Animal Rule

On the latter point, FDA has promulgated a rule (the animal rule) that allows alternatives to human testing for effectiveness and relies on surrogate endpoints. The regulation was originally proposed on October 5,1999, and went into effect on June 30, 2002. 

These might involve implementation of the animal rule, such as animal challenge studies, and surrogate endpoints for CBW defensive agents. 

Support human safety and efficacy when human clinical trial is not feasible or ethical ( animal rule )... 

Unprocessed agricultural crop products - unprocessed animal products when rules introduced - processed foods -animal rules published July 1999, becoming law in August 2000... 

For the case of T. gondii, we found that intraperitoneal tachyzoite injection induces a rapid influx of IL-12-positive PMN (fig. 2). However, although neutrophils are only a minor population in control animals injected with endotoxin-free PBS, approximately 75% of these PMN are IL-12-positive [62]. A similar result was found in noninjected animals, ruling out the possibility that injection alone provides a stimulus for PMN IL-12 induction. Furthermore, approximately 40% of the neutrophils in peripheral blood from noninfected mice are lL-12-positive, arguing against exit from the peripheral blood as a stimulus for lL-12 synthesis [62]. 

The complexity arises from the need to perform efficacy testing of a candidate compound. Because of the inability to perform this testing in human subjects, the FDA Animal Rule for efficacy has been introduced (vida infra). 

The Animal Rule requires that sponsors of product development demonstrate efficacy in at least two animal species that accurately represent the infectious disease in humans. In some cases, this requirement is extremely difficult because of the limited knowledge base related to some of tlie infections (e,g. viral hemorrhagic diseases) most relevant to military personnel. Thus, it is important to remember that there remains a significant amount of basic pathophysiology that needs to be performed in animal model research as well as efficacy testing. 

Since the correlates of protection are a major milestone for countermeasure development through the Animal Rule , this capability is critical for countermeasure development. It is important to realize that the anticipated design of procedures needed to meet the animal rule requirements shall begin early in the R D process as it may change how pivotal experiments are performed. 

In this chapter, a brief history of chemical warfare use in humans, their classification, use of alternative methods of animal testing, particularly in vitro toxicology tests, structure activity relationships, and the use of the 3Rs including "Animal Rule" (FDA, 2009, 2010) and "human-on-a-chip" to possibly test warfare agents are described. 

Johnson Johnson s Levaquin (levofloxacin), an antibiotic intended to treat pneumonic plague, became the first product to receive FDA (2012a) approval via the Animal Rule. The product received approval based on testing in African green monkeys infected with pneumonic plague. None of the placebo control group survived contact with the virus, whereas 94% of the Levaquin group survived. 

The FDA s (2012b) approval of raxibacumab marks just the second approval xmder the Animal Rule, and it is also the first monoclonal antibody. The drug is also notable in that it is intended to treat inhalation anthrax—the pathogen perhaps most responsible for the formation of the animal efficacy rule. 

Both approvals come as the FDA and other government entities are looking into ways to refine the Animal Rule process and the protections it affords to the human subjects it is intended to protect. 

Members of the Alliance for Biosecurity (Gronvall et al., 2007) have made three recommendations for effective implementation of Animal Rule. 

Aebersold (2012) reviewed the FDA experience with medical coimtermeasures xmder the Animal Rule. The author concludes that even though only a few drugs or biologicals have been approved since the Animal Rule became effective, several investigational drugs have been placed in the National Strategic Stockpile for use as medical coimtermeasures, if needed. 

ALTERNATIVE ANIMAL TOXICITY TESTING OF CHEMICAL WAREARE AGENTS TABLE 45.3 Agents Approved Using Animal Rule ... 

The FDA has also clarified suggested issues, one of which is an animal model qualification program. The qualification process is limited to animal models used for product approval under the Animal Rule (www.fda.gov/... 

The Animal Rule states that the FDA can rely on the evidence from animal studies to provide substantial evidence of the effectiveness of a drug only when all of the... 

Sullivan ef al. (2009) have reviewed the usefulness of the Animal Rule in the development and regulatory... 

Aebersold, R, 2012. FDA experience with medical countermeasures under the animal rule. Adv. Prev. Med. 2012,11. . AltTox, 2013. Non-animal methods for toxicity testing, (accessed 20.01.14). 

FDA, 2009. Draft guidance for industry animal models—essential elements to address efficacy under the Animal Rule. . 

Sullivan, N.J., Martin, J.E., Graham, B.S., et al., 2009. Correlates of protective immunity for Ebola vacdnes implications for regulatory approval by the Animal Rule. Nat Rev. Microbiol. 7, 393-400. 

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