Biomarkers have potential to transform clinical trials. However, biomarker discovery should be more closely linked to trial contexts of use (COUs) to realize this potential. We will demonstrate how to translate pathophysiology into biomarkers, especially if preclinical models are not available or do not fully represent the disease. We suggest an approach to 1) define the COU, 2) search literature linking pathophysiology to the COU, and 3) validate candidate biomarkers analytically and clinically against established disease endpoints. Importantly, the COU drives the biological discovery, analytical validation, and clinical validation. We will present a case study identifying cytokeratin-18 (CK-18) as a biomarker for nonalcoholic steatohepatitis (NASH) drug development. We will demonstrate how we validated CK-18 against different clinical outcomes and analytical tests for different COUs. This integrated reverse engineering biomarker identification approach using COU and pathophysiology against clinical endpoints can be used for many diseases and reverse-translates into new mechanistic insights.
Define context of use of a biomarker for a clinical trial.
Visualize the pathophysiology of NASH and how understanding biological pathways can be used to discover biomarkers.
Determine how to link a biomarker to a useful clinical endpoint and validate a biomarker assay making it ready for clinical trial use and regulatory submissions.