4
Recommendations with Accompanying Analysis of Limitations Imposed by Current Department of Defense Structure for Managing Acquisition of Vaccines Against Infectious Diseases

Substantial shifts have occurred in the geopolitical, budgetary, and psychological framework within which the Institute of Medicine (IOM) committee that has prepared this report began its work 2 years ago. The September 11, 2001, terrorist attacks heightened the nation’s sense of vulnerability, and contamination of the U.S. mail with anthrax spores focused the public’s attention on bioterrorism and infectious disease threats. To the Department of Defense (DoD), however, the reality of infectious disease threats predated this recent national interest. DoD’s longstanding interest in the use of vaccines to protect military personnel against infectious disease threats is reflected in this committee’s charge as well as in DoD’s separate request to an expert panel led by Franklin Top, Jr., (DoD, 2001d) for advice on its vaccine production capability. These two reports and the recent statement by the IOM Council (IOM, 2001) encouraging the creation of a National Vaccine Authority share a common sense of urgency in suggesting that changes are needed in the processes by which the government acquires vaccines. At the same time, the President’s fiscal year (FY) 2003 budget proposal, the heightened public perception of infectious disease threats, and the attention now focused on biodefense provide unparalleled opportunities for change and set the stage for DoD to act.

Thus far in this report, the committee has presented mostly factual, descriptive information about the need for vaccines, their use in the U.S. military, and the organizational procedures through which DoD advances a vaccine from the point of recognizing the need for a vaccine to making it available for use by military personnel. Here, the committee presents its discussion of those organizational, procedural, and scientific components and provides its analysis of how the pieces might be made to fit better and how the overall process of vaccine acqui-



The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement



Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.

OCR for page 55
Protecting Our Forces: Improving Vaccine Acquisition and Availability in the U.S. Military 4 Recommendations with Accompanying Analysis of Limitations Imposed by Current Department of Defense Structure for Managing Acquisition of Vaccines Against Infectious Diseases Substantial shifts have occurred in the geopolitical, budgetary, and psychological framework within which the Institute of Medicine (IOM) committee that has prepared this report began its work 2 years ago. The September 11, 2001, terrorist attacks heightened the nation’s sense of vulnerability, and contamination of the U.S. mail with anthrax spores focused the public’s attention on bioterrorism and infectious disease threats. To the Department of Defense (DoD), however, the reality of infectious disease threats predated this recent national interest. DoD’s longstanding interest in the use of vaccines to protect military personnel against infectious disease threats is reflected in this committee’s charge as well as in DoD’s separate request to an expert panel led by Franklin Top, Jr., (DoD, 2001d) for advice on its vaccine production capability. These two reports and the recent statement by the IOM Council (IOM, 2001) encouraging the creation of a National Vaccine Authority share a common sense of urgency in suggesting that changes are needed in the processes by which the government acquires vaccines. At the same time, the President’s fiscal year (FY) 2003 budget proposal, the heightened public perception of infectious disease threats, and the attention now focused on biodefense provide unparalleled opportunities for change and set the stage for DoD to act. Thus far in this report, the committee has presented mostly factual, descriptive information about the need for vaccines, their use in the U.S. military, and the organizational procedures through which DoD advances a vaccine from the point of recognizing the need for a vaccine to making it available for use by military personnel. Here, the committee presents its discussion of those organizational, procedural, and scientific components and provides its analysis of how the pieces might be made to fit better and how the overall process of vaccine acqui-

OCR for page 55
Protecting Our Forces: Improving Vaccine Acquisition and Availability in the U.S. Military sition might be improved. Wherever possible, the committee cites specific evidence to support its conclusions. However, in a number of instances no such data were available and the committee was forced to rely on the perceptions of those interviewed by the committee or on indirect evidence, often in combination with the past experiences of committee members in their interactions with both military and civilian vaccine acquisition systems. In such cases, the committee has made every effort to note the lack of hard evidence supporting its contention. Protecting the health of military personnel is essential to national security. The committee presented in Chapter 1 historic evidence that infectious diseases have posed significant threats to the health of the nation’s armed forces. Chapter 3 describes those vaccines that are available to the military for the prevention of infectious diseases. A review of the data presented in this report (e.g., Chapter 3) makes it clear that no vaccine is available for many of the infections that have previously posed problems for U.S. forces on overseas deployments (e.g., dengue, diarrhea, and tick-borne encephalitis, to name a few of those listed in Table 1-2). Thus, it is clear that infectious diseases remain a major concern even as the twwenty-first century unfolds. The considerable number of overseas deployments of U.S. forces on warfighting and peacekeeping missions in recent years suggests that the risk of exposure of military personnel to both naturally acquired and intentionally released infectious agents remains real and present. Vaccines are often the most cost-effective way to protect individuals from infectious diseases, but their value is easily overlooked both within the civilian public health sector and within the military community. For example, a successful antiballistic missile defense system may provide dramatic evidence for its utility when it destroys an incoming warhead, but a safe and effective vaccine leaves no trace of its success when the immune response that it has engendered in the immunized soldier thwarts the early stages of a potentially lethal infection and prevents an incapacitating illness or death. On the basis of its review of the circumstances surrounding the loss of the adenovirus vaccines and the lack of an available licensed plague vaccine (Table 3-3) and (until very recently) an anthrax vaccine, as outlined below, the committee believes that DoD must assign a higher priority to vaccine acquisition than it has in the past. For the purposes of this discussion, the committee defines acquisition as the process by which DoD ensures that appropriate vaccines are available for the protection of its forces. This process represents a continuum extending from the first recognition of need, to the setting of priorities, to the maintenance of a technology base permitting internally conducted or externally contracted product-oriented research, advanced product development, and clinical studies leading to licensure (whether or not DoD is in partnership with an industrial entity), as well as the establishment and maintenance of effective manufacturing facilities and, ultimately, the procurement (purchase) and stockpiling of vaccine for use by DoD for protection of members of the U.S. armed forces.

OCR for page 55
Protecting Our Forces: Improving Vaccine Acquisition and Availability in the U.S. Military The committee’s main conclusion is that DoD’s current vaccine acquisition procedures, coupled with its complex annual budgeting process, significantly hamper its vaccine acquisition activities and thwart effective coordination with vaccine manufacturers. The evidence that led the committee to this conclusion is laid out in the pages that follow. These limitations result in an inability to develop the vaccines that are needed (as evidenced by the large number of vaccines listed in Table 3-5 that are no longer being actively developed for protection of the armed forces), instability in essential vaccine-related research programs (which is reflected in wide fluctuations in budget authority, as described below), and the failure to have available for immediate use those vaccines that are critical for the protection of military personnel, as cited above. The ultimate cost of this inefficient acquisition process is that military readiness is placed at risk. Some militarily important vaccines are not available, in whole or in part, because of poorly aligned acquisition processes and an inadequate commitment of financial resources rather than because of unmet scientific or technological hurdles. This is particularly true for the vaccines listed in Table 3-5, including, for example, the attenuated Junin virus (Argentine hemorrhagic fever) vaccine, for which evidence supporting substantial clinical efficacy has been amassed in a trial carried out among civilian populations in South America (Maiztegui et al., 1998). DoD’s current approach to vaccines originates with the best intentions, involves skilled individuals, millions (but not sufficient millions) of dollars, and intricate planning. Nevertheless, the committee’s assessment after hearing from many of those involved in the acquisition process, as well as several executives from the companies that manufacture vaccines, is that the current vaccine acquisition process has limitations that make the path from basic research to procurement and use of vaccines both inefficient financially and cumbersome. These limitations result in occasional outright failure (as in the case of the loss of the adenovirus vaccines) and unacceptable delays (in the case of the anthrax vaccine) in vaccine acquisition. The lack of vaccines when and where they are needed risks the success of future military operations and the health of personnel and potentially places national security in jeopardy. The committee’s recommendations cover four broad aspects of the acquisition process: Organization, authority, and responsibility Program and budget Manufacturing Regulatory status of special-use vaccines After first presenting its nine recommendations in Box 4-1, the committee provides a discussion, building its case with examples and presenting the reasoning that has resulted in each recommendation.

OCR for page 55
Protecting Our Forces: Improving Vaccine Acquisition and Availability in the U.S. Military BOX 4-1 Committee Recommendations Organization, Authority, and Responsibility The committee recommends that the Department of Defense: Combine all DoD vaccine acquisition responsibilities under a single authority within DoD that attends to the entire spectrum of responsibility—from definition of a potential threat against which a vaccine is needed through research and development, advanced product development, clinical trials, licensure, manufacture, procurement, and continued maintenance of manufacturing practice standards and regulatory compliance. Consolidate the infrastructure, funding, and personnel for DoD programs for the acquisition of vaccines against weaponized biological agents and naturally occurring infectious diseases. Ensure that there is an effective, ongoing senior advisory group—one providing perspectives from both within and outside of DoD—to assess program priorities and accomplishments, to act as a proponent for vaccines and other infectious disease countermeasures, and to maintain active relationships with current science and technology leaders in the academic, government, and corporate sectors. Program and Budget The committee recommends that the Department of Defense: Provide budget resources commensurate with the task. Actively encourage the development, distribution, and use of a well-defined and validated research priority-setting mechanism. Such a mechanism could involve the use of prioritized, weighted lists of infectious disease threats and formal scenario-planning exercises and would require the use and synthesis of infectious disease surveillance and epidemiologic information. Include programming goals that ensure greater strength and continuity in the science and technology base for the full spectrum of infectious disease threats, including research related to the epidemiology of infectious diseases, the nature of protective immunity, and both early and advanced vaccine product development. Leverage DoD research efforts by building greater interactions and an effective formalized coordinating structure that links DoD research activities to vaccine development activities carried out by the Department of Health and Human Services and other public and private groups. Manufacturing The committee recommends that the Department of Defense: Work toward improving manufacturing arrangements to ensure consistent vaccine availability by addressing issues related to long-term commitments, predictable volumes and prices, indemnification, and intellectual property issues. These arrangements should include consideration of the development of vaccine-specific partnerships between the federal government and individual private manufacturers, a consortium of private vaccine manufacturers, and government-owned, contractor-operated vaccine production facilities. Regulatory Status of Special-Use Vaccines The committee recommends that the Department of Defense: Vigorously seek a new paradigm for the regulation of special-use vaccines that remain in investigational new drug application status with the Food and Drug Administration and that have no reasonable prospects for licensure under the current rules. The new paradigm should take into account the circumstances of the vaccine’s anticipated use in setting requirements for the demonstration of safety and efficacy.

OCR for page 55
Protecting Our Forces: Improving Vaccine Acquisition and Availability in the U.S. Military ORGANIZATION, AUTHORITY, AND RESPONSIBILITY Early in the committee’s deliberations, one DoD representative attempted to clarify the DoD process for setting vaccine research and development priorities with an illustrative slide, presented here as Figure 4-1 (and earlier as Figure 2-1). It clearly conveys the complex gauntlet awaiting the potential acquisition of a new vaccine from the time of the first conception of its need through the late stages of development. Figure 4-1 also vividly demonstrates the absence of a single organizational locus of authority and responsibility for that process. Not only is no individual in charge, but too many individuals and entities are responsible for other, unrelated activities in addition to their responsibilities for vaccines and the development of effective countermeasures against infectious disease threats. The committee believes that DoD’s vaccine acquisition program does not—and cannot—work effectively with its management structured in this fashion. Perhaps the best example of how such diffuse management arrangements thwart effective vaccine acquisition is the loss of the adenovirus type 4 and 7 vaccines that the U.S. military used very effectively for many years to prevent acute respiratory disease among trainees. The committee heard from representatives of both DoD and the vaccine manufacturer (Wyeth) concerning the events that led up to the decision by the latter to cease manufacture of the vaccine because of its inability to make changes to its manufacturing facility required by the Food and Drug Administration (FDA) under the terms of its existing contract with DoD. What the committee heard was the inability of the manufacturer to identify any single point of authority within DoD that was sufficiently knowledgeable about the issues and sufficiently empowered to make changes in the contract with the manufacturer necessary to maintain vaccine production. No single entity in DoD had sufficient breadth of authority or responsibility to approve further research and development or to authorize modifications to the manufacturing facility once the vaccine had become licensed, even though this meant that production of the vaccine would cease and that future procurement would not be possible. The end result was the recurrence of serious adenovirus respiratory infections among basic trainees, a problem that continues to the present. This particular issue was the subject of an interim report (IOM, 2000a; also provided as Appendix A to this report) released by the IOM committee that has prepared this report. Although one cannot be certain that a consolidation of all responsibility for vaccine acquisition within a single authority in DoD would have prevented the loss of these vaccines, the committee is convinced that the disjointed authority for advanced vaccine development and vaccine procurement that exists within DoD contributed significantly to the lack of the additional investment required for continued production of this vaccine.

OCR for page 55
Protecting Our Forces: Improving Vaccine Acquisition and Availability in the U.S. Military FIGURE 4-1 Military infectious disease-related research, development, and acquisition activities: USAMRMC interfaces with army and Office of the Secretary of Defense organizations. The acronyms and abbreviations included in this figure are identified in the caption to Figure 2-1 of this report. SOURCE: Glenn (2000).

OCR for page 55
Protecting Our Forces: Improving Vaccine Acquisition and Availability in the U.S. Military Another expert committee commissioned by DoD recently reached a similar conclusion (DoD, 2001d). Soon after IOM constituted the committee that has authored this report at the request of the U.S. Army Medical Research and Materiel Command (USAMRMC), the Deputy Secretary of Defense directed the Acting Assistant Secretary of Defense for Health Affairs (ASD[HA]) and the Director of Defense Research and Engineering to form a group, chaired by Franklin Top, Jr., and charged it with a task—based on the requirements outlined in P.L. 106-398—that significantly overlapped that of the IOM committee. Working independently and with different emphases, the two committees identified similar systemic problems and arrived at similar recommendations to address them, including the need for centralized and coordinated management and strengthened, supportive expert advice. These committees are not the first to note organizational and procedural problems within the DoD’s acquisition processes. The DoD Reorganization Act of 1986 called on DoD to “reduce and streamline the defense bureaucracy” (Republican Policy Committee, 1986). DoD, itself, has recognized the need to reform its acquisition system—agency wide. In 1994, the Secretary of Defense released a report entitled Acquisition Reform: Mandate for Change outlining the need to change the acquisition system. It noted, “The problem is that the DoD acquisition system is a complex web of laws, regulations, and policies. . . While each rule individually has (or had) a purpose for its adoption, and may be important to the process as a whole, it often adds no value to the product itself, and when combined, contributes to an overloaded system that is often paralyzed and ineffectual, and at best cumbersome and complex” (DoD, 1994, pp. 5, 6). In 2001, DoD again addressed the inefficiency of the acquisition system in its Quadrennial Defense Review Report, which notes that “two major institutional processes—the planning, programming and budgeting system and the acquisition process—create a significant amount of the self-imposed institutional work in the Department. Simplifying these processes will support a streamlining of the entire organization [the Department of Defense]” (DoD, 2001c, p. 52). The General Accounting Office (GAO), in testimony before Congress on February 27, 2002, notes that despite DoD’s heavy dependence on acquisition—“close to $100 billion annually to research, develop, and acquire weapon systems and tens of billions more services and information technology” (GAO, 2002, p. 1)—its acquisition system is inefficiently managed. GAO studies found that responsibility for acquiring services is diffuse and “with little visibility or control at the DoD- or military department level” (GAO, 2002, p. 3). The report notes that DoD “is seeking to adapt the same revolutionary business and management practices that helped the commercial sector gain a competitive edge” (GAO, 2002, p. 3). The GAO outlines, in its testimony, several suggested changes that may improve the efficiency of the DoD acquisitions system, including restructuring programs so that requirements and needs are better matched, making sure that decision makers are open to funding the lifecycle of a product, and assuring that

OCR for page 55
Protecting Our Forces: Improving Vaccine Acquisition and Availability in the U.S. Military those making decisions—in terms of time and money spent on a product—are sufficiently knowledgeable about the product and are persons vested with the authority “to make informed tradeoff decisions” (GAO, 2002). Diffuse Management Responsibility As detailed above, no identifiable decision maker within DoD has the responsibility and authority for vaccine acquisition. No single organizational agent within DoD drives the vaccine acquisition system or acts as a galvanizing motivator. No single organizational unit within DoD has the authority to address problems arising with licensed products to maintain product availability. Because no single authority within DoD oversees the vaccine acquisition effort, the DoD decision-making structure for vaccine acquisition is fragmented at each step of the process, including research, development, production, licensure, and the purchase and stockpiling of vaccines. The fragmentation of these processes hinders the creation of priorities and the acquisition of vaccines that the military needs. It leads to misalignment of resources, creates disparities between vaccine research efforts and relevant military medical operations, and leaves large gaps within the research and development process. It prevents any long-term stability across the many years during which a new vaccine is conceptualized, moves through the preclinical and clinical research stages, and finally, is licensed. Furthermore, just as budgetary authority is disjointed, so is program authority. Even the various research and development components—technology base and advanced development—do not share an effective prioritization mechanism. The committee was unable to identify a single list of priorities for vaccine acquisition that each of these separate DoD entities involved in the vaccine acquisition continuum uses. This disconnect can result in the misdirection of resources. Consolidating responsibility and authority for the acquisition of vaccines within a single organizational entity or vaccine authority would provide a seamless process by which DoD could acquire vaccines to provide the protection that its forces require. Vaccine acquisition would be enhanced by developing and imposing a common means of prioritization at all levels of the vaccine acquisition effort, by eliminating unnecessary bureaucracy and overlapping, redundant programs, by improving communication among those responsible for different aspects of the vaccine acquisition continuum, by eliminating the waste of program resources, and by managing vaccine acquisition as part of a higher-priority DoD acquisition category (e.g., acquisition category I). Having expended considerable time in attempting to understand the complexities of the current acquisition process, the committee concludes that DoD should create a single vaccine authority by concentrating responsibility and authority for the entire vaccine life cycle—up to, but not including, policy and clinical decisions concerning the use of vaccines. This entity should be the con-

OCR for page 55
Protecting Our Forces: Improving Vaccine Acquisition and Availability in the U.S. Military trolling authority for the acquisition of vaccines and related biological countermeasures and not simply a coordinating body. It should report to the highest levels within DoD. To succeed, this vaccine authority must have the following: sufficient authority to influence vaccine development, including adequate budgetary authority with assured funding for operations (such as for the procurement of vaccine products after the research period) and control over any government-owned manufacturing facility, such as the government-owned, contractor-operated (GOCO) facility now being considered by DoD; adequate staffing to manage and accomplish all phases of the acquisition process, from priority setting to vaccine research and development, product development, manufacture, and stockpiling; personnel with the financial, regulatory, and legal expertise required for all aspects of the vaccine acquisition process integrated within a single office; clearly defined relationships with the ASD(HA), the DoD and army offices involved with providing funding for science and technology-related activities and program direction, and the commanding general of USAMRMC; a placement in the DoD organizational hierarchy that would allow it to control decisions throughout the vaccine acquisition process and to coordinate decisions related to policies for vaccine use; and a stable, adequate, and well-defined budget. The committee does not have a specific recommendation about where within DoD the operational elements of a single vaccine authority should be placed. It did consider, however, the qualifications and characteristics that a single vaccine authority would possess and how it would work. The committee believes that placement of the vaccine authority at a high level in DoD—at the Pentagon, with the individual in charge of the authority reporting to the highest levels of DoD— is necessary to achieve the task. That organizational placement would not preclude USAMRMC’s holding the operational lead for vaccine-related activities. A November 2001 statement from the IOM Council proposed the development of a somewhat similar authority, the National Vaccine Authority, to confront the problems that the public health sector faces in acquiring limited-use vaccines. The problems that the IOM Council sought to address have much in common with those that are part of the scope of this committee’s charge. The IOM Council’s statement argues that the creation of a single National Vaccine Authority would help to ensure the availability of vaccines that have limited commercial potentials but that are critically needed for the civilian sector. Although the committee recommends the creation of a single vaccine acquisition authority within DoD, it recognizes that a vaccine is more than a product that can be built simply to predetermined specifications, purchased on bid from the manufacturing sector, and stockpiled for future use. A vaccine is part of a complex and continuously evolving biological system that is intended to protect

OCR for page 55
Protecting Our Forces: Improving Vaccine Acquisition and Availability in the U.S. Military the warfighter against an infectious disease. As with any complex system, a vaccine requires constant, well-integrated, and coordinated attention to each facet of its development and maintenance, including disease surveillance, prioritization, research and development, and product refinement in a continuously changing regulatory environment. The committee cites DoD’s recent loss of the adenovirus type 4 and 7 vaccines as prima facie evidence of the need for DoD to adopt a systems approach to vaccine acquisition that spans all steps in the acquisition process. Recommendation 1. Combine all DoD vaccine acquisition responsibilities under a single authority within DoD that attends to the entire spectrum of responsibility—from definition of a potential threat against which a vaccine may be needed through research and development, advanced product development, clinical trials, licensure, manufacture, procurement, and continued maintenance of manufacturing practice standards and regulatory compliance. Fragmented Acquisition Programs for Vaccines and Related Biological Countermeasures for Weaponized and Naturally Occurring Infectious Disease Threats The health of warfighters is at risk both from natural infectious disease threats and from weaponized forms of infectious disease agents that might be intentionally deployed against U.S. forces in combat settings or against civilian populations as agents of terror. Whether natural or weaponized, these two forms of infectious disease threats share much in common. A number of specific pathogens such as those causing plague or hemorrhagic fevers are real and present threats in both contexts. Vaccines have been shown to be capable of providing protection against both natural and weaponized infectious disease threats, drawing in each case on what is a common science and technology base. The maintenance of separate acquisition programs for threats to military operations from naturally occurring infectious diseases and threats from the intentional and hostile use of biological materials inhibit DoD’s ability to make rational decisions related to vaccine acquisition. This complex arrangement arose from DoD’s response to congressional direction to consolidate activities related to the acquisition of chemical and biological warfare defense measures. Thus, DoD created the Joint Vaccine Acquisition Program (JVAP) to manage the advanced development of vaccines to protect warfighters against weaponized infectious disease agents. Although well intended, the creation of JVAP has led to new problems. Separate management prevents unified thinking on the acquisition of vaccines such as those against the plague bacterium and the Rift Valley fever virus, each of which could be a natural and a weaponized threat to military

OCR for page 55
Protecting Our Forces: Improving Vaccine Acquisition and Availability in the U.S. Military personnel. Limited expertise and equally limited budgetary resources are divided in the present scheme, in which DoD has split the responsibility and the authority for the procurement of vaccines against naturally occurring and potentially weaponized infectious disease threats and has established no unifying prioritizing mechanism with which it can manage its limited vaccine development resources. JVAP was intended to streamline acquisition procedures and raise visibility of the need for biodefense products, but these potential benefits have not yet been realized in the acquisition of new vaccine products. The committee could identify no justification for the separation in the acquisition processes for vaccines against naturally occurring and potentially weaponized infectious disease threats. There is substantial overlap in the agents, technical approaches, and hurdles to be overcome in developing vaccines against the infectious agents that comprise both types of threats. The problem here is not simply that JVAP and USAMRMC’s infectious disease program are duplicative. That would be true if both sets of programs were functioning adequately. The reality is that the loss of previously available vaccines and the failure to produce new products indicate that neither program is operating effectively—in part because they are separate. The costs and risks are therefore even higher. In its second recommendation, the committee seeks to fuse the positive characteristics of JVAP—providing a single point of contact and the authority to use a higher DoD acquisition category—and the medical research expertise and experience of the various components of USAMRMC. Recommendation 2. Consolidate the infrastructure, funding, and personnel for DoD programs for the acquisition of vaccines against weaponized biological agents and naturally occurring infectious diseases. Lack of Sufficient Advisory Structure The committee recognizes the need for and strongly recommends the creation of an ongoing, senior advisory structure to guide high-level decision making related to the acquisition of vaccines and other medical countermeasures against infectious disease threats. The proliferation of prestigious panels now looking at vaccine acquisition and availability is a potent indication of the lack of a center of strong advocacy and advice at present. Previously, the Armed Forces Epidemiological Board (AFEB), which reports to the surgeons general of the various services, played a major positive role in military vaccine development. DoD now supports AFEB under the authority and budget of ASD(HA) and also calls upon AFEB for advice concerning a broad range of health care and environmental issues. The committee notes that its present scope is much broader than infectious diseases and that AFEB, as it is

OCR for page 55
Protecting Our Forces: Improving Vaccine Acquisition and Availability in the U.S. Military vaccines, factors that run the risk of driving up substantially the costs of the Phase II and III clinical studies required for licensure. In addition, research involving agents on the Category A list of select agents now involves increasingly complex regulatory and legal oversight because of the USA Patriot Act of 2001,5 which imposes significant responsibilities on the employer with respect to those employees that it uses in such research, including the exclusion of persons from certain countries, those who have sustained legal difficulties, or those who have received other than honorable discharges from military service. There is the risk that additional rules now under consideration may substantially enhance the burdens associated with research on these agents and thus drive both industrial and academic research laboratories toward less regulated areas of research and vaccine development. Indemnification issues. Even when all available precautions are taken, there is still an intrinsic risk that a company may be subjected to litigation as a result of an unexpected adverse reaction to a vaccine. Except for the vaccines covered by the National Vaccine Injury Compensation Program, no federal compensation is available. Without a large revenue stream as insurance, product liability becomes a potentially unacceptable risk. One former industry executive observed that GlaxoSmithKline may not have stopped production of the Lyme disease vaccine, despite substantial liability issues, if the market had been better (Associated Press, 2002). Liability is further complicated for work with military populations, sometimes characterized as a captive pool. Even when working under strict rules and complying with all FDA requirements, industry would want the federal government to indemnify or provide product liability insurance. Industry cites the compensation claims that followed the mass use of the swine flu vaccine in 1976 as an indication that indemnification is necessary. Insiders cite as a more recent example the government’s refusal to indemnify Wyeth for the risk of claims related to the anthrax vaccine as a critical factor in the company’s decision not to produce the vaccine during the Gulf War. In summary, the normal conduct of business for industry involves tendering and cost bidding. However, the process does not operate in this fashion when industry is called on to work with the U.S. military. The DoD makes no continuing, long-term funding commitment to industry, it pays no attention to investments for infrastructure or the need for an acceptable profit margin to support the infrastructure, and makes no commitment to purchase a stable or predictable volume of vaccine over time. Single-phase contracts are unsatisfactory for the planning of construction or for the allocation of scarce human resources by industry, especially when the next phase might go to another entity. 5   Uniting and Strengthening America by Providing Appropriate Tools Required to Intercept and Obstruct Terrorism (USA Patriot Act) Act of 2001, P.L. 107-56:175b (2001).

OCR for page 55
Protecting Our Forces: Improving Vaccine Acquisition and Availability in the U.S. Military Industry representatives also voiced expectations that military managers may attempt to influence management decisions that they believe are more properly made by industry and that the budgets proffered by the military will often be insufficient to meet the task requested of industry. The overall impression held by industry, which the committee cannot refute, is that DoD has never been willing to commit sufficient resources to justify the investment that a company would need to make with its own limited resources to produce the products requested. DoD has not been able to adequately fund the infrastructure needed, maintain facilities, or ensure adequate volumes of future purchases. It fails to appreciate the needs for the large industrial vaccine manufacturer to have a stable market for its products and to collect a sufficient margin on its sales to ensure its future growth and survival within a very competitive international marketplace. The perspectives described above make clear why established, large manufacturers have little interest in developing vaccines that would be used only by the military to protect its forces against infectious diseases and for which a profitable commercial market would not be found in the civilian sector. Meanwhile, although small newcomers to the vaccine industry may be willing to bid on projects of limited scope, such untested partners cannot reliably provide the vaccines that the military requires. This was demonstrated in the recent failure of a small company to provide the plague vaccine. The committee believes that DoD could better attract the interest of industry by working to mitigate the concerns of industry outlined above. An initial step would be to create a centralized, empowered authority within DoD that would manage all interactions and negotiations with the industry, from early partnerships in research and development to the final procurement and stockpiling of licensed products. This would require a change in military organization such as the establishment of a single vaccine authority, as discussed above in Recommendation 1. The concentrated responsibility would permit the companies to deal with DoD representatives who are both (1) knowledgeable about vaccines and public health and (2) given the authority to commit the necessary resources. The single vaccine authority could negotiate with active and potential industry partners for multiyear, multiphase contracts (or another suitable financial-legal arrangement) with clear milestones for both parties. These would allow the construction of additional facilities and the maintenance of a cadre of personnel who would produce the requested vaccines for clinical trials and who, after licensure, would manufacture vaccine lots for continued use. The presence of a single vaccine authority within DoD would allow informed consideration of industry requests such as the consideration of cost-plus terms for the research and development phase; fixed-cost contracts for the later development, manufacture, and distribution phases; or, after successful licensing, sale of facilities to industry. The single vaccine authority could also negotiate the financing and future ownership of fixed assets; pricing policy, including price ceilings; incentives—

OCR for page 55
Protecting Our Forces: Improving Vaccine Acquisition and Availability in the U.S. Military including, for example, the available tax advantages (for research and development, production, and distribution); and staffing arrangements. DoD might consider how to make better use of legislation to stimulate production of special-use vaccines—those for which a profitable market base is limited—that are particularly needed and unavailable for military use. U.S. orphan drug legislation has stimulated a notable increase in the introduction of drugs to treat rare diseases (FDA, 2002d; Lichtenberg, 2001), but vaccines—although within the purview of the Orphan Drug Act—have worldwide sales that are relatively small compared with drug sales (AEI, 1997) and have realized smaller gains following introduction of orphan product legislation. For instance, as of 1997 only 8 of 152 approved orphan products were vaccines (Lang and Wood, 1999). The financial incentives offered by the Act, such as tax credits, are not helpful to a tax-exempt government developer but it is unclear to this committee why this legislation has not generated more interest from manufacturers for vaccines for military use. DoD and FDA might explore alternative applications of or changes to current law to encourage private industry (as partners or contractors) and DoD itself to produce special-use vaccines. DoD must assure potential manufacturers that the costs and benefits are reasonably predictable and somewhat guaranteed. An element in any such a calculation would be a consideration of the opportunity costs, that is, what it would cost industry to develop a product wanted by the military in terms of a reduction in its ability to pursue other, potentially more profitable products. The need for long-term financial support for the maintenance of the availability of critical vaccines cannot be overemphasized. Funds must be committed to maintain production facilities so that current good manufacturing practice requirements are met as necessary. A predictable market would involve the generation and maintenance of a vaccine stockpile, the purchase of guaranteed volumes in the future, and reasonable assumptions regarding pricing. The lack of a policy that is acceptable to industry regarding indemnification against nonnegligent, adverse reactions is a major obstacle to DoD’s ability to attract industry participation in the vaccine acquisition process. DoD should examine the indemnification approaches that the federal government uses for childhood vaccines and civilian employees of the army to see if they might be adapted to use for vaccines for the protection of forces. DoD and its potential partners in industry must delineate a set of mutually acceptable ground rules for the division of responsibility for the early steps in research, particularly those that lead to proof of principle, and the appropriate handling of the intellectual property that may emerge from joint research endeavors. The burgeoning success of technology management offices within many universities provides strong evidence that the fruits of research can financially benefit laboratories outside the industrial sector. Such benefits are appropriate and should not slow the pace of industrial partnership; rather, they should serve as an impetus for further collaboration between DoD laboratories and industrial vaccine manu-

OCR for page 55
Protecting Our Forces: Improving Vaccine Acquisition and Availability in the U.S. Military facturers. Companies will be attracted to DoD partnerships if the companies are allowed to retain intellectual property rights for use in civilian markets. DoD needs to ensure that the ownership of its intellectual property is being properly and adequately exploited to leverage its research activities. Greater attention to the potential value of intellectual property may be of benefit to the overall DoD research effort. A Government-Organized Consortium of Major Vaccine Manufacturers The committee considered the possibility that government–industry partnerships might be managed through an industry consortium that would be formed to deal with the military’s requests for special-use vaccines. Such a consortium could be a single industrial vaccine authority working in partnership with the single DoD authority envisioned as described above to distribute the real and intangible costs of military vaccine development among multiple corporate entities in the industry. Such a consortium could field individual requests from DoD and work to locate an interested and qualified manufacturer that would enter into specific discussions with DoD. The mechanism could effectively distribute among the companies that are members of the consortium the opportunity costs involved in investing in the development of vaccines whose manufacture is requested by the federal government. Participation in the consortium could be recognized as a moral imperative, possibly facilitating the acceptance by shareholders of less than optimal business investments made by company boards in the interest of national and international security. The consortium idea has its proponents and its detractors. Successful examples of different commercial entities with competing interests that have worked together for the benefit of all participants include SEMATECH’s experience with semiconductors (SEMATECH, 2002) and Airbus Industrie’s experience with the aviation industry (Airbus, 2002). An advantage particularly apt to vaccine development is the ability of a consortium to maximize the use of limited technical and professional expertise and other vaccine research and development resources. Although one can easily envision the problems that would need to be overcome to get competing industrial entities to work together in such a fashion, it seems plausible that the development of special-use vaccines by those with the greatest expertise would be particularly cost-effective. A wariness of the need to share proprietary information is a concern, however. The idea of a consortium of major vaccine manufacturers has been proposed previously, but the reception to the proposal has been tepid. Several industry executives expressed the opinion, however, that it may now be a reasonable goal given the events of September 11, 2001, and the subsequent anthrax attacks. Any such consortium arrangement would require coordination with the Department of Justice, however, to ensure that consortium members would not be subject to collusion or antitrust investigations for these activities. Presumably, industry’s

OCR for page 55
Protecting Our Forces: Improving Vaccine Acquisition and Availability in the U.S. Military concerns over potential antitrust action by the government would be minimized if the government itself took an active step to organize and promote the consortium. Government-Owned Contractor-Operated Vaccine Production Facilities Even with improved relations and successful partnerships between DoD and industry, it is unlikely that the private sector will produce all of the vaccines that the U.S. military needs. For that reason, DoD has explored the development of its own production facility. The Salk Institute operated its Government Services Division (TSI-GSD) at Swiftwater, Pennsylvania, and produced vaccines for DoD until 1995.6 DoD has not had a manufacturing resource similar to TSI-GSD since then, however. The committee notes that as part of an accelerated program of medical biodefense measures the Defense Authorization Act for FY 20027 authorizes DoD to design, construct, and operate a vaccine production facility and to contract for the private production of vaccines there. Evidence supporting the need for a dedicated manufacturing resource can be found in Table 3-5. Table 3-5 lists eight vaccines that DoD had developed and that TSI-GSD manufactured under contract with the federal government. None of these vaccines are currently in production and thus their availability is severely restricted. None of these vaccines, which were or still are administered as INDs, have commercial markets that have interested or are likely to interest an industrial manufacturer of vaccines to invest in their further development. In these circumstances, if DoD is to make needed vaccines available to its forces, it must have access to a production facility outside of the commercial market. All the items listed in Table 3-4 and some of those listed in Table 3-5 are likely candidates for production in a government facility. However, the committee emphasizes that regulatory requirements would prevent a single government-owned facility from producing all the vaccines needed. To produce more than one product, DoD would have to build the vaccine manufacturing plants with a modular design that would allow separate manufacturing suites to be used for different types of vaccines. Government-funded manufacturing facilities could be operated through various models. First, DoD could operate its own facility. Second, if it developed these facilities as government-owned contractor-operated (GOCO) entities, a capable contractor could provide dedicated staff and the facility could operate with a flexibility not allowed by government personnel and budget rules. Third, such facilities could be operated by an industrial consortium, one that could mobilize expertise as required from the ranks of those working within its separate component corporations. 6   TSI-GSD ceased all operations in 1998. 7   National Defense Authorization Act for Fiscal Year 2002, P.L. 107-107 (2001).

OCR for page 55
Protecting Our Forces: Improving Vaccine Acquisition and Availability in the U.S. Military It is important to acknowledge that use of a GOCO facility would be expensive for at least three reasons. First, manufacturers would exert strong pressure by competing for employees who are highly experienced in the manufacture of vaccines. This means that salaries would need to be competitive with the best in the industry. Despite this, the employment of a highly skilled and experienced private-sector workforce could make up for the higher nominal cost of salaries in terms of efficiency and flexibility and could provide a greater ultimate return on the government’s investment. On the other hand, staffing of the GOCO facility by industry would create more competition for scarce expertise. Second, the use of a GOCO facility would require the federal government to take on the full capital cost of building a production facility. This would be expensive because the facilities would require the use of high-containment technology not only for production but also for the testing of products. Although this approach could drive up the initial investment costs, it could provide corporate entities with an incentive to develop products that might not have sufficient market potential to be profitable otherwise. However, if the federal government makes a decision to invest capital for the construction of vaccine production facilities, an alternative to the GOCO concept would be to work out arrangements with specific companies, in which the federal government would subsidize construction of vaccine production facilities that the manufacturer could use to produce other vaccines when the facility was not in use for the production of vaccines for the U.S. military. This is the mirror image of the suggestion made by some that a GOCO facility might manufacture vaccines for the civilian sector when it was not in use making vaccines for the military, an idea that is anathema to the industry. Because the former situation would shift operations and management costs to the manufacturer, some within the industry are of the opinion that this would be a more efficient and less costly approach than the GOCO approach. Third, and finally, as with any vaccine manufacturing arrangement, a GOCO facility would receive the strong FDA oversight that is essential to maintaining the efficacy and safety of vaccines. Such oversight is especially vital during the rush to respond to emergencies. The steps that need to be taken to comply with all regulatory requirements are costly, however. In addition, bacterial and viral vaccines provide unique challenges in terms of production and quality and safety control compared with the challenges for other types of pharmaceuticals. After weighing the available evidence, the committee agreed that DoD should consider establishing a GOCO vaccine manufacturing facility, although it did not believe that the development of such a facility would in any way mitigate the need for DoD to revamp its system for managing the overall process by which it acquires vaccines, including integrating the upstream research and development activities and the downstream production and procurement activities, as outlined above. DoD’s fragmented and complex organization for vaccine acquisition must become more efficient and cost-effective, regardless of who operates the actual manufacturing process.

OCR for page 55
Protecting Our Forces: Improving Vaccine Acquisition and Availability in the U.S. Military Recommendation 8. Work toward improving manufacturing arrangements to better ensure consistent vaccine availability by addressing issues related to long-term commitments, predictable volume and price, indemnification, and intellectual property issues. These arrangements should include consideration of the development of vaccine-specific partnerships between the federal government and individual private manufacturers, a consortium of private vaccine manufacturers, and government-owned, contractor-operated (GOCO) vaccine production facilities. REGULATORY STATUS OF SPECIAL-USE VACCINES At present, the USAMRMC Special Immunizations Program (SIP) manages the use of 14 vaccines whose future availability is highly endangered. By and large, these vaccines are required for the protection of laboratory workers and other individuals who are at exceptional risk of exposure to the pathogens against which these vaccines are directed. Nine of these vaccines remain unlicensed and are available only under IND status, despite use over the past 30 years in varying numbers of recipients. Long-term use of these products under continued IND status is problematic. FDA uses IND status to provide a basis for clinical investigations that ultimately lead to the demonstration of the safety and efficacy of a vaccine for use by humans; IND status is thus a step on the pathway toward licensure. The use of IND status to make a vaccine available for a specifically circumscribed but ongoing use without any formal intent of advancing the product through the regulatory pipeline toward the goal of licensure by FDA ignores the intent of an IND classification. The committee believes such practices should end. If DoD needs these vaccines, it needs to establish active development programs for eachone. The committee realizes, however, that there are several substantial obstacles to moving these products from IND status to full licensure by FDA. Demonstration of efficacy may be difficult for these vaccines, because most of the vaccines that SIP manages are designed to prevent rare infections whose natural occurrences are unpredictable. That greatly limits the possibility of completing conventional clinical efficacy trials with these vaccines. The ability to conduct experimental challenge tests with these vaccines is severely limited or absolutely prohibited by well-accepted ethical rules guiding experimentation involving human subjects. Although FDA recently finalized a rule that allows greater acceptance of efficacy data stemming from animal challenge experiments in making determinations for licensure (FDA, 2002c), the facilities and resources capable of conducting such animal challenge experiments are severely limited. The U.S. govern-

OCR for page 55
Protecting Our Forces: Improving Vaccine Acquisition and Availability in the U.S. Military ment operates only two functional Biological Safety Level 4 (BSL-4) laboratories. Furthermore, studies with animals to demonstrate the efficacy of these vaccines would require more rhesus monkeys than are now available. Increasing those laboratory capabilities would entail considerable expense, although the committee notes that the President’s proposed FY 2003 budget may provide the funds to increase the number of BSL-4 facilities. Importantly, however, the costs of completing more extensive efficacy studies with animals with each of the vaccines whose development has been arrested at the IND level could exceed the financial benefit that would be provided if the vaccines were available as fully licensed products. Although the committee recognizes that direct financial benefit is not the only incentive to move from IND status to fully licensed status, it recognizes that cost-effectiveness analyses will be applied to any future programs that are proposed with this intent. Demonstrating to FDA’s satisfaction that these vaccines are sufficiently safe to warrant licensure also poses special problems. For licensure of a product, FDA requires, rightfully, that safety testing involve sufficient numbers of subjects to detect vaccine-related adverse events that might occur at relatively low frequencies. This typically entails the enrollment of 10,000 or more subjects in Phase III clinical trials. These numbers may be justified for prelicensure studies of vaccines that are to be used universally or in large numbers of recipients, but studies of that size are tremendously difficult to conduct for vaccines whose use by DoD is intended to be restricted to small numbers of individuals (such as potentially exposed military personnel) no matter how critical the need. The committee is aware that if a special-use vaccine were to be licensed by FDA, it could be used outside of the SIP framework, and could be prescribed by a physician for civilian travelers to areas in which the target disease is endemic or in response to an outbreak or a terrorist action. Committee discussion of how to help DoD acquire and maintain special-use vaccines was, therefore, couched in a speculative framework. One approach considered was to base licensure of these special-use products on safety standards that are established with a level of confidence appropriate for the number of intended recipients. For example, in the case of a vaccine with very limited intended use, it might be reasonable to base licensure on the results of safety trials involving much smaller numbers of subjects. A lack of serious adverse events among 300 subjects receiving the vaccine in a clinical study would predict that the vaccine would not produce a serious side effect more than 1 percent of the time. This level of risk might be acceptable if only small numbers of persons were intended to receive the licensed product, particularly if the risk of exposure was substantial and the consequences of infection in a nonimmunized person were severe. Such information concerning the limitations on safety data could be provided as part of package insert and could be used to guide decisions concerning the risks versus the benefits of immunization with that special-use vaccine under specific circumstances. In contrast, when considering the licensure of a vaccine for use in the civilian sector, FDA has

OCR for page 55
Protecting Our Forces: Improving Vaccine Acquisition and Availability in the U.S. Military consistently sought evidence demonstrating a significantly lower risk of serious adverse events. Basing safety evaluations on such statistical considerations would not be intended to short-circuit the requirement that licensed products be demonstrated to be safe as well as effective but would aim to establish parameters for safety that would recognize the expected use of the vaccine and the numbers of military personnel who might use it. Limitations on the database supporting safety would therefore need to be considered as part of the policies guiding the use of these vaccines, and these should be considered along with the magnitude and severity of the risk in the absence of immunization. If such a system were put into operation, postlicensure surveillance for adverse events would assume a new level of importance. Importantly, such surveillance is likely to be more feasible, under the conditions of ongoing military operations, than the usual data collection practices involved in the conduct of Phase III studies of a product with IND status. In effect, when standard, large-scale clinical trials of safety cannot be done, rather than prohibit the use of a vaccine that would protect warfighters against highly dangerous pathogens, a better overall strategy would be to use the vaccine according to a new FDA licensure arrangement and conduct active postlicensure surveillance for adverse events. Yet additional problems face licensure of these vaccines with IND status because the basic research on some of these products was carried out long ago. Some data regarding the process used to manufacture the remaining stocks are not available for FDA review. For other products, it may be necessary to repeat earlier work with newer and more costly technologies. Despite these financial implications, there are other costs, such as the substantial political costs and the crisis of trust that DoD incurred when veterans objected to the use of INDs during the Gulf War. The concern—which continues today—may have been fueled in part by people equating “investigational” with “unsafe.” To avoid such understandable concerns, DoD could work with FDA to define a new category, one that might be suitably placed between IND status and full licensure or that might be a subset of licensure. The committee does not intend to imply that products being used only as an IND and manufactured years ago are either safe or effective (although they may well be). Neither is it dismissive of the critical need to demonstrate the safety and efficacy of vaccines as an important factor in the future protection of warfighters against infectious disease threats. It also recognizes that some IND products may never be suitable for licensure. What it does seek is a pragmatic solution to an impossible set of circumstances that threaten to limit access to useful preventive measures during military operations that entail demonstrable risks of infectious diseases. The committee suggests that DoD work with FDA to identify options related to the status of vaccines that have not been licensed. Ideas to be considered for a new FDA-sanctioned status extend from a status that is no more than a change in terminology to a status that reflects a wholesale new approach to licensure that

OCR for page 55
Protecting Our Forces: Improving Vaccine Acquisition and Availability in the U.S. Military recognizes alternative mechanisms to the assessment of the safety and efficacy of vaccines in humans that could be applied to vaccines that are to have only limited routine use or that would be used only under unusual circumstances when the risks of infection are perceived to be exceptionally high. The Defense Authorization Act of 20028 mandates a study to examine how the government might accelerate the approval process for biodefense vaccines. Although the committee would have included vaccines against naturally occurring infectious diseases in that scope explicitly, it believes that methods devised to overcome the obstacles to the acquisition of biodefense vaccines will be applicable to vaccines designed to address both kinds of exposures. Achieving success in whichever direction DoD chooses to go will require that scientists effectively communicate a sense of urgency through the program and budget hierarchies. Recommendation 9. Vigorously seek a new paradigm for the regulation of special-use vaccines that remain in IND application status with the FDA and that have no reasonable prospects for licensure under current rules. The new paradigm should take into account the circumstances of the vaccine’s anticipated use in setting requirements for the demonstration of safety and efficacy. CONCLUSION Military scientists have a notable record of accomplishment when it comes to vaccines, including primary or significant roles in the development of vaccines against meningococcal meningitis, hepatitis A, Japanese encephalitis, and other dangerous infectious diseases. Partly because of the success of the DoD research programs, the public and even DoD nonmedical research personnel know little about them or the threats that their products have ameliorated. For example, the prior availability and the benefits of the adenovirus type 4 and 7 vaccines went unnoticed by most training center commanders until the vaccines were lost from the armamentarium and adenovirus disease reemerged at military training installations. By creating a single vaccine authority and a credible advisory board and responsibility over the entire life cycle of a vaccine, from priority setting to stockpiling of licensed products, DoD would enhance not only the effectiveness but also the visibility of its vaccine program, improving the chance of its being provided with a budget of sufficient magnitude to allow it to accomplish its mission. It is a mission of enormous importance. Immunization is often the most effective means of preventing infectious diseases, either in civilian or military populations, and whether caused by naturally encountered infectious agents or purposeful exposures related to bioterrorism or biological warfare. 8   National Defense Authorization Act for Fiscal Year 2002, P.L. 107-107 (2001).

OCR for page 55
Protecting Our Forces: Improving Vaccine Acquisition and Availability in the U.S. Military The committee urges DoD to work more aggressively with decision makers in the U.S. Congress and in the executive branch to recognize that infectious disease agents—whether they occur naturally or are weaponized as agents of biological warfare or terror—threaten military operations and, therefore and implicitly, the welfare of the nation. Decision makers must recognize (1) the past, imminent, and possible future successes of vaccines in minimizing those threats; (2) the strong track records and reputations of military research programs in developing vaccines used by the U.S. military as well as in civilian settings; (3)the contributions that DoD’s medical research efforts make to foreign policy and national security; (4) the threats to continued vaccine development and the ultimate use of vaccines posed by organizational and fiscal limits; and, consequently, (5) the need for adequate, stable funding and strong management authority. Such changes would allow DoD to optimally advance and exploit the technology available for vaccine development, and to provide the best possible protection of the nation’s armed forces against infectious diseases. In summary, DoD’s vaccine acquisition system, despite its distinguished history, diffuses responsibility and is inadequately funded; therefore, it cannot produce the effort required to respond to the magnitude of its task.