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

Abstract

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.

Model‐Informed Drug Development for Anti‐Infectives: State of the Art and Future

“…Modeling and simulation approaches allow for effective dosing regimens in humans to be identified, which are expected to deliver exposures in humans that exceed the efficacious exposures in the animal models and produce a benefit similar to that observed in the animal models. 193,200 Animal models can facilitate rapid responses to emerging infection diseases by providing means of demonstrating proof of pharmacological plausibility for a new or approved therapy, deriving potential efficacious exposures, and providing initial data to support development decisions. More importantly, modeling and simulation approaches and translational medicine are critical for translating information to support clinical trials.…”

“…Efficacy is extrapolated to humans based on exposures and achievement of the target efficacious exposures derived from the animal model and dose/exposure‐response relationships as described above. Modeling and simulation approaches allow for effective dosing regimens in humans to be identified, which are expected to deliver exposures in humans that exceed the efficacious exposures in the animal models and produce a benefit similar to that observed in the animal models 193,200 …”

Dose Selection in a Pandemic: A Framework Informed by the FDA Animal Rule

“…The dose selection framework outlined in the US Food and Drug Administration (FDA) Animal Rule regulation provides an approach for dose determination in settings of urgent need with limited information. The genesis of the Animal Rule development pathway followed the 2001 anthrax attacks on the US government and journalism outlets and underscored the importance of bio-preparedness and response (2) Under the Animal Rule, selection of an effective dose requires integration of a drug's mechanism of action and antimicrobial activity, pharmacokinetic (PK) and pharmacodynamic (PD) knowledge gained from preclinical experience (both in vitro and in vivo), and any known PK and PD characteristics of the drug or biologic in humans (3). Similarly, this information exists in various forms for new drugs in development or drugs marketed for indications other than the pandemic-related need.…”

“…The dose selection framework outlined in the FDA Animal Rule regulation provides an approach for dose determination in settings of urgent need with limited information. The genesis of the Animal Rule development pathway followed the 2001 anthrax attacks on the US government and journalism outlets and underscored the importance of bio‐preparedness and response 2 . The FDA Guidance for Industry entitled Product Development Under the Animal Rule outlines essential components and considerations for developers of medical countermeasures for indications where adequate and well‐controlled efficacy studies in humans cannot be ethically conducted or are not feasible, as is the case with weaponized pathogens 3 .…”

Antimicrobial Dose Selection under the Animal Rule

“…The genesis of the US Food and Drug Administration's (FDA's) "Animal Rule" development pathway followed the 2001 anthrax attacks on the US government and journalism outlets and underscored the importance of bio-preparedness and response. 1 The Animal Rule (21 Code of Federal Regulations (CFR) 314.600-650 for drugs; 21 CFR 601.90-95 for biological products) provides a unique regulatory pathway for drugs and biologics intended to treat serious or lifethreatening conditions caused by exposure to lethal or permanently disabling agents when it is unethical to conduct human efficacy studies, and field trials after an accidental or deliberate exposure are not feasible. 2 The FDA's Animal Rule does not apply to products that can be approved based on efficacy standards described elsewhere in the FDA's regulations, nor does it address the safety evaluation for the products to which it does apply.…”