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Introduction

STATEMENT OF TASK

There are many challenges associated with producing appropriate animal models for testing countermeasures, including methodological issues in generating aerosols, dose delivery, and characterization of the model. Further, the use of animals in the drug approval process is a relatively new approach for the regulatory community, presenting issues that also need to be considered.

To address these challenges, the National Institute for Allergy and Infectious Disease (NIAID) asked the National Research Council to convene a committee to consider these issues. The specific charge to the committee is as follows:

The ability of the scientific community to develop new interventions to protect against biological terrorism agents hinges on the ability to test the effectiveness of interventions in animal models, because humans may not be deliberately exposed to the agents. For some pathogens, the disease produced when an agent is aerosolized is quite different than that produced via other exposures and thus it is necessary to test the effectiveness of interventions on animals that are exposed to the agents in aerosol form. Developing animal models of human exposure to inhaled infectious agents is a formidable endeavor for a number of reasons, including reproducibility issues that complicate interpretation of intervention studies. Under the direction of a committee, a 1-2 day workshop will be organized to bring together experts in using animal models to test interventions against aerosolized biological terrorism agents with specialists in other areas of biological



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1 Introduction STATEMENT OF TASK There are many challenges associated with producing appropriate animal models for testing countermeasures, including methodological issues in generating aerosols, dose delivery, and characterization of the model. Further, the use of animals in the drug approval process is a relatively new approach for the regulatory community, presenting issues that also need to be considered. To address these challenges, the National Institute for Allergy and Infectious Disease (NIAID) asked the National Research Council to convene a committee to consider these issues. The specific charge to the committee is as follows: The ability of the scientific community to develop new interventions to protect against biological terrorism agents hinges on the ability to test the effectiveness of interventions in animal models, because humans may not be deliberately exposed to the agents. For some pathogens, the disease produced when an agent is aerosolized is quite different than that produced via other exposures and thus it is necessary to test the effectiveness of interventions on animals that are exposed to the agents in aerosol form. Developing animal models of human exposure to inhaled infectious agents is a formidable endeavor for a number of reasons, including reproducibility issues that complicate interpretation of intervention studies. Under the direction of a committee, a 1-2 day workshop will be organized to bring together experts in using animal models to test interventions against aerosolized biological terrorism agents with specialists in other areas of biological 7

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8 DEVELOPING COUNTERMEASURES AGAINST AEROSOLIZED AGENTS sciences, including aerosol toxicology, to encourage the application of the latest biological information, technology and experience to testing of aerosolized biological agents. The committee will use the workshop to inform their report, which will consider whether there are opportunities for improving current approaches to animal testing of interventions against aerosols by applying knowledge from other fields of science. COMMITTEE PROCESS On July 6th – 7th, 2005, the Committee on Animal Models for Testing Interventions Against Aerosolized Bioterrorism Agents convened a workshop at the National Academy of Sciences building in Washington D.C. (see Appendix A for agenda). Researchers experienced in using animal models to test countermeasures against aerosolized bioterrorism agents interacted at this workshop with specialists in other areas of the biological sciences. Some of the speakers helped to place the task in a larger context—analyzing, for example, the Animal Rule of the U.S. Food and Drug Administration (FDA)—while others provided more technical information such as methods for choosing appropriate animal models or characterizing the challenge aerosols. The workshop’s presentations and discussions brought to the fore the latest pertinent scientific experience, information, and technology, which then informed the committee’s report on whether opportunities exist for improving current approaches. ANIMAL RULE A serious set of limitations comes from the inherent difficulty of testing countermeasures against infections that are, by definition, naturally rare or nonexistent in the human population and that cannot ethically be tested for efficacy in humans because they might cause serious injury or even death. In response to these concerns, the FDA, which is responsible for licensure of medical products in the United States, developed the Animal Rule, which has been in effect since 2002. This rule states that the agency may grant marketing approval for a new drug product (21 CFR 314 subpart I) or biological product (21 CFR 610 subpart H) based on adequate and well-controlled animal efficacy studies when human efficacy studies cannot be conducted because it is unethical to expose human volunteers to the toxic substance—whether biological, chemical, or radiological—in question. Further details and implications of this important regulatory development will be discussed in Chapter 6. Importance of Animals in Research on Aerosol-Mediated Disease Compounding the research difficulties caused by prohibited studies with human volunteers is the fact that data acquired using computer simulations or

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9 INTRODUCTION cell cultures and other in-vitro techniques cannot effectively address many of the efficacy and safety issues critical to the development of vaccines and other countermeasures. Fortunately, several reliable laboratory animal models have been developed by members of the biomedical community who have studied a wide range of inhaled materials including infectious agents. Rodents are particularly useful in the initial phases of efficacy, toxicity, and lethality investigations, which are used to provide data for the design of more definitive studies. Larger mammals, including rabbits, pigs, sheep, ferrets, dogs, and nonhuman primates have proven invaluable as models in studies of chronic toxicity, infectivity, vaccine efficacy, and dermal and pulmonary physiology (Patterson and Carrion 2005). Nonhuman primates are phylogenetically closest to people (Sibal and Samson 2001) and thus are considered of great importance to these studies. BIOLOGICAL WEAPONS CONVENTION Work with bioterrorism agents imposes some unique difficulties. In addition to the numerous scientific concerns, such as developing appropriate models and ensuring suitable biosecurity and biosafety for work with dangerous pathogens, there are also legal and regulatory issues. Some constraints are imposed by legislation designed to limit access to such pathogens. At the national level in the United States, these laws include the Select Agent Rule (42 CFR Part 73) and the U.S. Patriot Act (2001), together designed to control the availability of dangerous pathogens and to regulate access to these agents. International controls are important as well. First signed in 1972, the Biological Weapons Convention (BWC), formally known as the 1972 Convention on the Prohibition of the Development, Production, and Stockpiling of Bacteriological (Biological) and Toxin Weapons and on Their Destruction, was designed to prevent use of biological agents for offensive purposes. As of December 2004, 153 countries (including the United States) had signed and officially ratified the BWC, and 16 additional countries had signed but not yet officially ratified it (BWC 2004). The treaty is the key international agreement in this area, and is perceptually important even though it lacks specific enforcement measures (Taylor 1999). Article I of the treaty states: Each State party to this Convention undertakes never in any circumstances to develop, produce, stockpile, or otherwise acquire or retain: (1) Microbial or other biological agents, or toxins whatever their origin or method of production, of types and in quantities that have no justification for prophylactic, protective, or other peaceful purposes; (2) Weapons, equipment, or means of delivery designed to use such agents or toxins for hostile purposes or in armed conflict.

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10 DEVELOPING COUNTERMEASURES AGAINST AEROSOLIZED AGENTS In the global arena, it is essential that scientific research with dangerous pathogens comply with the BWC itself and, probably more difficult, avoid creating the perception throughout the international community that the countries involved in the research are attempting to evade the treaty. Careful attention to public information and openness is thus required. KEY ISSUES EXAMINED The key issues examined by the Committee and discussed in this report are: 1. Selection of appropriate animal models. 2. Generation and characterization of aerosols of bioterrorism agents. 3. Determination of the dose of select agents following inhalation. 4. Determination of the experimental designs for developing vaccines and therapeutics for inhaled select agents. 5. Resource issues related to inhalation studies of select agents. The committee felt it was important to clearly define the animal studies that were considered as part of this report. The statement of task asked “whether there are opportunities for improving current approaches to animal testing of interventions against aerosols [emphasis added].” The committee focused on improving and standardizing animal studies that generate efficacy data. Due to scientific and regulatory demands, these studies require consistent and reproducible exposures that result in a disease state that approximates the human disease. Animal studies to establish human dose response or to simulate “real world” scenarios were outside the scope of the committee’s task. Seventy-two select agents, including biotoxins but excluding plant pathogens, are currently being regulated by the U.S. Centers for Disease Control and Prevention (CDC) or the U.S. Department of Agriculture (42 CFR 73, 7CFR 331, 9 CFR 121). In addition, the CDC has categorized these pathogens and biotoxins into three categories (A, B, and C), based on their potential for use as bioterrorism agents (Rotz and others 2002). Category A agents, being amenable to large-scale dissemination in a bioterrorism attack, have the greatest potential for mass casualties. As such, development of countermeasures to Category A agents have been given the highest priority; however, it is beyond the scope of the Committee’s charge to discuss pathogens or biotoxins individually, except where data from specific studies are used as illustrations. Similarly, it is beyond the scope of the charge to make a specific recommendation for the appropriate challenge dose for any bioterrorism agent or to identify specific vaccines, therapeutics, or other countermeasures that could be developed.