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

Abstract

In 2011, the US Food and drug Administration (FDA) developed a strategic plan for regulatory science that focuses on developing new tools, standards, and approaches to assess the safety, efficacy, quality, and performance of FDA-regulated products. In line with this, the Division of Applied Regulatory Science was created to move new science into the Center for Drug Evaluation and Research (CDER) review process and close the gap between scientific innovation and drug review. The Division, located in the Office of Clinical Pharmacology, is unique in that it performs mission-critical applied research and review across the translational research spectrum including in vitro and in vivo laboratory research, in silico computational modeling and informatics, and integrated clinical research covering clinical pharmacology, experimental medicine, and postmarket analyses. The Division collaborates with Offices throughout CDER, across the FDA, other government agencies, academia, and industry. The Division is able to rapidly form interdisciplinary teams of pharmacologists, biologists, chemists, computational scientists, and clinicians to respond to challenging regulatory questions for specific review issues and for longer-range projects requiring the development of predictive models, tools, and biomarkers to speed the development and regulatory evaluation of safe and effective drugs. This article reviews the Division’s recent work and future directions, highlighting development and validation of biomarkers; novel humanized animal models; translational predictive safety combining in vitro, in silico, and in vivo clinical biomarkers; chemical and biomedical informatics tools for safety predictions; novel approaches to speed the development of complex generic drugs, biosimilars, and antibiotics; and precision medicine.

Principles and procedures for handling out-of-domain and indeterminate results as part of ICH M7 recommended (Q)SAR analyses

“…The reviewers assess the information provided by the pharmaceutical applicant, including information on the software and models used, the results from the software, the overall conclusions and any associated expert review documentation for consistency with the ICH M7 guideline and to ensure the results and expert review are valid. In cases where the reviewer has questions or concerns, the (Q)SAR submission is provided to FDA/CDER’s internal Computational Toxicology Consulting Service (CTCS) for evaluation ( Rouse et al, 2017 ). It should be noted that the reviewer will not re-run the predictions, but the Computational Toxicology Consultation Service staff may.…”

Expanding the Role of Early Health Economic Modelling in Evaluation of Health Technologies Comment on "Problems and Promises of Health Technologies: The Role of Early Health Economic Modeling"

“…Particularly, CTS can inform better study protocols, including the choice of the endpoints that are relevant to different stakeholders, and calculation of the most appropriate sample size, to maximize the probability of obtaining statistically significant estimates. These methods have raised increasing interest among regulators, both in the United States and Europe 18 , 19 but their use for HTA purposes is still broadly unexplored.…”

3D cell culture models: Drug pharmacokinetics, safety assessment, and regulatory consideration

“…3,4,18 In addition to these performance guidelines, reliability and robustness of systems must be ensured for use on the late stages of drug development, regulatory context, or supporting clinical trials. Applied research is being developed in the FDA Division of Applied Regulatory Science in the Center for Drug Evaluation and Research (CDER), 19 where a commercially-available liver MPS developed at the Massachusetts Institute of Technology 20 is being characterized for studying reliability and robustness of its use in drug toxicity and PK applications. The characterized liver system cultures hepatic cells in a 3D platform exposed to flowing culture medium, 20,21 which enhances and prolongs metabolic activity.…”