Biomarkers as drug development tools: discovery, validation, qualification and use

The 21st Century Cures Act, approved in the USA in December 2016, has encouraged the establishment of the national Precision Medicine Initiative and the augmentation of efforts to address disease prevention, diagnosis and treatment on the basis of a molecular understanding of disease. The Act adopts into law the formal process, developed by the FDA, of qualification of drug development tools, including biomarkers and clinical outcome assessments, to increase the efficiency of clinical trials and encourage an era of molecular medicine. The FDA and European Medicines Agency (EMA) have developed similar processes for the qualification of biomarkers intended for use as companion diagnostics or for development and regulatory approval of a drug or therapeutic. Biomarkers that are used exclusively for the diagnosis, monitoring or stratification of patients in clinical trials are not subject to regulatory approval, although their qualification can facilitate the conduct of a trial. In this Review, the salient features of biomarker discovery, analytical validation, clinical qualification and utilization are described in order to provide an understanding of the process of biomarker development and, through this understanding, convey an appreciation of their potential advantages and limitations.The use of biomarkers for drug development, clinical investigation and management is fundamental to the success of molecular medicine. This Review discusses the framework for the development of biomarkers as drug development tools, including discovery, analytical validation, clinical qualification and utilization.Key pointsA biomarker is a characteristic that is objectively measured and evaluated as an indicator of a normal biological process, a pathological process or a biological response to a therapeutic intervention.Biomarkers increase the success rate of drug development programmes and thereby accelerate the availability of new therapeutics.Biomarker development is a multistep and iterative process beginning with biomarker discovery in disease and non-disease samples.The analytical validation phase of biomarker development is characterized by analysis of the performance metrics of the biomarker to ensure that the test is reliable, reproducible and of adequate sensitivity and specificity.Qualification is a graded evidentiary process that links a biomarker with biological and clinical end points.Utilization of biomarkers for clinical applications is dependent on their clinical utility for disease diagnosis, disease staging and treatment selection.

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