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Cost-utility Analysis of Rotavirus Vaccines Including the Latest Evidence and Data as of June 2020 in Japan

Kurosawa, Teruyoshi MD*; Watanabe, Hiroshi MD, PhD*; Takahashi, Kenzo MD, MHS, PhD

Author Information
The Pediatric Infectious Disease Journal: February 2021 - Volume 40 - Issue 2 - p 162-168
doi: 10.1097/INF.0000000000002938

Abstract

Rotavirus (RV) is an important pathogen of acute gastroenteritis in children, with an estimated 610,000 deaths worldwide annually.1 Even in developed countries, RV vaccines are highly effective as the only countermeasure against the infection.2

Universal mass vaccination (UMV) programs for RV were first implemented by Brazil and the United States in 2006 and Finland in 2009.3,4 In Japan, a monovalent and a pentavalent RV vaccine were approved for production and marketing in 2011 and 2012, respectively; however, the UMV for RV will finally be implemented from October 2020. The fact that the vaccines are not always cost-effective can be cited as one of the reasons for this delay.5

In previous studies of health economic analyses in Japan,6–10 the vaccines were generally classified as “not cost-effective” from the healthcare payer perspective (HPP), but they were generally cost-effective from the societal perspective (SP). However, the items and values used in each study were heterogeneous, and a more accurate study is required. Clinically significant values that are rarely considered in the existing literature also need to be incorporated such as the effect of vaccine herd immunity on the community, intussusception as a vaccine side effect, and the occurrence of complications of RV, which may include convulsions with gastroenteritis, RV encephalopathy, nosocomial infections, and death. Moreover, in Japan, the “Research guideline for evaluating the cost-effectiveness of vaccination” (the Guideline)11 was presented in 2017. According to the Guideline, cost-utility analysis should be performed as much as possible, and standardization of productivity loss and discount rate and other factors should be considered.

In the present study, we conducted a cost-utility analysis of RV vaccines with the Guideline, including the latest evidence and data in Japan.

MATERIALS AND METHODS

Model

We adopted the simple decision-tree model proposed by Bakir et al12 (See Figure, Supplemental Digital Content 1, http://links.lww.com/INF/E158). Based on the annual births in Japan,13 we assumed a cohort of 864,000 children in a 5-year-period time horizon. We incorporated Japanese epidemiologic data. The discount rate in the base cases was set at 2% for both the cost and effect, according to the Guideline.11

We compared the cases with and without UMV and calculated the incremental cost-effectiveness ratio (ICER) from the HPP and SP. As base cases, scenario 1 included items based on existing studies, and scenario 2 included the additional items described above.

The details of the rationale for each item are described elsewhere (see Text, Supplemental Digital Content 2, http://links.lww.com/INF/E159) and are summarized below.

Disease Burden

Scenario 1 examined the age-related incidence of RV gastroenteritis (RVGE), divided into ambulatory visits and hospitalizations (see Table, Supplemental Digital Content 3, http://links.lww.com/INF/E160).

Scenario 2 examined hospitalization for RV infection separately for RVGE, convulsions, encephalopathy, and nosocomial infections. Deaths and sequelae (paralysis, mental retardation, etc.) were considered as prognoses of encephalopathy. Cases of death due to causes other than encephalopathy were also included (see Text 1-1 to 1-8, Supplemental Digital Content 2, http://links.lww.com/INF/E159).

We estimated that 6 days would be required for a patient to recover from the symptoms of RVGE and that the patient would be hospitalized for 5 of these days (see Text 3-1, 2, Supplemental Digital Content 2, http://links.lww.com/INF/E159). In the case of nosocomial infection, the additional hospital stay was set to 3 days14 (see Text 3-3, Supplemental Digital Content 2, http://links.lww.com/INF/E159). RV encephalopathy is often “clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS),” so the hospital stay was set to 10 days (see Text 3-4, Supplemental Digital Content 2, http://links.lww.com/INF/E159).

For the utility scores of RVGE, UK figures15 have been used in other studies in Japan,6,8 and we also used these (see Text 2-1,2, Supplemental Digital Content 2, http://links.lww.com/INF/E159). The scores for convulsion, encephalopathy, and nosocomial were the same as those for RVGE. The utility score for sequelae of encephalopathy was included from the year after the illness (see Text 2-3, Supplemental Digital Content 2, http://links.lww.com/INF/E159).

Vaccines

Although the number of vaccinations differs between 2 and 3, monovalent and pentavalent vaccines do not account for additional indirect costs because of concomitant vaccination with other UMVs (see Table, Supplemental Digital Content 3, http://links.lww.com/INF/E160). In fact, both are used in Japan, so their effectiveness, safety, and cost were considered equivalent and were not distinguished in other studies.6,8–10 The vaccination coverage rate was 94% in the base cases, according to the coverage of the National Immunization Program for other UMVs (H Sakiyama, personal communication) (see Text 4-1, Supplemental Digital Content 2, http://links.lww.com/INF/E159).

In scenario 2, the vaccine effectiveness rate included herd immunity. In Japan, based on real-world data, relational expressions of coverage rate and effectiveness including herd immunity have been proposed,16 and they can be used in a static model (see Text, 4-2,3, Supplemental Digital Content 2, http://links.lww.com/INF/E159). There are no data for the rates of reduction in nosocomial infections, convulsions, encephalopathy, and death due to RV; thus, we assumed that in the base case, the rates would be equal to those for severe RV infection. According to a nationwide survey,17,18 we also considered that RV encephalopathy would not decrease in the sensitivity analyses (see Text 1-4, Supplemental Digital Content 2, http://links.lww.com/INF/E159). In some studies, the vaccine efficacy did not decrease over time,19,20 and waning was not considered in the present study.

In scenario 2, the burden of intussusception (as an adverse effect) was calculated. However, another report found that the incidence of intussusception did not increase,21 and sensitivity analyses also examined populations in which the incidence did not exceed the natural rate (see Text 1-9, Supplemental Digital Content 2, http://links.lww.com/INF/E159).

Direct Costs

We included the costs associated with ambulatory visits and hospitalization for the treatment of RVGE (see Table, Supplemental Digital Content 3, http://links.lww.com/INF/E160). Scenario 2 also includes costs for other complications. Only death without encephalopathy was not included because it was considered to be sudden death (see Text 5-1 to 5-7, Supplemental Digital Content 2, http://links.lww.com/INF/E159).

The cost of the vaccination was set at Japanese Yen (JPY) 30,000 (USD 278; as of March 29, 2020 [the same exchange rate is used throughout this study]) per course in the base case, which is the sum of the drug fee and inoculation technique fee.

Indirect Costs

Family labor losses were accounted for from the SP (see Table, Supplemental Digital Content 3, http://links.lww.com/INF/E160). According to a previous study,8 the average hourly wage of a woman in Japan was JPY 1492 (USD 14).22 This calculation included a work loss of 8 hours per day for ambulatory visits and 2 hours per day during hospitalization. The reasons are as follows. First, currently in Japan, the role of caring for a child often falls on the mother. Second, when children are hospitalized, it is very common for Japanese mothers to stay with their children for several hours during hospitalization (see Text 5-8, Supplemental Digital Content 2, http://links.lww.com/INF/E159). Labor losses associated with sequelae of encephalopathy were not included. Vaccines are often administered concomitantly with other vaccines and are not associated with an additional indirect labor cost. In addition, we did not consider the parents’ quality-adjusted life year (QALY) or other factors from the SP.

Evaluation of Base Cases

Substituting the above figures into the model, we calculated the ICERs from the HPP and SP. In Japan, willingness-to-pay (WTP) is considered to be up to JPY 5 million (USD 46,296) per gain of 1 QALY,23 so we compared the ICER to the WTP in each scenario. In scenario 2, we calculated the break-even prices for vaccines with an ICER of JPY 5 million and of JPY 0.

Sensitivity Analyses

In scenario 2, a one-way sensitivity analysis was performed by changing each parameter, as shown in Table (Supplemental Digital Content 3, http://links.lww.com/INF/E160). A Tornado diagram was created, and parameters affecting the ICER were estimated. Next, a probabilistic sensitivity analysis was performed using the 10,000 times Monte Carlo method by changing each parameter, as shown in Table (Supplemental Digital Content 3, http://links.lww.com/INF/E160), and a scatterplot of the cost/QALY gained and an acceptability curve were created. Based on this, an acceptable probability equal to the WTP was calculated. Microsoft Excel 2019 was used for all of the analyses.

RESULTS

Base Cases

In scenario 1, from the HPP, the ICER was JPY 6,057,281 (USD 56,086), which surpassed the WTP, whereas from the SP, the vaccines were cost-saving (Table 1).

TABLE 1. - Results of the Base Cases
Scenario 1 Scenario 2 Scenario 2–1
No Vacc (Prop) Vacc (Prop) Difference (Prop) No Vacc (Prop) Vacc (Prop) Difference (Prop) Difference (Ratio)
Direct Cost(JPY)
 Ambulatory visits 8,861,618,252 (58%) 2,454,668,256 (9%) −6,406,949,996 (−52%) 8,797,880,706 (56%) 114,455,649 (0%) −8,683,425,057 (−88%) −2,276,475,061 (136%)
 RVGE hosp. 6,350,891,801 (42%) 628,738,288 (2%) −5,722,153,513 (−47%) 5,458,301,195 (35%) 838,618,426 (3%) −4,619,682,769 (−47%) 1,102,470,744 (81%)
 Convulsion hosp. 1,081,562,491 (7%) 166,172,258 (1%) −915,390,233 (−9%) −915,390,233
 Encephalopathy hosp. 7,612,276 (0%) 1,169,557 (0%) −6,442,719 (0%) −6,442,719
 Encephalopathy sequela 5,278,532 (0%) 810,999 (0%) −4,467,533 (0%) −4,467,533
 Nosocomial 273,696,520 (2%) 42,050,986 (0%) −231,645,535 (−2%) −231,645,535
 Vaccination 0 (0%) 24,364,800,000 (89%) 24,364,800,000 (199%) 0 (0%) 24,364,800,000 (95%) 24,364,800,000 (246%) 0 (100%)
 Intussusception 0 (0%) 6,497,280 (0%) 6,497,280 (0%) 6,497,280
 Subtotal 15,212,510,053 (100%) 27,448,206,544 (100%) 12,235,696,491 (100%) 15,624,331,721 (100%) 25,534,575,154 (100%) 9,910,243,433 (100%) −2,325,453,058 (81%)
Indirect Cost(JPY)
 Ambulatory visits 37,331,391,337 (98%) 10,340,795,400 (99%) −26,990,595,936 (98%) 37,062,883,802 (98%) 482,167,986 (80%) −36,580,715,816 (98%) −9,590,119,880 (136%)
 RVGE hosp. 768,286,262 (2%) 76,060,340 (1%) −692,225,922 (3%) 660,306,923 (2%) 101,450,164 (17%) −558,856,759 (2%) 133,369,163 (81%)
 Convulsion hosp. 107,979,339 (0%) 16,590,045 (3%) −91,389,294 (0%) −91,389,294
 Encephalopathy hosp. 709,845 (0%) 109,061 (0%) −600,784 (0%) −600,784
 Nosocomial 33,563,442 (0%) 5,156,718 (1%) −28,406,724 (0%) −28,406,724
 Intussusception 0 (0%) 581,637 (0%) 581,637 (0%) 581,637
 Subtotal 38,099,677,599 (100%) 10,416,855,740 (100%) −27,682,821,859 (100%) 37,865,443,351 (100%) 606,055,611 (100%) −37,259,387,740 (100%) −9,576,565,881 (135%)
Total Cost(JPY) 53,312,187,652 37,865,062,284 −15,447,125,368 53,489,775,072 26,140,630,765 −27,349,144,307 −11,902,018,939 (177%)
QALY
 Ambulatory visits −2388.4 (88%) −661.6 (95%) 1726.8 (86%) −2372.4 (86%) −30.9 (34%) 2341.6 (88%) 614.8 (136%)
 RVGE hosp. −325.4 (12%) −32.2 (5%) 293.2 (15%) −279.9 (10%) −43.0 (48%) 236.9 (9%) −56.4 (81%)
 Convulsion hosp. −45.6 (2%) −7.0 (8%) 38.6 (1%) 38.6
 Encephalopathy hosp. −0.5 (0%) −0.1 (0%) 0.4 (0%) 0.4
 Encephalopathy death −4.5 (0%) −0.7 (1%) 3.8 (0%) 3.8
 Encephalopathy sequela −9.6 (0%) −1.5 (2%) 8.1 (0%) 8.1
 Nosocomial −20.7 (1%) −3.2 (4%) 17.5 (1%) 17.5
 Death(without encephalopathy) −26.1 (1%) −4.0 (4%) 22.1 (1%) 22.1
 Intussusception 0.0 (0%) −0.1 (0%) −0.1 (0%) −0.1
 Total −2713.8 (100%) −693.8 (100%) 2020.0 (100%) −2759.1 (100%) −90.4 (100%) 2668.7 (100%) 648.7 (132%)
ICER (JPY/QALY)
 Healthcare payer 6,057,281 3,713,488 −2,343,794 (61%)
 Societal Dominant (−7,647,099) Dominant (−10,248,054) (−2,600,955) (134%)
Hosp. indicates hospitalization; ICER, incremental cost-effectiveness ratio; Prop, proportion to subtotal; QALY, quality-adjusted life-year; Ratio, ratio to Scenario 1; RVGE, rotavirus gastroenteritis.

In scenario 2, the ICER was JPY 3,713,488 (USD 34,384) from the HPP, which is lower than the WTP, and the vaccines were still cost-saving from the SP. The ICER from the HPP was improved in comparison to scenario 1. The item that contributed the most to the reduction in ICER in scenario 2 was the vaccine effectiveness rate for ambulatory visits. Without the vaccination, direct costs, indirect costs, and QALY reduction for ambulatory visits accounted for 56%, 98%, and 86% of all, respectively, and their drastic reduction with the herd immunity effect led to a decrease in the ICER. Among the new items in scenario 2, the effects of convulsions, encephalopathy, nosocomial infections, and death were individually small, but when combined, direct costs accounted for approximately 10% of the total, and the QALY accounted for a few percent. The effects of intussusception were small in terms of both cost and QALY.

From the HPP in scenario 2, the break-even prices of the vaccination were JPY 34,227 (USD 317) when the ICER is equal to the WTP, and JPY 17,798 (USD 165) for cost-saving, respectively.

Sensitivity Analyses in Scenario 2

In the one-way sensitivity analysis, a Tornado diagram was created from the HPP (Fig. 1). The parameters with wide ICER fluctuation were the utility score, vaccine effectiveness rate, direct cost for ambulatory visits, and vaccination cost. In particular, the ICERs exceeded the WTP at the upper limit of the utility score and the lower limit of the vaccine effectiveness rate for ambulatory visits. Fig. 2 shows a scatterplot created based on a probabilistic sensitivity analysis from the HPP, and Fig. 3 shows the acceptability curve. The acceptable probability equal to the WTP was 54.8%. Almost the same results were obtained from the SP, and all ICERs were dominant in cost-saving (data not shown).

FIGURE 1.
FIGURE 1.:
Tornado diagram of the one-way sensitivity analysis from the HPP in scenario 2. Ten parameters were selected in descending order of variation from the HPP. The straight line indicates the WTP of JPY 5 million. The ICERs exceeded the WTP of JPY 5 million at the upper limit of the utility score for ambulatory visits and the lower limit of the vaccine effectiveness rate for ambulatory visits. HPP indicates healthcare payer perspective; ICERs, incremental cost-effectiveness ratios; JPY, Japanese Yen; WTP, willingness-to-pay.
FIGURE 2.
FIGURE 2.:
Scatterplot of the probabilistic sensitivity analysis performed using the 10,000 times Monte Carlo method from the HPP in scenario 2. The horizontal axis is the incremental cost, and the vertical axis is the incremental QALY. The slope connecting each point to the origin is the ICER, and the larger the slope, the greater the cost-effectiveness. The straight line indicates the WTP of JPY 5 million. The points above this line indicate a cost-effective ICER. HPP indicates healthcare payer perspective; ICERs, incremental cost-effectiveness ratios; JPY, Japanese Yen; QALY, quality-adjusted life-year; WTP, willingness-to-pay.
FIGURE 3.
FIGURE 3.:
Acceptability curve of the probabilistic sensitivity analysis performed using the 10,000 times Monte Carlo method from the HPP in scenario 2. The horizontal axis is the ICER threshold per 1 QALY gained, and the vertical axis is the acceptable probability (the probability that the ICER will be below each threshold). The straight line indicates the WTP of JPY 5 million. The value at the intersection of this line and the acceptability curve was 54.8%, and thus, the probability that the ICER would be below the WTP was considered to be 54.8%. HPP indicates healthcare payer perspective; ICERs, incremental cost-effectiveness ratios; JPY, Japanese Yen; QALY, quality-adjusted life-year; WTP, willingness-to-pay.

DISCUSSION

We examined a cost-utility analysis of RV vaccines for Japanese children under 5 years of age. In scenario 1, the ICER exceeded the WTP from the HPP, whereas the vaccines were cost-saving from the SP. This is similar to the results of previous studies.6–8 The reasons are that Bakir et al’s model12 was valid, and the items incorporated in scenario 1 were the same as those in the existing research.

Scenario 2 incorporated clinically significant factors. The ICER became lower than the WTP from the HPP, and the vaccines were still cost-saving from the SP. The vaccine effectiveness rate for ambulatory visits contributed most to the improvement in the ICER over scenario 1. The decrease in the number of patients above the efficacy rate described in premarketing randomized controlled trials24,25 has been shown to be due to herd immunity, particularly in ambulatory visits.16 The number and cost of ambulatory visits accounted for the majority of the total, and the reduction due to herd immunity had a strong effect.

The occurrence of intussusception, which was a problem with the previous generation of the vaccine, is considered to be small with the current vaccines; however, the incidence of intussusception has been reported to temporarily increase immediately after the first vaccination, and several studies of health economic analyses have examined this issue.26–32 As intussusception is more common in Japan than in other countries,33 the actual number of excess cases due to a vaccine side effect may show a greater increase. However, the effects of intussusception were found to be small. This result is consistent with a risk-benefit analysis that found that 480 RVGE hospitalizations were averted, whereas 1 case of intussusception occurred as a side effect.34

In scenario 2, the break-even price from the HPP tended to be higher, although simple comparisons cannot be made because the conditions differed from previous studies.6,9 According to the one-way sensitivity analysis of scenario 2, the uncertainty of the utility score, vaccine effectiveness, direct cost for ambulatory visits, and vaccination cost were considered to be high. This is similar to findings reported in previous studies.6–8

In their probabilistic sensitivity analysis, Hoshi et al8 reported an acceptable probability of 9.9% for a vaccine cost of JPY 30,000 and the WTP of JPY 5 million, so an improvement was seen in this study. We found that the decrease in ICER, higher break-even price, and decrease in acceptance probability in comparison to the existing literature were all attributed to the decrease in the number of patients due to the effect of herd immunity, and intussusceptions as a side effect did not significantly affect them.

Our study strengths are as follows. First, we performed a more accurate analysis in comparison to the previous studies6–10 (See Table, Supplemental Digital Content 4, http://links.lww.com/INF/E161). The reasons for the higher accuracy are that first, we compiled a large amount of data over the years from vaccine introduction, and second, we added important new items in scenario 2. In particular, the herd immunity effects were implemented for the first time in Japan. Although some studies on health economic analyses in other countries included them,26–31,35,36 previous studies in Japan6–10 did not. The inferred herd immunity effects of this study can be used in a static model,16 and they had a great impact on the results.

The present study has some limitations. First, we used the simple decision-tree model of Bakir et al.12 By using the simplified model, 10,000 Monte Carlo methods could be performed with the variation of nearly 40 parameters. Although it may be less accurate than that in Markov models with short cycle intervals, Bakir et al noted that this simple decision-tree model is comparable to more complex models. In fact, the value of the ICER in scenario 1 is close to that of the Markov model by Hoshi et al.8 Thus, we believe that this model is valid, and it is assumed that the error is small, even in scenario 2. Second, there is parameter uncertainty. As noted in Supplemental Digital Content 2; http://links.lww.com/INF/E159, figures were taken and summarized from the Japanese data as much as possible. However, the size of the original datasets was not always large and the quality varied. In particular, in scenario 2, uncertainty increased due to the introduction of new parameters. This uncertainty was evaluated by performing sensitivity analyses, and it was found that intussusception, encephalopathy, and death did not have a significant effect, indicating that robustness was increased. As pointed out in previous studies,6–8 the uncertainty needs to be studied in the future because the utility score and the effectiveness of vaccines for ambulatory visits vary widely in a one-way sensitivity analysis. Third, the validity of parameters needs to be examined. The 5 days of hospitalization for RVGE used in this study is not necessarily long compared with the 6.3–15.0 days used in Europe before vaccine introduction.37 Furthermore, the Japanese version of the diagnosis procedure combination/per-diem payment system data in 2017 shows almost the same lengths of time (see Text 3-2, Supplemental Digital Content 2, http://links.lww.com/INF/E159). The 10-day period used for encephalopathy hospitalization was based on expert opinion, but no data to confirm this is available. MERS, which accounts for most cases of RV encephalopathy, is mild, and patient recovers within 14 days, but RV encephalopathy also includes other disease types requiring longer hospitalization. Also, the ICER did not change so much in the one-way sensitivity analysis, probably because there are not many patients with RV encephalopathy. Nosocomial infections may be reduced by standard precautions taken by medical staff, but they never drop to zero, and this item is also included in health economic analyses of other countries.27,28 Nosocomial infections before vaccine introduction in Europe and the United States were reported to account for 14.3%–50.8% of all RV hospitalizations in general pediatric wards,38 and the value in this study is considered to be more conservative. As there is no clear standard for calculating indirect costs, we followed the methods of a previous study.8 When wages are averaged between men and women, and parents accompany their children during hospitalization, the ICER from the SP will be lower, so the robustness of this study will be guaranteed. The time horizon in this study was set to 5 years, which has been adopted by many previous studies in Japan and other countries.39 RV infections are more common in infants, so a value of 5 years is considered reasonable; however, a longer time horizon would further reduce the ICER due to the consequences of sequelae and death. Following a previous study,8 the WTP in this study was set at JPY 5 million. However, Ohkusa and Sugawara calculated the WTP to be JPY 6 million (USD 55,556),40 and another previous study6 adopted this value. If the WTP were JPY 6 million, the acceptable probability of scenario 2 would increase to 66.3%. Fourth, some of the items considered in previous studies were not considered in this study. For example, it is known that once infected with RV, a child becomes difficult to reinfect, and even if reinfected, the child’s disease severity is lower.41,42 Others have pointed out the waning efficacy of vaccines. In addition, reduced efficacy rates have been reported due to incomplete vaccination.43 However, these are expected to be included in the real-world effectiveness rate16 and are not completely ignored in this study. Moreover, only the reduction in the number of patients was considered, and the reduction in severity due to vaccination was not taken into account. A recent study reported that a vaccinated group treated on an ambulatory visit basis showed milder disease severity,44 whereas another showed that the disease severity of a vaccinated group was not milder when treated on ambulatory visits or by hospitalization,45 and the evaluation has not been determined. If the disease severity of vaccinated patients becomes milder, the vaccination will be more cost-effective. Furthermore, indirect costs of vaccination are not considered in this study. Most of the time, RV vaccines are administered concomitantly with other vaccines, but if they are administered separately, the ICER from the SP increases. Conversely, the ICER will decrease if parents’ QALY, economic losses from death, and indirect costs due to sequelae are considered. However, we did not include these factors, considering that all values would either increase robustness or could be negligible.

In conclusion, the ICERs were lower than those reported in previous studies, and we believe that the herd immunity effect, especially for ambulatory visits, was the factor that contributed most to this decrease. It is important to continue to monitor RV infection trends and to assess cost-effectiveness after UMV is implemented in October 2020.

ACKNOWLEDGMENTS

We thank Drs. Masakazu Mimaki and Ai Hoshino for their valuable feedback on MERS, and Dr. Hiroshi Sakiyama for providing vaccine coverage data.

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Keywords:

rotavirus vaccine; cost-utility; cost-benefit; analysis; herd immunity

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