oversight

Medical Readiness: Issues Concerning the Anthrax Vaccine

Published by the Government Accountability Office on 1999-07-21.

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

                          United States General Accounting Office

GAO                       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., EDT
                          MEDICAL READINESS
Wednesday,
July 21, 1999

                          Issues Concerning the
                          Anthrax Vaccine
                          Statement of Kwai-Cheung Chan, Director Special Studies
                          and Evaluations, National Security and International
                          Affairs Division




GAO/T-NSIAD-99-226
                      Mr. Chairman and Members of the Subcommittee:

                      We are pleased to be here today to share the results of our work on the
                      anthrax vaccine. As you know, questions have been raised about the
                      Department of Defense’s (DOD) anthrax immunization program because
                      of concerns related to (1) the safety and efficacy of the vaccine and
                      (2) problems found over the past few years by the Food and Drug
                      Administration (FDA) during its inspection of the facility that was
                      manufacturing the vaccine. We reported our findings on these issues to
                      you in previous testimonies.1

                      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.
                      Although a version of the anthrax vaccine was shown to be effective
                      against cutaneous exposure, the vaccine has not been tested against
                      inhalation anthrax in humans. 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.

                      As requested, we will discuss (1) the extent to which data support the need
                      for six initial shots and an annual booster of the anthrax vaccine, (2) the
                      relative merits and weaknesses of a passive surveillance system in
                      determining adverse events,2 (3) the available data on differences in
                      adverse reaction rates between men and women receiving the anthrax
                      vaccine, and (4) the disadvantages of the current vaccine and the status of
                      federal efforts to develop an improved anthrax vaccine.



Results in Brief      No studies have been done to determine the optimum number of doses of
                      the anthrax vaccine. A study done during the early 1950s showed that
                      animals could be protected against cutaneous anthrax using a three-dose
                      schedule. However, the number of doses was increased to six when three
                      people who had received three doses of the vaccine were infected after
                      exposure to anthrax. In a study of the vaccine’s human efficacy published


                      1
                        Medical Readiness: Safety and Efficacy of the Anthrax Vaccine (GAO/T-NSIAD-99-148, Apr. 29, 1999)
                      and Contract Management : Observations on DOD’s Financial Relationship With the Anthrax Vaccine
                      Manufacturer (GAO/T-NSIAD-99-214, June 30, 1999).
                      2
                       Clinical events reported to a passive surveillance system are usually termed adverse events rather than
                      adverse reactions because causally-related events to the vaccine is not usually possible.




              Leter   Page 1                                                                          GAO/T-NSIAD-99-226
        in 1962, a six-dose schedule was used, and the researchers concluded that
        the vaccine provided protection against cutaneous exposure to anthrax. 3
        In 1998, the current manufacturer of the vaccine submitted an FDA
        application (Investigational New Drug) to determine whether the number
        of shots in the initial schedule could be reduced from six to five. Although
        annual boosters are given, the need for this frequency and the amount of
        the booster dose has also not been evaluated.

        DOD submits data on adverse events associated with the anthrax vaccine
        to the Vaccine Adverse Events Reporting System (VAERS).4 This system
        has several advantages. It alerts FDA/CDC to previously unreported or
        unexpected increases in reported adverse events. It is also a relatively
        affordable way to supplement the data collected on vaccines before they
        are licensed. However, it is a passive surveillance system, which means
        that FDA/CDC 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 than they would be
        in an active surveillance system. In an active system, which is generally
        more costly to administer, vaccine recipients are monitored to find out if
        they had any adverse events after being inoculated.

        In addition to reporting data to VAERS, DOD has conducted three efforts to
        actively collect data on adverse reactions after servicemembers received
        the anthrax vaccine. Data from these efforts show that women reported
        twice the rate of adverse reactions than men for both local (e.g., swelling)
        and systemic (e.g., malaise and chills) reactions. In addition, a higher
        proportion of women than men reported making an outpatient medical visit
        after a vaccination, and more than twice the percentage of women reported
        that they missed one or more duty shifts after their vaccinations than did
        men.

        The anthrax vaccine has several disadvantages. The amount of protective
        antigen in the vaccine cannot be precisely measured, and it varies from lot
        to lot. Also, the requirement for a six-dose schedule and annual booster
        shots, rather than a smaller number of doses, complicates the logistics of
        inoculating all of DOD’s troops and increases the cost of the vaccine
        program. Knowledge of anthrax infection and studies of experimental


        3
        P.S. Brachman et al., “Field evaluation of a human anthrax vaccine,” American Journal of Public
        Health, vol. 52 (1962), pp. 632-645.
        4
            The system is an FDA/Centers for Disease Control and Prevention (CDC) system.




Leter   Page 2                                                                        GAO/T-NSIAD-99-226
             anthrax vaccines indicate that a second-generation vaccine with a more
             precise amount of protective antigen could be developed and that fewer
             doses of the vaccine would be required. However, a second-generation
             vaccine has not been fully tested, and the testing required for licensing
             alone would take about 3 years. FDA approval of the manufacturing of the
             vaccine would take longer. In 1995, the U.S. Army Medical Research
             Institute of Infectious Diseases (USAMRIID)5 developed a
             second-generation recombinant vaccine (that is, a vaccine produced
             through DNA extraction) against anthrax. The vaccine was tested on
             animals, but clinical trials were not conducted in humans. DOD currently
             considers such a vaccine an unfunded requirement. The Department of
             Health and Human Services recently funded several active research grants
             to develop a second-generation recombinant vaccine because of a
             perceived growing bioterrorism concern. In developing a new vaccine,
             researchers also believe they should consider the impact of new and
             engineered strains of anthrax.



Background   DOD currently plans to vaccinate all 2.4 million servicemembers against
             anthrax using the vaccine licensed in 1970 by the Division of Biologics
             Standards, National Institutes of Health (NIH). As of July 14, 1999, more
             than 300,000 servicemembers had received at least one dose of the vaccine.
             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.

             Some studies have been done on the short-term effects of the licensed
             vaccine. We previously testified that the number of adverse reactions
             reported in these studies partly depended on whether an active or passive
             surveillance system was used to monitor adverse reactions.6 Also, we
             reported that the long-term safety of the vaccine has not been investigated
             but that DOD is considering a study to examine long-term effects of the
             vaccine.




             5
              USAMRIID, an organization of the U.S. Army Medical Research and Materiel Command, conducts
             research to develop strategies, products, information, procedures, and training programs for medical
             defense against biological warfare threats and naturally occurring infectious diseases that require
             special containment. It is located at Fort Detrick, Maryland.
             6
                 Medical Readiness (GAO/T-NSIAD-99-148, Apr. 29, 1999).




             Page 3                                                                        GAO/T-NSIAD-99-226
Data on the Need for   The original inoculation schedule of three doses was based on a regimen
                       developed using animals in the early 1950s. However, three people (two in
Six Shots Are Not      Fort Detrick and one in a private wool mill) who received three doses of
Available              the vaccine became infected after exposure to anthrax. The number of
                       doses was then increased to six for the human efficacy study published in
                       1962. The study did not provide enough information to determine whether
                       the vaccine was effective against inhalation anthrax. There were no
                       studies done to determine the optimum number of doses of the vaccine.
                       Also, according to DOD researchers, the choice of six doses was arbitrary.
                       The license for the vaccine, which was granted to the Michigan Department
                       of Public Health (MDPH),7 calls for the six-dose schedule and annual
                       boosters used in the human efficacy study, and DOD has followed this
                       regimen. In September 1998, BioPort submitted to FDA an application
                       (Investigational New Drug) 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, NIH, 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 NIH requested a reevaluation, to
                       date, no such reevaluation has been done.



The Relative Merits    DOD submits data on adverse events associated with the anthrax vaccine
                       to VAERS. VAERS is a passive surveillance system to alert FDA and CDC of
and Weaknesses of      adverse events that may be associated with licensed vaccines. Information
Passive Surveillance   is voluntarily reported to VAERS by health care providers, patients, or
                       families, who are encouraged to report any adverse events after a person
Systems in             receives a vaccine.
Determining Adverse
Events                 VAERS has several advantages. It is a relatively affordable way to
                       supplement data on short-term adverse events that are collected using
                       active means during the clinical trials before a vaccine is licensed. Most
                       important, however, VAERS serves as a signal for the detection of
                       previously unreported adverse events and/or unexpected increases in


                       7
                        MDPH was granted the original license to produce the anthrax vaccine. In 1995, the facility changed its
                       name to the Michigan Biologic Products Institute. In 1998, the facility was sold, and its name was
                       changed to BioPort.




                       Page 4                                                                          GAO/T-NSIAD-99-226
reported events. Prelicensing clinical trials are limited in detecting the
range of adverse reactions because of the small samples, short durations,
and the homogeneous population used as subjects. In addition, both the
general public and doctors can report adverse events to the system, and the
data is open to public scrutiny.

VAERS also has several disadvantages. Studies show that adverse events
are often underreported in a passive surveillance system.8 A former FDA
commissioner acknowledged the underreporting of adverse events in
passive surveillance systems and cited one study showing that “only about
1 percent of serious events” attributable to drug reactions are reported to
FDA.9 Reporting of adverse events appears to depend on several factors,
such as the clinical seriousness of the event, the length of time between the
shots and the event, and health care workers’ awareness of and obligation
to report particular adverse events. Also, outcomes with delayed onset
after vaccination or outcomes not generally recognized to be associated
with vaccination are often underreported. According to the National
Vaccine Information Center, there is no mechanism within VAERS for
a 1-, 3-, or 10-year follow-up to evaluate vaccine reactions that have a long
latency period. According to CDC, the limitations of VAERS data suggest it
is not a valid source for assessing the rate of adverse events.

In an active surveillance system, health care workers monitor people that
have been vaccinated to find out if they have had adverse reactions. Such
systems are generally used during clinical trials and are more costly to
administer than passive systems because of the additional infrastructure
and personnel required. However, such systems are sometimes used to
obtain information when questions arise about the safety of a vaccine after
licensing.




8
 S. Rosenthal and R. Chen, “The Reporting Sensitivities of Two Passive Surveillance Systems for
Vaccine Adverse Events,” American Journal of Public Health, vol. 85 (1995), pp. 1706-1709; R.T. Chen et
al., “The Vaccine Adverse Event Reporting System (VAERS),” Vaccine, vol. 12 (1994), pp. 542-550; and
R.T. Chen, “Special Methodological Issues in Pharmacoepidemiology Studies of Vaccine Safety,” Ed.
B.L. Strom, Pharmacoepidemiology (Chicester: John Wiley and Sons, 1994).
9
 D.A. Kessler, “Introducing MEDWatch: A New Approach to Reporting Medication and Devise Adverse
Effects and Product Problems,” Journal of the American Medical Association, vol. 269 (1993), pp.
2765-2768, and H.D. Scott, et al., “Rhode Island Physicians’ Recognition and Reporting of Adverse Drug
Reactions,” Rhode Island Medical Journal, vol. 70 (1987), pp. 311-316.




Page 5                                                                         GAO/T-NSIAD-99-226
Women Report More   In addition to DOD’s reporting of adverse events to VAERS, DOD has
                    conducted three efforts to actively collect data that can be used to examine
Adverse Reactions   gender differences in adverse reactions after servicemembers have
Than Men            received the anthrax vaccine. The first effort, conducted by USAMRIID,
                    included data on shots given at Fort Detrick during 1977-96. The second
                    effort, conducted in 1999 by a DOD physician stationed in Korea, was a
                    survey given to servicemembers 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 third 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. None
                    of the efforts used a control group. Also, all three relied on self-reported
                    data and were not adjusted for factors such as occupation, physical activity
                    level, and age. Because of differences in the way data were collected,
                    reaction rates are not strictly comparable among the different efforts.

                    According to the data gathered in all three efforts, a higher proportion of
                    females reported reactions to the anthrax vaccine than did their male
                    counterparts. Tables 1 and 2 summarize the rates of reported reactions to
                    the vaccine during the two efforts at Fort Detrick and in Korea. The
                    researchers at Fort Detrick determined that the statistical difference was
                    significant10 in the reported reaction rates of males and females after their
                    second and subsequent shots. The researchers for the other two efforts did
                    not report whether the difference in reported reaction rates was
                    statistically significant.




                    10
                      Tests of significance deal with the question of whether a difference is real or just a chance variation. It
                    does not deal with the question of how important the difference is or what caused the difference. The
                    test does not check the design of the study. If a test is significant at the 99-percent level, the results
                    could be due to chance 1 percent of the time.




                    Page 6                                                                              GAO/T-NSIAD-99-226
Table 1: Gender Differences in the Reported Rate of Reactions to the Anthrax
Vaccine, From Fort Detrick Data (1977-96)
                                                    Males percent                    Females percent
Dose number                                     (number of doses)                  (number of doses)
First                                                   3.75 (1,013)                          3.86 (259)
Second                                                    3.06a (979)                        7.29a (247)
Third                                                     1.71a (938)                        5.06a (237)
                                                             b
Fourth and subsequent                                   3.40 (5062)                          7.06b (737)
Note: As a result of GAO’s recalculation, the percentages reflect minor differences from those
reported by the researcher.
a
 The gender difference in reported reaction rates is statistically significant at the 99-percent
confidence level.
b
 The gender difference in reported reaction rates is statistically significant at the 99.99-percent
confidence level.
Source: DOD.




Table 2: Preliminary Data on Gender Differences in the Reported Rate of Reactions
to the Anthrax Vaccine, From Korea Survey (1999)
                                                    Males percent                    Females percent
Dose number                                     (number of doses)                  (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.


The data gathered in Korea shows that after the first two shots, more than
twice the proportion of women reported the systemic reactions of fever,
malaise, or chills than men (see table 3).




Page 7                                                                            GAO/T-NSIAD-99-226
Table 3: Preliminary Data on Gender Differences in Systemic Reactions, From Korea
Survey (1999)
Numbers in percent
                          Fever                        Malaise                        Chills
Dose
number                  Male      Female               Male     Female               Male      Female
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 effort also demonstrates gender differences in reported
reactions (see table 4). 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.




Page 8                                                                         GAO/T-NSIAD-99-226
Table 4: Gender Differences in Reported Local Reactions, Outpatient Medical Visits,
and Missed Duty, From Tripler Army Medical Center Survey (1998-99)
Numbers in percent
Reaction                                     Dose 1       Dose 2       Dose 3       Dose 4
Moderate to severe redness
 Male                                           17.5         20.4         17.2         31.6
 Female                                         49.1         46.9         51.4         39.8
Swelling of lower arm
 Male                                            9.7          9.5          9.2          7.1
 Female                                         13.4         13.5         13.0          8.4
Pain limiting motion of elbow
 Male                                            9.7          8.7          7.6          7.9
 Female                                         17.1         13.5         11.7          8.6
Localized itching
 Male                                           25.2         25.7         24.5         27.7
 Female                                         62.6         60.4         57.9         39.2
Lump or knot
 Male                                           63.9         64.4         60.5         65.5
 Female                                         89.9         87.8         83.6         73.2
Muscle soreness
 Male                                           66.6         64.7         61.8         60.4
 Female                                         79.7         76.4         70.8         61.6
Outpatient medical visit
 Male                                            5.3          2.0          2.7
                                                                                          a
 Female                                         10.0         13.8          3.9
Missed one or more shifts of duty
 Male                                            2.2          2.0          0.9
                                                                                          a
 Female                                          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.




Page 9                                                                GAO/T-NSIAD-99-226
Status of Federal      According to researchers and the Institute of Medicine of the National
                       Academy of Sciences, the current anthrax vaccine has several
Efforts to Develop a   disadvantages.11 The amount of protective antigen in the vaccine is variable
Second-Generation      from lot to lot because the manufacturing process cannot precisely
                       quantify the antigen.12 Also, there is some evidence that the current
Anthrax Vaccine        anthrax vaccine may have diminished efficacy against certain virulent
                       strains of anthrax (Bacillus anthracis). And the required six-dose schedule
                       and annual boosters complicate the logistics of inoculating all of DOD’s
                       troops and increase the cost of the vaccine program.

                       According to DOD research, a second-generation recombinant vaccine
                       created with a process that is fully defined, quantified, and controlled in
                       terms of protective antigen, can be developed and that fewer doses could
                       be required.13 DOD research also shows that a recombinant vaccine could
                       be created using modern techniques to produce highly purified protective
                       antigen. This process not only would remove unwanted bacterial proteins
                       but also would enable precise amounts of the purified protective antigen to
                       be incorporated into the vaccine. A further potential benefit is that,
                       compared to the current vaccine, the protective antigen could be produced
                       in a nonspore-forming organism. As a result, according to DOD officials,
                       manufacturers could use their buildings and equipment to produce the
                       anthrax vaccine as well as other vaccines.

                       In 1995, USAMRIID developed a new recombinant protective antigen
                       vaccine against anthrax. This vaccine was successfully tested in
                       experiments using animals but has not been tested on humans. USAMRIID
                       officials stated that this testing would take about 3 years, and FDA
                       approval of the manufacturing of the vaccine could take years longer. DOD
                       considers further development of this vaccine candidate an unfunded
                       requirement. In response to the perceived threat of bioterrorism, the


                       11
                          P.S. Brachman and A. Friedlander, “Anthrax,” Vaccines, ed. S.A. Plotkin and E.A. Mortimer, Jr.,
                       (Philadelphia: W.B. Saunders Company, 1994), p. 737, and Chemical and Biological Terrorism:
                       Research and Development to Improve Civilian Medical Response, Institute of Medicine (Washington,
                       D.C.: National Academy Press, 1999), p. 135.
                       12
                        Chemical and Biological Terrorism: Research and Development to Improve Civilian Medical
                       Response, Institute of Medicine (Washington, D.C.: National Academy Press, 1999), p. 135.
                       13
                        B. Ivins et al., “Immunization Studies with attenuated strains of Bacillius anthracis,” Journal of
                       Infection and Immunity, vol. 52 (1986), pp. 454-458; B.E. Ivins, “The Search for a New-Generation
                       Human Anthrax Vaccine,” Clinical Immunology Newsletter, vol. 9 (1988), pp. 30-32; and Y. Singh et al.,
                       “Study of Immunization Against Anthrax with the Purified Recombinant Protective Antigen of Bacillus
                       anthracis,” Journal of Infection and Immunity, vol. 66 (1998), pp. 3447-3448.




                       Page 10                                                                        GAO/T-NSIAD-99-226
                   Department of Health and Human Services’ National Institute of Allergy
                   and Infectious Diseases formed a working group to develop and test a
                   second-generation anthrax vaccine. The Institute recently funded several
                   active research grants in this regard.

                   In developing a second-generation recombinant anthrax vaccine,
                   researchers believe they will need to address the additional problem of
                   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 has been observed in experiments on animals.
                   However, the reasons for the variation have not been scientifically proven.


                   Mr. Chairman, this concludes my formal statement. If you or other
                   members of the Subcommittee have any questions, we will be pleased to
                   answer them.



Contacts and       For future contacts regarding this testimony, please contact Kwai-Cheung
                   Chan at 512-3652. Individuals making key contributions to this testimony
Acknowledgments    included Sushil Sharma, Howard Deshong, and Nancy Ragsdale.




(713043)   Leter   Page 11                                                   GAO/T-NSIAD-99-226
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