key: cord-287067-rrsgl377
authors: Beutels, Philippe; Scuffham, Paul A; MacIntyre, C Raina
title: Funding of drugs: do vaccines warrant a different approach?
date: 2008-11-30
journal: The Lancet Infectious Diseases
DOI: 10.1016/s1473-3099(08)70258-5
sha: 
doc_id: 287067
cord_uid: rrsgl377

Summary Vaccines have features that require special consideration when assessing their cost-effectiveness. These features are related to herd immunity, quality-of-life losses in young children, parental care and work loss, time preference, uncertainty, eradication, macroeconomics, and tiered pricing. Advisory committees on public funding for vaccines, or for pharmaceuticals in general, should be knowledgable about these special features. We discuss key issues and difficulties in decision making for vaccines against rotavirus, human papillomavirus, varicella-zoster virus, influenza virus, and Streptococcus pneumoniae. We argue that guidelines for economic evaluation should be reconsidered generally to recommend (1) modelling options for the assessment of interventions against infectious diseases; (2) a wider perspective to account for impacts on third parties, if relevant; (3) a wider scope of costs than health-care system costs alone, if appropriate; and (4) alternative discounting techniques to explore social time preference over long periods.

In many high-income countries, public funding of preventive vaccines is assessed based on the same criteria as the funding of curative pharmaceutical drugs. Such routine drug assessment processes consider evidence on quality, safety, effi cacy, and cost-eff ectiveness. Because of the increase in the number of diff erent vaccines available and advances in the science behind decision making, we have drawn on existing literature and practices to develop the arguments around potential disparities with other pharmaceuticals when assessing vaccines for public funding. These arguments revolve around vaccine-specifi c features of herd immunity and eradication, which are not evident in pharmaceuticals, and features for which the eff ects of quality-of-life losses in very young children, parental care and work loss, time preference, macroeconomics, and uncertainty substantially infl uence cost-eff ectiveness estimates. Vaccines may increasingly be judged as unacceptable if these features are not acknowledged. We also illustrate these points for fi ve specifi c vaccines that are currently under consideration for widespread use in high-income countries. We use the term "cost-eff ectiveness" in a broad sense throughout this article, encompassing cost-utility and cost-benefi t analysis, although there are technical diff erences. 1 

In 1993, Australia was the fi rst country to make evidence on cost-eff ectiveness a mandatory part of funding decisions of drugs. The Australian Pharmaceutical Benefi ts Advisory Committee is a rigorous and well-run system for evaluating drugs for acute care, chronic disease, palliation, and more recently vaccines. Many other countries have adopted a similar philosophy towards cost-eff ectiveness considerations for funding pharmaceuticals (eg, Belgium, Finland, Norway, Canada [Ontario] , Portugal, Sweden, Netherlands, UK, and USA [some organisations]), but they deal with preventive public-health measures, such as mass vaccination, in diff erent ways. Some countries have specifi c advisory groups to make funding recommendations on vaccinations (eg, UK Joint Committee on Vaccination and Immunisation, US Advisory Committee on Immunization Practices). Often, cost-eff ectiveness evidence for vaccines is assessed in the same manner as for any drug. Nevertheless, as we discuss below, vaccination has special features that make it particularly challenging to assess. Furthermore, vaccination constitutes one of the largest preventive health programmes around the world, and increasing pressures on health-care budgets are as much a challenge for the use of vaccines as for other drugs.

Vaccines provide primary prevention of future morbidity and mortality. Thus, unlike secondary prevention interventions, such as statins for cholesterol lowering, vaccines are targeted before, or in the initial stages of, the recipient's potential risk exposure. Additionally, the recipient may or may not benefi t on an individual basis. Vaccination may even harm some recipients through vaccine-associated adverse events (panel); for example, 3-5% of varicella-zoster virus (VZV) vaccine recipients report a localised rash. 2 The individual perception of risks of disease and risks of adverse events drives the demand Panel: Why many vaccines require a diff erent approach • Primary prevention in healthy people, but with possibility of adverse events • Unvaccinated or poorly vaccinated people may experience benefi cial or, more rarely, detrimental impact from herd immunity • Many vaccines prevent short-lived illness in very young children, causing extra family care and work loss, for which evaluation methods lack credibility and acceptability • The cost-eff ectiveness of many vaccines is highly sensitive to the choice of discount method • Some infections are eradicable • Some emerging infections (eg, SARS, pandemic infl uenza) would have a major macroeconomic impact that goes beyond lost productivity of sick people SARS=severe acute respiratory syndrome.

for vaccines, and may dominate the infl uence of other factors, such as price. 3 The need to show protective effi cacy beyond the typical duration of clinical trials generally aff ects the assessment of vaccines more than therapeutic pharmaceuticals, primarily because the endpoints may not be immediate. In fact, the clinical endpoints might not show clinical effi cacy at the time of trial reporting because the numbers required can be extremely large. Clinical endpoints of mortality or hospital admissions might require follow-up of thousands to millions of participants over as long as several decades. As such, some vaccines have been funded on the basis of immunogenicity data or intermediate endpoints alone (eg, meningococcal C conjugate vaccine 4 and human papillomavirus [HPV] vaccine in several countries). 5, 6 Vaccination not only protects vaccine recipients, but reduces exposure of unvaccinated people to infection through herd immunity. 7 Herd immunity, in addition to lowering the incidence of infection in the unvaccinated, is well known to lead to an increased average age at infection. 7 Vaccination is therefore not always entirely benefi cial to public health because some childhood infections are more severe if contracted in adolescence or adulthood. Furthermore, vaccination itself may modify vaccine eff ectiveness over time because of factors such as strain replacement and cross reactivity. Some of these indirect eff ects improve the cost-eff ectiveness (eg, non-exposure of most of the unvaccinated, cross reactivity), whereas others may reduce the costeff ectiveness (eg, shift in the average age of infection, serotype replacement). For most vaccination programmes, the sum of these eff ects substantially improves cost-eff ectiveness, but sometimes the reverse may be true. 8, 9 Convincing evidence for the extent of herd immunity, and the duration of immunity, may only come from widespread use in another country, not from clinical trials. For example, the population impact of vaccinations against VZV and Streptococcus pneumoniae in the USA are of major interest to other countries. 10 Appropriately parameterised dynamic transmission models could also provide credible estimates of herd-immunity eff ects. Lieu and colleagues 11 were the fi rst to estimate the costeff ectiveness of a vaccine based on dynamic model simulations. 12 Such models, which take into account the above indirect eff ects, are gradually becoming more widespread, but are not yet part of the traditional toolbox of epidemiologists or health economists. All these features add to the uncertainty under which vaccine funding decisions are made, as opposed to those of other drugs.

For whatever the reason some people decline vaccination for their child, they may trade the uncertain value of direct protection for the certainty of avoiding the risk of vaccine-associated adverse events and the cost of vaccination, while potentially counting on a "free ride" from herd immunity induced by others being vaccinated. The risk perceptions driving this trade-off are distorted as a result of imperfect information. Reductions in vaccine-preventable disease make people believe that their child's risk of disease has decreased. However, their risk is highly dependent on historical and future rates of exposure and vaccination in the rest of the population and can quickly rebound when uptake declines. 13, 14 Therefore, government intervention in the form of subsidies or public funding is required to ensure that vaccine uptake remains high enough to guarantee benefi cial herd immunity. 15 The UK's recent struggle with the measles, mumps, and rubella vaccine uptake illustrates this point. 16 For other pharmaceuticals, this kind of trade-off is not even conceivable.

Potential global eradication is another feature that sets some vaccines apart. For example, polio has been eliminated in high-income and middle-income countries. The risk of acquiring paralytic polio from the live oral polio vaccine is thus particularly sensitive to public scrutiny. However, replacing the oral vaccine with the risk-free inactivated polio vaccine is far more expensive, and would be judged unacceptable if cost-eff ectiveness were the only criterion under consideration. 17 Nevertheless, until polio is eradicated globally, vaccination must continue or polio will again become endemic, as shown by occasional outbreaks in unvaccinated communities. 18 Although not usually quantifi ed in cost-eff ectiveness analysis, 14, 19 the prospect of eradication and concerns over the public's perception about the entire vaccination programme has led to the replacement of oral vaccine by inactivated vaccine in nearly all highincome countries. 20 Some infections have the capacity to aff ect not only patients and their direct contacts (ie, their family, health-care provider, employer) in terms of economic costs and medical eff ects, but they may also aff ect health-care use, and expectations and behaviour of consumers and investors. For instance, pandemic infl uenza is likely to lead to capacity problems within the health-care system, aff ecting the timely treatment of patients with infl uenza in addition to those with unrelated illnesses. Additionally, it would have a macroeconomic impact that goes beyond lost productivity to employers of sick patients, because virtually everyone-employers, con sumers, and investors-would adapt their intentions under its perceived threat. 21, 22 The latter was also shown in countries aff ected by the 2003 outbreak of severe acute respiratory syndrome. 23 Finally, affl uent countries pay much higher prices than poorer countries. 24 This system of tiered pricing is not unique to vaccines, but might be most relevant for new vaccines (eg, rotavirus, pneumococcal, and HPV) and medications (eg, highly active antiretroviral therapy) with great lifesaving potential in poor countries. Some economists argue that market prices set for high-income countries need to be much higher to suffi ciently stimulate Personal View innovation through market mechanisms, rather than rely on publicly funded research. 25 Conversely, if a vaccine is added to a low-income country's national programme, it is likely to become cheaper for high-income countries through price discrimination mechanisms. 26 Clearly, decision making becomes more complex if such moral or opportunistic considerations are thought to be important.

There are some methodological aspects to which the cost-eff ectiveness of vaccines is particularly sensitive. First, the defi nition of the analytical viewpoint is crucial. Guidelines for economic evaluation, as used by most advisory committees, generally focus on direct health-care costs and do not consider indirect costs to society (eg, the value of lost productive and leisure time from illness or caregiving). These indirect costs can be very large for infectious diseases that aff ect virtually the entire population, even for generally benign illness. For example, the cost-eff ectiveness of childhood VZV vaccination is unlikely to be thought acceptable from the health-care budget perspective, but is possibly cost-saving from a societal perspective. 8, 11, 27 Second, the use of quality-adjusted life-years is widely advocated as the best measure currently available for valuing health states. However, standardised quality-oflife estimates for short-term diseases in young children are virtually non-existent, and the appropriate methods to measure them are subject to debate. [28] [29] [30] Additionally, the impact of a child's illness on the quality of life of caregivers can be substantial, just as it is for lifethreatening and severe chronic diseases in adults (eg, cancer). 31 However, such indirect quality-of-life losses are typically not accounted for. These impacts have the potential to change decisions, for instance on rotavirus vaccine. 32 Finally, the peace of mind off ered through the reassurance of vaccine protection is a quality-of-life improvement of prevention programmes that is routinely ignored in economic evaluation. 33 A third issue is the impact that discounting has in accounting for time preference. Discounting is a technique that aims to put costs and benefi ts occurring at diff erent timepoints on the same basis of comparison. Discounting scales down future events, such that, the further into the future they occur or the higher the discount rate, the less important they are to a decision maker in the present. In health economics, there is continued debate about whether the discount rate for health outcomes should be lower than or equal to that for costs. 34, 35 For curative therapies, most benefi ts accrue immediately or shortly after the intervention is initiated, and the cost-eff ectiveness of these interventions is therefore largely independent of these methodological disagreements on discounting. Conversely, the costeff ectiveness of most prevention programmes is highly sensitive to discounting because of the long time spans over which benefi ts accrue. A slight decrease in discount rate-eg, from 5% to 3%-could change the costeff ectiveness of vaccination from unacceptable to attractive. Country-specifi c recommend ations on discount rates vary to the extent that a vaccine could be deemed cost eff ective in one country and cost-ineff ective in another for this reason alone (table 1).

In the standard discount procedure, as recommended in all guidelines known to us, the discount rate is constant, implying that preferences between outcomes are held constant through time and depend only on the length of the time interval between them. One can argue that discounting at a constant rate exaggerates the importance we give for the present over the future. [46] [47] [48] This assertion is backed by psychological empirical evidence, which suggests that the diff erence between equidistant outcomes is thought less important the further into the future the outcomes occur. 47 So-called "slow" discounting procedures could be used for cases in which the discount rate decreases and falls close to zero for the more distant future (eg, 3·5% for years 0-10, 1·5% for years 11-20, 0% thereafter), thus yielding a higher present value of benefi ts. 49, 50 Additionally, time preference may exist only to the time until risk exposure, and not the time until health consequences from risk exposure arise (eg, cervical cancer is the health consequence of a much earlier exposure to HPV). 51 Adjustment of the discount procedure to account for these aspects is not current practice, but would substantially improve the estimated cost-eff ectiveness of prevention versus cure. 49, 50 Currently, policy makers are presented with very wide cost-eff ectiveness ranges for preventive public-health actions when sensitivity to discounting is illustrated to them. In 1968, Baumol 52 noted the "sorry spectacle" that economists provided through their diverging understandings on this subject, and his assertion that "little help is provided to the decision maker who is confronted with such an enormous range of Finally, the equity impact of vaccination is far less predictable than for most drugs. Generally, the less healthy or less wealthy are those least likely to be vaccinated, and thus more likely to experience the eff ect of herd immunity from other people receiving vaccination. As shown for measles in Bangladesh, 53 this eff ect is often equitable, but the reverse may also occur for poorly executed vaccination programmes. 54 The redistribution eff ects on health and wealth are thus less straightforward in the prediction of decisions on vaccination compared with those used for therapeutic medicines.

The fi rst generation of vaccines, such as measles, pertussis, and polio vaccines, were against serious childhood diseases that were common worldwide. Little analysis was done before their introduction because their benefi ts were obvious and their costs were low in an era when there was less pressure on the health-care budget. New vaccines are much more expensive and often aimed at less common or less serious diseases, particularly in wealthy countries. Thus, whether these vaccines are worth introducing is less clear. We will explain key aspects of the cost-eff ectiveness of current vaccines, while focusing on high-income countries.

Rotavirus is the commonest cause of dehydrating gastroenteritis in the world and accounts for most gastroenteritis hospital admissions in children under 4 years of age. Deaths are infrequent because of good medical care in high-income countries (eg, about three deaths per year in the UK). 55 A challenge to the evaluation of both current oral rotavirus vaccines is the estimation of the part of the gastroenteritis disease burden specifi cally attributable to rotavirus, as well as assessing the extent to which these vaccines would invoke herd immunity. In high-income countries, the main benefi t of rotavirus vaccines is the prevention of parental care and productivity losses in virtually all households with infants or toddlers. However, as we have outlined, gains in quality-adjusted life-years in such young children and their parents, as well as parental care and work loss, are not standard features in cost-eff ectiveness analyses. Given the current price setting (€80-120 per fully vaccinated child) and the recommended schedule for these vaccines (two doses Rotarix [GlaxoSmithKline]; three doses Rotateq [Merck]), they are unlikely to be judged as cost eff ective unless these so-called "soft" benefi ts are also included. 32, [56] [57] [58] But if they are, why should they not also be considered for all other health-care interventions, thus potentially reshuffl ing the comparison between all health-care programmes (including the other vaccines discussed here)? Table 2 describes potential consequences of including soft costs and benefi ts at various levels of government decision making.

HPV vaccines are eff ective against the two HPV serotypes associated with most cervical cancers, and one of these vaccines also protects against two of the serotypes that cause genital warts. Eff ectiveness against cervical cancer would have to be modelled based on the premise that HPV infection is a necessary condition for cervical cancer to develop, although often only decades later. The cost- Programmes that prevent disease, with a proportionately larger aggregated impact on the quality of life and productivity of patients and/or their families, become more cost eff ective compared with other vaccination programmes ·· HPV=human papillomavirus. *Costs and benefi ts arising to parties generally not considered relevant in guidelines for economic evaluation of pharmaceuticals for which public funding is sought. These third parties can consist of people not receiving the intervention, parents of patients, employers of patients, and employers in general. †Cost-benefi t analyses do not routinely inform other sector decisions in many countries (eg, education, transport infrastructure, military, etc.). Politics may dominate rational decision rules in other sectors more than in health care. ‡Produced by GlaxoSmithKline. §Produced by Merck. ¶Produced by Wyeth. Personal View eff ectiveness of HPV vaccines depends heavily on the choice of the discounting approach used. 59,60 Furthermore, mathematical models for HPV vaccination ideally have to build in complexities related to herd-immunity eff ects from vaccinating cohorts of girls only and boys additionally, the optimum frequency of cervical cancer screening, and type-specifi c progressive infection and replacement, all over long time periods, which makes this a very complex programme to assess properly. 59, 61 However, a more simple approach, based on static models, could give insights on the basic question: should we vaccinate girls before their sexual debut? 60 Such models would underestimate the benefi ts of HPV vaccination, and therefore would only be helpful for policy if they resulted in favourable cost-eff ectiveness ratios. The static models that have been published so far have tended to be favourable. 59, 60, 62 Policy makers could therefore quickly decide about vaccinating a limited number of cohorts before their sexual debut, and have reasonably confi dent cost-eff ectiveness evidence to support this decision. However, they cannot rely on such analyses to decide on more complicated aspects of the programme, such as the breadth of the programme in girls and boys. In view of the high costs of this programme (€250-350 per fully vaccinated individual), the uncertainty surrounding these more complicated decisions could unnecessarily postpone policy on the more basic issue.

VZV childhood vaccination prevents chickenpox in vaccinated children and is likely to protect these vaccinees against shingles later in life. Since chickenpox infects virtually all children by age 12 years, the accumulated societal savings, including avoided parental care and productivity losses, are likely to be greater than the costs of vaccination at a price of €15-50 per fully vaccinated person. However, childhood VZV vaccination increases the occurrence of shingles in adults and this may be such that it counteracts these societal savings and leads to adverse health eff ects. 63 A further complication is that with single-dose infant vaccination many teenage breakthrough cases can still be expected, but the addition of a second dose to prevent this would make it a much less cost-eff ective programme. Modifi ed VZV vaccine in adults was recently shown to prevent shingles, and was shown by static models to be cost eff ective. 64, 65 Finally, vaccination of susceptible pre-adolescents is an alternative strategy that has consistently been shown to be cost eff ective to the health-care budget, and is thus independent of the wider societal perspective. 66 However, it is not advocated by public-health specialists, because it would only prevent a small part of all chickenpox disease, albeit the most severe proportion. 8, 11, 27 Clearly, the simultaneous modelling of all these strategies and considerations requires complex models and data from various sources to establish eff ectiveness. Empirical studies alone cannot answer all these questions.

Infant infl uenza vaccination may be a cost-eff ective way of preventing seasonal infl uenza and pneumonia in young children directly and the elderly indirectly through herd immunity. 67,68 However, vaccinating a child partially to save a grandparent from experiencing serious illness does not only raise concerns over intergenerational equity, but also the eff ectiveness of such an approach could only be shown if put into practice on a large scale, or by applying an appropriately parameterised model. 69 Seasonal variations in incidence, severity of disease, and vaccine effi cacy are complicating factors that contribute to uncertainty. Furthermore, preparing for pandemic infl uenza demands very large investments, and this can only be shown to be worthwhile by modelling. 70 A policyrelevant approach to modelling the cost-eff ectiveness of pandemic infl uenza vaccination would entail considering macroeconomic impacts across sectors and across countries. 21 Clearly, deciding on the best options to prevent and control infl uenza requires an analytical framework and applied modelling work that substantially digresses from usual drug assessments.

The currently available seven-valent pneumococcal conjugate vaccine (PCV7), which costs about €100-150 per vaccinated child, is eff ective against invasive and non-invasive disease caused by seven serotypes of S pneumoniae. Because of its high price, in the short term the cost-eff ectiveness of PCV7 depends in most high-income countries on the inclusion of positive herd-immunity eff ects in adults, which were observed after 1 year of widespread use in the USA. 71 If the long-term eff ect of its widespread use, consisting of a mix of herd immunity, serotype replacement, antibiotic resistance, and cross reactivity, remains benefi cial and if the cheaper three-dose schedule confers near-equivalent protection to the original four-dose schedule, PCV7 vaccination programmes are judged to be cost eff ective in high-income countries. 71 To budget for this vaccine, European policy makers should accept imputations from herd-immunity eff ects observed in other countries in the short term as well as uncertainties with both positive and negative impacts of the programme in the longer term.

Advisory processes on drug funding can be generally eff ective at selecting which pharmaceuticals, and which subgroups of patients, should be subsidised to make the most of scarce health-care resources. Vaccines are diff erent and more complex than most drugs assessed by such processes for the reasons we have outlined. This implies that such processes should be more fl exible in accepting the best available quantifi ed evidence of the unique features of vaccination programmes, and that decision makers and their advisers should be aware of these features if they cannot be quantifi ed. The best Personal View available evidence depends on the type of infection and vaccine, and the time of its consideration.

Guidelines for economic assessment of pharmaceuticals dictate the approach to use to make such analyses acceptable for a country's decision makers. Since economic evaluation is not an exact science, such guidelines are made on the basis of compromises between the people designing them and therefore can be changed (table 1) .

Economic evaluation requires quantifi cation of the eff ects of interventions, as well as valuing these eff ects. In terms of quantifying the eff ects of vaccination, governments should adapt their guidelines to specify modelling options for the assessment of interventions against infectious diseases. This should enable submitters and drug-reimbursement committees to better understand which models are acceptable (or unacceptable) under which circumstances. Crucially, drug-reimbursement committees must be represented by the required expertise to properly understand and evaluate complex vaccine models.

In terms of valuing the eff ects of vaccination, we do not plead for a special case, but for a level playing fi eld. That is, we argue that not all aspects of ill health and time preference are currently captured by recommended techniques for economic evaluation, and that this may disadvantage the cost-eff ectiveness of interventions against diseases in children relative to interventions against diseases in adults, and prevention relative to cure. Therefore, guidelines should also be adapted in general terms to allow for (1) a wider perspective to account for eff ects on third parties, if these are aff ected substantially by specifi c interventions (eg, parents experiencing a quality-of-life impact through the illness of their child); (2) a wider scope of costs to be included, if appropriate, than health-care system costs alone (eg, irrecoverable losses caused by modifi ed behaviour when faced with a large public-health threat); and (3) alternative discounting techniques to deal with social time preference over long time periods.

Large uncertainties about the value and distribution of particular variables imply that timely vaccine decisions may need to be taken with more uncertainty than decisions on other drugs. This should not deter the widespread use of new safe and effi cacious vaccines, if-all things considered-these are unlikely to be judged cost-ineff ective relative to other interventions. Furthermore, other criteria, including the programme's acceptability, feasibility, budget, and equity impact, are also important. A WHO guide for the standardisation of economic evaluations of immunisation programmes, which will become shortly available for public use, could be used as a starting point for governments to adapt their guidelines with respect to some of the issues mentioned here. 72 

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PB acknowledges funding from Simulation Models for Infectious Disease Processes (SIMID), a strategic basic research project funded by the Institute for the Promotion of Innovation by Science and Technology in Flanders (project number 060081). We thank the anonymous referees for their helpful comments.