Mr. Chairman and Members of the Committee, I am
Dr. Kathryn Zoon, Director, Center for Biologics Evaluation and Research (CBER), Food
and Drug Administration (FDA or Agency). I appreciate this opportunity to discuss with you
vaccine licensing generally, and specifically, the safety and efficacy of the anthrax
vaccine, currently manufactured by BioPort Corporation (the predecessor manufacturer was
known as Michigan Biologics Product Institute (MBPI) and prior to that, Michigan
Department of Public Health (MDPH)). Let me begin with a brief overview of the process for
a vaccine to be licensed.
CBER is responsible for evaluating the safety, purity, efficacy and potency of the
products we regulate. These products include biological products such as vaccines,
products derived from human blood, and many products produced by recent advances in
biotechnology. The scope of regulatory responsibility extends to both licensed or approved
products and unlicensed products under investigation.
From a regulatory perspective, there are four stages in vaccine development:
- the pre-Investigational New Drug (IND) stage (before the product is used in people);
- the IND stage (where human use occurs under limited study conditions);
- the license application stage for vaccines (where FDA reviews the results of the
clinical studies and the manufacturing process); and,
- the post-licensure stage (following approval of the product for marketing).
Before a new vaccine can be studied in people, a sponsor must submit an IND application
to FDA. In the application, the sponsor:
- describes the composition, source, and method of manufacture of the product and the
methods used in testing its safety, purity, and potency;
- provides a summary of all laboratory and pre-clinical animal testing performed; and,
- provides a description of the proposed clinical study and the names and qualifications
of each clinical investigator.
Once the sponsor submits the IND, FDA has 30 days to review the application to
determine whether or not the study may proceed. FDA may prohibit a sponsor from conducting
a study for a number of reasons, including when the study volunteers will be exposed to
unwarranted risks, by putting the IND on "clinical hold".
The IND process generally is described as having three phases prior to product
approval; however, the distinctions between these phases are not absolute. Phase 1 trials
are focused on basic safety and, for vaccines, Phase 1 trials also usually evaluate the
immune response elicited by the vaccine. These trials are usually small generally
between 20 and 100 subjects and they frequently are done in healthy "normal
volunteers" and may last just several months. Phase 2 trials often include several
hundred subjects, are often randomized, and last anywhere from several months to several
years. These trials usually include individuals who are at high risk for the infectious
disease of interest. Unless severe reactions or a lack of effectiveness surface during the
first two phases, the sponsor may decide to perform one or more Phase 3 studies that can
include up to several thousands of people. These Phase 3 trials are intended to provide
the definitive measure of effectiveness, as well as continue the evaluation of the
products safety. The size of the efficacy trial will be affected by the expected
incidence of disease that the vaccine is intended to prevent. If at the end of Phase 3
trials the manufacturer believes there are adequate data to show the vaccine is safe and
effective for its intended use, the manufacturer submits a license application to the
Licensing a new vaccine is only one stage of FDAs oversight of vaccine safety.
Following issuance of the license, there is continued post-marketing surveillance of the
product by monitoring adverse events, e.g., the Vaccine Adverse Events Reporting System
(VAERS), and of the manufacturers production activities, including compliance with
good manufacturing practices. Manufacturers generally submit samples of each licensed
vaccine lot and the results If their own tests for potency, safety, and sterility to the
Agency before release of each lot of the licensed product, because of the complex
manufacturing processes for most biological products. In addition, licensed establishments
are inspected regularly by FDA.
Let me now turn to anthrax.
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 (inhalation). Skin
contact with live infected animals, or with the hide, hair or bones of an infected animal
may lead to infection of a persons skin, known as cutaneous anthrax infection. This
is the most common manifestation of anthrax in humans, accounting for more than 95 percent
of cases. Untreated cutaneous anthrax infection is associated with a death rate estimated
to be approximately 20 percent. Eating undercooked or raw, infected meat can cause
gastrointestinal anthrax infection. Breathing in airborne spores 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.
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.
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. The only known effective
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. In the past decade, there have
been no confirmed reports of human anthrax 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
HISTORY OF THE ANTHRAX VACCINE
Philip S. Brachman et al. conducted clinical trials on the anthrax vaccine during the
1950s . This controlled field study involved workers in four mills in the Northeastern
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, in which 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 who did not receive vaccine
or placebo 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
anthrax 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), 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 MDPH.
The data submitted to the Division of Biologic Standards described CDCs
experience with approximately 16,000 doses of anthrax. This vaccine was administered to
approximately 7,000 study participants. 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
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 month and 18 months,
thereafter, with yearly boosters.
THE PANEL REVIEW
The Public Health Service Act, under which biologics 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 for evaluating a safety study today.
Since licensure in November 1970, livestock workers, veterinarians, lab workers and
researchers who are at risk for infection have used the anthrax vaccine. 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 April 1999, we understand that approximately 1,200,000 doses
were distributed. We understand additional doses have been distributed since then,
however, we do not have final numbers.
It is not possible to give a precise number of persons who received the vaccine prior
to use in Operation Desert Shield and Operation Desert Storm. We estimate that
approximately 7,000 subjects 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 or that some doses were used for annual boosters.
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 had received the recommended six doses
of the vaccine.
VACCINE ADVERSE EVENT REPORTING - ANTHRAX
With regard to safety data, FDA and CDC jointly operate 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 patients 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
Since the beginning of VAERS operations in 1990, through October 1, 1999, 425
reports of adverse events associated with use of the anthrax vaccine have been reported to
VAERS. Of those, FDA considers 29 serious events. These reports are for diverse
conditions, with no clear patterns emerging at this time. Some of these events are
described below. The remaining 396 reports describe a variety of symptoms and conditions,
including injection site edema (swelling with fluid in tissue), injection site
hypersensitivity, rash, headache and fever.
The 29 serious events were reported to have occurred or been diagnosed at times ranging
from 45 minutes to four and one half months after vaccination. Some individuals
experienced adverse events following the first dose; others received up to 5 doses before
event onset. Most of these individuals reporting adverse events during the current anthrax
vaccination program have recovered. Seven patients were hospitalized for severe 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. Two individuals experienced Guillain-Barré syndrome. Three weeks after
receiving the vaccine, another individual was diagnosed with bipolar disorder and, at last
follow-up, has not recovered. One individual experienced signs and symptoms of transverse
myelitis. One individual experienced onset of multi-focal inflammatory demyelinating
disease and has since clinically recovered. Another individual experienced onset of lupus
and, at last follow-up, has not recovered.
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. 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 identifying
potential problems, the reports on anthrax vaccine received thus far do not raise any
specific concerns about the safety of the vaccine. As more people receive the vaccine, the
numbers of adverse events reported will increase. FDA continues to view the anthrax
vaccine as safe and effective for individuals at risk of exposure to anthrax.
As mentioned above, 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. FDA reviews the lot release
protocols showing results of applicable tests and lot samples are submitted for possible
testing by FDA. The manufacturer may not distribute a lot of the product until
FDAs 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.
MEMORANDUM OF UNDERSTANDING (MOU) WITH THE DEPARTMENT OF DEFENSE (DoD)
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 application
regulations concerning INDs and IRBs.
The MOU addressed 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 Act 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.
FDA's CONSULTATION WITH DoD
REGARDING THE ANTHRAX VACCINE IMMUNIZATION PROGRAM
FDA has not had an official role in the development or operation of the Department of
Defenses Anthrax Vaccine Immunization Program, 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 eighteen months. Subsequently, FDA learned that the DoD plan had been
In July 1998, DOD requested that CDC, in conjunction with the Health Resources and
Services Administration, National Vaccine Injury Compensation Program (VICP), 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 the VICP in the
fall of 1998 as the Anthrax Vaccine Expert Committee (AVEC). AVEC, coordinated by VICP,
has met eight times since 1998. These experts have been reviewing all VAERS reports for
the anthrax vaccine. Representatives of 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.
Upon learning that some DoD personnel may be receiving their anthrax vaccine doses
significantly later than the FDA approved schedule, both Dr. Jane E. Henney, Commissioner
of the Food and Drug Administration, and I, recently sent letters to DoD. In the letters
we asked DoD to expeditiously investigate this matter as we are unaware of any data
demonstrating that any deviation from the approved intervals of doses found in the
approved labeling will provide protection from anthrax infection. We will continue to
monitor this issue.
Mr. Chairman, we believe the anthrax vaccine is a safe and effective vaccine for the
prevention of anthrax disease an often-fatal disease when used according to
the FDA approved label. Our confidence in this vaccine, like all vaccines, is based upon
four components: first - the review of manufacturing and 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 and analysis of adverse event reports. So far, the data gathered from
VAERS reports on anthrax vaccine do not signal concerns about the safety of the vaccine.
The Agency will continue to closely monitor and investigate reports of serious adverse
events received on all vaccines, including anthrax, to assure that only safe products are
on the market.
I appreciate the Committees interest in this very important topic and would be
happy to answer any questions.