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RECORD VERSION

STATEMENT BY

BRIGADIER GENERAL EDDIE CAIN

JOINT PROGRAM MANAGER

JOINT PROGRAM OFFICE FOR BIOLOGICAL DEFENSE

FALLS CHURCH, VIRGINIA

BEFORE THE

NATIONAL SECURITY, VETERANS AFFAIRS AND INTERNATIONAL RELATIONS SUBCOMMITTEE

COMMITTEE ON GOVERNMENT REFORM

FIRST SESSION, 106th CONGRESS

ANTHRAX VACCINE IMMUNIZATION PROGRAM (AVIP)

APRIL 29, 1999

 

NOT FOR PUBLICATION
UNTIL RELEASED
BY THE
SUBCOMMITTEE ON NATIONAL SECURITY,
VETERANS AFFAIRS AND INTERNATIONAL RELATIONS

 

Introduction

Chairman Shays, Representative Blagojevich and Distinguished Committee Members, I am honored to appear before your Committee today to address the production and supplemental testing of the Department of Defense's (DoD) Anthrax Vaccine.

I am Brigadier General Eddie Cain, Joint Program Manager of the Joint Program Office for Biological Defense (JPOBD). I have served in my present position since June 1998.

The JPOBD provides centralized program management for the advanced development and production of all DoD biological defense (BD) vaccines. Major areas of responsibility include the development, licensing, stockpiling and testing of BD vaccines.

 

Background

Anthrax is a major biological warfare threat faced by United States forces. More than ten countries, including Iraq, have or are suspected of developing a biological warfare capability. Anthrax is the biological weapon most likely to be encountered because it is highly lethal, easy to produce in large quantities, and relatively easy to develop as a weapon due to the stability of its spore stage. If anthrax is used as a biological weapon, disease will most likely occur by inhalation of anthrax spores. Death is the usual outcome once clinical symptoms appear regardless of any post-exposure treatment. Death from anthrax, however, is preventable by immunization with the licensed vaccine.

The responsibilities for funding, management and oversight of the DoD Anthrax Vaccine contracts were assumed by the JPOBD in 1995 from the U.S. Army Medical Research and Development Command (USAMRDC), currently the U.S. Army Medical Research and Materiel Command, headquartered at Fort Detrick, Maryland.

 

Memoranda of Understanding (MOUs)

The Committee requested that DoD address the purpose and operation of any past or current MOUs between DoD and the Food & Drug Administration (FDA). I am not aware of any MOUs between DoD and FDA that specifically deal with the licensed Anthrax Vaccine. Since 1987 there have been two general MOUs between DoD and FDA. The first MOU, "Investigational Use of Drugs, Antibiotics, Biologics, and Medical Devices by the Department of Defense", was signed in May 1987. This MOU formalized agreements that DoD would comply with Federal regulations for DoD sponsored clinical research as pertains to 21 CFR 312 or 21 CFR 812. FDA agreed to special expedited review for DoD requirements to meet national defense conditions including stockpiling considerations for future use. FDA also agreed to maintain a cadre of personnel who have appropriate security clearances if research projects involve potential security issues. The second MOU, "Quality Assurance Support for Medical Materiel Having Military Application", was signed in June 1991. The latter MOU formalized the relationship and defined the responsibilities of USAMRDC and FDA to each other during the research, development and pre-marketing acquisition of medical materiel for military application. This MOU expired June 1997.

 

 

Supplemental Testing

As you know, the Secretary of Defense (SECDEF) announced in his December 15, 1997 press release that the Anthrax Vaccine Immunization Program (AVIP) would start only after several conditions were met. One of those conditions was "supplemental testing to assure sterility, safety, potency and purity of the vaccine". FDA had previously released these anthrax vaccine lots for use. DoD, however, for added assurance directed JPOBD to contract with BioPort, formerly Michigan Biologic Products Institute (MBPI), to conduct supplemental testing, with external oversight, on all lots of anthrax vaccine in the DoD stockpile.

 

The supplemental testing is based on tests required by FDA for lot release, and provides an added level of confidence in the potency and purity of the anthrax vaccine in our stockpile. BioPort has performed, and continues to perform supplemental testing on all licensed lots of anthrax vaccine that were in DoD's original stockpile. Mitretek Systems Inc. performs independent oversight and provides a quality assurance function for DoD within the BioPort production facility. Mitretek's staff observes all aspects of the supplemental testing and provides a written report to JPOBD on the acceptability of the testing and test results. JPOBD reviews all data prior to releasing any lot for shipment and use.

Supplemental testing began in January 1998, and originally was scheduled for completion in November 1998. As of April 1999, eight licensed lots have passed all supplemental testing requirements. JPOBD has approved these eight lots for use.

 

During the conduct of supplemental testing BioPort and Mitretek Systems Inc. identified an inconsistency in the control values in potency assays conducted in June and September 1998. Based on this inconsistency, JPOBD suspended supplemental testing and sent a "Tiger Team" of subject matter experts to help resolve the problem. Corrective action is being implemented. We expect to resume testing within six months and do not anticipate any impact on the immunization plan.

 

Manufacturing Facility

In support of DoD Directive 6205.3, "DoD Immunization Program for Biological Warfare Defense", dated November 26, 1993 and in anticipation of the SECDEF announcement to immunize the total force, JPOBD evaluated the anthrax production capabilities and determined that it would require renovation to ensure it would meet FDA regulatory requirements. JPOBD initiated discussions with the manufacturer in the summer of 1996 to shut down the production line for renovation. The final feasibility study was completed in May 1997. Cost estimates and design work were started, and construction in a number of ancillary areas was initiated in 1997. Production line operations were suspended in January 1998 so that production line renovation could begin.

The physical aspects of the renovation were completed in January 1999 on schedule. Completion of the renovation also requires validation of the manufacturing equipment and the production process. The process validation includes producing consistency lots of anthrax vaccine for review by FDA. We expect this to be completed by January 2000.

 

Stockpile

There is sufficient anthrax vaccine to support the immunization plan through December 1999. As of 15 April 1999, doses available for immediate use include one undistributed lot that has completed supplemental testing along with four additional lots recently released by FDA. These latter four lots are not part of the original DoD stockpile and did not undergo supplemental testing because lot release data were recently completed and submitted to FDA for review and approval.

No lots are under mandatory quarantine. Twenty-one lots of the original stockpile are voluntarily quarantined by BioPort pending resolution of supplemental testing or FDA regulatory issues. JPOBD is working closely with BioPort to resolve these issues prior to making any lots available for DoD use.

 

Adverse Reactions

The Anthrax Vaccine Immunization Program (AVIP) Office, Office of the Army Surgeon General, provided the following information:

"The safety of the vaccine is the most closely scrutinized aspect of the entire Anthrax Vaccine Immunization Program, or AVIP. We monitor very closely for trends and events that may indicate problems and we have an immunization tracking system that can readily allow us to analyze these problems by unit, by lot, or by location.

"Since DOD began the AVIP during the National Command Authorities directed contingency OPERATION Desert Thunder in March of 1998, DOD submitted 49 individual VAERS-1 Forms, representing the vaccine adverse events from over 810,000 individual vaccination events in more than 260,000 Service Members, representing a 0.006% incidence rate. Only 8 of these 49 Vaccine Adverse Event Reporting System Forms indicated a requirement for either hospitalization or loss of duty for more than 24 hours. Of these 49 reports, 26 are characterized as local hypersensitivity reactions. This includes local erythema or redness at the site of vaccination, a subcutaneous nodule or knot under the skin, tenderness, and perhaps swelling. Of these 26 local reactions, 9 were classified as mild-local redness at the injection site (1-2 centimeters in diameter); 10 were classified as moderate-local redness (greater than 1-2 centimeters but less than 5 centimeters in diameter) and perhaps a subcutaneous nodule; 7 were classified as severe local reactions-redness exceeding 5 centimeters in diameter or perhaps swelling at the site which, in some cases, actually extends to the lower forearm. It is important to note and compare that other US National vaccines with similar components and constituency, such as tetanus toxoids and typhoid for example, have nearly identical adverse events associated with their use. The remaining 23 of 49 adverse events are classified as systemic reactions. Systemic reactions range from hives, muscle and joint pain, nausea, fever, and chills. Again, these rare adverse events are commonly cited in the medical literature with many other vaccines. In fact, you should note systemic reactions occur with greater incidence with the Mumps, Measles and Rubella Vaccine, Hepatitis B Vaccine, and Diphtheria, Tetanus and Pertussis Vaccines, effectively given as part of our National vaccination programs. One US Navy sailor experienced a more serious systemic reaction after his third vaccination referred to as Guillian-Barre Syndrome (GBS). The etiology of this syndrome is still unknown, although it has been associated with recent infectious disease and vaccinations. The CDC reports that the vast majority, 95 percent of patients with GBS, do not report receiving any vaccine in the weeks prior to developing symptomatically. GBS gained some notoriety during the 1976 national vaccination against swine influenza and was found to increase the rate of GBS slightly less than one case per one hundred thousand vaccinations. Subsequent influenza vaccines prepared from other virus strains have not been clearly associated with an increased frequency of GBS. More recent studies suggests the rate may be as low as 1-3 cases per 1,000,000 people vaccinated. The possible risk of developing GBS following immunization is so small, however, that it is difficult to study and accurately estimate.

"The 49 VAERS events outlined for you represent all reports submitted through our reporting system within all Department of Defense Military Treatment Facilities. The FDA implemented their vaccine adverse event reporting system, commonly referred to as VAERS, in November of 1990. VAERS is the responsibility of the Division of Biostatistics and Epidemiology in the Center for Biologics Evaluation and Research. It is also monitored at the CDC by the National Immunization Program, Vaccine Safety and Development Activity. Since 1990, only 101 adverse events have been reported to the FDA as temporally associated to the anthrax vaccine. These reports come from disparate sources and may actually be submitted directly by any individual suffering an adverse event. Since this is a passive surveillance system, this open approach encourages the submission of any and all events that may represent a significant trend. The FDA cites that only 9 of these 101 reports represent a serious event. Serious events are defined by the FDA as those that are life-threatening, result in a chronic illness or condition, or require hospitalization. The FDA assesses that none of these events are causally related to the anthrax vaccine and do not represent a sentinel trend in adverse health effects associated with the vaccine. All adverse events reported within the DoD have resolved and all have returned to duty.

"It is also important to distinguish the difference between adverse events and side-effects associated with the vaccine. While our system does not discourage reporting any VAERS temporally associated with the vaccine, many of those reports submitted represent side-effects. Any case that results in either loss of duty for more than 24 hours or hospitalization must be reported through the DoD as an adverse event. Conversely, side-effects do not effect either duty performance or any other activity of daily living. The history on the use of this vaccine in the United States, which was licensed more than 28 years ago, suggests that the side effects associated with its use are minimal. The product insert for the vaccine cites that as many as 30-percent of recipients will experience a mild, local reaction. The clinical data submitted to the FDA when the vaccine was first licensed in 1970 estimated 16-percent or less would experience a mild local reaction, as few as 4-percent would experience a moderate local reaction, and less than 1-percent would have a serious local reaction including swelling at the site of inoculation that may extend down the extremity. Less than 1-percent of the study group experienced any type of systemic reaction. Studies on reactions and side-effects by the US Army Medical Research Institute for Infectious Diseases, USAMRIID, conducted from 1977 to 1996 validates the earlier reports and the low reactogenicity of this vaccine.

"All the members of the AVIP collective team-the Surgeons General, the Joint Program Office, the Joint Staff, and the Assistant Secretary of Defense for Health Affairs, have endeavored to continuously monitor the health of our people to protect against any adverse health effect. Under the direction of the Army Surgeon General, Tripler Army Medical Center launched an internal survey of more than 600 assigned clinicians to closely evaluate every conceivable side effect that had any temporal correlation to the anthrax vaccination. We encouraged the survey participants to report any side-effects, irrespective of the degree of severity, to develop an accurate projection of the vaccine's effect on the service member's health and the degree to which it impaired his duty performance. Less than 5-percent sought medical care for side-effects after any of the first three doses, and most of these side-effects, according to the principal investigator, were determined to be from illness not related to the vaccine. Only 3 VAERS were reported from the population, none of which required hospitalization. This survey will continue, with no established endpoint, until we have sufficient data to confirm the historical rates associated with this vaccine.

"The Army Surgeon General, acting on behalf of the Executive Agent, has also requested the assistance of an external review panel to analyze each of the reported VAERS. Presently, the Vaccine Injury Compensation Program (VICP), from the Department of Health and Human Services is evaluating 100% of all VAERS received by the FDA related to the anthrax vaccine. The VICP has met three times now and reviewed 59 of the 84 reported VAERS. Their recommendation is for, "no change in the current DoD anthrax immunization program except to initiate observational studies, preferably with a control group, as soon as possible.

"The Army Surgeon General has proposed a longitudinal, cohort study to assess both near-term and long-term reactions. This item will be discussed at a clinical conference scheduled for May 1999. Attendees include clinicians from all Services, the Armed Forces Epidemiological Board, the CDC, and the Center for Bioterrorism at Johns Hopkins University.

"Mr. Chairman, Representative Blagojevich, Distinguished Committee Members, Force Health Protection is the concept embedded in Joint Vision 2010 which not only identifies how we will manage battlefield casualties in the next millennium, but how we must leverage our medical resources to maintain a healthy and fit force, and prevent casualties throughout the operational spectrum. The AVIP epitomizes this paradigm by using superior technologies to add another dimension of protection against emerging threat of anthrax as a biological weapon of mass destruction. Leveraging the superior technologies of the future, this program provides a template for managing all health readiness metrics and ensures a hyper-fit force that will be preeminent in any form of conflict. We continue to monitor the safety of this program to ensure and protect our most valued asset-the individual soldier, sailor, airman and marine. "

Conclusion

 

Anthrax vaccine is a key element in protecting service members against the lethal threat of anthrax. DoD is working with BioPort, the only licensed anthrax vaccine manufacturer to ensure there is a supply of this safe and effective vaccine.

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