Good afternoon, Mr. Chairman and distinguished members. I am honored to appear before your committee today to discuss the near-term and long-term role of vaccines in preparedness against biological warfare and terrorism. I am Dr. Anna Johnson-Winegar, Deputy Assistant to the Secretary of Defense for Chemical and Biological Defense.
At your request, I will focus my remarks on force protection and, in particular, on current and planned capacity to immunize against, or contain, outbreaks of disease that may result from intentional exposures to biological warfare (BW) threat agents. These may include a number of etiologic, or disease-causing, agents and you asked that the Department address anthrax, smallpox, tularemia, plague, and hemorrhagic fevers, et cetera. I am also prepared to address my understanding of the current Food and Drug Administration (FDA) regulatory environment for developmental testing and licensure of vaccines for protection against BW threat agents and the role of the private sector in the development of needed vaccines.
Vaccines are and will remain the cornerstone of force protection against BW threats for the foreseeable future, near and far-term. Prevention of the devastating and life-threatening health effects posed by BW threats by prior immunization is the quintessential element of our comprehensive strategy that also includes detection, avoidance, diagnostics, therapeutics, individual and collective protection, and decontamination. The DoD Technology Area Review and Assessment (TARA) has characterized the medical biological defense research program as a "well-balanced strategic roadmap focused on warfighter requirements." I will focus my testimony on the medical aspects of force protection, emphasizing the DoD vaccine program and capacity in preparedness against BW and terrorism.
I should also mention that in accordance with the Government Performance and Results Act, performance metrics in the form of Technology Readiness Levels and exit criteria have been developed in support of the medical biological defense program. All aspects of the program are encompassed within the Joint Future Operational Capabilities.
We are all familiar with the difficulties, complexities, and frustrations encountered in FDA-compliant manufacturing of sufficient quantities of the anthrax vaccine. I don't intend to review these at this point. Rather, it is important to understand that anthrax vaccine represents an old, well-established technology. For many, the "lesson-learned" has been that research and development of a vaccine technology, though necessary, is not by itself sufficient to fulfill our force protection needs. FDA-compliant production capability and sufficient capacity are essential for force protection. Establishment and licensure of vaccine production facilities, whether public or private, are relatively expensive, technically complex and long-lead time projects within every vaccine research, development, licensure, and procurement program.
In his July 13, 2000 testimony before the House Armed Services Committee, Subcommittee on Military Personnel, concerning anthrax vaccine, the Deputy Secretary of Defense testified that he had directed that an independent panel review and report on DoD's overall management of acquisition of vaccine production. The report of the Independent Panel was submitted to the Congress this year as part of the Department's response to Section 218 of the Floyd D. Spence National Defense Authorization Act for Fiscal Year 2001, Public Law 106-398. The Section 218 report addresses a number of issues concerning acquisition of biological defense vaccines.
The Independent Panel found that vaccines are the lowest risk, most effective protection against BW threats; better than antibiotics and enable force projection. As we have previously testified, the Department has not been successful in attracting large, established vaccine manufacturers to support our biological defense vaccine needs. The Independent Panel found that participation by the pharmaceutical industry is an essential element of success in securing a ready and reliable access to FDA-licensed, safe, and effective vaccines for protection against BW threat agents. Barriers to industry participation include the size and scope of our vaccine requirements, episodic DoD production requirements that lead to idle manufacturing that is contrary to both industry practices and efficient and effective FDA compliance, industry concerns about program stability and political considerations, Defense procurement practices and DoD acquisition procedures that are inconsistent with the vaccine industry's best practices and model for success. The Panel recommended that application of a combined, integrated approach by Defense and industry will enable a successful program.
Specific findings of the Independent Panel include the following key points that are presently under review and consideration by Defense Department leadership.
* The scope and complexity of the DoD vaccine requirement is too great for either the DoD or the pharmaceutical industry to accomplish alone. Presently in the United States, the FDA has licensed vaccines that protect against approximately 20 diseases having substantial public health consequences. The DoD biological defense vaccine program has requirements approaching that number. The pharmaceutical industry, as evidenced by recent shortages in flu and tetanus vaccines, is at full capacity. The Panel recommended establishment of a government-owned, contractor-operated (GOCO/COCO)1 vaccine production facility and that long-term, up-front government commitment would be essential to pharmaceutical industry support.
* Resources do not match requirements. Using an eight-vaccine scale, the Panel estimated that the DoD acquisition of vaccine production would require between $2.4B to $3.2B in research and development costs over a 7- to 12-year period. Furthermore, resources for a GOCO/COCO with an initial capacity of three to four products, pilot production, and production scale-up would require approximately $370M in initial construction; this is in close agreement with the Department's estimate of $386M.
* Management Organization. The Panel recommended a lean, streamlined vaccine acquisition management organization. Vaccine acquisition is different from weapons acquisition and success requires different procedures. Strong technical leadership is imperative, both throughout the workforce and at all levels of management. Personnel practices must enable hiring and retaining highly qualified and experienced people. Stable, long-range funding with maximal ability to move resources to
match requirements is essential. Procurement practices need to more closely approximate industry practices. The programs must be fully integrated from discovery through licensure. Private sector advisory boards are required to support strategic planning at the executive level and program execution at the program manager level.
Over the past 2 years, I have hosted regular meetings of a federal interagency working group on vaccine acquisition. Participants have included representatives from the Department of Health and Human Services (DHHS)-including the FDA, the National Institutes of Health, the Public Health Service and the Office of The Surgeon General of the United States, the National Security Council, the Office of Management and Budget, and the Office of Science and Technology Policy. These meetings have been productive and general agreement has been reached on approaches such as recommended above and the need for a GOCO/COCO vaccine production facility to complement private sector capacity and capabilities for public health and Defense vaccine needs.
In November 2000, as addressed in the Section 218 report, a concept study was conducted to develop a new conceptual cost estimate and schedule for design, construction, fit-up, and qualification to FDA regulatory requirements for vaccine development, licensure, and manufacturing as promulgated in Title 21 Code of Federal Regulations, Food and Drugs. The first eight DoD-critical products planned included:
As noted, the preliminary costs for designing, building, and validating the GOCO/COCO facility are estimated to be $386M. The life-cycle cost for operations is estimated at approximately $915M over the 25-year life cycle; other government life-cycle costs are estimated to be $259M.
The Surgeon General of the United States, by letter dated January 31, 2001, supported establishment of a GOCO/COCO vaccine production facility. He noted that the list of DoD-required vaccines is very similar to those that would confront U.S. public health. The Surgeon General also observed that civilian participation could contribute to the successful planning and operation of the GOCO/COCO and that it is important that the GOCO/COCO have sufficient flexibility to accommodate evolving production requirements, both for new vaccines and for fulfilling future civilian sector needs.
As requested in your October 9th letter, and before discussing the DoD biological defense vaccine R&D programs, I would like to describe the FDA processes governing these vaccines. This survey should facilitate review of the R&D programs.
The vaccine approval process is long and complex. From discovery to market can take 15 years, although the vast majority of vaccine candidates do not get into clinical, that is human, trials let alone approved. The Pharmaceutical Research and Manufacturers of America reports that for every 5,000 drugs discovered in the research and development laboratories 20 drugs will go on to preclinical trials. Of these 20 drugs, only 5 will undergo human clinical trials and only 1 will eventually get approved. We do not have information on whether the numbers related to vaccine discovery are the same as those related to the drug discovery process. It should be noted that FDA regulates drugs and vaccines in a similar manner. Since most biological products also meet the definition of "drug", I have generally used the term drug to encompass both drugs and biological products.
Below is a discussion of the stages of drug development as they relate to vaccines to protect against BW and terrorist use of BW agents. Included in the discussion is the way the current Guidelines issued by the FDA would apply to this class of vaccines. The important difference is that it is not ethically possible to demonstrate through controlled clinical testing, the current standard, that a vaccine is safe, effective, and will protect against BW agents.
Preclinical Testing. Pharmaceutical companies conduct laboratory and animal studies to determine if the vaccine under study affects the targeted disease. In addition to efficacy, the safety of the vaccine candidate is also evaluated. This process usually takes 31/2 to 6 years. It is during these studies that for vaccines intended to protect against BW threats, that the animal models for surrogate efficacy are developed and validated.
Investigational New Drug Application (IND). If the preclinical testing demonstrates that the vaccine has efficacy in the surrogate model, an IND is made to the FDA. The IND becomes effective if the FDA does not place the IND on clinical hold within 30 days and it is only once the IND is in effect that human clinical trials may legally begin. The initial IND must include the method of manufacture (this can be, and usually is, refined during the drug development process); the proposed mechanism of action in humans; the results of the preclinical testing, including any toxic side effects and the surrogate model; how, where, and by whom the human clinical studies would be performed; and some information on the chemical structure of the vaccine.
Phase 1 Clinical Trials. Phase 1 studies for vaccines usually involve 10-30 healthy adult volunteers. This initial phase of clinical study is designed to test for safety by determining what happens to the drug in the human body - by studying its pharmacological and toxicological actions in humans. Dose-ranging studies are also performed during Phase 1 studies to determine the maximum tolerated dose and the minimum dose that will result in a measurable effect. About two thirds of drugs that enter clinical trials complete Phase 1 studies.
Phase 2 Clinical Trials. Phase 2 studies usually involve 30 to 100 healthy adult volunteers. This phase is designed to test for preliminary evidence of efficacy (i.e., does the drug do what it is supposed to do - produce effects that mimic the surrogate efficacy model). During Phase 2 studies, formulation buffers are studied and the final formulation buffer is determined. About one-third of the experimental drugs tested complete Phase 1 and 2 studies.
Phase 3 Clinical Trials. Phase 3 studies usually involve 1,000-3,000 patients in clinics and hospitals. These large, multicenter clinical trials are designed to prove conclusively that the drug works better than the standard treatment for the disease in question and/or a placebo. Most Phase 3 studies are randomized to the various arms of the study and double-blind, neither recipients nor test scientists know whether the study compound or a placebo is being administered. It is usual to discuss the design of the Phase 3 trial with the FDA prior to commencing the trial. By obtaining the agreement of the FDA, it is more likely that the product will ultimately be approved. All of the patients are asked to list any side effects that occur while they are in the study. Phase 3 testing usually takes around 3 years and approximately 80% of the drugs that enter this phase successfully complete the testing.
It is prior to this Phase, and to a lesser extent the other Phases, that FDA's proposed rule "New Drug and Biological Drug Products; Evidence Needed to Demonstrate Efficacy of New Drugs for Use against Lethal or Permanently Disabling Toxic Substances When Efficacy Studies in Humans Ethically Cannot Be Conducted" would guide these discussions. These discussions take place at a meeting with the FDA called "End of Phase 2/pre-Phase 3 meeting." At this meeting, agreement is reached between the FDA and the drug company on the design of the Phase 3 clinical trial.
The proposed rule can be summarized as described below:
Scope. (1) Drugs and biological products that reduce or prevent serious or life-threatening conditions caused by exposure to lethal or permanently disabling toxic chemical, biological, radiological, or nuclear substances; (2) products are expected to provide meaningful therapeutic benefit over existing therapies; (3) traditional human efficacy trials are not feasible or ethical; and (4) use of animal efficacy data when scientifically appropriate.
Proposed Rule. FDA has proposed to amend its new drug and biological products regulations so that FDA may approve a product for which safety has been established and requirements of 21 CFR 601.60 have been met based on adequate and well-controlled animal trials when results of those animal studies establish that product is reasonably likely to provide clinical benefit in humans. The FDA will rely on evidence from animal studies only where there exists reasonably well-understood mechanism of toxicity of agent, how the product prevents the toxicity, the effect is independently substantiated in multiple species, and studies include species expected to react with a response predictive for humans. The proposed rule would continue to require clinical testing data on product safety and immunogenicity.
Areas of ongoing discussion include issues such as agents that are only relevant for primates; animal study endpoint clearly related to desired benefit in humans; generally, enhancement of survival or prevention of major morbidity; selection of an effective dose in humans; and kinetics and pharmacodynamics and other relevant data, in animals and humans.
New Drug Application (NDA). Once the Phase 3 clinical trials are completed, the drug manufacturer compiles and analyzes all the data. If the data demonstrate the safety and effectiveness, as defined prospectively in the Phase 3 study design, of the drug, an NDA or Biologic License Application (BLA) is filed with the FDA. The average review time for an NDA/BLA is 2 years. However, this time can be reduced by about 1 year if the product is given priority review. Priority review means that the FDA must complete its initial review of the application within 6 months. FDA approval gives the manufacturer the right to market the drug exclusively under a trademark name for the period of exclusivity remaining for the drug.
Approval of the product based on the proposed rules is subject to three requirements. The first is postmarketing studies to verify and describe the product's clinical benefit when feasible and ethical. Such postmarketing studies may not be feasible with biological defense vaccines until an exigency arises. The second requirement provides restrictions to assure safe use and distribution. The third requirement requires labeling for users that explain that product's approval based on efficacy studies conducted in animals alone.
The proposed rule does not apply if product approval can be based on standards described elsewhere in FDA's regulations. For example, accelerated approval based on human surrogate markers or clinical endpoints other than survival or irreversible morbidity.
Phase 4 Studies. Phase 4 studies (when required) are designed for any additional data collection from patients after the drug has received FDA approval. These studies are normally required for products approved using FDA-accelerated approval rules for products approved using surrogate markers for efficacy. The data collected would confirm the efficacy of the product in long-term studies. For example, FDA currently approves cancer drugs based on evidence that the drug causes a tumor to shrink; the Phase 4 study would confirm that tumor shrinkage is correlated with long-term survival. Once the results of the Phase 4 study are analyzed and they demonstrate that the approval based on the surrogate marker are confirmed, the product is given a full approval. If however, the results of the Phase 4 study show that the surrogate marker for efficacy does not reflect efficacy, approval of the product could be withdrawn. Products for protection against BW threats would be approved using this mechanism.
I will now focus my remarks on those medical biological defense subprogram areas of immediate concern as identified in your letter of October 9, 2001. There are three major and integrated components of the medical biological defense Research, Development and Acquisition program - diagnostics, vaccines, and therapeutics. Vaccines and therapeutics are also subdivided into three areas: bacterial (e.g., anthrax, tularemia, and plague), viral (e.g., smallpox and hemorrhagic fevers), and toxins (botulinum, staphylococcal enterotoxins, and ricin).
Diagnostics. The DoD continues to actively pursue the development of diagnostic capabilities. It has developed the reagents and applied the technology to sample and detect the presence of BW agents in biological fluids. As new capabilities are developed and verified, they are inserted into existing, fielded systems.
There is an ongoing Defense Technology Objective (DTO) to develop a common platform/ device capable of diagnosing rapidly and early-on the presence of infectious disease and BW agents in clinical specimens. Two leading technologies are immunologically based membranes to detect host immune response to antigens (including their products) of biological agents, and miniaturized polymerase chain reaction (PCR) to detect and identify the nucleic acids of biological agents. An integrated specimen processing/gene amplification cartridge for rapid identification of anthrax spores has been designed and technical data package for a second generation portable PCR system is being completed in preparation for transition to advanced development this fiscal year.
The DoD TARA assessed the program as "Green" and characterized it as comprehensive and aggressive, with good collaboration and leveraging of technology and expertise, noting a need for intra-DoD and Federal Interagency standards for diagnostic reagents, sampling, and processes.
Anthrax (Bacillus anthracis) Vaccine. As you are aware, the DoD has a contract with Bioport Corporation to manufacture an anthrax vaccine licensed by the FDA since 1970. This contractor is the sole source of the licensed product, a matter of continued concern to the Department that is reflective of the factors limiting vaccine production and success that I mentioned earlier. Bioport has filed its response to the FDA pre-approval inspection. This is an important step in FDA approval of the Bioport BLA and resumed, FDA-compliant production of anthrax vaccine.
We are maintaining an aggressive R&D program to identify ways of enhancing the immunogenicity of vaccines through immunomodulators, as well as pursuing the development of a replacement anthrax vaccine using recombinant technology. This recombinant protective antigen (rPA) anthrax vaccine is a DTO that is showing considerable promise. Safety and efficacy studies are ongoing in laboratory models, and a potential surrogate marker of vaccine efficacy is being evaluated. In nonclinical studies, the rPA candidate demonstrated protection against inhalation exposure to anthrax. A major advantage of this technology is that resulting products and manufacturing processes are generally reproducible, yielding a consistently pure, potent, and safe product. Further, it does not have the associated facility containment problems seen with AVA production. A Technical Data Package has been prepared to support transitioning this candidate to development. The candidate rPA anthrax vaccine has transitioned to advanced development in FY01. At present the Joint Vaccine Acquisition Program (JVAP) Project Management Office projects attainment of baseline stockpile quantities in FY07 and BLA submission in FY10. The JVAP added this next generation anthrax vaccine to its prime systems contract with DynPort Vaccine Company (DVC) in FY01.
The DoD TARA assessed the rPA DTO as "Green," noting the industrial partnering for the production and purification under FDA current good manufacturing practice (cGMP) regulations.
Tularemia (Francisella tularensis) Vaccine. A tularemia vaccine candidate was one of the three vaccines in the JVAP base contract with DVC. This candidate is in advanced development and is completing process definition at Cambrex BioScience, Inc., in Baltimore. New assays will be required before clinical trials may be initiated and DVC has subcontracted with the Defense Science and Technology Laboratory (DSTL), UK to develop a new potency assay and assays for identity. Phase 1 studies are planned for FY03 with baseline stockpile quantities planned for FY06 and BLA submission scheduled for FY07.
Plague (Yersinia pestis) Vaccine. A plague vaccine was first made by Miles Cutter who then sold this line of business to Greer Laboratories. Greer then became the sole manufacturer of a licensed plague vaccine and provided DoD with the vaccine for several years. Greer apprised DoD of the impact of limited sales and required facility upgrade costs before determining it was no longer fiscally sound to continue production of the vaccine. Although this vaccine was effective against transdermal exposure to plague, it was relatively ineffective against aerosol challenge in animal studies.
The DoD has an ongoing R&D effort focused on developing a recombinant vaccine, immunomodulators, and treatment modalities for plague. There is a DTO for the recombinant plague vaccine that demonstrates efficacy in laboratory models, even against aerosol exposure. The U.S. Army Medical Research Institute for Infectious Diseases (USAMRIID) and DSTL, UK, are conducting research programs on a recombinant plague vaccine. The purification process is well under way and protective antigens, besides F and V, are being pursued. The JVAP is in the process of exercising its DVC contract option to add a plague vaccine and a Phase 1 clinical trial is planned for FY04.
The DOD TARA rated the status of the DTO as "Green," noting the potential vulnerability of a single antigen vaccine to genetically altered plague.
Smallpox (vaccinia) Vaccine. Prior to 1972, smallpox vaccination was a routine practice. The licensed vaccine was produced by Wyeth Laboratories and the remaining but extremely limited supply is under the control of the Centers for Disease Control and Prevention (CDC). Due to the potential problem of severe cutaneous reactions to the vaccine, vaccinia immune globulin, which is also in limited supply, should be available to treat this adverse reaction in the event of its occurrence.
The DoD has an ongoing R&D program to identify potential antiviral drugs, alternatives to vaccinia immune globulin, and a new smallpox vaccine. A model of human smallpox has been developed in nonhuman primates. The dose and schedule of the lead antiviral drug for treating smallpox have been initially established.
A smallpox vaccine was included as one of the three vaccines in the JVAP base contract with DVC. DVC subcontracted with BioReliance where the product is in cGMP production, a Phase 1 clinical trial is planned for January 2002, and a Milestone C consistency lot production decision is scheduled early this FY. The JVAP schedule is to have established baseline stockpile quantities in FY02 and the BLA submission is scheduled for FY04.
A Phase 1 clinical trial has been completed for vaccinia immune globulin and a manufacturing capability is being developed. DoD and DHHS are discussing how best to produce smallpox vaccine.
Hemorrhagic Fever Vaccine. There are a number of hemorrhagic fever (HF) viruses (e.g., Ebola and Marburg) for which the Department has an ongoing R&D effort to develop vaccines and treatment modalities. Progress has been made in characterizing HF virus infections, identifying potential surrogate markers of immunity, and establishing laboratory models for evaluating the safety and efficacy of candidate vaccines and therapeutics. Initial studies testing prime-boost candidate vaccines for HF (Marburg) have been completed and the results show promise. The DNA of the antigen of interest "primes" the immune system and the antigen serves as a "booster," stimulating the immune system to rapidly respond to the antigen. The candidates are in advanced development. A DTO for a HF virus (i.e., Ebola) vaccine is planned for FY03.
Q-Fever (Coxiella burnetii) Vaccine. A Q-fever vaccine was included as the third vaccine in the JVAP base contract. That development effort that was being conducted in collaboration with an Australian company was terminated. Foremost among many concerns with the candidate product was the need to conduct skin test screening for potential allergic reactions among recipients. We are evaluating other approaches.
Toxins. We have an ongoing R&D effort to develop safe and efficacious countermeasures against toxins, such as SEB, botulinum, and ricin. Monoclonal antibodies that neutralize botulinum neurotoxin serotype A and staphylococcal enterotoxin serotypes A, B, C1, and D have been generated. Recombinant vaccine candidates for botulinum serotypes D and G have been initially produced and are undergoing early efficacy evaluation. Reagents and assays to support development of candidate recombinant ricin vaccines are planned for completion this FY. Formulation studies of lead inhibitors of botulinum and SEB are ongoing. A recombinant botulinum, bivalent (AB) vaccine is in development as an exercised option on the JVAP contract with DVC. This candidate vaccine is in process definition at Diosynth-RTP, Princeton, NJ. Clinical trials are planned for FY04, and baseline stockpile is planned to be obtained in FY08 with BLA submission planned for FY11.
There is no DTO for toxins. A DTO, Medical Countermeasures for Staphylococcal Enterotoxins, has been successfully completed and a pre-IND meeting has been held with the FDA.
Other Medical Biological Defense DTOs. The Department has ongoing R&D supporting four other DTOs - Multiagent Vaccines for Biological Threat Agents, Medical Countermeasures for Brucellae, Medical Countermeasures for Encephalitis Viruses, and Needleless Delivery Methods for Recombinant Protein Vaccines. The DoD TARA recommended completion of the multivalent Venezuelan equine encephalitis (VEE) work and termination of the associated DTO. A VEE vaccine is undergoing demonstration and validation studies and the JVAP is in the process of exercising an option on its DVC contract to include a VEE vaccine. The JVAP schedule is to establish the baseline stockpile for VEE vaccine in FY08 and submit the BLA in FY11. There were no specific recommendations regarding the other three DTOs.
Finally, the Defense Advanced Research Projects Agency (DARPA) conducts high risk, high payoff research for the DoD. Genetic vaccine technologies and novel approaches to immunization are among the areas of the DARPA biomedical research portfolio that could contribute important capabilities to our long-term readiness posture.
In summary, the DoD vaccine program is technically very complex and our requirements are diverse and challenging. For the near-term, our vaccine-dependent medical readiness for force protection against BW and terrorist use of BW agents will be limited. Over the long-term we are committed to effective immunization as our cornerstone of force protection. Realization of this goal will require changes in our business practices, expanded participation by the pharmaceutical industry complemented by a GOCO/COCO vaccine capability, and a long-term national commitment to the program's success.
1 Discussed as an option but not recorded in the Independent Panel's report, a contractor-owned, contractor-operated (COCO) capability is equivalent to a GOCO and going forward the abbreviation GOCO/COCO is used.
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