Will New Recommendations From NIH Curb Use of the Animal Efficacy Rule?

By Kurt R. Karst – 

A recent report from the National Institutes of Health (“NIH”) Council of Councils Working Group on the Use of Chimpanzees in NIH-Supported Research leaves unanswered questions about the future utility of FDA’s so-called “Animal Efficacy Rule” for NIH-funded research intended to develop medical countermeasures. 

The NIH Working Group report is rooted in recommendations made by the Institute of Medicine (“IOM”) in a December 2011 report, titled “Chimpanzees in Biomedical and Behavioral Research: Assessing the Necessity,” in which the IOM concluded that most current biomedical use of chimpanzees is unnecessary.  The IOM also recognized, however, that chimpanzee use could still serve an important role in some research areas, but recommended that such use be governed by a set of principles and criteria.  The NIH, which accepted the IOM report, charged a working group with, among other things, developing a plan of action to implement the guiding principles and criteria identified in the IOM report.  In the interim, NIH implemented a policy of not funding new research projects involving chimpanzees, but currently funded research may continue.  The policy remains in effect until the NIH considers and issues policy implementing the IOM recommendations.

According to the NIH Working Group report, on which the NIH is seeking public comment:

For rare but serious diseases, product-driven studies may need to consider the FDA Animal Rule.  This greatly raises the expectations for the applicability of animal model studies and would raise expectations about the true value of data from chimpanzee experiments.  For example, the combination of animal and strain of pathogen used would likely be selected so that lethality occurred in untreated animals but not in treated animals.  If a decision were made to use chimpanzees, it might be necessary to use staged experiments with smaller numbers of animals per study along with data accumulated from multiple studies.  Whether the FDA Animal Rule would accommodate this is unknown.

FDA’s “Animal Efficacy Rule,” which was finalized in May 2002 (see here), provides that in certain circumstances, and where where human efficacy trials are not feasible or ethical, animal studies can be relied on to provide substantial evidence of effectiveness of a drug or biological product.  Specifically, FDA can rely on the evidence from animal studies to provide substantial evidence of the effectiveness of a drug or biological product when:

1. There is a reasonably well understood pathophysiological mechanism for the toxicity of the chemical, biological, radiological, or nuclear substance and its amelioration or prevention 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, which is generally the enhancement of survival or prevention of major morbidity; and
4. The data or information on the pharmacokinetics and pharmacodynamics of the product or other relevant data or information in animals and humans is sufficiently well understood to allow selection of an effective dose in humans, and it is therefore reasonable to expect the effectiveness of the product in animals to be a reliable indicator of its effectiveness in humans.

Evaluation of the drug or biological product for safety in humans is still required, and cannot be addressed by animal studies alone.  In addition, approval under the Animal Efficacy Rule is subject to certain postapproval commitments.

FDA has been working to address various elements of the Animal Efficacy Rule by issuing guidance on animal models and by developing an Animal Model Qualification Program (see here, here, and here).  Thus far, only a few products have been approved under the Animal Efficacy Rule.  In February 2003, FDA approved NDA No. 020414 for pyridostigmine bromide to increase survival after exposure to Soman "nerve gas" poisoning.  In December 2006, FDA approved NDA No. 022041 for CYANOKIT (hydroxocobalamin for injection) for the treatment of known or suspected cyanide poisoning.  In April 2012, FDA approved NDA supplements for LEVAQUIN (levofloxacin) Injection, Tablets, and Oral Solution for the treatment and prophylaxis of plague due to Yersinia pestis in adults and pediatric patients 6 months of age and older.  And in December 2012, FDA granted a license (BLA No. 125349) for raxibacumab injection to treat inhalational anthrax. 

The NIH Working Group report is not inconsistent with a 2011 consensus report from the National Research Council, titled “Animal Models for Assessing Countermeasures to Bioterrorism Agents.”  That report addresses the challenges stemming from developing and testing medical countermeasures against biothreat agents in animal models.  Among other things, the report recommends the development of a comprehensive strategy to reduce the dependency on nonhuman primates by maximizing the value of data derived from all research.