Cerebrospinal Fluid Biomarkers for Alzheimer's Disease: A View of the Regulatory Science Qualification Landscape from the Coalition Against Major Diseases CSF Biomarker Team

Abstract

Alzheimer's disease (AD) drug development is burdened with the current requirement to conduct large, lengthy, and costly trials to overcome uncertainty in patient progression and effect size on treatment outcome measures. There is an urgent need for the discovery, development, and implementation of novel, objectively measured biomarkers for AD that would aid selection of the appropriate subpopulation of patients in clinical trials, and presumably, improve the likelihood of successfully evaluating innovative treatment options. Amyloid deposition and tau in the brain, which are most commonly assessed either in cerebrospinal fluid (CSF) or by molecular imaging, are consistently and widely accepted. Nonetheless, a clear gap still exists in the accurate identification of subjects that truly have the hallmarks of AD. The Coalition Against Major Diseases (CAMD), one of 12 consortia of the Critical Path Institute (C-Path), aims to streamline drug development for AD and related dementias by advancing regulatory approved drug development tools for clinical trials through precompetitive data sharing and adoption of consensus clinical data standards. This report focuses on the regulatory process for biomarker qualification, briefly comments on how it contrasts with approval or clearance of companion diagnostics, details the qualifications currently available to the field of AD, and highlights the current challenges facing the landscape of CSF biomarkers qualified as hallmarks of AD. Finally, it recommends actions to accelerate regulatory qualification of CSF biomarkers that would, in turn, improve the efficiency of AD therapeutic development.

Keywords: Alzheimer’s disease; Coalition Against Major Diseases; biomarker qualification; cerebrospinal fluid biomarkers.

Fig.1

Qualification of clinical biomarkers, regardless of target patient population, is focused on acquiring sufficient patient level anonymized data to support a given “context-of- use” (COU) for clinical trial decision making. The greater the impact this clinical decision (i.e., COU) has on the patient, the greater the evidence that will be required to support a qualification recommendation by a regulatory agency. The focus of CAMD’s work is to provide sufficient evidence for the use of CSF biomarkers for trial enrichment in the pre-dementia stage of AD. Note: At the time of this publication, no clinical biomarker has been qualified as a validated surrogate endpoint for any neurological indication.

Fig.2

There are two independent biomarker acceptance pathways through which biomarkers can be integrated into drug development for a specific COU. The first is typically sponsored by a single company, and is focused on delivering a companion diagnostic assay that supports a single therapeutic product. The second is typically done collectively by a consortium that provides a diverse range of clinical data across multiple studies to support a specific COU that would have applicability across multiple treatment modalities. This figure summarizes the high-level considerations of each pathway.

Fig.3

Current global initiatives focused on AD CSF biomarkers. Involvement of worldwide consortia in the standardization of CSF biomarker analysis at the level of the assay, the sample, and the laboratory. Grey box: the need for the future. ADNI, Alzheimer’s disease neuroimaging initiative; AIBL, The Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing; CAMD, Coalition Against Major Diseases; GBSC, Global Biomarker Standardization Initiative; IFCC, International Federation of Clinical Chemistry; JPND, EU Joint Programme - Neurodegenerative Disease Research (JPND); QC, quality control; SOP, standard operating procedure.