Transcript Slide 1

Cost-Effectiveness of Pneumococcal Polysaccharide Vaccination in Adults: A
Systematic Review of Conclusions and Assumptions
Isla
1
Ogilvie ,
Antoine El
1BioMedCom
2,3
Khoury ,
Yadong
2
Cui ,
Erik
 Pneumococcal disease (PD) due to S. pneumoniae includes both non-invasive
infections—such as community acquired pneumonia (CAP), otitis media, and
other upper respiratory tract infections—,and invasive disease (IPD), and is a
major cause of morbidity and mortality in adults, leading to substantial clinical
and economic burden worldwide1
 The US Active Bacterial Core Surveillance program reported an incidence for
IPD of 43.3 per 100,000 children under 1 year of age and 39.6 per 100,000 for
the population aged over 65 years in 2007;2 the incidence of CAP is also higher
among the elderly population than for other age groups3-6
 A literature search recovered 31 cost-effectiveness studies pertaining to the
use of PPV-23 for the prevention of pneumococcal disease in adults
 Eleven studies comparing the cost-effectiveness of PPV-23 vaccination with
no vaccination were included in this analysis14-24
Figure 1: Literature search and study inclusion
Literature search: Abstracts identified
 The most recent Cochrane Review of randomized clinical trials (RCT) concluded
that PPV-23 is protective against IPD in healthy adults from high-income
countries, but evidence is equivocal for its effectiveness against IPD in patients
with chronic illness;10 efficacy findings from observational studies concluded that
PPV-23 provides protective efficacy for IPD in immunocompetent adults,
including those over 55 years of age10
 Previous reviews of the cost-effectiveness of PPV-23 reported that vaccination
was cost effective;11,12 however, to our knowledge, no systematic review of the
literature on the cost-effectiveness of PPV-23 has yet been done
Aim
The objective of this study was to conduct a structured and systematic review of the
recent literature on the economic evaluations of pneumococcal polysaccharide
vaccination in adults.
31 studies
Possible studies identified
18 studies
13 studies
Excluded: Only total costs reported
PPV-23 costs assessed with another intervention
Studies included in analysis:
1 study
1 study
11 studies
Comparative analysis of economic evaluations
Cost-effectiveness ratios from the studies were compared by disease; age
group; country; and perspective (societal or healthcare); the majority reported
that vaccination was cost-effective (< $50,000 per life-year gained [LYG] or per
quality-adjusted life-year [QALY] gained) for the prevention of IPD in adults
Impact of indication on cost-effectiveness
 All but one of the studies evaluated the cost-effectiveness of PPV-23 for the
prevention of IPD only, in the base-case analysis; incremental costeffectiveness ratios (ICERs) ranged from $9,810 to $26,160 per LYG and
from -$9.08 (cost-saving) to $53,955 per QALY.
 For studies examining pneumococcal pneumonia, cost-effectiveness ranged
from -$221 per LYG (cost-saving) to $30.4 per LYG and from cost-saving to
$3,379 per QALY17,21
Evers, 2007
30,000
Ament, 2000
25,000
Smith, 2008
20,000
Sisk, 1997
15,000
Sisk, 2003 (50-60 year olds)
10,000
5,000
0
 Although the EVIDEM instrument can be used to assign a score for each study
based on a quantitative assessment, we opted to adapt the instrument by using
only the qualitative evaluation component of it, and to focus our analysis on the
relevance, strength and limitations of the assumptions and conclusions of the
studies
Structured assessment of the relevance and strengths of studies, using the EVIDEM
instrument, revealed that most studies most studies used relevant patient populations,
outcomes, and perspectives; all studies compared vaccination with PPV-23 to no
vaccination
US (blacks)
US
US
Sweden
Spain
Scotland
France
Belgium
Sweden
Spain
 Studies that specifically included pneumococcal pneumonia reported lower costeffectiveness ratios, compared to those studies limited to IPD
 This gap in the available efficacy data affected the relevance and strengths of all
studies examined.
 The relevance and strength of economic evaluations was also affected by the
variability of IPD incidence rates reported in different countries, which partly
explains the large variability in ICERs
 Limitations of this study
 The comparison of ICERs across countries is challenging given different
settings, study design, strength of the study, currency and outcomes. Although
ICERs have been standardized to a single currency and year and plotted on
the same graph (Figure 2), comparison across countries may not be feasible
because of the variation in purchasing power across these nations
Vaccine efficacy assumptions
 Structured assessment showed that the efficacy and effectiveness data for PPV-23
vaccination against IPD available to these studies limited the strength and relevance
of most of the studies
 The subjective nature of assessing the relevance and strength of a study; an
instrument promoting transparent critical analysis and reporting of studies was
combined with a deliberative process and expert validation
 Efficacy estimates for vaccine-related types of bacteremic pneumococcal disease
varied between studies, from 22%–75%21,27
 All but one of the economic analyses reviewed utilized incidence rates and
serotype distributions measured before the introduction of PCV-7, 29 and
therefore the studies may not reflect the current context.
Table 1: Sources of vaccine efficacy data
Study
Shapiro,
199127
US
Population/setting
Case-control study; N=1054 patients
with IPD confirmed by isolation of
vaccine serotype S. pneumoniae: 1054
controls were matched by age,
underlying illness, and site of
hospitalization; Median age: 67.6 years;
age range 18-99 years
Butler, 199328
US
Indirect cohort study; N=2837 persons
with IPD confirmed by isolation of S.
pneumoniae; Median age 57 years for
vaccinated; 50 years for unvaccinated)
Protective efficacy (%: 95% CI)
Studies using data
Aggregate protective efficacy of PPV-23 against serotypes in the vaccine in
immunocompetent patients by age group and time since vaccination
Age (years)
Time since vaccination: Protective efficacy (%: 95% CI)
<3 years
3–5 years
>5 years
<55
93 (82–97)
89 (74–96)
85 (62–94)
55-64
88 (70–95)
82 (57–93)
75 (38–90)
65-74
80 (51–92)
71 (30–88)
58 (-2–83)
75-84
67 (20–87)
53 (-15–81)
32 (-67–72)
≥ 85
46 (-31–78)
22 (-90–68)
-13 (-174–54)
Efficacy
Duration of
protection
14-18,
20,23,24
14-18, 22-24
Protective efficacy (%: 95% CI)
Duration of protection (%: 95% CI)
Efficacy for immunocompetent patients
stratified by age
Age
Protective efficacy (%: 95%CI)
Overall
60% (30%-77%)
65-74 years 70% (30%–87%)
≥ 75 years 78% (54%–89%)
Vaccine efficacy and time since vaccination†
Interval Protective efficacy (%: 95%CI)
<2 years
51% (22%–69%)
2-4 years
54% (28%–70%)
5-8 years
71% (24%–89%)
≥ 9 years
80% (16%–95%)
17
17
Sims, 198829
US
Case-control study; 85 patients with
pneumococcal bacteremia; 152
matched controls
Efficacy against IPD
All: 81%
n/a
Farr, 199530
US
Multicenter, case-control study; 244
controls and 122 patients hospitalized
for IPD; aged ≥ 55 years
Efficacy against IPD
All: 70% (37%– 86%)
n/a
Melegaro,
200431
International
Meta-analysis of efficacy studies for
PPV-23 against pneumonia and IPD in
the elderly (≥ 65 years old)
Mangtani,
200332
International
Systematic review of RCTs and
observational studies on the efficacy of
PPV-23 against IPD
Efficacy against IPD (≥ 65 years old)
All: 65% (-49%–92%)
Efficacy against IPD (≥ 65 years old): RCTs: 30%–47%
Observational studies: 47%–81%
Non-bacteremic pneumonia/IPD: 37.5%
n/a
n/a
 Further economic evaluations may be warranted based on new data on vaccine
efficacy and the epidemiology of IPD in adult populations
19,21
References
17
22
21
60,000
1
Butler JC. Epidemiology of pneumococcal disease The pneumococcus. Washington, DC: 2004. p. 148-68.
2
Centers for Disease Control and Prevention. Active Bacterial Core Surveillance (ABCs) report emerging infections program network Streptococcus pneumoniae, 2007-provisional. 2008.
www.cdc.gov/ncidod/dbmd/abcs/survreports/SPNEUMO_2007_provisional.pdf. (Accessed 3 Sep 2008).
3
Ruiz-Gonzalez A, Falguera M, Nogues A, Rubio-Caballero M. Is Streptococcus pneumoniae the leading cause of pneumonia of unknown etiology? A microbiologic study of lung aspirates in consecutive
patients with community-acquired pneumonia. Am J Med. 1999;106(4):385-90.
4
Nelson JC, Jackson M, Yu O, Whitney CG, Bounds L, Bittner R, et al. Impact of the introduction of pneumococcal conjugate vaccine on rates of community acquired pneumonia in children and adults.
Vaccine. 2008;
5
Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of
community-acquired pneumonia in adults. Clin Infect Dis. 2007;44 Suppl 2:S27-S72
6
Brown PD, Lerner SA. Community-acquired pneumonia. Lancet. 1998;352(9136):1295-302.
7
Morrow A, De Wals P, Petit G, Guay M, Erickson LJ. The burden of pneumococcal disease in the Canadian population before routine use of the seven-valent pneumococcal conjugate vaccine. Can J Infect
Dis Med Microbial. 2007;18(2):121-7.
8
Makela PH, Butler JC. History of immunization Pneumococcal Vaccines: the impact of conjugate vaccine. Washington, DC: 2008. p. 19-27.
9
De Graeve D, Beutels P. Economic aspects of pneumococcal pneumonia: a review of the literature. Pharmacoeconomics. 2004;22(11):719-40.
10 Moberley SA, Holden J, Tatham DP, Andrews RM. Vaccines for preventing pneumococcal infection in adults. Cochrane Database Syst Rev. 2008;(1):CD000422
11 Beutels P, Postma MJ. Economic evaluations of adult pneumococcal vaccination strategies. Expert Rev Pharmacoeconomics Outcomes Res. 2001;1(1):47-58.
13 Goetghebeur M, Wagner M, Khoury H, Levitt R, Erickson LJ, and Rindress D. Evidence and value: impact on decisionmaking – the EVIDEM framework and potential applications. BMC Health Services
Research 2008;8:270
14 Evers SM, Ament AJ, Colombo GL, Konradsen HB, Reinert RR, Sauerland D, et al. Cost-effectiveness of pneumococcal vaccination for prevention of invasive pneumococcal disease in the elderly: an update
for 10 Western European countries. Eur J Clin Microbiol Infect Dis. 2007;26(8):531-40.
15 Ament A, Baltussen R, Duru G, Rigaud-Bully C, De Graeve D, Ortqvist A, et al. Cost-effectiveness of pneumococcal vaccination of older people: a study in 5 western European countries. Clin Infect Dis.
2000;31(2):444-50.
16 Merito M, Giorgi RP, Mantovani J, Curtale F, Borgia P, Guasticchi G. Cost-effectiveness of vaccinating for invasive pneumococcal disease in the elderly in the Lazio region of Italy. Vaccine. 2007;25(3):458-65.
17 De Graeve D, Lombaert G, Goossens H. Cost-effectiveness analysis of pneumococcal vaccination of adults and elderly persons in Belgium. Pharmacoeconomics. 2000;17(6):591-601.
18 Smith KJ, Zimmerman RK, Lin CJ, Nowalk MP, Ko FS, McEllistrem MC, et al. Alternative strategies for adult pneumococcal polysaccharide vaccination: A cost-effectiveness analysis. Vaccine.
2008;26(11):1420-31.
19 Parsons HK, Tomlin K, Metcalf SC, Brazier JE, Dockrell DH. The economic cost of invasive pneumococcal disease and the potential for reduction by vaccination in an adult population in South Yorkshire.
QJM. 2006;99(5):348-9.
20 Postma MJ, Heijnen ML, Jager JC. Cost-effectiveness analysis of pneumococcal vaccination for elderly individuals in The Netherlands. Pharmacoeconomics. 2001;19(2):215-22.
2007 US$ 50,000
50,000
Merito, 2007
40,000
Postma, 2001
30,000
Mangtani, 2005
20,000
Melegaro, 2004
Parsons, 2006 (All ages)
10,000
UK (Max ICER)
0
UK (Min ICER)
Firstly, an evaluator analyzed each study and provided comments for each dimension
All evaluations were then reviewed by a second investigator
Comments were validated by an independent expert
70,000
UK
 Transparent reporting for each dimension of the instrument was combined with a
three-step deliberative process to reach a consensus on potential limitations in
relevance and strength of studies.
Relevance and strengths of the economic evaluations
 Most studies used a duration of protection of the vaccine of between 5 and 6.5 years
based on Shapiro et al, 1991 which found that vaccine efficacy fell with time since
vaccination;27
UK
target population, intervention and setting, comparator, perspective and costs
outcome measures, parameter estimates and sources, time horizon, discount rate,
event pathway/model, sensitivity analysis, and conclusions
 The majority of studies reported that vaccination of over 65 year olds with PPV-23
was a cost-effective (less than US$50,000 per LYG or per QALY), and in some
cases a cost-saving, strategy for the prevention of IPD
 While PPV-23 is known to offer protective efficacy against IPD the precise level of
efficacy is unclear especially in elderly and high risk groups
 Three studies assumed that vaccine efficacy against pneumococcal pneumonia was
the same as for IPD,15,17,21 this affected the strength of their economic analyses
80,000
Italy
 It allows analysis and reporting of the relevance and strengths of an economic
evaluation in a structured fashion by prompting systematic consideration of the
following 11 dimensions:
 This review identified 11 economic evaluations comparing PPV-23 vaccination with
no vaccination
12 Postma MJ, Heijnen ML, Beutels P, Jager JC. Pharmacoeconomics of elderly vaccination against invasive pneumococcal infections: cost-effectiveness analyses and implications for The Netherlands. Expert
Rev Vaccines. 2003;2(4):477-82.
2b) Base-Case cost-effectiveness per life year gained (LYG)
Cost effectiveness (2007 US$ per LYG)
 The relevance and strengths of each study was assessed using a semiquantitative instrument designed to explore economic evaluations, developed as
part of the EVIDEM framework13
US (non-blacks)
 Assessment of relevance and strengths of the economic evaluations
Scotland
Belgium
 All costs were standardized to 2007 US$ using the consumer price index and the
appropriate exchange rate for 2007
Conclusion
 Incidence rates of IPD and pneumococcal pneumonia were also a major source of
variability in cost-effectiveness results for many studies, as were case-fatality
rates 14-17,20-24,26
CI: confidence interval; IPD: invasive pneumococcal disease; PPV-23 pneumococcal polysaccharide vaccine -23 serotypes
†Matched analysis of vaccinated and unvaccinated patients; all ages
‡High risk patients were defined as those with COPD, bronchogenic carcinoma and other chronic conditions
-5,000
 Revaccination was included in two UK cost-effectiveness studies,21,22 and in the
two multicounty European studies,14,15 as well as in one US study18
 Structured assessment revealed that the relevance and strength of the studies was
limited by data available on vaccine effectiveness, and by data on incidence and
case-fatality rates of IPD and pneumonia
40,000
35,000
 Revaccination with PPV-23 is currently recommended in many European
countries, but is not recommended routinely in the US
 Sensitivity analysis was performed in 10 of the studies; vaccine efficacy was a
critical parameter in most studies and accounted for the largest variation in costeffectiveness values in 4 studies14,15,20,24
45,000
Netherlands
 The funding source of each study was also considered
50,000
Italy
type of economic analysis; time horizon; perspective; setting; study cohort
base-year currency; costs (including vaccination costs; hospitalization costs; medication
costs; physician visits, and indirect costs such as productivity);
discount rate; data sources for incidence and mortality of pneumococcal disease;
vaccine-efficacy assumptions; cost-effectiveness ratios and results of sensitivity analysis.
2007 US$ 50,000
Germany
 To provide an overview of the selected studies, the data was systematically
extracted:
55,000
Netherlands
 The impact of setting, design and model parameters on cost-effectiveness ratios
were explored in a comparative analysis of the economic studies identified
Critical parameters
2a) Base-case cost-effectiveness per quality adjusted life year (QALY)
France
Comparative analysis of economic evaluations
 Most studies investigated the cost-effectiveness of PPV-23 vaccine against IPD in
≥ 65 year olds; in general, vaccination was cost-effective for this age group, and
cost-saving in one US study24
Figure 2: Cost-effectiveness of vaccinating adults (≥ 65 years of age unless otherwise indicated)
against IPD with the 23-valent pneumococcal polysaccharide vaccine
England/Wales
 An extensive literature search was conducted to identify articles published from
1997 to 2007 pertaining to the economic evaluation of the PPV-23 vaccine
against pneumococcal disease in the adult population.
 Cost-effectiveness for the ≥ 65 years old population varied from country to
country but was below $50,000 per LYG or per QALY in most cases
Denmark
Literature search
 Two related European studies compared cost-effectiveness from country to
country;14,15 other studies were from Belgium,17 Italy,16 the Netherlands,20
the UK19,21,22 and the US23,24
Cost effectiveness (2007 US$ per QALY)
Methods
 Only one study used incidence data from the post-PCV-7 era (2003–2004) and
reported that the cost-effectiveness of vaccinating over 65 year olds with PPV-23
was $3,714.52 per QALY18
 Base-case values ranged from $9,810 to $34,375 per LYG,16,20 and from -$9.08 per
QALY (cost-saving) to a cost of $53,955 per QALY15
Cost-effectiveness by country



1
Goetghebeur
Revaccination
 The introduction of PCV-7 has been associated with a marked decrease in disease
incidence caused by PCV-7 serotypes in the elderly population as well as among
infants25
Cost-effectiveness, effect of age and comorbidities
Excluded: not relevant/no cost data
 Currently a 23-valent pneumococcal polysaccharide vaccine (PPV-23) is widely
used for the prevention of pneumococcal infections;8 PPV-23 is indicated
primarily for the immunization of adults, and children with chronic diseases9



Mireille
Cost-effectiveness of vaccination with PPV-23 in the post-7-valent
pneumococcal conjugate vaccine (PCV-7) era
Results
 An invasive infection such as IPD poses significant demands on healthcare
resources because it generally leads to hospital admission; one Canadian study
estimated that the economic burden was 2004 US$500,000 per 100,000 persons
of the Canadian population7


John D.
2
Grabenstein ,
Consultants inc., Montreal, Quebec, Canada; 2Merck & Co., Pennsylvania, USA; 3University of Arkansas for Medical Sciences, Arkansas, USA
Introduction


2
Dasbach ,
Impact of perspective and costs on cost-effectiveness
Most studies used a healthcare perspective, excluding indirect costs; one
study used a societal perspective (including lost productivity) and estimated a
base-case ICER of $10,999 per LYG for the vaccination of ≥ 65 year olds21
Epidemiological assumptions for IPD and pneumococcal pneumonia
 Structured assessment also revealed that data sources for the incidence of IPD and
case-fatality due to IPD also affect relevance and strengths
 Studies used IPD incidence data from a variety of sources including public-health
surveillance; ICD-9 codes for pneumococcal-related hospitalizations; local clinical
microbiology laboratory data; and data from published sources
 There was substantial variation in the input values used for incidence rates of IPD;
from 20.5 to 50 cases per 100,000 population for 65 to 74 year olds
 This variation in input values accounts for much of the variation in cost-effectiveness
ratios between and within studies
 Case-fatality rates were also obtained from a range of data sources including publichealth surveillance, hospital-registration data, and international literature
 The range of case-fatality rates used by these studies was large, ranging from
4.65%–30% for the 65 to 74 year old age group
21 Mangtani P, Roberts JA, Hall AJ, Cutts FT. An economic analysis of a pneumococcal vaccine programme in people aged over 64 years in a developed country setting. Int J Epidemiol. 2005;34(3):565-74.
22 Melegaro A, Edmunds WJ. The 23-valent pneumococcal polysaccharide vaccine. Part II. A cost-effectiveness analysis for invasive disease in the elderly in England and Wales. Eur J Epidemiol.
2004;19(4):365-75.
23 Sisk JE, Whang W, Butler JC, Sneller VP, Whitney CG. Cost-effectiveness of vaccination against invasive pneumococcal disease among people 50 through 64 years of age: role of comorbid conditions and
race. Ann Intern Med. 2003;138(12):960-8.
24 Sisk JE, Moskowitz AJ, Whang W, Lin JD, Fedson DS, McBean AM, et al. Cost-effectiveness of vaccination against pneumococcal bacteremia among elderly people. JAMA. 1997;278(16):1333-9.
25 Hicks LA, Harrison LH, Flannery B, Hadler JL, Schaffner W, Craig AS, et al. Incidence of pneumococcal disease due to non-pneumococcal conjugate vaccine (PCV7) serotypes in the United States during the
era of widespread PCV7 vaccination, 1998-2004. J Infect Dis. 2007;196(9):1346-54.
26 Plans P. [Cost-effectiveness of 23-valent antipneumococcical vaccination in Catalonia (Spain)]. Gac Sanit. 2002;16(5):392-400.
27 Shapiro ED, Berg AT, Austrian R, Schroeder D, Parcells V, Margolis A, et al. The protective efficacy of polyvalent pneumococcal polysaccharide vaccine. N Engl J Med. 1991;325(21):1453-60.
28 Butler JC, Breiman RF, Campbell JF, Lipman HB, Broome CV, Facklam RR. Pneumococcal polysaccharide vaccine efficacy. An evaluation of current recommendations. JAMA. 1993;270(15):1826-31.
29 Sims RV, Steinmann WC, McConville JH, King LR, Zwick WC, Schwartz JS. The clinical effectiveness of pneumococcal vaccine in the elderly. Ann Intern Med. 1988;108(5):653-7.
30 Farr BM, Johnston BL, Cobb DK, Fisch MJ, Germanson TP, Adal KA, et al. Preventing pneumococcal bacteremia in patients at risk. Results of a matched case-control study. Arch Intern Med.
1995;155(21):2336-40.
31 Melegaro A, Edmunds WJ. The 23-valent pneumococcal polysaccharide vaccine. Part I. Efficacy of PPV in the elderly: a comparison of meta-analyses. Eur J Epidemiol. 2004;19(4):353-63.
32 Mangtani P, Cutts F, Hall AJ. Efficacy of polysaccharide pneumococcal vaccine in adults in more developed countries: the state of the evidence. Lancet Infect Dis. 2003;3(2):71-8..
Acknowledgements
The authors wish to thank Philippe de Wals MD, PhD, from Laval University, Quebec City, Québec, Canada for his
expert validation of the analysis of relevance and validity of economic evaluations included in this review as well as
for his suggestions and comments on the manuscript. We would also like to thank Lonny Erickson PhD and Randy
Levitt PhD from BioMedCom for their contributions to the analysis of the literature as well as Donna Rindress from
BioMedCom for her suggestions and comments. This study was funded by Merck & co.