Anthrax Vaccine: Safety and Efficacy Issues (Testimony, 10/12/1999,
GAO/T-NSIAD-00-48).

Pursuant to a congressional request, GAO discussed the results of its
ongoing examination of the safety and efficacy of the anthrax vaccine,
focusing on the: (1) need for a six-shot regimen and annual booster
shots; (2) long- and short-term safety of the vaccine; (3) efficacy of
the vaccine; (4) extent to which problems the Food and Drug
Administration (FDA) found in the vaccine production facility in
Michigan could compromise the safety, efficacy, and quality of the
vaccine; and (5) effects of the anthrax vaccine on children, pregnant
women or lactating women.

GAO noted that: (1) no studies have been done to determine the optimum
number of doses of the anthrax vaccine; (2) although annual booster are
given, the need for a six-shot regimen and annual booster shots have not
been evaluated; (3) the long-term safety of the licensed vaccine has not
been studied; (4) however, the Department of Defense (DOD) is designing
studies to examine the vaccine's long-term effects; (5) data on the
prevalence and duration of short-term reactions to the vaccine are
limited but suggest that women experience a higher rate of adverse
reactions than men do; (6) FDA's system for collecting data on adverse
events associated with the vaccine, which DOD uses, relies on vaccine
recipients or their health care providers to report adverse events; (7)
the Brachman reported on 379 subjects that received this vaccine; (8)
the study concluded that individual reactions to the vaccine were
relatively minor; (9) about 35 percent had local reactions, a figure
that varied during the inoculation series; (10) in addition to this
study, some data was collected to support licensing of the vaccine but
is of limited use because some participants had already received the
earlier vaccine; (11) post-licensing data are limited because only a
limited number of doses were distributed by the manufacturer from 1974
through 1989; (12) also, FDA did not establish its Vaccine Adverse Event
Reporting System until 1990; (13) this system, which DOD uses, alerts
FDA and the Centers for Disease Control (CDC) to increases in adverse
events; (14) however, it is a passive surveillance system, which means
that FDA and CDC must rely on vaccine recipients or their health care
providers to report any adverse events after receiving the vaccine; (15)
since DOD's mandatory inoculation program began in 1998, DOD has
conducted two efforts to actively collect data on the short-term safety
of the vaccine; (16) these data also allow one to examine gender
differences in adverse reactions after servicemembers have received the
anthrax vaccine; (17) according to the data gathered in both efforts, a
higher proportion of females reported reactions to the anthrax vaccine
than did their male counterparts; and (18) the anthrax vaccine is not
intended to be administered to children, pregnant or lactating women,
and consequently no studies have been conducted to determine the
specific effects of administering the anthrax vaccine to these groups.


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

 REPORTNUM:  T-NSIAD-00-48
     TITLE:  Anthrax Vaccine: Safety and Efficacy Issues
      DATE:  10/12/1999
   SUBJECT:  Immunization programs
             Immunization services
             Safety standards
             Product evaluation
             Quality control
             Biological warfare
             Chemical warfare
             Military personnel
             Product safety
IDENTIFIER:  DOD Anthrax Immunization Program
             CDC/FDA Vaccine Adverse Events Reporting System
	     
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Before the Committee on Government Reform, House of Representatives

For Release on Delivery
Expected at 1:00 p.m., EDT
Tuesday,
October 12, 1999

ANTHRAX VACCINE

Safety and Efficacy Issues

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

*****************


GAO/T-NSIAD-00-48

See Medical Readiness: Issues Concerning the Anthrax Vaccine (GAO/T-NSIAD-
99-226,
July 21, 1999) and Medical Readiness: Safety and Efficacy of the Anthrax
Vaccine 
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/Footnote1/ of the anthrax vaccine.
My testimony is based on previous studies/Footnote2/ we have conducted to
determine 
(1) the need for a six-shot regimen and annual booster shots, (2) the 
long- and short-term safety of the vaccine, (3) the efficacy of the
vaccine and (4) the extent to which problems the Food and Drug
Administration (FDA) found in the vaccine production facility in Michigan
could compromise the safety, efficacy, and quality of the vaccine.
Finally, I would like to discuss the effects of the anthrax vaccine on
children, pregnant women or lactating women.

As you know, concerns have been raised about the Department of Defense's
(DOD) anthrax immunization program since DOD began vaccinating its 2.4
million active duty and reserve members in 1998. For example, some active
and reserve military personnel expressed concerns regarding the safety and
efficacy of the anthrax vaccine after the FDA found problems during the
inspection of the vaccine production facility. In addition, some Gulf War
veterans are suffering from unexplained illnesses that they believe might
have been caused by anthrax vaccinations received during the war. 

The original anthrax vaccine was developed in the 1950s and was first
produced on a large scale by the Merck Pharmaceutical Corporation. After a
1962 study on the vaccine's effect on mill workers, its manufacturing
process was changed and the Michigan Department of Public Health took over
as the vaccine's producer. This changed vaccine, which is the vaccine
being given to U.S. military personnel, was licensed in 1970 by the
Division of Biologics Standards, National Institutes of Health. FDA is
currently responsible for licensing new vaccines and ensuring vaccine
safety.

Summary

No studies have been done to determine the optimum number of doses of the
anthrax vaccine. Although annual boosters are given, the need for a 
six-shot regimen and annual booster shots have not been evaluated.

The long-term safety of the licensed vaccine has not been studied.
However, DOD is designing studies to examine the vaccine's long-term
effects. Data on the prevalence and duration of short-term reactions to
the vaccine are limited but suggest that women experience a higher rate of
adverse reactions than do men. FDA's system for collecting data on adverse
events associated with the vaccine, which DOD uses, relies on vaccine
recipients or their health care providers to report adverse
events./Footnote3/ Studies have shown that such systems may not accurately
reflect the incidence of events due to underreporting. However, data from
two recent DOD efforts to identify the prevalence of adverse events
associated with anthrax vaccine show that a higher proportion of women
reported both local and systemic reactions to the vaccine than their male
counterparts. In addition, more than twice the proportion of women
reported that they missed one or more duty shifts after their vaccinations
than did males. 

A study on the efficacy of the earlier vaccine concluded that it provided
protection to humans against anthrax penetrating the skin but did not
provide information to determine its effectiveness against inhalation
anthrax. In the 1980's, DOD began testing the efficacy of the licensed
vaccine in animals, focusing on its protection against inhalation anthrax.
The studies showed that the vaccine protected some animals against
inhalation anthrax. However, the level of protection varied for different
species and the results cannot be extrapolated to humans. DOD recognizes
that correlating the results of animal studies to humans is necessary and
told us that it is planning research in this area. DOD also plans to
develop a second generation anthrax vaccine and, as part of this effort,
will need to address whether strains of deliberately engineered or
naturally occurring anthrax can overcome the protective immunity of such a
vaccine.

FDA's inspections of the vaccine production facility in 1997 and 1998
found a number of deficiencies. The deficiencies that FDA identified in
its February 1998 inspection fall broadly into two categories: those that
might affect only one or a limited number of batches that were produced
and those that could compromise the safety and efficacy of any or all
batches. The facility was shut down in early 1998. A new company, which
purchased the facility in mid-1998, is addressing these issues.

Finally, you expressed concerns about the effects of the anthrax vaccine
on children, pregnant women, or lactating women. The anthrax vaccine is
not intended to be administered to children, pregnant women, or lactating
women. No studies have been conducted on the vaccine's effects on these
groups.

Background

In December 1997, the Secretary of Defense announced that all U.S. forces
would be inoculated against the potential use of anthrax on the
battlefield. Initial immunization consists of three shots given at 0, 2,
and 4 weeks followed by three additional shots given at 6, 12, and 18
months. DOD has recognized that some of the concerns about using the
current vaccine might be mitigated in the future through actions such as
testing and research and adjustments to the program based on new data.

The inspection process for ensuring vaccine safety is more stringent and
complex than for chemical drug because vaccines have three distinguishing
features. First, either they have no clearly chemically defined
composition, or chemical analysis is extremely difficult. Second, proper
evaluation of vaccines generally requires measuring their effects in
animals. 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.

From the 1970s until 1998, DOD had been procuring the anthrax vaccine from
a facility owned by the State of Michigan, the only facility in the
country licensed to produce the vaccine. In 1997 and 1998, FDA identified
numerous manufacturing problems at the facility. In response to concerns
about the potential loss of anthrax vaccine production, DOD began funding
renovation of the facility. Production facilities were shut down in early
1998. In the summer of 1998, the State of Michigan sold the facility to
the BioPort Corporation for $25 million. DOD contracts were then
transferred to BioPort. BioPort is addressing manufacturing problems.

Data on the Need for Six Shots and Annual Boosters Are Not Available

No studies have been done to determine the optimum number of doses of the
anthrax vaccine. The immunization schedule of three doses used for the
earlier vaccine was based on a regimen developed using animals in the
early 1950s. However, the number of doses was arbitrarily increased to six
when three people (two at Fort Detrick and one in a private wool mill) who
received three doses of the vaccine became infected after exposure to
anthrax. In a study of the vaccine's human efficacy published in 1962, a 
six-dose schedule was used, and the researchers concluded that the vaccine
provided protection against anthrax penetrating the skin. The study did
not provide enough information to determine whether the vaccine was
effective against inhalation anthrax. The license for the vaccine, which
was granted in 1970, calls for the six-dose schedule and annual boosters
used in the human efficacy study, and DOD has followed this regimen. In
September 1998, the manufacturer submitted an Investigational New Drug
application to FDA to determine whether the number of shots in the initial
schedule could be reduced from six to five.

In November 1971, the Division of Biologics Standards, National Institutes
of Health, noted an apparent increase in reports of adverse reactions
after individuals received booster shots. The Division considered it
advisable to reevaluate the need for annual boosters and possibly the
amount of the booster dose. Although the record is unclear as to whether
or not the Division requested the manufacturer to conduct a reevaluation,
no such reevaluation has been done to date.

Vaccine Safety

The long-term safety of the licensed vaccine has not been studied.
However, DOD is designing studies to examine the vaccine's long-term
effects.

With regard to short-term safety, data on the prevalence and duration of
short-term reactions to the vaccine are limited but suggest that women
experience a higher rate of adverse reactions than men. A study on the
earlier vaccine's safety was done by Philip Brachman and published in
1962./Footnote4/ Brachman reported on 379 subjects that received this
vaccine. The study concluded that individual reactions to the vaccine were
relatively minor. About 35 percent had local reactions, a figure that
varied during the inoculation series. Some recipients developed more
severe edema, or swelling, that extended to the mid-forearm or wrist. Two
individuals had systemic reactions in addition to the edema. In addition
to this study, some data was collected to support licensing of the vaccine
but is of limited use because some participants had already received the
earlier vaccine and it is not possible to identify who received which
vaccine.

Post-licensing data are limited because only a limited number of doses--
about 68,000--were distributed by the manufacturer from 1974 through 1989.
Also, FDA did not establish its Vaccine Adverse Event Reporting System
until 1990. This system, which DOD uses, alerts FDA and the Centers for
Disease Control to increases in adverse events. However, it is a passive
surveillance system, which means that FDA and the Centers for Disease
Control must rely on vaccine recipients or their health care providers to
report any adverse events after receiving the vaccine. Studies show that
adverse events are reported significantly less frequently with passive
surveillance systems than they would be in an active system where vaccine
recipients are monitored to find out if they had any adverse effects.

Since DOD's mandatory inoculation program began in 1998, DOD has conducted
two efforts to actively collect data on the short-term safety of the
vaccine. These data also allow one to examine gender differences in
adverse reactions after servicemembers have received the anthrax vaccine.
The first effort, conducted in 1999 by a DOD physician stationed in Korea,
was a survey given to service members when they reported for their initial
six-dose schedule of shots; it asked questions about their reactions to
the previous shot. Results from this effort reflect the researcher's
preliminary analysis of the data. The second effort, conducted in 1998-99
at Tripler Army Medical Center, Hawaii, included a survey on adverse
reactions to the first three shots when individuals reported for their
fourth shot and later included a follow-up survey on adverse reactions to
the fourth shot.

According to the data gathered in both efforts, a higher proportion of
females reported reactions to the anthrax vaccine than did their male
counterparts. Table 1 summarizes the rates of all reported reactions to
the vaccine in Korea. The data show that a higher proportion of females
reported reactions than males.

Table****Helvetica:x11****1:    Preliminary Data on Gender Differences in
                                the Reported Rate of Adverse Reactions to
                                the Anthrax Vaccine, From Korea Survey
                                (1999)

Note: This represents a preliminary analysis of the data by the
researcher, and at the time of our review, data on reactions to
the third shot were not available.
-----------------------------------------------------------------------
|                      :                Males :              Females  |
|                      :                      :                       |
| Dose                 :   Percent (number of :   Percent (number of  |
|                      :               doses) :               doses)  |
|---------------------------------------------------------------------|
| First                :          42.1 (2036) :           71.6 (495)  |
|---------------------------------------------------------------------|
| Second               :          44.4 (1953) :           74.0 (474)  |
-----------------------------------------------------------------------

Source: DOD 1999.

The data gathered in Korea also show that after the first two shots, more
than twice the proportion of women than men reported systemic reactions of
fever, malaise, or chills than did men (see table 2).

Table****Helvetica:x11****2:    Preliminary Data on Gender Differences in
                                Systemic Reactions, From Korea Survey (1999)

Note: This represents a preliminary analysis of the data by the
researcher, and at the time of our review, data on reactions to
the third dose were not available.
-------------------------------------------------------------------------
|         :       Fever       :      Malaise       :      Chills        |
|-----------------------------------------------------------------------|
| Dose    :    Male :  Female :    Male :   Female :    Male :  Female  |
| number  :         :         :         :          :         :          |
|         : (percen : (percen : (percen : (percent): (percen : (percen  |
|         :      t) :      t) :      t) :          :      t) :      t)  |
|-----------------------------------------------------------------------|
| First   :     0.9 :     2.8 :     6.0 :     15.6 :     1.5 :     5.5  |
|-----------------------------------------------------------------------|
| Second  :     1.7 :     4.8 :     7.1 :     15.4 :     1.9 :     4.0  |
-------------------------------------------------------------------------

Source: DOD.

The Tripler survey also demonstrates gender differences in reported
reactions (see table 3). These data show that a higher proportion of women
reported making an outpatient visit after a vaccination than their male
counterparts. In addition, more than twice the proportion of women
reported that they missed one or more duty shifts after their vaccinations
than did males. In light of the fact no gender specific data were
available from the pre-licensure studies, these findings underscore the
need for monitoring to better understand the specific effects of this
vaccine in different groups.

Table****Helvetica:x11****3:    Gender Differences in Reported Local
                                Reactions, Outpatient Medical Visits, and
                                Missed Duty, From Tripler Army Medical
                                Center Survey (1998-99)

Note: Between 421 and 471 men and between 74 and 83 women
responded to each question on the survey.
---------------------------------------------------------------------------
| Reaction                :      :  Dose 1 :  Dose 2 :  Dose 3 :  Dose 4  |
|                         :      : (percen : (percen : (percen : (percen  |
|                         :      :      t) :      t) :      t) :      t)  |
|-------------------------------------------------------------------------|
| Moderate to severe      : (m)  :    17.5 :    20.4 :    17.2 :    31.6  |
| redness                 :      :         :         :         :          |
|-------------------------------------------------------------------------|
|                         : (f)  :    49.1 :    46.9 :    51.4 :    39.8  |
|-------------------------------------------------------------------------|
| Swelling of lower arm   : (m)  :     9.7 :     9.5 :     9.2 :     7.1  |
|-------------------------------------------------------------------------|
|                         : (f)  :    13.4 :    13.5 :    13.0 :     8.4  |
|-------------------------------------------------------------------------|
| Pain limiting motion    : (m)  :     9.7 :     8.7 :     7.6 :     7.9  |
| of elbow                :      :         :         :         :          |
|-------------------------------------------------------------------------|
|                         : (f)  :    17.1 :    13.5 :    11.7 :     8.6  |
|-------------------------------------------------------------------------|
| Localized itching       : (m)  :    25.2 :    25.7 :    24.5 :    27.7  |
|-------------------------------------------------------------------------|
|                         : (f)  :    62.6 :    60.4 :    57.9 :    39.2  |
|-------------------------------------------------------------------------|
| Lump or knot            : (m)  :    63.9 :    64.4 :    60.5 :    65.5  |
|-------------------------------------------------------------------------|
|                         : (f)  :    89.9 :    87.8 :    83.6 :    73.2  |
|-------------------------------------------------------------------------|
| Muscle soreness         : (m)  :    66.6 :    64.7 :    61.8 :    60.4  |
|-------------------------------------------------------------------------|
|                         : (f)  :    79.7 :    76.4 :    70.8 :    61.6  |
|-------------------------------------------------------------------------|
| Outpatient medical      : (m)  :     5.3 :     2.0 :     2.7 :       a  |
| visit                   :      :         :         :         :          |
|-------------------------------------------------------------------------|
|                         : (f)  :    10.0 :    13.8 :     3.9 :          |
|-------------------------------------------------------------------------|
| Missed one or more      : (m)  :     2.2 :     2.0 :     0.9 :       a  |
| shifts of duty          :      :         :         :         :          |
|-------------------------------------------------------------------------|
|                         : (f)  :     5.0 :     5.1 :     3.9 :          |
---------------------------------------------------------------------------

aData were not available

Source: DOD.

Vaccine Efficacy

Studies on the efficacy of anthrax vaccine have been limited to a study of
the efficacy of the earlier vaccine for humans, and studies of the
efficacy of the licensed vaccine for animals. 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. There has been no specific study of the
efficacy of the licensed vaccine in humans. Rather, its efficacy in 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.

Beginning in the late 1980s, DOD began studying the efficacy of the
licensed anthrax vaccine 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 but
are protected by the live spore veterinary vaccine./Footnote5/

Research using monkeys showed for the first time that monkeys could be
protected against aerosol exposure./Footnote6/ However, several studies
have shown no direct comparison of immunity in humans to that in monkeys.
DOD officials recognize that correlating the results of animal studies to
humans is necessary and told us that DOD is planning research in this
area. DOD also plans to develop a second generation anthrax vaccine, and
as part of this effort, it will need to address whether strains of
deliberately engineered or naturally occurring anthrax can overcome the
protective immunity of such a vaccine. A variation in virulence among
anthrax strains and a variation in relative resistance to vaccine-induced
immunity have been observed in experiments on animals. However, the
reasons for the variation have not been scientifically proven.

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 consistent quality. 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. DOD conducted inspections, however, and identified
deficiencies during a March 1992 inspection, including the absence of
stability studies.

FDA's subsequent inspections of the production facility in 1997 and 1998
found a number of deficiencies. The deficiencies that FDA identified in
its February 1998 inspection fall broadly into two categories: those that
might affect only one or a limited number of batches and those of a
generic nature that could compromise the safety and efficacy of any or all
batches. The facility received warning letters from FDA, including one in
March 1997 stating its intent to revoke the facility's license. In 1998,
the manufacturer closed its plant, which is now being renovated. DOD has
directed that supplemental testing for purity, potency, sterility and
safety be done on the lots approved by FDA before the current vaccination
program began.

Effects of the Vaccine on Children and Pregnant and Lactating Women

The anthrax vaccine is not intended to be administered to children,
pregnant or lactating women, and consequently no studies have been
conducted to determine the specific effects of administering the anthrax
vaccine to these groups. Before approving vaccines or drugs for marketing,
FDA currently requires the submission of clinical data broken down by
(among other things) gender and age. FDA then evaluates these data to
determine efficacy and safety for specific subgroups of the general
population. In addition, depending on FDA's assessment of clinical data,
specific labeling requirements pertaining to potential effects on pregnant
women, nursing mothers and pediatric use may also be required. However,
the Division of Biologics, National Institutes of Health, which licensed
the vaccine in 1970, did not require the submission of data broken down
this way.




Mr. Chairman, this concludes my statement. I will be happy to answer any
questions you may have.

Contacts and Acknowledgments

For future contacts regarding this testimony, please contact Kwai-Cheung
Chan at (202) 512-3652. Individuals making key contributions to this
testimony included Sushil K. Sharma, Jonathan R. Tumin, and Howard Deshong.

(713049)

--------------------------------------
/Footnote1/-^Safety means relative freedom from harmful effects to persons
  affected directly or indirectly by a product that has been prudently
  administered, taking into consideration the character of the product in
  relation to the condition of the recipient at the time. Efficacy 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.
/Footnote2/-^(GAO/T-NSIAD-99-148, April 29, 1999).
/Footnote3/-^Clinical events reported to a passive surveillance system
  such as FDA's are usually termed adverse events rather than adverse
  reactions because there is usually insufficient evidence that the
  vaccine, rather than other health conditions, caused the reported events.
/Footnote4/-^P.S. Brachman et al., "Field Evaluation of a Human Anthrax
  Vaccine," American Journal of Public Health, vol. 52 (1962), pp. 632-645.
/Footnote5/-^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.
/Footnote6/-^B.E. Ivins, et al., "Efficacy of a standard human anthrax
  vaccine against Baccillus anthracis aerosol challenge in rhesus
  monkeys," Proceedings of the International Workshop on Anthrax,
  Salisbury Medical Bulletin, Special Supplement no. 87 (1996) pp.125-126.