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Prepublication Copy UNCORRECTED PROOF Vaccines for the 21st Century:
Kathleen R. Stratton, Jane S. Durch and Robert S. Lawrence, Editors Committee to Study Priorities for Vaccine Development Division of Health Promotion and Disease Prevention INSTITUTE OF MEDICINE NATIONAL ACADEMY PRESS Notice | Committee | Contents | Executive Summary NATIONAL ACADEMY PRESS • 2101 Constitution Avenue, N.W. • Washington, D.C. 20418 NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance.
The Institute of Medicine was chartered in 1970 by the National Academy of Sciences to enlist distinguished members of the appropriate professions in the examination of policy matters pertaining to the health of the public. In this, the Institute acts under the Academy's 1863 congressional charter responsibility to be an adviser to the federal government and its own initiative in identifying issues of medical care, research, and education. Dr. Kenneth I. Shine is president of the Institute of Medicine.
This project has been funded in whole with Federal funds from the National Institutes of Allergy and Infectious Diseases, National Institutes of Health, under Contract No. N01-AI-45237. The views presented are those of the Institute of Medicine Committee to Study Priorities for Vaccine Development and are not necessarily those of the funding organization.
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Copyright 1999 by the National Academy of Sciences. All rights reserved.
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COMMITTEE TO STUDY PRIORITIES FOR VACCINE DEVELOPMENT Robert S. Lawrence, M.D. (Chair), Associate Dean for Professional Education and Programs and Professor of Health Policy and Management, Johns Hopkins School of Hygiene and Public Health, Baltimore, MD
Contents EXECUTIVE SUMMARY, 1
Executive Summary In 1985, the Institute of Medicine (IOM) released two related reports entitled 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 important 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 publication of that report. 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. • 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, costs for use of the vaccine, and costs for 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 benefit 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 for each of the vaccines studied an estimate of the cost of achieving the anticipated health benefit, 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 for many people receiving a small health benefit as a result of a reduction of a minor form of illness can be the same number as the number of QALYs achieved by averting a very small number of deaths. 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 contrasts 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 IOM Homepage at www.nas.edu/iom for information). The committee developed several examples of hypothetical candidate vaccines, which are discussed in the report. These somewhat simplistic 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 committees offers a single recommendation:
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 urges great caution 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, some of the candidate vaccines would save money while also saving QALYs and some of the candidate vaccine strategies would incur costs for each QALY gained. The four groups are:
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, • 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, • Coccidioides immitis vaccine to be given to resident infants born in and immigrants of any age to 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 into 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. The Level I candidate vaccines contained several candidate vaccines discussed in the IOM report on prioritization from 1985. 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 non-infectious, 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 now are recognized as important for protection against measles and rubella, for example. Another challenge will be immunization of pregnant women against streptococcus, Group B. The report discusses the particular barriers, particularly legal, to the development of vaccines to be administered during pregnancy. The model assumes that barrier is overcome. The model also assumes that immunization of pregnant women can become a standard part of prenatal care. The committee has, as stated several times in the report, 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 burdens 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 for dengue hemorrhagic fever in a report focused on U.S. public health problems 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 Level IV. 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), 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 maximum health benefit from the candidate vaccines. Vaccine delivery poses significant barriers to effective prevention and control of infectious disease. Children in the U. S. 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 two years of age. Compliance with recommended immunizations by 2 years of age is far below that achieved by 5 years of age, primarily because of mandatory immunization for school entry. The promise of combination vaccines is real 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 routes, e.g., oral, intranasal or cutaneous delivery should receive consideration. At the same time, the committee knows that market forces and corporate alliance will drive the availability of combination products. The model 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 always are 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 to the individual and to insurers of vaccines 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 individual, communities, health care providers, and policy makers. It is not until the system fails and illness surges (such as with antibiotic resistance, nosocomial infections, measles outbreaks in the late 1980's or food borne illness) that we pay the price for interventions, such as vaccines, 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, the vaccine manufacturers, and research and program policymakers. |