Introduction

Mr. Chairman and Members of the Committee, I am Dr. Kathryn Zoon, Director, Center for Biologics Evaluation and Research, Food and Drug Administration (FDA or Agency). I appreciate the opportunity to discuss the safety and efficacy of the anthrax vaccine, currently manufactured by BioPort, Corporation. As the Committee requested, I will explain FDA's Memorandum of Understanding (MOU) with the Department of Defense (DOD). I will describe events at the time of approval of the vaccine and our experience since then. Lastly, I will describe the compliance history of BioPort Corporation. Let me start by briefly explaining the MOU with DOD.

Memorandum of Understanding with Department of Defense

On May 21, 1987, FDA entered into the current MOU with DOD. This replaced the previous MOU signed in 1974. The 1987 agreement established procedures to be followed by DOD and FDA regarding the investigational use of drugs, biologics and medical devices. The MOU affirms that clinical testing of new drugs will be done in accordance with applicable regulations concerning Investigational New Drug Applications (INDs) and Institutional Review Boards (IRBs). The MOU addresses the possibility of a need for expedited review of an IND by FDA to meet DOD requirements concerning National defense considerations. Under the MOU, DOD is responsible for classifying medical research and development as it relates to information that may be made public under Freedom of Information Regulations. It should be stressed that this agreement, however, does not allow DOD to perform research on humans without submitting an IND and it requires DOD to comply with all FDA regulations.

Background

Anthrax is a highly infectious disease caused by spores of a bacterium known as Bacillus anthracis. These spores resist destruction and may be present in the soil for decades, occasionally infecting grazing animals that ingest the spores. Goats, sheep and cattle are examples of animals that may become infected. Human infection may occur by three routes of exposure to anthrax spores: cutaneous, gastrointestinal, and pulmonary. Skin contact with live infected animals, or with the hide, hair or bones of an infected animal may lead to infection of a person's skin, known as cutaneous anthrax infection. This is the most common manifestation of anthrax in humans, accounting for more than 95 percent of cases. Eating undercooked or raw infected meat can cause gastrointestinal anthrax infection. Breathing in airborne spores may lead to pulmonary anthrax, also known as inhalation anthrax.

Experience has shown that inhalation anthrax has a very high mortality rate, with estimates ranging from 80 percent to 90 percent or higher. Untreated cutaneous anthrax infection is associated with a death rate estimated to be approximately 20 percent.

Inhalation anthrax infection has two phases. During the first phase, which occurs within one to five days after inhalation of the spores, the patient has influenza-like symptoms, such as a cough, malaise, fatigue and mild fever. Several days later these symptoms may subside, but are rapidly followed by the second, more severe stage of disease. During the second phase, the patient experiences sudden onset of severe respiratory distress, and sometimes chest pain accompanied by fever. Chest x-rays may show fluid in the lung. Within a day, septic shock and death will likely occur.

The only known effective prevention against anthrax is the anthrax vaccine. Treatment of cutaneous anthrax infection involves administration of antibiotics. In the case of pulmonary anthrax infection, therapy has been of limited benefit, except when given immediately after exposure.

Prior to use of the anthrax vaccine, cases of human anthrax infection in the United States were much more prevalent. According to data from the Centers for Disease Control and Prevention, (CDC) there were approximately 130 reported cases of anthrax infection per year at the start of this century. In the past decade, there have been years with no reported cases of human anthrax infection in the United States. It is difficult to assess exactly how much of this dramatic reduction is due to the vaccine, but immunization with the anthrax vaccine of people at risk, along with vaccination of animals against anthrax, have likely contributed to this favorable decline. Elsewhere in the world, human anthrax cases continue to be reported, especially in countries with predominately agricultural economies.

History of the Anthrax Vaccine

Clinical trials on the anthrax vaccine were conducted by Philip S. Brachman et al. during the 1950's¹. This controlled field study involved workers in four mills in the northeastern United States that processed imported animal hides. This selected population was at risk because the mill workers routinely handled anthrax-infected animal materials. Prior to vaccination, the yearly average number of human anthrax infection was 1.2 cases per 100 employees in these mills.

For this trial, employees who had not previously contracted anthrax were selected and divided into two groups. The groups were balanced with regard to their age, length of employment, department at the mill, and the particular job they performed. The trial was a single-blinded study, where the participants were not told whether they received the vaccine or placebo. Individuals who did not participate in the controlled study [because they were ineligible (i.e., had a history of prior anthrax) or chose not to receive the injections] were also monitored for anthrax. These individuals were referred to as the observational group.

During the trial, 26 cases of anthrax infection were reported at the mills - five inhalation and 21 cutaneous. Of the five inhalation cases, two individuals had received the placebo, while three individuals were in the observational group. Four of the five people who developed inhalation anthrax died. No cases of inhalation anthrax occurred in vaccine recipients. Of the 21 cutaneous cases, 15 individuals had received the placebo, three individuals were in the observational group, two individuals were partially immunized and one individual was fully immunized. Based upon a comparison between the populations completely vaccinated versus the populations receiving placebo, the authors calculated a vaccine efficacy level of 92.5 percent.

On April 14, 1966, CDC submitted an IND for the anthrax vaccine to the Division of Biologics Standards, which was then part of the National Institutes of Health (NIH) and later transferred to FDA. The method of preparing this vaccine was similar, but not identical, to the vaccine used in the Brachman et al. study. The vaccines in both studies were based on the immunity induced by the protective antigen (PA). Persons receiving the vaccine made by the two different methods demonstrated similar peak immune responses (antibody concentration) following the initial three doses.

Textile employees and laboratory workers were immunized under this IND. A number of lots of investigational vaccine used by CDC under this IND were manufactured by the Michigan Department of Public Health (MDPH).

The data submitted to the Division of Biologic Standards described the CDC's experience with approximately 16,000 doses of anthrax vaccine from four lots manufactured at MDPH. These MDPH lots were administered to approximately 7,000 study participants.

For the four MDPH lots used for vaccinations, reported local reactions at the immunization site ranged between 3 percent to 36 percent of the initial series of doses, and 3 percent to 33 percent of the booster doses, depending on the lot. Reported mild reactions were 3 percent to 20 percent of all doses. Reported moderate local reactions were 1 percent to 3 percent of doses. Severe reactions were reported for less than 1 percent of doses. Systemic reactions were reported in four cases during the five-year reporting period. These reactions included fever, chills, nausea and general body aches, and were reported to have been transient.

The Division of Biologics Standards determined that the data submitted by CDC supported licensure of the vaccine. On November 10, 1970, the Division of Biologics Standards issued a product license to MDPH to manufacture anthrax vaccine.

Approved labeling for the anthrax vaccine states that immunization with this product is recommended for individuals who may come in contact with animal products that may be contaminated with Bacillus anthracis spores; and for individuals engaged in diagnostic or investigational activities which may bring them in contact with Bacillus anthracis spores. It is also recommended for persons at high risk, such as veterinarians and others handling potentially infected animals.

The approved labeling also states that anthrax vaccine is to be administered subcutaneously (injected under the skin). After the initial dose of 0.5ml, further doses of 0.5ml are administered at two weeks, four weeks, six months, 12 months and 18 months, with yearly boosters thereafter.

The Panel Review

The Public Health Service Act, under which biologicals such as vaccines were licensed, required evidence of safety, purity and potency. After the Division of Biologic Standards was transferred from NIH to FDA, expert panels were assigned to review information on biological products, including vaccines that had been on the market prior to the transfer. The review was initiated in order to verify whether existing data supported the safety and efficacy of marketed biological products.

Biological products were divided into one of six categories. FDA assigned responsibility for initial review and recommendation for all products in these six categories to separate independent advisory panels of outside scientific experts, collectively known as the Advisory Review Panel. The Advisory Review Panel also was charged with advising FDA, in the form of a report, on classification of these products into one of the following categories: Category I - safe, effective and not misbranded; Category II - unsafe, ineffective or misbranded; Category III - insufficient information, further testing required.

Based upon their review of available data, the Advisory Review Panel recommended that the anthrax vaccine manufactured by MDPH be classified as a Category I product and that appropriate licenses be continued based upon substantial evidence of safety and effectiveness of this product. The safety data from the CDC trials and the efficacy data from the Brachman et al. trials were the basis for these findings. These findings were published in the Federal Register on December 13, 1985.

Today, it would be difficult to repeat the efficacy studies. This is because there are no evident populations in the United States where prophylactic vaccine protection against natural exposure to anthrax could be evaluated in a clinical field trial, such as was done in the Brachman et al. study. Specifically, the incidence of naturally occurring anthrax in humans is low and sporadic in occurrence, making identification of a trial target population difficult. Likewise, it would be unethical to perform challenge/protection studies in humans. In addition, human immunogenicity and safety data would be required. The safety database obtained by CDC under the IND would be considered a reasonable pre-licensure database to evaluate a safety study today.

Post-Marketing Experience

Since licensure in November 1970, the anthrax vaccine has been used by livestock workers, veterinarians, lab workers and researchers who are at risk for infection. The manufacturer provided FDA the following information regarding distribution. From 1974 to 1989, approximately 68,000 doses were distributed. In 1990, approximately 268,000 doses were distributed. Between 1991 and the present, we understand that approximately 1,200,000 doses were distributed.

It is not possible to give a precise number of persons who received the vaccine prior to use in Operation Desert Storm and Operation Desert Shield. We estimate that approximately 7,000 patients received approximately 16,000 doses of the vaccine during clinical trials conducted by the CDC. In addition, between 1974 and 1989, our files show approximately 68,000 doses were distributed. This is sufficient to vaccinate about 11,000 people with the full six-dose regimen of the currently approved anthrax vaccine. It is possible that some doses distributed were not used, or that some individuals did not receive the full course of the vaccine. Thus, it is not possible to accurately report the precise number of people vaccinated between 1974 and 1989.

According to the CDC, from 1962 to 1974, 27 cases of anthrax occurred in the "at-risk" populations in the United States. Of those, 24 cases occurred in unvaccinated individuals, one case after the person had been partially immunized with one dose of the vaccine and two cases after individuals had been partially immunized with two doses of the vaccine. No documented cases of anthrax were reported for individuals who have received the recommended six doses of the vaccine.

Vaccine Adverse Event Reporting - Anthrax

With regard to safety data, FDA and CDC jointly operate a system called the Vaccine Adverse Event Reporting System (VAERS). FDA uses this system to track adverse events possibly associated with licensed vaccines. Reporting of adverse events associated with the use of anthrax vaccine is voluntary for individual healthcare providers. The vaccine manufacturer, however, must report to FDA all reports of adverse events of which they are aware.

The report of an adverse event to VAERS is not documentation that a vaccine caused the event, only that the event occurred soon after the vaccine was administered. Doctors and other healthcare providers are encouraged to report serious or unexpected adverse events following vaccination, whether or not they believe that the vaccination was the cause of the adverse event. Since it is difficult to distinguish a coincidental event from one truly caused by a vaccine, the VAERS database contains events of both types.

It should be emphasized that adverse event reports can be made by a health care professional, a patient or anybody else. If a patient's physician does not file a VAERS report, the patient can do so. FDA encourages individuals to report to VAERS any clinically significant adverse event occurring after the administration of any vaccine licensed in the United States. Reports to VAERS may be made in writing or by calling a toll-free number, 1-800-822-7967. Reporting instructions are available on the Internet at www.fda.gov/cber/vaers.html.

From the time the VAERS system started operating in 1990 until April 1, 1999, there have been 101 reports of adverse events associated with use of the anthrax vaccine reported to the VAERS system. Of those, 87 were non-serious events and 14 were considered serious events. Non-serious events include the following symptoms: injection site edema (swelling with fluid in tissue), injection site hypersensitivity, rash, headache and fever.

Of the 11 serious reactions reported during the current anthrax vaccination program, most individuals have recovered. Three patients were hospitalized for injection site reactions. One individual experienced a more widespread allergic reaction. One individual was hospitalized with a confirmed case of aseptic meningitis nine days after vaccination. Another individual experienced Gullain-Barré syndrome within 24 hours of the third dose. He was unable to walk for nine days. He gradually recovered and had symptom resolution within five months of the vaccination. Three weeks after receiving the vaccine, another individual experienced bipolar disorder and has not recovered.

It should be emphasized, once again, that it is not always possible to attribute a cause and effect relationship between a reported event and a vaccination. With the exception of injection site reactions, all of the adverse events noted above do occur in the absence of immunization.

While the data gathered from the VAERS system can serve as a useful tool in spotting potential problems, the data gathered from the VAERS reports on anthrax vaccine, thus far, do not signal concerns about the safety of the vaccine. As more people receive the vaccine, the numbers of adverse events reported will increase.

Lot Release

Because of the complex manufacturing processes for most biological products, each product lot undergoes thorough testing for purity, potency, identity, and sterility. Manufacturers may release lots only after this testing is documented. FDA may require lot samples and protocols showing results of applicable tests to be submitted for review and possible testing by FDA. In this case, the manufacturer may not distribute a lot of the product until FDA's Center for Biologics Evaluation and Research releases it. The lot release program is part of our multi-part strategy that helps assure product safety by providing a quality control check on product specifications. The anthrax vaccine is subject to lot release.

Michigan Biologics Product Institute / BioPort Corporation

The BioPort Corporation facility in Lansing, Michigan is the only manufacturer licensed by FDA to manufacture anthrax vaccine. Originally, the facility was operated by the Michigan Department of Public Health. In 1996, the facility became known as the Michigan Biologics Products Institute (MBPI), an entity controlled by the State Government of Michigan. Currently, the facility is known as BioPort Corporation based upon the September 1998 transfer of ownership from MPBI to BioPort Corporation.

FDA has inspected this facility on many occasions during the past decade, identifying a number of deficiencies requiring correction. In particular, FDA conducted an inspection of MBPI in November 1996. During that inspection, FDA investigators documented numerous significant deviations from the Federal Food, Drug, and Cosmetic Act, FDA's regulations and the standards in MBPI's license. Based upon the documented deviations, FDA issued a Notice of Intent to Revoke Letter (NOIR) to MBPI in March 1997. The NOIR letter did not mandate the closure of the facility or lead to seizure of finished product. The letter, however, did state that if MBPI's corrective actions proved to be inadequate, they would run the risk of having their license revoked.

MBPI responded to the NOIR with a "Strategic Plan for Compliance" presented to FDA in April 1997. This plan called for the periodic submission of data to FDA that would serve as evidence of MBPI's progress towards achieving compliance with FDA's regulations. Under the plan, FDA would review this data and then monitor MBPI's progress through follow-up inspections. In February 1998, FDA conducted a follow-up inspection of the MBPI facility to evaluate MBPI's compliance with its strategic plan.

The February 1998 inspection disclosed significant deviations from FDA's regulations. These deviations included, but were not limited to, the manufacture of the anthrax vaccine. In addition, the inspection resulted in a request by FDA that MBPI quarantine 11 lots of anthrax vaccine held in storage, pending review of additional information to be submitted by BioPort regarding the lack of investigations into possible problems with potency, sterility and particulate matter. These lots are still in quarantine, and will remain in quarantine until the company submits required information to the Agency. FDA noted that MBPI had made progress in achieving its compliance goals, but additional work remains in order to correct the deviations related to the manufacture of the anthrax vaccine.

Pursuant to its purchase of the MBPI facility in September 1998, BioPort agreed to abide by the strategic plan and other commitments for corrective actions made by the management of MBPI.

It should be noted that MBPI halted production of anthrax vaccine sublots in January 1998 to begin a comprehensive renovation of the anthrax production facilities. No anthrax vaccine has been produced since BioPort became owner of the facility.

In its most recent inspection of BioPort Corporation in October 1998, FDA found continuing improvement. FDA believes that the products not quarantined by BioPort are safe and effective for the labeled indications. FDA found that the firm had made progress toward meeting objectives under its strategic plan in bringing the facility into full compliance. Based on BioPort's progress to date, FDA is hopeful that the company will continue to demonstrate improvement. Further FDA inspections should verify BioPort's compliance with regulations for the manufacture of all products, including anthrax vaccine. We will continue to work closely with BioPort to ensure that the goals outlined in their strategic plan are met.

Conclusion

Mr. Chairman, we believe anthrax vaccine is a safe and effective vaccine for the prevention of anthrax disease - an often-fatal disease. Our confidence in this vaccine, like all vaccines, is based upon four components: first - the clinical trials and subsequent clinical laboratory experience with the vaccine; second - ongoing inspections of the manufacturing facility; third - our lot release requirements; and fourth - our ongoing collection of adverse event reports. We will continue our efforts in all four of these areas, with the anthrax vaccine and all vaccines, to assure that only safe products are on the market.

I appreciate the Subcommittee's interest in this very important topic and would be happy to answer any questions.