Medical Readiness: Safety and Efficacy of the Anthrax Vaccine (Testimony,
04/29/99, GAO/T-NSIAD-99-148).

Pursuant to a congressional request, GAO discussed the results of its
ongoing examination of the safety and efficacy of the anthrax vaccine,
focusing on: (1) the short- and long-term safety of the vaccine; (2) the
efficacy of the vaccine; and (3) problems the Food and Drug
Administration (FDA) found in the vaccine production facility in
Michigan that could compromise the safety, efficacy, and quality of the
vaccine.

GAO noted that: (1) the anthrax vaccine being given to U.S. military
personnel was licensed in 1970; (2) before the vaccine was licensed, the
vaccine and the manufacturing process were changed, creating a similar
vaccine, produced by the Michigan Department of Public Health (MDPH),
which was the one eventually licensed; (3) the safety study conducted
before licensing used both the original vaccine and MDPH vaccine; (4)
knowledge to date about the safety of the vaccine includes the results
of the original study and a 1998 Department of Defense (DOD) study of
500 vaccine recipients; (5) while these studies identified varying rates
of adverse reactions, they did not question the safety of the vaccine;
(6) the long-term safety of the vaccine has not yet been studied; (7)
prior to the time of the licensing, no human efficacy testing of the
MDPH vaccine was performed; (8) however, a study was done on the
efficacy of the original vaccine; (9) this study concluded that the
vaccine provided protection to humans against anthrax penetrating the
skin; (10) in the 1980s, DOD began testing the efficacy of the licensed
vaccine on animals, focusing on its protection against inhalation
anthrax; (11) DOD recognizes that correlating the results of animal
studies to humans is necessary and told GAO that it is planning research
in this area; (12) careful control of the manufacturing process is
essential to ensure the quality of the product; (13) FDA inspections of
the facility where the licensed vaccine was manufactured uncovered
numerous problems; (14) the facility received warning letters from FDA,
including one in March 1997, stating its intent to revoke the facility's
license; (15) the facility closed its plant in 1998 and is now being
renovated; (16) FDA requires the manufacturer to meet specifications for
sterility, stability, purity, and potency; and (17) in addition to the
lot release testing required by FDA, DOD is conducting supplemental
testing of each lot from this plant before distributing the vaccine.

--------------------------- Indexing Terms -----------------------------

 REPORTNUM:  T-NSIAD-99-148
     TITLE:  Medical Readiness: Safety and Efficacy of the Anthrax
	     Vaccine
      DATE:  04/29/99
   SUBJECT:  Biomedical research
	     Immunization services
	     Biological warfare
	     Chemical warfare
	     Safety standards
	     Public health research
	     Product safety
	     Product evaluation
	     Noncompliance
	     Quality control
IDENTIFIER:  DOD Anthrax Immunization Program
	     Michigan

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GAOSEAL.EPS GAO United States General Accounting Office

Testimony Before the Subcommittee on National Security, Veterans'
Affairs, and International Relations, Committee on Government
Reform, House of Representatives

For Release on Delivery Expected at 10: 00 a. m., EST Thursday,
April 29, 1999

MEDICAL READINESS Safety and Efficacy of the Anthrax Vaccine

Statement of Kwai- Cheung Chan, Director, Special Studies and
Evaluations, National Security and International Affairs Division

GAO/T-NSIAD-99-148

Page 1 GAO/T-NSIAD-99-148 Medical Readiness

Mr. Chairman and Members of the Subcommittee: We are pleased to be
here today to discuss the results of our ongoing examination of
the safety and efficacy 1 of the anthrax vaccine, which is being
done at your request. My testimony presents preliminary findings
on

(1) the short- and long- term safety of the vaccine, (2) the
efficacy of the vaccine, and (3) problems the Food and Drug
Administration (FDA) found in the vaccine production facility in
Michigan that could compromise the safety, efficacy, and quality
of the vaccine. We plan to issue the final report on our review
this fall.

As you know, concerns have been raised about the Department of
Defense's (DOD) anthrax immunization program since the Department
began vaccinating the first of 2.4 million active duty and reserve
members. For example, some Gulf War veterans are suffering from
unexplained illnesses that they believe might have been caused by
anthrax vaccines that they received during the war. Also, some
active duty military personnel expressed concerns regarding the
safety and efficacy of the anthrax vaccine after the FDA found
problems during the inspection of the facility that was
manufacturing the anthrax vaccine. With this background, I will
discuss our results.

Results in Brief The anthrax vaccine being given to U. S. military
personnel was licensed in 1970. Before the vaccine was licensed,
the vaccine and the manufacturing process were changed, creating a
similar vaccine, produced by the Michigan Department of Public
Health (MDPH), which was the one eventually licensed. 2 The safety
study conducted before licensing used both the original vaccine
and MDPH vaccine. Knowledge to date about the safety of the
vaccine includes the results of the original study and a 1998

DOD study of 500 vaccine recipients. While these studies
identified varying 1 Safety means relative freedom from harmful
effects to persons affected directly or indirectly by a product
that has been prudently administered, taking into considerations
the character of the product in relation to the condition of the
recipient at the time. Efficacy is not an absolute term. It is a
measure of a product's ability to produce a given response. An
effective vaccine will provide a certain degree of protection for
a certain period of time.

2 The original license for the production of anthrax vaccine was
issued to MDPH. In 1995, the facility changed its name to the
Michigan Biologic Products Institute. In 1998, the facility was
sold, and its name was change to BioPort. The term MDPH will be
used to refer to the licensed facility throughout this testimony.

Page 2 GAO/T-NSIAD-99-148 Medical Readiness

rates of adverse reactions, they did not question the safety of
the vaccine. The long- term safety of the vaccine has not yet been
studied. Prior to the time of licensing, no human efficacy testing
of the MDPH vaccine was performed. However, a study was done on
the efficacy of the original vaccine. This study concluded that
the vaccine provided

protection to humans against anthrax penetrating the skin. In the
1980s, DOD began testing the efficacy of the licensed vaccine on
animals, focusing on its protection against inhalation anthrax.
DOD recognizes that correlating the results of animal studies to
humans is necessary and told us

that it is planning research in this area. Careful control of the
manufacturing process is essential to ensure the quality of the
product. The FDA inspections of the facility where the licensed
vaccine was manufactured uncovered numerous problems. The facility
received warning letters from FDA, including one in March 1997
stating its intent to revoke the facility's license. The facility
closed its plant

in 1998 and is now being renovated. FDA requires the manufacturer
to meet specifications for sterility, stability, purity, and
potency. In addition to the lot release testing required by FDA,
DOD is conducting supplemental testing of each lot from this plant
before distributing the vaccine.

Background The nature and magnitude of the military threat of
biological warfare (BW) has not changed since 1990, both in terms
of the number of countries

suspected of developing BW capability, the types of BW agents they
possess, and their ability to weaponize and deliver those BW
agents. Inhalation anthrax is considered by DOD to be the primary
BW threat because of its lethality, ease of production, and
weaponization.

The original anthrax vaccine was developed by George Wright in the
1950s and first produced on a large scale by Merck. After a 1962
study on the vaccine's effects in mill workers, its manufacturing
process was changed, and MDPH took over as the vaccine's producer.
This changed vaccine was licensed in 1970 by the Division of
Biologics, National Institute of Health, to be manufactured by
MDPH.

Vaccines have three distinguishing features that contrast with
those of chemical drugs. First, either they have no clearly
chemically defined composition, or simple chemical analysis is
insufficient for effective characterization. Second, proper
evaluation of them (qualitatively or quantitatively) is usually
done by measuring their effects in vivo (in the

Page 3 GAO/T-NSIAD-99-148 Medical Readiness

living organism). Finally, quality cannot be guaranteed from final
tests on random samples but only from a combination of in- process
tests, end- product tests, and strict controls of the entire
manufacturing process.

Vaccine Safety Studies have been performed to examine the safety
of both the original vaccine and the licensed vaccine. These two
vaccines were made using different processes and have different
data to support their safety. While these studies identified
varying rates of adverse reactions, they did not question the
safety of the vaccine. The long- term safety of the vaccine has
not yet been studied.

Data on Safety of the Original Vaccine A study on the original
vaccine's safety was done by Philip Brachman and

published in 1962. 3 Brachman reported on 379 subjects that
received this vaccine. About 35 percent had local reactions, a
figure that varied during the inoculation series. Some recipients
developed more severe edema that extended to the mid- forearm or
wrist. Two individuals had systemic reactions in addition to the
edema. The researchers actively collected data on adverse
reactions to the vaccine, and the study concluded that individual
reactions to the vaccine were relatively minor. Data on Safety of
the Licensed Vaccine

After the original vaccine was developed, MDPH was granted a
license for a similar vaccine that differed from the original
vaccine in three ways. First, the manufacturing process changed
when MDPH took over. Second, the

strain of anthrax that Merck used to grow the original vaccine was
changed, and another strain was used to grow the MDPH vaccine.
Finally, to increase the yield of the protective antigen (which is
believed to be an important part of the vaccine's protective
effects), the ingredients used to

make vaccine were changed from the original vaccine. Four safety
studies have been done that include the licensed vaccine. The
results of those studies are presented in table 1. The Center for
Disease Control collected data on the Investigational New Drug
(IND) study, DOD collected data for both the Pittman study and the
Tripler Army Medical Center (TAMC) Anthrax Survey, and DOD is
currently collecting reports on

3 P. S. Brachman et al., Field evaluation of a human anthrax
vaccine, American Journal of Public Health, vol. 52 (1962), pp.
632- 645.

Page 4 GAO/T-NSIAD-99-148 Medical Readiness

adverse events. The number of adverse reactions appears to
depends, in part, upon whether the mechanism for monitoring
reactions is active or passive. (Active monitoring means that the
vaccine recipients are contacted to ascertain any adverse
reactions after vaccine administration; passive monitoring means
that the onus is on the vaccine recipients to report any adverse
reactions after vaccine administration.) None of the studies
questioned the vaccine's safety.

Table 1: Reactions to Licensed Anthrax Vaccine Reported in Various
Studies

a This number represents the number of study participants who
received the first dose of the licensed vaccine. b These figures
represent the percentage of people who experienced this type of
reaction during the

study, even if they had previously been inoculated with the Merck
vaccine. c This figure also includes persons who had reactions of
unknown severity. d This figure represents the frequency of the
most common side effect, myalgia. e DOD testified that as of March
16, 1999, more than 223,000 servicemember have been immunized.
There had been 42 reports on adverse effects submitted to the FDA
and CDC. Only seven servicemembers required hospitalization or
experienced loss of duty for more than 24 hours. Vaccine Efficacy
Studies on the efficacy of the original and the licensed vaccines
have been

limited to a study of the efficacy of the original vaccine for
humans, and studies of the efficacy of the licensed vaccine for
animals. The study on the original vaccine concluded that the
vaccine offered protection against anthrax penetrating human skin.
The studies on the licensed vaccine

focused on the efficacy of the vaccine in protecting animals
against inhalation of anthrax. These studies, while showing some
positive results, may not be extrapolated to humans. DOD is
planning to conduct such correlating studies.

Local reactions (percent) Systemic reactions

(percent) Study Type of reporting

Number vaccinated

(or doses) Mild Moderate/ severe Mild Moderate/

severe

IND Active/ passive 3, 984 a 6  20 b 1  10 b None b .05 b Pittman
(1997) Active 508 16 5 29 c 14 TAMC (1998) Active 536 Not
addressed Not addressed 43 d 5

DOD (Current monitoring) Passive 223, 000 e e e e e

Page 5 GAO/T-NSIAD-99-148 Medical Readiness

Human Efficacy Study The only study of the efficacy of the vaccine
for humans was performed by Brachman, using the original vaccine.
The Brachman study claimed that the vaccine gave 93 percent (and a
lower confidence limit of 65 percent) protection against anthrax
penetrating the skin. It found that the number of individuals who
contracted anthrax by inhalation was too low to assess the
efficacy of the vaccine against this form.

Because the vaccine used in the Brachman study was different from
the licensed vaccine, additional data were submitted to the
Division of Biologics, Department of Health, Education, and
Welfare (HEW), to support the license application for the MDPH
vaccine. In a February 1969 memorandum, an HEW committee concluded
that based on the data, the assumption of efficacy appeared
speculative. Similarly, a 1991 Army document noted that it would
be scientifically incorrect to assume that this ( licensed)
vaccine would be totally efficacious under different

circumstances, that is, beyond the parameters of the study design.
Thus, assuming that the epidemiological evidence from the original
vaccine is applicable to the licensed vaccine, we can conclude
that the licensed

vaccine is efficacious against cutaneous exposure but that testing
still needs to be conducted on inhalation anthrax. In the absence
of a specific study, efficacy of the licensed vaccine for humans
has been inferred from other data, including a reduction in the
incidence of anthrax following immunization of at- risk
individuals and from animal experiments.

Animal Efficacy Studies of Licensed Vaccines

Beginning in the late 1980s, DOD began studying the efficacy of
vaccines on animals, using guinea pigs, rabbits, and monkeys. All
of these studies support the view that in these animals, the
licensed vaccine can protect against exposure to some strains of
anthrax either by inoculation or inhalation. It is clear, however,
that animal species differ in their

susceptibility. Studies of guinea pigs show that some anthrax
strains are more or less resistant to vaccines for humans (both
the U. S. and U. K. versions) but are protected by the live spore
veterinary vaccine. 4 4 P. C. B Turnbull, et al., Development of
antibodies to protective antigen and lethal factor components in
humans and guinea pigs and their relevance to protective immunity,
Infectious Immunology, vol. 52 (1988) pp. 356- 363.

Page 6 GAO/T-NSIAD-99-148 Medical Readiness

Research using monkeys showed for the first time that monkeys
could be protected against aerosol exposure. 5 However, in both
the guinea pig and monkey studies, protection did not correlate
with levels of antibodies to a protective antigen. Several studies
have shown no direct comparison of immunity in humans to that in
monkeys. Study findings suggest that the importance of various
specific immune mechanisms against inhalation

anthrax may vary in different animal species or . . . the ability
of the licensed human vaccine to stimulate cell- mediated immunity
may be greater in some species than others. A 1998 study comes to
the same conclusion and emphasizes the need for further studies.
In animals, the lack of correlation of protection with antibodies
to protective antigen has some important consequences. DOD
recognizes the importance of establishing a correlate of immunity
in humans. Recently, it has sought to develop a serologic
correlate of

immunity in an animal model to use for humans. Vaccine
Manufacturing Process

The quality of a vaccine is closely linked to its manufacturing
process, which must be rigorously controlled to ensure that
batches of vaccines produced on different occasions are of
reproducible and consistent quality. In general, quality is
achieved by applying the current good manufacturing practice. This
process is not static but involves manufacturers and

regulators in a continuing process of assessment and upgrades as
scientific progress, technical development, and experience help to
identify deficiencies and make improvements possible. Such
principles also apply to the facilities and equipment in which
products are manufactured. Accordingly, vaccine production is very
highly regulated to ensure that the products are of consistent
quality and safe and effective for the purpose( s) for which
regulatory approval was granted. Until 1993, FDA inspectors did
not inspect the MDPH facility where the anthrax vaccine was made.
According to FDA, access was not granted because its inspectors
had not been vaccinated against anthrax. FDA's inspections of the
MDPH facility found a number of deficiencies.

The deficiencies that FDA identified in its February 1998
inspection fall 5 B. E. Ivins, et al., Efficacy of a standard
human anthrax vaccine against Baccillus anthracis aerosol
challenge in rhesus monkeys, in Proceedings of the International
Workshop on Anthrax, Salisbury Medical Bulletin, Special
Supplement no. 87 (1996) pp. 125- 126.

Page 7 GAO/T-NSIAD-99-148 Medical Readiness

broadly into two categories: those that, although serious, might
affect only one or a limited number of batches that were produced
when the deficiency was extent and those of a generic nature that
could compromise the safety and efficacy of any or all batches.
DOD had also identified deficiencies during a March 1992
inspection, including the absence of stability studies. In 1998,
MDPH closed its plant, which is now being renovated. DOD has
directed that supplemental testing be done on the lots of vaccine
in the current inventory. Mr. Chairman, this concludes my
statement. I will be happy to answer any

questions you or members of the Subcommittee may have. (713030)
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