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Vaccines for the 21st Century: A Tool for Decisionmaking (2000)

Chapter: Overview of Analytic Approach and Results

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Suggested Citation:"Overview of Analytic Approach and Results." Institute of Medicine. 2000. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: The National Academies Press. doi: 10.17226/5501.
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4
Overview of Analytic Approach and Results

The committee was charged with developing an analytic framework and an associated quantitative model that can aid in setting priorities for vaccine research and development. The committee sought an approach that makes it possible to compare the different potential new vaccines on the basis of their anticipated impact on both costs and benefits. The committee has used a cost-effectiveness model adapted from the model developed for the previous Institute of Medicine (IOM) study of priorities for vaccine development (IOM, 1985a). The model was implemented with spreadsheet software run on a personal computer. This chapter reviews key strengths and limitations of cost-effectiveness models, provides an overview of key components of the committee’s analysis, illustrates certain features of the model with hypothetical vaccine examples, and describes the results obtained by the committee when the model was applied. The committee examined 27 separate cases, each representing a specific combination of pathogen or condition, a candidate vaccine, and a population targeted to receive the vaccine. The committee examined 26 candidate vaccines, but included two distinct target populations for one candidate, thus 27 separate cases (see Table 4–1). The specifics of the calculations are described in Chapter 5 for those readers who desire more detailed explanations.

A COST-EFFECTIVENESS APPROACH

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

Suggested Citation:"Overview of Analytic Approach and Results." Institute of Medicine. 2000. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: The National Academies Press. doi: 10.17226/5501.
×

Table 4–1 Vaccine Candidates

Vaccine

Target Population

Utilization (%)

Purchase $ (per dose)

Time to Licensure

Development $ (millions)

BORRELIA

 

 

Infants (restricted geography)

90

100

3

120

 

Migrants (restricted geography)

10

100

3

120

CHLAMYDIA

 

 

12-year-olds

50

50

15

360

COCCIDIOIDES IMMITIS

 

 

Infants (restricted geography)

90

50

15

360

 

Migrants (restricted geography)

10

50

15

360

CYTOMEGALOVIRUS

 

 

12-year-olds

50

50

7

360

ENTEROTOXIGENIC E. COLI

 

 

Infants

90

50

7

240

 

Travelers

30

50

7

240

EPSTEIN-BARR VIRUS

 

 

12-year-olds

50

50

15

390

HELICOBACTER PYLORI

 

 

Infants

30

50

7

240

HEPATITIS C

 

 

Infants

90

50

15

360

HERPES SIMPLEX VIRUS

 

 

12-year-olds

50

50

7

240

HISTOPLASMA CAPSULATUM

 

 

Infants (restricted geography)

90

50

15

360

 

Migrants (restricted geography)

10

50

15

360

HUMAN PAPILLOMA VIRUS

 

 

12-year-olds

50

100

7

360

INFLUENZA

 

 

Universal (every 5 years)

30

50

7

360

INSULIN-DEPENDENT DIABETES MELLITUS (therapeutic)

 

 

Early-stage patients

90

500

15

360

Suggested Citation:"Overview of Analytic Approach and Results." Institute of Medicine. 2000. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: The National Academies Press. doi: 10.17226/5501.
×

MELANOMA

 

 

Patients

90

500

7

360

MULTIPLE SCLEROSIS

 

 

Patients

90

500

15

360

MYCOBACTERIUM TUBERCULOSIS

 

 

High-risk populations

90

50

15

360

 

Universal in multidrug-resistant areas

60

50

15

360

NEISSERIA GONORRHEA

 

 

12-year-olds

50

50

15

360

NEISSERIA MENINGITIDIS B

 

 

Infants

90

50

7

300

PARAINFLUENZA

 

 

Infants

90

50

7

300

 

12-year-old females

90 or 10

50

7

360

RESPIRATORY SYNCTIAL VIRUS

 

 

Infants

90

50

7

360

 

12-year-old females

50

50

7

360

RHEUMATOID ARTHRITIS

 

 

Patients

90

500

15

360

ROTAVIRUS

 

 

Infants

90

50

3

120

SHIGELLA

 

 

Infants

90

50

7

240

 

Travelers

30

50

7

240

STREPTOCOCCUS GROUP A

 

 

Infants

90

50

15

400

STREPTOCOCCUS GROUP B

 

 

High-risk people, and either:

30

50

7

See below

 

12-year-old females or

50

50

7

300

 

Women in their first pregnancy

10 or 90

50

7

400

STREPTOCOCCUS PNEUMONIA

 

 

Infants

90

50

3

240

 

65-year-olds

60

50

3

240

Suggested Citation:"Overview of Analytic Approach and Results." Institute of Medicine. 2000. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: The National Academies Press. doi: 10.17226/5501.
×

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, some of the vaccines included in the study are intended to treat illness, while most will be used in the more familiar role of preventing disease.

Cost-effectiveness analysis was judged to be the most satisfactory way to make these comparisons. The basis of comparison typically 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—increasingly 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 (Gold et al., 1996). The concept of QALYs, developed in the 1970s, was designed as a method that could integrate the health improvements for an individual from changes in both the quality and quantity of life, and could also aggregate these improvements across individuals (Torrance and Feeny, 1989). 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.

Although cost-effectiveness analysis facilitates comparisons among interventions, comparisons across studies are often undermined by critical differences in assumptions and analytic techniques. A report by the Panel on Cost-Effectiveness in Health and Medicine (Gold et al., 1996), convened by the U.S. Public Health Service, reviews the field and provides recommendations intended to improve the quality and comparability of studies. In its assessment of potential new vaccines, the committee has generally followed the recommendations of that panel. An analysis such as the one performed by the present committee is a valuable tool in a variety of contexts 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 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.

Suggested Citation:"Overview of Analytic Approach and Results." Institute of Medicine. 2000. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: The National Academies Press. doi: 10.17226/5501.
×

Reasons for Using Cost-Effectiveness Analysis

Several factors make cost-effectiveness analysis particularly well-suited to the committee’s assessment of vaccine development priorities. It is a well-established tool for informing decisions regarding the allocation of resources related to health and health care. Comparisons of the benefits of preventing or treating very different forms of illness are made possible by measuring all health benefits in terms of QALYs. Cost-benefit analysis is similar in many respects to cost-effectiveness analysis but relies on valuing benefits in monetary terms. Cost-effectiveness analysis values health consequences in terms of their impact on the health of a community, while cost-benefit analysis values those consequences in terms of the monetary willingness of citizens to pay for them. Cost-effectiveness analysis is generally preferred for health-related studies because many health policymakers and analysts question the appropriateness of measuring the value of additional life expectancy or other health benefits in monetary terms, and because they have ethical qualms about using willingness to pay (and, implicitly, ability to pay) as a basis for guiding resource allocation.

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 a population. Sensitivity analyses are discussed later in the chapter.

Limits of Cost-Effectiveness Analysis

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. Moreover, 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

Suggested Citation:"Overview of Analytic Approach and Results." Institute of Medicine. 2000. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: The National Academies Press. doi: 10.17226/5501.
×

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. Moreover, 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 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. Although ethical issues are discussed in greater detail in Chapter 6, a few ethical concerns should be mentioned here in the context of cost-effectiveness analyses. Some of these 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 as the number of QALYs achieved by averting a very small number of deaths. Some question the appropriateness of using such trade-offs. (See Chapter 6 for additional discussion.)

Whether these quality-adjusted years of life should be counted equally across all ages is a separate concern. The committee specifically chose not to follow the practice of some analysts who have assigned a greater value to the economically productive adult years than to years at younger or older ages (Murray and Lopez, 1996). The committee’s principal analysis follows the standard practice for QALY-based analysis of assuming that a QALY, once calculated, is not directly affected by age. The structure of the model, however, would permit others to perform analyses that incorporate age- or condition-specific weighting of QALYs.

Not addressed by the model are issues of equity in the allocation of resources. Some might argue that the needs of specific populations such as those defined by race, ethnicity, socioeconomic status, or health status should be given a higher priority than would be suggested by a strict ranking of cost-effectiveness ratios. The responsibility for judging what constitutes an equitable allocation should lie with accountable policymakers.

Analytic Perspectives

The analysis reflects several decisions by the committee regarding the approach to be used. These decisions resulted in the adoption of a societal per

Suggested Citation:"Overview of Analytic Approach and Results." Institute of Medicine. 2000. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: The National Academies Press. doi: 10.17226/5501.
×

spective for measuring health effects and costs; a domestic perspective for identifying diseases of significance; an incremental perspective regarding the benefits that the vaccines under study would bring in comparison to current forms of care; and a steady-state perspective for assessing likely levels of vaccine use.

A societal perspective for measuring health effects and costs in the United States means that 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 can be contrasted with a more selective perspective, such as that of a particular government agency, health plan, or vaccine manufacturer, that might be 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.

The analysis also reflects the domestic perspective in the charge to the committee. The vaccine candidates analyzed in depth were selected on the basis of their relevance to health status in the United States, not globally. Thus, for the vaccines that are likely to be used in many countries in addition to the United States, the analysis includes only a portion of the total health benefits and savings in costs of care that can be expected for relatively little additional investment in vaccine development. Excluded from the analysis are other vaccines that would be valuable for conditions that are important health problems in other countries, such as malaria and schistosomiasis, but that pose little threat in the United States. The committee would have liked to have examined the effect of a global perspective on the results of the analysis. To do so would have greatly increased the committee’s task and would have introduced sufficient uncertainties into the estimates that their relevance for domestic policy would be greatly undermined. Additional discussions of conditions of particular importance outside of the United States appear in Chapters 3 and 7.

The cost-effectiveness ratios calculated for this study represent the estimated incremental changes in costs and health effects that can be expected with the use of a new vaccine compared to those from the use of current forms of prevention and treatment. For the vaccines against influenza and Streptococcus pneumoniae, the analysis must also consider the costs and health effects associated with the use of existing vaccines.

The committee has based its analysis on the patterns of annual vaccine use that are expected at the point at which a “steady-state” of usage has been achieved. When a vaccine is first introduced, initial patterns of use can be expected to be unstable and to differ from those that will be seen in later years when

Suggested Citation:"Overview of Analytic Approach and Results." Institute of Medicine. 2000. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: The National Academies Press. doi: 10.17226/5501.
×

a more stable level of use has been reached. During this period of instability, both costs and health benefits will vary from year to year in ways that are difficult to estimate and that will differ from the typical costs and health benefits expected at steady-state levels of use. Several factors are likely to contribute to the early variation and instability in patterns of use. As the health care system and the public become more familiar with a vaccine, levels of use in a vaccine’s planned target population are likely to increase over time. The initial period of vaccine use is also likely to be affected by efforts to “catch up” on coverage. For preventive vaccines, this would involve administering additional doses of vaccines to groups beyond the target population, thus increasing the cost of vaccine delivery and altering the assumptions regarding the timing of health benefits relative to vaccination. Similarly, for some therapeutic vaccines, a catch-up effort might include administering the vaccine to a portion of the population of patients who already have a condition in addition to newly diagnosed cases. Treating these patients might contribute some added health benefits in the early years of vaccine use, as well as added costs, that would not match the levels associated with what the committee’s analysis has assumed to be a typical level of vaccine use. (In the case of diabetes and perhaps other therapeutic vaccines, however, such catch-up vaccination efforts will not be effective in treating established cases of illness.)

Time Horizon and Discounting

The conditions that the committee studied have different time lines for development of a vaccine, the age at which the vaccine would be given, and the age at which health effects and related costs would be experienced. For example, one vaccine might be available in 3 years for use in infants to prevent a condition that usually occurs within the first 2 years of life. Another vaccine might require 15 years in development for use in adolescents to prevent a condition that usually occurs at about age 50. For the first vaccine, benefits might be observable within 5 years, but for the second one, more than 50 years would be needed to realize the benefits of the vaccine.

To provide a common point of comparison for the analysis, the health effects and costs for each case are calculated on an “annualized” basis and are discounted to their present values. The annualized estimates reflect the lifetime stream of health effects and costs that result from cases occurring during 1 year. The costs of vaccine development, which are assumed to be independent of the number of people who will use the vaccine, are prorated, or “amortized,” to produce an estimate of annual costs.

Determining the “present value” of these health effects and costs requires the use of discounting to adjust their value on the basis of the interval between the present and the time at which the health effect or the cost will occur in the future. A standard assumption in cost-effectiveness analysis is that future dollars and health benefits have a lower value than dollars and health benefits available in the present. The scale of this “time preference” for present over future con-

Suggested Citation:"Overview of Analytic Approach and Results." Institute of Medicine. 2000. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: The National Academies Press. doi: 10.17226/5501.
×

sumption is captured by the discount rate, which has been set at 3% for the committee’s basic analysis, as recommended in the review of cost-effectiveness methods (Gold et al., 1996). The discount rate is also used to amortize the fixed expenditure for vaccine development. Because some analysts question the appropriateness of discounting health effects (for a discussion of the issue, see Gold et al., 1996), the committee tested the impacts of using no discounting in its sensitivity analyses, which are reviewed later in this chapter.

MODEL OVERVIEW

The essential calculation for the cost-effectiveness ratio for each candidate vaccine is the net cost (i.e., the costs of vaccine development plus the costs of administering the vaccine to the target population, minus the saving in cost of care expected with the use of the vaccine) divided by the expected gain in health benefits. Interested readers are referred to several recent publications (e.g., Gold et al. 1996, Russell et al., 1996).

Health Benefits: The Denominator

Measuring the health benefits of vaccine use requires a quantitative assessment of a condition’s “burden of illness” in terms of both morbidity and mortality. The difference between the current burden of illness associated with each condition and the level that would be expected if a vaccine were in use represents the health benefit attributable to the vaccine. To compare the vaccines under study, the measure of the burden of illness must be applicable to widely varied conditions (e.g., pneumonia, meningitis, diarrhea, urethritis, melanoma, diabetes). The committee made this comparison using QALYs, a standard measure of burden of illness and health benefits for cost-effectiveness analyses (Gold et al., 1996).* QALYs reflect the combined impact of morbidity and mortality on the health-related quality of years of life lived. The measure can be applied to the total lifetime or to a specified interval such as the time spent with a temporary disability. The key steps in calculating health benefits are briefly reviewed here and illustrated further in Box 4–1. The entire process is reviewed in greater detail in Chapter 5 and summarized in Box 5–1.

*  

A substantial literature exists on the theory and practice of quantifying health status and the burden of illness. Key issues include defining the domains of health status, developing instruments to measure health status, determining preferences for health states, and applying health status measures to quality of life adjustments. Some sources that readers may wish to consult include Bergner et al., 1981; Drummond et al., 1987; Kaplan and Anderson, 1988; Ware and Sherbourne, 1992; Patrick and Erickson, 1993; McDowell and Newell, 1996; IOM, 1998.

Suggested Citation:"Overview of Analytic Approach and Results." Institute of Medicine. 2000. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: The National Academies Press. doi: 10.17226/5501.
×

BOX 4–1 Illustrating the Calculation of a Vaccine’s Health Benefits

The basic features of the calculation of QALYs can be illustrated with a simple scenario. Assume 100,000 cases of an illness X, occurring at an equal rate at all ages and no deaths. Half of the cases of disease result in a mild illness determined to have an HUl-based quality-adjustment weight of .90 and half in a moderate illness with a quality adjustment weight of .70. Either form of illness is assumed to last 2 weeks (.0384 years).

The quality-adjustment weights for illness X must be adjusted for the underlying health status of the population. Using survey-based data on general health status, the average quality-adjustment weight for the health status of the population without this illness is .896. Thus the adjustment weight for the mild form of illness becomes .806 (.90 • .896) and the weight for the moderate form of illness becomes .627 (.70 • .896).

To calculate QALYs, these adjustment weights are multiplied by the time spent with the illness. With a 2-week duration, a case of mild illness occurring in a given year accounts for .031 QALYs (.806 • .0384). With the same 2-week duration, a case of moderate illness accounts for .024 QALYs (.627• .0384). For an individual in the general population not experiencing this illness, the same 2-week period would represent .034 QALYs (.896 • .0384).

Use of a vaccine that prevents illness X would result in a gain of .003 QALYs for a case of mild illness (.034–.031) and .010 QALYs for a case of moderate illness (.034–.024). With cases distributed evenly between mild and moderate illness, the average gain would be .007 QALYs [(.5 • .003) + (.5 • .010)]. With 100,000 cases per year, the annual gain for the population would amount to 700 QALYs (.007 • 100,000). (The complete analysis would also require discounting QALYs for the interval between age at vaccination and average age of onset of illness X.)

Quality Adjustments: Weighting

To calculate QALYs, a quality-adjustment weight is applied to each period of time during which a person experiences a changed health state due to a particular condition, and these quality-adjusted time periods are added together. In theory, “perfect health” carries a weight of 1.0, giving full value to periods to which it applies. Death carries a weight of 0.0. A health state judged to be equivalent in quality to death would also have a weight of 0.0, meaning that time spent in that health state would have a QALY value of 0.0. A condition considered worse than death can be assigned a negative weight. These quality-adjusted periods can be summed over a person’s expected lifetime (or some other specified period of time).

Suggested Citation:"Overview of Analytic Approach and Results." Institute of Medicine. 2000. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: The National Academies Press. doi: 10.17226/5501.
×

Several methods are available for determining the quality-adjustment weights to be applied to calculate QALYs. For this purpose, the committee selected the Health Utilities Index (HUI) Mark II (see, e.g., Patrick and Erickson, 1993; Feeny et al., 1995; Torrance et al., 1995; McDowell and Newell, 1996). The HUI Mark II characterizes morbidity by using seven health attributes (sensation, mobility, emotion, cognition, self-care, pain, and fertility), each of which is divided into three, four, or five levels. Each level has a fixed quantitative score representing the “preference” for that level relative to full health or death. For the HUI Mark II, these preferences are derived from analyses of responses of a random sample of parents in a Canadian community (Torrance et al., 1995). As illustrated in Box 4–2, the score for normal function in any attribute is 1.0. Deviations from that level of functioning are scored somewhere between 0 (death) and 1. The score for limitations in sensory functions even with equipment (e.g., glasses or hearing aids) is 0.86. The score for severe pain not relieved by drugs and leading to constant disruption of normal activities is 0.38.

Other quality-adjustment systems considered by the committee include the Disability-Distress Index (DDI) (Rosser, 1987; Rosser, et al., 1992; Kind and Gudex, 1994), the Quality of Well-Being Scale (QWB) (Kaplan and Anderson, 1988), and the World Bank/World Health Organization disability used to calculate disability-adjusted life years (DALYs) (Murray and Lopez, 1996). The HUI Mark II system was preferred to these alternatives because the multiple levels of its seven component attributes provided an explicit and flexible framework for the committee to use in characterizing the morbidity associated with diverse conditions included in the analysis. The HUI Mark II permits the identification of 24,000 unique health states versus 29 for DDI and 6 for DALYs. The QWB was not chosen because its weights tend to overvalue mild health problems. Some authors have attributed this problem with the QWB to the fact that the weights were obtained by rating scale methods rather than explicit tradeoff elicitation (Eddy, 1991). The HUI Mark II system was favored over DALYs because its weights are derived from community-based health-state preferences rather than expert judgment and are determined without regard to age. Another factor in the committee’s decision to use the HUI Mark II was the availability from the Canadian National Population Health Survey of age-specific health status weights for a general population (Wolfson, 1996). Although the committee found the HUI to be the most suitable instrument for its purposes, the model can accommodate quality-adjustment weights derived in other ways.

Morbidity Scenarios

The committee, with the advice of outside experts, developed morbidity scenarios to describe the characteristic patterns of illness associated with each condition under study. A scenario consists of a sequence of acute or chronic health states of specified duration that are experienced by a specified proportion of patients. The scenarios also capture the premature mortality associated with a

Suggested Citation:"Overview of Analytic Approach and Results." Institute of Medicine. 2000. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: The National Academies Press. doi: 10.17226/5501.
×

condition, but is delayed 1 or more years beyond the onset of the condition. For example, some infants infected with group B streptococcus at birth survive with neurologic impairment for several years but die by about age 10.

BOX 4–2 HUI-based Quality-adjustment Weight for Ectopic Pregnancy

Attribute

Description

 

Utility Function

 

1. Sensory

1. Able to see, hear, and speak normally for age

1.00

 

 

2. Requires equipment to see or hear or speak

 

0.95

 

 

3. See, hears, or speaks with limitations, even with equipment

 

0.86

 

 

4. Blind, deaf, or mute

 

0.61

 

1. Sensory Total

b1=1.0

2. Mobility

1. Able to walk, bend, lift, jump and run normally for age

 

1.00

 

 

2. Walks, bends, lifts, jumps, or runs with some limitations, but does not require help

 

0.97

 

 

3. Requires mechanical equipment (such as canes, crutches, braces, or wheelchair) to walk or get around independently

 

0.84

 

 

4. Requires the help of another person to walk or get around and requires mechanical equipment as well

0.73

 

 

5. Unable to control or use arms and legs

 

0.58

 

2. Mobility Total

b2=.73

3. Emotion

1. Generally happy and free from worry

 

1.00

 

 

2. Occasionally fretful, angry, irritable, anxious, or depressed (or suffering night terrors—for children)

 

0.93

 

 

3. Often fretful, angry, irritable, anxious, depressed, (or suffering night terrors—for children)

 

0.81

 

 

4. Almost always fretful, angry, irritable, anxious, or depressed

0.70

 

 

5. Extremely fretful, angry, irritable, or depressed, usually requiring hospitalization or psychiatric institutional care

 

0.53

 

3. Emotion Total

b3=.7

4. Cognitive

1. Learns and remembers normally for age (e.g. schoolwork—for children)

 

1.00

 

 

2. Learns and remembers more slowly than normally for age (e.g. schoolwork, for children)

0.95

 

Suggested Citation:"Overview of Analytic Approach and Results." Institute of Medicine. 2000. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: The National Academies Press. doi: 10.17226/5501.
×

 

3. Learns and remembers very slowly and usually requires special assistance in learning situations

 

0.88

 

 

4. Unable to learn and remember

 

0.65

 

4. Cognitive Total

b4=.95

5. Self-care

1. Eats, bathes, dresses, and uses the toilet normally for age

 

1.00

 

 

2. Eats, bathes, dresses, or uses the toilet independently with difficulty

 

0.97

 

 

3. Requires mechanical equipment to eat, bathe dress, or use the toilet independently

0.91

 

 

4. Requires the help of another person to eat, bathe, dress, or use the toilet

 

0.80

 

5. Self-care Total

b5=.9 1

6. Pain

1. Free of pain and discomfort

 

1.00

 

 

2. Occasional pain; discomfort relieved by nonprescription drugs or self-control activity without disruption of normal activities

 

0.97

 

 

3. Frequent pain; discomfort relieved by oral medicines with occasional disruption of normal activities

 

0.85

 

 

4. Frequent pain; frequent disruption of normal activities; discomfort requires prescription narcotics for relief

0.64

 

 

5. Severe pain; pain not relieved by drugs and constantly disrupts normal activities

 

0.38

 

Pain Total

b6=.64

7. Fertility

1. Able to have children with a fertile spouse

 

1.00

 

 

2. Difficulty in having children with a fertile spouse

0.97

 

 

3. Unable to have children with a fertile spouse

 

0.88

 

Fertility Total

b7=.97

Health State: Utility Function

1.06 • (b1 • b2 • b3 • b4 • b5 • b6 • b7) –.06

 

 

 

 

[1.06 • (1.0 • .73 • .70 • .95 • .91 • .64 • .97) –.06=.23]

 

 

HUI=.23

For most of the conditions included in the committee’s analysis, several scenarios were required to depict the associated morbidity. To illustrate some of the features of these scenarios, the scenarios developed for Neisseria meningitidis B are presented in Box 4–3.

Suggested Citation:"Overview of Analytic Approach and Results." Institute of Medicine. 2000. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: The National Academies Press. doi: 10.17226/5501.
×

BOX 4–3 Morbidity Scenarios: Neisseria meningitidis B

 

Duration

HUI

Meningitis (ICU)

ICU

2 days

0.24

Inpatient after ICU

5 days

0.28

Meningitis (no ICU)

Inpatient

5 days

0.39

Meningitis complications

Acute complications (gangrene, arthritis, heart failure, etc.)

10 days

0.27

Meningitis sequelae

Neurologic sequelae (cranial nerve damage, deafness, etc.)

(remaining lifetime)

0.60

Bacteremia/Sepsis

ICU (Waterhouse Friederichsen)

4 days

0.16

Inpatient after ICU

10 days

0.44

Bacteremia/Sepsis (no ICU)

Inpatient

5 days

0.71

Bacteremia/Sepsis—complications

Acute complications (cardiac, DIC, pneumonia, etc.)

10 days

0.59

Bacteremia/Sepsis—sequelae

Amputation, etc.

(remaining lifetime)

0.63

NOTE: ICU=intensive care unit; DIC=disseminated intravascular coagulation.

Once the morbidity scenarios were developed, the committee reviewed each health state and assigned a level in each of the seven attributes of the HUI Mark II. Box 4–2 shows the committee’s attribute scoring for one health state (ectopic pregnancy). The quality-adjustment weight for the health state was obtained by combining the scores for each attribute using the multiplicative HUI Mark II formula. Box 4–4 shows examples of the quality adjustment weights obtained for several health states.

Quality Adjustments for Average Population Health States

To measure the health benefits associated with an intervention such as the use of a new vaccine, it is necessary to compare health status with and without the intervention. The quality-adjustment weights for each condition’s morbidity scenarios (described above) are used to calculate QALYs lived without the intervention. Quality-adjustment weights reflecting the average health status of the population are used to calculate QALYs lived with the intervention. To measure the impact of mortality and lifetime impairment, life-expectancy was “quality adjusted” for the average health status of the population and discounted to its present value. For example, the life expectancy at birth is 75.5 years in the 1993 life tables used in the committee’s analysis. The discounted quality-adjusted present value of that life expectancy is 26.8 years. For a person 50 years old

Suggested Citation:"Overview of Analytic Approach and Results." Institute of Medicine. 2000. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: The National Academies Press. doi: 10.17226/5501.
×

BOX 4–4 Examples of Quality-Adjustment Weights Obtained Using the Health Utility Index

today, the life-expectancy is 29.2 years; the discounted quality-adjusted present value of that life expectancy is 15.7 years.

The average health status in the population represents the maximum level of health that can be achieved by use of the vaccines under study. Although an individual might be considered to experience periods of perfect health, represented by a quality-adjustment weight of 1.0, the health status of a population will reflect a range of individual quality levels and should not be represented by a quality-adjustment weight set at 1.0. The committee adopted HUI Mark II-based age- and sex-specific health status results from the Canadian NPHS (Wolfson, 1996) to serve as the quality-adjustment weights for the health status of the U.S. population. The weighted average of the population HUI ranges from 0.92 for people 44 years of age and under to 0.66 for people 85 years of age and older.

Disease Incidence and Death Rates

Estimates of current age-specific incidence and mortality for each condition were assembled on the basis of the published literature, the advice of experts in clinical medicine and epidemiology, and the judgment of committee members. Although data are available from surveillance systems for some of the condi-

Suggested Citation:"Overview of Analytic Approach and Results." Institute of Medicine. 2000. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: The National Academies Press. doi: 10.17226/5501.
×

tions included in the analysis, the completeness of reporting varies by condition. Some estimates are based on data from state- or community-level studies. Others rest largely on expert judgment. The specific sources of data for each condition are described in the Appendixes. For all conditions, the analysis uses incidence data, that is, the number (or rate) of new cases that would be expected during 1 year. For chronic illnesses such as multiple sclerosis, these data will differ from the estimates of prevalence that are often reported.

Time Intervals

As described in a previous section, discounting is applied to future health benefits as well as costs. The timing of the health benefits expected from the use of the potential new vaccines included in the committee’s analysis will vary depending on the intervals between the typical age at immunization and the age at onset of an illness or the age at death. The intervals calculated for the analysis are the following: the time from vaccination to the average age at onset of illness, and the difference between the average age at onset of illness and average age at the time of illness-related death. The latter is of interest for those acute conditions for which the age at death from the condition differs markedly from the overall age of patients with that condition. The time interval related to premature death following a period of chronic illness is accounted for separately.

Age at vaccination was determined by the vaccination strategy, as reflected by the target population. Most cases fall into one of the following categories:

Target Population

Age at Vaccination

Infants

6 months

Adolescents

12 years

Pregnant women

Average age of mothers at first births, minus 2 months (24.7 years)

New cases (therapeutic vaccines)

Age at diagnosis (assumed to equal average age at onset)

See Table 4–1 for information on the designated target population for each candidate vaccine.

QALYs Gained with Vaccine Use

To calculate health benefits anticipated with vaccine use, the QALYs associated with each health state were combined. First, the state-specific QALYs were summed for each morbidity scenario. By using the scenario totals, the QALYs lived with the condition under study were subtracted from the QALYs for the general population without the condition. This provides an estimate of the QALYs that could be gained in each scenario with vaccine use.

Suggested Citation:"Overview of Analytic Approach and Results." Institute of Medicine. 2000. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: The National Academies Press. doi: 10.17226/5501.
×

The scenario-specific QALYs to be gained were multiplied by the proportion of cases of illness experiencing that scenario and were summed across all scenarios. This total was multiplied by the number of cases, or by the number of deaths for the QALYs associated with mortality, to calculate the overall benefit that the use of a vaccine for the condition under study would be expected to have in the population. If subpopulations were used in the analysis, the results were calculated for each subpopulation, and the subpopulation results were summed to produce an estimate of the total health benefit.

Costs: The Numerator

Costs associated with the development and use of a vaccine provide the numerator of the cost-effectiveness ratio for each of the cases considered by the committee. The cost components include the costs of vaccine development, the cost of vaccine use, and the reduction in health care and related costs that would be expected with vaccine use. All cost estimates are presented in constant dollars.

Cost of Research and Development

The costs of future research and clinical trials needed to complete development of a vaccine and have it licensed are a mix of public- and private-sector expenditures, of which the private-sector component is especially difficult to estimate. In the absence of real data regarding these development costs, they were assumed to fall at one of six levels: $120 million, $240 million, $300 million, $360 million, $390 million, or $400 million. The committee assigned each candidate vaccine to one of these cost levels on the basis of its assessment of the current stage of the vaccine’s development (see Table 4–1). For many conditions under study, work is being done on more than one type of candidate vaccine. The committee did not think that differences among the candidate vaccines in terms of development costs (or cost per dose or effectiveness) were likely to be significant enough to warrant separate analysis.

The committee also considered the time required to achieve licensure of a vaccine. Since specific evidence on which to base fine distinctions among the candidate vaccines was not available, the committee assigned each candidate vaccine to one of three development intervals: 3, 7, or 15 years. Discounting incorporated this development interval to adjust for the differences in when the associated costs and benefits of the vaccines will be realized.

Suggested Citation:"Overview of Analytic Approach and Results." Institute of Medicine. 2000. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: The National Academies Press. doi: 10.17226/5501.
×
Cost of Vaccine Use

The cost of vaccine use is a function of the cost per dose of the vaccine, the cost to administer the vaccine, the number of doses each person must receive to be fully immunized, and the size of the population targeted to receive the vaccine.

A vaccine’s cost per dose is represented in this analysis by an estimated purchase price rather than the marginal cost of producing a single dose. Because the committee felt that it could not accurately predict detailed differences in the price of future vaccines, it chose to assume that the cost of prophylactic vaccines would be either $50 or $100. It was assumed that the cost of therapeutic vaccines would be significantly higher and was set at $500 (see Table 4–1). The marginal cost of administering a dose of vaccine was assumed to be small and was set at $10. For most vaccines, it was assumed that three doses would be needed to achieve full immunity.

The cost of vaccine use is also influenced by the size and nature of the population targeted to receive the vaccine. As the size of the target population increases, costs increase because more doses of vaccine must be administered.

Health Care Costs

In much the same way that it was necessary to establish a common measure of health effects that could be used to compare very different conditions, it was also necessary to establish a common basis for comparing the costs of care associated with those conditions. Costs for specific services are represented in the committee’s analysis by charges for those services. Charges vary regionally and among health care providers within a region. Published cost-effectiveness studies on some of the conditions were reviewed by the committee, but because those studies draw their cost data from a variety of sources, they were not always consistent and could not be directly compared. Furthermore, such studies were not available for every condition under consideration, making it necessary for the committee to assemble those cost data in any case.

The morbidity scenarios developed for use in the calculation of health benefits associated with a vaccine also provided the basic framework for the calculation of health care costs that would be averted with vaccine use. For each morbidity scenario, the committee developed a companion “clinical scenario” that specified the health services required, including hospitalizations, procedures, medications, office visits, rehabilitation services, and long-term institutional care. An appropriate unit of service (e.g., hospital days or doses of medication) was specified and the amount of care received was defined in terms of those units. Costs also were specified in terms of units of service. In addition, for each form of care, the committee specified the proportion of patients within the scenario that received that form of care. It was assumed that all costs of care associated with the condition under study would be averted with vaccine use.

Suggested Citation:"Overview of Analytic Approach and Results." Institute of Medicine. 2000. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: The National Academies Press. doi: 10.17226/5501.
×

For all conditions, the committee estimated cost of care on the basis of national data. For inpatient hospitalizations, hospital costs were estimated by using average national diagnosis-related group payments by the Health Care Financing Administration (HCFA) (St. Anthony’s DRG Guidebook, 1995). Outpatient costs and inpatient physician visits were also estimated from HCFA data (HCFA, 1995). For these costs, the committee estimated general categories of costs (outpatient physician visit with and without tests, etc.) and applied these to the morbidity scenarios. See Box 4–5 for examples of unit costs.

Vaccine Efficacy and Utilization

An additional component of the committee’s analysis took into account assumptions about the efficacy of each vaccine under study and the extent to which the target population would use the vaccine. An efficacy or utilization

BOX 4–5 Examples of Health Care Cost Estimates Used

Suggested Citation:"Overview of Analytic Approach and Results." Institute of Medicine. 2000. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: The National Academies Press. doi: 10.17226/5501.
×

rate of less than 100% will reduce the health benefits and savings in the cost of care that can be expected. A lower utilization rate will also have the effect of reducing the costs associated with vaccinating the target population.

With regard to efficacy, it was assumed that preventive vaccines would achieve an efficacy level of 75%. The efficacy of therapeutic vaccines was assumed to be 40%. This lower estimate reflected the committee’s belief that therapeutic vaccines would be expected to achieve a lower threshold of efficacy than for preventive vaccines for both licensure approval by the FDA and for acceptance by patients and medical care providers. In fact, many therapeutic drugs are approved for licensure or for new indications with an efficacy of 40% or lower.

Each candidate vaccine was also assigned a utilization rate of 10, 30, 50, 60, or 90% (see Table 4–1). The committee’s utilization rate assignments were guided by an examination of the coverage rates achieved for existing vaccines, which were assumed to suggest rates that could be anticipated for new vaccines. Also considered were specific factors that might influence the rate at which a particular vaccine would be used. For example, a 50% utilization rate by an adolescent target population for a vaccine for a sexually transmitted disease (STD) reflects the committee’s assessment of the difficulty in reaching this population and possible reluctance of parents to acknowledge a child’s risk and therefore the potential benefit of a vaccine. For vaccines targeted to pregnant women, two alternatives were considered plausible: the utilization rate would stabilize at 10% due, in part, to persistent concerns about potential adverse effects on the fetus, or the utilization rate would reach 90% because use of the vaccine becomes an accepted element of good prenatal care.

In the past, more extensive use of some vaccines has been hindered by an inadequate supply. For this analysis, however, it was assumed that adequate supplies would be available to meet the demand for all vaccines.

Cost-Effectiveness Ratios

The final stage/step of the analysis is the calculation of the cost-effectiveness ratio for each candidate vaccine, the basis for comparisons among the vaccines. Three sets of cost-effectiveness ratios were calculated. The first ratio examines the potential impact of the vaccine on morbidity and costs under the assumption that the vaccines are available immediately without any additional cost or time for development and that they are fully efficacious and are used by the entire target population. This comparison focuses attention on what might be considered an ideal vaccine benefit. The second cost-effectiveness ratio factors in the adjustments for incomplete efficacy and use, which tend to increase the cost of achieving the anticipated health benefit. The final ratio shows the impact of the time and money needed to develop these vaccines. Some vaccines that promise substantial benefit require a longer and more expensive period of development, whereas others that offer smaller benefits are ex-

Suggested Citation:"Overview of Analytic Approach and Results." Institute of Medicine. 2000. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: The National Academies Press. doi: 10.17226/5501.
×

pected to be available more quickly and cheaply. In general, the committee found that the adjustments for efficacy and utilization had a more substantial impact on a vaccine’s cost-effectiveness than the additional time and cost needed for development. Although these adjustments changed the cost-effectiveness ratios, only a few vaccines shifted in their cost-effectiveness relative to the other vaccines.

For each of the conditions included in the study, multiple sensitivity analyses could be performed to test alternative assumptions regarding the morbidity scenarios, the quality-adjustment weights, the costs of care and vaccine development, utilization rates, and numerous other factors. Because 26 conditions were considered, however, the committee was not able to undertake a detailed case-by-case approach to sensitivity analysis. As an alternative, a series of hypothetical cases for vaccine x were developed to illustrate the effects that changes in various factors (e.g., numbers of cases, age distribution of patients, severity of illness, unit costs of care, and so on) would produce in the cost-effectiveness ratio.

The committee chose to perform sensitivity analyses for vaccine x with limited set of factors of significance across all conditions. One of these analyses addressed the debate within the committee and in the cost-effectiveness literature over the appropriateness of discounting future health benefits. The basic analysis used a 3% discount rate for both health benefits and costs. Two sensitivity analyses were performed: (1) the discount rate for health benefits was set at zero, whereas the rate for costs was maintained at 3% and (2) the discount rate was set at zero for both health benefits and costs. The results of these analyses are discussed later in this chapter.

Exclusions from the Analysis

Several factors excluded from the committee’s analysis are reviewed briefly. In theory, the analysis should also consider the impact of vaccine use on the time costs borne by patients in obtaining treatment or vaccination for any of the conditions studied and by parents, spouses, or other unpaid caregivers who provide care to individuals who experience any of these conditions. For some conditions, these costs could be substantial. For example, an analysis of the cost-effectiveness of a varicella vaccination program estimated an annual savings of $325 million (discounted 1990 dollars) in parents’ time lost from work (Lieu et al., 1994).

The committee felt, however, that it lacked adequate information to make a consistent assessment across the various conditions of the time involved in obtaining treatment or of the extent of care from unpaid caregivers. It is readily apparent that sick children will require care from parents or other adult caregivers, but it is less clear whether adults who are ill routinely receive similar unpaid care from others and, if they do, how much care they receive. Therefore, the committee chose not to include these costs in its analysis. If suitable time cost

Suggested Citation:"Overview of Analytic Approach and Results." Institute of Medicine. 2000. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: The National Academies Press. doi: 10.17226/5501.
×

estimates were to become available, however, they could readily be incorporated into the model.

The committee also excluded from the analysis the possible impact of vaccine use on the cost of current public health services such as disease surveillance or contact-tracing programs. A reduction in the number of cases of a single condition may not translate into a direct proportional change in the cost of public health services, which may be used in conjunction with a variety of other conditions as well. For example, a vaccine that prevents one type of STD will tend to reduce the burden on some services, but those services will continue to be needed in connection with other STDs.

It should also be noted that the committee’s analysis does not include as a cost factor a monetary value for changes in income associated with time lost to illness or use of a vaccine. This feature of the model reflects a widely accepted assumption in cost-effectiveness analysis (see Gold et al., 1996) that this opportunity cost of illness, in terms of both lost wages and time lost from unpaid work or leisure, is captured by the quality adjustment weights assigned to periods with and without illness. Thus, the cost of lost work is accounted for in nonmonetary terms rather than being excluded from the analysis.

This analysis could also include the impacts of the possible adverse effects of a vaccine, but the committee made an explicit decision not to incorporate this component. Adverse effects would generally result in a reduction in the health benefits produced by vaccine use and an increase in the costs of care. They could also limit the public’s acceptance of a vaccine. Estimating the magnitudes of these factors for each vaccine candidate would require assessments of the frequency of adverse effects, their nature and severity, the kinds of care required, and public reaction to them. The committee agreed that making meaningful predictions regarding any aspect of possible adverse effects of future vaccines would be very problematic and that there was no basis for distinguishing differences among the vaccines included in the study.

There is a reasonable basis for concluding that exclusion of adverse effects from the analysis has not altered the results in any meaningful way. Evidence regarding existing vaccines (IOM, 1991, 1994a, 1996a) suggests that adverse effects are infrequent and that very few are severe. This is consistent with preliminary analyses performed for the 1985 IOM report on the development of new vaccines, which found that estimated numbers of adverse effects produced minimal changes in the measures of disease burden and cost and did not alter the relative rankings of candidate vaccines. That committee also decided not to include estimates of adverse effects in the final analyses for its report. Although the present committee chose not to incorporate an estimate of adverse effects in its quantitative analysis, the issue of vaccine safety is of serious concern and is discussed further in several publications by other committees and forums held by the IOM (IOM, 1991; 1994a,b; 1996a; 1997a,b).

It is likely that some of the vaccines considered by the committee will become components of combination vaccine products similar to the familiar DTP products currently in general use. For vaccines intended for universal use, espe-

Suggested Citation:"Overview of Analytic Approach and Results." Institute of Medicine. 2000. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: The National Academies Press. doi: 10.17226/5501.
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daily among infants and children, combination products have the advantage of reducing the number of separate vaccine doses that must be administered, which can aid efforts to achieve desired levels of vaccine utilization. Including combination vaccines in the analysis is not difficult in principle, but would add to the burden of assessing expert judgment on utilization, costs, and effectiveness of the vaccines if available in combination forms. Many vaccine combinations might be possible, and the committee had no basis for selecting any specific combinations as more or less likely. Therefore, combination products were not included in the analysis.

The committee was originally asked to include in its analysis the contraceptive vaccines that are in development. Although the scientific foundation for research and development of a contraceptive vaccine is clear and such vaccines are being studied and can be expected to provide a needed addition to the array of contraceptive options that are currently available, an analysis of their anticipated cost-effectiveness within the framework adopted for this study poses particularly difficult ethical and philosophical problems that the committee felt unqualified to address.

Trying to measure the health benefits produced by a contraceptive vaccine would require a determination of whose health is affected by an unintended pregnancy (the mother’s health, the child’s health, or the health of others in the family), what those effects are (psychological distress or a normal life expectancy), and how long they last. For the most part, the benefits of contraceptive vaccines are not health-related but relate instead to the economic and psychological well-being of the mother. Therefore, societal priorities for such vaccines should be based on a broader concept of benefit than quality-adjusted life years. For the other vaccines in the study, there is little question that the prevention or treatment of an illness is a desirable outcome. For a contraceptive vaccine, however, it is not clear whether prevention of a pregnancy can always be viewed as completely desirable. For a woman who does not wish to become pregnant, the outcome can be considered positive, but a concern is how to assess the health effects that result if a contraceptive vaccine prevents a desired pregnancy. Questions also arise regarding the costs to be considered in the analysis. For example, should the vaccine be credited with saving the cost of raising a child or with having prevented the productivity of that child? Until a clearer consensus is established regarding the answers to questions such as these, it seems inappropriate to include a contraceptive vaccine in a cost-effectiveness model.

Suggested Citation:"Overview of Analytic Approach and Results." Institute of Medicine. 2000. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: The National Academies Press. doi: 10.17226/5501.
×

EXAMPLES: HYPOTHETICAL VACCINE X

Before discussing the results obtained by applying the model developed for this report to the selected candidate vaccines, the committee provides some examples of results obtained from an analysis of a hypothetical candidate vaccine X directed for use for the prevention of disease X.

The characteristics of a base case scenario (Case 1) for vaccine X-1 are presented in Table 4–2. Candidate vaccine X-1 is under development and would be directed against disease X-1, which affects 100,000 people annually. Disease X-1 has a 1% case fatality rate (CFR). All age groups are affected equally. Half of the people experience a mild illness (2-week duration; HUI=.90) and half experience a moderate illness (2-week duration; HUI=.70). The health care costs include a physician visit for patients with mild cases and more extensive and more expensive treatment (including a brief hospitalization) for patients with moderate illness. The candidate vaccine will be licensed within 7 years, after expenditures of $240 million in additional research and development costs. The vaccine will cost $50 for each dose of the 3-dose series, which will be given in infancy. The vaccine will be 75% effective, and 90% of the target population (i.e., infants) will be vaccinated.

In such a hypothetical scenario, the cost per QALY gained by use of the vaccine is approximately $125,000. The number of QALYs lost to disease X-1 is 7,000, almost 6,800 of which are due to the effects of mortality. With the specified assumptions regarding effectiveness and utilization, only 4,700 QALYs would be gained if the vaccine were available immediately. Discounting to allow for the time needed for vaccine development reduces the annualized present value of the QALYs gained to 3,300.

The discounted cost of care saved by this vaccine strategy is approximately $43 million. Program costs for vaccinating all infants with three doses of the $50 vaccine amount to $720 million; adjustments for the rate of utilization and discounting for vaccine development time reduces the annualized present value of those costs to approximately $450 million. Although the investment required to bring this vaccine to licensure is estimated to be $240 million, the amortized amount attributed to a single year is $7.2 million. The net cost (development cost plus delivery costs minus health care savings) is approximately $420 million.

The following examples (Table 4–3) are based on modifications of Case 1 and will demonstrate the effects of changes in target population, program considerations, disease severity, and discounting. This section closes with a description and example of how the cost-effectiveness model developed for research and development prioritization can be used by other policymakers to plan vaccine programs, for example. The chapter then closes with the results obtained for the 26 candidate vaccines chosen by the committee for further illustration.

Suggested Citation:"Overview of Analytic Approach and Results." Institute of Medicine. 2000. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: The National Academies Press. doi: 10.17226/5501.
×

Target Population

If the disease only affects children under 5 years of age (Case 2), the cost per QALY gained by vaccination drops to less than $30,000. Key factors influencing this dramatic difference between the two examples are the greater number of QALYs gained in Case 2 (12,000 in Case 2 compared with 3,300 in Case 1) and the cost of care saved ($114 million in Case 2 compared to $43 million in Case 1). The gain in QALYs is higher in Case 2 for two main reasons. First, averting deaths of 1,000 infants and children “recovers” or “saves” many more years of future life than does averting the same number of deaths at older ages. Second, the vaccine benefits are realized much sooner after immunization in Case 2 than in Case 1, in which some of the vaccinees will not benefit from the vaccine until decades after their immunization as an infant. The model assumes that costs and health benefits in the present are more highly valued than those accrued in the future.

If Case 2 is changed such that the disease strikes only those older than 65 years of age, the cost per QALY gained by vaccination increases to more than$1 million (Case 3). However, that scenario assumes that the affected people are vaccinated during infancy and will not reap the benefits of the vaccine for more than six decades. A more reasonable vaccination strategy might be to vaccinate people much closer to the time that they might experience the disease. In such a scenario (Case 4), 100,000 cases of disease still occur each year. Because there are far fewer people 60 years of age than there are infants, the costs of an adult immunization program are lower than those of a program aimed at infants. Thus, by this adult immunization strategy, the cost per QALY gained drops to approximately $70,000.

There are two key factors that explain why, if in both examples the vaccine is administered to the vulnerable age group, the cost per QALY gained in Case 4 is more than twice that in Case 2. First, the maximum interval between vaccination and time to benefit in Case 2 is less than 5 years. In Case 4, some vaccinees experience the benefit in 5 years, but other vaccinees will not realize the benefit until 20 years after the vaccination. The second factor is that the number of QALYs saved by vaccination against a disease that affects those under 5 years of age exceeds the QALYs saved by a vaccination against the same number of people 60 years of age or older. This is explained by the effect of age on baseline health status, as discussed in an earlier section of this chapter.

Program Considerations

Case 4 illustrates the selection of a target population based on age-related risk. Other important bases for selection of a target population (and tailoring of a vaccine program) are geography or preexisting condition. If disease X-5 affects 100,000 people of all ages each year and has a 1% case fatality rate, and if the cases are restricted in some identifiable manner (e.g., geographic area), a vacci-

Suggested Citation:"Overview of Analytic Approach and Results." Institute of Medicine. 2000. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: The National Academies Press. doi: 10.17226/5501.
×

Table 4–2 Vaccine X-1: Mild/Moderate Illness with Deaths, Uniform Ages (cases: 100,000/year)

Deaths (from acute infection)

1%

 

Morbidity scenarios

Distribution of Cases

Duration

HUI

Health Care Costs

Mild

50%

2 weeks

0.90

1 MD visit=$50

Moderate

50%

2 weeks

0.70

1 MD visit=$50

Severea

0%

4 weeks

0.40

Brief hospitalization=$5,000

3 MD visits=$150

Permanent impairmenta

0%

Remaining lifetime

 

Brief hospitalization=$5,000

ICU hospitalization=$4,500

Characteristics of Vaccine Use and Development

Target population for vaccination

4 million infants

Cost of vaccine per dose

$50

Doses required

3

Vaccine effectiveness

75%

Utilization of vaccine

90%

Time to adoption at anticipated utilization

5 years

Cost for vaccine development

$240 million

Time for vaccine development

7 years

Discount Rates (r)

 

Health benefits

3%

Costs

3%

Suggested Citation:"Overview of Analytic Approach and Results." Institute of Medicine. 2000. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: The National Academies Press. doi: 10.17226/5501.
×

Cost per QALY gained with vaccine

 

a.

Immediately available vaccine (100% efficacy and use, no development cost or time)

$89,660

b.

Immediately available vaccine with likely effect and use (no development cost or time)

$123,816

c.

Vaccine available with addition of development cost and time

$125,980

 

QALYs to Be Gained

Net Cost

Cost of Care Saved

Delivery Costs

Development Costs

a.

Baseline

 

Immediately available vaccine (100% efficacy and use, no development cost or time)

7,026.64

$630,009,848

$89,990,152

$720,000,000

$240,000,000

b.

Adjustments for Vaccine Efficacy and Utilization

 

Anticipated vaccine efficacy: 75%

5,269.98

 

$67,492,614

N/A

N/A

 

Anticipated vaccine utilization: 90%

4,742.98

$587,256,647

$60,743,353

$648,000,000

N/A

c.

Adjustment for Vaccine Development Costs and Time

 

Vaccine available with addition of development cost and time

3,326.63b

$419,089,997

$42,604, 166b

$454,494,162b

$7,200,000c

aNot applicable for Vaccine X-1; relevant for other Vaccine X examples.

bAnnualize present value=(adjusted baseline)/(l+r)Tuse , where Tuse is the time to adoption at the anticipated utilization rate plus time to vaccine licensure.

cAmortized development cost=Development costs×r.

Suggested Citation:"Overview of Analytic Approach and Results." Institute of Medicine. 2000. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: The National Academies Press. doi: 10.17226/5501.
×

nation strategy that targets 500,000 high-risk infants leads to a cost per QALY gained of $6,000 (Case 5). This change can be attributed entirely to the reduction in the cost of the delivery program. The number of vaccinees and, therefore, the delivery costs in Case 5 are one-eighth those in Case 1.

Another vaccine program component of great interest to readers of the report is the cost of the vaccine itself. If the cost per dose of the vaccine is assumed to be twice the cost estimated for Case 1, the program costs almost double to $110 million versus $60 million in Case 1 (the $10 added per dose for administration of the vaccine does not change) and the cost per QALY saved increases from approximately $125,000 to approximately $240,000 (Case 6).

Disease Severity

Several other scenarios are instructive. Consider Case 7, which differs from Case 1 only in that there are no deaths. If the disease X-7 results in the mild and moderate illnesses described for Case 1, the cost per QALY gained with a vaccine is well in excess of $3 million. The program costs and costs of care are the same as those for Case 1, but only a small number of QALYs are gained when no deaths result. If, however, disease X-8 has a 100-fold higher incidence than X-7, then a vaccine X-8 strategy becomes cost saving. The number of QALYs saved with a vaccine strategy increase by 100 fold. Vaccine delivery and development costs remain the same, and the health care costs increase 100 fold. The net cost of a vaccine strategy changes from a cost of over $400 million to a savings of almost $4 billion.

Another instructive example is the role that long-term disability plays in cost-effectiveness applications. If instead of the mild/moderate disease and CFR of 1% associated with disease X-1, there is severe disease and a 1% rate of long-term, serious sequelae (instead of a 1% CFR), the cost per QALY gained by vaccination is $80,000 (Case 9). In this scenario, use of the vaccine results in a moderate gain in QALYs and a substantial savings in the costs of care.

Discounting

As discussed in the beginning of this chapter, the committee followed the recommendations of the Panel on Cost-Effectiveness in Health and Medicine and applied a 3% discount rate for both costs and health benefits. Because discounting is a difficult concept for some readers, the committee has modified Case 1 to show the effects of discounting for costs only and of discounting for neither costs nor health benefits. The numbers of QALYs to be gained under Case 1 increase significantly absent discounting for health benefits: from approximately 3,300 QALYs (with a 3% discount rate applied) to 25,500 QALYs with no discounting. This approximately 8-fold difference in the denominator of the cost-effectiveness ratio leads to a proportional decrease in the cost per

Suggested Citation:"Overview of Analytic Approach and Results." Institute of Medicine. 2000. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: The National Academies Press. doi: 10.17226/5501.
×

TABLE 4–3 Assumptions and Results of “Vaccine X” Analyses

Vaccine X

Case 1: Mild/Moderate Illness with Deaths, Uniform Ages

Case 2: Mild/Moderate Illness with Deaths, in Children

Case 3: Mild/Moderate Illness with Deaths, in the Elderly

Cases

100,000/yr

100,000/yr

100,000/yr

Age-specific incidence

uniform

all<5

all 65+

Deaths (from acute infection)

1%

1%

1%

Morbidity scenarios

 

Mild scenario

50%

50%

50%

Moderate scenario

50%

50%

50%

Severe scenario

0%

0%

0%

Permanent impairment

0%

0%

0%

Target Population

infants

infants

infants

(infants, adolescents, etc.)

4,000,000

4,000,000

4,000,000

Cost of Vaccine/dose

$50

$50

$50

Discount Rates

 

Health benefits

3%

3%

3%

Costs

3%

3%

3%

a. Immediately available vaccine (100% efficacy and use, no development cost or time)

$/QALY

$89,660

$18,580

$837,629

QALYs to be gained

7,027

25,826

826

Net cost

$630,009,848

$479,838,815

$692,003,742

Cost of care saved

$89,990,152

$240,161,185

$27,996,258

Delivery costs

$720,000,000

$720,000,000

$720,000,000

Development costs

$0

$0

$0

b. Immediately available vaccine with likely effect and use (no development cost or time)

$/QALY

$123,816

$27,873

$1,128,135

Net cost

$587,256,647

$485,891,200

($608,845,879)

Cost of care saved

$60,743,353

$162,108,800

$18,897,474

Delivery costs

$648,000,000

$648,000,000

$648,000,000

Development costs

$0

$0

$0

c. Vaccine available, expected use, and effectiveness with addition of development cost and time

$/QALY

$125,980

$28,462

$1,146,543

QALYs to be gained

3,327

12,227

391

Net cost

$419,089,997

$347,994,312

$448,439,854

Cost of care saved

$42,604,166

$113,699,851

$13,254,308

Delivery costs

$454,494,162

$454,494,162

$454,494,162

Development costs

$7,200,000

$7,200,000

$7,200,000

NOTE: “C” is the primary analysis reported in the results section

Suggested Citation:"Overview of Analytic Approach and Results." Institute of Medicine. 2000. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: The National Academies Press. doi: 10.17226/5501.
×

Vaccine X

Case 4: Mild/Moderate Illness with Deaths, in the Elderly

Case 5: High-Risk Infant Target Population

Case 6 High Cost Vaccine ($100)

Cases

100,000 /yr

100,000 /yr

100,000 /yr

Age-specific incidence

all 65+

uniform

uniform

Deaths (from acute infection)

1%

1%

1%

Morbidity scenarios

 

Mild scenario

50%

50%

50%

Moderate scenario

50%

50%

50%

Severe scenario

0%

0%

0%

Permanent impairment

0%

0%

0%

Target Population

60 years of age

high risk infants

infants

(infants, adolescents, etc)

2,000,000

500,000

4,000,000

Cost of Vaccine/dose

$50

$50

$100

Discount Rates

 

Health benefits

3%

3%

3%

Costs

3%

3%

3%

a. Immediately available vaccine (100% efficacy and use, no development cost or time)

$/QALY

$41,176

$1

$175,049

QALYs to be gained

4,796

7,027

7,027

Net cost

$197,476,989

$9,848

$1,230,009,848

Cost of care saved

$162,523,011

$89,990,152

$89,990,152

Delivery costs

$360,000,000

$90,000,000

$1,320,000,000

Development costs

$0

$0

$0

b. Immediately available vaccine with likely effect and use (no development cost or time)

$/QALY

$66,197

$4,271

$237,668

Net cost

$629,102,526

$20,256,647

$1,127,256,647

Cost of care saved

$18,897,474

$60,743,353

$60,743,353

Delivery costs

$648,000,000

$81,000,000

$1,188,000,000

Development costs

$0

$0

$0

c. Vaccine available, expected use, and effectiveness with addition of development cost and time

$/QALY

$69,368

$6,435

$239,833

QALYs to be gained

2,271

3,327

3,327

Net cost

$157,503,581

$21,407,605

$797,835,132

Cost of care saved

$76,943,500

$42,604,166

$42,604,166

Delivery costs

$227,247,081

$56,811,770

$833,239,298

Development costs

$7,200,000

$7,200,000

$7,200,000

NOTE: “C” is the primary analysis reported in the results section

Suggested Citation:"Overview of Analytic Approach and Results." Institute of Medicine. 2000. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: The National Academies Press. doi: 10.17226/5501.
×

Vaccine X

Case 7: Mild/Moderate Illness, No Deaths, Uniform Ages

Case 8: Mild/Moderate Illness, No Deaths, Uniform Ages, High Incidence

Case 9: No Deaths with Moderate/Severe Disease, Impairment

Cases

100,000 /yr

10,000,000 /yr

100,000 /yr

Age-specific incidence

uniform

uniform

uniform

Deaths (from acute infection)

none

none

none

Morbidity scenarios

 

Mild scenario

50%

50%

0%

Moderate scenario

50%

50%

50%

Severe scenario

0%

0%

50%

Permanent impairment

0%

0%

1%

Target Population

infants

infants

infants

(infants, adolescents, etc)

4,000,000

4,000,000

4,000,000

Cost of Vaccine/dose

$50

$50

$50

Discount Rates

 

Health benefits

3%

3%

3%

Costs

3%

3%

3%

a. Immediately available vaccine (100% efficacy and use, no development cost or time)

$/QALY

$2,597,233

($341,305)

$10,174

QALYs to be gained

$243

$24,257

$3,623

Net cost

$630,009,848

($8,279,015,232)

$36,857,314

Cost of care saved

$89,990,152

$8,999,015,232

$683,142,686

Delivery costs

$720,000,000

$720,000,000

$720,000,000

Development costs

$0

$0

$0

b. Immediately available vaccine with likely effect and use (no development cost or time)

$/QALY

$3,586,639

($331,411)

$76,420

Net cost

$587,256,647

($5,426,335,282)

$186,878,687

Cost of care saved

$60,743,353

$6,074,335,282

$461,121,313

Delivery costs

$648,000,000

$648,000,000

$648,000,000

Development costs

$0

$0

$0

c. Vaccine available, expected use, and effectiveness with addition of development cost and time

$/QALY

$3,649,335

($330,784)

$80,618

QALYs to be gained

115

11,484

1,715

Net cost

$419,089,997

($3,798,722,390)

$138,272,951

Cost of care saved

$42,604,166

$4,260,416,552

$323,421,211

Delivery costs

$454,494,162

$454,494,162

$454,494,162

Development costs

$7,200,000

$7,200,000

$7,200,000

NOTE: “C” is the primary analysis reported in the results section

Suggested Citation:"Overview of Analytic Approach and Results." Institute of Medicine. 2000. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: The National Academies Press. doi: 10.17226/5501.
×

Vaccine X

Case 10: Discounting for Costs Only

Case 11: No Discounting

Cases

100,000/yr

100,000/yr

Age-specific incidence

uniform

uniform

Deaths (from acute infection)

1%

1%

Morbidity scenarios

 

Mild scenario

50%

50%

Moderate scenario

50%

50%

Severe scenario

0%

0%

Permanent impairment

0%

0%

Target Population

infants

infants

(infants, adolescents, etc)

4,000,000

4,000,000

Cost of Vaccine/dose

$50

$50

Discount Rates

 

Health benefits

0%

0%

Costs

3%

0%

a. Immediately available vaccine (100% efficacy and use, no development cost or time)

$/QALY

$16,671

$12,305

QALYs to be gained

$37,790

$37,790

Net cost

$630,009,848

$465,000,000

Cost of care saved

$89,990,152

$255,000,000

Delivery costs

$720,000,000

$720,000,000

Development costs

$0

$0

b. Immediately available vaccine with likely effect and use (no development cost or time)

$/QALY

$23,022

$18,656

Net cost

$587,256,647

$475,875,000

Cost of care saved

$60,743,353

$172,125,000

Delivery costs

$648,000,000

$648,000,000

Development costs

$0

$0

c. Vaccine available, expected use, and effectiveness with addition of development cost and time

$/QALY

$16,430

$18,656

QALYs to be gained

25,508

25,508

Net cost

$419,089,997

$475,875,000

Cost of care saved

$42,604,166

$172,125,000

Delivery costs

$454,494,162

$648,000,000

Development costs

$7,200,000

$0

NOTE: “C” is the primary analysis reported in the results section

Suggested Citation:"Overview of Analytic Approach and Results." Institute of Medicine. 2000. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: The National Academies Press. doi: 10.17226/5501.
×

QALY saved to $16,000. If the model includes no discounting for either costs or health benefits, the cost per QALY saved (compared to case 1) is approximately $19,000 (see Cases 10 and 11). The committee reiterates, however, that both costs and benefits should be discounted.

An Idealized Scenario

The committee believes that the model it recommends can and should have far more utility beyond informing research and development priority considerations. For example, a policymaker might want to evaluate and inform decisions about the value of investments in new vaccine delivery programs. Such a policymaker might also wish to evaluate those options in an idealized scenario. Therefore, the committee offers several examples, using the Vaccine X scenarios described above, of results obtained in the idealized scenario; that is, vaccines against disease X-1 through X-9 have just become available, they are all 100% effective, and there is a means to ensure that the entire target population is vaccinated immediately. The following discussion illustrates results that might be important if there is now a desire to find out the cost-effectiveness of an investment in a vaccine program against one of these nine diseases, if that program were to begin today. Because the model includes discounting for both costs and benefits, components of the model with a time factor are particularly affected by this change in analysis.

The cost-effectiveness ratios for vaccines X-1 through X-9 in the idealized scenario change in some fairly predictable ways. Vaccine strategies appear more cost-effective when analyzing this “idealized scenario” compared to the primary analysis reported by the committee (less-than-perfect utilization and efficacy, including development costs and time until program is stabilized). The denominator (health benefits) is higher (approximately two-fold) compared to the standard analysis in every case. The factors responsible for this are the positive change by increasing utilization and effectiveness and the absence of the negative impact of discounting the health benefits during the 12 years until the vaccine program is fully implemented (7 years for vaccine licensure and another 5 years for vaccine use to stabilize).

The numerator of the cost-effectiveness ratio is changed in the idealized scenario in several ways, and not always in ways that will be intuitively obvious. Costs for vaccine development ($7,200,000 for these vaccines) are zero in this analysis. Delivery costs increase in the idealized scenario because utilization is 100% and, therefore, 10% more vaccine needs to be purchased. Delivery costs are also increased because they do not need to be discounted to account for the time for vaccine licensure and for usage to stabilize. The cost of care saved with a vaccine strategy is higher in the idealized scenario because more people experience health benefits due to higher efficacy and utilization. In addition, the discounting is not applied for the 12-year lag required for licensure and for usage to stabilize. The net costs can be higher or lower in this scenario compared to the

Suggested Citation:"Overview of Analytic Approach and Results." Institute of Medicine. 2000. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: The National Academies Press. doi: 10.17226/5501.
×

standard analysis depending on the change in delivery costs relative to the change in health care costs saved.

Summary

In summary, the hypothetical cases discussed above illustrate key factors that influence the cost per QALY gained with a new vaccine. These include the following:

  • the number of vaccinees compared to the number of cases,

  • the interval between the time of vaccination and the time at which disease is averted (i.e., the time at which the vaccinee experiences health benefits and savings in costs of care are realized),

  • the number of QALYs to be gained by protection from disease for one age group compared with that for another age group (for the same number of calendar years), and

  • mortality or long periods spent in a disabled state.

RESULTS

The committee was not charged to recommend which candidate vaccines should be developed. It has focused on developing a conceptual framework and a quantitative model for that framework to aid researchers and policymakers in planning research and development efforts for the plethora of candidate vaccines that have emerged over the last 10 years. As described in a preceding section, this model can aid policymakers in planning for use of new vaccines once licensed.

The primary measure used to report these results is a cost-effectiveness ratio of cost per QALY gained based on the annualized present value of the component costs and QALYs. As described in Chapter 3, there were many considerations in choosing these 26 diseases for which a vaccination strategy was considered feasible and appropriate. The committee chose a range of conditions (in terms of factors such as target populations, incidence of disease, and health states) for which a vaccination strategy might be used. The committee expected that the final results of the exercise would range widely.

The candidate vaccines fall into four reasonably distinct groupings or levels: candidate vaccines that would save money and QALYs; candidate vaccines that would require small costs (<$ 10,000) for each QALY gained; candidate vaccines that would require modest yet reasonable costs (<$100,000) for each QALY gained; and candidate vaccines that would require large costs (more than and much more than $100,000) per QALY gained.

Suggested Citation:"Overview of Analytic Approach and Results." Institute of Medicine. 2000. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: The National Academies Press. doi: 10.17226/5501.
×

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,

  • 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),

  • 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, 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 candidate vaccines 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):

Suggested Citation:"Overview of Analytic Approach and Results." Institute of Medicine. 2000. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: The National Academies Press. doi: 10.17226/5501.
×
  • Group A streptococcus vaccine to be given to infants,

  • 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)

  • parainfluenza virus vaccine to be given to infants and to women in their first pregnancy, and

  • rotavirus vaccine to be given to infants.

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 into geographically defined high-risk areas,

  • Coccidioides immitis vaccine to be given to resident infants born in and immigrants of any age into 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 application of the committee’s framework and model are both predictable and surprising. On a pragmatic and qualitative level, the framework developed for the assessment of these vaccines is an advance from that developed in 1985. The spreadsheets will be available for anyone who wishes to experiment with the model and change assumptions or data. The measure of health benefits, QALYs, is being used by many in the health field, so it is a much more familiar concept than that used in 1985.

The Level I candidate vaccines include several that were discussed in the 1985 IOM report on vaccine priorities. The four infectious diseases (cytomegalovirus, influenza A/B, Group B streptococcus, and streptococcus pneumoniae) with Level I candidate vaccines continue to have a staggering burden of disease for many reasons: the numbers of infected people, the seriousness of the health states caused by the infection, and the incidence of long-term sequelae (death and permanent impairment) and subsequent loss of quality of life (as measured in QALYs). A common factor in the analysis for these four vaccine strategies is the relatively short interval between vaccine administration and realization of health benefits for many of the affected people.

The inclusion in Level I of candidate therapeutic vaccines suggests that vaccine strategies for noninfectious, chronic conditions hold much promise. These results are seen even though the estimated efficacy (40%) is much less than that for the preventive candidate vaccines (75%). The acceptance, however,

Suggested Citation:"Overview of Analytic Approach and Results." Institute of Medicine. 2000. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: The National Academies Press. doi: 10.17226/5501.
×

was estimated to be very high, and the interval from vaccination to realization of health benefits is very short. In the absence of experience with therapeutic vaccine strategies, it is not clear that the results obtained were predictable at the outset of this analysis. The committee hopes that the results will encourage continued research into the use and benefits of this relatively new class of vaccine strategies.

As mentioned, the results presented above are based on the full analysis described at the beginning of the chapter. Readers might question the effects of changing certain assumptions or components of the model, and the committee tested the effects of changing certain assumptions. To illustrate how the model could be used by vaccine program planners, the committee assumed that the vaccines are currently available (i.e., requiring no more time or costs for development). There was no change in the assignment of vaccines to Levels I-IV. When the committee further assumed that the vaccines are currently available, 100% effective, and utilized by 100% of the target population (i.e., the ideal scenario; an analysis requested of the committee by the project sponsor, NIH), five vaccines shifted into an adjacent category. Specifically, four vaccines in Level II—chlamydia, melanoma (therapeutic), mycobacterium tuberculosis, and respiratory syncytial virus—moved into Level I. A fifth vaccine, against Coccidioides immitis, moved from Level IV to Level III.

Challenges

Licensure of the Level I candidate vaccines poses several challenges for vaccination programs and health care providers. For example, the committee believes that a CMV vaccine would best be administered during puberty to protect neonates from CMV infection. This would require acceptance by parents, children, and health care providers that the potential for sexual activity among young adolescents argues for ensuring that the vaccine is administered to 12-year-olds (the proxy age used in the modeling). This also will require a health care milieu that is more capable than it is now of routine vaccination at ages other than infancy. 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. Similar incentives are not yet as widespread for the newly emerging “adolescent” or “pubertal” vaccination visits that are now recognized as being important for protection against measles and rubella, for example.

Another challenge will be immunization of pregnant women against Group B streptococcus. Previous chapters discussed the barriers, particularly the legal barriers, to the development of vaccines to be administered during pregnancy. The committee’s analysis assumes that these barriers have been overcome. The analysis also assumes that immunization of pregnant women can become a standard part of prenatal care. With an alternative assumption that few pregnant

Suggested Citation:"Overview of Analytic Approach and Results." Institute of Medicine. 2000. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: The National Academies Press. doi: 10.17226/5501.
×

women will be immunized, the development of a Group B streptococcus vaccine becomes much less favorable (see Level III).

A third challenge will be acceptance of vaccines using DNA-based technologies. The committee has not factored into the analysis the effect that fear or reluctance might have on the extent to which this emerging technology might be used. The final challenge relates to therapeutic vaccines. Their effectiveness will depend on the early detection of an incipient disease; the committee has not envisioned how this might be done, especially for the therapeutic vaccine for insulin-dependent diabetes mellitus (IDDM). The committee assumes that, during the 15 years of development that remain until the expected licensure of these candidate vaccines, clinical research will provide a better understanding of the population at risk of IDDM and a means of screening for early signs of pancreatic ϑ-cell destruction.

The Level II candidate vaccines include many of the candidate vaccines from the 1985 IOM report on vaccine priorities. This set includes candidate vaccines for sexually transmitted diseases, important pediatric viral infections, bacterial and viral infections associated with long-term chronic disease states, and a therapeutic vaccine directed against a cancer, melanoma. The challenges posed by the licensure of these candidate vaccines are similar to those discussed above for the most favorable set. Vaccines to be administered during puberty require health care delivery systems and practices not yet adequately developed.

The placement in Level II of a vaccine directed against tuberculosis illustrates an interesting point. Although tuberculosis is a very serious disease with high associated health care costs, the number of new cases of tuberculosis is much lower than the number of new cases of many of the other diseases considered in the committee’s analysis. However, the assumption by the committee that the vaccine would be given to high-risk populations in a very targeted manner means that program costs are low compared with the cost of annual immunization of the birth cohort of almost 4 million infants.

The Level III candidate vaccines include vaccines to be given during puberty (or during pregnancy, but with a low utilization rate) to protect newborns and infants and vaccines to be administered during infancy to prevent diseases in infants and all others. Challenges related to immunization of pregnant women and of adolescents were discussed above. The committee has assumed that utilization of all vaccines during puberty will be in a midrange of approximately 50%. A Group B streptococcus vaccination strategy that targets girls during puberty or pregnant women with an assumption of a 10% utilization rate falls into Level III. An assumption of a high rate of utilization during pregnancy moves the Group B streptococcus vaccination strategy into the cost-saving set (Level I) of candidate vaccines, as discussed above.

The committee began its deliberations before the licensure of a rotavirus vaccine in 1998. The committee finalized its analysis of rotavirus vaccine with two separate assumptions. One analysis assumed that licensure was imminent in 3 years and required development costs. The other analysis assumed that licen-

Suggested Citation:"Overview of Analytic Approach and Results." Institute of Medicine. 2000. Vaccines for the 21st Century: A Tool for Decisionmaking. Washington, DC: The National Academies Press. doi: 10.17226/5501.
×

sure had occurred and that there were no more development costs. Both analyses place rotavirus vaccine in Level III.

The Level IV candidate vaccines include those whose development might seem less compelling because of limited disease burden, primarily because of low numbers of cases. Several of the candidate vaccines in this category would be used by restricted populations. These populations are limited by geography (e.g., Borrelia burgdorferi, Histoplasma capsulatum, and Coccidioides immitis vaccines) or by occupation or activity. For example, the shigella and enterotoxigenic Escherichia coli vaccines are targeted to overseas travelers, including members of the military.

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 efforts related to Level IV candidate vaccines can be justified in several ways. 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, increasing the disease burden and making the need for these vaccines more compelling. The discussion of the development of the polio vaccine (Chapter 2) demonstrates that disease epidemiology can indeed change in a relatively short time, making what once seemed like a minor disease a much bigger concern; in this case, ongoing research on poliovirus and poliovirus vaccines contributed greatly to the speedy development of two complementary vaccine strategies once the need was recognized. These Level IV candidate vaccines could also be important due to the burden of disease in other countries, which is not factored into this analysis. The committee argued in Chapter 3 that the 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. An analysis of international disease burden would be likely to result in a more favorable cost-effectiveness result for such candidate vaccines.

As this chapter illustrates, a cost-effective analysis is an important tool available to policymakers concerned with vaccine research and development, as well as with vaccine program implementation. Not every scenario could be analyzed and presented, but an important tool has been developed and recommended for use. Prominent candidate vaccines have been used to illustrate the model. The availability of the software and spreadsheets used in the analysis of Vaccine X and of the 26 candidate vaccines means that dialogue around vaccine research and development priorities can continue with a common tool and a common language.

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Vaccines for the 21st Century: A Tool for Decisionmaking Get This Book
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Vaccines have made it possible to eradicate the scourge of smallpox, promise the same for polio, and have profoundly reduced the threat posed by other diseases such as whooping cough, measles, and meningitis.

What is next? There are many pathogens, autoimmune diseases, and cancers that may be promising targets for vaccine research and development.

This volume provides an analytic framework and quantitative model for evaluating disease conditions that can be applied by those setting priorities for vaccine development over the coming decades. The committee describes an approach for comparing potential new vaccines based on their impact on morbidity and mortality and on the costs of both health care and vaccine development. The book examines:

  • Lessons to be learned from the polio experience.
  • Scientific advances that set the stage for new vaccines.
  • Factors that affect how vaccines are used in the population.
  • Value judgments and ethical questions raised by comparison of health needs and benefits.

The committee provides a way to compare different forms of illness and set vaccine priorities without assigning a monetary value to lives. Their recommendations will be important to anyone involved in science policy and public health planning: policymakers, regulators, health care providers, vaccine manufacturers, and researchers.

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