gained about that product. Ideally, NIAID uses multiple products to ensure the robustness and neutrality of the animal models. Further product specific refinements may be required, but are left to the sponsors or advanced development contracts in the context of pivotal, product-specific studies. NIAID’s independent investment in the development of product-neutral animal models has been quite successful and this white paper will share examples of the most important product-neutral lessons learned and guiding principles to apply to other animal models moving forward. NIAID’s approach has resulted in the development of several animal models that are now waiting on product licensure decisions as the ultimate demonstration of their utility.

Safety testing of vaccines and therapeutics typically begins in animals, where initial assessments help product sponsors and FDA understand the potential risks in humans. Data are then collected over several phases of clinical trials, with adverse event reporting as well as post-licensure monitoring contributing to our overall understanding of the safety of drugs and vaccines. As new information comes to light, changes in a product’s label may be warranted, such as added warnings regarding special populations. Efficacy results are similar to safety results in that accrual of data supports continued development and use of the product.

Product licensure under the Animal Rule is only different from the usual pathway in that all the efficacy data comes from animal studies, by bridging data that can be obtained in both animals and humans, such as immunogenicity for vaccines and pharmacokinetics for drugs. Data that supports safety and contributes to the bridge to animal efficacy and therefore, presumably, human efficacy, must still be accrued in human subjects. FDA reviews all clinical trial protocols before execution, though there is no regulatory requirement for all animal efficacy protocols to be reviewed prior to execution. Even animal safety protocols need not be reviewed prior to execution, though executing protocols without prior review by FDA runs the risk that the data collected may not support the intended use in subsequent studies, whether human or animal.

The rigor required of any assay, animal study or clinical trial is directly determined by the decisions that will be based upon the resulting data. As a product progresses along its development pathway, increased rigor is demanded from the component assays, reagents, animal models, etc. Once each component is developed to a standard sufficient to support product licensure, further use in supporting other products of a similar nature should be straightforward.

Currently for biodefense product development against biological threats, no product is yet licensed under the Animal Rule for wide use in an event or even an emergency, therefore none of the animal models or assays has been determined to be sufficiently well developed. Indeed, the data in hand at the time of an emergency will be assessed as to their adequacy to support use of a product, therefore anticipating the nature of the emergency is the only way to potentially gauge the rigor required of the data prior to licensure; a hypothetical emergency is not the same as an actual emergency. There are two products licensed under the Animal Rule, both for chemical agents where the mechanism of action in animals and humans is extremely similar, and these products have limited licenses for use in military or first responder applications. Experience with Emergency Use Authorization for all biodefense medical countermeasures is equally limited.

Infectious disease animal models represent a dynamic system, with myriad possibilities for the relationship between host and pathogen. Both the host and the pathogen are biologic systems themselves, fraught with genetic and epigenetic variability, that when combined results in a highly dynamic situation with even more variability. An additional challenge peculiar to biodefense is that it may be difficult to relate the animal model to the human disease; we may have an incomplete picture of human disease, it may be outdated, or we may have no information at all in the case of emerging diseases. The challenge becomes even greater when using the animal model to assess the efficacy of a countermeasure—yet another player in the host-pathogen-countermeasure dynamic and yet another uncertainty in bridging efficacy in animals to humans. Will the countermeasure impact the host and

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