Translating New Science Into the Drug Review Process: The US FDA’s Division of Applied Regulatory Science

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  Figure 1.. The FDA Division of Applied Regulatory Science (DARS) uses multiple avenues of research to close the gap between scientific innovation, translational research, and drug review. DARS applies in vitro and in vivo laboratory research, in silico computational modeling, and informatics and integrated clinical research to develop new regulatory science tools, perform post-market analyses, and assimilate innovative science into the drug review process to enhance drug safety and efficacy.

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  Figure 2.. Digital image analysis of Kim-1 immunohistochemical staining of cisplatin-induced kidney injury used for quantitative injury assessment did not improve on pathologist semiquantitative evaluation. Figure shows 20× whole slide image (A) with magnified example (B) of Kim-1 positive staining (brown); corresponding positive pixel image analysis (B, D), with yellow, orange, and red representing weak positive, positive, and strong positive, respectively; reproduced from Shea et al.16

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  Figure 3.. DARS utilizes advanced “humanized” mouse models to improve drug safety assessment. These models, optimized in DARS laboratories, provide an enhanced predictive ability for human immune and liver responses to drugs, thereby improving the ability to recognize in an animal model potential adverse events that are specific to humans. These models can also inform the assessment process for determining the similarity between complex biological drugs (biosimilars). Scheme for immune-humanized mouse model is shown above.

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  Figure 4.. The 4 components of the Comprehensive in vitro Proarrhythmia Assay (CiPA)

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  Figure 5.. An illustration of the relation of the body surface electrocardiogram (ECG) to the underlying ventricular action potentials. Arrows pointing into the action potential are inward currents (calcium and late sodium) and arrows pointing out denote outward currents (hERG potassium). Blocking the calcium or late sodium current primarily shortens the early parts of repolarization (J-Tpeak), whereas hERG potassium channel block prolongs both early (J-Tpeak) and late repolarization (Tpeak-Tend). Thus, the J-Tpeak interval can differentiate drugs that only block hERG (eg, dofetilide, high torsade risk) from those that block hERG and inward currents (eg, ranolazine, low torsade risk). Drug-induced changes in heart rate-corrected QT (QTc), heart rate-corrected J-Tpeak (J-Tpeakc), and Tpeak-Tend are shown for dofetilide (left) and ranolazine (right). Both drugs prolong QTc; however, only dofetilide prolongs J-Tpeakc, and the absence of J-Tpeakc prolongation suggests that a drug is an hERG potassium channel block that has “balanced” inward current block and is not associated with torsade; reproduced from Johannesen et al.41

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  Figure 6.. DARS chemical informatics projects are focused on endpoints of regulatory interest, linked through chemical structure. Research activities include (1) database development for model training and validation; (2) development of web-based applications to enable direct structure-based searching by CDER staff; and (3) (Q)SAR model development to support drug safety review. Databases and models are used to respond to regulatory review consultation requests.

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  Figure 7.. DARS utilizes target-adverse event profiles to predict adverse events. DARS researchers utilize adverse event data from the FDA Adverse Event Reporting System, FDA drug labels, and peer-reviewed literature and databases containing drug and target information to connect adverse events to drug targets.

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  Figure 8.. DARS is using hollow fiber culture systems to investigate the factors critical to antibiotic resistance emergence and evaluate treatment strategies to suppress emergent resistance. This in vitro system allows culture of pathogenic bacteria and exposure of those bacteria to single and combination antibiotic treatments to discover the critical elements for evolution of resistance and how to best treat infections to suppress emergent resistance. Results will inform in vivo assessment of antibiotic resistance in mouse models and clinical trials.