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.
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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US Food and Drug Administration. Paving the Way for Personalized Medicine: FDA’s Role in a New Era of Medical Product Development (FDA, 2013).
National Research Council (US) Committee on A Framework for Developing a New Taxonomy of Disease. Toward Precision Medicine: Building a Knowledge Network for Biomedical Research and a New Taxonomy of Disease (National Academy of Sciences, 2011).
Weaver, W. Molecular biology: origin of the term. Science 170, 581–582 (1970).
Kurreck, J. & Stein, C. Molecular Medicine: An Introduction (Wiley-VCH, 2016).
Ziv, E., Durack, J. C. & Solomon, S. B. The importance of biopsy in the era of molecular medicine. Cancer J. 22, 418–422 (2016).
Akers, J. C. et al. A cerebrospinal fluid microRNA signature as biomarker for glioblastoma. Oncotarget 8, 68769–68779 (2017).
Eitan, E. et al. Age-related changes in plasma extracellular vesicle characteristics and internalization by leukocytes. Sci. Rep. 7, 1342 (2017).
Hunter, D. J. et al. A pathway and approach to biomarker validation and qualification for osteoarthritis clinical trials. Curr. Drug Targets 11, 536–545 (2010).
Blanco, F. J. Osteoarthritis year in review 2014: we need more biochemical biomarkers in qualification phase. Osteoarthritis Cartilage 22, 2025–2032 (2014).
Amur, S., LaVange, L., Zineh, I., Buckman-Garner, S. & Woodcock, J. Biomarker qualification: toward a multiple stakeholder framework for biomarker development, regulatory acceptance, and utilization. Clin. Pharmacol. Ther. 98, 34–46 (2015).
Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin. Pharmacol. Ther. 69, 89–95 (2001).
Kraus, V. B., Blanco, F. J., Englund, M., Karsdal, M. A. & Lohmander, L. S. Call for standardized definitions of osteoarthritis and risk stratification for clinical trials and clinical use. Osteoarthritis Cartilage 23, 1233–1241 (2015).
US Food and Drug Administration. Considerations for Use of Histopathology and its Associated Methodologies to Support Biomarker Qualification. Guidance for Industry (FDA, 2016).
Swinney, D. C. The value of translational biomarkers to phenotypic assays. Front. Pharmacol. 5, 171 (2014).
Kraus, V. B. et al. Application of biomarkers in the development of drugs intended for the treatment of osteoarthritis. Osteoarthritis Cartilage 19, 515–542 (2011).
National Cancer Institute. NCI best practices for biospecimen resources. NCI https://biospecimens.cancer.gov/bestpractices/2016-NCIBestPractices.pdf (2016).
Oddoze, C., Lombard, E. & Portugal, H. Stability study of 81 analytes in human whole blood, in serum and in plasma. Clin. Biochem. 45, 464–469 (2012).
Institute of Medicine. Evolution of Translational Omics: Lessons Learned and the Path Forward (Institute of Medicine, 2012).
Manolis, E., Koch, A., Deforce, D. & Vamvakas, S. The European Medicines Agency experience with biomarker qualification. Methods Mol. Biol. 1243, 255–272 (2015).
US Food and Drug Administration. Guidance for Industry: Bioanalytical Method Validation (FDA, 2013).
Kraus, V. B. et al. OARSI clinical trials recommendations: soluble biomarker assessments in clinical trials in osteoarthritis. Osteoarthritis Cartilage 23, 686–697 (2015).
American Academy of Family Physicians. Clinical Laboratory Improvement Amendments (CLIA). AAFP http://www.aafp.org/practice-management/regulatory/clia.html (2018).
US Food and Drug Administration. Good Laboratory Practice for Nonclinical Laboratory Studies (FDA, 2017).
Organisation for Economic Cooperation and Development iLibrary. OECD series on principles of good laboratory practice and compliance monitoring. OECD iLibrary http://www.oecd-ilibrary.org/environment/oecd-series-on-principles-of-good-laboratory-practice-and-compliance-monitoring_2077785x (2018).
US Food and Drug Administration. S7A Safety Pharmacology Studies for Human Pharmaceuticals, Guidance for Industry (FDA, 2001).
Wagner, J. A., Williams, S. A. & Webster, C. J. Biomarkers and surrogate end points for fit-for-purpose development and regulatory evaluation of new drugs. Clin. Pharmacol. Ther. 81, 104–107 (2007).
US Food and Drug Administration. Guidance for Industry: Qualification Process for Drug Development Tools (FDA, 2010).
US Food and Drug Administration. Guidance for Industry and FDA Staff: Qualification Process for Drug Development Tools (FDA, 2014).
European Medicines Agency. Qualification of Novel Methodologies for Drug Development: Guidance to Applicants (EMA, 2014).
United States House of Representatives. Text of House amendment to the Senate amendment to H. R. 34 - Tsunami Warning, Education, and Research Act of 2015. United States House of Representatives http://docs.house.gov/billsthisweek/20161128/CPRT-114-HPRT-RU00-SAHR34.pdf (2016).
European Medicines Agency. Novel Methodologies (EMA, 2018).
European Medicines Agency. Qualification of Novel Methodologies for Medicine Development (EMA, 2018).
US Food and Drug Administration. Guidance for Industry: E16 Biomarkers Related to Drug or Biotechnology Product Development: Context, Structure, and Format of Qualification Submissions (FDA, 2011).
US Food and Drug Administration. Drug Development Tools (DDT) qualification programs. US FDA https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugDevelopmentToolsQualificationProgram/ (FDA, 2017).
Jog, N. R. & James, J. A. Biomarkers in connective tissue diseases. J. Allergy Clin. Immunol. 140, 1473–1483 (2017).
US Government Publishing Office. Clinical laboratory improvement amendments of 1988. US GPO https://www.gpo.gov/fdsys/pkg/STATUTE-102/pdf/STATUTE-102-Pg2903.pdf (1988).
US Food and Drug Administration. Overview of IVD regulation. US FDA https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/IVDRegulatoryAssistance/ucm123682.htm#1 (2018).
Bauer, D. C. et al. Classification of osteoarthritis biomarkers: a proposed approach. Osteoarthritis Cartilage 14, 723–727 (2006).
Veidal, S. S., Bay-Jensen, A. C., Tougas, G., Karsdal, M. A. & Vainer, B. Serum markers of liver fibrosis: combining the BIPED classification and the neo-epitope approach in the development of new biomarkers. Dis. Markers 28, 15–28 (2010).
Liu, T., Wang, X., Karsdal, M. A., Leeming, D. J. & Genovese, F. Molecular serum markers of liver fibrosis. Biomark. Insights 7, 105–117 (2012).
van Spil, W. E., Degroot, J., Lems, W. F., Oostveen, J. C. & Lafeber, F. P. Serum and urinary biochemical markers for knee and hip-osteoarthritis: a systematic review applying the consensus BIPED criteria. Osteoarthritis Cartilage 18, 605–612 (2010).
Kraus, V. B. et al. Predictive validity of biochemical biomarkers in knee osteoarthritis: data from the FNIH OA biomarkers consortium. Ann. Rheum. Dis. 76, 186–195 (2017).
Laslett, L., Pelletier, J.-P., Cicuttini, F., Jones, G. & Martel-Pelletier, J. Measuring disease progression in osteoarthritis. Curr. Treat. Opt. Rheum. 2, 97–110 (2016).
Artus, M., Campbell, P., Mallen, C. D., Dunn, K. M. & van der Windt, D. A. Generic prognostic factors for musculoskeletal pain in primary care: a systematic review. BMJ Open 7, e012901 (2017).
Sasinowski, F. & Varond, A. FDA’s flexibility in subpart H approvals: assessing quantum of effectiveness evidence. Food Drug Law J. 71, 135–200 (2016).
Thomas, D. et al. Clinical development success rates 2006–2015: Biotechnology Innovation Organization (BIO), Biomedtracker and Amplion. BIO https://www.bio.org/sites/default/files/Clinical%20Development%20Success%20Rates%202006-2015%20-%20BIO,%20Biomedtracker,%20Amplion%202016.pdf (2016).
Kepplinger, E. E. FDA’s expedited approval mechanisms for new drug products. Biotechnol. Law Rep. 34, 15–37 (2015).
US Food and Drug Administration. Guidance for Industry: Expedited Programs for Serious Conditions – Drugs and Biologics (FDA, 2014).
Smith, C. L. & Stein, G. E. Viral load as a surrogate end point in HIV disease. Ann. Pharmacother. 36, 280–287 (2002).
US Food and Drug Administration. Biomarkers used as outcomes. US FDA https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugDevelopmentToolsQualificationProgram/BiomarkerQualificationProgram/ucm535926.htm (2017).
Gupta, S., Chaudhary, K. & Mishra, N. in Recent Advances in Drug Delivery Technology (eds Keservani, R., Sharma, A. & Kesharwani, R.) 125–158 (IGI Global, 2017).
Gong, L. et al. Celecoxib pathways: pharmacokinetics and pharmacodynamics. Pharmacogenet. Genomics 22, 310–318 (2012).
US Food and Drug Administration. List of cleared or approved companion diagnostic devices (in vitro and imaging tools). US FDA https://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/ucm301431.htm (2017).
Kesselheim, A. S. & Avorn, J. New “21st Century Cures” legislation: speed and ease versus science. JAMA 317, 581–582 (2017).
Wechsler, M. E. et al. Active albuterol or placebo, sham acupuncture, or no intervention in asthma. N. Engl. J. Med. 365, 119–126 (2011).
Teutsch, S. M. et al. The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) initiative: methods of the EGAPP working group. Genet. Med. 11, 3–14 (2009).
Goodsaid, F. M., Frueh, F. W. & Mattes, W. Strategic paths for biomarker qualification. Toxicology 245, 219–223 (2008).
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.
The author declares no competing interests.
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- 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.
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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