Safety biomarkers qualification

Several consortia, primarily driven by pharmaceutical industry members and encouraged by health authorities, have been formed to evaluate and qualify safety biomarkers for use in early clinical drug development trials. In the remainder of this manuscript, we will focus on the safety biomarker qualification efforts of the Critical Path Institute s (C-Path) Predictive Safety Testing Consortium (PSTC), as well as the PSTC collaborations with the Foundation for the National Institutes of Health s Biomarkers Consortium s (FNIH BC) Kidney Safety Project (KSP) and the Innovative Medicines Initiative s (IMI) Safer and Faster Evidence-based Translation Consortium (SAFE-T). Both of these collaborations are driven by the common goal of modernizing safety science through the qualification of clinical safety biomarkers for use in drug development. 

Dennis EH, Walker EG, Baker AF, Miller RT. Opportunities and challenges of safety biomarker qualification Perspectives from the Predictive Safety Testing Consortium. Drug Dev Res. 2013. 74(2) 112-26. 

Dieterle F et al. Renal biomarker qualification submission a dialog between the FDA-EMEA and Predictive Safety Testing Consortium. Nat Biotechnol. 2010 5 455-462. 

The lessons learned from the preclinical qualification of renal safety biomarkers have demonstrated that it is also clear that no single biomarker will be the answer and that a panel approach of novel biomarkers alongside a more intelligent use of currently used biomarkers represents the way forward to inform all stakeholders. Moreover, novel translational biomarkers that reflect the mechanistic basis of DILI are fundamental to efforts in translational research. Despite significant progress in preclinical renal injury biomarker qualification, to date, clinical biomaiker qualification studies are ongoing to achieve this objective. 

Several key aspects should be considered in (seating scientific expectations specific to qualification of safety biomarkers. A brief list of considerations is presented in the following for safety biomarkers that are supported by both translational nonclinical data and clinical trial data ... 

Finally, it is critical to identify the qnickest path to qualification and the implementation of safety biomarkers in well-controlled clinical trials, becanse the only way to nnderstand the advantages and disadvantages of a biomarker will be throngh its broad application. 

Guffroy M, Pinches M, Jayadev S, Blomme EA, Beushausen SA, Barlow VG, CoUins N, Waring J, Honor D, Snook S, Lee J, Rossi P, Walker E, Mattes W. Renal biomarker qualification submission A dialog between the FDA-EMEA and Predictive Safety Testing Consortium. Nat Biotechnol. 2010a. 28(5) 455-62. 

A variety of biomarkers have been shown to be valuable individually for one or several toxicant or disease situations. Few of these biomarkers have been systematically evaluated for the plethora of situations that might provoke false positive responses. Acceleration of the current pace of biomarker evaluation and qualification demands (a) the availability of panels of biomarker-assays that can be comparatively evaluated on well-defined common sample sets, (b) fit-for-purpose performance evaluation in controlled animal studies with carefully benchmarked histological endpoints and samples from well-defined focused clinical trial cohorts, and (c) ready availability of banked blood and urine sample archives from clinical trial populations with carefully documented morbidities such as the Framingham Heart Study,45 or the Drug-Induced Liver Injury Network (DILIN) prospective study,46 to name a few. Availability of such panels of validated biomarker assays and well-documented preclinical and clinical samples, as well as increased cooperation between animal model researchers and clinical researchers will enable individual biomarkers to be qualified for sensitivity of specifically defined adverse events, qualified for appropriate specificity using samples of defined benign events, and collected into panels that yield complementary information about the health and safety of animals and patients. 

However, the development and clinical integration of potential hepatic biomarkers over the past 60 years have revealed only a limited nnmber of candidates (Antoine et al., 2009a Matheis et al., 2011 Moggs et al., 2012) compared to research focus placed on drng efficacy (Watkins, 2011). Furthermore, the delayed qualification and ultimate scientific acceptance of a potential DILI biomarker have been hindered by what has been previonsly thonght of as the competing interest between the varions stakeholders. Safety assessment... 

The identification and eventual qualification of sensitive and specific DILI biomarkers that hold translational promise between preclinical and clinical studies is urgently required to actualize improved safety screening in drug development and sensitive clinical diagnosis of DILI for patient treatment stratification. An added benefit of novel biomarkers would be to provide enhanced understanding of the fundamental mechanisms that result in chnical DILL... 

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. 

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