STATEMENT BY

MARK A. ELENGOLD

DEPUTY DIRECTOR, OPERATIONS

CENTER FOR BIOLOGICS EVALUATION AND RESEARCH

FOOD AND DRUG ADMINISTRATION

BEFORE THE

COMMITTEE ON GOVERNMENT REFORM

UNITED STATES HOUSE OF REPRESENTATIVES

October 3, 2000

INTRODUCTION

Mr. Chairman and Members of the Committee, I am Mark A. Elengold, Deputy Director, Operations, Center for Biologics Evaluation and Research (CBER), Food and Drug Administration (FDA or the Agency). I appreciate the Committee's interest in the Anthrax Vaccine Adsorbed and the opportunity for FDA to update the Committee of the regulatory status of BioPort Corporation (BioPort), and the Agency's experience with adverse event reports for the anthrax vaccine. Let me assure you that we will continue to help ensure that only safe and effective products are marketed and that these products meet high standards of quality.

ANTHRAX DISEASE / ANTHRAX VACCINE

As previously stated before the Committee, anthrax is an infectious disease caused by spores of a bacterium known as Bacillus anthracis. Human infection may occur by three routes of exposure to anthrax spores: cutaneous, gastrointestinal, and pulmonary (inhalation). Breathing in airborne spores of anthrax bacterium may lead to 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. Prior to the use of anthrax vaccine, cases of human anthrax infection in the United States (U.S.) were much more prevalent. The only FDA approved medical prevention against anthrax is the anthrax vaccine. 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.

The clinical trials on the anthrax vaccine were conducted by Philip S. Brachman et al., during the 1950's¹ and CDC in the 1960's. The Michigan Department of Public Health (MDPH) (now BioPort) manufactured four lots of the vaccine used in the CDC study. On April 14, 1966, CDC submitted an investigational new drug (IND) application for anthrax vaccine to the Division of Biologics Standards, which was then part of the National Institutes of Health (NIH) and later transferred to FDA (now CBER). 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.

Based upon their review of available data, a 1985 Advisory Review Panel recommended that the anthrax vaccine manufactured by MDPH be classified as a Category I product (safe, effective and not misbranded) and that appropriate licenses be continued based upon substantial evidence of safety and effectiveness of this product. These findings were published in the Federal Register (December 13, 1985, Vol. 50, No. 240 p. 51002-51117).

There are also relevant non-human primate efficacy data. Previously, data had been provided to FDA indicating that anthrax vaccine protects non-human primates against a high challenge of inhalation anthrax with the Ames Strain (which is non-homologous, or dissimilar, to the vaccine strain). More recent data on animal efficacy was published in summary form by Arthur Friedlander, M.D., et al., in the Journal of the American Medical Association on December 8, 1999. This publication noted that non-human primates had a high level of protection against two more non-homologous strains, in addition to the Ames Strain. The Department of Defense (DoD) has committed to submit the new data to FDA under an existing IND.

INSPECTIONS

There is currently only one FDA-licensed facility for the production of the anthrax vaccine. The MDPH originally operated the facility, which then was transferred to the Michigan Biologics Products Institute (MBPI), and finally, in September 1998, the facility was sold to BioPort.

FDA has inspected this facility on many occasions during the past decade, identifying a number of deficiencies requiring correction. In particular, FDA conducted a surveillance inspection of MBPI in November 1996. During that inspection, FDA investigators documented numerous significant deviations from the Food, Drug, and Cosmetic (FD&C) Act, FDA's regulations and current good manufacturing practices (GMPs). Based upon the documented deviations, FDA issued a Notice of Intent to Revoke (NOIR) letter 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, the facility would run the risk of license revocation. MBPI responded to the NOIR with a "Strategic Plan for Compliance" presented to FDA in April 1997.

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.

FDA also noted in the February 1998 inspection 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. During the October 1998 inspection of BioPort, FDA found continuing improvement.

FDA believes that the previously manufactured and CBER released products, not presently 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 GMP compliance. Based on BioPort's progress to date, FDA is hopeful that the company will continue to demonstrate improvement. We will continue to work closely with BioPort to ensure that the goals outlined in their strategic plan are met.

It should be noted that MBPI halted production of anthrax vaccine sublots in January 1998, prior to MBPI sale to BioPort, to begin a comprehensive renovation of the anthrax production facility. Although there has been a resumption of manufacturing in order to produce lots in support of the license application supplement to include the renovated facility, no lots of anthrax vaccine manufactured in the renovated facility have been released.

Due to the rules of confidentiality, FDA cannot generally disclose details of, or even acknowledge the existence of, a pending application or supplement unless that information has already become public. In the case of BioPort, press reports and information made public by BioPort have disclosed various aspects about anthrax vaccine. Because the information has been made public, FDA can disclose that BioPort does have a pending supplement for renovations to their anthrax vaccine manufacturing facility. BioPort may not release product produced in the renovated facilities until this supplement is approved. FDA will generally assess manufacturing renovations by a review of a prior approval supplement and by performing a pre-approval inspection.

In order to examine the manner in which BioPort implemented the renovations to the manufacturing facility, FDA conducted a pre-approval inspection from November 15 through November 23, 1999. It should be noted that the November 1999 pre-approval inspection was more focused in scope and purpose from the February and October 1998 surveillance inspections. At the conclusion of the November inspection, BioPort received a Form FDA 483 with observations and possible deviations in some of the following areas: validation, failure to investigate, manufacturing deviations, deviation reporting, aseptic processing, filling operations, standard operating procedures, stability testing, and environmental monitoring. All observations on the Form FDA 483 must be addressed adequately before FDA will approve this supplement.

LOT RELEASE

Because of the complex manufacturing processes for most biological products, each product lot undergoes thorough testing for purity, potency, identity, and sterility. The anthrax vaccine is subject to lot release. Before a lot of anthrax vaccine can be used, the manufacturer must submit a sample of the vaccine lot and a lot release protocol to the Agency. The lot release documents contain the results of the manufacturer's tests for potency, safety, sterility and any additional assays mandated by their license and a summary of relevant manufacturing details. FDA reviews the manufacturing and testing information provided in the lot release protocol and may elect to perform confirmatory testing on submitted samples. The manufacturer may not distribute a lot of the product until CBER releases it. The lot release program is one component of FDA's multi-part strategy that helps assure products quality.

No lots of anthrax vaccine manufactured in the renovated facility have been released.

VACCINE ADVERSE EVENT REPORTING SYSTEM

Following FDA issuance of an approved license, there is continued post-marketing surveillance of the product by monitoring adverse events. For vaccines, this is accomplished through the Vaccine Adverse Event Reporting System (VAERS), which was initiated in 1990 and is jointly managed by FDA and CDC. VAERS receives reports from vaccine manufacturers, private practitioners, State and local public health clinics, and vaccinees themselves (or their parents or guardians). VAERS accepts all reports of suspected adverse events after administration of any U.S. licensed vaccine to individuals in any age group. Vaccine manufacturers, however, must report to FDA all reports of adverse events of which they are aware.

VAERS is a "passive" surveillance system. This means that it relies on health professionals, patients or guardians to submit reports of adverse reactions following vaccination. (An "active" surveillance system, in contrast, would follow all individuals in a defined population to determine their responses to vaccination.) To encourage reporting of any adverse event suspected of being vaccine-induced, the criteria for reporting to VAERS are non-restrictive. In effect, the system accepts and includes any report submitted, no matter how tenuous the possible connection with vaccination might seem.

Generally, VAERS does not establish causality but is essential to the discovery of potential rare adverse consequences of medical products that may not become evident until many thousands or millions of people have been exposed to them.

VAERS REPORTS FOR THE ANTHRAX VACCINE

FDA receives adverse event reports on the anthrax vaccine through a system similar to other adverse event reporting systems within the Agency. They are filed directly by health professionals as well as by patients or families. Reporting of adverse events associated with the use of anthrax vaccine is voluntary for individual healthcare providers but, as stated above, the vaccine manufacturer must report to FDA all reports of adverse events of which they are aware. It should be emphasized that adverse event reports can be made by a healthcare professional, a patient or anyone. If a patient's physician does not file a VAERS report, the patient can do so. FDA protects the confidentiality of patients reporting adverse events. FDA encourages individuals to report to VAERS any clinically significant adverse event occurring after the administration of any vaccine licensed in the U.S. 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 http://www.fda.gov/cber/vaers/vaers.html.

CBER handles numerous inquiries from individuals concerning the anthrax vaccine. Individuals who believe they have experienced an adverse reaction are encouraged to report and provide information on filing a VAERS report. Forms are mailed and faxed to individuals upon request and individuals also are referred to FDA's website.

Since the beginning of VAERS operations in 1990, through September 15, 2000, 1561 reports of adverse events associated with use of the anthrax vaccine have been reported to VAERS. FDA understands, based upon information from BioPort, that from 1990 to present, approximately 2,000,000 doses of the vaccine have been distributed.

Of those reports, 76 are considered serious events, which are events considered either fatal, life threatening, or resulting in hospitalization or permanent disability. These reports are for diverse conditions, such as hospitalization for severe injection-site reaction, Guillain-Barr' syndrome, widespread allergic reaction, aseptic meningitis and multi-focal inflammatory demyelinating disease. There are no clear patterns emerging at this time. The remaining reports describe a variety of symptoms, including injection site hypersensitivity, injection site edema (swelling with fluid in tissue), injection site pain, headache, joint pain and pruritus (itching).

None of these events, except for the injection site reactions, can be attributed to the vaccine with a high level of confidence, nor can contribution of the vaccine to the event reported be entirely ruled out. With the exception of injection site reactions, all of the adverse events noted above occur in the absence of immunization.

While the data gathered from the VAERS system can serve as a useful tool in identifying potential problems, the reports on anthrax vaccine received thus far do not raise any specific concerns about the safety of the vaccine. With all vaccines, as the number of people that receive the vaccine increases, so will the number of adverse events reported to FDA. Thus, our knowledge of the vaccine will grow accordingly. FDA continues to view the anthrax vaccine as safe and effective for individuals at high risk of exposure to anthrax, when used in accordance with the approved labeling.

THE ANTHRAX VACCINE IMMUNIZATION PROGRAM OF DoD

FDA did not have an official role in the development or operation of the DoD's Anthrax Vaccine Immunization Program (AVIP), including the AVIP tracking system or the program's adverse event reporting system. In March 1997, DoD briefed FDA about their draft plan for the possible use of the anthrax vaccine to inoculate U.S. military personnel according to the FDA-approved labeling for six doses administered on a specified schedule over 18 months. Subsequently, FDA learned that DoD had formally adopted this plan.

In July 1998, DoD requested that the Department of Health and Human Services (DHHS) organize and coordinate a program to evaluate VAERS reports for the anthrax vaccine. In response to the request by DoD, a group of non-government medical experts was convened by DHHS in the fall of 1998 as the Anthrax Vaccine Expert Committee (AVEC). AVEC has met approximately every three to six weeks since fall of 1998. These experts have been reviewing all VAERS reports for the anthrax vaccine. Representatives of National Vaccine Injury Compensation Program (VICP), FDA, CDC and DoD have attended meetings, and FDA has provided information to assist the committee in its deliberations. AVEC is unique in that it provides an independent civilian expert assessment of adverse events reported for the anthrax vaccine.

CONCLUSION

We appreciate the Committee's interest in the Anthrax Vaccine, Adsorbed and BioPort. FDA will continue to work with BioPort, as we would with any manufacturer, in an appropriate manner to resolve all situations involving pending submissions and inspectional issues. By manufacturing products in a facility that is operating in a full state of GMP compliance, FDA can help assure that any product that is released by the company is safe and effective. Additionally, we will continue to monitor adverse event reports that are submitted through VAERS. FDA continues to believe that the vaccine is safe and effective protection for those individuals at high risk for exposure to Bacillus anthracis when used in accordance with the label.

¹Philip S. Brachman, M.D., Herman Gold, M.D., Stanley A. Plotkin, M.D., F. Robert Fekety, M.D., Milton Werrin, D.V.M., F.A.P.H.A., and Norman Ingraham, M.D., F.A.P.H.A., Field Evaluation of a Human Anthrax Vaccine, AJPH Vol. 52, 632-645, 1962.