Anthrax Info - DoD.doc

With more than two years experience implementing the Anthrax Vaccine Immunization Program (AVIP), the results affirm that it is the right thing to do. The anthrax vaccine, licensed in 1970, is effective and has an excellent safety record. Although a supply shortage has forced a temporary slowdown in the program, the Defense Department will resume the program as soon as the shortage resolves.

Anthrax is readily weaponized, highly lethal, and poses a clear threat. More than 1.95 million doses of anthrax vaccine have been given to more than 490,000 Service Members. Six independent civilian reviews since 1978 have affirmed the safety and effectiveness of anthrax vaccine. Thirteen studies involving more than 366,000 vaccine recipients establish the safety profile of anthrax vaccine.

Although local reactions at the injection area are not uncommon, such reactions are usually mild and short-lived. There have been few serious adverse events (defined by hospitalization or loss of work time greater than 24 hours). As one of the 13 safety studies, the DoD uses the recognized Vaccine Adverse Event Reporting System (VAERS) to evaluate adverse events. VAERS is jointly operated by the Centers for Disease Control & Prevention (CDC) and the Food & Drug Administration (FDA). Reported reactions are similar to other commonly prescribed immunizations, including those required for school children and vaccines mandatory for military personnel. No unexpected patterns of adverse events have been detected.

The evidence of vaccine effectiveness against aerosol exposure to anthrax is persuasive. It is unethical to enter human subjects into experiments in which they are exposed to inhalational anthrax spores, but results from studies using non-human primates show that the vaccine is 95% effective in preventing inhalational anthrax, whereas all unvaccinated animals succumbed from infection.

Previous concerns about production facility deficiencies in meeting current Good Manufacturing Practices (GMP) have been addressed by FDA action and DoD assistance to the facility, with a supplemental testing program as an additional quality-control check. As with all vaccines, each lot of anthrax vaccine has passed extensive tests for safety, sterility, purity, and potency before release.

Balancing the risks of immunization (low, similar to all licensed vaccines) versus the risks of disease from failing to vaccinate, the scales tip decidedly in favor of immunization. The consequences of unvaccinated unit members becoming biological warfare casualties would be tragic enough, but the consequences would be graver than their deaths alone. Their individual deaths may jeopardize the capability and survival of entire military units, as well as the success of the military mission.

Just as vaccines are required for school children for the good of the community, anthrax vaccine is mandatory for military personnel as an important force health protection measure. The Secretary of Defense, after assuring a program of high quality, directed the implementation of the Anthrax Vaccine Immunization Program for the Total Force.

It is very important that DoD be recognized as forthright, honest, and credible. The DoD began with an assertive program to inform people about the value of anthrax vaccination. We are steadily enhancing DoD’s education efforts by installing a toll-free information line (877-GET-VACC) and an authoritative Internet web site (www.anthrax.osd.mil).

It is the policy of the United States government to protect the Armed Forces against clear biological warfare threats when a safe and effective vaccine is available. The FDA-licensed anthrax vaccine is such an agent.

BACKGROUND

On December 15, 1997, Secretary of Defense Cohen approved the plan to immunize the Total Force against anthrax, contingent on four conditions: (1) supplemental testing of anthrax vaccine lots in the stockpile to assure their potency, purity, sterility, and general safety, consistent with Food and Drug Administration (FDA) standards; (2) approval of the Services’ implementation plans for execution and communication; (3) implementation of a system for fully tracking anthrax vaccinations; and (4) review of the health and medical aspects of the program by an independent expert. Each of these conditions was fulfilled.

Eventually, the Total Force of approximately 2.4 million Americans, including more than 1 million members of the National Guard and Reserves, will receive the FDA-licensed anthrax vaccine. The program also extends to the U.S. Coast Guard. The Anthrax Vaccine Immunization Program (AVIP) will be implemented in three phases over a seven- to eight-year period. Forces expected to deploy to high-threat areas will be the first immunized against anthrax. This phase, referred to as Phase I, includes Service Members and mission-essential DoD civilians assigned or deployed to areas designated by the Joint Staff as high-threat: Southwest Asia (SWA) and Korea (i.e., Northwest Asia, NWA). Phase I began in March 1998, due to increasing tensions in SWA. The Secretary himself was one of the first people vaccinated against anthrax. Phase I extended to forces deployed to Korea and surrounding waters on August 16, 1998. Secretary Cohen and General Shelton have already received their sixth dose in the anthrax vaccination series.

Early deploying forces supporting SWA and NWA, both Active and Reserve Component personnel, will be vaccinated in Phase II. Phase II begins once assured production is available from the manufacturer. Phase III will include the remainder of the force, both Active and Reserve Component, and new personnel. As of October 2000, more than 1.95 million doses of anthrax vaccine have been given to over 490,000 Service Members in the DoD Anthrax Vaccine Immunization Program (AVIP).

THE CURRENT SLOWDOWN

On July 17, 2000, the Secretary of Defense ordered an orderly, temporary slowdown slowdown of the AVIP until additional FDA-approved vaccine becomes available. Vaccination will continue in the high-threat areas (Southwest Asia and Korea) for personnel assigned or deployed on the ground for 30 days or more. People outside the high-threat areas will defer further vaccinations until additional vaccine is available.

Each dose of a vaccine is like climbing a ladder. Even the first dose of anthrax vaccine begins the process of protection. Anti-anthrax antibodies are detectable in 60% to 84% of people who receive just one dose of vaccine. After two doses, 95% to 100% have detectable antibody concentrations. The full vaccination series is still needed for full protection.

The Defense Department has already assessed the effect of interruptions in the anthrax vaccine schedule. In 1992-93, a study was conducted among 281 Fort Bragg soldiers who had received 1, 2, or 3 doses of anthrax vaccine 18 to 24 months earlier during Persian Gulf War. These soldiers received one additional dose of anthrax vaccine. From 92% to 100% of these soldiers responded with a ~ 100-fold increase in antibody level. Based on these findings and a general understanding of the human immune system, deferred vaccinations resume where left off. There is no need to start vaccination schedules over from the beginning.

HISTORY OF THE ANTHRAX VACCINE

The anthrax vaccine given to U.S. forces was licensed by the federal government on November 4, 1970. For 30 years, anthrax vaccine has been recommended for at-risk veterinarians, laboratory workers, and others at occupational risk in the U.S. The manufacturer distributed about 68,000 doses of anthrax vaccine between 1974 and 1989. An estimated 150,000 Service Members received 250,000 doses of anthrax vaccine during the Persian Gulf War of 1990-91. The FDA-licensed anthrax vaccine is effective and has an excellent safety record. It is a sterile, non-infectious product made by filtering anthrax bacteria. It is impossible to contract the disease from the vaccine, because an avirulent strain is used.

Immunization with anthrax vaccine requires six doses administered over 18 months to complete the primary series. Doses are administered at 0, 2, and 4 weeks, and 6, 12, and 18 months (where the first dose is given at "week 0"). Yearly boosters are administered thereafter to maintain immunity. Although protection levels increase as shots in the series are given, the entire six-shot series is needed.

THREAT ASSESSMENT

The biological warfare (BW) threat to U.S. forces is real. At least seven countries, including several hostile to Western democracies - Iran, Iraq, Libya, and North Korea - now possess or are pursuing offensive BW capabilities. It is within the reach of not only rogue nations, but also transnational terrorist groups. Anthrax tops the DoD threat list. When inhaled, anthrax is highly lethal, far more potent than the same quantity of the deadliest chemical warfare agent. Small amounts of anthrax can produce large numbers of casualties. A 1993 report by the U.S. Congressional Office of Technology Assessment estimated that between 130,000 and 3 million deaths could follow the aerosolized release of 100 kg of anthrax spores upwind of the Washington, DC, area - truly a weapon of mass destruction. The accidental aerosolized release of anthrax spores from a military microbiology facility in Sverdlovsk in the former Soviet Union in 1979 resulted in at least 79 cases of anthrax infection and 68 deaths and demonstrated the lethal potential of anthrax aerosols. An anthrax aerosol would be odorless, invisible, and capable of traveling many miles.

Anthrax is, by far, the easiest biological agent to produce and weaponize. Production of anthrax as a biological weapon does not require special equipment or advanced technology. It is extremely stable and can be stored almost indefinitely as a dry powder. It can be loaded in advance, as a freeze-dried powder, in munitions or disseminated as an aerosol with crude sprayers. While protective clothing and gas masks provide excellent front-line defense, their effective use requires rapid and early detection of the agent. Detection devices are not sufficient to completely protect against the threat. They may not detect an agent in time to warn personnel to don protective gear before exposure would occur.

EFFICACY OF THE ANTHRAX VACCINE

The evidence of efficacy of the FDA-licensed anthrax vaccine is based upon data from both human and animal research. The vaccine, licensed in 1970, induces immune response through a protein called protective antigen. The same protective antigen in the licensed vaccine was involved in the pivotal, placebo-controlled clinical study conducted in humans of anthrax vaccine [Brachman, et al. American Journal of Public Health 1962;52:632-45]. This study was conducted in a group of wool-mill workers in New Hampshire from 1955 to 1959.

Cutaneous anthrax (anthrax contracted through the skin) was an occupational health hazard among the mill workers for many years before the study. One group of workers was vaccinated, one group received a placebo, and another group was simply observed. The study revealed that vaccination resulted in a statistically significant reduction in the incidence of anthrax between vaccine recipients and those not vaccinated. People who were vaccinated developed disease 92.5% less often than those not vaccinated. Standard statistical analyses indicate that if this study were repeated, we would expect to see disease reduction between 65% to 100%.

During the course of the study, there was an outbreak of the inhalation form of anthrax at one of the four mills. Five cases of inhalation anthrax occurred among 448 unvaccinated people at that mill, with zero cases among 149 fully vaccinated people. Despite the obvious trend, the number of cases of inhalation anthrax was insufficient for the difference between groups to be conclusive statistically. A follow-on study by the CDC for the period 1962 to 1974 reported on 27 cases of cutaneous anthrax among unvaccinated (or only partially vaccinated) workers in or near the mills, compared to no cases among those fully vaccinated.

In non-human primates, the animal model that best approximates humans, the FDA-licensed anthrax vaccine is able to provide > 95% protection against an aerosol challenge. In five studies of Rhesus monkeys given either one or two doses of anthrax vaccine, 62 of 65 vaccinated animals survived lethal aerosol challenge with hundreds of times the fatal dose. In the various studies with non-human primates, a total of 18 unvaccinated animals were challenged and all died. Similarly, 114 of 117 vaccinated rabbits survived inhalational spore challenge, whereas all 28 unvaccinated rabbits died.

In summary, although the available research on vaccine effectiveness against inhalational anthrax is not definitive, the human and animal evidence of efficacy are persuasive. Because the occurrence of naturally occurring anthrax (especially inhalational anthrax) is exceedingly low, there is no opportunity to conduct well-controlled field trials. Anthrax spores are, of course, too lethal to test on humans. Thus, there is no way to conduct human challenge studies of any vaccine or therapeutic agent against inhalational anthrax. For these reasons, the only feasible approach is to rely on the human data available, supplemented by animal research. The efficacy of the vaccine in various species against geographically diverse strains of anthrax appears at Appendix A. The effectiveness of the vaccine against supposedly "vaccine-resistant" strains of anthrax is discussed in Appendix B.

SAFETY OF THE ANTHRAX VACCINE

Short-Term Safety

Several studies show that anthrax vaccine is a safe vaccine, with an incidence of side effects after injection similar to other common vaccines. Like any medicine, any vaccine will occasionally cause adverse reactions. Usually these are mild, like a sore arm or "flu"-like symptoms. Symptoms at the injection site often can be treated with over-the-counter antihistamines (for itching) or pain relievers like ibuprofen. Pretreatment of people who developed injection-site reactions previously may minimize reactions to subsequent doses. Serious reactions are rare, but they can happen with any vaccine.

Our understanding of common side effects after vaccination come from multiple active-surveillance studies stretching from the 1950s to the 1990s. The older studies were conducted in civilian occupational settings (coordinated by CDC researchers), among U.S. Army research laboratory workers at Fort Detrick, Maryland, and elsewhere, and among U.S. military personnel in Korea, Hawaii, North Carolina, and elsewhere. To date, thirteen studies of more than 366,000 vaccine recipients establish the safety profile of anthrax vaccine. In aggregate, these multiple studies are the basis for DoD confidence in anthrax vaccine.

Based on data obtained during 30 years of experience with anthrax vaccine, it is expected that up to 30% of people receiving the vaccine will experience some mild adverse effects, most commonly local reactions such as redness and soreness around the injection site. Between 1% and 5% have a local reaction 1" to 5" in diameter. Less than 1% have larger reactions. Significant events beyond the injection site occur in less than 1% of anthrax vaccine recipients. Women develop injection-site reactions up to twice as often as men, but the reactions typically resolve quickly for both genders. Some vaccine recipients report symptoms that commonly occur among unvaccinated people (e.g., headaches). These rates of adverse reactions are similar to those for other vaccines, including the generally mandatory childhood vaccines, DTP (diphtheria-tetanus-pertussis), MMR (measles-mumps-rubella), and other vaccines administered to military personnel, such as hepatitis A, yellow fever, and other vaccines.

For purposes of comparison, the studies of the current anthrax vaccine submitted in the licensing application to the FDA showed that in 16,000 doses approximately 3% to 20% exhibited mild reactions and fewer than 1% severe side effects. In the case of hepatitis A vaccine, soreness at the injection site was reported by 56% of adult vaccine recipients. Headache was reported by 14%. For the typhoid Vi vaccine, local tenderness was reported by 98%, pain by 56%, malaise by 24% and headache by 11%. The pneumococcal vaccine, which is a recommended vaccine for all Americans over the age of 65, has a 71% rate for localized soreness. The recently licensed Lyme disease vaccine produced localized pain in 93% of recipients and fever in 2.5%. The hepatitis B vaccine reports a local reaction rate of 17% and a systemic reaction rate of 15% in adults.

To monitor unusual adverse events attributed to anthrax vaccine, DoD guidance directs health-care providers to use the Vaccine Adverse Event Reporting System (VAERS). The Department of Health and Human Services established VAERS in November 1990 as a national surveillance system for vaccines, as the successor to earlier adverse-event monitoring systems. DoD has participated in VAERS since its inception in 1990. Indeed, DoD has contributed safety data to various medication-monitoring systems for many decades.

VAERS is considered a passive system, because it relies on health-care providers to report adverse events they see in clinical practice. The strength of VAERS is in recognizing unexpected and rare adverse events. It is co-managed by the FDA and the CDC.

VAERS uses established surveillance methods. Passive systems like VAERS are known to underreport the true number of adverse events, although they underestimate common events more than rare events. For anthrax vaccine and all other vaccines, DoD requires its providers to report through the VAERS system all cases of (1) loss of duty for more than 24 hours; (2) hospitalization for any reaction; and (3) suspected contamination of a vaccine container. In addition, DoD encourages its health-care professionals to report all adverse events they consider important and clinically relevant, even if the event does not meet the aforementioned criteria. It is also important to mention that patients may report adverse events directly to VAERS if they wish.

DoD relays all reports of adverse events after any vaccination to the FDA. This is part of DoD's long-standing participation in FDA's Vaccine Adverse Event Reporting System (VAERS). At the request of DoD, the Department of Health and Human Services (DHHS) established an Anthrax Vaccine Expert Committee (AVEC) in October 1998 to review VAERS forms related to anthrax vaccine. A distinguished university professor chairs this review committee of civilian physicians with expertise in immunology, internal medicine, neurology, rheumatology, and microbiology. The AVEC independently reviews all anthrax vaccine-related reports received by VAERS. The Committee meets every 4 to 6 weeks, along with representatives of DoD, CDC, FDA, and DHHS, to review all the new anthrax adverse events reports submitted in the interim. The AVEC reviews the quality of the submitted information, evaluates the reported event in the context of expected and unexpected adverse events to vaccines, and assesses the causal relationship of the event with anthrax vaccine. The Committee also looks for any clinically significant patterns in the aggregate data. A committee report is generated and is sent to the Office of the Army Surgeon General through the National Vaccine Program Office in DHHS. To date, the AVEC reports it has found nothing unexpected in the side-effect profile of anthrax vaccine. The type of review performed by the AVEC is unprecedented for a licensed vaccine.

As of October 10, 2000, the independent Anthrax Vaccine Expert Committee (AVEC) had reviewed 1,203 VAERS reports related to anthrax vaccination. At this time, more than 1.95 million doses of anthrax vaccine had been administered to over 490,000 people. Forty-eight of the 1,203 reports involved hospitalization; the civilian panel found that 10 of the 48 certainly or probably were caused by anthrax vaccine. All ten involved allergic, inflammation reactions at the injection site. Another 172 of the 1,203 reports involved loss of duty greater than 24 hours (but did not involve hospitalization); the civilian panel found that 115 of the 172 certainly or probably were caused by anthrax vaccine. These 115 reports described injection-site reactions (71 reports), various rashes (17), viral-like symptoms (9), acute allergic reactions (7), itching (4), or other symptoms. Some reports described multiple symptoms. The balance of the 1,203 reports, 983, were categorized as other than serious, involving neither hospitalization nor loss of duty greater than 24 hours. These reports have been individually assessed as well, without finding unexpected patterns of side effects.

The FDA-licensed anthrax vaccine was also used during the Persian Gulf War to immunize approximately 150,000 American personnel against Iraq’s biological weapons. Several national civilian scientific groups, including the Presidential Advisory Committee on Gulf War Veterans’ Illnesses, the Institute of Medicine, the National Institutes of Health, and the Defense Science Board, have closely examined this issue and found no evidence to link the FDA-licensed anthrax vaccine with illnesses among Gulf War veterans. These reports can be viewed in their entirety on the Internet at addresses listed in Appendix C.

Severe reactions reported close in time after vaccination have been few. With over 1.95 million anthrax vaccinations given to over 490,000 Service Members under the Anthrax Vaccine Immunization Program, the low incidence of reported serious adverse events confirms expectations regarding the short-term safety of the vaccine.

In reviewing safety and adverse reactions regarding any vaccine, it is important to be mindful of the context. As stated by the CDC (in CDC Publication, "Surveillance for Adverse Events Following Vaccination," September 1997;

Immunizations have reduced the incidence of many vaccine-preventable diseases in the United States (and many other countries) by more than 95% compared with the pre-vaccine era. . . . As the proportion of the population vaccinated increases, however, the number of persons who experience an adverse event following vaccination also increases due either to true reactions caused by the vaccination or coincidental events not caused by the vaccination. In recent years, the annual number of reports to the Vaccine Adverse Event Reporting System (VAERS) have exceeded the total number of reports of routine childhood vaccine-preventable diseases … [due to the effectiveness of vaccines in preventing infectious disease].

Vaccines are usually administered to healthy persons and often are mandatory; therefore, they are held to a higher standard of safety than other medications. However, as with all medications, no vaccine is perfectly safe or effective. Vaccines can induce minor adverse events such a local reaction or fever. Very rarely, they can induce serious adverse events . . . . To assure that vaccines are as safe as possible and to maintain public confidence in vaccines, close monitoring of the incidence of adverse events, adequate scientific evaluation of possible associations, and appropriate responses to newly identifies risks of vaccines are essential.

A summary of short-term studies that reviewed side effects is attached at Appendix D.

Long-Term Safety

The DoD leadership, its physicians, and its research experts are confident of the safety and efficacy of anthrax vaccine. The confidence is based on experience with anthrax vaccination of more than 1,500 laboratory workers at Fort Detrick, Maryland, and other studies. Most of these workers received 150 to 200 vaccinations and skin tests; some received more than 300 such injections during their tenure at Fort Detrick. Many received annual booster doses of anthrax and other vaccines for 10 to 20 or more years. The first report of this group of vaccine recipients was published in the Bulletin of the Johns Hopkins Hospital in 1958. Two follow-up reports were printed in the Annals of Internal Medicine in 1965 and 1974. An updated manuscript is being prepared now. These studies concluded that long-term follow-up examination "failed to demonstrate any evidence of illness attributable to the immunizations."

An extension of this long-term study is underway to determine, in even greater detail, whether individuals who received multiple vaccines, including anthrax vaccine, during their past employment at Fort Detrick demonstrated any adverse health effects over the long term. A total of 570 study and control volunteers have been enrolled in this case-control study begun in 1996. All volunteers signed an informed-consent document. The study methods include a 9-page health history questionnaire, extensive blood tests and urinalysis. The questionnaire queries mental and physical conditions of progeny as well as the health of volunteers. Study end points include symptoms, symptom complexes (including the complex of symptoms reported by veterans of the Persian Gulf War), diseases, and abnormal laboratory and urine tests. Study subjects will be compared to two to three race-, gender-, and age-matched control subjects to determine if any long-term medical effects exist among this unique group of study subjects. Analysis of the data from the extensive health history questionnaire and numerous laboratory tests is currently in progress.

Our leaders respect the concerns expressed by Service Members about the possibility of long-term health effects and want to address these concerns using the most appropriate scientific knowledge and practices. We will continue our ongoing commitment to ensuring the health of our men and women as we implement the AVIP.

On August 24, 1999, the Anthrax Vaccine Immunization Program Agency convened a team of civilian and military medical experts to set a research agenda to gather additional information about the long-term safety of anthrax vaccine. In designing these studies, DoD draws on the accumulated experience of some of the nation’s best vaccine researchers at CDC and FDA. At the initial committee meeting, the attendees suggested two major groups of studies: retrospective (look-back) studies to collect additional information more quickly, and prospective (look-forward) studies that are more scientifically rigorous, but take longer. The retrospective studies are underway. The prospective studies are being planned.

One of the methods is a surveillance technique used by CDC in post-marketing studies: large, linked databases. DoD uses the large, linked database approach in its long-term research efforts through access to its immunization tracking programs database and though the medical databases maintained by the Defense Medical Surveillance System (DMSS). This study clearly shows that anthrax-vaccinated people are hospitalized at the same rate as unvaccinated people.

EFFECTS ON REPRODUCTIVE HEALTH

According to the CDC's Advisory Committee on Immunization Practices (ACIP), "there is no convincing evidence of risk from vaccinating pregnant women with inactivated virus or bacterial vaccines or toxoids." Similarly, no evidence exists that indicates any other adverse reproductive effects including effects on fertility, miscarriage, or birth defects. Indeed, some inactivated vaccines are specifically advocated by the ACIP, the American College of Obstetricians & Gynecologists, the American Academy of Pediatrics, and the American College of Physicians for susceptible women during their pregnancy. These vaccines protect against tetanus, influenza, hepatitis B, and meningococcal disease.

Inactivated vaccines licensed by the FDA include anthrax vaccine and a host of other vaccines that protect children and adults against diseases such as tetanus, hepatitis A, and diphtheria. The FDA does not require, as a condition of licensure, reproductive toxicity studies to determine the effect of these sterile, inactivated vaccines on pregnancy, fertility, or other reproductive outcomes. As a result, the package insert for anthrax vaccine, as well as these other FDA-licensed vaccines, note that animal reproductive studies have not been conducted for the vaccine and that the vaccine has not been evaluated for its potential to impair fertility. This results from the virtual absence of reproductive problems caused by vaccines throughout the 20th century.

Even though the FDA-licensed anthrax vaccine is a bacterial vaccine that contains only non-living components of anthrax organisms and is non-infectious, prudent medical practice is to defer immunizations during pregnancy unless clearly needed. Pregnant women should not receive anthrax vaccine unless anthrax exposure occurs or is imminent. Service Members who believe that they may be pregnant are instructed to inform their health-care provider. Anthrax immunizations will be deferred until the pregnancy is over. Since the vaccine contains no infectious substance, there is no reason for a woman to delay becoming pregnant, nor to stop breast-feeding after receiving a dose of anthrax vaccine. These guidelines are consistent with those of the ACIP, the American College of Obstetricians & Gynecologists, the American Academy of Pediatrics, and the American College of Physicians.

ANTHRAX VACCINE PRODUCTION ISSUES

The State of Michigan opened its first laboratory to manufacture vaccines and antibodies in Lansing in 1925, 75 years ago, receiving license #99 to manufacture biological medications. On 7 July 1998, the State of Michigan approved the sale of the United States' only licensed manufacturer of anthrax vaccine to a for-profit company. The organization known as the Michigan Biologic Products Institute (MBPI) was sold effective 5 September 1998 to become BioPort Corporation. The facility's license is now listed as license #1260, with the sale of MBPI to BioPort Corporation.

BioPort, whose headquarters remain in Lansing, Michigan, is owned by multiple shareholders. The two main companies that make up BioPort are Intervac, headed by William Crowe and Faud El-Hibri, and Michigan Biologic Products Inc., which is made up of seven managers from the era when the State of Michigan owned the plant, headed by Robert Myers. The former state employees were specifically permitted by the Michigan State Legislature to bid on the sale. The legislators hoped that retaining local management as investors would help keep the plant and its 174 jobs in Michigan. Admiral William Crowe, Jr., is a former chairman of the Joint Chiefs of Staff and the U.S. ambassador to Britain until 1997. Fuad El-Hibri, a German citizen of Lebanese descent, transformed a British government plant for vaccine production into a successful private venture.

As Admiral Crowe testified to the U.S. Congress in October 1999, the government's decision to vaccinate the Armed Forces was made after several years of internal analysis that culminated in a December 1997 decision. These events occurred well before the State of Michigan chose to sell its vaccine-production facilities to BioPort Corporation.

Over the years, the State of Michigan appropriated money to upgrade and expand its existing facility in a staged fashion, as improvements in current Good Manufacturing Practices (cGMPs) were adopted by the U.S. pharmaceutical industry. In January 1993, the anthrax vaccine manufacturing facility at BioPort was inspected by FDA as part of a routine program. To improve its operations, a renovation to the Lansing facility was approved by the State of Michigan in July 1993.

The manufacturer closed the anthrax vaccine production line in January 1998 for planned renovation. Although the decision to close the facility for planned renovation was part of the manufacturer’s facility improvement strategy, it was, in part, also based on a 1996 DoD assessment that concluded that the facility was inadequate to meet future production requirements. This renovation project cost $3.7 million and included upgrades of the anthrax vaccine manufacturing space along with the addition of a negative air pressure sink, a reach-in environmental chamber, and a state-of-the-art closed inoculation system.

In 1994, after the renovation schedule had been approved by Michigan authorities, the FDA conducted a rigorous inspection of Michigan's plasma-derivatives operation. Then, in 1995, the FDA issued a warning letter to Michigan concerning plasma operations and rabies vaccine manufacturing.

After a November 1996 inspection, findings showed that corrections to the previous areas had not been completed. The FDA issued a "Notice of Intent to Revoke" (NOIR) letter in March 1997, threatening to begin a multi-step process to revoke Michigan's license to manufacture vaccines.

The renovations to the physical plant (based on plans initiated in 1996, with construction beginning in early 1998) were completed in January 1999. FDA conducted a preliminary on-site inspection of the new facility in November 1999. The week-long visit ended with a report of 30 findings for the manufacturer to resolve before the new facility can be licensed by the FDA. No lot of vaccine will be released from the new facility until the FDA independently validates it.

As an additional quality check, the Secretary of Defense ordered DoD to establish a process for supplemental testing of stockpiled vaccine by the manufacturer to assure its sterility, safety, potency and purity. The supplemental testing program reaffirms FDA standards, to assure Service Members and the public that the vaccine stockpile is safe and potent. Supplemental testing repeats tests required by the FDA for lot release. An independent contractor (Mitretek Systems, Inc., McLean, Virginia) oversees supplemental testing by the manufacturer. Supplemental tests performed by the manufacturer include:

· General Safety: Follows Title 21 Code of Federal Regulations (CFR) section 610.11 guidelines. General safety is determined in the following manner: two animals each of two species (mouse and guinea pig) are given doses of the vaccine and observed for 7 days for adverse effects; and the passing result is that each animal survives the test period, gains weight, and does not show any adverse reaction. Twenty vials per lot are tested for general safety.

· Potency: Follows 21 CFR 610.10 guidelines. Potency is determined in the following manner: three serial dilutions of vaccine are used plus one control group (no vaccine) to vaccinate guinea pigs; 14 days after vaccination, all guinea pigs are injected with known amounts of virulent anthrax; average time to death is calculated for each group; and the passing result is that the test vaccine is no less potent than the reference vaccine. Two vials per lot are tested for potency.

· Sterility: Follows 21 CFR 610.12 guidelines. Sterility testing is performed on the final product to detect the presence of microorganisms. Twenty vials per lot are tested for sterility, using two separate culture media: fluid thioglycollate medium and soybean-casein digest medium.

· Purity: No formal 21 CFR requirements for i...

Anthrax Info - DoD.doc

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