Role of systems modeling in regulatory drug approval

The science of quantitative clinical pharmacology continues to advance at a rapid pace such that regulators must constantly evaluate the most appropriate applications of modeling, simulation, and other innovations in the public health context. FDA continues to target improvements in regulatory science, including the development of scientific tools that can bridge the gap between cutting-edge discoveries and real-world diagnostics and therapeutics and to this end has identified innovation through modeling and simulation as a major scientific priority area. Physiological based pharmacokinetic (PBPK) models, which utilize system-and drug-specific information, are being increasingly used during drug discovery and development and informing regulatory review including drug labeling. A multi-step approach may be appropriate when planning to use PBPK to determine the likely effects of drug and/or gene interactions on drug pharmacokinetics and subsequent need for dedicated studies. Published FDA guidance documents related to drug interactions and early phase pharmacogenomic evaluation have included recommendations for the use of PBPK where appropriate. As pharmacology and clinical pharmacology move forward from reductionist approaches toward integrative systems approaches to address problems, efforts are ongoing to leverage the new science that is evolving in systems pharmacology. This is focused on the prediction of adverse drug events using the tools of cheminformatics, bioinformatics, and systems biology. Systems pharmacology will need to be put into the larger translational science context to reach full potential in regulatory decision-making.