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Executive Summary

In 1985, the Institute of Medicine (IOM) released two related reports titled New Vaccine Development: Establishing Priorities Vol. 1, Diseases of Importance in the United States and Vol. 2, Diseases of Importance in Developing Countries (IOM, 1985a,b). The project had been commissioned by the National Institutes of Health (NIH) as part of its planning for the future. The committee developed a quantitative model that could be used by decisionmakers to prioritize the development of vaccines against a number of disparate infectious diseases considered significant threats to public health. Data on 14 candidate vaccines against diseases of domestic importance were analyzed with the model. Several of the candidate vaccines considered in that report have in fact been licensed since its publication.

Ten years later, NIH requested that IOM convene a committee to assess the progress that has been made since publication of the reports in 1985, to discuss important barriers to vaccine research and development, and to develop another quantitative model for prioritizing vaccine development. There are several important differences between the landmark project released in 1985 and the current project.

  • The current model focuses on conditions of domestic public health importance. There is no second report on international concerns.

  • Candidate vaccines were to be analyzed with the model if they could be developed (achieve licensure) within the next two decades.

  • The committee was explicitly asked to consider therapeutic vaccines directed against chronic conditions such as autoimmune diseases and cancers.



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Vaccines for the 21st Century: A Tool for Decisionmaking Executive Summary In 1985, the Institute of Medicine (IOM) released two related reports titled New Vaccine Development: Establishing Priorities Vol. 1, Diseases of Importance in the United States and Vol. 2, Diseases of Importance in Developing Countries (IOM, 1985a,b). The project had been commissioned by the National Institutes of Health (NIH) as part of its planning for the future. The committee developed a quantitative model that could be used by decisionmakers to prioritize the development of vaccines against a number of disparate infectious diseases considered significant threats to public health. Data on 14 candidate vaccines against diseases of domestic importance were analyzed with the model. Several of the candidate vaccines considered in that report have in fact been licensed since its publication. Ten years later, NIH requested that IOM convene a committee to assess the progress that has been made since publication of the reports in 1985, to discuss important barriers to vaccine research and development, and to develop another quantitative model for prioritizing vaccine development. There are several important differences between the landmark project released in 1985 and the current project. The current model focuses on conditions of domestic public health importance. There is no second report on international concerns. Candidate vaccines were to be analyzed with the model if they could be developed (achieve licensure) within the next two decades. The committee was explicitly asked to consider therapeutic vaccines directed against chronic conditions such as autoimmune diseases and cancers.

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Vaccines for the 21st Century: A Tool for Decisionmaking Vaccines directed against human immunodeficiency virus are not within the scope of this project because of the rather prominent place that such vaccines already have within NIH. THE ANALYTIC FRAMEWORK A variety of analytic methods are available for comparative assessments to support priority-setting and resource allocation decisions. In selecting the approach to be used for this study, the committee had to have a means of comparing the anticipated health benefits and costs of vaccine use across drastically different forms of illness, ranging from pneumonia, ulcers, and cancers to temporary and long-term neurologic impairments. Furthermore, although some of the vaccines included in the study are intended to treat illness, most will be used in the more familiar role of preventing disease. The committee adopted a cost-effectiveness approach that makes it possible to compare potential new vaccines on the basis of their anticipated impact on morbidity and mortality and on the basis of the costs for health care, use of the vaccine, and vaccine development. The analysis cannot provide the value judgments required to determine whether expected health benefits and costs justify a particular investment in vaccine development. The aim of the analysis is to clarify trade-offs in decisions to invest in the development of one vaccine as compared to another. The basis of comparison is a cost-effectiveness ratio that is expressed as cost per unit of health benefit gained. Monetary costs—the numerator of the ratio—reflect changes in the cost of health care that are expected to result from the use of an intervention such as a new vaccine plus costs associated with developing and delivering the intervention. Health benefits—the denominator of the ratio—are measured in terms of quality-adjusted life years (QALYs) gained by using the intervention under study. QALYs are a measure of health outcome that assigns to each period of time a weight, ranging from 0 to 1, corresponding to the health-related quality of life during that period, where a weight of 1 corresponds to optimal health, and a weight of 0 corresponds to a health state judged equivalent to death. These are then aggregated across time periods. The concept of QALYs, developed in the 1970s, was designed as a method that could integrate for an individual the health improvements from changes in both the quality and quantity of life, and could also aggregate these improvements across individuals. QALYs provide a summary measure of changes in morbidity and mortality that can be applied to very different health conditions and interventions. Interventions that produce both a health benefit and cost savings are inherently cost-effective, but many other interventions that do not save costs produce benefits at costs that are judged to be reasonable. An analysis such as the one performed by the present committee is a valuable tool for decisionmakers who must set priorities and allocate resources. It simplifies a complicated picture in which vastly different forms of illness and health benefits

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Vaccines for the 21st Century: A Tool for Decisionmaking must be compared and related to a variety of costs. It cannot, however, address all of the qualitative judgments that shape policy decisions. The cost-effectiveness approach also provides a framework within which the components of the analysis can be specified in detail and evaluated by those who use the results. This is particularly helpful for the committee’s analysis, which, of necessity, rests on many estimates and assumptions about the characteristics of future vaccines and their likely impact on health and costs. The detailed specification of the components of the model also facilitates sensitivity analyses for the testing of alternative estimates and assumptions, either for individual patients or for all patients. The cost-effectiveness analysis used by the committee can provide an estimate of the cost of achieving the anticipated health benefit for each of the vaccines studied, but it cannot determine whether that health benefit is worth the cost. That decision is a value judgment and should reflect consideration of many factors that are not included in the analysis. For example, the committee’s analysis does not consider what resources will or should be available for vaccine development or how many vaccine candidates should be given priority for development. Furthermore, the analysis does not address the allocation of resources between vaccine development and the development and use of other forms of prevention or treatment. Although priority setting and resource allocation can be informed by economic analyses, they require value judgments that cannot be captured by a cost-effectiveness model. It is also important to note that the results of the analysis depend on the accuracy and appropriateness of the data and the assumptions that are used, a point of particular relevance to the committee’s work. Assumptions were necessary both to compensate for the limitations of the available data on current disease incidence and costs of care and to simplify some analytic tasks. Furthermore, the vaccines that are the focus of the study are still in development, making it necessary to rely on expert judgment for values such as costs of vaccine development and time until a vaccine will be licensed for use. Those who use the committee’s analysis or similar types of studies should keep in mind that although the results are quantified they should not be treated as precise measures. ETHICAL ISSUES Cost-effectiveness analysis raises several ethical issues, especially in the context of priority setting. Some ethical concerns are a function of value judgments incorporated into the model, and others are related to issues that are not addressed. For example, within the model, all QALYs are considered equal without regard to the nature of the health benefit that they measure. Thus, the number of QALYs gained through many people receiving a small health benefit as a result of a reduction of a minor form of illness can be the same as the number of QALYs gained by averting a very small number of deaths.

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Vaccines for the 21st Century: A Tool for Decisionmaking The analysis is based on a societal perspective on health effects and costs in the United States; that is, all significant health outcomes and costs are taken into consideration, regardless of who experiences them. Thus, if use of a vaccine reduces hospital care costs, the analysis does not have to distinguish between cost savings that accrue to individuals and savings that accrue to insurers. The societal perspective is in contrast to a more selective perspective, such as that of a particular government agency, health plan, or vaccine manufacturer used to examine these factors in other analyses. For these more selective analyses, the assessment of health effects might be limited to the members of a health plan or to a particular age group such as the Medicare population. Similarly, the costs (or savings) included in the analysis would be limited to those that would be incurred by the particular agency or organization. Costs borne by individuals or other organizations would not be considered in the analysis. A societal perspective, however, examines all costs and the health experience of the entire population. RESULTS The committee intends this model to be used as a dynamic instrument. The basic model and the mathematics used to create the model are described in detail in the report. In order to facilitate such use of this model, it can be accessed electronically free of charge (see the IOM home page at www.iom.edu/vaccinepriorities for more information). The committee developed several examples of hypothetical candidate vaccines, which are discussed in the report. These simplified examples are useful both for understanding key components of the model (and the effects of changes in those key components) and for those who wish to access and manipulate the model itself. The committee believes that this model has great utility even for those not charged with prioritizing vaccine development. Because only part of the model accounts for vaccine development time and costs, the model can be used after licensure of a vaccine to study and plan for vaccination program implementation. The committee will not recommend which vaccines should be accorded research and development priority; it was not charged with doing so. In fact, the committee offers a single recommendation: Policymakers (government agencies, research coordinators, private industry, philanthropic groups) charged with prioritizing vaccine development and vaccination program implementation should use as an aid in that prioritization process a model, such as that developed for this report, that is quantitative and relatively unbiased toward a specific vaccine candidate. Such a model should use standardly accepted data and techniques such as measures of health impact, and discounting.

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Vaccines for the 21st Century: A Tool for Decisionmaking The committee selected 26 candidate vaccines (in addition to the hypothetical examples) to illustrate the conceptual framework and the analytic model that it developed. The committee struggled early in its deliberations to select the candidate vaccines to be analyzed in this report. These 26 candidate vaccines are of interest to many people, could be developed within the next two decades, are directed against conditions of domestic importance, and illustrate important components of the model. The committee was guided in their choices by a set of exclusion criteria. The following were bases for exclusion: (1) potentially vaccine-preventable conditions for which other preventive interventions were deemed more appropriate; (2) conditions for which basic science information was insufficient to predict vaccine development and licensure within 20 years; and (3) diseases of primarily non-domestic health importance. These exclusion criteria were used in the analysis undertaken for this report in order to limit the task in front of the committee. The exclusion criteria were not intended to guide public policy on vaccine R&D investments by either the public or private sector. The primary analysis used by the committee is the annualized present value of the costs per quality-adjusted life year (QALY) gained by a vaccine strategy. The committee strongly cautions against focusing on a single ranking of candidate vaccines. In fact, the committee has deliberately chosen not to present a detailed ranking for the candidate vaccines. Any such ranking taken out of context of the rest of the report would assume an importance that is inappropriate given the uncertainty surrounding the data and the caveats about the modeling assumptions. The committee has placed candidate vaccines within general levels that reflect the results of the total analysis. The candidate vaccines fall into four reasonably distinct groupings or levels. That is, use of some of the candidate vaccines would save money while also saving QALYs and some of the candidate vaccination strategies would incur costs for each QALY gained. The four groups are: Level I Most Favorable Saves money and QALYs Level II More Favorable Costs<$10,000 per QALY saved Level III Favorable Costs>$10,000 and<$100,000 per QALY saved Level IV Less Favorable Costs>$100,000 per QALY saved. Seven candidate vaccines fall into the most favorable (I) category: those with which a vaccination strategy would save money. The Level I candidate vaccines are as follows (in alphabetical order): cytomegalovirus (CMV) vaccine administered to 12-year-olds, influenza virus vaccine administered to the general population (once per person every 5 years or one-fifth of the population per year), insulin-dependent diabetes mellitus therapeutic vaccine, multiple sclerosis therapeutic vaccine,

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Vaccines for the 21st Century: A Tool for Decisionmaking rheumatoid arthritis therapeutic vaccine, Group B streptococcus vaccine to be well-incorporated into routine prenatal care and administered to women during first pregnancy and to high-risk adults (at age 65 years and to people less than age 65 years with serious, chronic health conditions), and Streptococcus pneumoniae vaccine to be given to infants and to 65-year-olds. Nine candidate vaccines fall into the more favorable (II) category: those with which a vaccination strategy would incur small costs (less than $10,000) for each QALY gained. The Level II vaccine candidates are as follows (in alphabetical order): chlamydia vaccine to be administered to 12-year-olds, Helicobacter pylori vaccine to be administered to infants, hepatitis C virus vaccine to be administered to infants, herpes simplex virus vaccine to be administered to 12-year-olds, human papillomavirus vaccine to be administered to 12-year-olds, melanoma therapeutic vaccine, Mycobacterium tuberculosis vaccine to be administered to high-risk populations, Neisseria gonorrhea vaccine to be administered to 12-year-olds, and respiratory syncytial virus vaccine to be administered to infants and to 12-year-old females. Four candidate vaccines fall into the favorable (III) category: those with which a vaccination strategy would incur moderate costs (more than $10,000 but less than $100,000) per QALY gained. The Level III vaccine candidates are as follows (in alphabetical order): parainfluenza virus vaccine to be given to infants and to women in their first pregnancy, rotavirus vaccine to be given to infants, Group A streptococcus vaccine to be given to infants, and Group B streptococcus vaccine to be given to high-risk adults and to either 12-year-old females or to women during first pregnancy (low utilization). Seven candidate vaccines fall into the less favorable (IV) category: those with which a vaccination strategy would incur significant costs (more than $100,000 and up to well more than $1 million) per QALY gained. The Level IV vaccine candidates are as follows (in alphabetical order): Borrelia burgdorferi vaccine to be given to resident infants born in and immigrants of any age to geographically defined high-risk areas,

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Vaccines for the 21st Century: A Tool for Decisionmaking Coccidioides immitis vaccine to be given to resident infants born in and immigrants of any age of geographically defined high-risk areas, enterotoxigenic Escherichia coli vaccine to be given to infants and travelers, Epstein-Barr virus vaccine to be given to 12-year-olds, Histoplasma capsulatum vaccine to be given to resident infants born in and immigrants of any age of geographically defined high-risk areas, Neisseria meningitidis type b vaccine to be given to infants, and Shigella vaccine to be given to infants and travelers or to travelers only. Several of the Level I candidate vaccines were also discussed in the 1985 IOM report on vaccine prioritization. The disease burden of the four infectious conditions in Level I remains staggering due to many factors: the numbers of infected people, the seriousness of the health states caused by the infection, and the long-term sequelae (death and permanent impairment) and subsequent loss of quality of life (as measured in QALYs). The inclusion of candidate vaccines that are therapeutic suggests that vaccine strategies for noninfectious, chronic conditions holds much promise for improving health. The inclusion in Levels I and II of candidate vaccines to be administered in puberty should serve as an indication for planning by vaccination program implementers for new approaches to encouraging the use of vaccines. The appropriate use of these candidate vaccines will require acceptance by parents, children, and health care providers that all people entering puberty are potentially sexually active. This also will require a health care milieu that is more capable than it is now of routine vaccination at puberty. Factors such as health beliefs, health care practices, performance measurements for health plans, and school entry laws have contributed to relatively successful childhood immunization efforts. These do not yet exist for the newly emerging “adolescent” or “pubertal” vaccination visits that are now recognized as important for continued protection against measles and rubella, for example. Another challenge will be immunization of pregnant women against Group B streptococcus. The report discusses the barriers, particularly legal barriers to developing vaccines to be administered during pregnancy. The model assumes that these barrier are overcome and that immunization of pregnant women can become a standard part of prenatal care. As stated several times in the report, the committee has not recommended which vaccines should be accorded development priority, nor will it recommend which vaccines should not be developed. Research and development of Level IV candidate vaccines can be justified on several levels. Research on these vaccines can lead to fundamental discoveries important to other candidate vaccines in the future or to other areas of basic research. Disease patterns could change and a need for these vaccines could become more compelling. These vaccines could be important due to disease burden in other countries, which is not factored in as part of this analysis. The committee argues in the report that inclusion of a candidate vaccine for malaria or dengue hemorrhagic fever in a report analyzing

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Vaccines for the 21st Century: A Tool for Decisionmaking U.S. public health burden was less compelling than inclusion of other candidate vaccines, and might fall into Level IV. An analysis of international disease burden for these candidate vaccines would likely lead to results that fall into more favorable levels. OBSERVATIONS In the course of developing and illustrating this model, the committee discussed general issues relating to the funding of research, neglected opportunities for vaccine research and development, the qualitative judgments integral to this modeling exercise, and vaccine program concerns. The committee closes the report with a series of observations that it hopes are as seriously considered as the analytic model that was the focus of this project. Stable and sufficient funding of basic research by the federal government (which has an added benefit of recruiting young investigators from all fields of biomedical science into vaccinology), as well as creative funding mechanisms and research alliances, are crucial to assure that effective, safe, and needed vaccines will be carried through the development stage into licensure. Research and development is an expensive enterprise currently supported through a natural and fluid mix of public and private funding. New knowledge resulting from basic research funded by the federal government and private foundations is the integral first step that allows applied research and development to move forward into the private sector. Although private industry supports basic research, the most important role it plays is to assume the costs of applied research and development. The committee can envision situations, however, where the need for a vaccine is compelling but for which the return on investment cannot be guaranteed. Examples of impediments to making a profit include possible litigation, a small target population, lack of acceptance of a vaccine strategy for a specific condition, and high costs expected of newer vaccines. Sometimes the market fails, and without subsidization candidate vaccines become neglected. The committee discussed other barriers to achieving the maximum health benefit from the candidate vaccines. Vaccine delivery poses significant barriers to effective prevention and control of infectious disease. Children in the United States can receive up to 6 different vaccines (adding up to a maximum of 32 antigens, 6 visits to a health care provider, and 16 injections) before 2 years of age. Compliance with recommended immunizations by 2 years of age is still below that achieved by 5 years of age, primarily because of mandatory immunization for school entry. Combination vaccines promise to reduce some of the barriers to compliance but will not be a panacea. The combinations will help increase acceptance and utilization of vaccines, but clinical trial design issues are not trivial. The committee hopes that government, the medical community, the public, and vaccine manufacturers carefully think about rational approaches to combination vaccines and vaccine schedules. Furthermore, noninjection

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Vaccines for the 21st Century: A Tool for Decisionmaking routes (e.g., oral, intranasal, or cutaneous delivery) should receive consideration. At the same time, the committee knows that market forces and corporate alliances will drive the availability of combination products. The committee’s analysis demonstrates that not all candidate vaccines will save money. Some new vaccines might be very expensive to purchase and develop. The target population might be very small. However, the health benefits for some people might still be compelling. Use of these vaccines will require a shift from an expectation that vaccines are always cost-saving to an acknowledgment that the health benefits of some vaccines might be worth the cost. Many vaccines are not covered by health care plans—neither indemnity plans nor managed care. Financial incentives to insurers or to individuals might be crucial for encouraging the use of vaccines. However, the cost of vaccines to the individual and to insurers is not the only impediment to vaccine use. Vaccines, like other public health successes such as clean water, fluoridation to prevent caries, and food safety measures are a victim of their own success; people forget how dangerous vaccine-preventable disease can be and become complacent. This false sense of security strikes individuals, communities, health care providers, and policymakers. It is not until the system fails and illness surges (such as with antibiotic resistance, nosocomial infections, the measles outbreaks that occurred in the late 1980s, or food-borne illness) that we pay the price for interventions, such as vaccines, that are not yet developed or implemented. The committee urges careful consideration, but not rigidity, in the use of evidence-based approaches, such as the qualitative framework and quantitative model developed for this report, for prioritization of research, development, and use of vaccines as well as other preventive and therapeutic interventions. The committee, while acknowledging the limitations of modeling exercises in general and of the one it developed and used in particular, does believe that modeling is useful and important when attempting to compare widely divergent vaccine-preventable conditions. It hopes that the inferences derived from the model will be useful to the vaccine science community, vaccine manufacturers, and research and program policymakers.

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