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Certain compounds that induce liver injury clinically are not readily identified from earlier preclinical studies. Novel biomarkers are being sought to be applied across the pharmaceutical pipeline to fill this knowledge gap and to add increased specificity for detecting drug-induced liver injury in combination with aminotransferases (alanine and aspartate aminotransferase)--the current reference-standard biomarkers used in the clinic. The gaps in the qualification process for novel biomarkers of regulatory decision-making are assessed and compared with aminotransferase activities to guide the determination of safe compound margins for drug delivery to humans where monitoring for potential liver injury is a cause for concern. Histopathologic observations from preclinical studies are considered the principal reference standard to benchmark and assess subtle aminotransferase elevations. This approach correlates quite well for many developmental compounds, yet cases of discordance create dilemmas regarding which standard(s) indicates true injury. Concordance amongst a broader set of biomarker injury signals in a qualification paradigm will increase confidence, leading to accepted and integrated translational biomarker signals during safety assessment processes across the pharmaceutical industry, with academia, in government and in contractor laboratories.

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The recently issued FDA/EMEA (US Food and Drug Administration/European Medicines Agency) guidelines pertaining to qualification of biomarkers are an important development in the regulatory approval process for new drug applications. 1,2 A qualified biomarker approved by regulatory authorities allows sponsors across industry to use that marker in new drug applications on the basis of a single submission rather than requiring each sponsor to present a separate justification with each new drug application. Nevertheless, there are a number of unanswered questions regarding the specific criteria that such a biomarker should meet in order to be considered as adding value to historical clinical end points and preclinical pathology observations. There are also questions regarding the optimal methods of collecting and evaluating scientific evidence for the clinical qualification of a biomarker. We propose a novel application to assist and accelerate the drug development process by prioritizing biomarker candidates and evidence, an application based on Bradford Hill's principles of causality association. The Process of regulaTory Biomarker QualificaTionFollowing the FDA/EMEA review of requirements related to preclinical safety biomarkers of nephrotoxicity, there is now clarity about the evidentiary data that regulators expect to be shown in support of applications for the qualification of biomarkers for use in drug development. Furthermore, sev eral criteria that have been applied to preclinical biomarker qualification may be applicable to the clinical setting as well, with the exception of the requirement for access to biopsy samples of target organs for histopathological assessment. The final FDA/EMEA qualification of preclinical nephro toxicity biomarkers identified limitations of the data sets, including a lack of additional recovery studies, an extensive use of retrospective data, basing histopathology scores on use of a single kidney section, use of the current good lab oratory practice pathology review standard for biomarker qualification, and the applicability of bio marker immuno histochemical data to indicate the anatomical location of injury within the kidney. 1,3,4 This feedback from regulatory authorities is a guide for biomarker researchers in the phar maceutical industry and academia to organize their approach to the crucial task of attaining qualification of safety and additional biomarkers.The starting point for qualification is to clearly identify and characterize the requirements a biomarker is expected to fulfill for the sponsor and its context for use in a new drug appli cation. This requires a clear definition of the problem to be addressed by use of the candidate biomarker and the stage of drug development at which it will be applied. There is limited literature describing the criteria for qualification of clinical biomarkers for drug testing. Altar et al. 5 described a set of seven evidentiary standards for biomarkers and diagnostics in a systematic manner. The biomarkers were graded from A (substan...

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