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1 Ending Half-Measures for Countermeasures: The Challenge and Major Recommendations T he biodefense efforts of the Department of Defense (DoD) are poorly organized to develop and license vaccines, therapeutic drugs, and antitoxins to protect members of the armed forces against biological warfare agents. The development and licensure of new vaccines and drugs is a diffi- cult, expensive, and time-consuming process. Moreover, biodefense prod- ucts pose special scientific, regulatory, and ethical challenges because it is generally unacceptable to expose humans to biowarfare agents to estab- lish the efficacy of those products. Accelerating the development and li- censure of such products will require strong and creative scientific leader- ship and a sustained commitment of adequate financial and other resources. Current DoD efforts, however, are characterized by fragmenta- tion of responsibility and authority, changing strategies that have resulted in lost time and expertise, and a lack of financial commitment commensu- rate with the requirements of program goals. These factors, together with high regulatory hurdles for obtaining Food and Drug Administration (FDA) approval,1 mean that since the Gulf War of 19901991 DoD has gained no new vaccines and only a few drugs to protect its military per- sonnel against biological warfare agents. 1It was not possible to license new vaccines or drugs against biological warfare agents until July 2002, when the FDA's "Animal Efficacy Rule" became effective (FDA, 2002). The Animal Efficacy Rule allows the use of efficacy data from animal studies when tests of effi- cacy in humans are not ethical or feasible, as is generally the case with medical biodefense countermeasures. 19

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20 GIVING FULL MEASURE TO COUNTERMEASURES This serious situation exists despite declarations by Presidents, Secre- taries of Defense, congressional committees, and advisory groups (Bush, 2002; Clinton, 1994; Cohen, 1997; Defense Science Board, 2001, 2002; Perry, 1996; U.S. Congress, House Armed Services Committee, 1993) that bio- logical warfare poses a significant threat to the safety and effectiveness of the nation's armed forces, despite targeted DoD programs initiated in 1998 and 2002 to vaccinate large numbers of military personnel against anthrax and smallpox (Chu, 2002; Cohen, 1998), and despite a DoD commitment to acquire vaccines against all validated biological warfare threats (DoD, 1993). Moreover, there is concern that advances in bioengineering will make possible the rapid introduction of new biological threats that may prove even more challenging to counter than the already serious threats posed by naturally occurring organisms (Defense Science Board, 2002; MacKenzie, 2003). This report presents the findings and recommendations of a commit- tee of the Institute of Medicine (IOM) and the National Research Council (NRC) convened to conduct a study mandated by Congress.2 The charge to the committee is to recommend strategies for accelerating the DoD re- search, development, and licensure processes for new medical biodefense countermeasures.3 Based on the study charge to address strategies for accelerating these processes, the committee focused its attention on the organization and management of these processes, rather than on details of specific scientific approaches. The committee was not asked to assess the nature or extent of any biological warfare threat or to compare the value to DoD of developing medical countermeasures against biological warfare agents relative to the pursuit of its other obligations. The commit- tee viewed its task as resting on the premise that biological weapons pose a genuine threat to the health of military personnel, and therefore addi- tional FDA-licensed medical countermeasures are urgently needed. THE CURRENT CONTEXT FOR THE DEVELOPMENT OF MEDICAL COUNTERMEASURES The context in which DoD is working to develop new vaccines and drugs to counter biowarfare agents has changed during the past 10 years, especially since 2001 (see Box 1-1). Continuing scientific and technological 2The study was called for in the National Defense Authorization Act for Fiscal Year 2002, P.L. 107-107 (2001). The study charge, the expertise of the committee, and the committee's approach to the study are discussed in the Preface. 3In this report, the term "licensed" is used to connote approval by FDA of either a Biologics License Application or New Drug Application.

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ENDING HALF-MEASURES FOR COUNTERMEASURES 21 advances in molecular biology, genomics, combinatorial chemistry, and understanding of microbial structure and replication are expanding the range of potential biological threats as well as offering opportunities to identify new countermeasures. For example, antibiotic resistance can be readily engineered into microbes, and some alterations could hinder the effectiveness of some vaccines (MacKenzie, 2003). Even so, the potential for new bioengineered pathogens does not eliminate the need for coun- termeasures against more familiar biological threats and continued work on products currently in development pipelines. In addition, advances in biotechnology and scientific understanding are facilitating the explora- tion of new types of countermeasures such as broad-spectrum antibiotics and antivirals, as well as possibilities for multivalent vaccines and rapid development of antibodies. For decades, DoD carried out the nation's only significant effort to develop medical biodefense countermeasures. Now, however, a substan- tial biodefense research effort is under way within the Department of Health and Human Services. The government has responded to the expe- rience of domestic bioterrorism with a major increase in funding for the National Institute of Allergy and Infectious Diseases (NIAID) of the Na- tional Institutes of Health (NIH)--initially $1.7 billion for fiscal year (FY) 2003 and $1.6 billion requested for FY 2004--to support new research and the renovation or construction of special laboratory facilities necessary for research involving biological threat agents (DHHS, no date). In addition, the proposal by President Bush for "Project BioShield" aims to create in- centives for the pharmaceutical industry to manufacture and license medi- cal countermeasures by making up to $6 billion available over the next 10 years to purchase those products for a national stockpile (White House, 2003). In contrast, DoD's funding for its research and development pro- gram for medical countermeasures against at least 10 biological agents amounts to only $267 million for FY 2003 (DoD, 2003a; Evans, 2003).4 The upsurge in funding and effort aimed at protecting the civilian population against bioterrorism will undoubtedly result in the develop- ment of new technologies and products that can also aid in protecting military personnel against the risks of biological warfare. Although there is considerable overlap in potential threat agents for the battlefield and 4DoD funding for FY 2003 includes program elements for medical biological defense in the Chemical and Biological Defense Program (under budget activities 6.16.5) and biomedical components of the biological warfare defense program of the Defense Advanced Research Projects Agency. The funding totals for medical biodefense exclude costs presently covered in accounts of the military services for salaries and benefits for military personnel and for operating certain facilities.

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22 GIVING FULL MEASURE TO COUNTERMEASURES BOX 1-1 Events Related to the Development of Medical Biodefense Countermeasures November 1969 United States renounces use of biological weapons April 1972 Medical protection functions of Biological Defense Research Laboratory at Ft. Detrick transferred from the Army Materiel Command to USAMRIID, under the Army Medical Department March 1975 United States ratifies Biological and Toxin Weapons Convention May 1985 DoD Directive 5160.5 reaffirms the Department of the Army as the executive agent for research and development for chemical and biological defense August 1990July 1991 Gulf War deployment; licensed anthrax vaccine administered to U.S. troops; Botulinum toxoid vaccine in Investigational New Drug (IND) status administered without formal process of informed consent November 1993 P.L. 103-160 (50 U.S.C. 1522) mandates overall coordination and integration of the chemical and biological warfare defense program (both medical and nonmedical components) by a single office within the Office of the Secretary of Defense; oversight is to be exercised through the Defense Acquisition Board process November 1993 DoD Directive 6205.3 calls for developing the capability to acquire vaccines against all validated biological warfare threats 1994 Joint Service Agreement for Joint Nuclear, Biological, and Chemical Defense Management; Joint Program Office for Biological Defense chartered (April)

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ENDING HALF-MEASURES FOR COUNTERMEASURES 23 August 1995 Iraq reports weaponization of biological agents to United Nations Special Commission October 1996 FDA Vaccines and Related Biological Products Advisory Committee provides guidance to DoD on the types of human antibody and animal challenge studies to conduct to support the effectiveness of a botulinum toxoid vaccine December 1996 Joint Vaccine Acquisition Program Management Office established November 1997 Prime contract awarded by DoD to DynPort Vaccine Company for development and licensure of biodefense vaccines September 1999 10 U.S.C. 1107 and Executive Order 13139: Administration to members of the armed forces of INDs or drugs used for purposes not approved by the FDA must adhere to requirements for informed consent unless a waiver is granted by the President September Distribution of anthrax spores through the October 2001 U.S. postal system; five deaths result July 2002 FDA "Animal Efficacy Rule" goes into effect (21 C.F.R. Parts 314 and 601: New Drug and Biological Drug Products; Evidence Needed to Demonstrate Effectiveness of New Drugs When Human Efficacy Studies Are Not Ethical or Feasible) February 2003 Charter issued for Joint Requirements Office for Chemical, Biological, Radiological, and Nuclear Defense (JRO-CBRN) April 2003 Implementation plan issued for management of the Chemical Biological Defense Program (transfers management of all science and technology activities to the Defense Threat Reduction Agency)

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24 GIVING FULL MEASURE TO COUNTERMEASURES the civilian community, the perceived risks posed by these agents can be different in the two settings. Furthermore, there are important differences between the planning for protection against bioterrorism versus biologi- cal warfare (DoD, 1993, 2000; Fauci, 2003; Linden, 2002). The military has considered vaccination to be the primary medical strategy for battlefield protection of a defined and relatively small population. Mass vaccination of the civilian population against a range of potential biological threats is less appropriate and much less feasible. For DoD, the aim is to protect service members in a manner that allows them to maintain their combat effectiveness and limits the need for medical personnel and equipment to treat casualties. In addition, DoD seeks to deter and defeat the use of bio- logical weapons by having troops medically protected. Having the capac- ity for rapid diagnosis and postexposure treatment is also essential for DoD, but it is less desirable as a primary strategy for protecting troops on the battlefield than it is for responding to a bioterrorism event in the civil- ian population. The military and civilian biodefense programs also differ in their ap- proach to achieving the development, FDA licensure, and manufacture of medical countermeasures. The aim of efforts supported by the increased funding for NIAID is to help ensure that new candidate countermeasures are discovered and developed to a stage at which initial studies of safety and efficacy are promising (i.e., Phase 1 or 2 clinical trials). The provisions for government purchases for a national stockpile as proposed under Project BioShield are intended to provide sufficient financial incentive for commercial firms to undertake the work necessary to complete the testing and licensure process for products that they manufacture. The DoD ap- proach is to support the initial research to identify candidate countermea- sures and to include in the terms of its cost-plus-award-fee prime systems contract an explicit requirement for the development and delivery of FDA- licensed products that it can administer to military personnel. What has not changed are the challenges in developing any new vac- cine or drug, including the cost and the substantial risk of failure, even in late stages of the process. The congressional Office of Technology Assess- ment (OTA) in 1993 estimated the average cost of bringing a new drug to licensure to be $237 million (1990 dollars) (U.S. Congress, OTA, 1993). More recent estimates have ranged from $110 million to $802 million (2000 dollars) (DiMasi et al., 2003; Public Citizen, 2001). As few as one candidate in 5,000 reaches clinical testing, and only 20 percent of candidates that begin clinical testing reach licensure (FDA, 1999; NVAC, 1999; PhRMA, 2000; Struck, 1996). Such estimates are based primarily on data for new drugs; equivalent estimates for vaccines and other biologics are rarely pre- sented (IOM, 2003). The process is also time consuming (see Box 1-2 for a brief outline of

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ENDING HALF-MEASURES FOR COUNTERMEASURES 25 the process). An industry estimate of from 7 to 12 years for vaccine dis- covery and development was presented to the committee (Grant, 2003). For five vaccines reviewed by the National Vaccine Advisory Committee, the time from the beginning of Phase 1 trials to licensure ranged from 2 to 21 years (NVAC, 1999). FDA (1995) has cited a range of 4 to 20 years for drug development. New techniques made possible by scientific advances in fields such as genomics, proteomics, and high-throughput screening are likely to speed the discovery of some candidate countermeasures, but are unlikely to accelerate some of the most time-consuming parts of the product de- velopment process, including the crucial assessment of product safety in human volunteers and efficacy based on animal data under new FDA regulatory guidelines (the "Animal Efficacy Rule") (FDA, 2002). FDA li- censure of vaccines and drugs requires the submission of data demon- strating the efficacy of the product under review. For biodefense coun- termeasures, however, efficacy studies in humans are generally not feasible or ethical, presenting a barrier to licensure. FDA first provided guidance on the use of efficacy data from animal studies in combination with data on immune responses in humans in 1996 (Wykoff, 1998) and finalized regulations on the use of animal data in 2002 (FDA, 2002). The new regulations have now opened the path to licensure for new biodefense countermeasures; however, the use of animal-based efficacy testing is still an unfamiliar process and thus likely to require consider- able time and effort to become regularized. PROBLEMS HINDERING THE DOD EFFORT Although DoD has maintained a research base for medical biodefense countermeasures for many years when few others were working in this field, the committee views the ineffective and inadequate organization and funding of the medical biodefense component of the Chemical and Biological Defense Program as a clear indication that DoD leaders lack an adequate grasp of the commitment, time, scientific expertise, and finan- cial resources required for success in developing vaccines and other phar- maceutical products. Repeated changes in organization and strategy have not addressed those deficiencies, generating instead a flux that has ulti- mately resulted in disjointed and ineffective management. Fragmentation of Responsibility and Authority Successful development and licensure of pharmaceutical products, especially vaccines, requires knowledgeable oversight and the creation of an integrated and accountable development team whose collective exper-

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26 GIVING FULL MEASURE TO COUNTERMEASURES BOX 1-2 Factors in the Pace of Countermeasure Development and Licensure The pace of efforts to develop and license vaccines, therapeutic drugs, and antitoxins to protect against biological warfare agents is determined by progress during four broad stages: discovery, early development, advanced development (clinical testing and scale-up of manufacturing), and licen- sure of the product by the FDA. Following licensure, these products are also likely to be subject to requirements for postmarketing surveillance because of the need to validate their efficacy in humans and to accumulate additional evidence on their safety. The discussion below uses an industry estimate for the time required at each stage in the development of a vac- cine (Grant, 2003). Any given product might progress more slowly or quickly than these estimates. Discovery: 2 to 3 years Identification of a candidate drug or vaccine an- tigen draws on basic research regarding a pathogen's mechanism of action and the host's response to infection. An animal model for the disease is often a valuable research tool. Additional research identifies potential molecular targets for drug or antitoxin development or antigens that might be appropriate for a vaccine. Advances over the past decade in molecular biology, genomics, and proteomics are helping accelerate discovery with techniques for rapid screening of large numbers of antigens or chemical compounds such that a substance may be identified for further evaluation in less than a year. Early Development: 2 to 3 years A potential new drug or vaccine antigen is produced in limited quantities for laboratory and animal testing to estab- lish proof of concept--that the drug or vaccine candidate can be adminis- tered safely and shown to block the action of a pathogen or generate a protective immune response. A candidate product must be characterized and initial manufacturing processes must be developed and documented. Many candidates are abandoned as information accrues regarding their behavior in living systems and the feasibility of manufacturing them. Given sufficient priority and with adequate personnel and resources, the pace at this stage is set by scientific approaches and technical hurdles. For candidate products to be taken on to human testing, an acceptable IND application must be filed with FDA. The application must include data on safety and biological activity from laboratory and animal tests; manu- facturing processes; standards for establishing the safety, purity, potency, and consistency of pilot lots for human use; and detailed plans for the

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ENDING HALF-MEASURES FOR COUNTERMEASURES 27 initial clinical testing. FDA must be apprised of the initiation of each stage of human testing. Data from those tests must be submitted to FDA as prod- uct development and testing proceeds. Human testing may go forward as long as FDA raises no objections. Clinical testing begins with Phase 1 studies, which are usually carried out with fewer than 100 people and provide initial data on the safety, pharmacokinetics (how the body handles a product), and if measurable, biological activity of a candidate product. Factors affecting the rate at which clinical studies proceed include the quality and organization of the docu- ments submitted to FDA, the pace of approvals by institutional review boards, the rate of recruitment of study participants, and the period of time over which the action of the product must be evaluated. Advanced Development: 2 to 3 years Products that remain in consider- ation proceed to Phase 2 studies, for tests in a few hundred people. Phase 2 testing for traditional drug candidates provides data on safety and bio- logical activity at different dosage levels in patients. Phase 3 studies usually involve no fewer than 5,000 participants and provide definitive data on safety and efficacy. For most biodefense products, ethical considerations make it impossible to conduct human studies to demonstrate efficacy. In- stead, evidence of efficacy in animals must be correlated with surrogate markers of the human response to the countermeasure. The time that will be required for this newly established pathway to product approval is un- certain. FDA requirements for specific types of testing and for review of data submissions and manufacturing processes also affect development time. Manufacturing processes must be scaled up to full production levels and shown to be reproducible. For vaccines, several years of effort may be required to establish final manufacturing procedures because the biologi- cal processes involved are subject to inherent variability. Chemical pro- cesses to produce drugs usually have less variability and thus can be devel- oped more rapidly. Preparation and Review of Product License Application: 1 to 3 years At the conclusion of clinical testing and scale-up of production, an applica- tion is submitted to FDA for product licensure. FDA determines whether the data are sufficient to demonstrate the safety and efficacy of the candi- date product and to show that the manufacturing and testing procedures are satisfactory. License applications for products designated as priority or fast track are normally acted on within 6 months. The pace of FDA action is affected by such factors as the quality and completeness of the data submissions, the overall numbers of products under review, and the avail- ability of staff to perform reviews.

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28 GIVING FULL MEASURE TO COUNTERMEASURES tise includes basic science, FDA regulatory matters, animal and human testing, development of manufacturing processes, production of pilot lots, and full-scale manufacturing. Despite nominally centralized oversight of the Chemical and Biological Defense Program within the Office of the Secretary of Defense, the DoD effort is in practice fragmented among multiple chains of command and burdened by organizational complexity. Research is now overseen by the Defense Threat Reduction Agency (DTRA) and executed predominantly by personnel under the U.S. Army Medical Command, while advanced development is managed by the Joint Program Executive Office for Chemical and Biological Defense under the Army Acquisition Executive. Program requirements are established within the Joint Chiefs of Staff, and budgets are dispersed among all of these organizations and their chains of commands (who often perceive other uses of these resources as being of higher priority). This arbitrary divide between research and advanced development--despite being the standard model for the development of weapons systems--creates a dif- fusion of authority and responsibility that has resulted in inefficiencies, inadequate funding, and a lack of accountability for efforts to develop vaccines and drugs for medical biodefense. Losing Time and Expertise Through Organizational Adjustments and Changing Strategies Over the past decade, the Chemical and Biological Defense Program has been subject to repeated reorganizations intended to make it function more effectively. These reorganizations have entailed creating brand new organizational units or giving existing units new and unfamiliar respon- sibilities for managing research and development for vaccines and other pharmaceutical products. In 1993, Congress required that all of DoD's chemical and biological defense activities, both medical and nonmedical, be overseen by a single office within the Office of the Secretary of Defense.5 This responsibility was assigned to what was then the Assistant to the Secretary of Defense for Atomic Energy (since redesignated as the Assistant to the Secretary of Defense for Nuclear and Chemical and Biological Defense Programs [ASTD(NCB)]). At the same time, Congress also directed that oversight of the program be exercised through the Defense Acquisition Board process. This requirement resulted in the transfer of responsibility for advanced 5National Defense Authorization Act for Fiscal Year 1994, P.L. 103-160 (1993, 50 U.S.C. 1522).

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ENDING HALF-MEASURES FOR COUNTERMEASURES 29 development of medical countermeasures from the U.S. Army Medical Command, which had successfully licensed vaccines developed through the Army's infectious disease research program, to the newly created Joint Program Office for Biological Defense, which had responsibility for both medical and nonmedical products. In 1996, the Joint Vaccine Acquisition Program was established within the Joint Program Office specifically to manage the advanced development and licensure of candidate vaccines by a prime systems contractor. During the spring of 2003, a reorganization affected all phases of the Chemical and Biological Defense Program. In particular, a new Joint Re- quirements Office for Chemical, Biological, Radiological, and Nuclear Defense was established. Also, responsibility for management of research and early product development was transferred from the U.S. Army Medi- cal Command to DTRA, an organization that has historically focused pri- marily on nuclear threats. DTRA has little resident expertise in managing or conducting the biomedical research necessary for the development of vaccines, drugs, and other medical countermeasures against biowarfare agents. In addition, since the early 1990s the DoD strategy for producing biodefense vaccines has changed three times in response to concerns about affordability and cost-effectiveness (Johnson-Winegar, 2000). Initial plan- ning for a government-owned, contractor-operated vaccine production facility gave way to investigation of a contractor-owned, contractor-oper- ated approach. The strategy adopted in the mid-1990s, and currently be- ing followed, is the use of a prime systems contract, which was awarded in late 1997. From the time responsibility for advanced development was removed from the U.S. Army Medical Command until the prime systems contract was awarded, DoD had no mechanism in place through which to pursue the advanced development of candidate countermeasures, and even with the prime systems contract in place, the first clinical trials did not begin until 2000. With these repeated reorganizations and shifts in approach and with no one official clearly responsible for overall program results, time has been lost again and again while new units are organized and begin to recruit staff with relevant expertise, or worse yet, operate without ad- equate expertise. The willingness of upper-level decision makers within DoD to repeatedly make such changes indicates to the committee an awareness of the problem but a lack of understanding of the level of expe- rience, expertise, and leadership, as well as the organizational impera- tives, necessary to shepherd candidate vaccines and drugs through the long and difficult research, development, and licensure process.

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ENDING HALF-MEASURES FOR COUNTERMEASURES 33 Biomedical Component of DARPA Total DARPA Biological Warfare Biological Warfare Defense Program Defense Program Missile Defense Agency 2,886.4 3,360.3 43.1 58.5 3,451.6 52.6 83.0 3,909.9 72.6 124.3 3,456.8 87.7 146.2 4,119.3 97.9 171.9 6,728.3 78.6 162.0 6,685.8 53.0 137.3 7,620.9 cal biodefense component of the Chemical and Biological Defense Program. Military per- sonnel included 76 scientists and engineers and 134 technical support or other personnel. Military pay and allowances for these personnel for FY 2000 totaled $17.7 million. Opera- tions and maintenance costs for USAMRIID for FY 2000 were $0.4 million. USAMRIID also had 113 civilian scientists and engineers and 120 civilian technical support personnel; the salaries and related costs for the civilian personnel engaged in medical biodefense research are included in the table. Funds for the separate DoD research and development program on infectious diseases are not included in this table. CBDP, Chemical and Biological Defense Program; DARPA, Defense Advanced Research Projects Agency. SOURCES: DoD, no date, 19972003, 2002; Evans, 2003. 2002; GAO, 2002; IOM, 2002; Rettig and Brower, 2003; Top et al., 2000), including the following: the need for a single high-level authority within DoD that attends to the full spectrum of responsibility from threat definition through re- search and development, advanced product development, clinical trials, licensure, manufacture and procurement, and maintenance of manufac- turing practice standards and regulatory compliance (Defense Science Board, 2002; IOM, 2002; Rettig and Brower, 2003; Top et al., 2000); the importance of having an ongoing, senior, external advisory group to maintain active relationships with current science and technol-

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34 GIVING FULL MEASURE TO COUNTERMEASURES $8,000 $7,000 $6,000 millions) $5,000 ($ $4,000 Authority $3,000 Budget $2,000 $1,000 $0 1996 1997 1998 1999 2000 2001 2002 2003 2004 Fiscal Year Medical Biodefense, CBDP Other, CBDP Medical Biodefense, DARPA Other Biodefense, DARPA Missile Defense Agency FIGURE 1-1 Budget authority for the medical biodefense component of the Chemical and Biological Defense Program and other selected DoD research, de- velopment, testing, and evaluation programs, FY 19962004. The medical biodefense component of the Chemical and Biological Defense Program includes activities related to vaccines, therapeutics, and diagnostics. The amounts for FY 2004 are the amounts requested in the President's FY 2004 budget. The data cover the budget categories of basic research (budget activity 6.1), applied research (6.2), advanced technology development (6.3), advanced component development and prototypes (6.4), and system development and demonstration (6.5). Excluded are amounts in the accounts of the military services for salary and benefits for military personnel participating in these activities and costs of facilities operated by the military services (e.g., USAMRIID). Funds for the separate DoD research and de- velopment program on infectious diseases are not included. NOTE: CBDP, Chemical and Biological Defense Program; DARPA, Defense Ad- vanced Research Projects Agency. SOURCES: DoD, 19972003, 2002; Evans, 2003. ogy leaders in the academic, corporate, and government sectors (IOM, 2002; Top et al., 2000); and the substantial investment required to successfully develop vac- cines in particular, noting that DoD expenditures had not met those needs (IOM, 2002; Top et al., 2000). Although changes have been made that appear to respond to some of these recommendations, the fundamental problems remain. Moreover, the

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ENDING HALF-MEASURES FOR COUNTERMEASURES 35 committee believes that some of the recent actions will actually exacer- bate the problems. In particular, in mid-2003 DoD implemented a recom- mendation from the Defense Science Board (2002) to assign responsibility for management of the science and technology component of the entire Chemical and Biological Defense Program to DTRA. No acceleration of medical biodefense science and technology should be anticipated from this change. Not only does DTRA have little experience or expertise in biomedical and pharmaceutical research, it adds yet another layer of man- agement between key senior decision makers and the actual performance of research and development tasks for medical countermeasures. RECOMMENDATIONS FOR CHANGE A decision by DoD and national leaders to make DoD's program to develop medical countermeasures against biological warfare agents a genuine priority is the essential first step to set the stage for an effective program. Thus, to ensure that DoD has an effective research and develop- ment program for medical biodefense countermeasures, the committee makes the following recommendation: 1. The Secretary of Defense and Congress must make the DoD pro- gram for medical biodefense countermeasures a high priority. If that commitment is made, it has to be accompanied by major orga- nizational and managerial changes: organizing the program to promote accountability and effective coordination throughout all phases of research, development, and prod- uct approval; installing leaders broadly knowledgeable in biotechnology with specific expertise in the development of vaccines and other pharmaceuti- cal products; supporting the development of a strong scientific infrastructure, including scientific personnel with expertise in pharmaceutical product development and facilities for research and animal testing; and providing necessary funding to achieve program goals. DoD should look to NIH as a model for promoting excellence in basic research and discovery science, and to the pharmaceutical industry for guidance in successful management of product development, a model that points to the importance of consolidating authority and responsibility. DoD's aim should be to have a program capable of meeting the need for

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36 GIVING FULL MEASURE TO COUNTERMEASURES not only vaccines and drugs based on conventional approaches, but also future products that emerge from today's exploration of new scientific concepts. An organizational approach that creates competing lines of au- thority and multiple reporting relationships, as the current matrix scheme does, is not adequate to address the multiple management and scientific challenges that DoD faces. The program requires a single, highly knowledgeable leader who re- ports to a senior DoD policy official and whose sole responsibility is the direction of that program. The program director has to have budgetary control and full authority over--and accountability for--the entire range of program tasks, from basic research through product manufacturing. The program leadership and staff need to bring to the program substan- tial expertise in vaccine and pharmaceutical research, product develop- ment, and manufacturing, including the rapidly evolving contributions of biotechnology. The organizational framework that shapes the planning, budgeting, management, and operation of the program has to be tailored to accom- modate the following distinctive features of this work: For vaccines, the time from identification of a candidate product through FDA licensure is at least 7 to 12 years. It is too soon to know how long the development of new types of countermeasures (e.g., multivalent vaccines or immune modulators) will take, but important basic research remains to be done. The work with biological systems that vaccines require is inher- ently unpredictable. The risk of failure--which can result from problems with efficacy, safety, or manufacturing processes--remains high, even in relatively late stages of the development of pharmaceutical products. The overall cost of pharmaceutical product development varies, and much of the cost is incurred during the later stages of clinical testing. Vaccines and other pharmaceutical products must be tested and licensed in compliance with FDA oversight and regulation. FDA licensure of a vaccine is tied to a specific manufacturing facil- ity. The need for human testing of vaccines and other pharmaceutical products demands attention to legal and ethical issues. Many of these factors distinguish the development process for medi- cal countermeasures from the engineering tasks that have driven the evo- lution of DoD's system for managing the development of new weapons systems and other products. Furthermore, the present artificial separation between DoD's program

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ENDING HALF-MEASURES FOR COUNTERMEASURES 37 to develop medical countermeasures against biological warfare agents and its parallel research and development program aimed at producing vac- cines and other pharmaceutical products against infectious diseases of military significance should be eliminated. These two programs address similar scientific and technological questions and demand closely related expertise and facilities. Moreover, since concerns about biological warfare threats are expanding to include a wider range of naturally occurring and novel biological agents, the line between the two programs is becoming even less distinct and meaningful than it was in the past. Also, Congress should seek guidance from DoD and others to assess the continuing appropriateness of its requirement that DoD devote close to 80 percent of its funding for medical biodefense research to work against biological agents that have been validated by intelligence assess- ments as near-term threats.7 With a changing understanding of the range of potential threat agents and the ease with which some of them may be created, DoD may require greater flexibility in allocating funds between work on countermeasures against well-established threats and those that may not yet be validated. In addition, DoD has to work with its counterparts in other govern- ment agencies to find ways to overcome other substantial obstacles to progress, especially the limited pool of specialized scientific expertise and research resources and the pharmaceutical industry's limited interest so far in producing these specialized products that have only a limited com- mercial market. Given that no federally owned facilities for full-scale manufacture of vaccines or drugs currently exist, industry must be con- sidered an essential partner in efforts to make medical biodefense coun- termeasures available to DoD. The committee considered a range of options for achieving these or- ganizational, managerial, and scientific goals. After careful consideration and weighing the advantages and disadvantages of the various options, the committee recommends the creation of a new DoD agency: 2. Congress should authorize the creation of the Medical Biodefense Agency, a new DoD agency responsible for the research and development program for medical countermeasures against 7National Defense Authorization Act for Fiscal Year 1993, P.L. 102-484 (1992). A validated threat agent is defined in this legislation as one that is named in the biological warfare threat list published by the Defense Intelligence Agency (DIA) and is identified as a biowarfare threat by the Deputy Chief of Staff of the Army for Intelligence. A validated near-term threat is one that has been, or is being, developed or produced for weaponization within 5 years, as assessed and determined by the Defense Intelligence Agency (P.L. 102-484, Section 231).

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38 GIVING FULL MEASURE TO COUNTERMEASURES biological warfare agents. The committee recommends the follow- ing features for this agency: It should report directly to the Under Secretary of Defense for Acquisition, Technology, and Logistics. The functions of existing medical biodefense programs should be transferred to the new Medical Biodefense Agency, along with their personnel and funding, including the medical biodefense component of the Chemical and Biological Defense Program (in- cluding units within the Army such as USAMRIID) and related ac- tivities in DARPA. The research and development program for medical countermeasures against infectious diseases should also be transferred into the Medical Biodefense Agency. The Medical Biodefense Agency should function on the premise that to speed the development of countermeasures it is nec- essary to benefit fully from research and development efforts be- yond DoD's intramural program so as to bring the expertise and creativity of industry and the academic community to the task. The Medical Biodefense Agency should ensure that DoD's medical biodefense activities are coordinated with and take full ad- vantage of the related activities of NIH and that DoD's efforts are focused on meeting unique DoD needs. The proposal for the Medical Biodefense8 Agency is discussed in de- tail in Chapter 2, as are alternative approaches considered by the commit- tee. The committee considers the establishment of a newly designated agency as an essential step to accomplish program goals as well as to dem- onstrate the seriousness of DoD's commitment to its efforts to develop medical countermeasures against biological warfare agents. This action will help make the currently disjointed and poorly functioning program more effective by enhancing its stature and making the program leader- ship more directly accountable for performance. Because the committee is strongly persuaded that creation of the Medical Biodefense Agency will be the most effective means of improv- ing DoD's research and development program for medical biodefense countermeasures, much of the discussion and many of the recommenda- tions throughout the report are framed in reference to this agency. In the event the Medical Biodefense Agency were not created, the need to estab- lish a substantially more effective infrastructure for the DoD medical 8The term "biodefense" is used in this report to refer to defense against naturally occur- ring infectious diseases as well as biowarfare agents.

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ENDING HALF-MEASURES FOR COUNTERMEASURES 39 countermeasures program, as well as the need to address other critical challenges affecting that program, will remain and should be addressed by DoD. Those efforts can and should be guided by the same consider- ations that the committee discusses as the basis for its proposals for the Medical Biodefense Agency. To promote accountability for action and progress by DoD and the Medical Biodefense Agency, an external review committee that is inde- pendent of DoD should also be established. The members of this commit- tee should be experts drawn from academia, the biotechnology and phar- maceutical industries, and other segments of the private sector who are qualified to judge the plans and performance of the DoD research and development program for medical biodefense countermeasures. 3. Congress should establish an external review committee of ex- perts in the development of vaccines and drugs to review and evalu- ate the program and performance of the DoD research and develop- ment program for medical biodefense countermeasures each year. The committee should report its findings each year to the Secretary of Defense and the Congress. The committee considers it highly preferable to maintain DoD control over the program to develop medical biodefense countermeasures to en- sure that unique DoD needs are given high priority. However, DoD has failed to respond adequately to previous reports with similar recommen- dations for change. The committee believes that the development of bio- logical warfare countermeasures requires the same urgency as work on medical bioterrorism countermeasures; therefore if DoD does not take steps sufficient to make the countermeasure development program effec- tive, the committee recommends, as a last resort, transferring all or part of that responsibility from DoD to an agency responsible for promoting the development of medical countermeasures for bioterrorism defense. The external review committee should be charged with assessing progress af- ter a 3-year period to recommend whether such a transfer should be made. The review committee must establish criteria for judging appropriate progress during this relatively brief interval, but it would be unreason- able to expect full resolution of all the problems currently affecting DoD's efforts to develop medical biodefense countermeasures. If a transfer was considered appropriate, NIH appears, at present, to be the best alternative to a DoD-based program because of its depth of scientific expertise and its substantial funding to support work on medi- cal defenses against bioterrorism. However, NIH has little tradition of product development or history of focus on military-specific needs, and

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40 GIVING FULL MEASURE TO COUNTERMEASURES among many competing national public health priorities this additional task may not be given sufficiently high priority. 4. If the review committee finds that after a 3-year period of opera- tion the DoD research and development program for medical bio- defense countermeasures has failed to make progress that the com- mittee considers appropriate, Congress should transfer from DoD, in part or in whole, responsibility for the development of medical biodefense countermeasures and reassign that responsibility to an agency responsible for promoting the development of medical countermeasures for bioterrorism defense, such as the NIH or an- other agency considered appropriate. The committee believes that the changes it is recommending for the development of medical biodefense countermeasures are consistent with the intent of DoD's own transformation initiative. The Secretary of De- fense has described the war on terrorism as a "transformational event" that calls for rethinking current approaches to DoD's tasks (Rumsfeld, 2003). He sees a need for DoD to encourage a "culture of creativity and prudent risk-taking" to accomplish the transformation that he advocates for the department. Transformation is to extend beyond warfighting to the way in which the department is organized to support military person- nel in the field (DoD, 2003b). It will require "commitment and attention from the [d]epartment's senior leadership" (DoD, 2003b, p. 3). The growth of asymmetric threats, including biological threats, is cited as one of the specific reasons for transformation. The strategies for accomplishing this transformation include (among others) encouraging innovative leadership and promoting rapid and innovative research and development pro- grams. Many issues must be addressed for DoD to have an effective research and development program for medical countermeasures against biologi- cal warfare agents. Those issues and the steps recommended by the com- mittee are discussed in the remainder of this report. They are, however, secondary to the fundamental need for a strong and continuing commit- ment to the task. REFERENCES Bush GW. 2002. Remarks by the President at the signing of the Public Health Security and Bioterrorism Preparedness and Response Act of 2002, June. Chu DS. 2002. Policy on Administrative Issues Related to Smallpox Vaccination Program (SVP). [Online]. Available: http://www.smallpox.mil/media/pdf/SPadminIssues policy.pdf [accessed November 18, 2003].

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