) biomarkers with a link to the pathophysiology in the brains of affected subjects, their obligatory role and integration in clinical trial protocols will only be realized when the biomarkers can be endorsed by authorities worldwide. Therefore, the Coalition Against Major Diseases (CAMD), a consortium under the umbrella of the non-profit organization Critical Path Institute, aims to develop and qualify specific CSF proteins for enrichment in clinical trials of patients with early AD. Through collaborative partnerships between industry, academia, regulatory agencies, and patient advocacy groups, CAMD focuses on the development and regulatory qualification of clinical trials tools, such as CSF biomarkers, to increase the efficiency and speed and diminish the risks and costs of drug development. The CSF measures proposed for qualification will be applicable independent of the specific drug's mechanism of action/target and independent of the particular assay. We will differentiate the process for regulatory approval of an “in vitro diagnostic assay” and a “companion diagnostic.” Critical success factors for achieving regulatory endorsement include precompetitive data sharing, consensus science, engagement of diverse stakeholders and alignment with other public-private partnerships, including efforts to establish reference methods and materials. The approach will focus on CSF amyloid-beta 1-42, tau and/or phosphorylated tau, analytes known to be linked to the pathological hallmarks of AD. At present, the use of CSF immunoassay formats with regulatory approvable analytical performance characteristics will support the quantification of these analytes. The development of a robust evidentiary package to support the qualification of CSF amyloid and tau markers for use in clinical trials of patients with AD requires significant resources and commitment from a wide range of stakeholders. Successful FDA biomarker qualification of CSF markers is expected to accelerate the advent of new therapies for patients with AD.