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

Abstract

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.

Key points

  • A 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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Fig. 1: Biomarker relationships with the causal pathway of disease.
Fig. 2: Framework for biomarker development.

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Acknowledgements

The author acknowledges funding support from the NIH (NIH/NIA P30 AG028716), which supported the salary of V.B.K. for biomarker-related research during the time she was engaged in researching and writing this manuscript.

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Correspondence to Virginia B. Kraus.

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Glossary

Good laboratory practice

(GLP). A management system consisting of a set of principles to assure the quality and integrity of non-clinical laboratory studies that support research or marketing permits for products regulated by government agencies.

Investigational new drug applications

Requests to the FDA for approval to test an investigational drug in humans.

New drug applications

Requests to the FDA for approval of a new pharmaceutical agent for sale and marketing in the USA.

Biologics licence applications

Requests to the FDA for approval of a new biological agent (such as immunotherapies, proteins and growth factors) for sale and marketing in the USA.

Companion diagnostics

A special type of biomarker that provides information that is essential for the safe and effective use of a corresponding therapeutic product.

Truth standard

A gold standard that serves as a reference against which the accuracy of a test can be determined.

In vitro diagnostics

Tests, performed on samples that have been taken from the human body (such as blood or tissue), to monitor a patient’s health status.

Surrogates

Biomarkers intended to substitute for a clinical end point that predict clinical benefit or harm (or lack of benefit or harm) based on epidemiological, therapeutic, pathophysiological or other scientific evidence.

Patient-reported outcomes

(PROs). Reports on a patient’s health status and/or function that come directly from the patient.

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Kraus, V.B. Biomarkers as drug development tools: discovery, validation, qualification and use. Nat Rev Rheumatol 14, 354–362 (2018). https://doi.org/10.1038/s41584-018-0005-9

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