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Review

A critical literature review of health economic evaluations of rotavirus vaccination

Samuel Aballéa Creativ-Ceutical; Paris, France

Aurélie Millier Creativ-Ceutical; Paris, FranceCorrespondence[email protected]

Sibilia Quilici Sanofi Pasteur Msd; Lyon, France

Stuart Caroll Sanofi Pasteur Msd; Berkshire, UK

Stavros Petrou University Of Warwick; Warwick, UK

Mondher Toumi University Lyon I; Lyon, France

Abstract

Two licensed vaccines are available to prevent RVGE in infants. A worldwide critical review of economic evaluations of these vaccines was conducted. The objective was to describe differences in methodologies, assumptions and inputs and determine the key factors driving differences in conclusions. 68 economic evaluations were reviewed. RV vaccination was found to be cost-effective in developing countries, while conclusions varied between studies in developed countries. Many studies found that vaccination was likely to be cost-effective under some scenarios, such as lower prices scenarios, inclusion of herd protection, and/or adoption of a societal perspective. Other reasons for variability included uncertainty around healthcare visits incidence and lack of consensus on quality of life (QoL) valuation for infants and caregivers. New evidence on the vaccination effectiveness in real-world, new ways of modeling herd protection and assessments of QoL in children could help more precisely define the conditions under which RV vaccination would be cost-effective in developed countries.

Keywords: :

Introduction

Rotavirus gastroenteritis (RVGE) is currently the most common cause of severe gastroenteritis in infants and young children in both developed and developing countries, with seasonal peaks according to latitude and climate. Rotavirus (RV) is transmitted by the faecal-oral route. It infects cells in the intestine, inducing gastroenteritis, leading to severe diarrhea and sometimes death through dehydration.Citation¹^-Citation⁴

RVGE causes 114 million episodes of diarrhea, 25 million clinic visits, 2.4 million hospital admissions, and more than 500,000 deaths in children up to age 5 y worldwide annually.Citation³^,Citation⁴ It is estimated that annually in Europe almost 700,000 children younger than 5 y will visit a medical practitioner as outpatients, almost 87,000 will be admitted to hospital, and 231 will die because of RV-associated disease.Citation⁵

Two vaccines are currently available for the prevention of RVGE. RotaTeq (Merck and Co., Inc., West Point, PA, USA), is a live pentavalent vaccine that contains five RV vaccine strains produced by reassortment. It is an oral vaccine, which requires three doses between ages 6 and 32 weeks. Rotarix (GlaxoSmithKline Biologicals, Rixensart, Belgium), is a live attenuated monovalent vaccine containing human RV strain RIX4414. It is given orally in 2 doses 4-week apart, between 6 and 24 weeks of age. Both vaccines are indicated for the prevention of RVGE in infants and children.

The cost-effectiveness of these vaccines has been evaluated in many studies, and several literature reviews are available so far. A first review by Bilcke and Beutels was published in 2009.Citation⁶ It was based on 19 economic analyses of RV vaccination, in 9 developing and 9 developed countries. The main objectives were to describe and assess methodological and modeling choices, and key conclusions were the need for sensitivity analysis and for accounting for herd protection.

In 2011, Tu et al.Citation⁷ published a systematic review that focused on economic studies performed in developing countries. The authors identified 15 studies, and concluded that despite being confirmed as cost effective, this does not imply that RV immunization is affordable in developing countries. For these countries, this would require heavy financial support from international organizations such as the GAVI Alliance’s fund (Global Alliance for Vaccines and Immunisation).

In 2011, PloskerCitation⁸^,Citation⁹ focused on economic analyses of Rotarix in developed countries, including a discussion of some of the limitations of these studies and possible explanations for the wide variability in results of these analyses, many of which involved indirect comparisons with RotaTeq. Explanations included differences in the selection of data sources or assumptions used to populate the models. Another review published in 2011 focused on economic analyses of Rotarix in developing countries.Citation¹⁰^,Citation¹¹ Plosker concluded that the introduction of the vaccine would be very cost effective compared with no RV vaccination program, considering a large range of vaccine prices.

In 2011, Postma et al.Citation¹² reviewed three models* used to estimate the cost-effectiveness of RV vaccination, and stated that despite differences in the approaches and inputs, the cost-effectiveness results of the models were quite similar.

The objectives of this article are to provide a comprehensive review of RV economic evaluations, considering both products, for developed and developing countries, and to critically appraise these studies. The differences in methodologies, model assumptions and model inputs were investigated in order to provide insight on reasons for variability in results between studies.

Search Methodology

This review considered all economic evaluations performed worldwide on RotaTeq and Rotarix published between October 2001 and September 2011. Several search engines were used: Pubmed, Google scholar and NHS Economic Evaluation Database (NHS EED). In addition, we looked for abstracts presented at recent conferences, using health economic and clinical congress websites, such as the International Society for Pharmacoeconomics and Outcomes (ISPOR), the European Society for Paediatric Infectious Diseases (ESPID), and the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESGHAN). We used the following search strategy in Medline: (“rotavirus”[MeSH Terms] OR “rotavirus”) AND (“economic model” OR “budget” OR “economic” OR “cost” or “costs” OR “decision analytic model” OR “cost-effectiveness” OR “cost-utility” OR “cost-benefit” OR “cost benefit” OR “cost utility” OR “resource” OR “fees” OR “consumption”).

Screening of references and extraction of data were performed by two reviewers independently, and all disagreements were resolved by consensus. Information relevant to epidemiological aspects (e.g., incidence rate, hospitalization rate), immunity and vaccine (e.g., herd protection, efficacy/effectiveness inputs, vaccination coverage rate) and economic evaluation methods (e.g., type of analysis, type of model, type of outcome) was extracted from each manuscript.

Overview of Studies

describes the 68 economic evaluations identified by the literature searches and reviewed. 53 of these studies were journal articles. The remaining studies were posters (14 references) or abstracts (1 reference). One study was not vaccine-specific, 34 studies considered only Rotarix, 16 studies considered only RotaTeq, and 17 considered both vaccines. Out of the latter 17 studies, 13 reported distinct results for both vaccines vs. no vaccination, 3 studies considered Rotarix and RotaTeq as equivalent, and 1 compared the two vaccines, reporting an ICER of Rotarix vs. RotaTeq. Eighteen studies were sponsored by GlaxoSmithKline, 9 by Sanofi Pasteur MSD and 3 by Merck; no industry funding was reported for 38 studies. The number of publications increased after 2001 (from 1 in 2001, to 5 in 2006, to 27 in 2009). Out of the 68 studies reviewed, 31 were based in Europe, 10 in Latin America, 18 in Asia/Pacific, 4 in Africa, 3 in the United States and 2 in developing countries across the world.

Table 1. Overview of included studies

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Fifty-eight studies presented results of a Cost-Effectiveness Analysis (CEA^†). Outcome measures used in these CEAs included quality-adjusted life-years (QALYs) gained (22 studies), lives saved (27), disability-adjusted life years averted (25), admissions avoided (20), cases avoided (19) and life-years gained (13). The 22 studies reporting an incremental cost per quality-adjusted life years (QALY) gained are also classified as Cost-Utility Analyses (CUA) in .

Fifty-five studies provided results of a Budget Impact Analysis (BIA^‡), i.e., estimated the impact of vaccination on the budget of a health care payer.

Finally, 23 threshold analyses were conducted. A threshold analysis provides the maximum price for which the assessed intervention (vaccination program) is estimated to be cost-effective (or cost-saving), for a given value of the willingness to pay for a QALY or the health outcome of interest.

Results of economic evaluations

All costs are presented using the currency of the original study, and are also presented in 2012 euros in brackets.

Developed countries

Cost-effectiveness and cost-utility analyses

Tables with detailed results of economic analyses are available as supplementary digital content. These include results of the CEAs or CUAs, vaccine efficacy data, RVGE incidence data, average yearly incidence of RVGE-related hospitalizations (both community-acquired and hospital-acquired), average yearly incidence of physician visits, average yearly incidence of emergency department visits, annual death rates, and inputs and sources used by studies using QALYs and DALYs.

In Europe, variability between countries was large. Jit et al.Citation⁴³^,Citation⁴⁴ evaluated the incremental cost per QALY gained in Europe, using the same methodology for different countries, and estimated it at €15,000 (2012 euro value: €17,500) in Finland, €88,000 (€100,000) in the Netherlands, €64,000 (€75,300) in Belgium, €65,000 (€72,800) in France and €110,000 (€136,000) for the UK for Rotarix, and at €27,000 (€31,500) in Finland, €94,000 (€107,000) in the Netherlands, €75,000 (€88,200) in Belgium, €84,000 (€94,000) in France and €150,000 (€185,000) for the UK for RotaTeq, from the Third-Party Payer (TPP) perspective. Furthermore, results varied substantially between studies within countries. In the UK, estimations of the ICER for the monovalent vaccine from the TPP perspective varied between £23,298 (€35,400) for RotarixCitation⁴² and €150,000 (€188,300) for RotaTeq,Citation⁴³ per QALY gained. Substantial differences in incremental costs per case avoided were also noted for the UK, which was largely due to different case definitions. In the Netherlands, results from the societal perspective also showed large variability: one study suggested that vaccination was cost-effective,Citation³² two that it was not cost-effective,Citation³³^,Citation³⁴ and one concluded that it depends on negotiated price.Citation³⁵ In Belgium, results of different studies seemed relatively close, with cost per QALY gained varying between €51,000 (€63,100) for RotarixCitation¹³ and €75,000 (€88,200) for RotaTeqCitation⁴³^,Citation⁴⁴ from the TPP perspective.

In the US, results of Widdowson et al. appeared as rather unfavorable to vaccination, with a base case ICER of $197,190 (€188,300) per life-year saved from a societal perspective.Citation⁷² However, from the same perspective, Shim et al. predicted that vaccination would be cost-saving.Citation⁷³ Weycker et al. did not provide any ICER for vaccination vs. no vaccination, but compared Rotarix with RotaTeq, and concluded that Rotarix dominated RotaTeq in health economic terms.Citation⁷⁴ Nevertheless it has been shown by Toumi et al. that these results relied on biased assumptions in favor of Rotarix, which are not supported by clinical evidence.Citation⁸¹

In Australia, Newall et al.Citation⁵⁶ examined the cost-effectiveness of both vaccines. The results were only slightly different: Rotarix would cost $60,073 (€59,000) per QALY gained and RotaTeq $67,681 (€66,500) per QALY gained from a TPP perspective.

Budget impact analyses

Although most studies suggest that the net costs of vaccination are positive, some concluded that vaccination is cost-saving from a societal perspective (Australia,Citation⁵⁶ Belgium,Citation¹³ Italy,Citation²⁹^,Citation³⁰ UK,Citation³⁹^,Citation⁴¹ and USACitation⁷³). However, the results of these studies were often contradicted by other results for the same countries. For example, for the UK, Largeron et al.Citation³⁹ and Lorgelly et al.Citation⁴¹ predicted that vaccination would save £5,700 (€5,580) and £4.5 million (€4,34 million) respectively, from a societal perspective over 5 y, whereas Martin et al.Citation⁴² predicted that vaccination would increase net costs by £33.4 million (€31.6 million) over 5 y from the TPP perspective. Net cost estimates from a TPP perspective in the UK ranged from £26.7 million (€25.8 million)Citation⁴¹ to £41.5 million (€40.6 million).Citation⁴⁰ The range of budget impact estimates from a societal perspective is also wide for France: Trichard et al.Citation¹⁷ estimated the net cost of vaccination at €22.4 million (€25.5 million), while Melliez et al.Citation¹⁹ estimated it at €68.9 million (€78.4) but it seems that Melliez et al. included only patient copayment and not productivity costs as opposed to Trichard and al.

Threshold analysis

Five studies reported a break-even price in developed countries (3 in Europe, 2 in USA). Estimated break even prices for cost-effectiveness according to Jit et al.,Citation⁴³ who conducted analyses from a TPP perspective for 5 countries, ranged from €56 (€69) for the UK to €102 (€119) for Finland per full-course vaccine cost of Rotarix, for a willingness to pay threshold of €30,000 per QALY. Unsurprisingly, cost-effective prices are much higher from a societal perspective than from a TPP perspective. Estimates of the threshold price for cost-effectiveness in the Netherlands were €67 (€76) per full course of Rotarix vaccination and €63.30 (€72) per full course of RotaTeq vaccination (for a willingness to pay threshold of €30,000 per QALY) according to Jit et al.Citation⁴⁴ from the TPP perspective and €77.71 (€84) (for €20,000 per QALY) according to Rozenbaum et al.Citation³⁵ per full course of vaccination from a societal perspective.

Developing countries

Cost-effectiveness and cost-utility analyses

In January 2000, with global immunization rates stagnating, the GAVI was launched to fund vaccines for children in the world's 70 poorest countries. In GAVI-eligible countries, Atherly et al.Citation⁸⁰ projected the cost-effectiveness of introducing RV vaccination to help policy makers in prioritizing resources to gain the greatest health improvements for their constituencies. For the baseline scenario, the estimated incremental cost-effectiveness ratio of RV vaccination was $43 (€33) per DALY averted for the entire period during 2007–2025, suggesting RV vaccination was very cost-effective.

In Latin America, results were clearly favorable to RV vaccination for all countries, except Chile. The primary reason for higher ICERs in Chile is the relatively low mortality estimate. Three studies were published for Brazil, and presented incremental costs per life-year gained a from TPP perspective ranging from €504 (€797)Citation⁴⁷ to approximately €790 (€1248).Citation⁴⁵ From a societal perspective, estimates varied from €292 (€461) to €520 (€820) per life-year gained. Rheingans et al. found that the incremental cost per DALY averted was higher for ‘lower-middle income countries’ than for ‘upper-middle income’ countries. Nevertheless, all results for cost per DALY averted were below $350 (€360) in both the Rheingans and Atherly studies,Citation⁷⁹^,Citation⁸⁰ considering vaccination with Rotarix.

For Asian and Oceanic countries, vaccination was found to be cost-effective. Two studies provided incremental costs per DALY averted for Vietnam; for a full course vaccination cost of $10 (€8), the estimated ICERs were $91 (€70) in one studyCitation⁶⁹ and $550 (€420) in another,Citation⁷⁰ from a TPP perspective. The study by Podewils et al.Citation⁷¹ showed that cost-effectiveness at different prices is highly dependent upon the level of income of studied countries. ICERs are more sensitive to price in developed countries: they can be relatively high as vaccination benefits in terms of life-years saved or DALYs averted are smaller, due to low RV-associated mortality, but also very low as potential cost offsets related to hospitalization avoided are larger than in developing countries. This comparison between developing and developed countries should be interpreted with caution, however, since results are not adjusted for purchasing power parities and the willingness to pay per DALY averted differs between these countries.

In Africa, all studies evaluated the cost-effectiveness of Rotarix, and found vaccination was very cost-effective.

Two studies evaluated the cost-effectiveness of Rotarix in Eastern European countries. In the base-case analyses, incremental costs per DALY averted were below $300 (€230) for both studies.Citation⁷⁹^,Citation⁸⁰

Budget impact analyses

Results were consistent in Latin America, with low variability between countries, and within the same country. For example, vaccination is estimated to reduce the economic burden of gastroenteritis due to RV significantly in Brazil, with 76%,Citation⁴⁶ 79%Citation⁴⁵ or 84%Citation⁵⁵ of the total healthcare cost avoided with introduction of vaccination. However a substantial net financial investment would be required. In Asian and Oceanic countries, Podewils and al.Citation⁷¹ distinguished between low-income, middle-income and high-income countries. There was variability in the percentage of costs avoided by vaccination (58% for low-income countries, 72% for middle-income and 83% for high-income countries, from a TPP perspective). In all cases, the cost of vaccination was higher than medical costs averted by vaccination.

Threshold analyses

Thirteen studies reported a break-even price in developing countries (10 in Asia,Citation⁵⁸^,Citation⁶⁰^,Citation⁶¹^,Citation⁶⁴^-Citation⁶⁷^,Citation⁶⁹^-Citation⁷¹ 2 in Latin AmericaCitation⁴⁵^,Citation⁵¹ and 1 in AfricaCitation⁷⁶). In Asia, estimated break even prices, under which vaccination would be cost-saving, ranged from $0.56 (€0.70) in IndiaCitation⁶⁰ to $55 (€49) in Hong-KongCitation⁵⁸ per full course, and was highly dependent on country features. In Kenya, the costs of vaccination were estimated to equal the costs prevented when the full course vaccine price was $2.07 (€3.68).Citation⁷⁶

Assumptions and inputs of economic evaluations

Given the wide range of results between studies, main assumptions and inputs used in the studies were reviewed to identify the main sources of variability.

Models structure

Type of models

Most existing models are classified as ‘static model’, as opposed to ’transmission-dynamic models’, i.e., they do not account for the potential reduction in force of infection (incidence among non-immune individuals) over time. The only identified transmission-dynamic model was the model developed in 2009 by Shim and Galvani,Citation⁷³ for the US. It may be noted that the model by Ho et al.Citation⁵⁸ was also presented as a dynamic model. However, this was a ‘dynamic model’ in the sense that new individuals entered the model every year (births), and some individuals were removed (deaths). Other models were mainly decision trees or Markov models.

Most models followed a single cohort of children, born over a period of 12 mo, from birth or vaccination to age 5 y. For some models the cohorts are divided into monthly sub-cohorts in order to account for seasonality. A few modelsCitation³⁴^,Citation⁵⁸^,Citation⁶⁵ considered multiple successive yearly birth cohorts.

Herd protection and transmission-dynamic models

Potential herd protection effects may benefit unvaccinated children.Citation⁸² Only one model, Shim and GalvaniCitation⁷³ assessed the cost-effectiveness of RV vaccination in the US based on a model accounting for the transmission-dynamics of RV infection. The comparison between results from Shim et al.Citation⁷³ and Widdowson et al.,Citation⁷² based on similar epidemiological input data but different model structures, indicates that indirect effects of vaccination would account for a reduction in of 41% in incidence of mild cases and 24% in incidence of hospitalisations (the transmission-dynamic model predicted a reduction in hospitalizations of 90% vs. 66% for the static model). Also, Shim et al.Citation⁷³ concluded that RV vaccination was cost-effective, whereas Widdowson et al. reported an ICER close to $200,000 (€190,000) per QALY gained. Authors argued that the substantial difference in their results compared with those of Widdowson et al.Citation⁷² was due to herd protection.

Timeframe

Most analyses (56/68) were conducted over a 5-y time-horizon, but accounted for life-years gained over a lifetime horizon. Benefits occurring beyond age 5 y are small, since the incidence of severe RVGE beyond 5 y is low.Citation⁸³ A few studiesCitation¹⁵^,Citation²¹ looked at the evolution of incremental benefits or ICERs over time and confirmed that a 5-y timeframe was appropriate. Five studies used longer time-horizons: 7 y,Citation⁵⁰ 10 y,Citation⁶⁵ 18 yCitation⁷⁴ and 20 y, including the study by Shim et al. based on a transmission-dynamic model,Citation³⁴^,Citation⁷³ respectively.

RV seasonality

Seasonality was not frequently integrated in the studies included, though incidence of RVGE tends to be highest during cooler and drier months in most developed settings.Citation⁸⁴ Only a few models accounted for RV seasonality, with a minimal impact, as based on sensitivity analyses.Citation¹³^,Citation¹⁹^,Citation²⁰^,Citation³⁶^,Citation⁵⁰

Natural immunity

Natural immunity (also referred as acquired immunity) was also integrated in some models. One Markov model have explicitly accounted for partial immunity provided by RV infections using different health-states for first, second and subsequent infections.Citation⁷⁰

Vaccine-specific data

Efficacy inputs were rarely comparable between Rotarix and RotaTeq. Large trials have been conducted for both vaccines, and demonstrated that the two vaccines are highly efficacious through two full RV seasons.Citation⁸⁵^-Citation⁸⁷ Clinical trials have demonstrated different levels of efficacy in countries with different income and mortality levels. Indeed, RV vaccine efficacy ranges from 90% in developed countries to 50% in developing ones, which could be partially explained by differences in RV strains circulation and infections' characteristics.Citation⁸⁸^,Citation⁸⁹

All models referred to results of these clinical trials. However, several forms of extrapolation of vaccine efficacy were used in models, in particular when both vaccines were considered, as the trials used different endpoints, different observation periods, and different regions.

Waning of vaccine protection over time was considered in several studies. Assumptions varied substantially between models, and waning rates were found to have moderate to large impact on results. For example, Giammanco et al. evaluated the impact of waning rate in their sensitivity analysis.Citation³⁰ Vaccine efficacy was assumed to decrease by 10% every year in the base case, and this rate varied from 5% to 15% in best and worst case scenarios. Results did not change significantly. Kim et al. estimated that vaccine efficacy against severe gastroenteritis reduced from 77% to 43% after 4 y, and found that results were moderately sensitive to waning.Citation⁷⁰ However, Bilcke et al. found that waning was one of the parameters with strongest influence on the ICER for vaccination vs. no vaccination.Citation¹⁵ They had used relatively large confidence intervals around efficacy parameters from the second season to account for waning (99 to 49% against hospitalizations, 75 to 44% against physician visits). Jit et al. accounted for waning by fitting an exponential decay curve to the first and second season vaccine efficacy for all RVGE cases, and reported for example that the ICER of €27,000 (€31,500) per QALY gained for RotaTeq in Finland would decrease to €17,000 (€19,800) when waning is not considered.

Efficacy between doses and efficacy of partial vaccination refer to two different concepts but were generally not distinguished in reviewed models. Efficacy between doses has shown to be high, roughly comparable to efficacy after a complete vaccination course,Citation⁹⁰ while efficacy of partial vaccination in the long-term is more uncertain. Assumptions varied between the 14 studies that accounted for it (for example for Rotarix, Podewils et al. used a 50% efficacy after 1 dose,Citation⁷¹ and Tate et al. used a 25% rateCitation⁷⁸). These assumptions were found to have little impact on results for both RV vaccines, but substantial impact on comparisons between vaccines. Serotype and genotype of RV were considered in one study, for the UK, using bootstrap sampling.Citation⁴⁰ This led to an increase of efficacy, compared with crude trial estimates.

Side effects of vaccination were not considered in most of the studies reviewed. Only a few models accounted for them, with a minimal impact on results when considered in sensitivity analysis.

Epidemiological inputs

Comparing inputs between models was not always possible, or at least not straightforward, due to differences in model structures. Furthermore, important differences exist in epidemiology and health care resource utilization inputs of developed and developing countries which make models inputs and outputs highly different. Indeed, most of the deaths due to RVGE happen in developing countries with poorer access to care whereas most of the burden in developed countries is linked to hospitalizations.

Authors used several sources, mainly surveillance systems, large health system databases, and the REVEAL studyCitation⁹¹ (prospective epidemiological study of RVGE in Europe).

In the studies reviewed, RVGE incidence rates could be month- or age-specific, and varied according to countries: annual incidence rates ranged from 4.7% in SpainCitation³⁷ to 24.4% in Thailand.Citation⁶⁷ It was found to be a pivotal parameter of some models, in which probabilities of hospitalizations, physician visits, emergency department visits and death were highly conditional upon RVGE incidence.

Annual hospitalization rates were also highly variable between countries, ranging from 0.0102% in UgandaCitation⁷⁸ to 3.36% in Kyrgyzstan.Citation⁶⁸ The input values were generally consistent within countries (except for France and Netherlands), because most values were obtained from the same local data sources. However, hospitalization rates were often surrounded with uncertainty, related to under-reporting in hospital statistics and the fact that the presence of RV is not systematically tested in cases of gastroenteritis. In addition, the REVEAL study,Citation⁹² which was the major data source for several studies, was performed during a season with relatively high incidence. The influence of hospitalization incidence on the results of economic evaluations is largely related to cost offsets due to hospitalization avoided, rather than QALY or DALYs changes associated with hospitalizations. The impact varies between developed and developing countries, with a smaller impact in developed countries.

Annual incidences of physician visits were also difficult to compare because of the differences in model structures (authors considered GP visits, GP or pediatrician visits, primary care…). The variability between countries was large, with annual rates ranging from 0.18%, for Uganda,Citation⁷⁸ to 17.8%, for Kenya and Korea.Citation⁵⁷^,Citation⁷⁶ Most of the values were based on large surveillance networks or large databases of physician records. There was also some variability within countries, but the impact on results was relatively small.

Emergency department (ED) visits was not a frequently reported outcome. First this might be linked to different health systems. Moreover, published data on emergency department visits are scarce. Authors often derived the incidence of ED visits based on a proportion of ED visits assumed to be attributable to RV, or referred to previous cost-effectiveness studies published for the same country or a close country. The variability in yearly incidence of ED visits between countries was moderate, ranging from 0% for France,Citation¹⁴ to 2.65% for Belgium,Citation¹⁸ and the impact on results was small.

Annual mortality rate was also found to be highly variable between developed and developing countries, with a low rate for developed countries (e.g., 0.0004% for France,Citation¹⁸ 0.000246% for FinlandCitation¹⁶), and a high rate for developing countries (e.g., 0.034% for Colombia,Citation⁴⁹ 0.05% for PeruCitation⁵³). The mortality rate has a very high impact in developing countries, but more surprisingly, the impact is also important for developed countries. For developed countries, mortality was determined using data from national hospital discharge or death notification databases. For developing countries, diarrhea mortality was often used to estimate RVGE mortality. Secondary sources and reviews were also used due to the lack of or limitations of surveillance systems.

Nosocomial infections (also designated as hospital-acquired infections) were explicitly considered in 28 studies, all concerning developed countries. RVGE is responsible for up to 40% of pediatric gastroenteritis nosocomial infections, leading to a mean increase in the length of stay of between 3 and 5 d.Citation⁹³ Lack of data about its incidence or costs was the most frequently cited reason for not considering them.

Costs

Most of the studies reviewed clearly specified the perspective used for the analysis. TPP, societal, government or patient perspectives were the most frequently used perspectives.

Categories of direct medical costs varied according to model structures and could include GP consultations, pediatrician consultations, specialists consultations, hospitalizations, emergency visits, hospital acquired RVGE cases (nosocomial infection), vaccinations (vaccine acquisition and vaccine administration, plus in some cases costs related to side effects), medication, laboratory tests, over the counter medications, dietary products, diagnostic tests and other relevant medical procedures. Hospitalizations costs are the less transparent (and least described) costs. The length of hospital stay was not homogeneous between countries, with a range from 2 to 5 d. Costs of nosocomial infections are mostly made up of extra hospital days. As for hospital length of stay, extra days for nosocomial infections were not similar between studies. Drug consumption was often based on expert opinion.

It is of importance to make the distinction between the vaccination costs (vaccine plus administration of vaccine when relevant) and the vaccine costs (vaccine regimen only). These costs were not always clearly reported in the studies. Hypothetical prices were used in 61 out of 68 studies. Listed prices were used in only 6 studies. Administration costs, mostly provided by dose, were considered in 41 studies, and included nurse time, secretarial employment for vaccination cost of healthcare personnel and training, cold-chain, storage space, and public education. Administration costs ranged from €2 to €10 per dose according to the country.

Direct non medical costs include transportations, nappies, parents’ accommodations, swipes, travel and other miscellaneous costs. This was usually based on published observational studies or expert opinion.

Indirect costs are mostly constituted of costs of lost productivity, due to caregivers (parents) taking time off work during illness because of treatment, illness or death. Different valuation approaches are used: lost wages (human capital) or lost productivity (friction costs, for Netherlands only).

Health-state utilities

The QALY measure was often used for developed countries, whereas the DALY measure was used for developing countries, as well as the Netherlands. DALY can be thought of as one lost year of healthy life, whereas as the QALY would represent one year gained in full health. An important distinction between QALYs and DALYs is that life-years gained are adjusted for quality of life in the QALY approach but not in the DALY approach (therefore DALYs averted are generally expected to exceed QALYs gained).Citation⁹⁴^,Citation⁹⁵

Several sources of utility data for RVGE are available.Citation⁹⁶^-Citation⁹⁹ The most frequently used source was Brisson et al., using Health Utilities Index 2 (HUI-2) utilities for children (rated by caregivers) and EQ-5D utilities for caregivers. There were some differences in the way the data were used: some studies included QALY changes for 1 or 2 caregivers per child while others ignored the Health-Related Quality of Life (HRQOL) of caregivers. Some studies accounted for the reduction in HRQOL for cases for which no medical care is sought (generally the same studies that ignored the HRQOL of caregivers) while others did not.

Sensitivity analyses conducted by several authors showed that parameters surrounding QALYs were among those with largest impact on ICERs.Citation²⁰^,Citation³¹^,Citation³⁵^,Citation⁴⁰^,Citation⁴³^,Citation⁵⁶^,Citation⁶⁵ In particular, results were found to be highly sensitive to inclusion of cases without medical attention.

Discount rate

Health benefits and costs were discounted at a rate of 3% in most studies. Impact of discount rate may be substantial when costs or benefits occur over a long period of time, which is the case for example when deaths are avoided in children.

Comparisons of RotaTeq vs. Rotarix

Fourteen studies distinguished the two vaccines, to compare both RotaTeq and Rotarix to no vaccination (13 studies), or to compare the two vaccines with each other (1 study). ICER values for Rotarix vs. no universal vaccination program were more favorable than those for RotaTeq when the two vaccines were evaluated separately in the same study, mainly because of favorable efficacy and price inputs.

All but oneCitation¹⁹ of the 14 studies distinguishing the two vaccines used different prices, and 8 studies reported higher prices for RotaTeq, although the actual prices at which the vaccine would be acquired in the context of mass vaccination programs were not known for any of the vaccines. Administration costs also have an important impact on cost-effectiveness conclusions given that the numbers of doses required for the two vaccines are different.

Discussion

This section provides a critical analysis of the assumptions and inputs used in the reviewed economic evaluations. A summary of what is done in studies, critical evaluations and our recommendations for future studies is available in .

Table 2. Summary of what is done, critical evaluation and recommendations for future studies

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Model structure

The existence of herd protection effects associated with RV was found to be subject to controversy; however, data collected through surveillance systems implemented to monitor effects of vaccination (large-scale vaccination programs) has provided first insights into potential indirect effects of vaccination. For example, two reviews of vaccination impact studies in the US and Australia suggest that there is some evidence of herd protection after the introduction of RV vaccination.Citation¹⁰⁰^,Citation¹¹⁶ For example, Payne et al. reviewed data collected in the US following the implementation of vaccination with RotaTeq and found that the impact of RV vaccination exceeded the expected reduction related to vaccination coverage rate and effectiveness only, thus supporting the hypothesis that vaccination would provide substantial herd protection effects.Citation¹⁰³

Only one economic model integrated herd protection,Citation⁷³ suggesting that indirect effects of vaccination would be substantial, and could be almost as high as direct effects against mild infection. However more sophisticated transmission-dynamic models, not used for the purpose of economic evaluation, suggested that indirect effects may be more modest than those predicted by Shim et al.Citation⁷³ A weakness of the model of Shim et al. was that it did not account for the progressive build-up of natural immunity with successive infections. The model by Van Effelterre et al.Citation¹⁰¹ predicted that indirect effects of vaccination would induce a reduction of 20 to 25% in RVGE incidence for coverage rates between 70 and 90%, and a reduction of 13 to 19% in moderate-to-severe RVGE. Two more recent publications using transmission-dynamic models tend to confirm that RVGE vaccination would provide both direct and indirect protection: Atkins et al. shows that herd protection accounts for about a quarter of the reduction in RVGE incidence,Citation¹⁰² and Atchinson et al.Citation¹⁰³ showed that at 91% vaccine coverage, there was an additional 3% reduction in reported cases is predicted compared with direct effects of vaccination alone.

The wider modeling community now very much acknowledges that herd protection needs to be included when evaluating RV vaccination and, although this should be rigorously tested as part of any sensitivity analysis and scenario analyses; it is fundamental to the thorough and complete assessment of cost-effectiveness. It is also essential to evaluate the impact of vaccination coverage. However, the impact of including herd protection, as inferred from the study of Shim et al., which is the only cost-effectiveness analysis based on a transmission-dynamic model, might be overestimated. Jit et al.Citation⁴³ have conducted sensitivity analyses incorporating herd protection effects predicted by Van Effelterre et al. They found that this has a “moderate impact” on the cost-effectiveness ratios; it changed the conclusion of the analysis for one country out of five. Therefore we would suggest that transmission-dynamic models should now be used, in order to evaluate the cost-effectiveness of vaccination under some limiting but transparent assumptions. Given the remaining uncertainty on the level of herd protection, it would also be essential to perform sensitivity analyses around this parameter.

RV seasonality was ignored in some models. As stated by Pitzer et al.,Citation⁸⁴ RV tends to be more common in cooler, drier months in most settings, but seasonal peaks have been noted to occur year-round in developing countries, and can vary over time in the same country. Additionally, the winter peak of RV infections may have an important impact on the health care systems organization. Concomitant epidemics of RV, influenza and respiratory syncytial virus infections are responsible for hospital overload and increased risk of nosocomial infections. Even if some models accounted for fluctuations in RVGE incidence between seasons, those issues of hospital overload and consequences in terms of nosocomial infections were usually ignored. When no local data are available, sensitivity analyses surrounding the effects of nosocomial infections should be performed, using data from comparable countries.

Natural immunity was generally not explicitly accounted for in models, except in the model by Kim et al.Citation⁷⁰ The immune correlate of protection from RV infection and disease are not fully understood.Citation¹⁰⁴ The degree and duration of protection will depend on age, host status and associated health conditions, and on the number of RVGE infections.Citation¹⁰⁴^,Citation¹⁰⁵ Most models accounted for the fact that the incidence of RVGE decreases with age, from birth to 5 y. This appears to be an adequate way to account for natural immunity in static models. However, for dynamic models, it is recommended to explicitly consider the protection conferred by an infection, and in particular differences in severity between primary and secondary infections.

Serotype might also be important to be taken into account. The range of RV strains circulating in Europe is diverse, and predominant and emerging strains vary between regions and from year to year.Citation⁸³ Currently in Europe, 5 common G/P combinations of RV predominate G1P,Citation⁸ G2,⁴G3P,Citation⁸ G4 P.⁸¹⁰⁶ In that context, it seems appropriate to adjust efficacy on the distribution of genotypes in the study setting.Citation¹⁰⁷

Finally, negative indirect effects of vaccination might also occur, such as serotype replacement,Citation¹⁰⁸ but there is no evidence at this time. This information will be useful for determining the necessity to incorporate such effects into future economic models, and if need be, for developing such models.

Vaccine efficacy and effectiveness

Although the efficacy of the two vaccines has been clearly demonstrated in large clinical trials, one may wonder whether vaccine effectiveness, referring to effect of vaccine in real life, is close to vaccine efficacy, as measured in clinical trials. There are several reasons why the effect of the vaccine in real life could be different from the effect measured in clinical trials. First, most patients received a full vaccine course in clinical trials. The effect of the vaccine in reality will depend on the proportion of patients receiving a full course of vaccination, and on the effect among patients who receive only a partial course of vaccination. These data might have been missing at the time of some evaluations but are now available, for example based on data collected following implementation of vaccination in the US.Citation¹⁰³^,Citation¹⁰⁹^-Citation¹¹¹ Second, efficacy was measured over pre-specified time windows in clinical trials, such as one year following last dose or one season following last dose. In economic evaluations, it is necessary to account for effects of vaccination between doses, and up to 5 y or seasons following vaccination. Efficacy estimates from clinical trials were lower for 2nd year/season after vaccination than for 1st year/season.Citation⁸⁶^,Citation¹¹² Waning rates were derived from these data and used for several models. However, a later study among Finnish children vaccinated with RotaTeq found that vaccine efficacy was sustained over 3.1 y,Citation¹¹³ which led Jit et al. to report results of cost-effectiveness analyses without waning. Third, the effect of vaccine in real-life will depend on the distribution of RV serotypes and genotypes in the studied setting. As this distribution changes over time, it may become increasingly important to account for it.

Real-life data did not always exist in the context of the economic assessment of vaccines, but several recent studies analyzed the effectiveness of vaccination in countries or regions where vaccination programs were implemented. A review of these studies showed that the routine use of RotaTeq has led to 81% to 100% reduction in RV hospitalizations and/or emergency department visits, which is consistent with results of clinical trials in developed countries.Citation⁸²^,Citation⁸⁸^,Citation¹¹⁴ However, vaccination effectiveness in developing countries was relatively low,Citation¹¹⁵ suggesting that cost-effectiveness ratios might be under-estimated in studies using the efficacy measured in trials as a proxy of effectiveness. This impact may be negligible for developed countries.

Thus, it seems appropriate to use efficacy estimates from pivotal trial publications for developed countries, but it is important to also take into consideration results of later analyses about effect of vaccination between doses, effect of partial vaccination and waning.

Epidemiology

Uncertainty exists around epidemiological inputs in all models. In developed countries, many inputs were obtained from administrative databases, but rotavirus may be underreported among patients admitted in hospital with diarrhea. Assessing mortality associated with rotavirus is also difficult because RVGE is sometimes reported as a secondary diagnosis among patients dying in hospital, but it is not known whether the patients would have survived in absence of RV infection. An observational study, REVEAL, we performed to assess the burden associated with rotavirus in European countries, but the season when it was conducted (2004–2005) was not representative of an average season. In developing countries, little data are available. Another issue is the lack of data sources for numbers of lost workdays per case and especially lost workdays assumed for cases without medical attention. This is important as lost productivity accounts for a large proportion of disease-related costs from societal perspective.Citation¹⁵^,Citation⁷²

Health-state utilities

There are a large number of issues surrounding elicitation of preference-based values for childhood health states. The main sources of utilities for children used were Brisson et al.,Citation⁹⁹ using HUI-2 which is not validated for children under 5, and Martin et al.,Citation¹⁰² using a non-validated adaptation of EQ-5D. A number of issues are worth mentioning here.

First, dimensions of health status to incorporate into health state descriptions may not be the same for children as for adults. For example, the ‘mobility’ dimension of the widely used EQ-5D instrumentCitation¹¹⁶ (I have no problems walking about / I have some problems walking about / I am confined to bed) has little relevance for children who are not yet able to walk. The same issue can be raised for the ‘self-care’ dimension. Furthermore, due to rapid developmental changes in childhood, it is difficult to identify a common set of dimensions across developmental stages.

A second issue is that of the individuals who should describe and value health states. Health state ratings should ideally be elicited from children themselves, but using proxies is sometimes unavoidable. A widely accepted view is that values should reflect preferences of the general population, and be elicited using a choice-based technique, such as time trade-off or standard gamble.Citation¹¹⁷^,Citation¹¹⁸ This would require people to imagine being in the health state of interest, as young children, which is not really possible. Therefore, we would suggest using alternative approaches, such as person trade-off or a contingent valuation study, in a representative sample of the general population, which would be asked to act as the social decision maker. The premise is that the participants in the valuation exercise are motivated by some notion of what is good for the society of which they are part. It would also be defensible to ask a group of parents to provide the values, but parental altruism may bias the resulting utilities.

Although there is no consensus on QALYs for caregivers, the assumption that the quality of life of parents is reduced due to RVGE episodes affecting their children seems acceptable. For example, parents may not be able to accomplish their usual activities (such as work) when they are caring for a sick child and may feel very anxious when his child is hospitalized. However whether the level of health that affects parents is very uncertain.

Finally, QALYs for RVGE cases not seeking medical attention are currently missing and are an obvious area for future research.

Vaccine prices

A majority of authors used assumptions in their input values, for vaccines prices because prices of the 2 vaccines are subject to uncertainties for mass vaccination programmes (where vaccine prices are subject to negotiation or tenders). Therefore, authors used hypothetical prices or did not report sources. This is particularly problematic for studies comparing both vaccines, using different hypothetical prices and reporting separate results for the two vaccines. Healthcare payers acknowledge in tender markets (such as the UK) that prices are different from the list prices. In a context of uncertainty surrounding vaccine prices, reporting threshold analyses (i.e., to determine the prices at which the vaccine is cost-effective for an accepted cost-effectiveness threshold), might be more relevant for use in decision-making than reporting a single cost-effectiveness ratio for a hypothetical price.

Comparisons of RotaTeq vs. Rotarix

It seems legitimate to conduct scenario analyses using vaccine efficacy data either from RotaTeq trials or from Rotarix trials. However, the basis for differentiating the two vaccines in some studies was not relevant. Indeed, no evidence of difference in efficacy between the two vaccines exists since case definitions, designs and endpoints used in respective clinical trials were different and no head-to-head trials have been conducted to allow a robust comparison of clinical efficacy. Furthermore, little difference in impact is expected between the two vaccines.Citation¹⁰⁶ Additionally, given that RV vaccines are very likely to be administered concomitantly with other pediatric vaccines, in particular in developed countries, differences in administration costs are likely to be small whereas many economic studies considered they were on average 50% higher for RotaTeq (3 doses) than Rotarix (2 doses). Lastly, in situations where prices are not known, one cannot rule out the possibility that the difference in administration in costs is offset by a difference in price. Therefore, we believe that cost-effectiveness direct comparisons between the two vaccines are not informative unless prices are known and further evidence is gathered on the relative effectiveness of one vaccine vs. another.

Conclusion

68 economic evaluations of RV vaccination were reviewed, including 58 cost-effectiveness analyses and 22 cost-utility analyses. Half of the studies concerned Europe. Other evaluations have been conducted in all other parts of the world. All studies for developing countries concluded in favor of vaccination, but conclusions for developed countries varied between studies. Some of this variability is expected: for example, the impact depends on disease burden, which is different between developed and developing countries (higher mortality in developing countries, limited access to care…). One of the key factors explaining such variability was the perspective used for estimating costs: analyses from a societal perspective consistently lead to more favorable results than analyses from a TPP perspective, as savings in terms of productivity loss avoided was taken into account. Furthermore estimates of QALYs gained were highly sensitive to the inclusion of cases without medical care attention (mild cases) and utility lost by caregivers. Thus, the variability around results of cost-effectiveness studies is not only related to methodological issues or insufficient data, but also to varying value judgments, with respect to the perspective from which costs, benefits and quality of life should be valued.

At the time of economic analyses, uncertainty existed around the cost-effectiveness of RV vaccination in developed countries. Further epidemiological research and observation of the impact of vaccination in real-world conditions has led to reduce this uncertainty. To consider the full RV vaccination economic value, we suggest transmission-dynamic models to be used to account for herd protection. Further research into the impact of RVGE on quality of life in young children would also be valuable. Lastly, in a context of uncertainty surrounding vaccine prices, reporting results of threshold analyses on prices might be more relevant than a fixed cost-effectiveness ratio.

Although CEAs are useful to inform decision makers, the incremental cost per QALY gained has some limitations, in particular in the context of the assessment of interventions for young children for whose quality of life evaluation is still controversial. Therefore, it would also be interesting to use other types of complementary analyses (cost-benefit, budget impact analyses or willingness-to-pay approach for example) to consider the full potential societal and economics benefits of RV vaccination.

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Acknowledgments

This article was funded by Sanofi Pasteur MSD. Sibilia Quilici and Stuart Caroll are employees of Sanofi Pasteur MSD. Samuel Aballéa and Aurélie Millier are employees from Creativ-Ceutical which received funding from Sanofi Pasteur MSD. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Footnotes

* Developers of models were contacted by a WHO officer to invite them to participate in the model comparison. The process resulted in three models provided to the authors: Roxanne (Rotarix™ Analyses of Economics) designed by GSK Pharmaceuticals, POLYMOD, developed by public financing within a European-Union project and CoRoVa (Consensus Rotavirus model Vaccination) designed by Sanofi Pasteur MSD but developed by the University of Groningen within the context of an unrestricted grant.

^† CEA is a form of economic analysis that compares the relative costs and outcomes (effects) of two or more courses of action. Typically the CEA is expressed in terms of a ratio where the denominator is a gain in health from a measure and the numerator is the cost associated with the health gain. CUA is a CEA using years (QALY) as outcome measure.

^‡ BIA is a tool used to predict and understand the potential financial consequences of introducing a new health-care intervention into a drug reimbursement system given inevitable resource constraints.

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A critical literature review of health economic evaluations of rotavirus vaccination

Abstract

Introduction

Search Methodology

Overview of Studies

Table 1. Overview of included studies

Results of economic evaluations

Developed countries

Cost-effectiveness and cost-utility analyses

Budget impact analyses

Threshold analysis

Developing countries

Cost-effectiveness and cost-utility analyses

Budget impact analyses

Threshold analyses

Assumptions and inputs of economic evaluations

Models structure

Type of models

Herd protection and transmission-dynamic models

Timeframe

RV seasonality

Natural immunity

Vaccine-specific data

Epidemiological inputs

Costs

Health-state utilities

Discount rate

Comparisons of RotaTeq vs. Rotarix

Discussion

Table 2. Summary of what is done, critical evaluation and recommendations for future studies

Model structure

Vaccine efficacy and effectiveness

Epidemiology

Health-state utilities

Vaccine prices

Comparisons of RotaTeq vs. Rotarix

Conclusion

Additional material

Acknowledgments

Footnotes

References

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