Today’s Challenges to De-Risk and Predict Drug Safety in Human “Mind-the-Gap”

Current gaps in drug safety sciences can result from the inability (1) to identify hazard across multiple target organs, (2) to predict and risk assess with certainty against drug safety liabilities for the major target organs, (3) to optimally manage and mitigate against drug safety liabilities, and (4) to apply principles of governance on the generation, integration, and use of experimental data. Translational safety assessment to evaluate several target-organ drug toxicities can only be partially achieved by use of current in vitro and in vivo test systems. What remains to be tackled necessitates the deployment of in vitro-human-relevant test systems to address human specific or selective forms of toxicities. Nevertheless, such models may only address in part some of the requirements in today's armament of biomedical tools essential for improving the discovery of drug candidates. Refinement of in silico tools, Target Safety Assessment and a greater understanding of mechanistic insights of toxicities might provide future opportunities to better identify drug safety liabilities. The increasing diversity of drug modalities present further challenges for nonclinical and clinical development requiring further research to develop suitable test systems and technologies. Our ability to optimally manage and mitigate safety risk will come from the greater refinement of safety margin estimates, provision and use of human-relevant safety biomarkers, and understanding of the translation from in silico, in vitro, and in vivo studies to human. An improvement of governance frameworks and standards at all levels within organizations, national, and international, can only help facilitate drug discovery and development programs.