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The Utility of Modeling and Simulation in Drug Development and Regulatory Review

https://doi.org/10.1002/jps.23570Get rights and content

ABSTRACT:

US Food and Drug Administration (FDA) has identified innovation in clinical evaluations as a major scientific priority area. This paper provides case studies and updates to describe the efforts by the FDA's Office of Clinical Pharmacology in its development and application of regulatory science, focusing on modeling and simulation. Key issues and challenges are identified that need to be addressed to promote the uptake of modeling and simulation approaches in drug regulation. Published 2013. This article is a U.S. Government work and is in the public domain in the USA. 102:2912–2923, 2013

Section snippets

INTRODUCTION

One important aspect of the United States Food and Drug Administration (US FDA)'s mission is to make drug therapies available to the American public in a timely manner. In its recent efforts to foster efficient and informative drug development, the US FDA has made priorities of promoting biomedical innovation, early communication with drug developers, and administrative and scientific flexibility.1 The US FDA approved 35 new molecular entities in fiscal year 2012. Approvals included

PHARMACOMETRIC MODELING

The utility of modeling and simulation in drug development and regulatory review has been well documented.10,12 Among the many applications, most of the OCP efforts have been focused on late phase decisions such as dosing and labeling or postapproval evaluation of unstudied doses or dosing regimens.10,11 Recently, we have increased efforts to apply modeling and simulation to assist in dose selection and trial design for late phase trials based on data obtained from early phase clinical trials.

PBPK MODELING

Physiologically based pharmacokinetic modeling has been used extensively in the past in the estimation of human exposure of environmental chemicals. Recent advancement in the understanding of physiological and biological processes, drug disposition including drug transport,19 and computer science, coupled with the availability of several specialized PBPK software packages, has contributed to more widespread use of PBPK in drug discovery, drug development, and regulatory review. PBPK has been

MECHANISM-BASED DRUG SAFETY EVALUATION USING SYSTEMS PHARMACOLOGY

As pharmacology and clinical pharmacology move forward from reductionist approaches toward integrative systems approaches to address problems, OCP has initiated an effort to leverage the new science that is evolving in systems pharmacology.34 This is focused on the prediction of adverse drug events using the tools of cheminformatics, bioinformatics, and systems biology.35 To move regulatory science forward in this area, the approach and the tools that still require development have recently

CONCLUSION AND FUTURE DIRECTIONS

United States Food and Drug Administration has been proactive in the development of regulatory science to address an array of public health challenges. Modeling and simulation have been important scientific investment areas for US FDA's OCP, and will continue to be a major area of growth. Modeling and simulation, tools of quantitative and systems pharmacology, will need to be put into the larger translational science context to reach full potential. Key issues will need to be addressed

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