Cost-effectiveness of a pentavalent rotavirus vaccine in Japan

Figures & data

Figure 1. Description of the RV5 Markov model.

Table 1. Model inputs used in analysis.

Parameter	Base case value (range for one-way sensitivity analysis)	Distribution/parameter values for PSA^a	Source
Birth cohort	1,091,156	Not included	Vital Statistics for Japan 200848
Resource utilization inputs for unvaccinated cohort
Deaths	19 (9–29)	Beta^b	Base Case: Kawai et al.57, Black et al.56; one-way: same as base case; PSA: Nakagomi et al.12
		r = 244 (# with events)
		n−r = 178 (# without events)
Hospitalizations	78,000 (43,100–96,022)	Beta^b r = 244 (# with events)	Base Case: Nakagomi et al.12; one-way: same as base case; PSA: Nakagomi et al.12
		n−r = 178 (# without events)
Office visits	678,218 (632,870–687,428)	Beta^b	Base Case: Sato et al.19; one-way: same as base case; PSA: Yokoo et al.13
		r = 1684 (# with events)
		n−r = 7672 (# without events)
Average hospital length of stay	5 days	Not included	Base case: Nakagomi et al.12
Distribution of healthcare contacts by age	<1 year: 14% 2 years: 43% 3 years: 18% 4 years: 18% 5 years: 7%	Dirichlet <1 year: 14% 2 years: 43% 3 years: 18% 4 years: 18% 5 years: 7%	Base Case: Yokoo et al.13; PSA: same as base case; used non-informative prior distributions
Vaccine efficacy
Between the first and second dose
Deaths and hospitalizations	88%	Log-Normal^c	Base Case: Dennehy et al.52; PSA: same as base case
		ln(RR) = −2.081
		se ln(RR) = 1.061
Office visits	55%	Log-Normal^c	Base Case: unpublished results from REST; PSA: same as base case
		ln(RR) = −0.630
		se ln(RR) = 0.438
Between the second and third dose
Deaths and hospitalizations	94%	Log-Normal^c	Base Case: Dennehy et al.52; PSA: same as base case
		ln(RR) = −2.888
		se ln(RR) = 0.7264
Office visits	69%	Log-Normal^c	Base Case: unpublished results from REST; PSA: same as base case
		ln(RR) = −2.300
		se(ln(RR) = 0.742
In the first year after the 3rd dose
Deaths and hospitalizations	96%	Log-Normal^c	Base Case: Vesikari et al.14; PSA: Boom et al 54.
		ln(OR) = −2.210
		se(ln(OR) = 0.485
Office visits	86%	Log-Normal^c	Base Case: Vesikari et al.14; PSA: same as base case
		ln(RR) = −1.973
		se(ln(RR) = 0.294
In the 2nd–5th years after the 3rd dose
Deaths and hospitalizations	96%	Log-Normal^c ln(OR) = −2.120	Base Case: Vesikari et al.14 (assumes efficacy for severe disease is maintained after 1st year of vaccination); PSA: Boom et al.54
		se(ln(OR) = 0.485
Office visits	78%	Log-Normal^c ln(RR) = −1.973 se(ln(RR) = 0.294	Base Case: Vesikari et al.14 (assumes a 10% drop in vaccine efficacy after the first year of vaccination); PSA: same as base case
In the first year after the 2nd dose with only two doses
Deaths and hospitalizations	81%	Log-Normal^c	Base Case: Boom et al.54; PSA: same as base case
		ln(OR) = −1.66
		se(ln(OR) = 0.7393
Office visits	69%	Log-Normal^c ln(OR) = −1.66 se(ln(OR) = 0.7393	Base Case; Dennehy et al.52 (assumes same efficacy as between 2nd and 3rd dose with three-dose regimen); PSA: derived from Boom et al.54 data (assumes VE is 10% of VE for hospitalizations and ED visits)
In the 2nd–5th years after the 2nd dose with only two doses
Deaths and hospitalizations	73%	Log-Normal^c ln(OR) = −1.66 se(ln(OR) = 0.7393	Base Case: Boom et al.54 (assumes a 10% drop in vaccine efficacy after the first year of vaccination); PSA: Boom et al.54
Office visits	62%	Log-Normal^c ln(OR) = −1.66 se(ln(OR) = 0.7393	Base Case: Dennehy52 Boom et al.54 (assumes a 10% drop in vaccine efficacy after the first year of vaccination); PSA: derived from Boom et al. data (assumes VE is 10% of VE for hospitalizations and ED visits)
In the first year after the 1st dose with only one dose
Deaths and hospitalizations	69%	Log-Normal^c ln(OR) = −1.171 se(ln(OR) = 0.489	Base Case: Boom et al.54; PSA: same as base case
Office visits	55%	Log-Normal^c ln(OR) = −1.171 se(ln(OR) = 0.489	Base Case; Dennehy et al.52 (Assumes same efficacy as between 1st and 2nd dose with three-dose regimen); PSA: derived from Boom et al.54 data (assumes VE is 10% of VE for hospitalizations and ED visits)
In the 2nd–5th years after the 1st dose with only one dose
Deaths and hospitalizations	62%	Log-Normal^c ln(OR) = −1.171 se(ln(OR) = 0.489	Base Case: Boom et al.54 (assumes a 10% drop in vaccine efficacy after the first year of vaccination); PSA: Boom et al.54
Office visits	49%	Log-Normal^c ln(OR) = −1.171 se(ln(OR) = 0.489	Base Case: Dennehy et al.52, Boom et al.54 (assumes a 10% drop in vaccine efficacy after the first year of vaccination); PSA: derived from Boom data (assumes VE is 10% of VE for hospitalizations and ED visits)
Parental work loss
Days of work loss for episodes involving deaths and hospitalizations	2.5 days	Gamma^d α = 2.77 β = 1.7	Base Case: Kawamura58; Van der Wielen et al.71
Days of work loss for episodes involving outpatient visits	2.5 days	Gamma^d α = 1.028 β = 4.321	Base Case: Kawamura58; Van der Wielen et al.71
Days of work loss for episodes not requiring healthcare	2.5 days	Gamma^d α = 1.028 β = 4.321	Base Case: Kawamura58; Van der Wielen et al.71
Proportion of parents who missed work
Percentage of working parents who missed work for episodes involving deaths/hospitalizations	56%	Empiric^e Range: 39–91%	Base Case: Mast et al.7; PSA: Van der Wielen et al.71
Percentage of working parents who missed work for episodes involving OP visits and no healthcare	21%	Empiric^e Range: 20–64%	Base Case: Mast et al.7; PSA: Van der Wielen et al.71
Vaccine coverage	94% 3 doses, 3% 2 doses, 3% 1 dose	Not included	Base Case: WHO Vaccine Preventable Monitoring System; available at: http://apps.who.int/immunization_monitoring/en/globalsummary/countryprofileselect.cfm
Costs of care and costs of vaccination (in ¥ 2011)
Hospital day	26,923 (21,538–32,307)	Log-Normal ln(µ) = 10.2 ln(se) = 0.13	Base Case: Diagnosis Procedure Combination55; one way: Assumes ±20% of base case estimates; PSA: Sato et al.19
Office visit	13,664 (10,931–16,397)	Log-Normal ln(µ) = 9.522 ln(se) = 0.13	Base Case: Sato et al.19; one way: Assumes ±20% of base case estimates; PSA: Sato et al.19
Day of missed work	12,717	Not included	Base Case: Kawamura58
Direct non-medical care for hospitalizations or deaths	8505	Not included	Base Case: Kawamura58
Direct non-medical outpatient visits and no healthcare	3611	Not included	Base Case: Kawamura58
Price per dose	5700	Not included
Administration fee per dose	2500 (1000–3500)	Not included	Base Case: Chunichi Shimbu, August. 28, 2012, and city of Nagoya http://www.city.nagoya.jp/kenkofukushi/page/0000034344.html60,61.
QALY decrements for
episodes involving deaths and hospitalizations	0.0058 (0.0022–0.0133)	Gamma α = 105.88 β = 0.00006	Base Case: Brisson et al.10; one-way: same as base case: PSA: same as base case
episodes involving OP visits	0.0058 (0.0022–0.0133)	Gamma α = 105.88 β = 0.00006	Base Case: Brisson et al.10; one-way: same as base case; PSA: same as base case
episodes involving no healthcare	0.0058 (0.0022–0.0133)	Gamma α = 105.88 β = 0.00006	Base Case: Brisson et al.10; one-way: same as base case; PSA: same as base case

^aThe choice of probability distribution for each parameter included in the probabilistic sensitivity analysis is in accordance with the recommendations in Briggs et al.63. The probability distributions chosen depend on the constraints imposed by the parameter being estimated as well as the data available from various published studies.

^bThe number of deaths and healthcare contacts by type attributable to rotavirus gastroenteritis (RGE) is often estimated as a percentage of all acute gastroenteritis (AGE) events. The Beta distribution was used to vary the proportion of all AGE events due to RGE.

^cThe log-normal distribution was used to vary the risk ratios which were then converted to relative rate reductions using the formula Relative Rate Reduction = 1 – Risk Ratio.

^dThe Gamma distribution is often used to represent the uncertainty in count (Poisson) data. In the absence of information specific to Japan, we used estimates of the mean and variance from the REVEAL study71 to vary the number of parental work days missed based on the type of healthcare utilization required.

^eIn the absence of information specific to Japan as well as the mean and variance of the proportion missing work we randomly sampled from an empirical distribution based on the REVEAL study71.

Table 2. Public health and economic impact of a universal vaccination program vs no vaccination program for the base case scenario.

	No vaccination program	Universal vaccination program	Net difference	Percentage change
Events
Deaths	19	1.5	−17.5	−92.1
Hospitalizations	78,000	6015	−71,985	−92.3
Outpatient visits	678,218	174,285	−503,933	−74.3
Work loss days	386,566	105,154	−281,412	−72.8
Rotavirus cases	606,285	250,268	−356,016	−58.7
Costs
Medical care costs	18,860,561,942	2,857,625,197	−16,002,936,745	−84.8%
Hospitalizations	10,018,388,395	599,959,427	−9,418,428,968	−94.0%
Outpatient visits	8,842,173,546	2,257,665,769	−6,584,507,777	−74.5%
Direct non-medical costs	2,481,374,583	898,370,476	−1,583,004,108	−63.8%
Indirect (work days lost)	4,701,658,763	1,287,850,630	−3,413,808,133	−72.6%
Societal costs	26,043,595,288	5,043,846,303	−20,999,748,985	−80.6%
Cost of vaccination	0	26,037,164,472	26,037,164,472	100%
Net direct medical care costs	18,860,561,942	28,894,789,669	10,034,227,727	53.2%
Net societal costs	26,043,595,288	31,081,010,775	5,037,415,481	19.3%
Quality-Adjusted Life Years (QALYs)	3925	1425	−2500	−63.7%
Children with rotavirus	1836	567	−1269	−69.1%
Parents of children with rotavirus	2089	858	−1231	−58.9%

Table 3. Cost-effectiveness results for universal vaccination vs no vaccination in a single birth cohort in Japan from birth through 5 years of age (in ¥).

Cost-effectiveness outcome	Payer perspective	Societal perspective
Cost per case avoided	28,185	14,149
Cost per hospitalization avoided	139,394	69,979
Cost per QALY gained^a	7,907,648	3,969,823
Cost per QALY gained^b	4,014,001	2,015,122

^aOnly includes the QALYs reported for the children with rotavirus derived from the HUI2.

^bIncludes the QALYs reported for the children with rotavirus as well as their parents.

Table 4. Public health and economic impact of universal RV5 for five birth cohorts in municipalities of varying sizes.

	Events		Costs
Birth cohort size	Hospitalizations	Outpatient visits	Net direct medical care costs	Net societal costs
1000
No vaccination program	71	622	17,284,936	23,867,894
Universal vaccination program	6	160	26,480,897	28,484,480
Net difference	66	462	9,195,961	4,616,586
3000
No vaccination program	214	1865	51,854,809	71,603,681
Universal vaccination program	17	479	79,442,691	85,453,439
Net difference	197	1386	27,587,882	13,849,758
5000
No vaccination program	357	3108	86,242,681	119,339,468
Universal vaccination program	27	799	132,404,485	142,422,398
Net difference	330	2309	45,979,804	23,082,930
10,000
No vaccination program	715	6216	172,849,363	238,678,936
Universal vaccination program	55	1597	264,808,970	284,844,796
Net difference	660	4619	91,959,607	46,165,860
20,000
No vaccination program	1430	12,431	391,180,299	477,357,872
Universal vaccination pogram	110	3195	529,617,940	569,689,591
Net difference	1320	9236	183,919,215	92,331,720

Figure 2. Results of one-way sensitivity analysis: impact of variations in key parameters on ICER, (a) payer perspective; (b) societal perspective: base case value (range).

Figure 3. Results of probabilistic sensitivity analysis, cost effectiveness plane, societal perspective. The solid line from the origin represents the cost-effectiveness threshold in Japan ¥5 million yen and each point represents the ICER results from each of the simulations in the PSA.

Statistics Bureau, Portal Site of Official Statistics of Japan: Subgroup Index for Japan 2011. 2013. Tokyo, Japan: Ministry of Internal Affairs and Communications

 Google Scholar

Kawai K, O'Brien MA, Goveia MG, et al. Burden of rotavirus gastroenteritis and distribution of rotavirus strains in Asia: a systematic review. Vaccine 2012;30:1244-54

 PubMed Web of Science ®Google Scholar

Black RE, Cousens S, Johnson HL, et al. Global, regional, and national causes of child mortality in 2008: a systematic analysis. Lancet 2010;375:1969-87

 PubMed Web of Science ®Google Scholar

Nakagomi T, Nakagomi O, Takahashi Y, et al. Incidence and burden of rotavirus gastroenteritis in Japan, as estimated from a prospective sentinel hospital study. J Infect Dis 2005;192(1 Suppl):S106-10

 Google Scholar

Sato T, Nakagomi T, Nakagomi O. Cost-effectiveness analysis of a universal rotavirus immunization program in Japan. Jpn J Infect Dis 2011;64:277-83

 PubMed Web of Science ®Google Scholar

Yokoo M, Arisawa K, Nakagomi O. Estimation of annual incidence, age-specific incidence rate, and cumulative risk of rotavirus gastroenteritis among children in Japan. Jpn J Infect Dis 2004;57:166-71

 Google Scholar

Dennehy PH, Vesikari T, Matson DO, et al. Efficacy of the pentavalent rotavirus vaccine, RotaTeq(R) (RV5), between doses of a 3-dose series and with less than 3 doses (incomplete regimen). Hum Vaccin 2011;7:563-8

 PubMed Web of Science ®Google Scholar

Vesikari T, Matson DO, Dennehy P, et al. Safety and efficacy of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine. N Engl J Med 2006;354:23-33

 PubMed Web of Science ®Google Scholar

Boom JA, Tate JE, Sahni LC, et al. Effectiveness of pentavalent rotavirus vaccine in a large urban population in the United States. Pediatrics 2010;125:e199-207

 PubMed Web of Science ®Google Scholar

Kawamura N. Economic burden derived from rotavirus enteritis on families of pediatric patients [abstract] Kawamura N. 41st Annual Meeting of the Japanese Society for Pediatric Infectious Diseases 2009. Fukui, Japan

 Google Scholar

Van der Wielen M, Giaquinto C, Gothefors L, et al. Impact of community-acquired paediatric rotavirus gastroenteritis on family life: data from the REVEAL study. BMC Fam Pract 2010;11:22

 PubMed Web of Science ®Google Scholar

Mast TC, Chen PY, Lu KC, et al. Epidemiology and economic burden of rotavirus gastroenteritis in hospitals and paediatric clinics in Taiwan, 2005–2006. Vaccine 2010;28:3008-13

 PubMed Web of Science ®Google Scholar

Ministry of Health Labor and Welfare. Diagnosis Procedure Combination 2010 [in Japanese]. 2010. Tokyo, Japan: The Ministry of Health Labor and Welfare

 Google Scholar

Rotavirus and Vaccination. Nagoya, Japan: Nagoya City's official information site http://www.city.nagoya.jp/kenkofukushi/page/0000034344.html [in Japanese]. [Accessed on 26 Dec 2012]

 Google Scholar

Asada N. Nagoya city announced the 50% financial support for rotavirus vaccination from October. Chunichi Shimbun, 2012. Nagoya, Japan

 Google Scholar

Brisson M, Senecal M, Drolet M, et al. Health-related quality of life lost to rotavirus-associated gastroenteritis in children and their parents: a Canadian prospective study. Pediatr Infect Dis J 2010;29:73-5

 PubMed Web of Science ®Google Scholar

Briggs A, Claxton K, Sculpher M. Decision modelling for health economic evaluation. USA: Oxford University Press, 2008

 Google Scholar