Biomarker definitions and their applications.

Biomarkers are critical to the rational development of medical therapeutics, but significant confusion persists regarding fundamental definitions and concepts involved in their use in research and clinical practice, particularly in the fields of chronic disease and nutrition. Clarification of the definitions of different biomarkers and a better understanding of their appropriate application could result in substantial benefits. This review examines biomarker definitions recently established by the U.S. Food and Drug Administration and the National Institutes of Health as part of their joint Biomarkers, EndpointS, and other Tools (BEST) resource. These definitions are placed in context of their respective uses in patient care, clinical research, or therapeutic development. We explore the distinctions between biomarkers and clinical outcome assessments and discuss the specific definitions and applications of diagnostic, monitoring, pharmacodynamic/response, predictive, prognostic, safety, and susceptibility/risk biomarkers. We also explore the implications of current biomarker development trends, including complex composite biomarkers and digital biomarkers derived from sensors and mobile technologies. Finally, we discuss the challenges and potential benefits of biomarker-driven predictive toxicology and systems pharmacology, the need to ensure quality and reproducibility of the science underlying biomarker development, and the importance of fostering collaboration across the entire ecosystem of medical product development. Impact statement Biomarkers are critical to the rational development of medical diagnostics and therapeutics, but significant confusion persists regarding fundamental definitions and concepts involved in their use in research and clinical practice. Clarification of the definitions of different biomarker classes and a better understanding of their appropriate application could yield substantial benefits. Biomarker definitions recently established in a joint FDA-NIH resource place different classes of biomarkers in the context of their respective uses in patient care, clinical research, or therapeutic development. Complex composite biomarkers and digital biomarkers derived from sensors and mobile technologies, together with biomarker-driven predictive toxicology and systems pharmacology, are reshaping development of diagnostic and therapeutic technologies. An approach to biomarker development that prioritizes the quality and reproducibility of the science underlying biomarker development and incorporates collaborative regulatory science involving multiple disciplines will lead to rational, evidence-based biomarker development that keeps pace with scientific and clinical need.