Cost Effectiveness of the New Pneumococcal Vaccines: A Systematic ...

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Nov 28, 2013 - Katelijne van de Vooren; Silvy Duranti; Alessandro Curto; Livio GarattiniEmail author ... Because of the limited information on vaccine effectiveness and lack ... Industry-sponsored models may be exercises in marketing rather ...
PharmacoEconomics (2014) 32:29–45 DOI 10.1007/s40273-013-0113-y

SYSTEMATIC REVIEW

Cost Effectiveness of the New Pneumococcal Vaccines: A Systematic Review of European Studies Katelijne van de Vooren • Silvy Duranti Alessandro Curto • Livio Garattini



Published online: 28 November 2013  Springer International Publishing Switzerland 2013

Abstract Introduction Diseases caused by Streptococcus pneumoniae (pneumococcus) are a major global public health problem. Despite their importance, information on the burden of the different pneumococcal diseases is limited and estimates vary widely. Objective and Methods We critically reviewed the full economic evaluations (FEEs) on the new pneumococcal conjugate vaccines (PCVs) conducted in the European Union (EU) to assess their potential contribution to public decision making. We selected the FEEs focussed on PCV10 and PCV-13 and published in English from January 2007 until June 2013. We screened the selected articles to assess their main methodological features using a common checklist composed of epidemiological, clinical and economic items. Results All the ten studies selected were based on modelling and the time horizon was always long term. Two studies focused on adults, the remaining eight on infants. Only one study based herd immunity on national data, eight used foreign data or modelling and the last did not consider it. National prices and tariffs were claimed to be sources for unit costs in all studies; however, half of them assumed price parity when one vaccine was not yet marketed, and the figures varied within the countries where more than one study was conducted. Conclusions supported the economic utility of pneumococcal vaccination in all studies, raising some concern only in (i) the independent study, which found that PCV-13 was borderline cost effective, and (ii) the study sponsored by both manufacturers, which estimated an K. van de Vooren  S. Duranti  A. Curto  L. Garattini (&) CESAV, Centre for Health Economics, IRCCS Institute for Pharmacological Research ‘Mario Negri’, Via Camozzi, 3 c/o Villa Camozzi, Ranica, 24020 Bergamo, Italy e-mail: [email protected]

incremental ratio slightly above the national threshold for both PCV-10 and PCV-13. Conclusion The European studies we analysed are mostly based on weak sources of data. Because of the limited information on vaccine effectiveness and lack of epidemiological and economic data, the need for extensive recourse to assumptions leads to great within- and between-study variability generated by authors’ choices. Key Points for Decision Makers • Pneumococcal vaccination seems to be a field in which economic evaluations built on modelling display their greatest limits in contributing to rational decision making. • Because of the limited information on vaccine effectiveness and lack of epidemiological and economic data, the need for extensive recourse to assumptions leads to great within- and between-study variability generated by authors’ choices. • Industry-sponsored models may be exercises in marketing rather than science, mainly aimed at supporting prices kept high by manufacturers.

1 Introduction Diseases caused by Streptococcus pneumoniae (pneumococcus) are a major global public health problem and can be classified as invasive or non-invasive [1]. Invasive pneumococcal disease (IPD) is any condition in which pneumococcus is detected in blood, cerebrospinal fluid or any other normally sterile body site; such conditions include bacteraemic pneumonia, meningitis and febrile

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bacteremia. Non-invasive pneumococcal diseases (NIPD), like acute otitis media (AOM), sinusitis and bronchitis, are more common but less serious [1, 2]. Pneumococci are transmitted by direct contact with respiratory secretions from patients and healthy carriers, and are also believed to be a frequent cause of non-bacteraemic pneumonia [2]. Despite their importance, information on the burden of the different pneumococcal diseases (PDs) is limited. Estimates vary widely and probably reflect the dynamic epidemiology of pneumococcal infections, differences in study design, seasonal variability and the inherent problem of obtaining an aetiological diagnosis of pneumonia in most cases. IPD is less common than NIPD, but its microbiological diagnosis is unambiguous, so its incidence is frequently used as an indicator of the overall burden of PDs. IPD isolates can also be used to study the distribution of the serotypes causing the most severe forms of PD. There are around 90 known serotypes of pneumococcus, though approximately 20 are responsible for more than 70 % of IPD in all age groups. The spectrum of prevalent capsular types varies with age, time and geographical area, although common disease-causing serotypes are consistently identified throughout the world [2]. The reported annual incidence of IPD in developed countries ranges from 8 to 34 cases/100,000 population, with the highest rates in children aged less than 2 years and in the elderly. The incidence is higher in people with functional or anatomic asplenia and in immunocompromised individuals. Costs and benefits of an immunisation programme against PD have been estimated in many countries and various reviews of full economic evaluations (FEEs) have been published. Two reviews assessed the cost effectiveness of the first pneumococcal conjugate vaccine (PCV)-7 in children. The first [3] focussed on methodology and assumptions, finding ample differences between studies (e.g. vaccine efficacy, incidence rates for invasive and non-invasive disease); accordingly, results varied widely. The second [4] focused on the cost effectiveness against AOM specifically, which seems to be a major economic driver for implementation of national immunization programmes. The authors concluded that current cost-effectiveness models depend on too many assumptions, precluding firm conclusions. The most recent review [5] focussed on the estimates of PCV-10 and PCV-13 efficacy. Again, efficacy against AOM, inclusion of indirect effects and cross protection varied widely across studies. Here, we critically reviewed the FEEs on the new PCVs (PCV-10 and PCV-13) conducted in the EU, in order to assess their potential contribution to public decision making. Since evaluating cost effectiveness for vaccines is mostly model based, [6] we limited our analysis to the EU so as to verify the credibility of the major epidemiological, clinical and economic inputs used to populate the models, comparing key assumptions and methodological choices in

K. van de Vooren et al.

a fairly homogeneous setting where we could detect their consistency. We also examined whether sponsorship by manufacturers influenced the results. The analysis is preceded by a short background on the market situation and the efficacy of the various pneumococcal vaccines, and their use in immunisation campaigns in Europe. 1.1 Vaccines Pneumococcal vaccines can be grouped as unconjugate and conjugate. The 23-valent (unconjugate) polysaccharide vaccine (PPV-23), covering 23 serotypes, has been marketed in Europe for decades (Table 1). It is indicated for children aged over 2 years and adults. However, despite studies over the last 30 years, its efficacy and effectiveness is still only poorly defined and thus controversial [7]. More recently, the European Medicines Agency (EMA) has approved three PCVs covering 7, 10 and 13 serotypes. PCV-7 and PCV-13 are manufactured by the same company, PCV-13 (the most recent one) replacing PCV-7 in practice. Thanks to the use of PCV-7, PD caused by its seven serotypes decreased substantially in developed countries, not only in the paediatric population targeted for vaccination, but also in non-vaccinated age-groups, with a ‘herd immunity’ effect [8]. However, by inducing serotype substitution too, other serotypes of pneumococcus have now become more common. PCV-13 includes six additional serotypes, protecting against—amongst others—serotype 19A, which has become the most prevalent [9]. The efficacy of PCV-13 was based originally on two clinical trials of PCV-7 [10–13]. Its potential efficacy, including the additional serotypes in the PCV-13 vaccine, has been supported by analysis of immune responses, a surrogate marker of efficacy. PCV-10 is produced by a different manufacturer and was launched between the two other PCVs, with three more serotypes than PCV-7 (all of which are also included in PCV-13). Most of its serotypes are conjugated to Haemophilus influenzae protein D, and in fact this vaccine is also known as PhiD-10. Its efficacy is based on a clinical trial with its precursor PhiD-11, which had all 11 serotypes conjugated to H. influenzae protein D. After this trial [14], the manufacturer modified the vaccine formulation. According to the EMA there is still not enough evidence that PCV-10 provides protection against non-typeable H. influenzae (NTHi) [5]. Today, in most European countries, pneumococcal vaccination is a voluntary, recommended or mandatory vaccination [15]. Campaigns for adults are still based on PPV-23 in general, although PCV-13 has also been indicated for adults, since 2011. The most widely mentioned vaccine for infant immunization in national documents is PCV-13. Although the real prices of vaccines vary a lot from one country to another, depending partly on how

Cost Effectiveness of the New Pneumococcal Vaccines

31

Table 1 Pneumococcal vaccines available in Europe Brand name

INN

Date of first market approval

Serotypes covered

Indication

Pneumovax

PPV-23 [42]

1981 (France)a

1, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 22F, 23F, 33F

Active immunisation for prevention of disease caused by pneumococcus in adults C50 years and children [2 years at increased risk for PD

Prevenar

PCV-7 [43]

2-2-2001 (EMA)

4, 6B, 9V, 14, 18C, 19F, 23F

Active immunisation against disease caused by pneumococcus in infants and children from 2 months up to 5 years of age

Synflorix

PCV-10 [44]

30-3-2009 (EMA)

1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F, 23F

Active immunisation against invasive disease and AOM caused by pneumococcus in infants and children from 6 weeks up to 5 years of age

Prevenar

PCV-13 [45]

9-12-2009 (EMA)

1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F

Active immunisation against invasive disease, pneumonia and AOM caused by pneumococcus in infants and children from 6 weeks up to 17 years of age Active immunisation for the prevention of invasive disease caused by Streptococcus pneumoniae in adults C50 years

AOM acute otitis media, EMA European Medicines Agency, INN international non-proprietary name, PCV polysaccharide conjugate vaccine, PPV pneumococcal polysaccharide vaccine a

National market authorization

health authorities purchase them (e.g. by tendering or not), the old PPV-23 is generally much cheaper.

articles to minimize discretionary effects, and any disagreement was resolved through discussion.

2 Methods

3 Results

We conducted a literature search on the PubMed international database to select the FEEs focused on PCVs and conducted in the EU countries, published in English from January 2007 until June 2013. The search terms used were ‘pneumococcal conjugate vaccine’ or ‘pneumococcal vaccine’, ‘cost’ or ‘cost-effectiveness’ or ‘economic evaluation’. We screened the selected articles to assess the main methodological features of the FEEs using a common checklist comprising (i) epidemiological and clinical items (incidence and case fatality rates, source of vaccination coverage, herd immunity, replacement and serotype distribution, source of utility values) and (ii) economic items (time horizon, discounting, perspective, cost items, sources of resource consumption and unit costs, results, sensitivity analysis) based on the checklist used to abstract studies in the EURONHEED (European Network of Health Economics Evaluation Databases) database [16]. We excluded by definition FEEs including only PPV-23 (with ‘do nothing’ as alternative) since we focused on new vaccines. Then we excluded comparisons in which the alternative vaccine was only PCV-7, its effectiveness now being inherent in the subsequent PCV-13. We also excluded studies of catch-up campaigns, since these cover a very specific situation referring to a short period. Since any critical assessment is, by definition, a subjective exercise, two reviewers assessed the selected

3.1 Literature Search Figure 1 summarizes the search strategy and its results. We retrieved 150 articles: 93 were discarded because they did not include an FEE on a pneumococcal vaccine, and were policy articles (16), reviews (11), burden of disease or partial EEs (20), clinical or epidemiological studies (32), or letters or comments (14). Further, 35 did not concern the EU setting, nine included only the old vaccines PPV-23 [17, 18] and PCV-7 [19–25], and three analysed a catch-up campaign [26–28]. Eventually, we selected ten articles [29–38]. We further excluded Greece from a multinational study including Germany and the Netherlands [35], since full-text analysis showed a lack of essential clarity on data sources for this country (most information came from unspecified manufacturers’ records). Table 2 summarizes the main characteristics of the ten selected articles. Two studies focused on adults (although in different age bands), the remaining eight on infants. The analyses concerned only six jurisdictions: the Netherlands and Germany (three analyses each, two on infants and one on adults), the UK (two studies on infants), Spain (one on infants, limited to the region of Valencia), Denmark (one analysis on infants) and Sweden (two on infants). At present, pneumococcal vaccination is generally recommended in all of them, except for infants in most Spanish

32 Fig. 1 Literature search. EU European Union, FEE full economic evaluation, PCV polysaccharide conjugate vaccine, PPV pneumococcal polysaccharide vaccine

K. van de Vooren et al.

Search terms: pneumococcal conjugate vaccine OR pneumococcal vaccine cost OR cost-effectiveness OR economic evaluation (combined with the previous terms by Boolean operator ‘AND’)

Potentially eligible studies (150) Exclusion criteria: Not a FEE (93) FEEs retrieved (57) Exclusion criteria: Not in the EU setting (35) FEEs in the EU setting (22) Exclusion criteria: Including PPV-23 or PCV-7 only (9) FEEs including PCV-10 and PCV-13 (13) Exclusion criteria: Catch up campaign (3) Meeting selection criteria (10)

EU = European Union; FEE= full economic evaluation

regions (including Valencia) and adults without additional risk factors in the Netherlands. Six studies included both a cost-effectiveness analysis (CEA) and a cost-utility analysis (CUA), three conducted only a CUA and the one remaining a CEA; two studies took a societal perspective, six a third-party payer’s viewpoint and two considered both. PCV-13 was included in all but one study as an alternative, PCV-10 in six. All studies were based on modelling and the time horizon was always long (mostly lifetime), although in three it seemed that cost estimates were limited to 1 year and one defined 10 years as a short-term period without discounting either costs or benefits. Only one study [32] applied a dynamic model, the most suitable to capture herd immunity effects [6]; all the others used a static model (prevailing decision trees on Markov models). All but one of the studies were sponsored by the manufacturer of the vaccine of reference, and five were co-authored by at least one employee of the company. Table 3 shows the results of the critical appraisal of the selected studies on the basis of epidemiological and clinical items. All studies based their estimates of incidence and case fatality rate of PDs on national data. Only one [35] based the vaccination coverage on a national source, one study [32] did not include vaccination coverage and all the

others used assumptions. Only one study [37] based herd immunity on national data, eight used foreign data or modelling and the last [30] did not consider it. All the ten studies included serotype distribution and used national data to estimate it. Only one study [35] partially used national values to quantify quality-adjusted life-years (QALYs), the remaining nine referring to foreign sources. All studies considered the same clinical endpoints. Table 4 gives an overview of the critical appraisal concerning economic items and results. All the studies considered direct costs for vaccination and treatment of pneumococcal-related pathologies, those on infants also including costs for long-term sequelae. Four studies, including the two focused on adult vaccination, assessed indirect costs due to work loss (and one of them also arguably considered co-payments). Their proportion was negligible in the two studies on adults, while it ranged from around 13 % [37] to even 40 % [33] of the total costs in the two studies on infants conducted from the societal viewpoint. National prices and tariffs were claimed to be sources for unit costs in all studies, four studies also recurring to assumptions. Only four used medical records to source resource consumption, four cited national and/or foreign literature. Five studies also referred to an expert panel to

Health Econ Rev (NA)

Clin Ther (2.321)

Clin Ther (2.321)

Vaccine (3.766)

Clin Ther (2.321)

J Med Econ (NA)

J Infect (4.126)

Vaccine (3.766)

BMJ (14.093)

Vaccine (3.766)

Kuhlmann et al. (2012) [29], DE

Rozenbaum et al. (2010) [30], NL

Klok et al. (2013) [31], DK, SE

Van Hoek et al. (2012) [32], UK

By et al. (2012) [33], SE

Knerer et al. (2012) [34], UK

Strutton et al. (2012) [35], DE, NL

Dı´ez-Domingo et al. (2011) [36], ESc

Rozenbaum et al. (2010) [37], NL

Talbird et al. (2010) [38], DE

PCV-10, PCV-13 (infants)

PCV-10 (infants)

No (infants)

PCV-10, PCV-13 PCV-10 (infants)

PCV-13 (infants)

PCV-10, PCV-13 (infants)

PCV-13 (infants)

CEA, CUA

CUA

CEA, CUA

CEA, CUA

CEA, CUA

CUA

CUA

CEA, CUA

CEA, CUA

Noa (adults) PCV-13 PCV-10, PCV-13 (infants)

CEA

Type of FEE

PPV-23 (adults)

National programme (target)

TPP

TPP, society

TPP

TPP

TPP

Society

TPP

TPP

Society

TPP, society

Perspective

PCV-10 vs. PCV-7

PCV-10 vs. NC PCV-13 vs. NC

PCV-13 vs. NC

PCV-13 vs. PCV-10

PCV-10 vs. PCV-13

PCV-10 vs. PCV-13

PCV-13 vs. NC

PCV-13 vs. PCV-10

PCV-13 vs. NC

PCV-13 vs. PPV-23 PCV-13 vs. NC

Alternatives

Static model (decisiontree)

Static model (decisiontree)

Static model (decisiontree)

Static model (decisiontree)

Static model (Markov)

Static model (Markov)

Dynamic model (dynamic transmission)

Static model (decisiontree)

Static model (decisiontree)

Static model (Markov)

Type of model (subtype)

10 years (no discounting)

Lifetime (4 % costs; 1.5 % benefits)

Lifetime (3 %)

Effectiveness: lifetime (5 % DE; 1.5 % NL)

Costs: 1 year;

Lifetime (3.5 %)

Lifetime (3 %)

30 years (3.5 %)

Effectiveness: lifetime (3%)

Costs: 1 year;

Lifetime (4 % costs; 1.5 % benefits)

Effectiveness: lifetime

Costs: 1 year;

Time horizon (discounting)

Yesb

Yesd

Yes

Yesb

Yesb

Yesb

No

Yesb

Yes

Yes

Sponsorship

d

c

b

a

Sponsored by both the manufacturers of the two conjugate vaccines

Setting limited to the region of Valencia

Co-authored by at least one employee of sponsoring company

PPV-23 only for subjects at risk

CEA cost-effectiveness analysis, CUA cost-utility analysis, DE Germany, ES Spain, FEE full economic evaluation, IF impact factor, NA not applicable, NC no campaign, NL the Netherlands, PCV polysaccharide conjugate vaccine, PPV pneumococcal polysaccharide vaccine, SE Sweden, TPP third-party payer

Journal (IF)

Study (year), country

Table 2 Main characteristics of FEEs selected

Cost Effectiveness of the New Pneumococcal Vaccines 33

Foreign [79] and national [80, 81] surveillance data; assumptions

[34]

National surveillance [62], National registry [63], primary care database, national literature [64]

SE

National surveillance; national registry [63]; national literature [72]; national retrospective study

National surveillance [56], national statistics [57], national cohort study [58], assumptions

DK

[31]

[33]

National surveillance [51]

[30]

Modelling [66]; national surveillance [67]; primary care database [68]

Hospital database [46]; expert panel; market survey

[29]

[32]

Incidence

References

National registry [63], regional surveillance [65]

SE

National [82] and EU [74] surveillance; national hospital database [81]; national GP database [83]

EU surveillance data [73]; regional surveillance [66]; national registry [63]

National hospital database [68]

Epidemiological study [59], national statistics [60]

DK

National surveillance [51]

Foreign literature; assumptions; unpublished data [47] from national surveillance network

Case fatality rate

Assumptions

Assumptions

Not included

Assumptions

Assumptions

Assumptions

Source of vaccination coverage

Foreign surveillance [13, 75, 84]

Foreign surveillance [74]

Modelling [68]

Foreign surveillance [90, 93]

Not included

Foreign surveillance [48, 49] adjusted with regional [50] data

Herd immunity

Table 3 Critical appraisal of studies reviewed on the basis of epidemiological and clinical items

Assumptions

Foreign surveillance [75]

Modelling [68]

Foreign surveillance [90, 93]

Foreign [52] and national [53] surveillance; foreign hospital database [54]



Replacement

National surveillance [62], assumptions

National surveillance [56], epidemiological study [61]

National surveillance [85, 86]

National surveillance [75]

National surveillance [68]

SE

DK

National surveillance [51]

National estimates based on regional [50] surveillance data

Serotype distribution

Foreign sources: surveys [71, 78]; meta-analysis [79]

Foreign sources: surveys [71, 76, 77]; longitudinal cohort study [27]; metaanalysis [78]; assumptions

Foreign sources: parents survey [69, 70]; longitudinal cohort study [71]

Foreign source [94] on a different pathology (diabetes); foreign survey [95]

Foreign source [55]



Source of utility

34 K. van de Vooren et al.

National literature [102–104]; national estimates based on regional surveillance [50, 105, 106]; expert panel

[38]

Market research; national hospital database [95]

National surveillance [51]

Foreign literature [107, 108]; foreign surveillance [109– 111]; national literature [112]

National surveillance [51, 101]

Regional surveillance [98]

DE

NL

Case fatality rate

Assumptions

Foreign surveillance [75, 85]

Foreign and national surveillance [51, 54, 101]

Assumptions

Foreign surveillance [89– 91]; foreign hospital database [92]; assumptions

Assumptions

Market data [96]

National surveillance [88]

Herd immunity

Assumptions

DE

NL

Source of vaccination coverage

CT clinical trial, DE Germany, NL the Netherlands, EU European Union, GP general practitioner

National surveillance [51, 100]

[37]

Market survey, national estimates based on regional surveillance [50]

DE

Regional surveillance [97–99]

National surveillance [87]

NL

[35]

[36]

Incidence

References

Table 3 continued

Foreign surveillance [75, 85]

Foreign and national surveillance [51, 54, 101, 102]

Assumptions

Foreign surveillance [90– 92]; foreign hospital database [93]; assumptions

Replacement

National estimates based on regional surveillance data [50]

National surveillance [88]

National surveillance [113]

National surveillance [51, 101]

National surveillance

DE

NL

Serotype distribution

Foreign source [94] on a different pathology (diabetes); foreign survey [95]

Foreign source [93] on a different pathology (diabetes); national survey [94]

Foreign sources: surveys [69, 78]; meta-analysis [79]; aassumptions

Foreign sources: surveys [69, 78]; longitudinal cohort study [72]; metaanalysis [79]

Foreign sources: surveys [69, 78]

DE

NL

Source of utility

Cost Effectiveness of the New Pneumococcal Vaccines 35

Vaccine and its administration; hospital admissions; GP consultations; drugs Vaccine and its administration; hospital admissions; outpatient consultations; diagnostics; drugs; sequelae Vaccine and its administration; hospital admissions; GP consultations; drugs; sequelae Vaccine and its administration; hospital admissions; outpatient consultations; GP consultations; sequelae Vaccine and its administration; hospital admissions; outpatient consultations; GP consultations; sequelae Vaccine and its administration; hospital admissions; outpatient consultations; drugs; sequelae

[30]

[35]

[34]

[33]

[32]

[31]

Vaccine; hospital admissions; outpatient consultations

Direct

Cost items

[29]

References

Work loss

Dominant

Dominant

Dominant

Prices; tariffs

Prices; tariffs [127, 128]

Prices [131, 132]; tariffs [53, 133– 136]; assumptions; expert panel

National literature [24]; expert panel

National [72, 125, 126] and foreign literature [67]; assumptions; expert panel National [51, 129, 130] and foreign literature; assumptions; expert panel

Scenario

One-way; analysis of extremes; probabilistic

One-way; scenario

Scenario

\£30,000/ QALY

Prices [122]; tariffs [123, 124]

Medical records; assumptions

Scenario

Dominant

Scenario

€4,723/ LYGa

Medical records; literature [51]

Work loss

Prices; assumptions

One-way; probabilistic

Dominant

Prices [115]; tariffs [116, 117]; national statistics [118, 119] Prices [120]; tariffs [121]

Medical records; expert panel [114]; national guidelines

Work loss; copayments

Indirect

Sensitivity analysis

ICER (baseline)

Source of unit costs

Source of resources consumption

Table 4 Critical appraisal of studies reviewed on the basis of economic items

PCV-13 is always cost saving if indirect effects are included

PCV-10 may have greater impact on overall disease burden than PCV-13

AOM-related parameters

Exclusion of indirect effects

PCV-10 was cost saving vs. PCV13

PCV-13 is cost effective, but results depend on its efficacy against NIPD

PCV-13 was cost saving vs. PCV10

PCV-13 is cost effective, but there is uncertainty about the proportion of pneumonia ascribable to S. pneumoniae

PCV-13 is cost saving

Conclusions

Vaccine efficacy against IPD; PCV-10 price; exclusion of indirect effects; AOMrelated parameters

Time horizon; efficacy against NIPD; discount rate

Indirect effects; serotype coverage; pre-PCV-7 epidemiology data

Vaccine efficacy; inpatient CAP incidence; duration protection of vaccines; discount rate

Vaccine price; inpatient incidence and costs of CAP; vaccine effectiveness against inpatient CAP

Most sensitive variables

36 K. van de Vooren et al.

Vaccine and its administration; hospital admissions; GP consultations; sequelae

Vaccine; hospital admission; outpatient consultations; sequelae

[37]

[38]

37 AOM acute otitis media, B-C ratio benefit-cost ratio; CAP community-acquired pneumonia, GP general practitioner, ICER incremental cost-effectiveness ratio, IPD invasive pneumococcal disease, LYG life-years gained, NIPD non-invasive pneumococcal disease, PCV polysaccharide conjugate vaccine, QALY quality-adjusted life-years gained, SA sensitivity analysis a It only refers to high-risk population

Vaccination with PCV-10 results in overall cost savings vs. PCV7 Duration of protection Scenario Prices [140]; tariffs [23, 126] Expert panel; assumptions

PCV-13 and PCV-10 are both cost effective, if schedules and prices can be lowered One-way; threshold; scenario; probabilistic

PCV-10: €52,947/ QALY; PCV-13: €50,042/ QALY Dominant Prices [122, 138]; tariffs [139, 141]; assumptions National [51, 122] and foreign literature [80] Work loss

Vaccine price; vaccination coverage; incidence and costs of hospitalized pneumonia; IPD and pneumonia inclusion; herd effect Vaccine efficacy against other aggressive serotypes; vaccination cost; case fatality rate; indirect effects One-way €12,794/ LYG; €10,407/ QALY Prices; tariffs [90, 137]; assumptions Medical records [89]; assumptions Vaccine and its administration; hospital admissions; outpatient consultations; sequelae [36]

Direct

Cost items References

Table 4 continued

Indirect

Most sensitive variables Sensitivity analysis ICER (baseline) Source of unit costs Source of resources consumption

Conclusions

A universal PCV-13 vaccination programme in the Community of Valencia would be a costeffective intervention from the payer’s perspective

Cost Effectiveness of the New Pneumococcal Vaccines

estimate resource consumption. All studies conducted a sensitivity analysis: results were most sensitive to effectiveness in five studies, to vaccine prices and indirect effects (like serotype substitution and herd immunity) in four and five, respectively. In general, in all studies, the conclusions supported the economic utility of pneumococcal vaccination, raising some concern only in the independent study [32] and in the one backed by both manufacturers [37], which analysed each of the two competing vaccines in comparison with no vaccination (without comparing them directly). The first study found that PCV-13 was borderline cost effective, with 53 % of the incremental cost-effectiveness ratio (ICER) simulations below the £30,000 UK threshold, while the second estimated the ICER was slightly above the Dutch threshold of €50,000 in the base case (PCV-10 €52,947 per QALY, PCV-13 €50,042 per QALY). The four studies that directly compared the two PCVs always concluded for the sponsored product. Here we conduct study-by-study analysis, in order to summarize the major methodological choices, estimates and assumptions for each of them, also citing the main data of the base case. 3.2 Adults 3.2.1 Kuhlmann et al. In this German study (sponsored by the PCV-13 manufacturer), various CEAs were conducted comparing PCV13 with PCV-23 or no campaign, from both the third-party payer and society perspectives. The analysis was based on a cross-sectional steady-state transition Markov model built on a hypothetical cohort of individuals C50 years with a time horizon of 100 years, although costs were calculated only on a yearly basis. IPD incidence and serotype distribution stemmed from regional surveillance during the period 2001–2003, the age-specific IPD incidence was adjusted with an arbitrary factor for underreporting, as were the odds ratios for IPD and communityacquired pneumonia (CAP) incidences in moderate- and high-risk populations. The outpatient CAP incidence was estimated by an expert panel, and case fatality rate was obtained from national data. Vaccination coverage (40 % for high-risk and 25 % for risk-free population) was based on assumptions and herd immunity on foreign surveillance adjusted with regional data. Effects due to serotype replacement were not included. A decennial booster was assumed to be necessary for PCV-13, while a PPV-23 booster was simulated every 5 years limited to high-risk subjects. Efficacy (PCV-13 93.9 % on IPD, 26 % on inpatient and 6 % on outpatient CAP; PPV-23 74 % on IPD and 0 % on CAP) was based on different sources

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(meta-analyses and PCV-7 clinical trial on infants), resource consumption from medical records and a market survey; official vaccine prices were used (PPV-23 €28.94, PCV-13 €64.26). Exhaustive information on total costs per item was not available since only incremental savings per disease were shown. The study concluded that PCV-13 was dominant in all the analyses. 3.2.2 Rozenbaum et al. This Dutch study (sponsored by the PCV-13 manufacturer) was based on a decision-tree model built on a hypothetical cohort of individuals C65 years, comparing PCV-13 vaccination with no campaign. A CEA and a CUA were conducted from the societal perspective, although indirect costs due to work loss are hardly relevant for elderly people (as highlighted by the authors themselves). Life-years gained, QALYs, resource consumption and costs were all extrapolated until death, with results expressed for the whole population and also split by type of risk. Incidence, case fatality rate and serotype distribution were drawn from national surveillance data, the last assumed to be the same for both bacteraemic and non-bacteraemic CAP, as was PCV-13 efficacy for IPD and NIPD in low- and high-risk individuals (60 %). Utility was sourced from a US study. Vaccination coverage was assumed to be equal to that of influenza vaccination: 65 % among low-risk and 83 % among high-risk individuals, although PPV-23 was already aimed at high-risk individuals in the Netherlands. The vaccine price was arbitrarily set at €50 per dose and the base-case costs were not fully reported. The authors concluded that vaccination should be cost effective compared with no campaign, although the proportion of CAP generated by S. pneumoniae raises uncertainty. 3.3 Infants 3.3.1 Klok et al. In this two-country study (sponsored by the PCV-13 manufacturer), a CEA and a CUA were conducted from the third-party payer’s perspective to compare PCV-13 and PCV-10. The study was based on a decision analytic model, derived from a previous one already published [35], with a time horizon of 1 year for costs and lifetime for efficacy. Vaccination coverage was assumed to be 100 % in both countries. Incidences of IPD, inpatient pneumonia and AOM were based on national data for Denmark, outpatient pneumonia incidence was assumed similar to the Swedish figure; all these variables were obtained from national data for Sweden (although AOM was adjusted to reflect the current incidence and the impact of PCV-7). PCV-10 and

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PCV-13 effectiveness were derived from the evidence on PCV-7, assuming a proportionally greater effect for the additional serotypes. A small extra effect was assumed for PCV-10 on NTHi-caused AOM, based on data from a clinical trial on Phid-11. Direct effects of vaccination were assumed to persist for life. PCV-7 indirect effects (sourced from foreign countries) were considered for PCV-13, but excluded for PCV-10. Utility came from Dutch and Canadian surveys for both countries. Prices, treated as confidential in Denmark, were assumed to be the same for both vaccines in both countries (Swedish krona [SEK] 518.95 and Danish krone [DKK] 451.33 = €59.58 current rate of exchange), based on Swedish pharmacy retail prices taken from another study included in this review [33]. No reference was given for healthcare unit costs, resource consumption was not shown, and the total healthcare costs per item were not reported for either country. The study concluded that PCV-13 dominated over PCV-10. 3.3.2 Van Hoek et al. In this English study, a CUA was conducted from the thirdparty payer’s perspective over a time horizon of 30 years. The analysis, based on a dynamic transmission model, simulated the effects of either introducing PCV-13 or stopping vaccination after PCV-7 (already used for campaigning in the UK at the time of the study). Updated epidemiological inputs were taken from UK databases. Coverage was not mentioned, but herd immunity and serotype substitution were included. PCV-13 efficacy was assumed to be 52 % against vaccine type carriage (26 % for partially protected) and 100 % against IPD, although 80 % efficacy against all serotypes in the first year was then mentioned in the discussion. Protection was assumed to wane after 10 years. Utility was based on various studies conducted in different countries (either on parents or adults to cover all the potential pathologies). The vaccine price was the official one (£49.60 = €57.76 current rate of exchange) since awarded prices are confidential in the UK, as noted by the authors. Total vaccination costs were not reported. The study concluded that PCV-13 is cost effective if NIPD infections are included. 3.3.3 By et al. In this Swedish study (sponsored by the PCV-10 manufacturer), a CUA based on a Markov model was conducted from the societal viewpoint over a lifetime horizon. Although ‘no vaccination’ was reported as an alternative (showing the lowest direct costs), the authors limited their comments in the results and discussion to the PCV-10 versus PCV-13 comparison. Vaccination coverage was

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assumed at 100 %, claiming that this should not distort the evaluation. Vaccine efficacy and general assumptions were derived from another modelling study focused on the impact of PCV-7 and PCV-10 in the UK, where inputs on pneumococcal and NTHi serotypes (adjusted for Sweden by the authors) were drawn from an expert panel. The PCV-10 efficacy against NTHi-caused AOM (35.6 %) was based on a clinical trial on PhiD-11. The proportions of AOM caused by S. pneumoniae (38 %) and NTHi (27 %) were based on foreign sources. Furthermore, in the absence of local data, equal indirect effects drawn from foreign sources were estimated for both PCV-10 and PCV-13. Utility estimates were based on foreign studies. The source of resource consumption was a Swedish study on PCV-7. The price was assumed to be the same for both vaccines and based on pharmacy retail prices (SEK 518.95 = €59.58 current rate of exchange). Although PCV-13 was predicted to reduce the burden of IPD more effectively, the study concluded that PCV-10 dominated over PCV-13 thanks to more AOM avoided. 3.3.4 Knerer et al. In this English study (sponsored by the PCV-10 manufacturer), based on a Markov model with a lifetime horizon, a CEA and a CUA were conducted to compare PCV-10 and PCV-13 from the third-party payer’s perspective, with a vaccination schedule different from the national current situation (four doses instead of three). Pre-PCV-7 incidence and case fatality rates stemmed from literature and national databases, while the prevalence of long-term sequelae came from a Canadian burden-of-disease study based on French and German data. The proportion of NTHi invasive disease and its mortality were based, respectively, on Dutch and European surveillance. Vaccination coverage was assumed to be 100 %. A fixed indirect effect (age \5 years: 15.4 %; age C5 years: 29 %) based on US data was applied to both vaccines, limited to IPDs. The PCV-10 efficacy against NTHi invasive disease (35.6 %, assumed to also be the same for AOM) was based on a clinical trial on PhiD-11. Cross-protection against two of the three additional serotypes in PCV-13 was also included for PCV10. Utility was derived from US and Canadian sources. Resource consumption was drawn from the literature or assumptions validated by unspecified experts’ opinions; unit costs were based on national tariffs and national literature for sequelae; the price for vaccines was assumed to be equal for both (£27.60 = €32.14 current rate of exchange). Although AOM parameters were particularly influential in the sensitivity analysis, the authors concluded that PCV-10 was dominant due to its greater impact on overall disease burden, mainly thanks to the estimated protection against NTHi.

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3.3.5 Strutton et al. In this European multi-country study (sponsored by the PCV-13 manufacturer), a CEA and a CUA were conducted from the third-party payer’s perspective to compare PCV13 and PCV-10. The study was based on a decision-analytic model, with a time horizon of 1 year for costs and lifetime for efficacy. Pre-PCV-7 incidence and mortality stemmed from national surveillance for the Netherlands and various sources (including a market survey) for Germany. PCV-10 and PCV-13 effectiveness were derived from evidence on PCV-7, assuming a proportionally greater effect for the additional serotypes and similar serotype coverage for AOM, pneumonia and IPD. PCV-7 indirect effects (sourced from foreign countries) were considered for PCV-13, but excluded for PCV-10. Vaccine coverage was obtained from national surveillance in the Netherlands (95 %) and market data in Germany (80 %), utility from Dutch and Canadian surveys for both countries. Resource consumption was based on a mix of national and foreign literature and assumptions, healthcare unit costs on tariffs in Germany and another FEE in the Netherlands, prices on the national official list in Germany (PCV-13 €49.00; PCV-10 €39.90) and assumptions in the Netherlands (PCV-13 €68.56; PCV-10 €57.13). The total healthcare costs per item were not reported at all for either country. The authors concluded that PCV-13 was cost saving in both countries if indirect effects were included, although this was the most influential parameter in sensitivity analysis. 3.3.6 Diez-Domingo et al. This Spanish study (sponsored by the PCV-13 manufacturer), was based on a decision tree built on ten hypothetical cohorts. A CEA and a CUA were conducted from the third-party payer’s viewpoint, comparing PCV-13 and no campaign over a lifetime horizon in the region of Valencia (where pneumococcal vaccination for infants had not yet been introduced). Incidence, case fatality rate and serotype distribution all stemmed from regional surveillance (although referenced imprecisely), while vaccination coverage (95 %) and indirect effects (5 % herd immunity and 25 % serotype replacement) were assumed. Efficacy (97 % for IPD, 42 % for in-hospital pneumonia and 9 % for AOM) was estimated referring to PCV-7 (extended to the six new serotypes); utility was sourced from foreign studies. Resource consumption was based on local medical records and local literature integrated by assumptions for unknown variables (e.g. complex AOM episodes); unit costs from national official tariffs, then an unreferenced exfactory price was used for the vaccine (€44.92) and a cost for its administration was arbitrarily assumed to be 10 % of

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the vaccine price. The authors concluded that the introduction of a universal programme with PCV-13 would be cost effective for regional authorities. 3.3.7 Rozenbaum et al. In this Dutch study (supported by both PCV-10 and PCV13 manufacturers), two CUAs based on a decision-tree analytic model (framed on a previous one) were conducted from both the third-party payer’s and societal viewpoint, comparing all the new vaccines or no campaign over a lifetime horizon. Pre-PCV-7 incidence and serotype distribution, case fatality rate and risk of sequelae were derived from Dutch studies on PCV-7, incidence of NIPD and AOM from national inpatient and outpatient records. Vaccination coverage was only mentioned in the discussion ([95 %), without a reference. A net indirect effect of 10 % was assumed only for IPD on the basis of English and Dutch data. Utility was drawn from foreign sources and a meta-analysis. Resource consumption was mainly obtained from national studies, healthcare unit costs from national literature. The PCV-13 official price was applied (€68.56), while that of PCV-10 was assumed (€62.25) since it was not available at the time of the study. Full information on total costs per item was not available since only incremental savings per disease were shown. Although they were not compared directly, the two vaccines were both considered cost effective, particularly lowering their schedules and prices. 3.3.8 Talbird et al. In this multi-country study (sponsored by the PCV-10 manufacturer) grouping a broad basket of countries (e.g. Canada and Mexico), a CEA and a CUA were conducted from the third-party payer’s viewpoint, comparing PCV-10 and PCV-7. Two analyses were conducted, the first based on a steady-state model on 1 year and the second for each of the first hypothetical 10 years of vaccination (without applying any discount rate). The German incidence came from a mix of national literature, estimates based on regional surveillance and an expert panel; case fatality rate (6.5 % for meningitis, 1.6 % for bacteraemia and pneumonia \18 years) from a mix of national and foreign sources. Vaccination coverage was assumed at 90 %; net indirect effects (age \5 years 15.4 %; age C5 years 29 %; assumed to be equal to PCV-7 for PCV-10) and serotype distribution were obtained respectively from foreign and national surveillance. PCV-10 efficacy (in-hospital pneumonia 25 %; NTHi-caused AOM 35.6 %; all-cause AOM 22.9 %) was sourced from clinical trials and an expert panel, and cross-protection on serotypes 6A and 19A was also assumed. Utility was estimated through foreign

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sources. Resource consumption was based on assumptions, and price parity was assumed for the two vaccines, although we did not find any figure. Only incremental savings were shown and the results of the second analysis were limited to Canada, claiming that the proportions of benefits and costs were similar for all countries in the study. The authors concluded that PCV-10 was always cost saving compared with PCV-7.

4 Discussion We reviewed the FEEs on new pneumococcal vaccines in EU countries. The main aim was to provide healthcare decision makers with a critical appraisal of the existing studies, focusing particularly on economic aspects since the previous reviews analysed the epidemiological and clinical issues in greater depth. We also investigated the influence of sponsorship on performance and results. A potential limitation of this study is that, as in all reviews where references are retrieved from a single international database, some studies may have been missed despite our best efforts. However, this risk should be minimal because of the large number of articles initially found. Our European review seems to confirm the difficulty of assessing the efficiency of pneumococcal vaccination, already pointed out in previous world-wide reviews [3–5], due to uncertainties related to crucial clinical and epidemiological parameters in the models, and to economic ones as well. Although all studies considered the same clinical endpoints, very different values were assigned to the vaccines’ efficacy against each one. Information on indirect effects, herd immunity and serotype substitution was based on an American source in most studies, though it is not clear whether these data can be extrapolated to European settings. Moreover, many studies used old serotype distributions (dating back to before PCV-7 was introduced) because of limited data. Almost all CUAs relied on foreign utility scores. Three studies [29, 31, 35] made the arguable methodological choice to extend the time horizon for effects to lifetime, while restricting it to the short term for costs, and one [38] considered each of the first 10 years of a hypothetical vaccination campaign as short-term analyses (without discounting costs and benefits). In addition, although only two studies [30, 36] did an FEE in a setting where pneumococcal vaccination on the population target was not yet recommended (so no real data on vaccination coverage were available), the remaining studies also based coverage on assumptions. In many studies we found very weak sources to estimate resource consumption and even unit costs. Furthermore, the

Cost Effectiveness of the New Pneumococcal Vaccines

distribution of healthcare costs per item in study arms was not available in most studies. The proportion of indirect costs, arguably included in the two studies on adults, was negligible in both, while it ranged widely in the two studies on infants conducted from the societal viewpoint. Although almost all studies claimed to refer to the official prices for vaccines (rather than purchasing prices as the third-party payer’s perspective would have required) and half of them assumed price parity when one vaccine was not yet marketed, the figures varied within the countries where more than one study was conducted, and was even missing in one of them [38]. Since most studies were sponsored, we might speculate that prices were often chosen to support the implementation of a sustainable vaccination strategy at the level set by the manufacturer, either before or after pricing negotiation with health authorities. Although many European countries purchase vaccines through tenders, which can significantly reduce the real prices [39], making vaccination campaigns much more cost effective, an FEE can justify a high price for a manufacturer, so an acceptable contribution margin can be achieved in each country [40]. Sensitivity analyses confirmed that variables more open to assumptions (like indirect effects and vaccine efficacy and price) affected results more often. In general, sponsored studies gave the impression of aiming at supporting the marketing strategies of the two manufacturers. The role of sponsorship seemed evident in the four studies [31, 33–35] that compared PCV-10 and PCV-13 directly. All four, co-authored by at least one employee of the sponsoring manufacturer, concluded in favour of the sponsored vaccine, which they all considered dominant. In general, vaccines are considered one of the most costeffective health interventions in developing and developed countries since they offer a relatively cheap way of preventing substantial morbidity and mortality [6, 40]. FEEs on pneumococcal vaccines are mostly model-based by necessity, implying that predictions are made using (everchanging) current knowledge sensitive to substantial variations in baseline assumptions [40]. In particular, estimates of long-term effectiveness and natural progression of disease stages are problematic [5], requiring many assumptions open to each author’s discretion. Furthermore, adding uncertain economic parameters can make the comparison of the results of these FEEs confusing, particularly when their choices might be affected by marketing strategies [41].

5 Conclusions Pneumococcal vaccination seems to be a field in which FEEs built on modelling display their limits in contributing to rational decision making. Because of the limited

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information on vaccine effectiveness and lack of reliable epidemiological and economic data, the need for extensive recourse to assumptions leads to great within- and between-study variability generated by authors’ choices, making them of scant utility for public policy purposes. In particular, industry-sponsored models may be exercises in marketing rather than science, mainly aimed at supporting prices kept high by manufacturers. Conflicts of Interest Katelijne van de Vooren, Silvy Duranti, Alessandro Curto, Livio Garattini declare no conflicts of interest. Author Contributions All authors contributed to the conception and design of this work, commented on drafts and approved the final manuscript. Silvy Duranti and Alessandro Curto acted as independent reviewers of the literature and abstracted the studies, Katelijne van de Vooren wrote the manuscript, Livio Garattini supervised all the study and acts as guarantor for the content of the paper.

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