Applications of Biomarkers in Drug Safety Studies

Examples of conventional biomarkers of drug toxicity are measurement of serum transaminases for liver toxicity, serum levels of urea nitrogen and creatinine for kidney toxicity, serum creatinine phosphokinase for muscle damage. These have generally been useful for detecting liver and kidney damage after it has occurred but cannot be used to identify patients at risk of developing side effects. Companies have hesitation in developing toxicity biomarkers as they are afraid that FDA will insist on their use, which might eliminate some drugs in development even though the value of the test may not be certain.

In the preclinical testing where toxicity is largely based on histopathology, noninvasive biomarkers appearing in body fluids can be used to develop interspecies bridging biomarkers that correlate well with minimal or mild histopathology based toxicity end points. Biomarkers of drug-specific mechanisms of toxicity can be incorporated to increase confidence in evaluating drug safety in clinical settings.

With better biomarkers to monitor early safety and toxicity in clinical trials, the traditional use of safety margins in clinical drug development can be improved. Several technologies described earlier in this report are used for drug safety studies at preclinical stage as well as during drug development. Various “omics” technologies are used in generating these biomarkers, particularly genomics, proteomics and metabonomics.

The Predictive Safety Testing Consortium (PSTC), one of nine consortia comprising the Critical Path Institute (C-Path), is a unique, public-private partnership that brings pharmaceutical companies together to share and validate safety testing methods with the advice of worldwide regulatory agencies, including the FDA, the European Medicines Agency, and the Japanese Pharmaceuticals and Medical Devices Agency. The corporate members of PSTC share a common goal: to find improved safety testing methods and approaches utilizing fluid- based safety biomarkers which accurately predict drug-induced tissue injury. Specifically, the primary goal of PSTC is the qualification of novel translational safety biomarkers for use in early clinical trials in order to enable safer investigations and development of new drug candidates. A publication has described the critical importance of improved safety biomarkers for the drug development process and the present state of the biomarker qualification process with regulatory agencies (Sauer et al. 2015). In addition, it highlights the work that the PSTC and its collaborative partners have done and continue to do to identify and qualify more selective and specific safety biomarkers. Finally, it describes ongoing efforts to better define the regulatory qualification process and an integrated translational safety strategy.

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