A framework and shared vocabulary to identify actionable protein biomarkers and enable optimal precision medicine: Myth-busting with unicorn biomarkers.
Abstract
Not all biomarkers are equal, and some arguably should not be classified as biomarkers at all. Despite an explosion in putative biomarker discoveries from high-throughput proteomic technologies, very few advance beyond initial excitement to become validated, clinically actionable tools. Most stall in a biomarker ‘valley of death’, where promising signals fail to meet robust technical, scientific, and regulatory standards for clinical use. We propose a framework to distinguish between unvalidated protein findings and validated biomarkers with specific utility. We highlight the need to separate exploratory protein measurements from biomarkers that meet predefined analytical criteria and progress through validation, including qualification as a reasonably likely surrogate endpoint (RLSE) or a validated surrogate endpoint (VSE). This review article delineates differences between biomarker discovery, development, regulatory qualification, and commercialisation pathways, emphasising nomenclature according to the BEST (Biomarkers, EndpointS, and other Tools) Resource, analytical validation in accordance with CLSI guidelines, clinical relevance, and alignment with regulatory frameworks, including the FDA’s Premarket Approval (PMA) and Biomarker Qualification Program (BQP), and the EU’s In Vitro Diagnostic Regulation (IVDR) and Drug Development Tool (DDT) programmes. We introduce the concept of the ‘unicorn biomarker’ – an extremely rare class of biomarker with validated multipurpose utility (diagnostic, prognostic, and pharmacodynamic/monitoring) – to highlight the value of such biomarkers in clinical decision-making. We propose that minimum technical and biological standards must be met before a molecular measurement can be designated a “biomarker”, as an association between a biological signal and disease state alone is insufficient. By raising the bar with unicorn biomarkers, this framework aims to guide researchers, regulators, and industry stakeholders in identifying actionable biomarkers and advancing precision medicine.
