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Vaccine 28 (2010) 2841–2845

Contents lists available at ScienceDirect

Vaccine

journa l homepage: www.e lsev ier .com/ locate /vacc ine

comparison of the use of economics in vaccine expert reviews

hilip Jacobsa,∗, Arto Ohinmaab,1

Department of Medicine, University of Alberta, CanadaSchool of Public Health, University of Alberta, 3rd Floor University Terrace, 8303–112 Street, Edmonton, AB T6G 2T4, Canada

r t i c l e i n f o

rticle history:eceived 9 December 2009

a b s t r a c t

We reviewed how health economics has been included in the vaccine expert review processes in a sam-ple of countries. We identified two kinds of review processes – those in which vaccines and drugs are

eceived in revised form 20 January 2010ccepted 28 January 2010vailable online 12 February 2010

eywords:accines

assessed using a common process, and those in which vaccines are assessed within the infectious dis-ease framework. In either process, the countries recommend that their national pharmaco-economic (i.e.,guidelines developed for drugs) guidelines be used to conduct the studies, although the guidelines them-selves differ between countries. As a result of these factors, the decision process and the study outcomescan differ between countries, but because the vaccine adoption process includes other criteria as well,

nece

ost-effectivenessolicy

economic factors will not

. Introduction

At the end of the 20th century, following a period of techno-ogical change and increased investment in vaccine research andevelopment, a series of new vaccines were introduced whose salesurpassed previous standards; these events resulted in a new era ofhe “blockbuster” vaccine [1]. In the wake of these changes, policy-

akers in many countries have begun to incorporate economicriteria in their expert vaccine reviews. In a 2007 survey of theaccine European New Integrated Collaboration Effort (VENICE), 11ut of 27 (39%) European expert committees considered economicspects before deciding on whether to include Human Papillo-avirus Vaccine (HPV) in their immunization schedules [2].Many of the tools (especially cost-effectiveness analysis) needed

or economic reviews were already available from the pharmaceu-ical policy area [8]. However, several researchers [3–5] and the

orld Health Organization [6] have identified some specific ele-ents that distinguish vaccines from mainstream pharmaceuticals.

he most notable of these is the infectious disease aspect of vac-ines, which quell the spread of disease between persons (termedexternalities” in economics).

As a result of the “external” effects of infectious diseases, vac-ines have been an important component of the public healthradition, where there is a community ethic. The disease impact ofharmaceuticals is focused more on the recipient of the drug, which

∗ Corresponding author. Tel.: +1 780 448 4881; fax: +1 780 448 0018.E-mail addresses: pjacobs@ihe.ca (P. Jacobs), arto.ohinmaa@ualberta.ca

A. Ohinmaa).1 Tel.: +1 780 492 6535.

264-410X/$ – see front matter © 2010 Elsevier Ltd. All rights reserved.oi:10.1016/j.vaccine.2010.01.056

ssarily alter the outcome.© 2010 Elsevier Ltd. All rights reserved.

may be why pharmaceuticals are more rooted in a market ethic.Pharmaco-economics, or the economic evaluation of pharmaceuti-cals, has been developed in this context. There is a tension betweenthe two ethics (See for example Ref. [7]), and how this tension playsout will influence the public process for recommending and fund-ing vaccines, and perhaps the decisions which emanate from theseprocesses. We conducted a cross-national review of how policy-makers in different countries have introduced economic analysisinto the vaccine review process.

2. Method

Economic evaluation is a discipline with which health out-comes and costs of alternative interventions are compared in aunified manner. The economic approach allows a decision–makerto balance health outcomes and costs together, thus determin-ing how much extra an additional unit of health (e.g., a qualityadjusted life year, or QALY) will cost. The components of aneconomic evaluation, or cost-effectiveness analysis, have been for-malized within national guidelines published by the InternationalSociety for Pharmaco-economics and Outcomes Research (ISPOR)(http://www.ispor.org/peguidelines/index.asp) to ensure that allsuch studies within a country are conducted using the same stan-dards.

The main components of economic studies can be found in anumber of documents, including Drummond and Jefferson [8] and

Szucs [4]. We briefly identify the key elements of an economic eval-uation, but a more detailed discussion relevant to vaccines canbe found in World Health Organization [6] and Walker et al. [5].In an economic evaluation the alternative interventions must beselected so as not to exaggerate the outcomes or under-estimate

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he costs of a study intervention. The economist must specify thetudy’s perspective, which identifies who bears the burden of theosts; these might be borne by a government payer, or governmentayer plus private sector (called the societal perspective). Timelinesf the study must include all relevant effects of the interventions;n the case of vaccines this can be very long-term, even a lifetime.he analyst must use appropriate health outcomes, which captureealth effects of health status and longevity. Effectiveness must benbiased. Additionally, in the case of vaccines, the “external” orerd effects may be important considerations. Costs must reflect theesources used, and must correspond to the study perspective. Theresent value of longer term costs and outcomes must be deflatedhrough the use of a discount factor. Discounting can significantlyeduce the current valuation that is placed on illness that is avoidedn the distant future. The cost-effectiveness, or cost-utility ratio ishen obtained, which expresses the incremental cost of an addi-ional unit of health outcome. This ratio may then be judged forolicy purposes by comparing it to a threshold, which representshe maximum value that a policy-maker would be willing to payrom the additional health outcome (e.g. QALY).

Economic evaluations have been widely used for studying vac-ines [6], as well as for pharmaceuticals, but there are differencesetween vaccines and pharmaceuticals, and in a large part theseifferences stem from the publicness aspect. A health technologyssessment for drugs focuses on clinical effectiveness and safety,nd cost-effectiveness. The counterpart for vaccines should includen analysis of infectious disease epidemiology, as well as vaccinefficacy and cost-effectiveness (WHO, 2009). Any indirect healthffects (herd immunity) resulting from the use of the vaccine willffect cost-effectiveness, and will be relevant to vaccine scheduleecommendations when these include economic considerations.hese indirect or external effects are not included in traditionalharmaco-economic studies.

We approached vaccine economic researchers or policy-makersn a convenience sample of countries where vaccines are reviewedn a public committee and where we had language facility. We alsoearched the internet for policy related documents associated withhe committee in each country. We obtained the following infor-

ation from each program: the organizational details regardingho makes the recommendation and the decision to adopt new

accines; the criteria that are used to reach a recommendationincluding whether economics is included); whether economics isonsidered formally or informally; if formally considered, what cri-eria are included in the national pharmaco-economic guidelinesSource: http://www.ispor.org/peguidelines/index.asp and relatedinks) which authors must use to prepare studies.

. Results

.1. Countries surveyed

We reviewed information on the use of health economics inaccine review from 10 countries – Australia, Belgium, England,inland, France, Hong Kong, the Netherlands, New Zealand, Swe-en, and the United States. Singapore, which we also contacted,id not use health economics as criteria. Both Hong Kong and Newealand use economics informally in the review process, withoutxplicit referral to guidelines. We present a description of the usef economics in the remaining eight countries.

.2. Description of process of formally using health economics

.2.1. AustraliaBefore 2006 the Australian vaccine expert committee, the Aus-

ralian Technical Advisory Group on Immunization (ATAGI) made

e 28 (2010) 2841–2845

recommendations to the federal Department of Health and Ageingthrough a federal advisory committee. Economic studies wereinformally considered. There were no manufacturer submissionsand, most importantly, vaccines were funded on a different basisfrom pharmaceuticals, which had a formal process in place sincethe early 1990s. In 2006 the federal health department instituteda requirement that vaccine manufacturers must make submis-sions, including economic studies to the Pharmaceutical BenefitsAdvisory Committee (PBAC), the same body that considers pharma-ceutical submissions. ATAGI was assigned an advisory role to PBAC(Source: http://www.medicinesaustralia.com.au/pages/images/Terry%20Nolan.pdf). The vaccine manufacturers’ submissionsare now reviewed by the Economic Sub-committee of the PBAC.PBAC has well-established pharmaco-economic guidelines for themanufacturers to follow in their submissions.

3.2.2. BelgiumManufacturers can have their vaccines reviewed in two places

– the pharmaceuticals committee and the Superior Health Coun-cil. If approved by the pharmaceutical committee, consumers canpurchase the vaccine with state subsidies. Alternatively, a requestfor adoption of the vaccine on the immunization schedule can bemade to the Superior Health Council, which makes recommenda-tions to the federal health minister. These are based on scientificcriteria other than economics (i.e., safety and efficacy). The fed-eral ministry commissions an independent economic study, andsince 2008 these have been based on pharmaco-economic guide-lines. Based on this information, and discussion among communityministers, vaccine provision policies and funding arrangements areset.

3.2.3. EnglandThe Joint Committee on Vaccine and Immunization (JVAC) is the

expert committee which makes vaccine recommendations to theDepartment of Health. Economic studies were used prior to 2009,but were not required. In its meeting minutes, JVAC announced thatit would require economic studies starting in 2009 [9]. The studiesare independently conducted under contract. There are no formaleconomic guidelines that are required, but it appears that studieswill generally follow those that are developed by the National Insti-tute for Health and Clinical Excellence (NICE), for pharmaceuticalsand general health interventions

3.2.4. FinlandVaccine recommendations in Finland are made by a National

Advisory Committee on Vaccines to the national Department ofSocial Services and Health. Since 2000, economic studies havebeen required as part of a four-step process, which is conductedby an expert committee that is selected for the vaccine underconsideration. This committee includes persons trained in clinicaldisciplines, epidemiology and economics and reports to a nationaladvisory committee. The four-step process followed by the tech-nical advisory committee includes the (1) determination of publichealth benefit, (2) individual safety, (3) public safety and (4) cost-effectiveness

The integration of the experts into a single study group ensuresthat the cost-effectiveness study and the epidemiologic trans-mission model are conducted cooperatively. The economic studyfollows the country’s pharmaco-economic guidelines.

3.2.5. France

The Technical Vaccine Committee (CTV) was formed in 1997,

and has reported since 2004 to the newly created High Council forPublic Health which is part of the health ministry. The committeeis a multidisciplinary team which has included a health economistsince its formation, and economic studies are most of the time

P. Jacobs, A. Ohinmaa / Vaccine 28 (2010) 2841–2845 2843

Table 1Pharmaco-economic guidelines, selected criteria and threshold.

Country* Recommended Perspective Outcome measure Discount rate for costs / outcomes

Australia Societal and health care system Use an appropriate measure 5%/5%Belgium All health care payments Measurement not specified 3%/1.5%England Health care and social service system QALY 3.5%/3.5%Finland Societal Use an appropriate measure 3%/3%France Societal Justify what is used Use 0%, 3%, and 5% for bothNetherlands Societal Natural units or QALYs 4%/1.5%Sweden Societal QALYs 3%/3%United States Societal Us an appropriate measure Discount required but rates not specified

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ource: http://www.ispor.org/peguidelines/index.asp and related links.* Hong Kong, New Zealand and Singapore excluded from the table because of no

art of the dossier which also include epidemiological data andisk-benefit information. CTV is responsible by law to elaboratehe vaccine strategy according to epidemiological data and stud-es reporting the benefit-risk ratio of the strategy, as well as fromealth economic analyses about the proposed vaccination program.TV may commission independent economic evaluation and man-facturers may also submit economic studies although there is noandatory requirement to do so. These studies follow the country’s

harmaco-economic guidelines.Once a new vaccine has been through the recommendation pro-

ess by CTV, it is considered by the Transparency Committee of theigh Health Authority, an independent public body that is man-ated by law to carry out specific missions on which it reportso Government and Parliament. The Transparency Committee con-iders the degree to which the government will reimburse for usef the vaccine. Transparency Committee dossiers may also includeconomic components [10].

.2.6. The NetherlandsAs in Belgium, vaccines can be approved by the pharmaceuti-

al review committee or the national immunization program. Toe included in the immunization schedule, the vaccine must beecommended by the National Immunization Program (NIP) [7].he NIP has developed an integrated framework to consider vac-ines, which sets out the components of a complete analysis [11].s in Finland, economics is integrated with the other disciplines toonduct evaluation studies.

The components in the NIP framework are the Vaccine, theathogen, the Disease, and Cost-effectiveness. Information fromhe first three components are used to conduct a cost-effectivenessnalysis. Information from the Vaccine component includes vaccineffectiveness and cost. Information from the Pathogen componentncludes disease transmission properties. And information fromhe Disease component includes the burden of the disease, costsf treatment, alternative preventive measures and work-loss dueo the illness. The economic analysis is conducted according to theountry’s pharmaco-economic guidelines and that incorporates thebove information.

.2.7. SwedenThe economic reviews of vaccines are conducted much like

hose of pharmaceuticals. A vaccine clinical review is conductedy the Swedish Institute for Infectious Diseases. The Dental andharmaceutical Benefits Agency, which subsequently requires anconomic review to determine whether the drug should be recom-ended for funding, has started to review vaccines since 2007. The

eview is based on a manufacturer’s study, and the economic com-onent is conducted according to the agency’s pharmaco-economicuidelines. The results are then reviewed by the National Board ofealth and Welfare, but the funding decision is determined by theounties, which pay for the vaccines out of local taxation.

l requirement for economic analysis in vaccines.

3.2.8. United StatesThe vaccine expert committee is the Advisory Committee on

Immunization Practice (ACIP) which reports to the Center for Dis-ease Control and Prevention (CDCP) of the federal Department ofHealth. Support for economic expertise mainly comes from the eco-nomic staff of the infectious disease unit of the CDCP. Studies canbe submitted by anybody, including the manufacturer, under inde-pendent contract, or internally to the government. There are strictguidelines as to how the study is to be conducted [12]. Submittedstudies are reviewed by economic staff of the Centers for DiseaseControl

3.3. Pharmaco-economic guidelines

In Table 1 we show the specific pharmaco-economicguidelines that might impact on vaccines (Source:http://www.ispor.org/peguidelines/index.asp). Though guide-lines include recommended methods to deal with each componentof an economic evaluation, we address only those ones which haveparticular relevance to vaccines [3,4].

• Study perspective. Most countries recommend a societal perspec-tive. Such a perspective includes government health care costsand non-governmental costs, such as personal losses of earningsand personal out-of-pocket costs (the latter two, taken together,form the personal perspective). Belgium takes a health servicesperspective, which implies that economists include only healthcare expenditures, to the exclusion of costs such as lost earningsfrom caregiving

• Discount rate. A positive discount rate is always specified in guide-lines, which implies that, once discounted, all future costs andbenefits have a lower present value. In the Netherlands and Bel-gium the discount rate for outcomes is lower than for costs. Inother countries, the recommended discount rates are the samefor outcomes as for costs

• Outcomes. The Quality adjusted life year (QALY) is the most com-monly used outcome measure, combining health related qualityof life and survival. Only Sweden and England lists QALYs as thepreferred outcome measure; in other countries the outcome indi-cator is left to the discretion of the economist

• Effectiveness and indirect health outcomes. This item (not listed inTable 1) refers to the impact of reduced disease of immunizedpersons on persons who have not been immunized (herd immu-nity). Indirect outcomes are not mentioned in the Australian or

Sweden guidelines, though they are not specifically discouragedeither. In two countries (Netherlands and Finland), indirect healthoutcomes (e.g., a dynamic model) are expected to be includedwhen appropriate, though this is not indicated in the generalpharmaco-economic guidelines

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. Discussion

The introduction of a series of high cost products since 2000 hasrought vaccines into the health finance spotlight. Many countriesre now adding economics as a criterion in their expert reviews,n addition to safety and efficacy. We have reviewed the economicecision criteria of 10 countries which have included economics

n their vaccine expert reviews. In Sweden and Australia vaccinesre reviewed together with pharmaceuticals. In Belgium economicss considered within the ministerial review, separately from thelinical review. In England, Finland, France, Hong Kong, the Nether-ands, New Zealand and the United States, the economic review isonducted in conjunction with the vaccine epidemiologic and clin-cal reviews. However, within this group the stance taken differsrom country to country. Economics is more thoroughly integratedith other (scientific) components of the review in Finland, Nether-

ands, and the United States, and least so in Hong Kong and Newealand.

We used the VENICE list, referred to above, to assess the degreef coverage that we attained in our convenience sample. Accordingo VENICE [2], 11 European countries recently considered eco-omics in their consideration of HPV vaccine. Missing from our listere Denmark, Iceland, Luxembourg, Italy, Norway, and Portugal.

o those European countries on our list, we added Australia, Newealand, Hong Kong and the United States.

The rationale behind a single pharmaco-economic review pro-ess that includes drugs and vaccines is that drugs and vaccines cane placed on a level playing field, that is, they are assessed using aommon threshold. That means that vaccines or drugs which havehe same cost-effectiveness will be regarded as equal, at least fromhe standpoint of economics. This rationale has been stated inustralia [13]. It is also the reason behind the Conservative partyroposal in England that vaccine review be moved to NICE, theeview body for drugs and health care interventions (other thanaccines). In a policy document, the party stated that, “. . .it is essen-ial for the future that vaccines and immunization programmesorm part of a consistent process of evaluation and advice. . ..”Source: http://www.conservatives.com/News/∼/media/Files/olicy%20Documents/NICE%20Policy%20Document.ashx). Theationale behind an integrated review (economics, clinical andpidemiological elements) that is followed in England, Finland, theetherlands and the United States is that indirect benefits of herd

mmunity can more readily be incorporated in the economic study.hese benefits can be considerable enough to change the cost-ffectiveness of some vaccines [14]. In addition, the integration ofconomics into the vaccine expert decision will raise the level ofwareness of economic issues within the public health (infectiousisease) community. It is still possible to provide a common yard-tick (the cost-effectiveness threshold) for both pharmaceuticalsnd vaccines, and still allow vaccines to be evaluated from anconomic standpoint within a public health context.

Most countries use the same economic guidelines for vaccinetudies as for pharmaceuticals. However, the rules of the game –harmaco-economic guidelines [19] – have grown up in the worldf pharmaceuticals, and may be biased against some vaccines. Thisias has been suggested by Szucs [4], Beutels et al. [3] and Beutelst al. [15] and it may be relevant in four areas.

The typical pharmaco-economic outcome measures, the QALY,is not available for young children; when young children are

involved, other measures are more appropriate. This consider-ation is not unique to childhood diseases, as many diseases donot fit well into the QALY framework. Most guidelines allow forthis, by permitting the economist to use appropriate measuresfor health outcomes.

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• Vaccines may prevent illness in young children, thus saving work-time of parents who are the caregivers when they are ill; in thiscase, a societal perspective should be chosen. Most guidelinesallow for this as well, by encouraging authors to take the societalperspective.

• Vaccines may prevent illness far into the future, and discountingof future benefits can seriously erode the present values of thebenefits [16]. Only the Dutch and Belgian guidelines reduce thepenalty on the future benefits of prevention with a differentialdiscount rate, which partially addresses the bias against preven-tion when using discount rates. All other guidelines favor currentover future benefits to a greater degree than Belgium and theNetherlands, discriminating against those vaccines which havefuture benefits. The bias does not apply to all vaccines, only tothose whose benefits occur well into the future.

• The presence of indirect health outcomes will require an addi-tional component of the analysis to capture benefits fromthe non-vaccinated, called the dynamic component [17]. Therecognition of these benefits will be assured when all aspects(epidemiology, safety, economics) of vaccines are reviewedtogether. If the review is conducted within the pharmaco-economic program, an additional effort would be needed toassure that there is a recognition of the herd effect.

We have posited that the organizational structure surround-ing the study team, and the guidelines given to the study team,will affect the economic analysis. These factors may not affect thefinal decisions to add a vaccine, however. There are factors, otherthan economics, which will affect both the recommendation of theexpert committee (if they do incorporate economics) as well asthe political decision to list a vaccine on the schedule [18]. As anexample, a number of countries which considered including HPVvaccine on their schedules conducted economic studies [2]. Mostof these countries included the vaccine on their public schedules,but Finland and Hong Kong did not [Data on listing obtained fromEurosurveillance, www.surosurveillance.org, and the InternationalCancer Society Network, http://appliedresearch.cancer.gov/icsn/].One cannot conclude that economics was the deciding factor inall of these instances. By including a formal economics study in thereview process, health policy-makers merely ensured that the issueof scarcity was not neglected.

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