Validation biomarker

New biomarkers will be useful in hepatotoxicity risk assessment if the data quality and validity can be established. The FDA defines a valid biomarker as one that can be measured in an analytical test system with well-established performance characteristics and has an established scientific framework or body of evidence that elucidates the significance of the test results [160]. Although there is no formerly agreed upon path, biomarker validation should include appropriate end-points for study (i.e., toxicology, histopathology, bioanalytical chemistry, etc.) and dose- and time-dependent measurements. An assessment of species, sex and strain susceptibility is also important to evaluate across species differences. More specific considerations for validation of gene and protein expression technologies are reviewed by Corvi et al. and Rifai et al. [144, 147]. 

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The following section discusses the three main steps of the biomarker validation process, or the fife cycle of a biomarker (1) its identification and development, (2) its validation using epidemiological methods, and (3) its application in etiological or clinical studies. 

Colburn, W. and Lee, J.W. Biomarkers, validation, and pharmacokinetic-pharmacodynamic modeling. Journal of Clinical Pharmacology 2003 42 997-1022. 

Colburn W A, Lee J W (2003). Biomarkers, Validation and Pharmacokinetic-Pharmacodynamic Modeling. Clin. Pharmacokin. 42 997-1022. 

Bodeker, B. Davies, A.N. Maddula, S. Baumbach, J.I., Biomarker validation—room air variation during human breath investigations, Int. J. Ion Mobil. Spectrom. 2010,13, 177-184. 

The qualification of novel DILI biomarkers will require application to biospecimens obtained from many different patient populations treated with many different drugs, both those that cause clinically important DILI and those that cause elevations in traditional liver chemistries but do not cause clinically important liver injury. It is important that pharmaceutical companies start now to archive samples and link these specimens to the relevant liver safety data. Ideally, liver safety data management tools should be standardized across the industry to facilitate the precompetitive collaborations on biomarker validation and qualification, such as eDISH (Watkins et al., 2011). Formal biomarker validation and qualification will warrant significant time to obtain regulatory-endorsed exploratory status via Letters of Support. 

Mandrekar SJ, Sargent DJ (2009). Clinical trial designs for predictive biomarker validation theoretical considerations and practical challenges. Journal of Clinical Oncology, 27(24) 4027-4034. 

Identify and characterize the potential biomarkers. Develop a robust assay for the biomarkers. Validate the biomarkers. 

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