Abstract
Background: 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 considerable evidence that links a reduction in hippocampal volume (HV) in the brains of affected subjects to the pathophysiology of the disease, the role and integration of HV as a biomarker in clinical trials will only be realized on a large scale when this marker is endorsed by regulatory agencies worldwide. In 2011, the European Medicines Agency (EMA) qualified HV measured by MRI as a biomarker. The Coalition Against Major Diseases (CAMD), a consortium within the non-profit organization the Critical Path Institute, aims to qualify with FDA the use of low baseline HV biomarker for enrichment in clinical trials of patients with early AD. The team is at the Consultation and Advice Stage of biomarker qualification. We will present lessons learned. Methods: 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 HV imaging biomarkers, to increase the efficiency and diminish the risks and costs of drug development. Results: The HV measures proposed for qualification will be applicable independent of the specific drug's mechanism of action or target, the MRI scanner that collected the imaging data, and the algorithm used to measure the HV. Our team has evaluated multiple algorithms in independent clinical cohorts that have longitudinal clinical follow-up, including ADNI. We will discuss our approach to repeatability and reproducibility issues. There is an urgent need to obtain biomarker data from relevant clinical trials to achieve regulatory success. Conclusions: The development of a robust evidentiary package to support the qualification of the HV imaging biomarker for use in clinical trials of patients with AD requires significant resources and commitment from a wide range of stakeholders. Successful qualification of this biomarker is expected to accelerate the advent of new therapies for patients at early stages of the disease.