Biomarkers in clinical trials for neurodegenerative diseases: regulatory perspectives and requirements

Biomarkers might play comprehensive roles in drug development for neurodegenerative diseases and particularly Alzheimer's disease (AD) and other dementias. Biomarkers can already be used to better define homogeneous study populations (e.g. enriched population at risk for AD) and to select the most promising drug candidates in their effective dosages for phase III clinical trials, so some biomarkers are currently in the process of implementation as primary, co-primary or secondary outcome variables into regulatory guideline documents, e.g. regarding phase II in drug development programs as outcome measures in proof of concept or dose finding studies. There are specific biomarkers available depending on the hypothesized mechanism of action of a medicinal product, e.g. impact on the amyloidogenic cascade or on tau-hyperphosphorylation. However, further validation of specific biomarkers in large-scale international controlled multicenter studies is necessary before they can be accepted as primary outcome measures in pivotal phase III clinical trials. There is an even stronger need for rigorous co-development of biological trait- and state marker candidates to provide evidence that a medicinal product affects the underlying disease process, which, together with clinical improvement, will be a precondition for a label of disease modification. Until now no biomarker has been sufficiently validated to be acceptable as a surrogate endpoint. Establishing of surrogate endpoints is an important goal in neurodegenerative diseases, particularly in their early (preclinical, presymptomatic) stages, as traditional clinical outcome measures might be too insensitive to change or need unfeasible treatment durations for clinical trial conditions. Improvements can only be accomplished by active synergistic collaboration between academic, industrial and regulatory partners.