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3 Challenges in the Research and Development of Medical Countermeasures Against Biological Warfare Agents T he policy and organizational changes that the committee has recom- mended for the Department of Defense (DoD) are a portion of what needs to be done to permit more effective progress toward the devel- opment and licensure of medical biodefense countermeasures. But DoD, along with others working to develop medical countermeasures, has to confront other important challenges as well. Academia and private sector firms are essential partners in government efforts to discover, develop, and manufacture medical countermeasures. However, various factors, including concerns about potential liability risks, have deterred the phar- maceutical industry from becoming involved in producing these special- ized products that have limited commercial markets. The regulatory process and the role of the Food and Drug Adminis- tration (FDA) also require attention. Determining the efficacy of biodefense products poses special challenges because ethical constraints prevent efficacy testing in humans. The adoption in 2002 of the "Animal Efficacy Rule," the regulatory mechanism that permits efficacy data to be obtained from tests using animals (FDA, 2002b), opens a pathway to li- censure. However, extensive research and testing will be needed to guide the application of this new regulatory tool. Furthermore, expediting the testing and review of high-priority biodefense products places heavy de- mands on FDA resources. In addition, accelerating the development and testing of countermea- sures will require ensuring the availability of adequate supplies of non- human primates and other laboratory animals, specialized laboratory fa- cilities with appropriate biosafety features, and facilities in which test lots 73
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74 GIVING FULL MEASURE TO COUNTERMEASURES of candidate countermeasures can be produced in compliance with FDA standards for current Good Manufacturing Practice (cGMP). The nation also faces a limited supply of scientific and technical personnel with the expertise needed to carry out the work at many stages in the development of medical countermeasures (Partnership for Public Service, 2003). In this chapter, the committee reviews these challenges and recom- mends steps that DoD, acting principally through the proposed Medical Biodefense Agency, should take on its own or in collaboration with others. ENGAGING ACADEMIA AND INDUSTRY Under the new DoD organization recommended by the committee, partnerships with the academic community and with biotechnology and pharmaceutical companies will be crucial to the success of the medical countermeasure development program. Early research and discovery leading to new candidates for vaccine and drug countermeasures should involve both intramural and extramural work, with the mix determined on the basis of assessments by the DoD program's leadership of the most effective way to achieve programmatic goals. With no government-owned facilities for full-scale vaccine or drug manufacturing, collaboration with experienced commercial partners is essential to move candidate countermeasures through the final stages of product development and licensure and into production. In addition, ac- cess to manufacturing expertise during the early stages of product devel- opment can help avoid wasted effort and inappropriate commitment of resources. At present, DoD's Joint Vaccine Acquisition Program has a contract with the DynPort Vaccine Company LLC (DVC) to develop and license biological defense vaccines for the U.S. armed forces. DVC does not have vaccine production facilities of its own but instead contracts with compa- nies possessing the necessary facilities and expertise. Potential Obstacles to DoD Partnerships with Academia and Industry DoD's need to collaborate with academia and industry in the devel- opment of medical countermeasures is clear. However, the discussions at the committee's public meetings, testimony to congressional committees, and comments in other contexts have highlighted factors that discourage collaboration with DoD as well as other government agencies that are exploring ways to encourage industry participation in the development and production of medical countermeasures to be used against bioterrorist
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CHALLENGES IN THE RESEARCH AND DEVELOPMENT 75 threats (e.g., Aventis Pasteur, 2002; Defense Science Board, 2000; Read, 2003; Top et al., 2000). Factors of concern to both academia and industry include the follow- ing: · Complex and cumbersome contracting requirements · Potential instability of government funding because of the annual appropriations process · Exposure to financial risks for product liability claims · Restrictions on work with pathogens designated as select agents1 · Lack of appreciation within DoD of the true costs of vaccine and drug development Factors primarily influencing larger pharmaceutical firms include the following: · Short-term opportunity costs in diverting limited manufacturing capacity and skilled personnel from other projects · Limited potential to obtain revenue or large profit margins from government contracting · A small or uncertain market beyond government purchases · Antitrust restrictions that limit collaboration among firms In light of the mixture of challenges that exist, several approaches or potential solutions have been proposed. The committee makes recommen- dations regarding some of these options below. Full Use of Existing Grant and Contract Mechanisms The committee expects the proposed Medical Biodefense Agency to make full use of all means at its disposal to ensure that the most suitable organization conducts the work needed to achieve program goals. Ex- amples of the types of agreements that might be employed are listed in Box 3-1. The current Medical Biological Defense Research Program, 1As mandated by the Public Health Security and Bioterrorism Preparedness Response Act of 2002 (P.L. 107-188), the Centers for Disease Control and Prevention (CDC) must maintain a list of "select agents," that is, biological agents and toxins considered to pose a public health or agricultural threat. As directed by P.L. 107-188, CDC (2002) has established re- quirements regarding the possession and use of select agents. These requirements concern registration, security risk assessments, safety plans, security plans, emergency response plans, training, transfers, record keeping, inspections, and notifications.
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76 GIVING FULL MEASURE TO COUNTERMEASURES BOX 3-1 Mechanisms for Engaging Academic Institutions, Industry, and Others in the Private Sector in Federally Funded Research and Development · Grants · Contracts · Cooperative Agreements · Small Business Innovation Research (SBIR) grants of up to $850,000 available to small, for-profit businesses for early stage research and devel- opment · Small Business Technology Transfer (STTR) grants of up to $600,000 available to fund cooperative efforts between small businesses and U.S. research institutions for early stage research and development · Cooperative Research and Development Agreements (CRADAs) to conduct research and development in a technical area of mutual interest to federal laboratories and a nonfederal party (industry, university, not-for- profit organization, or state or local government) · Dual-Use Science and Technology (DUS&T) development projects under which dual-use technology research or development is carried out sharing the costs between DoD and nongovernmental entities · Other Transactions: mechanisms other than a contract, grant, or cooperative agreement used with commercial firms that do not normally contract with DoD. They generally do not require compliance with federal laws and regulations that apply to procurement contracts, grants, and/or cooperative agreements. SOURCES: http://www.acq.osd.mil/sadbu/sbir/overview/index.htm.; Dual Use Science & Technology Process: Why Should Your Program Be In- volved? May 2002. http://www.dtic.mil/dust/dust_process_02.pdf; http: //www.dtic.mil/dust/; http://www.acq.osd.mil/cp/winegar_8-8-02_missouri stconf.pdf; Other Transaction Authority (OTA) for Prototype Projects. http: //www.acq.osd.mil/dp/dsps/ot/dspsot.htm; all accessed 8.13.03. through which basic research and early product testing are supported, makes use of many of these mechanisms. Roughly 40 percent of the planned budget allocation for fiscal year (FY) 2003 was for support of extramural efforts, including a portion of the core program and all of the projects requested by Congress or transferred from the Defense Advanced Research Projects Agency (DARPA) (Henchal, 2003; Linden, 2003).
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CHALLENGES IN THE RESEARCH AND DEVELOPMENT 77 The committee emphasizes in particular the usefulness of "other transaction" authority as a way to gain greater flexibility in the agreement process. This mechanism is specifically intended to facilitate collabora- tions with commercial firms that are not traditional DoD contractors, and it has been used successfully for this purpose by DARPA (Tether, 2002). "Other transactions" include any kind of transaction other than a con- tract, grant, or cooperative agreement. Their use is authorized for DoD research projects by 10 U.S.C. 2371 and for prototype projects relevant to weapons or weapons systems by section 845 of the National Defense Au- thorization Act for Fiscal Year 1994 (P.L. 103-160). The National Defense Authorization Act for Fiscal Year 2004 (P.L. 108-136), which was signed into law in late 2003 as this report was being completed, explicitly extends the authority for "other transactions for prototype projects" related to de- fense against nuclear, biological, chemical, or radiological attack. Agree- ments under this authority are usually exempt from the federal acquisi- tion laws and regulations that apply to standard contracts, grants, and cooperative agreements (see DoD, no date a; 2001; GAO, 2002). 5. The Medical Biodefense Agency should fully utilize "other trans- actions" authority as a means of encouraging academia and private sector firms to participate in the research and development of medi- cal biodefense countermeasures to meet DoD needs. Stability of funding for those awarded contracts and grants is another important consideration for potential partners. The committee urges mea- sures to enable the Medical Biodefense Agency to make long-term com- mitments of funds to its awardees in a manner that would expedite pro- gram execution, but would do so in an economically efficient way. The authority to sign multiyear contracts without full funding of termination liabilities would allow DoD to contract for the full scope of a project last- ing more than one year, but to budget for the project over several years as fiscal obligations become due. 6. Congress should authorize the Medical Biodefense Agency to sign multiyear contracts without a requirement for full, up-front funding of any termination liabilities. New Tools Available to DoD DoD is not alone in its need to form partnerships with potentially reluctant private companies to obtain medical countermeasures for biodefense. Plans to acquire countermeasures for a national stockpile for defense against bioterrorism also depend on commercial firms' being will-
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78 GIVING FULL MEASURE TO COUNTERMEASURES ing to complete development of and produce the vaccines and drugs to be included. For much of 2003, it was expected that Congress would pass legislation to implement Project Bioshield, a Bush administration proposal to address some of the potential obstacles to participation by commercial firms and to help speed certain research management and product pro- curement processes. The Project BioShield proposal included three principal features: (1) relaxing acquisition procedures for procuring property or services in sup- port of research and development for biomedical countermeasures and expediting the peer review process for Department of Health and Human Services (DHHS) grants, contracts, and cooperative agreements; (2) allow- ing DHHS to contract to purchase countermeasures that are still undergo- ing clinical testing; and (3) providing for emergency use of countermea- sures not yet approved by FDA (Gottron, 2003). As of December 2003, legislation to authorize Project BioShield had passed in the House (H.R. 2122) but was pending in the Senate (S. 15 and S. 1504) (Gottron, 2003). However, other legislation already approved by Congress has enacted some elements of the BioShield proposal. The ap- propriations bill for the Department of Homeland Security (DHS)2 makes $5,593 million available until September 30, 2013, for securing biodefense countermeasures. Of this amount, up to $3,418 million may be obligated during FY 2004 through 2008 and up to $890 million may be obligated in FY 2004. In addition, and of particular importance for DoD, are the BioShield- like provisions of the National Defense Authorization Act for Fiscal Year 2004 (P.L. 108-136). The extension of "other transactions" authority, which is not limited to DoD, has already been noted. The legislation also in- cludes a general provision authorizing increased financial thresholds for the use of simplified acquisition procedures "to facilitate the defense against or recovery from nuclear, biological, chemical, or radiological at- tack against the United States" (Sec. 1443). Other provisions of P.L. 108-136 apply specifically to DoD. Section 1601 includes provisions authorizing the Secretary of Defense to use streamlined acquisition procedures, "when appropriate," in procuring property or services for use in performing, administering, or supporting research and development of biomedical countermeasures. (Provisions related to laboratory construction and personnel are noted later in this chapter.) Section 1602 directs the Secretary of Defense to identify and pro- cure for a DoD stockpile the biomedical countermeasures needed to pro- 2Making appropriations for the Department of Homeland Security for the fiscal year end- ing September 30, 2004, and for other purposes, P.L. 108-90 (2003).
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CHALLENGES IN THE RESEARCH AND DEVELOPMENT 79 tect members of the armed forces against leading biological, nuclear, chemical, and radiological threats. Procurement is limited to "qualified countermeasures" that are (1) already approved by FDA or judged by the Secretary of Health and Human Services as likely to qualify for such ap- proval and (2) considered feasible to produce and deliver in the quantities needed by DoD within 5 years. The Secretary of Defense is authorized to use an interagency agreement with DHS and DHHS to obtain counter- measures for DoD from the Strategic National Stockpile and to transfer funds to the other agencies to cover the cost of replenishing the stockpile. The legislation establishes no formal requirement that manufacturers of countermeasures obtained for the DoD stockpile ensure that those prod- ucts ultimately receive FDA approval. Section 1603 is covered later in the chapter in the discussion of emergency use of medical countermeasures by DoD. It is difficult to anticipate whether the added funding and procure- ment authorities enacted so far--or the BioShield proposals, if passed and signed into law--will provide sufficient incentive for industry to enter into development agreements with DoD or DHHS. However, the relax- ation of acquisition procedures, expedited peer review, and market guar- antees appear to be constructive steps toward addressing some of the con- cerns of the private sector. Some argue, however, that additional incentives will be needed (e.g., Barbaro, 2003; Ludlam, 2003; Read, 2003; Ryan, 2003). For example, nei- ther the DoD authorization legislation nor the BioShield bills address in- dustry concerns regarding the need for indemnification against product liability claims. The proposed Biological, Chemical, and Radiological Weapons Countermeasures Research Act (S. 666), introduced in March 2003, is one attempt to try to address some of these other concerns, includ- ing tax and intellectual property rights considerations, liability concerns, limited antitrust exemptions, and incentives to increase research and manufacturing capacity. As of December 2003, neither the Senate nor the House had acted on this bill. Liability Considerations Most medical biodefense countermeasures are likely to receive FDA approval under the Animal Efficacy Rule and, thus, without direct evi- dence of efficacy in humans. Moreover, unlike products developed for a commercial market, most of the biodefense vaccines and some of the therapeutic products will be purchased only by government agencies and used only at the direction of those agencies. For major pharmaceutical firms, the possibility of substantial financial loss through product liability claims is a significant deterrent to their willingness to apply their exper-
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80 GIVING FULL MEASURE TO COUNTERMEASURES tise and resources to the development of new countermeasures. Smaller companies may initially be willing to accept greater financial risk, but they also have fewer resources to sustain their efforts to develop new products. Concerns about liability may extend as well to university re- searchers and other not-for-profit research organizations. Having heard from biotechnology and pharmaceutical industry rep- resentatives and from a consumer advocate, the committee is persuaded that it is important for the government to address industry concerns about product liability risks as part of efforts to accelerate the development of medical biodefense countermeasures. Among the possible alternatives is the approach adopted under the Homeland Security Act of 2002 for the use of the smallpox vaccine.3 When the vaccine is administered in response to an appropriate declaration by the Secretary of Health and Human Services, the vaccine manufacturer, as well as health care organizations and individuals involved in administer- ing the vaccine, are deemed to be employees of the Public Health Service for purposes of any liability claims. Suits for personal injuries allegedly caused by the vaccine must be brought against the federal government, which may seek recovery against manufacturers and other covered per- sons only for gross negligence, illegal conduct, willful misconduct, or vio- lations of government contract provisions. This is similar to the legisla- tion enacted in 1976 (P.L. 94-380) in response to liability and insurance concerns raised in connection with the swine flu program. The Homeland Security Act also included the "Support of Anti-ter- rorism by Fostering Effective Technologies Act of 2002," referred to as the SAFETY Act. The SAFETY Act includes a provision limiting the tort liabil- ity to sellers of designated antiterrorism technologies and providing for the use of the "government contractor defense,"4 after approval from the Secretary of Homeland Security (Department of Homeland Security, 2003). However, the limits under the SAFETY Act do not apply to harm caused when no act of terrorism has occurred, so this provision may not cover vaccines that might be used when an attack is only suspected or threatened (Gottron, 2003) or vaccines administered to U.S. troops to pro- 3Liability protections related to the smallpox vaccine were included in the Homeland Se- curity Act of 2002 (P.L. 107-296), passed in November 2002, and in amendments enacted in the Smallpox Emergency Personnel Protection Act of 2003 (P.L. 108-20), passed in April 2003. 4The government contractor defense is a judicially created doctrine barring claims against government contractors who meet certain requirements. The SAFETY Act provides that this defense is available upon approval by the Secretary of Homeland Security to those who sell to state and local governments and the private sector as well as to the federal government.
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CHALLENGES IN THE RESEARCH AND DEVELOPMENT 81 tect against potential battlefield (rather than bioterrorist) exposure to bio- logical agents. Another model is the National Vaccine Injury Compensation Program (P.L. 99-660), which is a federal "no-fault" system to provide compensa- tion for injuries related to specific childhood vaccines. This approach re- quires sufficient prior knowledge of the products and their associated adverse effects so that a list of covered injuries can be established. As a result, this model is not practicable for as-yet undeveloped vaccines and drugs for which adverse event profiles have not been determined. Another approach is contractual indemnification, which obligates the federal government to pay a contractor's costs incurred as a result of liti- gation. Through its prime system contract with DVC, DoD already makes indemnification available, on request, to DVC's subcontractors as an ex- tension of the indemnification provided to DVC. However, because com- panies can recover litigation costs only after they are incurred, this ap- proach can allow companies to fail before they are able to receive payment from the government. The committee favors an approach similar in concept to the Home- land Security Act model for the smallpox vaccine. The government would be the sole defendant in any suit alleging injury in connection with a des- ignated biodefense countermeasure, but would retain the right to seek indemnification from a manufacturer or other covered person for speci- fied actions, such as gross negligence, willful misconduct, or criminal acts. Experience with the swine flu program in 1976 suggests that this will pro- vide sufficient assurance for large pharmaceutical companies and others to participate in the development and manufacture of the needed prod- ucts, while retaining incentives for all participants to exercise appropriate care in the research, development, and manufacturing process. This ap- proach will require some form of legislation. Until such legislation can be enacted, the committee recommends that DoD and DHHS make maxi- mum permitted use of existing legislative authority to enter into indemni- fication agreements with persons who contract for research, development, and manufacture of biodefense countermeasures. 7. DoD and DHHS should make maximum permissible use of statu- tory indemnification authority under existing legislation to encour- age entities in the private sector, including universities and other research institutions and companies, to enter into agreements to develop and manufacture medical countermeasures against biowarfare agents. As soon as possible, legislation should be en- acted creating a system comparable to that for the smallpox vaccine under the Homeland Security Act, under which suits for personal injuries allegedly caused by biowarfare countermeasures may be
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82 GIVING FULL MEASURE TO COUNTERMEASURES brought only against the federal government, which would retain the right to recover damages resulting from such suits from manu- facturers or other covered persons if their misconduct (gross negli- gence, illegal acts, willful misconduct, or violation of government contract obligations) was shown to be the cause of the injuries. SUPPORTING THE REGULATORY PROCESS FDA has statutory responsibility for ensuring the safety and efficacy of drugs and biologics approved for human use,5 which gives the agency a crucial role in the development and licensure of medical biodefense products of interest to DoD. As a result, efforts to accelerate the develop- ment of medical countermeasures for DoD have to take into account fac- tors related to FDA. The committee focused on three issues that require further attention: application of the new Animal Efficacy Rule, ensuring that FDA has the resources necessary to expedite the review of product license applications for medical countermeasures, and planning for lim- ited or emergency use of medical countermeasures. Using the Animal Efficacy Rule The Animal Efficacy Rule, finalized by FDA in 2002, enables FDA to approve new vaccines and drugs when it is not ethical or feasible to con- duct human efficacy studies, a situation that applies to most biodefense products. Under this new rule, evidence of efficacy can be based on data derived from studies in more than one animal species "expected to react with a response predictive for humans" or in a single sufficiently well- characterized animal model (FDA, 2002b). In February 2003, FDA an- nounced the first product approval under the Animal Efficacy Rule: pyridostigmine bromide for pretreatment prophylaxis against exposure to the nerve agent soman (FDA, 2003a). A substantial amount of work must be done to validate animal mod- els as surrogates for humans in efficacy studies of biowarfare counter- measures. It will be necessary to establish the biologic plausibility of the equivalence of animal and human responses to the disease agents and to the countermeasures in question. DoD-sponsored investigators have helped develop some of the few existing animal models of human disease caused by biological warfare agents or of protection against those dis- 5Federal Food Drug and Cosmetic Act Section 505i; The Public Health Service Act, Regu- lation of Biological Products, Section 351 Subpart 1.
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CHALLENGES IN THE RESEARCH AND DEVELOPMENT 83 eases (e.g., Geisbert et al., 2002; Ivins et al., 1996, 1998; Jahrling, 2002; Pitt et al., 1996, 2001; Zaucha et al., 2001), but the National Institute of Allergy and Infectious Diseases (NIAID, 2002) has identified a need for additional work to develop animal models for almost all of the biological agents con- sidered to pose the most serious threat for bioterrorism (referred to as "Category A" agents).6 Although the committee believes that NIAID should be the primary sponsor of such work, the Medical Biodefense Agency should ensure that information on animal models developed by DoD investigators is avail- able to researchers and the product development community, including FDA. The Medical Biodefense Agency should also have adequate funding to help support development of the animal models that will be necessary to establish the efficacy of biodefense products intended to meet unique DoD needs. 8. The Medical Biodefense Agency and the National Institutes of Health (NIH) should cooperate in making information on animal models relevant for the development of medical biowarfare coun- termeasures available to qualified investigators. The DoD agency should work with NIH and engage FDA to develop additional ani- mal models that will be useful for specific agents or products of particular concern to DoD. The Medical Biodefense Agency should receive funding specifically for this task. The Animal Efficacy Rule is new, and there is still uncertainty about its interpretation and application. Although FDA will be the final judge of the data needed to provide evidence of efficacy, advances are required in the scientific field as a whole, accompanied by scientific discussion and consensus building regarding the best approaches. FDA should receive funding to support this additional work, which will help establish an es- sential scientific foundation for use of the Animal Efficacy Rule. 9. FDA should work with the scientific community to enrich the science base that the agency will have to draw on in order to apply the Animal Efficacy Rule. FDA should receive sufficient funding to support both intramural and extramural work on these issues. 6The CDC has established three categories of biological agents that are considered to be bioterrorism threats (http://www.bt.cdc.gov/agent/agentlist-category.asp). Category A agents are those considered to pose the most serious risk to national security; these agents are listed in Appendix A.
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92 GIVING FULL MEASURE TO COUNTERMEASURES Facilities for Research and Product Development and Testing Specialized facilities for research, development, testing, and evalua- tion are part of the essential infrastructure for the development of medical biodefense countermeasures. Work with most of the Category A agents requires facilities with high-level biosafety ratings (biosafety level [BSL] 3 or 4), putting the availability of these facilities on the critical path for coun- termeasure development. Furthermore, the military threat posed by most biological agents is generally considered to be from aerosol exposure. As a result, efficacy testing for candidate countermeasures for DoD requires facilities in which test animals can be subjected to aerosol challenge under high-level biocontainment conditions. At the present time, only a few BSL-3 and BSL-4 facilities are opera- tional, including those at USAMRIID. USAMRIID and Battelle Memorial Institute have the nation's primary facilities for aerosol challenge studies of nonhuman primates. As a result of increases in the number of candi- date countermeasures expected to be moving through the development pipeline, there is a need for additional biocontainment space for labora- tory research, for animal experiments involving aerosol exposure to bioagents, and for holding animals for as long as several months after exposure to assess the safety and efficacy of candidate countermeasures. Biocontainment facilities are complex, and the cost of designing, building, and operating them is high. NIAID will fund the construction of several additional BSL-3 laboratories and two BSL-4 laboratory research facilities that are expected to begin operation in the next 5 to 7 years (NIAID press release, 2003; Parker, 2003). These include additional intra- mural laboratories, one of which will be adjacent to USAMRIID, and ex- tramural facilities. DHS (no date) is also planning the construction of a major facility for biodefense research and analysis at Fort Detrick. This facility is expected to include a biocontainment laboratory and aerosol exposure capabilities. The existing major facilities at USAMRIID, however, are more than 30 years old and will not be useful much longer without extensive renova- tions. The estimated costs of replacing the USAMRIID facility to ensure the necessary scientific and physical capacity for modern research, test- ing, and evaluation are $1 billion over 8 years (USAMRIID, 2003). Al- though the Secretary of Defense has been given specific authority to use available construction funds to improve DoD laboratories that are neces- sary to carry out the department's research and development program for biomedical countermeasures,8 the committee saw no indication that funds have been budgeted for the work needed at USAMRIID. 8National Defense Authorization Act for Fiscal Year 2004, P.L. 108-136, Sec. 1601 (Novem- ber 2003).
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CHALLENGES IN THE RESEARCH AND DEVELOPMENT 93 It also is unclear whether sufficient facilities for holding, testing, and evaluation of animals in compliance with FDA regulations for Good Labo- ratory Practices9 have been planned (Parker, 2003). Such facilities have to support compliance with stricter standards for consistency than are nec- essary during earlier stages of product research and development. They will be needed to conduct the animal testing required by the Animal Effi- cacy Rule. The committee is concerned that the limited availability of such facilities already constitutes a bottleneck for the testing and evaluation process (Linden, 2002; Parker, 2003; Peuschel, 2002) and that the backlog will grow more severe as additional discovery efforts bear fruit. Another facilities issue is the capacity for cGMP production of candi- date vaccines and drugs before full-scale manufacturing begins. Clinical testing of candidate products requires the use of material produced in compliance with FDA regulations for cGMP,10 and cGMP production re- quires a sophisticated facility and skilled staff. Historically, vaccine and drug development has been the domain of industry; thus, licensed cGMP facilities, especially for vaccine production, are rare outside the industrial enterprise. For researchers who do not have an industry partner, lack of access to cGMP-compliant production facilities can be a major obstacle to clinical testing of candidate products (McCoy, 2003). Contract facilities are reported to have waiting times of 12 to 24 months (Shepard, 2003). This is a problem for developers of products to meet DoD needs, as well as for academic labs pursuing other niche products. In view of the targeted market for medical countermeasures against biowarfare agents, industry may have limited incentives to make cGMP facilities available to manufacture the small amounts of material needed for early clinical testing. Increased access to facilities designed to produce materials for at least Phase 1 and 2 clinical trials would aid the develop- ment of candidate vaccines and drugs. Ideally, such facilities should have the flexibility to allow dedicated use of space for a variety of parallel prod- ucts. For work on biodefense countermeasures, space meeting BSL-3 stan- dards is also needed. Within DoD, the Walter Reed Army Institute of Re- search opened a facility in 1999 for production of cGMP-grade vaccines, with 25,000 square feet of space and five clean rooms (DoD, no date b). This facility has limited capacity compared with one opened in July 2003 by St. Jude Children's Research Hospital, which has a 64,000 square foot facility with 16 clean rooms (Personal communication, E. Tuomanen, St. Jude Children's Research Hospital, September 9, 2003). 9Good Laboratory Practice for Nonclinical Laboratory Studies (21 C.F.R. Pt. 58 ). 10Current Good Manufacturing Practice in Manufacturing, Processing, Packing, or Hold- ing of Drugs; General (21 C.F.R. Part 210 ) and Current Good Manufacturing Practices for Finished Pharmaceuticals (21 C.F.R. Part 211 ).
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94 GIVING FULL MEASURE TO COUNTERMEASURES Because several different government agencies have research inter- ests related to the development of biodefense products, interagency coor- dination is essential. A planning and assessment process is needed so that comprehensive estimates can be developed for all government agencies of biodefense requirements for laboratory space and for animal testing and holding space at BSL-3 and BSL-4 levels. This planning process should also take into account the anticipated demands of the academic commu- nity and industry. A high-level process is needed to prioritize the use of the limited space available and to continue planning for any additional space needs. 12. The Medical Biodefense Agency should participate in interde- partmental efforts to make a formal assessment of the need for fa- cilities for animal testing and holding and for GMP-compliant manufacturing of material for clinical testing that will arise from research efforts to develop medical countermeasures to biowarfare or bioterrorism agents that are under way, planned, or likely. 13. The Medical Biodefense Agency should promote the develop- ment, and participate in a system for prioritizing the use, of special- ized government-owned testing facilities that are essential for re- search and development of medical biodefense countermeasures. 14. DoD should provide funding to carry out the renovations neces- sary to ensure that USAMRIID can continue operation of fully func- tional BSL-3 and BSL-4 facilities for laboratory and animal research. ENSURING THE AVAILABILITY OF A WELL-TRAINED WORKFORCE A key to success in the research and development efforts on medical countermeasures against biowarfare agents is a well-trained and experi- enced workforce. People with relevant scientific, regulatory, and acquisi- tion expertise are all integral to these efforts. At present, however, the supply of scientific and technical personnel is limited not only within DoD, but in the larger community of biowarfare and bioterrorism coun- termeasures development (IOM, 2002; NIAID, 2002; Partnership for Pub- lic Service, 2003; Top et al., 2000). A recent report expressed concern about the small and shrinking fed- eral workforce with medical and biological expertise relevant to respond- ing to a biological attack, noting that many federal employees with this expertise are nearing retirement age and that limitations on pay, poor hir- ing procedures, and unattractive work settings make recruitment of re-
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CHALLENGES IN THE RESEARCH AND DEVELOPMENT 95 placements very difficult (Partnership for Public Service, 2003). Some of these problems have been reported as particularly acute within DoD (De- fense Science Board, 1998, 2000, 2002) and were discussed with the com- mittee during its information-gathering meetings.11 Reports have also noted the limited expertise in biological sciences within DoD (Danzig and Berkowsky, 1997; NRC, 2001) and the apparent impact of the elimination of the military draft in the early 1970s on the numbers of researchers with medical and doctoral degrees coming through the military medical re- search laboratories (IOM, 2002; Top et al., 2000). The lack of sufficient personnel with necessary expertise in infectious diseases, microbiology, immunology, primate medicine, drug develop- ment and vaccinology, and vaccine manufacturing is a limiting factor in the rate at which biomedical countermeasures can be developed. The com- mittee notes in particular the need for people with expertise in aerobiol- ogy, in the development of animal models of human disease caused by biological warfare agents, and in the advanced development and manu- facture of medical products, particularly vaccines. There is also a shortage of veterinarians with the necessary expertise in laboratory animal medi- cine, management, and pathology, including those with special training in the care and use of nonhuman primates (NRC, 2004). In addition to personnel with these scientific and technical skills, DoD and other organizations involved in bringing medical products to licen- sure have a need for people who have a thorough understanding of the FDA regulatory process and, if possible, experience at FDA or in working with FDA to bring a product to licensure. Such regulatory expertise can inform the advanced development effort by helping to provide an under- standing of the varying areas of flexibility and constraint in the regula- tions and of FDA's needs for data and documentation. Some have pointed specifically to DoD's need to improve its regulatory expertise in support of the medical biodefense program (Rettig and Brower, 2003). Clearly, FDA requires a highly trained staff as well, with incentives and support to maintain a rapid pace of efficient and thorough reviews. Researchers and product developers within DoD also need an under- standing of the defense acquisition system, the management process by which DoD oversees the development and production of products and technologies to meet defined needs. Famous for its complexity, the DoD acquisition system has undergone recent changes in policy with a goal of fostering efficiency, creativity, flexibility, and innovation (DoD, 2003a, b, c). Understanding how to work within this system requires training and 11 See Appendix B for agendas for the committee's information-gathering meetings. Per- sonnel issues were discussed at the January 2003 meeting.
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96 GIVING FULL MEASURE TO COUNTERMEASURES experience. Such know-how is crucial for those who are managing devel- opment of medical countermeasures against biowarfare agents or natu- rally occurring infectious diseases. They must work not only within the law and regulations enforced by FDA, but also within DoD's rules for entering and progressing through its acquisition system, with milestones and evaluations to justify funding for continued development. Even though the committee advocates relying on the FDA regulatory process as the basis for technical judgments of progress in the development and performance of medical biodefense countermeasures, links with the DoD acquisition system must be maintained. Several approaches are needed to address the serious workforce short- age in the biodefense area. The pipeline of young scientists in training to carry out the work of basic research and early development will be en- hanced to some degree by recent research and training grants available through the NIAID biodefense research program (NIAID, 2003). How- ever, DoD has certain unique resources in the form of scientists and tech- nicians with aerobiology expertise and facilities suitable for aerosol expo- sures of laboratory animals. These unique resources should be used in training additional aerobiology investigators and technicians. DoD exper- tise could also contribute to the development of a curriculum for such training. Further, the NIAID training program is unlikely to adequately ad- dress the critical need for people with experience in advanced develop- ment and manufacture of vaccines and drugs. Most of the expertise in vaccine development and manufacturing resides within the commercial sector, primarily in the four large vaccine-producing companies. The com- mittee sees the need for additional training programs that involve the pharmaceutical industry as a resource and partner. A possible model for such a program exists in the National Institute of General Medical Sci- ences Biotechnology Training Program in which predoctoral trainees are expected to carry out an industrial internship (NIGMS, 2003). 15. The Medical Biodefense Agency should define the capabilities needed for its medical countermeasures workforce, collaborate with NIAID and industry to develop a training curriculum, and support training programs in the areas of special expertise needed for re- search and development of medical countermeasures. The Medical Biodefense Agency could contribute unique DoD resources in ar- eas of aerobiology and the development of animal models of hu- man diseases caused by biological warfare agents.
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CHALLENGES IN THE RESEARCH AND DEVELOPMENT 97 In addition to efforts to augment the supply of trained scientists, steps are needed to improve DoD's ability to hire and retain such scientists. The Medical Biodefense Agency will need the authority to offer competitive salaries and other incentives. The National Defense Authorization Act for FY 2004 (P.L. 108-136) includes provisions that may meet some of these needs. Specifically, DoD received authority to enter into up to 30 personal services contracts, with compensation at rates above those for department employees, to carry out research and development activities for biomedical countermeasures. This authority can be used when the services to be provided are deter- mined to be "urgent or unique" and if it is not practical to obtain those services in other ways. In addition, to accelerate research and develop- ment of biomedical countermeasures, the Secretary of Defense may hire scientific and technical personnel using special hiring authorities that in- clude up to 5 years of supplemental payments in addition to salary. Over- all, the department can hire up to 2,500 experts under such terms. Use of mechanisms such as the Intergovernmental Personnel Act (5 U.S.C. §§ 33713375; 5 C.F.R. Part 334) should also be encouraged to en- able the Medical Biodefense Agency to draw on expertise in other agen- cies and in academia and other not-for-profit organizations through tem- porary appointments. The agency should also explore mechanisms that could provide increased access to the expertise of industry employees. 16. DoD should use its authority under the National Defense Au- thorization Act for FY 2004 (P.L. 108-136) to offer more competitive salaries to technical experts to bring necessary expertise in biotech- nology and pharmaceutical research and development to the Medi- cal Biodefense Agency. Budgeting for the Medical Biodefense Agency should reflect the need to use such provisions to recruit experienced scientific and technical personnel. REFERENCES Albert V. 2003. Rapid development by Human Genome Sciences of a medical countermea- sure to protect against anthrax. Presentation to the Institute of Medicine and National Research Council Committee on Accelerating the Research, Development, and Acqui- sition of Medical Countermeasures Against Biological Warfare Agents, Meeting IV. Washington, DC. Aventis Pasteur. 2002. An Effective Action Plan for Anti Bioterrorism Vaccine Acquisition and Procurement. Position paper. Swiftwater, PA: Aventis Pasteur Inc. Barbaro M. 2003. Biodefense plan greeted with caution. Washington Post (May 2), p. E1. Bennett BT, Abee CR, Henrickson R (eds). 1995. Nonhuman Primates in Biomedical Research. Biology and Management. San Diego: Academic Press. Black H. 2003. Monkey trouble. The Scientist (July 28). [Online]. Available: http://www. biomedcentral.com/news/20030728/02 [accessed July 28, 2003].
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Representative terms from entire chapter: