6
Resource Issues

Beyond the technical considerations addressed in the preceding chapters of this report, a number of resource and regulatory issues also limit the development of appropriate animal models for countermeasures against aerosolized bioterrorism agents. These issues include personnel needs and training, infrastructure limitations on integrating advances in technology, and coordination with federal agencies. This chapter will consider these broad structural needs and some possibilities for addressing them, based in large part on discussions at the Animal Models for Testing Interventions Against Aerosolized Bioterrorism Agents Workshop.

PERSONNEL NEEDS AND TRAINING

Development and testing of animal models for countermeasures against aerosolized bioterrorism agents requires collaboration between the several different communities of scientists and clinicians with interests in aerosol models. Many of these professionals, however, have historically worked along parallel tracks. The infectious-disease and microbiology communities, for example, have long focused on the relevant diseases, but most experts in these areas lack the expertise, facilities, or interest to develop aerosol-inhalation techniques, say, to the necessary degree of rigor. Thus the characterization and standardization of the biological (both animal and microbial), aerosol, and dose-measurement properties of the countermeasures-development system requires experts in the diverse disciplines to understand each others’ needs and terminologies and work together to advance the state of the art.

In general, the Committee envisions a team approach, in which each team member has sufficient general understanding of the others’ disciplines to be able



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6 Resource Issues Beyond the technical considerations addressed in the preceding chapters of this report, a number of resource and regulatory issues also limit the development of appropriate animal models for countermeasures against aerosolized bioterrorism agents. These issues include personnel needs and training, infrastructure limitations on integrating advances in technology, and coordination with federal agencies. This chapter will consider these broad structural needs and some possibilities for addressing them, based in large part on discussions at the Animal Models for Testing Interventions Against Aerosolized Bioterrorism Agents Workshop. PERSONNEL NEEDS AND TRAINING Development and testing of animal models for countermeasures against aerosolized bioterrorism agents requires collaboration between the several different communities of scientists and clinicians with interests in aerosol models. Many of these professionals, however, have historically worked along parallel tracks. The infectious-disease and microbiology communities, for example, have long focused on the relevant diseases, but most experts in these areas lack the expertise, facilities, or interest to develop aerosol-inhalation techniques, say, to the necessary degree of rigor. Thus the characterization and standardization of the biological (both animal and microbial), aerosol, and dose- measurement properties of the countermeasures-development system requires experts in the diverse disciplines to understand each others’ needs and terminologies and work together to advance the state of the art. In general, the Committee envisions a team approach, in which each team member has sufficient general understanding of the others’ disciplines to be able 41

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42 DEVELOPING COUNTERMEASURES AGAINST AEROSOLIZED AGENTS to contribute usefully to the overall project. The Committee was impressed by the efforts made in this regard by some of the organizations (e.g., USAMRIID) represented at the July 2005 Workshop, and it commends these efforts. They illustrate what can be done when scientists with the appropriate combination of expertise collaboratively interact. The Committee also feels that building a community in this field in the near future is important, given the urgent needs and expectations in biodefense and the funding available from multiple agencies.. The various experts at the Workshop represented a cross-section of the skills that need to be brought together, their exchanges were highly informative, and these communications were welcomed by virtually all who participated. While that event was a salutary beginning, it was also apparent that further and continuing opportunities are needed to exchange information and to sustain the effort of building a broader community. Accordingly, the Committee recommends: • sufficient cross-training of physical and biological scientists with expertise in the aerosol, infectious-disease, microbiology, and aerosol-medicine fields to facilitate their ability to collaborate productively; • targeted ongoing opportunities for information exchange among these disciplines in order to encourage the formation of a community of researchers; and • the development of interdisciplinary teams to collaborate closely in the long-term; these teams should include strong biostatistical support. Information exchange and community building could be facilitated through a consortium of scientific societies (such as the American Association for Aerosol Research, the American Society for Microbiology, the International Society for Aerosols in Medicine, and the Society of Toxicology, among others) to develop targeted meetings or joint sessions at appropriate professional meetings (such as the Emerging Infectious Diseases or Biodefense Research meetings organized by the American Society for Microbiology). Federal partners can also play a key role in building the community, as several agencies, including the Department of Health and Human Services, the Department of Homeland Security, the Department of Defense, the Environmental Protection Agency, the Department of Energy, and the Department of Agriculture, have interests in this area (the specific role of FDA will be discussed later in this chapter). Meanwhile, the National Institute of Allergy and Infectious Disease (NIAID) has an extensive program in biodefense, including academically based Regional Centers of Excellence (RCEs) in Biodefense and Emerging Infectious Diseases as well as Regional Biocontainment Laboratories (RBLs) that can help by serving as unifying platforms for training and research. Indeed, several of

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43 RESOURCE ISSUES these centers are already developing training in selected areas, including laboratory-safety and emergency-response requirements (Connel, J., personal communication, 2005). In addition to the need to build a well-trained community, there are other personnel issues that can impede the development of this field, including the need for personnel protection and biosecurity. For example, vaccine availability for biomedical researchers is an issue. Although second-generation vaccines based on newer technologies are in the works or on the drawing board, none are generally available at this time. Moreover, the traditional anthrax vaccine is in short supply, while a previously licensed plague vaccine is no longer available in the United States. To add to the difficulty, it has generally been doubted that the previously licensed plague vaccine would be effective against aerosol exposure (Adamovicz and Andrews 2005). While these points only serve to emphasize the need for the kind of work on countermeasure development and validation that is the subject of this report, they also indicate some of the barriers to performing such work. INFRASTRUCTURAL ISSUES Biosecurity Closely related to personnel problems is the matter of infrastructure support. Many of the aerosolized agents require high levels of personal protection, such as gloves, masks, and biocontainment in secured facilities. There are currently two components to laboratory biosecurity: (1) biosafety, which includes physical containment and safe handling of the agent; and (2) physical security. Biosafety precautions are typically ranked in terms of Biosafety Levels 1–4 (with 4 being the highest). They “consist of combinations of laboratory practices and techniques, safety equipment, and laboratory facilities”; and the recommended biosafety level for an agent “represent those conditions under which the agent ordinarily can be safely handled” (CDC and others 1999). Work with select agents (see Table 6-1) imposes additional requirements for enhanced physical security of the laboratories and storage areas, for shipping of agents, and for controlled access. Such facilities therefore are specially designed and very expensive to construct and operate. Aerosol generation and exposure equipment, itself expensive and specialized, when used with the agents needs to be carefully adapted for containment and decontamination, further adding to the costs. Animal Resources The cost of the laboratory animals themselves is another important factor to be taken into account. As discussed elsewhere in this report, many investigators feel that the FDA Animal Rule will place more emphasis on using primates than

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44 DEVELOPING COUNTERMEASURES AGAINST AEROSOLIZED AGENTS TABLE 6-1 Select Agents and Toxins Identified by the U.S. Department of Health and Human Services and U.S. Department of Agriculture HHS Select Agents and Toxins USDA Select Agents and Toxins Abrin African horse sickness virus Cercopithecine herpesvirus 1 (Herpes B virus) African swine fever virus Coccidioides posadasii Akabane virus Conotoxins Avian influenza virus (highly pathogenic) Crimean-Congo haemorrhagic fever virus Bluetongue virus (Exotic) Diacetoxyscirpenol Bovine spongiform encephalopathy agent Ebola virus Camel pox virus Lassa fever virus Classical swine fever virus Marburg virus Cowdria ruminantium (Heartwater) Monkeypox virus Foot-and-mouth disease virus Reconstructed replication competent forms of Goat pox virus the 1918 pandemic influenza virus Japanese encephalitis virus containing any portion of the coding regions Lumpy skin disease virus of all eight gene segments (Reconstructed Malignant catarrhal fever virus (Alcelaphine 1918 Influenza virus) herpesvirus type 1) Ricin Menangle virus Rickettsia prowazekii Mycoplasma capricolum/ M.F38/M. mycoides Rickettsia rickettsii Capri (contagious caprine Saxitoxin pleuropneumonia) Shiga-like ribosome inactivating proteins Mycoplasma mycoides mycoides (contagious South American Haemorrhagic Fever viruses bovine pleuropneumonia) (Flexal, Guanarito, Junin, Machupo, Sabia) Newcastle disease virus (velogenic) Tetrodotoxin Peste des petits ruminants virus Tick-borne encephalitis complex (flavi) viruses Rinderpest virus (Central European Tick-borne encephalitis, Sheep pox virus Far Eastern Tick-borne encephalitis, Swine vesicular disease virus Kyasanur Forest disease, Omsk Vesicular stomatitis virus (Exotic) Hemorrhagic Fever, Russian Spring and Summer encephalitis) Overlap Select Agents and Toxins Variola major virus (Smallpox virus) Bacillus anthracis Variola minor virus (Alastrim) Botulinum neurotoxins Yersinia pestis Botulinum neurotoxin producing species of Clostridium Brucella abortus USDA Plant Protection and Quarantine Brucella melitensis (PPQ) Select Agents and Toxins Candidatus Liberobacter africanus Brucella suis Candidatus Liberobacter asiaticus Burkholderia mallei (formerly Pseudomonas Peronosclerospora philippinensis mallei) Ralstonia solanacearum race 3, biovar 2 Burkholderia pseudomallei (formerly Schlerophthora rayssiae var zeae Pseudomonas pseudomallei) Synchytrium endobioticum Clostridium perfringens epsilon toxin Xanthomonas oryzae pv. oryzicola Coccidioides immitis Xylella fastidiosa (citrus variegated chlorosis Coxiella burnetii strain) Eastern Equine Encephalitis virus Francisella tularensis Hendra virus Nipah virus Rift Valley fever virus Shigatoxin Staphylococcal enterotoxins T-2 toxin Venezuelan Equine Encephalitis virus

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45 RESOURCE ISSUES small animal species; and in many other cases only nonhuman primate models are sufficiently characterized to use for aerosol studies. Unfortunately, while use of nonhuman primate models may sometimes be necessary, nonhuman primates are expensive and in short supply (Robinson and Beattie 2003). The National Institutes of Health has recognized that acute shortages in availability of nonhuman primates may hamper biomedical studies, and it is anticipating the establishment of more sources of these animals (Robinson and Beattie 2003). The National Institutes of Health and other federal agencies involved in research utilizing nonhuman primates should coordinate their efforts to ensure adequate supplies of rhesus and cynomolgus macaques and other nonhuman primates. Though nonhuman primates are widely favored as test subjects in studies of aerosolized bioterrorism agents, they are often difficult to handle in high- containment laboratories; this description applies especially to macaques (Patterson and Carrion 2005). Requirements for social interactions, environmental enrichment, and other unique needs of nonhuman primates are also critical factors to be considered and adequately addressed. The number of research facilities that are capable of performing inhalation studies with these animals and meet these ancillary needs is quite limited. Programs to develop or expand inhalation research facilities may be needed to support bioterrorism studies. Because programs that focus entirely on the use of macaque models could prove extremely expensive, one interim solution may be the development of well-accepted and well-characterized alternative nonhuman primate models for these studies. At the Workshop, Dr. Leah Scott and her colleagues at the Defence Science and Technology Laboratory (Porton Down, United Kingdom) discussed the marmoset as an alternative nonhuman primate species with which they have worked successfully for the past two decades; and Dr. Louise Pitt and her colleagues at USAMRIID discussed their work in developing the vervet (African green monkey, Cercopithecus aethiops) model for pneumonic plague. An important common denominator was the amount of effort these investigators devoted to ensuring that the new animal model would be well characterized—a status that includes natural history (pathogenesis) studies, dose-response data, comparisons with past results (under comparable conditions) in other nonhuman primate species, and availability of needed reagents (such as those for immunological markers). Guidelines for validation, which need to include baseline pathogenesis and pathology studies, are therefore of great importance in animal-model development, and they are probably essential for any anticipated applications under the FDA Animal Rule. Such information is also of direct scientific value, lending additional insights into the host-pathogen interaction. It is also ethically, scientifically, and economically prudent to obtain the greatest amount of feasible data, with the least possible stress to the animal, from each experiment. Several participants in the Workshop—including Dr. Scott, Dr. Pitt, and their colleagues—described how their animals were monitored (by whole-body plethysmography) during the experiments, as well as their subsequent use of remote telemetry to provide electrocardiogram,

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46 DEVELOPING COUNTERMEASURES AGAINST AEROSOLIZED AGENTS electroencephalogram, electromyography, blood pressure, heart rate, body temperature, respiration, and activity data. Remote telemetry, coupled with a scoring system, is particularly promising for determining endpoints, thereby reducing distress among the animals and minimizing the handling of infected animals under containment conditions. As more advanced technologies become validated for assessing an animals’ dose and physiological state, these technologies can be readily incorporated. For example, there was considerable discussion at the Workshop about methods to determine actual inhaled dose of agent. The traditional approaches involve calculations from input and chamber samples, or sacrificing some of the animals to determine actual numbers of the agent in the lung. While these approaches are still necessary, recently developed technologies using bacteria with inserted light-emitting genes or other markers are making it possible to determine the number of inhaled bacteria by direct imaging in the living animal (Advance Research Technologies and GE Healthcare 2005; Contag and Bachmann 2002). At the moment, these imaging methods are more easily used with small animals than with larger species, but practical applications for larger species may well become available in the near future. This is but one example of a new advanced technology that has the potential to greatly improve the quality of animal-model data. It is likely that other new and equally useful technologies will become available in the foreseeable future. It is critical to develop suitable systems and resources for testing, validating, and rapidly incorporating useful new technologies as they become available. Availability of Data and Materials Given the limitations in expert personnel and resources, their collaborative use seems essential. Resource- and information-sharing also appear to the Committee as highly desirable ways to achieve greater leverage, reduce unnecessary duplication, and accelerate the process of developing new products. The Committee believes that effective data-sharing is one of the most critical (and potentially the most easily implemented) areas for immediate development. The Internet, after all, was originally created for just this purpose (Hafner and Lyon 1996). Information technology, already changing the way the biomedical community works, needs to be fully utilized in this regard. For example, extensive data on the characteristics of many animal models used in testing countermeasures are not available in the published literature. Access to such data could prevent unnecessary duplication, allow researchers to compare results with different animal models, help determine the relative advantages and disadvantages of those models, assure consistency by standardizing techniques, and allow data to be pooled for more rapid determination of results. Therefore, the Committee recommends that an easily searchable central database registry (or registries) on animal model data be established. Determination of the exact data types and format is probably best left to a working group, but data could include standard operating

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47 RESOURCE ISSUES procedures, efficacy established on meta-analysis, comparative analysis of different models, and countermeasure and animal-model failures for each agent, among others. The committee also recognizes that the infectious agent or toxin being studied should be well characterized—for example, it is very important that the strain being studied, together with its natural history, be well documented. The Committee recommends the establishment of a repository, which can supply investigators studying a particular agent with a well-characterized sample of that agent. The American Type Culture Collection (ATCC) maintains such a repository, but additional information to facilitate comparisons of animal-model systems and ensure consistent results should be added. There is also considerable precedent for reagent repositories, such as the AIDS Reagent Repository developed by NIAID. AGENCY CONSIDERATIONS Several federal agencies have major roles in biodefense—as scientific partners, regulators, or potential customers. Good interagency coordination is therefore highly desirable, as is good communication and collaboration between these agencies and biodefense researchers in government, academe, and industry. Probably no federal agency has a more critical role in the development of new countermeasures against bioterrorism agents than the FDA, the principal U.S. regulatory agency for medical countermeasures. As discussed earlier in this report, researchers are hopeful about the use of the FDA Animal Rule (21 CFR 314 Subpart I and 21 CFR 601 Subpart H), which permits the agency to base its marketing-approval decision—of a candidate vaccine, therapeutic, or diagnostic for a bioterrorism agent—on submitted animal efficacy data when the countermeasure cannot otherwise be tested for efficacy in humans. There are four general scientific requirements for submission of efficacy data under the Animal Rule: “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 (meaning the model has been adequately evaluated for its responsiveness) 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 or major morbidity; and

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48 DEVELOPING COUNTERMEASURES AGAINST AEROSOLIZED AGENTS 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” (21 CFR 601.91a and 21 CFR 314.610a). The committee believes that the Animal Rule and the apparent intent of the Rule—to provide flexibility for marketing approval of a new countermeasure against a bioterrorism agent—are laudable accomplishments and a major step forward in ensuring the nation’s preparedness against bioterrorism attacks. Once the Animal Rule was passed in June 2002, it took less than a year for pyridostigmine bromide to receive FDA marketing approval as a prophylactic treatment against soman. Prior to the passage of the Animal Rule, the Army had been seeking FDA approval for pyridostigmine for more than 15 years (McNeil 2003). Many obstacles in the FDA regulatory process still need to be addressed, however. The power of the Animal Rule is that the efficacy of a countermeasure can be demonstrated in a nonhuman species whose responses mimic and are predictive of the disease process in humans. However, the current lack of animal models is an impediment to gaining FDA approval; few animal models have been established that predict the human disease process associated with Category A select agents. This means that in addition to the efforts necessary to demonstrate the efficacy of a countermeasure, considerable time and resources will first need to be expended to establish the predictive value of the animal model. In addition, the FDA approval process requires that an animal model mimic or predict the human response to an agent at the disease stage for which the countermeasure is expected to be used. For regulatory purposes, countermeasures are categorized in one of three ways—(1) as prophylactics (administered before an exposure; e.g., most vaccines); (2) as post-exposure prophylactics (administered after an exposure but prior to the onset of the disease process; e.g., antibiotics, antivirals, and some vaccines); or (3) as symptomatic treatments (e.g., antibiotics and antivirals) (FDA 2002). Unfortunately, an acceptable animal model of exposure is not necessarily an acceptable model of the disease process. In the case of inhalational anthrax, there is a proposed rhesus macaque model for testing post-exposure prophylactics (FDA 2002); however, the disease progression and many of the clinical manifestations of inhalation anthrax in humans differ from those of the rhesus macaque (Vasconcelos and others 2003; Shafazand and others 1999; Ivins and others 1998; Zaucha and others 1998; Fritz and others 1995; Friedlander and others 1993). Therefore the FDA may or may not accept efficacy data for symptomatic treatments tested in the macaque model. Though efforts are being turned toward development and characterization of other

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49 RESOURCE ISSUES animal models, there is considerable concern that animal models acceptable to FDA cannot be developed for all of the select agents. The lack of acceptable animal models, if that turns out to be the case, could be a significant impediment to the creation of new countermeasures against bioterrorism agents. Without an acceptable animal model, there would be no pathway for achieving FDA approval of these countermeasures through the Animal Rule, thereby discouraging pharmaceutical industry efforts in this area. Already, the market for countermeasures against bioterrorism agents is considered modest, there are product-liability issues, and the cost of research, development, and testing of antibiotics—which have a 90-percent failure rate during that process—is high (Cassell 2002). However, countermeasures that cannot be approved through the Animal Rule because of a lack of acceptable model can be approved through the Emergency Use of an Investigational New Drug (IND) Rule (21 CFR 312). Under this rule, in an emergency situation the FDA may authorize use of an unapproved drug for specified use without submission of an IND. This authorization hinges on the declaration of a domestic emergency by the Secretary of Homeland Security, a military emergency by the Secretary of Defense, or a public health emergency by the Secretary of Health and Human Services. This rule is particularly advantageous when a drug that has already received FDA marketing approval for use against another disease or condition needs emergency-use authorization. In that case, safety has already been established for the drug and the focus of emergency approval is on indications of efficacy. Though countermeasures that have not previously received FDA marketing approval can be approved through the emergency-use authorization rule, it does not remove the fiscal barriers to the pharmaceutical industry’s development of novel countermeasures. Companies will not likely invest resources in researching and developing a novel countermeasure that may win FDA approval only if an emergency situation has been declared. Similarly, regarding countermeasures that have already received marketing approval, there is little incentive for companies to perform extensive efficacy testing for uses against bioterrorism agents. The practical implications of implementing the Emergency Use Rule also need to be considered. In the event of an emergency, will the recommended safety, efficacy, manufacturing, and alternative products data, discussions of risks and benefits, fact sheets for health care providers and recipients, and proposed labeling all be available for submission to the FDA in a matter of hours or days? If symptomatic patients are the first indication that a bioterrorism event has occurred, will there be sufficient time for the FDA to perform a review of the submitted data and information? Finally, it seems unlikely that a pharmaceutical company would manufacture and store an investigational drug in quantities sufficiently large enough to address a national bioterrorism incident. There may be a role for the U.S. Centers for Disease Control and Prevention and U.S. Department of Health and Human Services—which maintain and manage

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50 DEVELOPING COUNTERMEASURES AGAINST AEROSOLIZED AGENTS the National Strategic Stockpile—in addressing this particular issue, in terms of working with the FDA to focus new product development in areas of critical national need. Further, as both the Animal Rule and Emergency Use Rule are relatively new, there is very limited experience with approvals. For example, as of September 2005, only pyridostigmine bromide had been approved for a new label indication by use of the Animal Rule. The Committee therefore recommends that the FDA work with investigators to draft and finalize practical guidelines to help applicants ensure that they can meet the approval requirements. Though the Committee focused most of the report on technical and methodological issues, the resource and regulatory issues outlined in this chapter can hamper or facilitate progress. Access to information on animal models and previous research, as well as access to well characterized samples of agents, will directly affect decisions regarding the experimental design of countermeasure testing. In addition, collaboration between the research community and the FDA regarding the scientific requirements of the Animal Rule could increase the rate at which new countermeasures are tested and approved. The Committee recognizes that the FDA is in a critical position to help advise researchers involved in countermeasure testing, and the agency appears willing to serve this vital role.