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2 Organizing Research and Development for Medical Countermeasures to Accomplish Essential Functions T he question posed to the committee was framed in terms of identify- ing opportunities for the Department of Defense (DoD) to accelerate the research, development, and acquisition of medical countermea- sures against biological warfare agents. Drug and vaccine development is inherently challenging. As a result, the fundamental requirement for an effective program, and even more so for an accelerated program, is a firm and sustained commitment from DoD to make the task a high priority and to provide institutional and financial resources commensurate with the task. In the committee's view, a necessary part of DoD's commitment is a reorganization of the department's efforts so as to maximize its opportu- nities and ability to capture the benefits of scientific advances in the dis- covery and development of medical countermeasures and to adapt the best practices of the pharmaceutical and biotechnology industries to its public sector system. This reorganization should promote a set of func- tional goals, reviewed below, that the committee considers essential. As outlined in Chapter 1, the recommended reorganization of DoD's efforts should be accomplished through creation of the Medical Biodefense Agency, a new agency in DoD that consolidates responsibility and au- thority over the entire research and development process for medical biodefense countermeasures. The committee believes that the prospect for timely advancement of medical countermeasures against all present and future biological warfare threats will be enhanced by the establishment of this agency, whose only agenda will be the development of such prod- ucts. The Medical Biodefense Agency has to focus on products to meet the 44
ORGANIZING TO ACCOMPLISH ESSENTIAL FUNCTIONS 45 needs of military personnel, but it should also actively coordinate and collaborate with the related endeavors of the National Institutes of Health (NIH) to develop countermeasures for bioterrorism to benefit as much as possible from that work. The committee's proposal for this agency is de- scribed in more detail in this chapter. Other organizational options con- sidered and rejected by the committee are also discussed. A DOD AGENCY FOR ACQUISITION OF MEDICAL COUNTERMEASURES FOR BIOLOGICAL DEFENSE As the result of a congressional mandate,1 DoD's work on medical biodefense countermeasures is part of a program that addresses medical and nonmedical countermeasures against both chemical and biological warfare threats. Responsibility for centralized oversight of the Chemical and Biological Defense Program has been assigned to the Assistant to the Secretary of Defense for Nuclear and Chemical and Biological Defense Programs. However, the current operational reality is a fragmented pro- cess that puts research planning and activities for medical countermea- sures under the direction of the Defense Threat Reduction Agency in the Office of the Secretary of Defense, while the execution of those activities (i.e., basic and applied research in a laboratory setting) rests largely with personnel of the U.S. Army Medical Research and Materiel Command (USAMRMC). Management of the acquisition process for candidate coun- termeasures that have reached the stage of advanced development is the responsibility of the Joint Program Executive Office for Chemical and Bio- logical Defense, which operates under the direction of Army acquisition officials. The scientific and technical work of product development is be- ing carried out by a variety of private sector firms and integrated through the prime systems contract with DynPort Vaccine Company (DVC). Pro- gram planning and budgeting are directed from within yet another DoD organization, the Joint Chiefs of Staff (see Figure 2-1). To improve DoD's ability to effectively pursue the development and licensure of medical countermeasures against biological warfare agents, the committee strongly recommends the creation of the Medical Biodefense Agency, a new DoD agency with responsibility for all stages of the research and development process for these products. The committee's proposal for the Medical Biodefense Agency is guided by a set of functional goals, described in Box 2-1. By itself, creation of a new agency will not solve the problems that this committee and other observ- 1The National Defense Authorization Act for Fiscal Year 1994, P.L. 103-160 (1993).
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48 GIVING FULL MEASURE TO COUNTERMEASURES BOX 2-1 Essential Functions of the DoD Research and Development Program for Medical Countermeasures Against Biological Warfare Agents Establish and maintain knowledgeable leadership and effective management A DoD program to develop vaccines and other pharmaceutical prod- ucts should have strong, scientifically knowledgeable leaders at all levels. Together the program leadership and staff should bring expertise in areas ranging from basic research to animal and clinical testing to process devel- opment and product manufacturing (see Box 2-2). In addition, expertise in DoD acquisition and procurement is essential. The program also has to rely on others elsewhere in the government or in the academic community or industry to perform many scientific and technical tasks. Offer effective identification, evaluation, and prediction of, as well as advocacy for, medical biodefense needs Determining the need for medical countermeasures requires combining intelligence concerning biological threats, information on the characteris- tics of the threat agents, information on military planning for the use of medical countermeasures to maintain the effectiveness of forces on the battlefield, and the knowledge of the research and development commu- nity regarding medically and scientifically sound products. The focus should be on unique DoD needs or areas of expertise, considered within the context of work being planned or supported by other government agen- cies, the academic community, or the private sector. Encourage and facilitate coordination with the related efforts of other government agencies, the academic community, and the private sector DoD coordination with the Department of Health and Human Services and the Department of Homeland Security is essential to ensure that mili- tary service members benefit from the newer and better-funded drug and vaccine research and development efforts undertaken as part of the na- tional defense against bioterrorism. Coordination across these agencies should also help DoD identify needs unique to biowarfare defense that are unlikely to be addressed without DoD action. In addition, interagency cooperation should ensure that candidate prod- ucts from DoD and unique DoD expertise and laboratory facilities are ef- fectively used to support the nation's overall biodefense effort. A DoD pro- gram to develop vaccines and other biodefense countermeasures should also use the variety of mechanisms available, including grants, contracts,
ORGANIZING TO ACCOMPLISH ESSENTIAL FUNCTIONS 49 and cooperative research agreements, to cultivate partners in the academic community and the private sector through a strong and diverse set of extra- mural activities. Seek necessary resources An assumption of adequate financial resources underlies industry's esti- mate of a 7- to 12-year time frame for the development of pharmaceutical products. Accelerating the process is likely to require higher funding levels to speed work on particular candidate products and increase the number of candidates that can move through the research and development process at the same time. In addition, increased funding will be needed to allow for an increased risk of failure in efforts to develop candidate products in an accelerated program. With limited funding at present, the pace of product development is likely to be set by budget constraints rather than by scien- tific opportunity and product readiness. In addition to appropriate funding, the program requires access to other resources in the form of research and product development infrastructure. Key infrastructure components include a highly skilled workforce, appro- priate types and numbers of research animals, and specialized laboratory and production facilities. Many elements of this infrastructure are currently in short supply, not only for DoD but for the nation as a whole. Promote program stability The time required to bring vaccines and other pharmaceutical products from discovery to licensure by the Food and Drug Administration (FDA) demonstrates the need for continuity of effort and commitment, assump- tion of risk, and acceptance of a certain degree of failure. For DoD to contemplate meeting or improving upon industry's cycle time, disruptions to the planning and execution of the research and development program must be minimized. Both budgetary and program planning and execution should also allow for prompt responses to the likely occurrence of unfore- seeable problems that can arise at any stage of product development. Understand and promote the use of the best science for the task Because the discovery and successful development of medical biodefense countermeasures is a challenging and uncertain task requiring substantial and varied expertise in rapidly changing fields, as indicated above, DoD should support both intramural and extramural work. For its intramural activities, DoD should have the means to attract strong scien- tific and technical talent on a permanent or temporary basis. An environ- ment supportive of scientific exchange and rigor is needed to foster and maintain excellence in basic research and the product development pro- Continued
50 GIVING FULL MEASURE TO COUNTERMEASURES BOX 2-1 Continued cess. Mechanisms for obtaining independent, expert advice for overall pro- gram planning and for peer review of specific research proposals and pro- gram activities are also essential. Tailor the acquisition process for medical countermeasures to use only FDA's regulatory requirements as the basis for assessing the technical merits of candidate products For vaccines and other pharmaceutical products, including those in- tended for use as medical biodefense countermeasures, product testing and licensure are regulated by the FDA. DoD product development programs, however, are managed through the defense acquisition system, which is oriented to engineering methods and standards primarily for development and testing of mechanical and electronic equipment for weapons systems or software and equipment for information systems. For DoD to work effec- tively toward licensure of medical countermeasures, the acquisition pro- cess must be tailored to the requirements of FDA regulatory oversight, a step endorsed in principle in current DoD policy (DoD, 2003). Establishing the efficacy of biodefense countermeasures, which requires relying on evi- dence from animal studies, will pose unfamiliar challenges for both prod- uct developers and FDA. These new challenges make it especially impor- tant that the countermeasure development process in DoD rest on a strong base of both scientific expertise and knowledge of FDA regulatory stan- dards and requirements. Provide the means for obtaining expert advice on ethical and legal issues A DoD program to develop medical biodefense countermeasures re- quires access to expert advice on the ethical and legal issues raised by the testing and use of these products. Although these countermeasures are be- ing developed to protect military personnel, the clinical testing now under way is relying on civilian volunteers. Including military personnel in these studies poses the challenge of establishing truly voluntary participation in a military setting. However, depending solely on civilian volunteers who are unlikely to ever benefit from their participation and who may be respond- ing to economic incentives poses ethical questions as well (Tishler and Bartholomae, 2002). Well-informed ethical and legal advice will also be essential should consideration be given to emergency use of medical coun- termeasures not yet licensed by FDA.
ORGANIZING TO ACCOMPLISH ESSENTIAL FUNCTIONS 51 BOX 2-2 Intramural Expertise Needed for a DoD Research and Development Program for Vaccines and Other Medical Countermeasures · Defining product development priorities using information from intelligence sources on biological threats · Basic research to identify candidate countermeasures against spe- cific biological agents · Animal models · Process development and product development · Pilot lot manufacturing · Surrogate endpoint assessment in animal models and clinical trials · Design and execution of clinical testing for Phase 1, Phase 2, and Phase 3 trials of safety and efficacy · Analytical testing and quality control of candidate products · Preparation of testing and consistency lots in compliance with FDA requirements for Good Manufacturing Practice · Preparation and submission of product testing and licensing appli- cations to FDA · Full-scale manufacturing · Contracting and business strategy ers (Defense Science Board, 2002; IOM, 2002; Top et al., 2000) have identi- fied. There must also be a genuine commitment to the development of medical biodefense countermeasures from senior DoD leadership, a com- mitment that can be demonstrated by providing the new agency with out- standing leadership, supporting scientific excellence, and providing nec- essary resources. Key Requirements for the Medical Biodefense Agency The committee's recommendation calls for Congress to authorize the creation of the Medical Biodefense Agency to be responsible specifically and exclusively for all aspects of DoD's research and development pro- gram for medical countermeasures against biological warfare agents and infectious diseases of military significance. This agency and its director should report directly to a Senate-confirmed position in the Office of the Secretary of Defense, preferably the Under Secretary of Defense for Ac- quisition, Technology, and Logistics (see Figure 2-2). The functions of a variety of existing DoD organizations and activities should be brought together under the control of the Medical Biodefense
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54 GIVING FULL MEASURE TO COUNTERMEASURES Agency. This includes the responsibilities related to the development of medical countermeasures against biowarfare agents that currently lie within the following organizations: · Medical Chemical and Biological Defense Directorate, Defense Threat Reduction Agency; · Research Area Directorate for Chemical and Biological Defense, USAMRMC; · U.S. Army Medical Research Institute of Infectious Diseases, USAMRMC; and · Chemical Biological Medical Systems, Joint Program Executive Of- fice for Chemical and Biological Defense. The new agency should also assume responsibilities related to the development of infectious disease countermeasures in the following or- ganizations: · Research Area Directorate for Infectious Diseases, USAMRMC; · Pharmaceutical Systems Project Management Division, U.S. Army Medical Materiel Development Activity; and · Components of Walter Reed Army Institute of Research, USAMRMC. Other DoD activities related to research and development of pharma- ceutical products should be reviewed to determine whether it would be appropriate to incorporate them in the new agency as well. The Medical Biodefense Agency should be expected to coordinate with the remaining functions of the Chemical and Biological Defense Pro- gram (medical and nonmedical countermeasures against chemical war- fare threats, and nonmedical countermeasures against biological threats) through the Assistant to the Secretary of Defense for Nuclear and Chemi- cal and Biological Defense Programs, who also reports to the Under Sec- retary of Defense for Acquisition, Technology, and Logistics. The reasons for this recommendation and specific features of its implementation are discussed here. Creation of a New DoD Agency DoD's efforts to develop medical biodefense2 countermeasures have suffered because problems with the organization and management of 2Throughout the remainder of this report the term "biodefense" is used to describe de- fense against naturally occurring infectious diseases as well as biowarfare agents.
ORGANIZING TO ACCOMPLISH ESSENTIAL FUNCTIONS 55 medical countermeasures activities have not been addressed. Further, there is no indication that senior DoD leaders have given the develop- ment of these products the priority required for success. The creation of a newly designated agency reporting to an Under- secretary within the Office of the Secretary of Defense is a major step. The committee considers such a step necessary for two reasons: to integrate all elements necessary to support accomplishing the task of developing medi- cal biodefense countermeasures, and to centralize responsibility and au- thority for this task. Creating the new agency and placing it at a high level within DoD is intended to bring visibility and accountability to a program that is functioning poorly. Recommending that the Medical Biodefense Agency report directly to an undersecretary is also intended to indicate a high priority for these activities within DoD and to improve the agency's ability to advocate for appropriate funding levels. Furthermore, establish- ing the agency at this level should enhance the status of the program and help DoD attract highly qualified leaders who can improve its program by applying expertise from the successful development of other vaccines and drugs. Creation of the Medical Biodefense Agency will establish a more ap- propriate framework for managing and conducting the research and de- velopment that should lead to medical countermeasures licensed by FDA. The research and development process for vaccines and other pharma- ceuticals is most effective when it is based on early and continuing col- laboration among laboratory scientists, manufacturing engineers, clinical investigators, and regulatory affairs specialists. The committee's proposal would remedy the current organizational divide between laboratory sci- ence and subsequent stages of product development by placing all of those activities under the direct authority of the head of the new agency. The organizational aspects of the committee's recommendation for the Medical Biodefense Agency reflect the conclusion that a clear break with past approaches is necessary. Before deciding to recommend that the Medical Biodefense Agency report to the Under Secretary of Defense for Acquisition, Technology, and Logistics, the committee considered the merits of placing the program under the Assistant Secretary of Defense for Health Affairs because of the link that could be provided to military medical expertise. However, the preponderant focus of the Assistant Secretary's office on medical care and health insurance was viewed as having insufficient relevance to a research and development program for vaccines and drugs for biowarfare defense. In contrast, the Under Secre- tary of Defense for Acquisition, Technology, and Logistics is specifically responsible for overseeing the department's various research and devel- opment activities and the subsequent work necessary to bring to a fin- ished state products developed to meet DoD needs. The recommendation
56 GIVING FULL MEASURE TO COUNTERMEASURES for the Medical Biodefense Agency is aimed at creating a framework for such activity that is appropriate for pharmaceutical products. The committee also concluded that placing the new agency within an existing organization reporting to the Under Secretary, or perhaps within one of the Army components that has had a major role in medical coun- termeasures work in the past, offered little prospect of indicating a true change in priority for the program or improving its visibility and pros- pects for appropriate funding. Furthermore, attempting to implement a new and atypical approach for managing research, development, and ac- quisition within an existing organization that is otherwise structured to follow current practices seems to promise little support for the changes the committee considers essential. Scope of Responsibility The Medical Biodefense Agency should have responsibility for all as- pects of DoD-sponsored research and development for medical biodefense countermeasures. The products that would fall under the purview of this agency include vaccines, therapeutic drugs, antitoxins, and diagnostics directed against biological agents. All of these products require FDA li- censure for routine use. It is essential that the Medical Biodefense Agency have responsibility and authority for developing program plans and budgets. The program- matic tasks to be overseen or conducted should include basic research through advanced development. Thus, the agency would be responsible for activities that DoD defines as "science and technology" and for the acquisition programs for candidate products that move into advanced development. All of these activities should be under the new agency's direct control. The existing units currently carrying out these tasks would be absorbed into the new agency and reconfigured to create as efficient an organization as possible. The existing matrix organizational scheme that creates competing lines of responsibility and authority is not adequate. Of particular importance is ensuring that the Medical Biodefense Agency has the authority to manage the transition of candidate products from the science and technology stage into, and their progress through, the DoD acquisition system. At present, this transition occurs before clini- cal testing begins. Formal entry of a candidate product into the acquisi- tion system superimposes DoD reporting and review requirements on the already stringent documentation and reporting requirements associated with the FDA's regulation of clinical testing and product development in support of an application for licensure of a medical countermeasure. Premature transfer of candidate products into the acquisition system was cited in discussions with the committee as a factor in delays. In re-
ORGANIZING TO ACCOMPLISH ESSENTIAL FUNCTIONS 57 viewing DoD technology development programs more generally, the Gen- eral Accounting Office (GAO, 1999) recommended additional develop- ment of products within the science and technology framework but noted that necessary funding for such work is often more readily available only when a project has entered the acquisition system. To improve the devel- opment process for medical countermeasures, the Medical Biodefense Agency should have the authority to use funds from science and technol- ogy accounts (e.g., budget activity 6.3) to support Phase 1 and even Phase 2 clinical trials before a candidate product is subject to acquisition system review. In addition, the agency director requires the authority to allocate funding across budget activity categories in a manner that provides ap- propriate resources for the tasks deemed appropriate for each category. Because the committee expects the Medical Biodefense Agency to pro- mote the highest scientific standards, the agency's work would be con- ducted through a mix of intramural and extramural activities. Thus, the agency needs the authority to use grants, contracts, and a full range of other acquisition mechanisms to engage extramural partners. The agency also needs the authority to create training programs to help prepare new investigators and product developers. Mechanisms for meeting these needs are discussed in Chapter 3. Management of DoD's prime systems contract for the development, licensure, and initial manufacture of several biodefense vaccines should become the responsibility of the new agency. In addition, the new agency should have the option to develop partnerships with other drug and vac- cine companies or other entities, including academia, to carry medical countermeasures through clinical trials, scale-up, and licensure. However, given that vaccine development under the prime systems contract is still in the early stages, the committee believes that DoD must consider the possibility that private sector firms may ultimately be reluctant or unable to supply the manufacturing capacity necessary to meet its needs. Because the manufacturing facility is integral to the licensure of a vaccine, the Medical Biodefense Agency should have the authority and responsibility to explore a full range of options for vaccine production, including gov- ernment ownership or operation of such a facility (see DoD, 2001, 2002). The committee also recommends incorporating into the Medical Biodefense Agency's portfolio the DoD research and development pro- gram for vaccines and drugs to protect against infectious diseases of mili- tary importance. The infectious disease program is closely related to the medical biodefense program in terms of the scientific and technological challenges addressed. Bringing the two programs together would enable each of them to benefit from access to a broader range of intramural and extramural expertise. In addition, the prospect of commercial markets for at least some products from the infectious disease program has led to in-
58 GIVING FULL MEASURE TO COUNTERMEASURES dustry partnerships that might prove helpful in the development of biodefense products. Leadership and Staffing It is essential that the Medical Biodefense Agency have a highly quali- fied director who has strong experience in vaccine and drug research and development. The position can be open to either a civilian or military ap- pointment, but it should be filled at the flag, Senior Executive Service, or equivalent level on the basis of appropriate qualifications. For example, training in clinical medicine without experience in laboratory research or product development and testing would not be adequate. The agency should also have strong medical expertise in infectious diseases at senior management levels. Because vaccines and drugs are based on different scientific principles and require different approaches for development and production, it may be appropriate for the agency to have a senior deputy for each discipline. Every effort should also be made to fill managerial positions through- out the agency with persons having appropriate types and levels of ex- pertise (see Box 2-2). Even though the Medical Biodefense Agency will rely on extramural partners to perform many tasks, it is essential that the agency have a critical core of expertise available within its own staff. In addition to scientific and product development expertise, the skills of the agency staff have to include DoD acquisition and procurement policies and procedures. Chapter 3 discusses mechanisms that the Medical Bio- defense Agency might employ to attract the highly skilled staff it requires. It is crucial that the director have authority over the agency's budget and its full range of management and operational activities and be the advocate within DoD for appropriate funding and programmatic prior- ity. In addition, the director should be the agent of coordination for the Medical Biodefense Agency within DoD and the military services. The Medical Biodefense Agency has to be effectively represented within the high-level decision-making processes that set DoD and national priori- ties, and the agency director should be DoD's primary representative to other government agencies on matters related to the development of medi- cal countermeasures for defense against biological agents. In particular, the director of the Medical Biodefense Agency should be the principal DoD representative to the Interagency Working Group on Weapons of Mass Destruction Medical Countermeasures, chartered by the National Science and Technology Council to coordinate the efforts and responsi- bilities of federal agencies (Interagency Working Group on Weapons of Mass Destruction Medical Countermeasures, 2003). This responsibility will require that the agency and its director be well versed in medical
ORGANIZING TO ACCOMPLISH ESSENTIAL FUNCTIONS 59 biodefense issues related to both biowarfare and bioterrorism. Coordina- tion with other national efforts should ensure that DoD benefits maxi- mally from research and development efforts directed toward bioterror- ism countermeasures, while being able to focus its own efforts on the military's unique needs. Program Priorities and Planning The Medical Biodefense Agency should have the authority to deter- mine its program priorities and program plans in collaboration with the Joint Requirements Office for Chemical, Biological, Radiological, and Nuclear Defense. Requirements for new products to meet military needs, including medical countermeasures, are normally established by the military ser- vices through the Joint Chiefs of Staff. The committee is concerned that the current process incorporates too little expertise in vaccine and drug research and product development to assign the most scientifically ap- propriate priorities and to develop program plans and budgets for medi- cal biodefense countermeasures. The newly established Joint Require- ments Office for Chemical, Biological, Radiological, and Nuclear Defense (chartered in February 2003) promises to give new visibility and coher- ence to the requirements-setting process for the Chemical and Biological Defense Program as a whole. However, the organization's charter indi- cates only a single assigned medical materiel requirements position (Pace, 2003). For the Medical Biodefense Agency to be able to set priorities appro- priately, it must have access to information on biological threats and mili- tary force planning, as well as on the efforts undertaken or planned by NIH's National Institute of Allergy and Infectious Diseases (NIAID) or other federal agencies that might also help in meeting military needs. The information on the risk that various biological agents are thought to pose must be considered along with informed judgments of the scientific feasi- bility of countermeasure development and the pace at which develop- ment can be expected to proceed. Budget The committee believes that for its current scope the DoD program to develop medical biodefense countermeasures is underfunded based on the experience of other relevant government agencies and the private sec- tor. The committee also believes that the program should be better fo- cused before any substantial increase in funding occurs. The current pro- gram, supporting research and development activities on products against
60 GIVING FULL MEASURE TO COUNTERMEASURES more than 10 biologic agents--with 7 candidate products now in clinical testing--is ambitious by industry standards (Top et al., 2000) and too dif- fuse to be effective with the resources available. In addition, development costs can vary widely among pharmaceutical products and generally in- crease substantially as clinical testing progresses, making it necessary to consider the specific mix of projects to make a realistic estimate of annual funding needs. The committee advises that the agency's budget should initially be based on the funding currently allocated to the research and development activities for medical biological defense in the Chemical and Biological Defense Program ($189 million for fiscal year [FY] 2003 in budget activi- ties 6.1 through 6.5), funding for related activities currently supported by the Defense Advanced Research Projects Agency (DARPA) ($79 million for FY 2003), and funding for the research and development program for vaccines and drugs against infectious diseases ($54 million for FY 2003). Related management support funding for each of these program areas (budget activity 6.6) should also be included. In addition to this baseline of $322 million, the initial budget should include an increase of $100 million the first year, rising over the first 5 years to $300 million above the baseline amount. This increase reflects, in part, the expectation that more work will be done by civilian instead of military personnel and in non-DoD facilities, via a vibrant extramural pro- gram. The costs of salaries for military personnel and the operation of military facilities such as the U.S. Army Medical Research Institute of In- fectious Diseases (USAMRIID) do not appear in budgets for the Chemical and Biological Defense Program or the infectious disease program since they are presently covered in accounts of the military services. In addi- tion, some candidate products are moving into later, more costly phases of development. DoD and Congress should expect the new agency's fund- ing needs to increase further as more products reach this stage. Funds for renovating or replacing USAMRIID facilities should also be added to the Medical Biodefense Agency's budget. The committee emphasizes that once countermeasures are licensed, additional funding beyond this re- search and development budget will be needed for procurement of opera- tional quantities of those products. The committee did not use the average cost to the sponsor of develop- ing a new vaccine or drug in formulating its advice regarding the agency's budget. Controversy has surrounded the estimates that have been made over the past 25 years (U.S. Congress, OTA, 1993).3 As noted in Chapter 1, 3Despite these controversies, widespread consensus exists that the full cost to a sponsor of research and development, from discovery through clinical testing to FDA approval, should include the following components: (1) the amount spent for drugs (or vaccines) that success-
ORGANIZING TO ACCOMPLISH ESSENTIAL FUNCTIONS 61 the congressional Office of Technology Assessment (OTA) in 1993 esti- mated the average cost of bringing a new drug to licensure to be $237 million in 1990 dollars (U.S. Congress, OTA, 1993), and more recent esti- mates have ranged from $110 million to $802 million (2000 dollars) (DiMasi et al., 2003; Public Citizen, 2001). Concerns about the most widely quoted estimates have centered on the representativeness of the compa- nies and drugs on which researchers based the estimates, the accuracy of the unaudited costs reported, and the appropriateness of the methods used (e.g., whether to report pre-tax or after-tax costs) (DiMasi et al., 2003, Public Citizen 2003, U.S. Congress, OTA, 1993). For the present purpose, those estimates may also be somewhat unsatisfactory because they are derived primarily from data for new drugs rather than vaccines, which are the principal focus of DoD's product development efforts. The director of the Medical Biodefense Agency should be expected to review all current programs and to develop a strategic plan that will be- come the basis for appropriate budget requests in the future. As noted above, DoD and Congress should expect agency requests to increase over current levels as candidate vaccines and other products enter and move through the clinical testing process, traditionally the most costly stage of product development. For vaccines, another factor that may contribute to additional costs as the product development process moves forward is the need for dedicated manufacturing facilities (either small-scale or full production capacity) that can meet FDA requirements for compliance with current Good Manufacturing Practice (cGMP).4 External Scientific Advice and Oversight An External Review Committee A legislatively mandated external review committee should be established to provide input to the director of the Medical Biodefense Agency and to monitor progress in improving the effectiveness of DoD's efforts to develop medical biodefense counter- measures. The members of the review committee should be experts in various aspects of vaccine and drug research and development, drawn from academia, industry, and other relevant organizations in the private fully received approval for marketing; (2) the amount spent for products that failed at some point in the process; (3) the timing of expenditures on these costs; and (4) the cost of invest- ing capital in this research and development process instead of alternative uses. 4Current Good Manufacturing Practice in Manufacturing, Processing, Packing, or Hold- ing of Drugs; General (21 C.F.R. Part 210 [2003]); Current Good Manufacturing Practice for Finished Pharmaceuticals (21 C.F.R. Part 211 [2003]); and Biological Product Standards (21 C.F.R. Parts 600-680 [2003]).
62 GIVING FULL MEASURE TO COUNTERMEASURES sector (e.g., foundations). In consultation with the agency director, the review committee should develop a set of product-oriented performance criteria that can be used to evaluate the Medical Biodefense Agency. The review committee should meet at least twice a year to ensure that mem- bers gain a good understanding of both the scientific and operational as- pects of the agency's work. The committee should submit an annual evalu- ation of the agency's performance to the Secretary of Defense and the Congress. As discussed in Chapter 1, the review committee should also be charged with assessing the agency's progress after 3 years and recom- mending whether to continue with a DoD-based program to develop medical countermeasures. These review responsibilities should not be assigned to existing advi- sory groups such as the Armed Forces Epidemiology Board, the Defense Science Board, or the Defense Threat Reduction Agency's Threat Reduc- tion Advisory Council. Each of these groups must address a broad range of subjects, and they lack the specialized expertise in the development of pharmaceutical products that the committee considers necessary for this task. Scientific Advice and Peer Review Mechanisms for obtaining in- dependent, expert advice for overall program planning and for assess- ments of specific research proposals and program activities are also es- sential. The groups of scientists convened to conduct peer reviews of proposals submitted to NIH (the NIH "study sections") and the advisory committees for individual NIH institutes or for the Centers for Biologics and Drug Evaluation and Research at FDA are ready models for DoD to use to guide funding decisions about both intramural and extramural pro- grams. By calling on scientists from the broader research community, NIH and FDA gain the benefit of additional expertise and independent judg- ments of scientific merit and program priorities. For the Medical Biode- fense Agency, this type of collaboration with extramural scientists can be a source not only of guidance on program priorities and funding deci- sions, but also of additional scientific advice for intramural scientists and program managers. In addition, it can promote wider knowledge of and interest in the DoD research and development program. The periodic pro- gram area reviews commissioned from the American Institute of Biologi- cal Sciences (e.g., AIBS, 2001), while appropriate, do not offer the kind of prospective guidance or ongoing interaction with the larger scientific com- munity that the committee considers essential. The Scientific Steering Committees currently used by DoD for programmatic development and review do not take sufficient advantage of experts beyond DoD and other government agencies.
ORGANIZING TO ACCOMPLISH ESSENTIAL FUNCTIONS 63 Incorporating New Science for the Longer Term Much of the work in a DoD program to develop medical biodefense countermeasures must be focused clearly on bringing specific products to licensure. Yet new scientific and technical pathways are being opened up by rapid advances in biotechnology. A means should exist for a DoD coun- termeasures program to support a limited amount of highly innovative work that may prove useful only in the longer term. DARPA might serve as a model for this type of research support. DARPA program managers define topic areas of interest and use a variety of mechanisms (e.g., grants, contracts, SBIR[Small Business Innovation Research]/STTR [Small Busi- ness Technology Transfer] awards, and other transactions) to direct fund- ing for research projects to university and industry scientists. To encour- age fresh views on the most promising research needs or opportunities, DARPA program managers are recruited from outside DoD and usually serve for terms of only 4 years. The projects on medical biodefense coun- termeasures that DARPA itself has funded since FY 1998 will soon be ending. Incorporating a DARPA-like function within the Medical Biode- fense Agency would help ensure continuing access to innovative work in the rapidly evolving fields of vaccine and drug research. Potential Shortcomings of a Medical Biodefense Agency The committee recognizes the challenges posed by its recommenda- tion that a new DoD agency be created to conduct all aspects of the department's effort to develop medical countermeasures against biologi- cal warfare agents. Organizational change is disruptive, and substantial "cultural" differences among existing units must be reconciled to create a cohesive agency. The effectiveness of the Medical Biodefense Agency will also depend, in part, on its receiving strong support from senior DoD leaders, something the medical countermeasures effort does not appear to have had in the past. The new agency has to attract a highly qualified director and bring to the management of the program substantially more expertise in the de- velopment of vaccines and other pharmaceutical products, despite the widespread shortage of expertise in fields related to biodefense (Partner- ship for Public Service, 2003). DoD may have difficulty competing for the talent it needs with NIH and other government agencies, academia, and industry. Under the committee's recommendation, plans for advanced devel- opment of medical countermeasures, leading to FDA licensure and full- scale production, continue to rest primarily on contracting for services with companies in the private sector. In general, however, there have been
64 GIVING FULL MEASURE TO COUNTERMEASURES barriers to pharmaceutical firms' participation in this work, which are described further in Chapter 3. DoD has sought to overcome these barri- ers through the use of a prime systems contractor, DVC, which is manag- ing and integrating work being done by as many as two dozen other com- panies (DVC, 2003). However, DVC has yet to demonstrate that its "virtual company" can succeed in licensing a product. CONSIDERATION OF ALTERNATIVE APPROACHES After considering other alternatives, the committee concluded that it is necessary to create a DoD-based Medical Biodefense Agency for the development of medical biodefense countermeasures to ensure that unique DoD needs are addressed. The committee weighed and firmly re- jected as inadequate the option of making minor adjustments within the existing DoD organizational framework or consolidating the research and development activities for medical countermeasures under existing orga- nizations within DoD. Even if circumstances were to make alternatives such as these appealing to policymakers, it would remain necessary to find solutions to the same organizational and managerial problems, as well as the broader challenges discussed in Chapter 3, that led the com- mittee to its recommendation to create the Medical Biodefense Agency. Other alternatives considered by the committee looked beyond DoD. Because of the substantial resources that have recently been provided to NIAID to address the research and development of bioterror countermea- sures and because of NIAID's institutional strengths in sponsoring and executing basic research, the committee considered two options for del- egating a larger role to NIH for developing biowarfare countermeasures. One proposal preserved a core of DoD-based activities for budgetary and programmatic planning and management, while directing funding to re- search and development activities conducted by NIH and others outside DoD. The other proposal shifted all funding and programmatic responsi- bilities for the development of medical biodefense countermeasures from DoD to NIH, with a DoD advisory committee providing guidance to NIH on military needs and priorities The committee rejected these options in favor of recommending a DoD agency with the requisite resources for the task. Table 2-1 summarizes the advantages and disadvantages of these alternative approaches. Minor Modifications of the Existing DoD Program The committee considered the merits of limited changes that would preserve the basic outlines of the existing DoD framework (see Figure 2-1) while attempting to address the serious organizational and budgetary dis-
ORGANIZING TO ACCOMPLISH ESSENTIAL FUNCTIONS 65 connect between investigators responsible for the discovery and early development of candidate countermeasures and those responsible for ad- vanced development of these products. As described earlier in this chap- ter, both sets of activities are funded through the Chemical and Biological Defense Program, but they are conducted by organizations--USAMRMC and the Joint Program Executive Office for Chemical and Biological De- fense--that operate in two separate Army chains of command. Discussions at the committee's public meetings emphasized the diffi- culties that this organizational division creates by hindering essential col- laboration between basic scientists and advanced developers. The com- mittee also heard that current practice moves candidate products into advanced development at the start of clinical testing, a stage at which many products fail or require additional refinement, work that is most readily undertaken by the scientists involved in preparing a candidate product for clinical testing. The change considered by the committee in this option was to shift responsibility and funding for Phase 1 clinical studies from DVC and the Joint Program Executive Office to USAMRMC. Delaying the transfer of candidate products to advanced development until a later stage of clinical testing would reduce the risk of failure of an acquisition program because only those candidates that remain viable at the end of Phase 1 testing would be transferred. This change would also allow for more complete development of associated assays and reagents crucial for testing a vac- cine or drug. Under this scenario, budgets for advanced development would also include some funding to support early collaboration by DVC with USAMRMC scientists on product testing and scale-up considerations. In addition, all DoD units with responsibility for managing aspects of the medical biodefense countermeasures program would be expected to en- hance staff expertise in vaccine or drug development or regulation. Despite having the advantage of causing the least disruption in a pro- gram that has undergone many changes over the past decade, the com- mittee unanimously rejected this incremental change as inadequate to overcome critical underlying problems, including organizational frag- mentation, lack of appropriate expertise among program leaders and man- agers, and insufficient visibility and priority for the program. Consolidating Activities Within an Existing DoD Organization Also considered was the possibility of consolidating all the activities for research and development of medical countermeasures under one of various existing organizations within DoD. This option holds the advan- tage of working within an already functioning administrative structure
66 GIVING FULL MEASURE TO COUNTERMEASURES TABLE 2-1 Advantages and Disadvantages of Alternative Approaches to the Organization and Management of Research and Development of Medical Biodefense Countermeasures to Meet DoD Needs New DoD Agency with Intramural and Extramural DoD Agency Managing Program Extramural Program Advantages Integrated planning and Integrated planning and management of all stages management for research and of product development development of medical DoD control of program biodefense countermeasures priorities Some increased visibility and Increased visibility and priority for development of priority for development medical biodefense of medical biodefense countermeasures countermeasures Increased expertise among program Increased expertise among leadership and managers program leadership and Coordination with NIH work on managers bioterrorism countermeasures Enhanced coordination with encouraged NIH work on bioterrorism Expanded access to extramural countermeasures researchers Expanded access to extramural researchers Disadvantages Disruption of establishing Disruption of establishing a new a new agency agency Potential difficulty of Potential difficulty of attracting attracting qualified qualified director and agency staff director and agency staff Limited DoD control of program activities Loss of direct access to USAMRIID and possibly being somewhat less disruptive than establishing a new agency from the ground up. The committee saw little other benefit, however. An existing organi- zation also has an existing mission and culture that would have to adapt to not only accommodate but actively support the challenging task of de- veloping medical biodefense countermeasures. Furthermore, the committee's recommendation that management of all phases of counter- measure development, from basic science through FDA licensure, be con-
ORGANIZING TO ACCOMPLISH ESSENTIAL FUNCTIONS 67 NIH/DHHS Program with Consolidated Unit under Minor Changes within DoD Advisory Committee Existing Organization in DoD Existing DoD System Strong resources for managing Integrated planning and No change in intramural and extramural management of all stages of organizational basic science product development structure Substantial NIH funding for DoD control of program DTRA/USAMRMC research and development priorities funding of initial of related bioterrorism Does not necessitate new clinical testing countermeasures agency reduces risk of failure after candidate products transition to acquisition system DoD control of program priorities No DoD control of medical Disruption of establishing a No increase in biodefense priorities or new unit within an existing program visibility activities organization Organizational Reduced visibility of medical Limited or no increase in fragmentation biodefense countermeasures program visibility unresolved Likely loss of medical Potential for incompatibilities Lack of appropriate biodefense expertise in DoD of mission expertise among Loss of direct access to Difficulty of attracting program leadership USAMRIID qualified unit leader and staff and managers Limited NIH experience with product development Limited NIH experience with military medical needs solidated under a single director is a departure from DoD's standard prac- tices. An existing organization that is designed to support those standard practices could impede implementation of changes the committee consid- ers essential. Other concerns with this approach were noted earlier in the chapter. It fails to demonstrate a true change in the priority assigned to the devel- opment of medical countermeasures or to increase the visibility of the program or its prospects of successfully competing for adequate funding.
68 GIVING FULL MEASURE TO COUNTERMEASURES Embedding the medical biodefense countermeasures effort within an ex- isting organization could also make it more difficult to recruit leadership of the caliber needed for success. Alternatives That Remove Program Components from DoD DoD Funding and Management of an Extramural Research and Development Program The committee considered the option of an approach that combined DoD-based program planning, budgeting, and management with extra- mural execution of all research and development tasks. This option had many of the features of the committee's primary recommendation, includ- ing creation of a DoD agency that reports to the Under Secretary of De- fense for Acquisition, Technology, and Logistics. However, the research and development program would be exclusively extramural, rather than giving the agency director flexibility to carry out research through intra- mural or extramural programs as in the committee's recommended op- tion. It would still be necessary for the agency director and staff to have comprehensive expertise in the management of vaccine and drug research and development (see Box 2-2) and to have the advice of external experts, but none of the research or development would by carried out by DoD personnel. Under this scenario, the director of the DoD agency would be expected to formulate a budget to appropriately fund the program's activities. It is likely that the initial budget for this alternative would have to be at least as large as the budget using the committee's recommended approach. Programmatic goals would be met by commissioning and funding research through NIAID and by directly supporting research and devel- opment efforts in academia and industry, using all available funding mechanisms. As part of the shift to an entirely extramural execution of research and development, responsibility and funding for the operation of the USAMRIID laboratory facility would be transferred to NIAID. The committee would, however, expect that some of the work commissioned by DoD would require use of the USAMRIID facility. Therefore, the bud- get for the new DoD agency would include funding to help support the facility's renovation or replacement. DoD would rely on industry to develop candidate countermeasures through advanced development to FDA licensure and subsequent pro- duction of the products. The prime systems contractor relationship with DVC provides an established, though as yet unproven, mechanism for engaging industry services for this purpose. DoD would also be free to seek relationships with a broader range of companies.
ORGANIZING TO ACCOMPLISH ESSENTIAL FUNCTIONS 69 An NIH-Based Program with a DoD Advisory Committee The committee also discussed the option of complete termination of the DoD research and development program and transfer of its funding and programmatic responsibilities to NIH. Included in the transfer to NIH would be responsibility, funding, and staff for management and opera- tion of USAMRIID. Guidance on DoD needs would be provided to NIH through a DoD-appointed advisory committee. Work on biowarfare countermeasures might be assigned to NIAID, which is now the principal base for federally funded research related to medical countermeasures against bioterrorism, or to a newly created in- stitute focused specifically on military biomedical research needs or on biowarfare and bioterrorism defense more broadly. While creation of a new institute would pose some difficulties, any overlap in research inter- ests between this institute and NIAID would be resolved through the same types of interinstitute negotiations that already take place to resolve over- lapping interests among existing NIH institutes. A mechanism would be required to allow unique DoD needs and pri- orities to be represented in such an NIH-based program, for example through a DoD-appointed advisory committee composed of senior DoD officials and independent scientific experts from academia and industry. Strengths and Weaknesses of Removing Program Components from DoD The two alternatives that involve removing program components from DoD may have some advantages compared to the committee's pri- mary recommendation, but they have considerable disadvantages as well. Both would capitalize on the strengths of the nation's leading agency for biomedical research, ensuring strong scientific leadership for that work and access to cutting-edge research through both intramural and extra- mural projects. Bringing work on biowarfare countermeasures into NIH would also promote collaboration and coordination with the closely re- lated work on medical countermeasures against bioterrorism. The sub- stantial funding commitment supporting the NIH activities aimed at de- fending against bioterrorism can be expected to allow NIH to foster a more productive environment for both intramural and extramural re- search than is possible with the more limited funding available within DoD. Furthermore, in the face of stiff competition for highly skilled scien- tists and technicians, DoD would no longer have to face the challenge of attracting and retaining the workforce needed to conduct a high-quality intramural research program. A program that is entirely NIH-based would also avoid the pitfalls of the DoD acquisition system, which is de-
70 GIVING FULL MEASURE TO COUNTERMEASURES signed to oversee the development of engineering and weapons systems rather than pharmaceutical products. However, the committee expects close coordination and collaboration between the new DoD Medical Biodefense Agency and NIAID and NIH as a whole to be the rule as it carries out its mission. Since there is consid- erable overlap between the biological agents of concern for both terrorism and warfare, the agency will be expected to work closely with NIH to ensure that DoD benefits from research jointly applicable to both. By main- taining the reservoir of specialized expertise that the DoD intramural re- search program currently represents, the Medical Biodefense Agency can benefit from flexibility to draw on its internal program or on extramural efforts as most appropriate for DoD-specific needs. Because of crucial distinctions between biowarfare and bioterrorism and differences in the need for medical countermeasures appropriate for each, the option in which responsibility for the development of biowarfare countermeasures is given to NIAID or another entity within NIH has cer- tain drawbacks. One concern is that it would tend to reduce the expertise in medical biodefense and the development of medical countermeasures available within DoD to guide overall biodefense planning. Furthermore, NIH has little history of focusing on military-specific needs, and among many competing national public health priorities this additional task may not be given sufficiently high priority. An NIH-based program for the development of medical countermeasures would limit DoD's influence over the research priorities for these products. The proposed advisory committee is intended to ensure that DoD's interests are known to NIH decision makers, but DoD would have no direct authority to alter NIH decisions. The transfer of USAMRIID to NIH would be likely to bring additional scientific talent to this laboratory. Its biocontainment facilities for research on dangerous pathogens and its facilities for studies of aerosol exposures of animals are uniquely suited to biodefense research. As a part of NIH, the USAMRIID facilities could become available to support the larger na- tional biodefense research program. However, USAMRIID is a military medical resource beyond its contribution to biowarfare countermeasure development, and its wholesale transfer from DoD would be a significant loss for the military medical community. Furthermore, despite the talent and resources USAMRIID represents, NIH and the Department of Health and Human Services may not wish to shoulder costs for the facility's ur- gently needed renovation. Ensuring that biodefense vaccines and other pharmaceutical products move effectively toward FDA licensure and production is another impor- tant concern with an NIH-based program. Despite its strength in basic research, NIH has little tradition of product development (Fauci, 2003). In
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