A context-of-use framework is proposed for assessing circulating biomarkers along analytical readiness and clinical validation lanes to support cardiovascular drug development.
Circulating and urinary laboratory biomarkers are central to cardiovascular, kidney, and metabolic drug development, and they support diagnosis, risk stratification, dose finding, safety monitoring, and, in selected settings, endpoint definition. Yet only a few materially shape trial design or regulatory decisions, and still fewer meet stringent criteria for surrogate endpoints. This review proposes a context-of-use framework in which circulating biomarkers are assessed along 2 converging "evidence lanes": analytical readiness and clinical or statistical validation. The review outlines fit-for-purpose requirements for enrichment tools, pharmacodynamic and dose-ranging markers, safety biomarkers, and candidate surrogates, by emphasizing preanalytical, analytical, and postanalytical sources of variability. Particular attention is given to surrogate validation, highlighting frequent discordance between biological plausibility or prognostic strength and treatment-induced changes that reliably predict clinical benefit (eg, albuminuria, natriuretic peptides, and glycemic, inflammatory, and lipid markers). The review describes how biomarkers can be embedded prospectively in phase 1 through phase 4 trials to guide dose selection, enrich populations, trigger adaptive design decisions, and support postmarketing surveillance while generally retaining hard outcomes as the basis for efficacy claims. A dedicated section summarizes perspectives from major regulatory agencies, and another applies the framework to concrete cardiovascular examples, illustrating both successful and unsuccessful uses. Finally, the review discusses practical barriers-analytical variability, operational burden, and limited commercial incentives-and proposes shared solutions, including standardized assays, harmonized data standards, open access platforms, and cross-trial biobanks.
Aimo et al. (Sun,) conducted a review in Cardiovascular, kidney, and metabolic drug development. Biomarkers was evaluated. A context-of-use framework is proposed for assessing circulating biomarkers along analytical readiness and clinical validation lanes to support cardiovascular drug development.