Cost-effectiveness of adult immunization strategies Report

Cost-effectiveness of adult immunization strategies

Abbreviations

Table of Contents Abbreviations ...................................................................................................... 2 1 Introduction .................................................................................................... 3 1.1 1.2

Background on cost-effectiveness analysis ........................................................................... 3 Approaches to economic evaluation for vaccines .................................................................. 5

2 Review of the Economic evidence for adult immunisation ................................ 8 2.1

Methods of reviewing literature ............................................................................................ 8

3 Results .......................................................................................................... 11 3.1 3.2

Quantity of research available ............................................................................................ 11 Characteristics of the included studies ................................................................................ 12

4 Discussion ..................................................................................................... 27 5 Conclusions ................................................................................................... 28 6 References..................................................................................................... 29 Appendix 1 ........................................................................................................ 33

HERON Evidence Development

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Cost-effectiveness of adult immunization strategies

Abbreviations

Abbreviations Embase

Excerpta Medica Database

EU

European Union

HTA

Health Technology Assessment

ICER

Incremental Cost-Effectiveness Ratio

ISPOR

International Society of Pharmacoeconomics and Outcomes research

MEDLINE

Medical Literature Analysis and Retrieval System Online

MS

Microsoft

NHS EED

National Health Service Economic Evaluations Database

SAATI

Supporting Active Ageing through Immunisation

QALY

Quality Adjusted Life Year

HERON Evidence Development

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Cost-effectiveness of adult immunization strategies

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Abbreviations

Introduction

Since the establishment of the Expanded Programme on Immunization (EPI) in 1974 by the World Health Organization, immunization has been one of the most successful public health interventions globally 3. A number of new vaccines have been developed in recent years that offer potential reductions in the morbidity and mortality caused by a range of diseases along with improved quality of life, often at higher prices than existing vaccines 4. These economic factors, combined with the fact that new and more expensive vaccines will continue to be developed in the future, have meant that decision makers increasingly use some form of economic evaluation to ascertain which vaccines represent value for money. The purpose of economic analysis is to assist decision-makers to allocate scarce healthcare resources between interventions. Two key factors drive the importance of economic evaluation of vaccines:

1. Restrained national budgets: The global economic downturn of 2008 has resulted in public spending cuts on health, thereby making it difficult to maintain necessary levels of healthcare with limited resources. In the context of limited budget growth it is particularly important to ensure available resources are used efficiently 5. .

2. Crowded vaccine market: Recent reports on market forecasts for vaccines in Europe has predicted that the European vaccine market is expected to experience significant growth with a forecast to grow to $12.05 billion in 2018 6. This current imbalance in the demand of healthcare services by national healthcare agencies and supply of services (vaccines in this case) by the pharmaceutical industry has necessitated the economic evaluation of new interventions being introduced in the market. Efforts have been made by national health technology agencies to increase the uptake of immunizations among the general population. For example, the National Institute for Health and Clinical Excellence (NICE) in the UK has published guidance on reducing the differences in the uptake of immunizations including targeted vaccines among children and young people aged ≤19 years.7 The aim of this chapter is to evaluate the cost-effectiveness evidence of adult immunization strategies through a review of the relevant literature of the cost-effectiveness of vaccines in patients with influenza, pneumonia, invasive pneumococcal disease, pertussis, diphtheria, herpes zoster, and tetanus (to be defined as 'the seven key vaccine-preventable diseases' henceforth) across 27 European member states (EU-27).

1.1

Background on cost-effectiveness analysis

Economic evaluation in healthcare compares the cost and outcomes of alternative treatments or programmes. In the case of vaccination, the choice is normally between the new schedule being proposed and the current situation, which could be an existing vaccination schedule or no programme at all 8. Cost-effectiveness analysis is a form of economic evaluation that estimates the incremental cost and benefits (i.e., outcomes) of a new vaccine programme compared with current practice. The analysis usually calculates an incremental cost effectiveness ratio (ICER) which is defined as the difference in total costs between the new and existing (or current) intervention divided by the difference in outcomes. Costs typically considered in such analyses include the cost of the vaccination programme itself as well as the cost of treating the disease. These costs are usually considered from a healthcare payer perspective but some evaluations take a broader approach by incorporating societal costs which may include costs of lost productivity at work through absence due to sickness.

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The outcomes of an economic study may be measured in a number of ways. Some studies measure the outcome in terms of a clinical measure such as the reduction in the number of pneumonia cases. In this case the cost-effectiveness analysis may calculate the incremental cost per averted case of pneumonia. A more standardised approach used to value outcomes is to express the consequences of averting a disease in terms of Quality Adjusted Life Years (QALYs) gained which uses measures of health state utility to reflect patient preferences, see Box 1. For example, it may be used to compare vaccines in influenza in terms of cost per QALY gained. This type of analysis is called cost utility analysis and this approach is widely used by national reimbursement agencies because it enables comparison between interventions in different disease areas and makes it possible to assess whether the incremental cost per QALY of the new intervention falls below a pre-defined willingness-to-pay (WTP) threshold for a particular country. If:

ICER ≤ Rc: New intervention represents good value for money; hence cost-effective ICER > Rc: New intervention does not represent good value for money; hence cost- ineffective

Where, Rc represents some threshold ratio that corresponds to a decision maker’s willingness-topay for one unit of health gain 2. For instance, the willingness-to-pay threshold for one unit of QALY gain is £20,000 - £30,000 in the UK.

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Box 1: Quality Adjusted Life Years (QALYs)

Quality Adjusted Life Year (QALY) is a health outcome measure that expresses health as a function of both quality (expressed as utility values) and quantity (length of life) generated by healthcare interventions. Essentially, a QALY is estimated by multiplying the quality-adjustment weight for each health state by the time in the state and then summed to calculate the number of quality adjusted life years [Ref: Drummond 1997]. [Note: The utility values range from 0 to 1 where a utility of 1 indicate perfect health state and that of 0 indicates dead] Diagrammatic representation of QALY from an intervention versus no intervention

X-axis represents the utility scores at different time points; Y axis represents the time points.

Source: http://www.crecon.co.jp/pharmaco_english/pharmaco/page2.html

1.2

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Approaches to economic evaluation for vaccines

Previous studies have applied a variety of modelling techniques to assess the cost-effectiveness of immunization across Europe. Some of the common techniques include decision trees, Markov models, and dynamic models. A brief description of each of these mathematical models is presented below.

1.2.1

Decision Tree

A decision tree is the most common structure for decision models in economic evaluation that uses a tree-like structure of decisions (represented by decision node, along with the consequences including chance event outcomes (represented as chance nodes), costs, and utility). An illustration of a decision tree in presented in

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Figure 1.

Figure 1: Illustration of decision-tree

1.2.2

Markov model

An alternative method of modelling decision outcomes is through Markov models, where decisions are made based on a series of health states that a patient can occupy at any given point in time. Unlike decision trees, Markov models explicitly determine time elapses and the probability of a patient occupying a given health state (known as Markov state) is assessed over a series of discrete time periods, also known as cycles. The speed at which patients move between the Markov states are defined as transitional probabilities. A graphical representation of Markov model is presented in Figure 2. Figure 2: A diagrammatic representation of Markov model

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Source: Annemans and colleagues 20109

1.2.3

Dynamic modelling

Dynamic modelling (also known as system dynamics) is a mathematical technique used in assessing complex health problems, mainly infectious diseases such as HIV/AIDS, hepatitis, etc. Such models evaluate the interaction between populations, thereby taking into account how populations interact at a societal level, and how pathogens spread between groups of patients.

1.2.4

Discrete event simulation

This type of modelling technique (also known as individual patient sampling model) assesses the experience of individual patients with respect to the events of interest which are evaluated at discrete points in time.

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2

Review of the Economic evidence for adult immunisation

A number of cost-effectiveness studies of vaccines in the seven key vaccine preventable disease areas have been conducted. The aim of this work was to conduct a structured literature review to identify the existing economic evidence for adult immunization across EU-27 so that we can begin to outline the economic benefits of population wide vaccination programmes within a certain age group and to understand in which disease areas additional data and analyses are needed to frame such benefits.

Background to the literature review Every year resources are spent in treating many diseases which could be prevented by immunisation. For instance, the annual economic burden of treating pneumonia in adults across Europe is 10 billion Euros. Direct costs (in-patient care, outpatient care and drugs) account for 6.2 billion Euros and indirect costs (working days lost) for 3.6 billion Euros. 10 Comprehensive immunisation strategies/guidelines for adults may help in significantly reducing the burden of diseases which are preventable by vaccination. Active immunisation strategies for an elderly population may, for example, allow greater numbers to stay in the active workforce for a longer period of time and minimise the costs of treating the disease for a population. Therefore, there is a compelling rationale to synthesise evidence from the relevant literature to help create an understanding of the economic benefits of active immunisation in adults aged 50 years or above within the seven key vaccine-preventable diseases and this is one of the key aims of the Supporting Active Ageing Through immunisation (SAATI) partners. More specifically, the rationale behind the literature review can be explained as: To identify and summarise the existing economic studies that evaluated the costeffectiveness of immunization across the seven infectious diseases in the EU-27 countries To identify gaps in the existing economic evidence

2.1

Methods of reviewing literature

2.1.1

Search strategy

To ensure a comprehensive review of published evidence on cost-effectiveness of immunization across the seven disease areas, a number of sources were searched:

Databases Four databases were searched: Medical Literature Analysis and Retrieval System Online (MEDLINE®)

Excerpta Medica Database (Embase®) Cochrane Economic Evaluation Database (NHS EED) and Technology Assessment database

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MEDLINE® and Embase® were searched using the embase.com interface. NHS EED and Technology Assessment database were searched using the Cochrane library interface. All databases were searched from 1990-onwards to present in order to retrieve most relevant and recent evidence of the available data.

Conference proceedings Conference abstracts were hand-searched to retrieve the latest studies which have not yet been published in journals as full text articles or supplement results of previously published studies. The following list of conferences was searched for the current review: ISPOR-International (2011-2012) ISPOR-Europe (2010-2011)

Other sources Bibliographic searching of included evidence was conducted to address data gaps in relevant disease areas for EU-27. Appendix 1 presents the details of the full search strategy. The searches were conducted in the month of October 2012.

2.1.2

Inclusion and exclusion criteria

Any study designs reporting cost-effectiveness evidence for adult immunization strategies for the seven key vaccine-preventable diseases for patients aged ≥50 years of any race and gender were included within the scope of this structured literature search. Further, studies assessing costeffectiveness of immunisation strategies in high risk adult populations and in health care workers or laboratory staff at risk of exposure were also included if data were reported for older adults ≥ 50 years of age. With respect to the country settings, the primary focus was to consider data from EU-27 member states. Studies reporting different immunization strategies including different schedules and doses were included. Lastly, studies were limited to those published from 1990 onwards and in English language alone. Studies focussing on young children or adolescents and those published in any other European language, were excluded from this structured literature review.

2.1.3

Data extraction strategy

Data from the studies identified at the study inclusion stage were extracted using a list of outcomes to be considered. This list was developed in alignment with the SAATI objectives, a summary of which is presented in Box 2.

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Box 2: A summary of the data extracted

Study information Study objective Population of interest Year of study Country (ies) of study Population size Immunization strategies (including different schedules) Comparators

Evaluation framework Type of economic evaluation Methods of analysis Study perspective Cost year and currency Sources of clinical outcomes and costs Time horizon of model and discounting Assumptions related to herd immunity

Cost-effectiveness data Incremental cost effectiveness ratios (cost/QALY, cost/life year gained, etc) Any other cost-effectiveness outcomes Details of sensitivity analyses performed

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3

Results

3.1

Quantity of research available

A total of 2,154 studies were retrieved through the structured searches. Following the removal of duplicate citations and examination of the titles and abstracts of the remaining studies, 211 potentially relevant citations were retrieved for a more detailed inspection. Of these, 165 studies were excluded after double-screening and 46 studies were included for the purpose of this report. A PRISMA flowchart is presented in Figure 3 that summarizes the stages involved in this process of selecting the included studies. A graphical representation of the number of studies included across the seven key vaccine preventable diseases is presented in Figure 4. Figure 3: PRISMA flow diagram

#Mixed disease include more than one disease area of interest; HZV: Herpes Zoster; IPD: Invasive Pneumococcal Disease

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Figure 4: Studies included across the seven key vaccine preventable diseases

#Mixed diseases include more than one disease area of interest

3.2

Characteristics of the included studies

This section summarizes the characteristics of the included studies across each of the seven key vaccine preventable disease areas as outlined below:

3.2.1

Age group

This structured review focussed on the population aged 50 years and above. However the studies included in the review covered a varied range of age cohorts among those aged ≥50 years.

presents a schematic overview of the different age-groups included across four disease areas viz. herpes zoster, influenza, IPD, and pneumonia. No study was found for the remaining three disease areas- diphtheria, tetanus, and pertussis. The only study that targeted mixed disease included a population aged >65 years11. It is to be noted that for two diseases- herpes zoster12 and influenza13, 14, studies that targeted entire cohort of population were included within this review. The rationale for inclusion of these studies lies is that a major proportion of the included population were aged >50 years. Figure 5

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Figure 5: Age cohorts included across the disease areas in the included studies

3.2.2

Settings

The population of interest included across the disease areas are described below: Herpes Zoster: Of the 11 studies retrieved for this disease area, 4 were based in the UK12, 15-17; 2 each based in Germany18,19 and Belgium20; and 1 study each based in the Netherlands 21, Switzerland22 and France23. The main patient group of interest consisted of general population aged ≥50 years of age. However, an exception of this is the Swiss study that focussed on “high risk” groups aged 70-79 years22. Influenza: A total of 17 studies met the inclusion criteria. Of these, 4 studies were based in the UK 14, 24-26 ; 3 were based in Italy27-29; 2 studies each for France 30, 31 and the Netherlands 32, 33; and 1 study each for Poland34 and Spain35. The remaining 4 studies were based across multi-country: the study by Aballea and colleagues 36 conducted economic evaluation of vaccination strategies across Brazil, France, Germany and Italy; the study by Scuffham and colleagues 37 was based on England and Wales, France, and Germany; Lugner and colleagues 13 conducted their economic analysis based on evidence from Germany, the Netherlands, and the UK; and the study by Reygrobellet and colleagues38 was based in Slovakia and Czech Republic. Despite the inclusion of a non EU country by Aballea and colleagues 36, the study was nevertheless included as it focussed on 3 key EU nationsFrance, Germany and Italy. In addition, this study developed an international model which could help inform a global comprehensive modelling framework for the economic evaluation of influenza in the future.

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IPD: A total of 9 studies met the inclusion criteria within this disease area. Of these, 8 studies were based across the UK39-41, Belgium42, Germany43, Italy44, the Netherlands 45, and Spain46. The remaining study by Evers and colleagues 47 was based on multi-countries including Belgium, France, Scotland, Spain, Sweden, Denmark, UK, Germany, Italy and the Netherlands. Pneumonia: Within this disease area, 8 studies were included based in the UK48, the Netherlands49, 50 , Poland51, Germany52, Spain53, France54 and Finland55. Mixed disease: The structured search identified a study by Ament and colleagues 11 that assessed the cost-effectiveness of pneumococcal vaccination for IPD and pneumococcal pneumonia in elderly population across 5 countries- Belgium, France, Scotland, Spain, and Sweden. A detailed overview of the prevalence of cost-effectiveness evidence across the seven key preventable diseases in EU-27 is graphically presented in Figure 6. Figure 6: Available evidence across the disease areas in the EU nations- Settings

3.2.3

Modelling methodology

A variety of modelling approaches were used in the economic evaluations performed across the seven key preventable disease areas. These models were subject to substantial methodological and structural differences. The two key types of methodologies adopted were: decision trees and Markov models. Other modelling techniques adopted include discrete event simulations and transmission modelling. Below is a brief overview of the adopted methodologies across the disease areas: Herpes Zoster: The modelling techniques used in this disease area include a Markov model15, 17-19, 2123, 56 , transmission modelling12, and deterministic compartment static model20.

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Influenza: Transmission modelling13, 14, 24 and decision tree25, 27, 30, 34-36, 38 were the two commonly used modelling techniques in this disease area. However, Monte Carlo simulation technique was used by Doyle and colleagues 31 to assist health authorities in France in order to update the French pandemic plan whereas budget impact analysis was conducted by a UK based study26 to examine the budget impact of introducing influenza vaccination for healthy elderly population aged between 65 and 74 years. IPD: Markov model39-41, 44, 47, 52 and decision tree42 were the two main modelling techniques adopted across 8 studies; whereas the study by Guijarro and colleagues 46 conducted a budget impact analysis. Pneumonia: Like in IPD, Markov model48, 52, 54, 55 and decision tree49, 50 were the most common modelling techniques used across the included studies whereas only one study conducted a budgetimpact analysis applying a modified Markov structure55. Mixed disease: Cohort modelling approach was adopted while evaluating the cost-effectiveness of mixed diseases11. A schematic of the modelling methodologies applied in the economic analyses across the EU nations are presented in Figure 7. Figure 7: Available evidence across the disease areas in the EU nations- Methodology

3.2.4

Time horizon

For any economic evaluation, the time horizon considered in the analysis should be long enough to capture the entire difference in costs and outcomes of the alternative strategies. Of the studies included in this structured review, a vast majority of the studies were conducted for a lifetime horizon. However, an equal proportion of studies did not clearly state the time-horizon for which the analyses were performed. A comprehensive overview of the different time-horizons included in the economic evaluations across the seven key vaccines preventable diseases are presented in

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Figure 8.

Figure 8: Available evidence across the disease areas in the EU nations- Time horizon

A majority of the studies in herpes zoster included a lifetime-horizon9, 15, 17-19, 22, 23. On the contrary, a majority of the studies for influenza were conducted for short time horizons 13, 27, 28, 32, 34, 36. This could be explained by the seasonal epidemiological nature of the disease. Studies for IPD43-46 and pneumonia48, 49, 55 were conducted for a relatively long time periods ranging from 4-10 years.

3.2.5

Comparator

A range of comparators were included across the included studies as outlined below: Herpes Zoster: The most common comparator included no immunization strategy15-18, 21, 22, followed by comparison of immunization strategies targeting patients on different age-cohorts12, 19, 20, and a mix of the two comparisons 9.

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Influenza: The different strategies used for the comparative analyses could be sub-divided into four categories: 1. Vaccination versus no vaccination 24-27, 29, 32, 33 2. Re41imbursement for specific cohorts of population (e.g. high-risk groups, low-risk groups) versus all individuals across the entire spectrum of elderly population 13, 14, 34-36 3. Different doses of vaccination (such as Chemoprophylaxis Neuraminidase Inhibitors (NI), Chemoprophylaxis Ion-channel Inhibitors (ICI), intradermal vaccines, intramuscular vaccines)28, 30, 37, 38 4. Vaccination versus antiviral treatment31 IPD: The comparators used in the studies include no vaccination39, 42, 44, 45, 47; and different doses of vaccines such as Pneumococcal Conjugate Vaccine (PCV13) vs. 23-valent pneumococcal polysaccharide vaccine (PPSV23) 43, 52 Pneumonia: Similar comparators were as in the studies for IPD disease area. Mixed disease: No vaccination was used as a standard comparator in this case 11. A disease-wise classification of the different comparators used across the included studies is presented in Figure 9. Figure 9: Available evidence across the disease areas in the EU nations- Comparators

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3.2.6

Perspective

The perspective adopted within a study determines the different components of costs included and outcomes to be evaluated. A detailed classification of the perspective adopted across the included studies is presented graphically in

Figure 10.

As shown in the figure, a majority of the studies were conducted from the perspective of the healthcare provider, followed by studies adopting societal and payers perspective. It is to be noted that 8 of the 46 studies included in this review conducted their analyses from more than one perspective18, 19, 22, 25, 35, 36, 40, 52.

Figure 10: Available evidence across the disease areas in the EU nations- Perspectives

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3.2.7

Herd immunity

Herd immunity (also known as “community immunity”) describes a form of indirect protection conferred by the vaccine when vaccination of a certain group may result in considerable reduction of the disease transmission in the non-vaccinated population. This theory is mainly proposed in contagious diseases such as influenza since transmissions of the disease are likely to be disrupted when a proportion of the population is not susceptible to the disease. Therefore assumptions surrounding herd immunity will influence cost-effectiveness of the vaccination strategy under consideration57. Given its relevance, the assumptions used in the included studies surrounding herd immunity were extracted as outlined below: Lugner 201213 The study used the estimates of quality of life as weights for the scenario of pre-existing immunity to reflect the burden of illness. On assuming pre-existing immunity to be part of the population, the overall clinical attack rate reduced to about 27% in contrast to when the total population was assumed to be fully susceptible, the overall clinical rate was about 36%. Baguelin 201014 The study stated that vaccinating school children was the most cost-effective option after vaccination of high-risk individuals- rolling out the remaining doses to low-risk groups after a rapid roll-out of doses to high-risk group would benefit a high-risk group as well as they would be indirectly protected through herd immunity. Baguelin 201224 The study assumed that the impact of vaccination depended on the coverage of the vaccine in a nonlinear way because of the effect of herd immunity.

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3.2.8

Costs

Of the included studies across the seven key vaccine preventable disease areas, a wide range of cost components were used in the economic evaluations that could be sub-divided into direct and indirect costs. Direct costs are variable costs which are attributed directly to the diseases. These are the costs incurred from the perspective of the healthcare funder 58. For instance, costs associated with drugs, hospitalization, etc. could result directly from the disease. Indirect costs, on the other hand, include costs which are not directly attributable to the specific disease in question but nonetheless it has an impact on the overall economic costs associated with the disease. These are the costs from the societal perspective 58. For example, costs associated with loss of productivity might not be attributed directly to the disease but it influences the overall cost burden the disease might have on the economy. Table 1 summarises the different components of direct costs which can again be sub-divided into three categories- interventional costs, treatment costs and other costs. Table 1: Different components for direct costs

Direct costs Interventional costs

Treatment costs

Other costs

Vaccination costs

Costs of GP visit

Costs of specialists

Costs of antiviral treatments

Hospitalization costs

Administration cost

Costs of vaccine delivery

Costs of ambulatory patients

Costs of death

Costs of antibiotics

Ambulatory management costs

Primary care costs

Acquisition costs

Outpatient visits

Costs of adverse events

Immunization costs including costs of vaccines and supplies, promotion, delivery, vaccination and overhead

Costs of diagnostics tests Non pharmacologic treatments Medical care costs Costs of intensive care Treatment costs of vaccine side effects

The analyses that were conducted from the societal perspectives included indirect costs, in addition to direct costs. A summary of the different components of the indirect costs are presented in Table 2. Table 2: Different components for indirect costs

Indirect costs Costs of lost productivity Disease burden Costs of carers Working days loss Time cost for individual to receive vaccination Travel costs

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3.2.9

Health outcomes

A majority of the studies were cost-utility studies and the headline health outcome measure included Quality Adjusted Life Years (QALYs). Cost-effectiveness studies reported health outcomes in terms of clinical events such as number of cases avoided, life years gained, number of hospital admissions, etc. The studies conducting budget impact analyses assessed the net budget impact of introducing vaccination in elderly population26, 28, 46, 55. The different health outcome measures reported across the included studies are summarised in Table 3. Table 3: Health outcomes included across the included studies

Health outcomes Cost-utility analysis QALYs

Cost-effectiveness analysis Number of cases of disease under vaccinations and no vaccination

Budget impact analysis Net budget impact

Number needed to vaccinate to prevent one case of disease Burden of disease Vaccine effectiveness Life years gained Impact of vaccination programmes on disease incidence over time Number of cases reduced due to vaccination Mortality Number of hospital admissions Life-expectancy in unadjusted life years Morbidity days avoided Number of deaths prevented Number of GP consultations avoided as a result of vaccination Health events avoided Efficacy of vaccination Exacerbation of pre-existing lung disease, pneumonia, congestive heart failure, acute myocardial infarction, angina pectoris Life expectancy

3.2.10 Measures of cost-effectiveness results A series of incremental analyses was performed as a part of the cost-effectiveness analyses conducted across the included studies within this structured review, a summary of which is outlined in Table 4.

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Table 4: Measures of incremental analyses

INCREMENTAL ANALYSES Incremental cost per QALY gained Incremental costs per GP consultation avoided Incremental cost per hospital admission avoided Incremental cost per death avoided Incremental cost per life year gained

Other outcomes reported across the included studies are presented in Table 5. Table 5: Other reported outcomes

OTHER REPORTED OUTCOMES Direct cost per health events avoided Costs and incidences associated with -

Hospitalization

-

GP visits

-

Antibiotics

Costs of the disease Cost per life years saved Net cost per year of life saved Cost per life years saved Net value per case prevented

3.2.11 Cost effectiveness results An overview of the cost-effectiveness results as reported across the included studies are presented below. Herpes Zoster The general consensus across studies that compared vaccination strategy versus no vaccination strategies found vaccination to be cost-effective; immunization programmes which were not costsaving might still be cost-effective. Existing evidence indicated that if immunization was not costeffective in the short-term, it did not imply cost-ineffectiveness in the long run12. Results of the existing evidence indicated such a strategy to be a valuable preventive option when targeting populations aged 50-54 years19. However, immunization strategy targeting those aged 70 years and above appeared to be marginally cost-effective as seen in the case of the Netherlands. This could be due to combination effect of waning immunity after vaccination as well as a reduced efficacy of vaccination at high ages 15. Contrary to this, health economic evidence from a study conducted in a French setting23 indicated that vaccination policy for HZ targeting population from different age cohorts- those aged 65 and those aged ≥70 years to be cost-effective.

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Influenza The results of the studies conducted across multi-countries35, 37 found vaccination for influenza to be cost-effective across all the countries of interest. Another multi-country study Lugner 201213 concluded that vaccinating an elderly population (those aged >65 years) could be the best strategy for influenza if vaccines were available early in the pandemic and there was pre-existing immunity across the population. An exception to these findings, was the result found in the UK based study 26 where it was concluded that influenza vaccination of those aged between 65-75 years might not provide a cost-effective strategy for preventing the pandemic when compared to placebo. However this study was based on the results from a randomised clinical trial which was underpowered to show any differences in resource use and costs between vaccination and placebo. The French study by Doyle and colleagues 31 was the only study that compared vaccination strategy with antiviral treatments. The results suggested a strong role for the antivirals in an influenza pandemic, but generally in the case when an effective vaccine is not available before the pandemic arises. The Italian study by Garattani and colleagues 27 concluded that the economic advantage of extending influenza vaccination to healthy adult workers aged 50-64 years mainly relate to indirect costs such as costs associated with productivity loss. IPD The study by Evers and colleagues 47 conducted a multi-country analysis across 10 EU countries to analyse the cost-effectiveness of pneumococcal vaccination for IPD across those aged >65 years. The study observed substantial variation in the ICERs across the countries, with older populations generally having higher ICERs. On the other hand, the UK based study by Melegaro 39 recommended routine vaccination of all population aged ≥ 65 years as it was estimated to the dominating strategy with lower cost per life year gained compared to vaccinating high-risk groups only. Studies conducted across the UK41 and Germany43, 52 comparing the different doses of vaccination therapy concluded that adult vaccination with PCV13 was more cost-effective compared to that with PPV23. Pneumonia Two studies conducted in the Netherlands setting concluded vaccination with PCV 13 to be costeffective when compared with no vaccination 49 for both general population as well as high risk population aged ≥65 years. The Finnish study by Martikainen and colleagues 55 presented similar findings as the two Dutch studies.

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Cost-effectiveness of adult immunization strategies

Abbreviations

Table 6 presents a summary of the cost-effectiveness results reported across the disease areas.

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Cost-effectiveness of adult immunization strategies

Abbreviations

Table 6: Summary of the cost-effectiveness results Herpes Zoster Belgium

94% chance of vaccination being cost-effective at the unofficial €30k threshold with cost per QALY of €7,137 9 compared to no vaccination If vaccination price is €90 per dose, vaccination is cost-effective with an ICER of €5500 for all ages ≥60 years, under assumptions most in favour of vaccination. If the price drops to €45 per dose, vaccination is cost-effective for those aged 60-64 years even under assumptions least in favour of the strategy 20

The UK

Cost per QALY of vaccination compared to no vaccination is £20,41215 Vaccination strategy leads to an ICER of £13,077 per QALY (compared to no vaccination) for those aged above 50 years17 Vaccinating 65 years olds with life-long efficacy of 70% would be cost saving to healthcare providers at a cost per 16 course of lower than £30. Programmes that are not cost-saving may still be cost-effective. The optimum strategy is the two-dose policy with vaccination of the elderly

Germany

ICER for vaccination strategy for those aged above 60 years was €20,139

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When targeting a cohort aged 50-54 years, preventing one HZ-case costs approximately 400€ from payer's perspective and approximately 280€ from societal perspective. In this age-cohort the number needed to vaccinate was 6. When increasing the target-age to 85+ year olds, ICERs were 3,646€ (payer's perspective) and 3,634€ (societal perspective) per adverted HZ-case, respectively, indicating a lower cost-effectiveness of 19 vaccination in this age-cohort; and number needed to treat increased to 37 21

The Netherlands

The most optimal cost-effectiveness ratio for vaccination was found for 70 years olds at €21,716 per QALY

Switzerland

ICER for vaccination strategy was within the acceptable threshold of 25,538 CHF (23,646 USD) per QALY gained 22 in Swiss setting

France

ICER for vaccination of French elderly aged 70 years and above was estimated to be €7,217 per QALY gain

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Influenza Italy

The results of the prospective study estimated the cost–benefit ratio at €8.22, with a net saving of €110.20 for each vaccinated 29 The economic advantage of extending public influenza vaccination to healthy adult workers is still uncertain and mainly relates to the indirect costs of productivity losses, making the extension strategy more a labour than a health issue27 About 83% of the 12 million people of at least 65 years of age currently resident in Italy can be considered at high risk for influenza complications due to underlying chronic diseases. Absence of vaccination could lead to more than 2 million influenza-like-illness (ILI) cases, and 29,000 related deaths. The vaccination program with a coverage rate of 65.6% would lead to an estimated 1.5 million ILI cases (26.9% reduction) with a standard vaccine and to 1.3 million (35.8% reduction) with the MF59 adjuvanted vaccine with a relative increase of avoided cases of 33,1%. The standard vaccination program produced a moderate direct cost increase of about 50 million Euro (+4.6%), whereas the adjuvanted vaccine provided an estimated saving of about 74 million Euro ( 6.8%), both compared to the non vaccination. Cost savings were mainly related to hospital admissions avoided in the elderly population (≥ 65 years of age) 28

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The UK

The vaccination programme likely to be CE at WTP threshold of £20k-30k, and "very cost-effective" at GDP per 24 capita at £23k in 2011 as recommended by WHO The estimated cost per QALY were £6174 and £10 766 for NHS and all costs respectively. Extension of the current 25 immunisation policy has the potential to generate a significant health benefit at a comparatively low cost Incremental NHS cost per life-year gained: £244,000 ; Incremental NHS cost per QALY gained: £304,000 . The 26 analysis suggested that influenza vaccination in population aged 65-74 years would not be cost-effective. Extending vaccination to school age children from the high-risk groups would be the most-cost-effective 14 extension .

Poland

In Poland, the introduction of the public funding of influenza vaccination for people aged ‡65 years would cost PLN 79 million when an increase in coverage rate from 13.5% to 40% is assumed. 23 900 cases of influenza, 1777 hospitalizations and 548 premature deaths would be averted each year due to the influenza vaccination programme. Fifty-seven persons would need to be vaccinated to prevent one case of influenza. To prevent one hospitalization and one death due to influenza, 842 and 2809 individuals would need to be vaccinated, respectively. The new strategy would be very cost effective compared with the current situation with an incremental costeffectiveness ratio (ICER) of PLN26 118/QALY, which is below the 2009 yearly gross domestic product (GDP) per capita. 34

The Netherlands

The costs of influenza were estimated to be 31 million euros (EUR) for the influenza season 1995/96 in The Netherlands (EUR1» $US1.1). For the extended programmein 1997/98, i.e. all elderly people, the costeffectiveness ratio was estimated at EUR1820 per life-year gained. Subgroup analysis demonstrated that the programme had a more favourable cost effectiveness among the chronically ill elderly population (cost saving) than among the rest of the elderly population (EUR6900 per life-year gained).32 In elderly aged >65 years (n=630), the occurrence of any complication was reduced by 50% (95% CI 17, 70%). The 33 economic benefit was estimated at £50 per elderly vaccinee.

Spain

ICERs were estimated at € 14,919 per quality-adjusted life-year (QALY) gained and €9731 per life-year gained. From societal perspective, the corresponding results were €4149 per QALY and €2706 per life-year gained. 35 Extending routine influenza vaccination to people over 50 years of age is likely to be cost-effective.

France

The study found that adjuvanted trivalent vaccination resulted in fewer deaths and more life gained than standard vaccination. This was achieved with relatively little extra cost. At attack rate approaching 10%, adjuvanted vaccination is a dominant strategy (with cost per life year gain of €19,435) -implying a reduction in costs and increase in benefits 30. Without intervention, an influenza pandemic could result in 14.9 million cases, 0.12 million deaths, and 0.6 million hospitalisations in France. Twenty four per cent of deaths and 40% of hospitalisations would be among high risk groups. With a 25% attack rate, 2000–86 000 deaths could be avoided, depending on population targeted and intervention. If available initially, vaccination of the total population is preferred. If not, for priority populations, seasonal prophylaxis seems the best strategy. For high risk groups, antiviral treatment, although less effective, seems more feasible and cost effective than prophylaxis (respectively 29% deaths avoided; 1800 doses/death avoided and 56% deaths avoided; 18 500 doses/death avoided) and should be chosen, especially if 31 limited drug availability .

Multi-country

Vaccination strategies were most cost-effective across England&Wales, Germany and France . With the comprehensive vaccination strategy the costs per day of morbidity averted were €5.2 in France and €9.2 in Germany and the strategy was cost-saving (€0.6) in England and Wales. Depending on coverage rates, substancial reductions in morbidity and mortality can be achieved with vaccination strategies that cannot be obtained from any of the other strategies considered 37. All vaccination strategies were cost effective. In scenarios where the vaccine became available at the peak of the pandemic and there was pre-existing immunity among elderly people the ICERs for vaccinating high transmitters were €7325 (£5815; $10 470) per QALY gained for Germany, €10 216 per QALY gained for the Netherlands, and €7280 per QALY gained for the United Kingdom. Specifically, when the vaccine was available early in the pandemic and there was no pre-existing immunity, in Germany it would be most cost effective to vaccinate elderly people ( €940 per QALY gained), whereas it would be most cost effective to vaccinate high transmitters in both the Netherlands (€525 per QALY gained) and the United Kingdom (€163 per QALY gained). This difference in optimal strategies was due to differences in the demographic characteristics of the countries: Germany has a significantly higher proportion of elderly people compared with the Netherlands and the United Kingdom 13. Incremental cost-effectiveness ratios of intradermal vaccination versus intramuscular vaccine were €12,852/QALY in Slovakia and €10,375/QALY in Czech Republic. These values were below three yearly GDP per capita in these 2 countries and therefore could be seen as acceptable for health authorities. 38 Comparing new strategy-extending vaccination strategy to those aged ≥50 years to the current policy, the estimated mean costs per QALY gained were R$4,100, €13,200, €31,400 and €15,700 for Brazil, France, Germany,and Italy, respectively. Assuming a cost-effectiveness threshold ratio of €50,000 per QALY gained, the probabilities of the new policy being cost-effective were 94% and 95% for France, 72% and near 100% for Germany, and 89% and 99% for Italy, from the TPP and societal perspectives, respectively. 36

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IPD Belgium

Vaccinating 1000 adults between the ages of 18 and 64 years gains approximately 2 life-years in comparison with the no vaccination option. However, to realise these additional health benefits requires additional costs of 11 800 European Currency Units (ECU; 1995 values) per life-year saved. Vaccinating 1000 elderly people (≥65 years) 42 leads to >9 life-years gained as well as a small monetary benefit of ECU1250.

The UK

When compared to no vaccination, the incremental CE ratio (ICER) was estimated at £14,813 and £13,497/QALY gained, from the third party payer and the societal perspective, respectively. 40 The current UK recommendation does not appear to be the most costeffective strategy due to the low level of efficacy of the vaccine in high-risk groups (HRG) and their shorter life expectancy. Routine vaccination of all elderly appears to be more cost-effective. Holding all other parameters at their base case values, the current UK recommendations, which consist of vaccinating all HR elderly with PPV, gives a cost per life year gained of £9477. Vaccinating all 65+ years old, with or without high-risk conditions, results in being the dominating option with a lower cost per life year gained of (£8504) under base-case assumptions. 39 It is estimated that adult vaccination with PCV13 instead of PPSV23 is cost-effective at the current NHS list 41 price.

Germany

Vaccinating German at-risk adults and the elderly with PCV13 at current vaccine uptake resulted in an undiscounted NBI of €239 million in the base case, which is 22% higher than vaccinating with PPV23. According 43 to this analysis, PCV13 is likely to result in a significant impact on the healthcare budgets.

The Netherlands

Pneumococcal vaccination in the elderly was not found to be cost saving. At baseline, stochastic and univariate sensitivity analysis net costs per life year gained were estimated to be between 6000 and 16 000 euro (EUR) [EUR1 = 1.1 US dollars; cost level 1995]. A scenario analysis on alternative age-dependent vaccination strategies indicated even higher net costs per life year gained, up to EUR28 000 for vaccinating only those elderly aged 85 45 years and over.

Italy

Baseline net costs per event averted and life-year gained, at 2001 prices, were €34,681 (95%CI: €28,699 to €42,929) and €23,361, respectively (95%CI: €16,419 to €38,297) 44

Spain

There would be 2,392 IPD cases in Spanish HIV patients over 4-year time horizon (598 annual cases). The model predicts that the implementation of a PCV13 vaccination program for HIV population would be a cost saving measure due to IPD cases averted. Over the study period, PCV13 would prevent 646 IPD cases and 162 related deaths.46

Multi country

There was substantial variation in the cost-effectiveness ratios for individual countries; for persons ≥65 years of age, they ranged from €9,239 for Denmark to €23,657 for Sweden. In the eight countries for which CERs for the 47 three age groups could be calculated, the CERs generally increased for older age groups Pneumonia

France

The pneumococcal vaccination strategy was cost saving, assuming that the pneumococcal vaccination was given at the same time as the flu vaccination without increasing vaccination costs. 54

The UK

If it were effective against morbidity from pneumococcal pneumonia, the main burden from pneumococcal disease, the vaccine could be cost-neutral to society or the health sector at low efficacy (28 and 37.5%, respectively, without boosting and with 70% coverage). If it were effective against morbidity from bacteraemia only, the vaccine’s efficacy would need to be 75 and 89%, respectively. If protection against both morbidity and mortality from pneumococcal bacteraemia was 50%, the net cost to society would be £2500 per year of life saved (£3365 from the health-sector perspective). A vaccine with moderate efficacy against bacteraemic illness and death would be cost-effective. If it also protected against pneumonia, it would be cost-effective even if its efficacy were low. 48

Germany

From the third party payer’s (TPP) perspective, incremental costs were estimated at €28 million and the ICER was €17,700/QALY gained. From the societal perspective, PPV23 was associated with an increment of €14 million, and the ICER was €8579/QALY gained 52.

The Netherlands

ICER for vaccination remained below €80,000/LYG, except when the vaccine was assumed to protect only against bacteremic pneumonia, with a relatively low effectiveness (40%) in combination with a high vaccine price (€65), and indirect effects of serotyp replacement would largely offset the direct effect of vaccination. In this model analysis of a hypothetical cohort in the Netherlands, vaccination with PCV-13 might be considered cost-effective, both for the total population and for the high-risk population aged ≥65 years, from a societal perspective, over a 5-year time horizon. 49 Allowing for some uncertainty regarding key variables such as the vaccine efficacy and the hospital admission rate, the vaccination of all individuals above the age of 65 years is comparable in terms of cost-effectiveness to many existing health care interventions. The vaccination of individuals above the age of 55 years with chronic lung disease or chronic heart disease is similarly attractive from an economic point of view, as is the vaccination of individuals above the age of 65 years with diabetes mellitus.50

Poland

The incremental cost per QALY gained for vaccination in all elderly was PLN 3382 and was PLN 2148 for HR elderly. Ratios were even lower when actual in and outpatients’ costs instead of reimbursed costs were considered. 51

Spain

The introduction of the vacination programme would cost US$ 97,593,663. Over the subsequent five years, with a basal rate of 3 pneumoccocal pneumonias per 1000 person-years and a 66% vaccine efficacy- the programme

27

would result in a net benefit of US $127, 142, 481, a benefit/cost ratio of 2.3 and a benefit per case prevented of US $ 2.656. Benefit/cost ratios above 1 would be obtained for incidences above 1.5 cases per 1000 person 53 years . Finland

Approximately 35% of the 2.2 million Finns of over 50 years of age can be considered to be at moderate or high risk for PDs due to the underlying chronic medical conditions. The vaccination of these people with PCV13 could provide an estimated net budget savings of about €218 million compared to the current no-vaccination situation during the five years. Among the risk groups considered, the largest net savings (€66.2 million) could be expected to be obtained by vaccinating people with heart disease due to its high prevalence in the target population. The immunization of adults (>50 years) at higher PD-risk with PCV13 vaccine will potentially lead to substantial cost savings during the forthcoming years in Finland. 55

Multi-countryBelgium, France, Scotland, Spain, and Sweden

To prevent invasive pneumococcal disease in persons aged >65 years, CERs varied from >11,000 ecu per QALY for Spain to