According to the FDA, a biomarker is a "defined characteristic measured as an indicator of normal biological processes, pathogenic processes, or responses to an exposure or intervention, including therapeutic interventions."
Biomarkers enrich clinical research, but it is critical that communication from the generation of an idea to the development of a cure be transparent. Unfortunately, confusion prevails due to inadequate terminology, which hinders the effective use and clinical relevance of biomarkers.
Only a limited number of compounds are approved as drugs, despite the countless compounds that go through the time-consuming and costly clinical development phases, not to mention the issues of demonstrable efficacy or safety. If such a drug candidate fails at a later stage, the investment losses are devastating.
The validation of a biomarker is a lengthy regulatory, technical, and clinical process. Validation requirements are further complicated by regional differences. Both the FDA and the EU require clinical validation according to protocols and standards of the Clinical and Laboratory Standards Institute (CLSI), which provide guidelines for the highest quality assays, and both regions require two studies conducted under Good Clinical Practice (GCP). Technical validation is tied to CLSI protocols by the FDA. At the same time, the EU requires validation according to the EMA guidelines on validation of bioanalytical methods. However, this will change in the EU from May 26, 2022, as the new In Vitro Diagnostics Regulation (IVDR) will bring positive changes to the regulatory framework for medical devices and laboratory-developed tests to reflect technological advances and changes in medical science.
For the FDA, biomarker validation is a three-stage process that begins with a Letter of Intent that initiates the qualification process for the context of use in drug development. The second stage includes a Qualification Plan that defines the intended development of supporting qualification data. The final stage involves all of the data collected to support the qualification of the biomarker, known as the Full Qualification Package. Once qualified, the biomarker receives a recommendation from the FDA based on a comprehensive review.
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Translational tools such as blood-based biomarkers can provide important information about efficacy, safety, mode of action, and response to treatment in drug development. However, many of these biomarkers lack tissue specificity, leaving gaps between disease pathology and cellular origin, making these markers not fully translatable and pharmacodynamically modulable.
Collagen fragments, however, released into the bloodstream during protein formation and degradation, reflect tissue-specific turnover. Changes in tissue turnover can be quantified and used in preclinical and clinical research. This Protein Fingerprint technology enables more accurate measurement of pharmacodynamic modulation and supports the development of drug candidates at every clinical stage.
Nordic Bioscience has developed FDA-approved biomarkers, CTX-I, a marker of bone resorption, and osteocalcin, a marker of bone formation. A third biomarker, PRO-C6, which measures the adverse effects endotrophin in Heart Failure with preserved Ejection Fraction (HFpEF), recently received a Letter of Support from the FDA.
The FDA and NIH propose the BEST (Biomarkers, EndpointS, and other Tools) glossary to help interpret the distinctions between the clinical relevance of biomarkers and their different roles in both biomedical research and clinical practice and medical device development.
There are other alternatives to this nomenclature, but adapting a common reference point is critical for a common and consistent understanding. BEST is also extended to biomarker function as it relates to biomarker surrogate endpoints. See the biomarker definitions and terminology below.
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