FDA Issues Animal Efficacy Rule Concept Paper; Provides Essential Animal Model Elements

September 11, 2008

Human history is replete with examples of the use of lethal or debilitating agents in war and by terrorists.  As early as the 6th Century B.C., the Assyrians are reported to have poisoned the wells of their enemies with ergot of rye (causing ergotism), and Solon of Athens reportedly poisoned the water supply with hellebore, a purgative agent, during the siege of Krissa.  During World War I, munitions filled with the irritants ethyl bromoacetate and chloroacetone were used to limit the effectiveness of unprotected troops, and German troops at Ypres, Belgium discharged 180,000 kilograms of chlorine gas from 5,730 cylinders against the Allied positions.  More recently, in the fall of 2001, letters containing weapons-grade anthrax were mailed to locations in New York, Florida, and Washington, D.C. resulting in several deaths.

The likelihood that a terrorist attack using Chemical, Biological, Radiological, or Nuclear (“CBRN”) substances might occur in the United States led FDA to promulgate regulations on May 31, 2002 intended to expedite the development and approval of new drug and biological products.  The final rule, titled “New Drug and Biological Products; Evidence Needed to Demonstrate Effectiveness of New Drugs When Human Efficacy Studies Are Not Ethical or Feasible” (commonly referred to as the “Animal Efficacy Rule”), amended FDA’s drug and biologic regulations to “allow appropriate studies in animals in certain cases to provide substantial evidence of effectiveness of new drug and biological products used to reduce or prevent the toxicity of [CBRN] substances.”  Although given relatively little attention since it was promulgated, the Animal Efficacy Rule creates a new regulatory paradigm for measuring efficacy by permitting FDA to approve drugs and biologics for counterterrorism uses based on animal data when it is unethical or unfeasible to conduct human efficacy studies. 

Under the Animal Efficacy Rule (21 C.F.R. § 314.610, drugs; § 601.91, biologics), FDA can rely on the evidence from animal studies to provide substantial evidence of effectiveness only when:

1. There is a reasonably well-understood pathophysiological mechanism of the toxicity of the CBRN substance and its prevention or substantial reduction by the product;

2. The effect is demonstrated in more than one animal species expected to react with a response predictive for humans, unless the effect is demonstrated in a single animal species that represents a sufficiently well-characterized animal model for predicting the response in humans;

3. The animal study endpoint is clearly related to the desired benefit in humans (generally the enhancement of survival or prevention of major morbidity); and

4. The data or information on the kinetics and pharmacodynamics of the product or other relevant data or information, in animals and humans allows selection of an effective dose in humans.

Since it was promulgated in 2002, FDA has approved two products under the Animal Efficacy Rule: (1) Pyridostigmine Bromide (NDA #20-414) for prophylaxis against the lethal effects of Soman nerve agent poisoning; and (2) CYANOKIT (hydroxocobalamin) (NDA #22-401) for the treatment of known or suspected cyanide poisoning.

On September 9, 2008, FDA issued a draft concept paper, titled “Animal Models – Essential Elements to Address Efficacy Under the Animal Rule.”  According to FDA the draft concept paper “is intended to identify the critical characteristics of an animal model that should be addressed when efficacy of the product under development will be established under the Animal Rule. It should also help determine whether an animal model can be considered sufficiently well-characterized to propose that the effect demonstrated in a single animal species can be used to support approval/licensure.”  Essential elements identified by FDA include the characteristics of the CBRN agent that influence the disease or condition, host susceptibility and response to etiologic agent, natural history of disease (pathophysiologic comparability), and characterization of medical intervention.  FDA emphasizes throughout the draft concept paper that sponsors should initiate early and frequent discussion with FDA regarding the essential data elements for the development and evaluation of animal models.

Over the past few years, several companies have reportedly expressed interest in pursuing approval of their products under the Animal Efficacy Rule.  FDA’s concept paper should provide a useful aid in the development of such products.

By Kurt R. Karst

Categories: Drug Development