Modeling and simulation in dose determination for biodefense products approved under the FDA animal rule.

Development of effective medical countermeasures for biodefense is vital to United States biopreparedness and response in the age of terrorism, both foreign and domestic. A traditional drug development pathway toward approval is not possible for most biodefense-related indications, creating the need for alternative development pathways such as the FDA's Animal Rule. Under this unique regulatory mechanism, FDA-approval is based on adequate and well-controlled animal studies when it is neither ethical nor feasible to conduct human efficacy studies. Translation of animal efficacy findings to humans is accomplished by use of modeling and simulation techniques. Pharmacokinetic and exposure-response modeling allow effective dosing regimens in humans to be identified, which are expected to produce similar benefit to that observed in animal models of disease. In this review, the role of modeling and simulation in determining the human dose for biodefense products developed under the Food and Drug Administration's Animal Rule regulatory pathway is discussed, and case studies illustrating the utility of modeling and simulation in this area of development are presented.