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5 Proposed Studies on the Safety of the Anthrax Vaccine
Pages 56-81

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From page 56...
... and of possible new anthrax vaccine formulations. ~ An adverse event includes any undesirable condition that occurs following vaccination, whether or not it is causally linked to the vaccine.
From page 57...
... PROPOSED STUDIES ON THE SAFETY OF THE ANTHRAX VACCINE OBJECTIVES AND CRITICAL RESEARCH QllESTIONS FOR CDC RESEARCEI ON TIIE SAFETY OF TlIE ANTHRAX VACCINE 57 CDC's stated objectives for the safety component of its anthrax vaccine research program are displayed in Box 5-~. At the request of the committee, CDC also identified a set of critical research questions, shown in Box 5-2.
From page 58...
... ~ . ANTHRAX VACCINE ADSORBED: lIIlMAN REACTOGENICITY AND IMMUNOGENICITY TRIAL TO ADDRESS CHANGE IN ROUTE OF ADMINISTRATION AND DOSE REDUCTION This study, referred to as the human clinical trial, is intended to compare the immunogenicity and reactogenicity of AVA when given under the currently licensed regimen subcutaneous (SQ)
From page 59...
... , known allergies, physical activity level, smoking status, perceived general health status, number of previous doses of AVA, pre-injection titers of anti-protective antigen immunoalobulin _ _ ~ O C7 G and toxin neutralizing antibody, history of adverse events associated with previous doses of AVA or with doses of other vaccines, and study participants' beliefs at the conclusion of the study as to whether they had received doses of the vaccine or the placebo. The analysis will compare men and women in terms of the reactogenicity of the vaccine and the influence of various risk factors on the occurrence of adverse events.
From page 60...
... The other comparison will include all eligible women. The study protocol notes that these analyses will focus primarily on women who are not using pharmacologic methods of birth control and that special efforts may be necessary to recruit adequate numbers of women meeting this requirement.
From page 61...
... Finding: As described in the study protocol, the human clinical trial is generally responsive to the congressional mandate to evaluate the incidence of, risk factors for, and differences between men and women in local and systemic immediate-onset health effects associated with AVA and the effect of the route of vaccine administration on adverse events. The study win also provide a 42-month foBow-up period during which to monitor the occurrence of lateronset health effects.6 The committee noted one area of concern related to the proposed statistical analyses of reactogenicity.
From page 62...
... But because the SF-36 is designed Unmanly to detect substantial differences in health status as a result of disease or injury, it is unlikely to be sensitive enough by itself to make meaningful distinctions among small changes in a generally healthy population, such as the participants in the human clinical trial. The committee encourages CDC to supplement the SF-36 with other instruments, such as a symptom checklist or other validated assessment tools specifically related to possible adverse events or to specific complaints (e.g., fatigue, cognitive impairment, or reduced productivitys.
From page 63...
... The study population will be drawn from former workers at one textile mill that processed goat hair from the mid-1960s through the mid-199Os. The mill required vaccination against anthrax for its entire workforce, which averaged 800 to 1,000 workers at any given time.
From page 64...
... Some of the textile mill workers from the proposed study population may have begun receiving AVA on a regular basis from the time it became available in the 1960s, offering the possibility of as much as 30 years of follow-up. In addition, the plans to include two comparison groups—a community group and an occupational grou~reflect an awareness of some of the challenges of studying occupational health risks.
From page 65...
... Regardless, the events of interest regarding AVA are much less common than the rates evaluated in CDC's sample size calculations. An analysis of DMSS data, for example, found that postvaccination hospitalization rates among military personnel who received AVA were 92.5 per 100,000 for all neoplasms (ICD-9-CM codes 14~239~; 32.5 per 100,000 for all endocrine, nutritional, metabolic, and immunity disorders (ICD-9-CM codes 240-279)
From page 66...
... Concerns related to AVA will be the initial focus of these activities, but the VHC Network is expected to address issues related to other vaccines, as well. The three study proposals reviewed by the committee use an observational study design in a military population to replicate certain components of the human clinical trial (discussed above)
From page 67...
... The committee did not review or evaluate the clinical, educational, or quality improvement programs to be undertaken by the VHCs, confining its critique to the three research proposals submitted by CDC. Effects of Change of Route of Administration on Local Adverse Events Following AVA Vaccination As noted, this study mirrors key elements of the human clinical trial.
From page 68...
... To account for the anticipated inclusion of multiple observations of study subjects who receive more than one dose of AVA over the course of the study, repeated measures analyses will also be performed for differences by route of vaccine administration in the occurrence and number of adverse events and in the duration of adverse events and restricted activity. Committee Comments In general, the committee agrees with the appropriateness of conducting, as a complement to the human clinical trial, a cohort study to assess the effect of a change fiom SQ to IM administration of AVA on the occurrence of adverse events.
From page 69...
... 1~. Finding: A large cohort study intended to detect the occurrence of less common, medically significant adverse events following receipt of AVA would require the inclusion of a control group that has not received AVA and that is comparable in initial health status to the vaccinated cohorts.
From page 70...
... 3. Study Design AVA administered IM has an effect that is no different from that of a new/recombinant anthrax vaccine on the perceived general health and well-being of service personnel.
From page 71...
... Recommendation: CDC should not conduct the proposed VHC-based study of the effect of AVA vaccination on health-related quality of life. Effect of Hormonal Phase in the Female Population on the Occurrence of Adverse Events Following Immunization with AVA Menstrual cycle phases and levels of progesterone are considered possible risk factors for adverse events in women following vaccination with AVA.
From page 72...
... Several covariance structures will be evaluated. Committee Comments As with the other VHC-based studies, the committee agrees that it is reasonable to plan an observational cohort study as a complement to the related analysis of the association of hormonal status with adverse events that is included in the human clinical trial.
From page 73...
... ; .. ENHANCED SIGNAL DETECTION AND HYPOTHESIS TESTING FOR ADVERSE EVENTS FOLLOWING ANTHRAX VACCINATION CDC provided the committee with information on plans to use data from the Vaccine Adverse Event Reporting System (VAERS)
From page 74...
... It also lacks information on care received by military personnel from civilian hospitals or physicians and care that they receive once they leave active duty. AMSA routinely screens DMSS data for signals of adverse events following receipt of AVA but has lacked the resources to conduct studies to investigate associations that may be identified.
From page 75...
... To decide whether the hypotheses of possible associations between receipt of anthrax vaccine and certain adverse events generated by these analyses should receive further investigation, a systematic literature review will be conducted to determine whether the association has been reported and to evaluate the biologic plausibility of the association. Committee Comments The committee agrees that both VAERS and DMSS are valuable and essential resources for generating hypotheses regarding the occurrence of adverse events following vaccination, and that they should be routinely monitored for signals of adverse events related to use of AVA and all other vaccines administered to the military and civilian populations.
From page 76...
... :l Finding: DMSS is a uniquely valuable resource for testing hypotheses regarding medically significant health effects of exposure to AVA or other vaccines, especially those that might arise several months after vaccination but within the period of active duty. In the committee's view, CDC should be placing much greater emphasis on the hypothesis-testing aspect of this portion of the Anthrax Vaccine Safety and Efficacy Research Plan.
From page 77...
... v _, _ _, _ _, _ ~ , _ ~ _, , ,_, ~~ ,., ~~_ .,~,4~ Recommendation: To allow for analysis of health effects of AVA that might arise following the completion of active duty, CDC should investigate the use of DMSS data in conjunction with morbidity and mortality data from the Millennium Cohort Study and the health system of the Department of Veterans Affairs. Deaths of military personnel identified through DMSS could be tracked through resources such as the Beneficiary Identification and Records Locator Subsystem of the VA, the Social Security Administration, and the National Death Index.
From page 78...
... should be made available to support the use of DMSS data for testing hypotheses regarding health effects related to AVA or other vaccine exposures. Management and Oversight of Activities Related to Hypothesis Generation and Hypothesis Testing Committee Comments The committee also had concerns about the management and oversight of the hypothesis-generating and hypothesis-testing activities that CDC has described.
From page 79...
... with iron deficiency anemia more prone to develop systemic adverse events following AVA vaccination? Is macrophagic myofasciitis (MMF)
From page 80...
... . Anthrax Vaccine Safety and Efficacy Plan.
From page 81...
... 2002j. Section 13a: study summary: enhanced signal detection and hypothesis testing for adverse events following anthrax vaccination.


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