oversight

Anthrax Vaccine: Safety and Efficacy Issues

Published by the Government Accountability Office on 1999-10-12.

Below is a raw (and likely hideous) rendition of the original report. (PDF)

                             United States General Accounting Office

GAO                          Testimony
                             Before the Committee on Government Reform, House of
                             Representatives




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


                             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
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 efficacy1 of the anthrax vaccine. My
testimony is based on previous studies2 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.




1
 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.
2
 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
(GAO/T-NSIAD-99-148, April 29, 1999).




Page 1                                                                      GAO/T-NSIAD-00-48
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.3 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


          3
           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.




          Page 2                                                                  GAO/T-NSIAD-00-48
             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.




             Page 3                                                      GAO/T-NSIAD-00-48
Data on the Need for   No studies have been done to determine the optimum number of doses of
                       the anthrax vaccine. The immunization schedule of three doses used for
Six Shots and Annual   the earlier vaccine was based on a regimen developed using animals in the
Boosters Are Not       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
Available              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
                       1962.4 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


                       4
                       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-00-48
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.




Page 5                                                      GAO/T-NSIAD-00-48
Table 1: Preliminary Data on Gender Differences in the Reported Rate of Adverse
Reactions to the Anthrax Vaccine, From Korea Survey (1999)
                                                        Males                  Females
Dose                                Percent (number of doses) Percent (number of doses)
First                                                  42.1 (2036)                           71.6 (495)
Second                                                 44.4 (1953)                           74.0 (474)
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.
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 2: Preliminary Data on Gender Differences in Systemic Reactions, From Korea
Survey (1999)
                         Fever                       Malaise                        Chills
Dose                  Male         Female          Male          Female           Male         Female
number            (percent)      (percent)     (percent)       (percent)      (percent)      (percent)
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
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.
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.




Page 6                                                                           GAO/T-NSIAD-00-48
                   Table 3: Gender Differences in Reported Local Reactions, Outpatient Medical Visits,
                   and Missed Duty, From Tripler Army Medical Center Survey (1998-99)
                                                                   Dose 1    Dose 2    Dose 3          Dose 4
                   Reaction                                      (percent) (percent) (percent)       (percent)
                   Moderate to severe redness           (m)            17.5        20.4       17.2        31.6
                                                        (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 of elbow        (m)             9.7         8.7        7.6         7.9
                                                        (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
                                                                                                                 a
                   Outpatient medical visit             (m)             5.3         2.0        2.7
                                                        (f)            10.0        13.8        3.9
                                                                                                                 a
                   Missed one or more shifts of duty    (m)             2.2         2.0        0.9
                                                        (f)             5.0         5.1        3.9
                   Note: Between 421 and 471 men and between 74 and 83 women responded to each question on the
                   survey.
                   a
                   Data 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.




                   Page 7                                                                  GAO/T-NSIAD-00-48
                        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.5

                        Research using monkeys showed for the first time that monkeys could be
                        protected against aerosol exposure.6 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   The quality of a vaccine is closely linked to its manufacturing process,
                        which must be rigorously controlled to ensure that batches of vaccines
Process                 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.

                        5
                         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.
                        6
                         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.




                        Page 8                                                                    GAO/T-NSIAD-00-48
                         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   The anthrax vaccine is not intended to be administered to children,
                         pregnant or lactating women, and consequently no studies have been
on Children and          conducted to determine the specific effects of administering the anthrax
Pregnant and Lactating   vaccine to these groups. Before approving vaccines or drugs for marketing,
                         FDA currently requires the submission of clinical data broken down by
Women                    (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)    Leter        Page 9                                                       GAO/T-NSIAD-00-48
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