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 should not be termed biomarkers. 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 Reasonably Likely Surrogate Endpoints (RLSE) or Validated Surrogate Endpoints (VSE). This expert opinion delineates differences between biomarker discovery, development, regulatory qualifications and commercialization pathways, emphasizing nomenclature according to BEST Resource (Biomarkers, EndpointS, and other Tools), analytical validation (CLSI guidelines), clinical relevance, and alignment with frameworks of the US Food and Drug Administration (FDA), specifically Premarket Approval (PMA) or Biomarker Qualification Program (BQP), and the EU’s IVDR and Drug Development Tool (DDT) programs. We introduce the concept of the “Unicorn Biomarker” – an extremely rare class of biomarkers with validated multipurpose utility (diagnostic, prognostic, and pharmacodynamic/monitoring) to exemplify their value in decision-making. We propose that minimum technical and biological standards must be met before a molecular measurement can be designated a “biomarker”, beyond minimal criteria of association between biological signal and disease state. 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.
