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Executive Summary The Department of Defense's Anthrax Vaccine Immunization Program (AV1P) to vaccinate all troops against anthrax has become a controversial issue. On the one hand, inhalational anthrax disease has a high fatality rate, close to 100 percent, ant! the infectious organism, Bacillus anthracis, is consiclered to be the foremost threat for use in biological warfare. On the other hand, the anthrax vaccine and the AV]P have been subject to an unusual degree of concern from some service personnel and their families regarding possible adverse events associated with vaccination. The Congress has responded to these issues, mandating further study of the vaccine by the Department of Defense (DoD), the National institutes of Health (NIH), ant} the Centers for Disease Control and Prevention (CDC), both indiviclually and collaboratively. The CDC contracted with the Institute of Medicine (IOM) to establish an expert panel to review the completeness and appropriateness of their research plan to stucly the safety ant! efficacy of the anthrax vaccine, and to evaluate alternative routes and schedules of administration in order to reduce adverse effects while maintaining vaccine effectiveness. The study is planned for a total duration of 24 months. This interim report sets out the committee's findings, eight months into the project. Both the committee's review and the CDC's research program are ongoing and further clevelopments are expected. The key messages at this time reflect that interim status, and encourage further development (Box 11. In brief, the CDC's plan appears to include useful components that have not to date been integrated into a whole or comprehensive plan. No matter how meritorious the parts, however, the apparent lack of overall planning and coordination of the whole is a deficit that shouIc! be remedied. The committee could not fairly evaluate the plan for its completeness and appropriateness with respect to its goals, as long as the plan itself was not yet completely cleveloped. Based on the information presented regarding the components developed to date, however, the committee looks forward to further review of comprehensive, and of additional detailed, information as soon as it is available. As will be noted below, Congress explicitly called for cooperation between the CDC and the NIH and the DoD. This report is directed specifically toward the CDC's plans' and has not included any review of the overall research portfolios of the NTH and the DoD. When specific areas of potential coordination were apparent, the committee highlighted them, but the committee also assumes that other areas of coordination could emerge in the course of collaborative discussions.

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CDC ANTHRAX VACCINE SAFETY & EFFICACYRESEARCH PROGRAM Finally, the committee also strove to distinguish overall program review from cletailect and technical acivice on specific protocols The committee's assessment was that both sorts of advice could be useful to the CDC, but that sources other than TOM shouict be consulted for the latter. The committee's general recommendations, in Box 2 below, reflect these overall findings. BOX ~ Key Findings of Interim Report . The CDC either has not developed, or has not communicated, a comprehensive plan for the CDC's role in anthrax vaccine safety and efficacy research. . Despite the absence of a comprehensive plan, the CDC's research program includes appropri- ate and well-conceived scientific projects that are generally responsive to the Congressional mandate. . The CDC's research program also includes many particular projects that presently are quite un- derdeveloped or include unspecified elements. Areas of potential collaboration between the CDC, DoD and NIH exist and should be more fully exploited, notably, for example the use of DoD databases such as the Defense Medical Surveil- lance System (DMSS). The areas of potential deficit or concern can be remedied. BOX 2 General Recommendations for CDC,s Anthrax Vaccine Research Program General Recommendations The CDC should produce a comprehensive description of its research program, including state- ments of the goals of the program and how the plans now undertaken will meet those goals. In addition, the CDC should continue and complete development of the individual projects in the re- search program. The CDC should consider engaging protocol design consultants representing broad scientific ex- pertise who would provide immediate and direct consultation on specific technical matters of study design and execution. The CDC should continue and strengthen collaboration with DoD and NIH wherever possible, in- cluding for example much more extensive use of DoD databases such as the Defense Medical Surveillance System (DMSS).

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EXECUTIVE SUMMARY Congress has laid out the elements of the CDC's research mandate, namely, to study the safety and efficacy of anthrax vaccine by addressing: (~) risk factors for adverse reactions, including gender differences; (2) determining immunologic correlates of protection and documenting vaccine efficacy; and (3) optimizing the vaccination schedule and routes of - , ~ , , _ . . . - . ,~ . i. ,. . ~ . . . .. aumlnlstratlon to assure efficacy while mlmmlzlng the number of noses requlrec1 and the occurrence of adverse events. Congress separately mandated that the DoD enter into a contract with the Institute of Medicine for a study aimed at review of currently existing data on the safety and efficacy of the licensed vaccine (see Figure I,). The two contracts were independent ant! the charges distinct although related. In order to facilitate coordination, the committees share staff and include several members who serve on both committees. The CDC's research program addresses the safety and efficacy of the licensed anthrax vaccine (anthrax vaccine adsorbed, or AVA), using a multi-faceted approach located in two distinct parts of the agency, the National Center for Infectious Diseases (NCID) and the National Immunization Program (NIP) (see Box 31. The CDC's research plans include studies directed toward regulatory requirements for changing the labeling of the current AVA product, and other studies apparently designee! with a view to furthering scientific understanding more generally. Those goals are not inconsistent, but a comprehensive plan should describe their integration. The NCID research projects primarily address the dosing schedule, route of administration, ant! reactogenicity of the vaccine. The NIP research projects are concerned with tracking vaccine adverse events and evaluating perceptual factors that influence vaccine acceptability; the effects of educational efforts on the knowledge, attitudes, and beliefs (KAB) of service personnel about the anthrax vaccine wit! also be studiecl. BOX 3 Projects Presentec' to Date in CDC Research Program NCID - in clevelopment Part A: Anthrax Vaccine Adsorbed (AVA): A human reactogenicity and immunogenicity trial to address change in route of administration and dose reduction Part B: Non-human primate AVA dose-ranging, immunogenicity and challenge trial Part C: Anthrax pathogenesis, immunology, and correlates of protection against inhalational an- thrax Human leukocyte antigen sub-study NIP - in clevelopment or planned for cleve~opment Survey of knowledge, attitudes and beliefs (KAB) prevalent among military service per- sonnel and also of military health care provid- ers regarding the anthrax vaccine Survey of the KAB prevalent among military health care providers regarding practices of re- porting to Vaccine Adverse Event Reporting System (VAERS) Data-mining in the VAERS database SF-36 Survey of clinical trial participants Hormonal correlates of adverse events in fe- male clinical trial participants Long-term follow-up of any available previously immunized populations Meta-analysis of safety and efficacy studies on the anthrax vaccine

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4 DoD-sponsored stucly to evaluate the safety and efficacy of anthrax vaccine CDC ANTHRAX VACCINE SAFETY & EFFICACY RESEARCH PROGRAM CDC-sponsored study to eva/uafe CDC research plan on safely and ef- ficacy of anthrax vaccine Congressional actions regarding lOM study of anthrax vaccine research DoD Appropriations Act 2000 PL 106-79 DoD is directed to enter into a contract with the IOM to independently study the effectiveness and safety of the anthrax vaccine IOM letter report an anthrax vaccine safety 3/30/2000 r DoD contracted with IOM to study the safety and efficacy of the an- thrax vaccine . IOM Committee to Assess the Safety and Efficacy of the Anthrax Vaccine Meetings to date: October 3, 2000 January 29-30, 2001 April 17-18, 2001 | Final Reportd' leJune2002 | DHHS Appropriations Act, 2000 PL 106-113 CDC is provided $20 million for a collaborative effort to study the safety and efficacy of anthrax vaccine ! C CDC requested that IOM review the CDC research plan ~ , IOM Committee to Review the CDC Anthrax Vaccine Safety and Efficacy Research Program Meetings to date: October 31, 2000 February 8-9, 2001 April 18-19, 2001 1 Interim Report due June 2001 , ~ Final Report due August 2002 FIGURE ~ Origins of TOM Activities Related to the Anthrax Vaccine PROJECT-SPECIFIC FINDINGS AND RECOMMENDATIONS NCID-Directefd Projects in the Research Program The NCID research plans include a human clinical trial to evaluate changing the route of injection of the licensed vaccine AVA from subcutaneous to intramuscular, and reducing the total number of injections. The results of this work may be used to support a labeling change for the licensed product. Other NCID projects support and extend this work using animal trials and laboratory tests.

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EXECUTIVE SUMMARY Human Clinical Trial, or Part A s The human clinical trial wouIc! compare the effects of intramuscular administration with the currently recommender! subcutaneous injection of the anthrax vaccine and of reducing the total number of closes. The trial will last three and a half to four veers and enrollment ninny cn11 for total of 1300 participants from five study sites. ~ . ~ ~ ~ . . i` . rib. . . . ... . . .. . . . ~ . ~ . .~ . the committee found that the proposed research on changing the route of administration of the vaccine and reducing the number of doses required is appropriate. This trial is also necessary from a regulatory perspective in order to change the vaccine product labeling so that the military could change its practice and remain in accord with guiclelines of the Food and Drug Administration (FDA). The committee considers some potential moclif~cations, particularly to one stucly group, of the human clinical trial as perhaps advantageous, while recognizing that it may be difficult to implement any further changes at this ciate. . The committee recommends that, in the human clinical trial, the CDC should consider including a study group immunized at the start of the series (time zero), and one and six months later, followed by placebo, in order to assess adequacy of a simplified three-dose regimen in the development of immediate and long-term immunity to anthrax. The committee has not yet seen the methods section of the human clinical trial protocol, notably the specific types of statistical analyses that will be employed in the analysis of clinical trial data. The committee is concerned about the methods to be used. . The committee recommends careful selection of statistical methodologies, as certain techniques including intent-to-treat analysis may be less appropriate in developing conclusions for what will eventually be a military application than they would be for general civilian vaccine development. The committee notes also that the human clinical trials are intended to investigate gentler differences relater} to Diverse reactions, specifically mentioned in the Congressional mandate. Previous work (Pittman et al., submitted for publication) has shown a significantly higher frequency, ant! greater extent, of local adverse reactions to the anthrax vaccine when administered to women subcutaneously. The CDC plan for recruitment of volunteers anticipates a sufficient number of female subjects, 20 percent of total enrollment, to detect a difference of similar magnitude to that reported by Pittman, but not for a smaller difference. The CDC also plans a substucly of hormonal status that would further subdivide the female volunteers, so that the study would require a still larger number. As planned, the clinical trial would be powered adequately to detect a substantial difference related to sex (a biological parameter) or gender (a psychological and/or social phenomenon) in the rate of adverse reactions to subcutaneous inoculation, given successful recruitment of female subjects. However, several factors may complicate such recruitment. Belief among potential recipients that women may suffer more reactions (also inclicated by the Pittman study), and plans for recruiting study volunteers from, among other groups, first responders (traditionally professions employing more men than women), together cause the committee to doubt the likelihood of enrolling female volunteers in sufficient numbers to provide adequate power for the planned studies. As planned, this study will not have adequate power to address aspects of sex or gender differences beyonc! route of aclministration.

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6 CDC ANTHRAX: VACCINE SAFETY & EFFICACY RESEARCH PROGRAM . The committee recommends that the CDC consider, in addition to the proposed clinical trial, a prospectively designed pharmacoepidemiologic study of military vaccine recipients with both active surveillance and historical ciata from DMSS for moderate and severe adverse events in order to assess sex or gender and perhaps other risk factors for adverse events among military personnel receiving the anthrax vaccine. According to presentations made to the committee and subsequent inquiries by staff members, the DMSS aIreacly collects relevant ciata on all meclical visits in the military health care system, as well as data on anthrax vaccinations. The DMSS would thus be able to provide information on the date and ICD-9 code for visits within a given time frame following a visit for anthrax immunizations. Sex or gender difference is just one of several important items of information that could be investigated. Animal close ranging ancl challenge studies, or Part B The animal studies would compare different doses of vaccine to establish the appropriate dose for the rhesus macaque, the animal species of interest, and the effect of reducing the number of closes on the animals' circulating antibody and their ability to survive challenge with aerosolized B. anthracis. The committee fount! that supporting animal studies are of great importance in an anthrax vaccine safety and efficacy research program. It is not possible to do a human clinical trial of vaccine efficacy for inhalational anthrax: the disease has a high fatality rate, and improved working conditions in goat hair anti woolen mills, ant! use of synthetic materials, hav (fortunately) eliminated the major sources of naturally occurring cases in the United States. As a mode] for effects in humans, animals that can develop inhalational anthrax, rhesus macaques, will be immunized using different regimens. In earlier trials, however, the macaques receiver! the same dose as a human would, resulting in more vaccine per unit body weight than a human would receive. The CDC plans to do a dose-ranging study to establish the appropriate dose of vaccine for a rhesus macaque as a basis for future studies. The criteria for the choice of an appropriate close have not been clefined to date. The animals will be immunized with different clilutions of vaccine, after which their immune systems will be challenged by exposing them to a standard dose of aerosolized B. anthracis spores, to determine whether they have cleveloped protection against infection. Often such a series of close-ranging and challenge studies wouict be prececlec! by a passive antibody transfer study, in which antibody-containing serum from immunized humans is given to the animals so that they have passive immunity (that is, they have received antibodies but do not actively make their own antibodies because they have not been vaccinated). Then animals that have been given different amounts of the human antibodies would be challenged to help establish what blood concentration of antibodies is necessary for protection. The CDC's plans do not currently include a study to demonstrate passive transfer of human serum antibody to macaques and determine the level of antibody necessary for protection. The committee believes that this omission shouict be addressed. Furthermore, the close-ranging study the CDC plans to do would use a series of dilutions where the differences between dilution steps are large. The proposed series starts with a dilution of I:5, then proceeds with 1:2 dilutions, so the series is 1:5, 1:10, 1:20, etc. The committee remains concerned that important information may be unobserved because of the differences

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EXECUTI HE SUMMARY 7 between dilutions and recommends using a dilution series that would be two-foIc3 from the first step: ~ :2, ~ :4, ~ :8, etc. . The committee recommends that the CDC consider both the addition of a passive antibody transfer study, an(l that the animal trial (lose-ranging study design include a more gradual dilution series. Assays addressing correlates of immunity, or Part C The CDC plans a series of assays to establish expected levels of antibodies and other immune system responses, such as proliferation of specific cell types in the systems of immunized humans and animals. The committee found that the scientific account of immune correlates has developed rapidly and commendably in the case of the plans for most of the assays with some exceptions. As an example of such an exception, the CDC proposes to use microarray technology to assess whole-cell gene expression in response to vaccination or challenge. The CDC noted at the time of presentation that the technical proposal for use of this assay was still in development, indeed, at that time the rationale for the use of microarrays was not yet clear to the committee. The committee recommends that the use of microarrays receive further critical attention ant! precise evaluation of what information will be gleaner! and how it will be interpreted ant! applied to anthrax vaccine recipients. Human Leukocyte Antigen (HLAJ sub*tucly The CDC plans a substudy to evaluate the relation if any between HLA subtypes and the development of immunity following immunization against anthrax. The committee fount! that the rationale for the HLA substudy was not yet completely clescribed ant! recommencis further explanation of its role if it is to be part of the CDC's research program. NIP-Directed Projects of the Research Program The NIP has proposed studies that are quite varied in technique ant! rationale and, at the time of writing the interim report, also varied widely in level of development. The committee kept in mind the preliminary nature of some of the proposals while assessing the program. Perhaps the most fully cleveloped projects are studies intended! to assess knowledge, attitudes, anct beliefs (KAB) of service personnel about the anthrax vaccine, or of health care providers about the system for reporting adverse events occurring after a vaccination. The NIP is planning other studies as well, as mentioned later. Survey of knowledge, attitudes, ant! beliefs of military personnel about the anthrax vaccine This survey will be designed to assess the knowledge, attitudes, and beliefs of military service members about the anthrax vaccine, and will be followed with a second survey after a period of two to three years to assess change in knowledge, attitudes, ant! beliefs. The committee found that the rationale for investigating the KAB of service personnel was appropriate. The committee also found, however, that the plans for the study may be compresses! more than warranted. The study plans now call for, first, the use of military personnel focus groups to design a survey, then the administration of the survey, then the provision of such educational materials as the survey results indicate may be needed, and finally the administration of the survey a second time to a second group of military personnel. The committee suggests that if the

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8 CDC ANTHRAX VA CCINE SAFETY & EFFICA CY RESEARCH PROGRAM investigators were to invest more in the design phase of the study, not only with focus groups but also a pilot survey and perhaps cognitive ant! psychometric tests of the potential educational materials, they would then be in a position to design a better targeted survey and to make more informed determinations of parameters such as sample size. In public hearings, the committee heard from military service members outside the health care system about their perceptions of the military health care system. Because of the special role of health care providers in informing people and the influence they have on the KAB of their patients, the committee suggested that health care providers be studied separately about their KAB regarding AVA and the AV1P. Such a separate study might be combined with another planned survey of health care providers (see below). Additionally, both surveysor perhaps even a third, specifically directed surveymight profitably be designed to generate important information about perceptions of the military health care system per se. Concerns about the AV1P, and the use of civilian as well as military health care facilities, may have effects on the KAB of military personnel, as the military may be perceives! by some service personnel (however unfairly) as taking a less direct interest in the health of its troops. That perception then might affect the confidence ant! trust of military patients in their health care providers and the military health care system. . The committee recommends that the CDC consider expanding the design phase of the KAB study of military personnel regarding the anthrax vaccine to include cognitive and psychometric tests and a pilot survey in order to design both the educational interventions and the survey that will relate to them, in order to refine the sampling plan. Survey of knowledge, attitudes, and beliefs of military vaccinee providers about VEERS reporting The national passive surveillance system for medical events occurring after administration of United States licensed vaccines is called the Vaccine Adverse Event Reporting System (VAERS). The VAERS depends on spontaneous voluntary reporting, and like any such system, the VAERS typically receives fewer reports than the actual number of adverse reactions that occur. in the case of the anthrax vaccine, however, some service members and other concerned individuals suspect that the difference may be particularly great, possibly due to aspects of military culture in general or the AV]P in particular that may tend to discourage reporting to VAERS. This survey will be designed to assess the knowledge, attitudes, and beliefs of military and civilian health care providers regarding VAERS reporting, and will be followed with a second survey after a period to be determined to assess change in knowledge, attitudes, and beliefs. The committee found that the rationale for investigating the KAB of military vaccine providers toward VAERS reporting was appropriate, but cautioned that this activity together with associated educational interventions could affect the rate of VAERS reporting. Ongoing monitoring of VAERS reports on the anthrax vaccine therefore should be checked with an independent source of information about adverse events, and both systems compared to reports of adverse events about comparable vaccines. The committee suggests that data from the Defense Medical Surveillance System (DMSS), which tracks the medical encounters and other pertinent data on military personnel, might offer a source for such independent comparisons, and noted further that this is an example of an area of potential collaboration between the CDC and the DoD.

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EXECUTI HE SUMMARY 9 Further, the committee found that the survey of military vaccine providers regarding VAERS might be coupled with the segment of the survey cliscussed above, i.e., the KAB of health care providers about the anthrax vaccine. Thus, the survey discussed here court! be expanded to assess the KAB of health care providers regarding both VAERS reporting ant} the anthrax vaccine ant! perhaps other vaccines. Finally, the committee found that extensive previous research on VAERS reporting might justify reconsideration of the sample size, perhaps allowing a reduction in the number of subjects. The committee recommends that the CDC consider empaneling the design phase of the knowledge, attitudes, and beliefs (KAB) study of military vaccine providers regarding the Vaccine Adverse Event Reporting System (VAERS) reporting to include cognitive and psychometric tests and a pilot survey, in order to design both the educational interventions and the survey that will relate to them and possibly recluce the number of subjects. The committee recommends that the CDC consider including a stiffly of the knowledge, attitudes and beliefs (KAB) of health care providers regarding the anthrax vaccine in the study now designed to assess only KAB on the Vaccine Adverse Event Reporting System (VAERS) reporting. The committee recommends that the CDC make use of independent sources of information concerning vaccine adverse reactions in the military, such as the Defense Medical Surveillance System (DMSS), when assessing any monitoring of, or modification to, Vaccine Adverse Event Reporting System (VAERS) reporting practices and VAERS analyses. CDC proposalfor use of the Short Form 36 The NIP proposes to add to the human clinical trial an application of the Short Form 36 (SF- 36) to evaluate changes in self-reported health status over the course of the human clinical trial. The SF-36 is a very well developed survey instrument for assessing general perceptions of the respondents' own health. The committee found that the rationale for including in the human clinical trial a self- assessment of health status using the SF-36 was appropriate. However, the SF-36 can be augmented by existing, validated items to address populations more specifically. . The committee recommends that the CDC consider including additional items with the SF-36 specific to adverse events possibly associated with immunization, and clearly indicate how the use of the SF-36 will be included in the protocol. Remaining components of the research program directed by the NIP The committee found that the remaining components of the segment of the CDC's research program under the purview of the NIP were not developed in detail sufficient for assessment. These components inclucle data-mining in the VAERS database, hormonal correlates of adverse events in women, long term follow-up of populations immunized at least twenty years previously, and meta-analysis of studies on the safety and efficacy of the anthrax vaccine. The committee has not made specific recommendations on these projects, as they are still early in development.

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10 CDC ANTHRAX VACCINE SAFETY & EFFICACYRESEARCHPROGRAM The committee's recommendations for the interim are listed in Box 4. The committee looks forward to receiving further information and protocols as the CDC continues to develop its overall anthrax vaccine safety and efficacy research program. BOX 4 Collectec! Recommendations General Recommendations . . The CDC should produce a comprehensive description of its research program, including state- ments of the goals of the program and how the plans now undertaken will meet those goals. In addition, the CDC should continue and complete development of the individual projects in the re- search program. The CDC should consider engaging protocol design consultants representing broad scientific ex- pertise who would provide immediate and direct consultation on specific technical matters of study design and execution. The CDC should continue and strengthen collaboration with DoD and NIH wherever possible, including for example much more extensive use of DoD databases such as the Defense Medical Surveillance System (DMSS). Project-Specific Recommendations The committee recommends that, in the human clinical trial, the CDC should consider including a study group immunized at the start of the series (time zero), and one and six months later, fol- lowed by placebo, in order to assess adequacy of a simplified three-dose regimen in the devel- opment of immediate and long-term immunity to anthrax. The committee recommends careful selection of statistical methodologies, as certain techniques including intent-to-treat analysis may be less appropriate in developing conclusions for what will eventually be a military application than they would be for general civilian vaccine development. The committee recommends that the CDC consider, in addition to the proposed clinical trial, pro- spectively designed pharmacoepidemiologic study of military vaccine recipients with both active surveillance and historical data from DMSS for moderate and severe adverse events in order to assess sex or gender and perhaps other risk factors for adverse events among military personnel receiving the anthrax vaccine. The committee recommends that the CDC consider both the addition of a passive antibody trans- fer study, and that the animal trial dose ranging study design include a more gradual dilution se- r~es. The committee recommends that the use of microarrays receive further critical attention and pre- cise evaluation of what information will be gleaned and how it will be interpreted and applied to anthrax vaccine recipients. The committee recommends that the CDC consider expanding the design phase of the KAB study of military personnel regarding the anthrax vaccine to include cognitive and psychometric tests and a pilot survey in order to design both the educational interventions and the survey that will relate to them, in order to refine the sampling plan. The committee recommends that the CDC consider expanding the design phase of the KAB study of military vaccine providers regarding VAERS reporting to include cognitive and psycho- metric tests and a pilot survey, in order to design both the educational interventions and the sur- vey that will relate to them and possibly reduce the number of subjects. The committee recommends that the CDC consider including a study of the KAB of health care providers regarding the anthrax vaccine in the study now designed to assess only KAB on VAERS reporting. The committee recommencis that the CDC make use of independent sources of information con- cerning vaccine adverse reactions in the military, such as the DMSS, when assessing any moni- toring of, or modification to, VAERS reporting practices and VAERS analysis. The committee recommends that the CDC consider including additional items with the SF-36 specific to adverse events possibly associated with immunization, and clearly indicate how the use of the SF-36 will be included in the protocol.