A cost-utility analysis using Ontario health administrative data was performed. The study was informed by a companion ecological study comparing physician visits, emergency department visits, hospitalizations, and deaths between 1997 and 2004 in Ontario and nine other Canadian provinces offering targeted immunization programs. The relative change estimates from pre-2000 to post-2000 as observed in other provinces were applied to pre-UIIP Ontario event rates to calculate the expected number of events had Ontario continued to offer targeted immunization. Main outcome measures were quality-adjusted life years (QALYs), costs in 2006 Canadian dollars, and incremental cost-utility ratios (incremental cost per QALY gained). Program and other costs were drawn from Ontario sources. Utility weights were obtained from the literature. The incremental cost of the program per QALY gained was calculated from the health care payer perspective. Ontario's UIIP costs approximately twice as much as a targeted program but reduces influenza cases by 61% and mortality by 28%, saving an estimated 1,134 QALYs per season overall. Reducing influenza cases decreases health care services cost by 52%. Most cost savings can be attributed to hospitalizations avoided. The incremental cost-effectiveness ratio is Can$10,797/QALY gained. Results are most sensitive to immunization cost and number of deaths averted.

In July 2000, the province of Ontario, Canada, initiated a universal influenza immunization program (UIIP) to provide free seasonal influenza vaccines for the entire population. This is the first large-scale program of its kind worldwide. The objective of this study was to conduct an economic appraisal of Ontario's UIIP compared to a targeted influenza immunization program (TIIP).

Funding: This study was supported by an operating grant from the University of Toronto Research Program, which provided fellowship support for BA, and by an operating grant from the Public Health Agency of Canada. JCK was supported by a Canadian Institutes of Health Research Fellowship Award at the time of the study and is currently supported by an Ontario Ministry of Health and Long Term Care (MOHLTC) Career Scientist Award and a University of Toronto Department of Family and Community Medicine Research Scholar Award. This work was made possible with the support of the Institute for Clinical Evaluative Sciences (ICES), which is funded in part by the Ontario MOHLTC. The opinions, results and conclusions reported in this paper are those of the authors and are independent from the funding sources. No endorsement by ICES or the Ontario MOHLTC is intended or should be inferred. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript. The researchers are independent from the funders.

This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.

In Canada, an intervention is considered cost-effective from the point of view of a health care purchaser if it costs less than Canadian $50,000 to gain one QALY. These findings indicate, therefore, that for Ontario the introduction of the UIIP is economically attractive. Indeed, the researchers calculate that even if the costs of the UIIP were to double, the additional cost of saving one QALY by introducing universal immunization would remain below $50,000. Other “sensitivity” analyses undertaken by the researchers also indicate that universal immunization is likely to be effective and cost-effective in Ontario if other key assumptions and/or data included in the calculations are varied within reasonable limits. Given these findings, the researchers suggest that a UIIP might be an appealing intervention in other Canadian provinces and in other high-income countries where influenza transmission and health-care costs are broadly similar to those in Ontario.

The researchers used data on TIIP and UIIP vaccine uptake, physician visits, emergency department visits, hospitalizations for influenza, and deaths from influenza between 1997 and 2004 in Ontario and in nine Canadian states offering TIIPs, and Ontario cost data, in their “cost-utility” analysis. This type of analysis estimates the additional cost required to generate a year of perfect health (a quality-adjusted life-year or QALY) through the introduction of an intervention. QALYs are calculated by multiplying the time spent in a certain health state by a measure of the quality of that health state. The researchers report that the cost of Ontario's UIIP was about twice as much as the cost of a TIIP for the province. However, the introduction of the UIIP reduced the number of influenza cases by nearly two-thirds and reduced deaths from influenza by more than a quarter compared with what would have been expected had the province continued to offer a TIIP, an overall saving of 1,134 QALYs. Furthermore, the reduction in influenza cases halved influenza-related health care costs, mainly because of reductions in hospitalization. Overall, this means that the additional cost to Ontario of saving one QALY through the introduction of the UIIP was Can$10,797, an “incremental cost-effectiveness ratio” of $10,797 per QALY gained.

Some experts argue, however, that universal vaccination might provide populations with better protection from influenza. In 2000, the province of Ontario in Canada decided, therefore, to introduce a universal influenza immunization program (UIIP) to provide free influenza vaccination to everyone older than 6 months, the first large program of this kind in the world. A study published in 2008 showed that, following the introduction of the UIIP, vaccination rates in Ontario increased more than in other Canadian provinces. In addition, deaths from influenza and influenza-related use of health care facilities decreased more in Ontario than in provinces that continued to offer a TIIP. But is universal influenza vaccination good value for money? In this study, the researchers evaluate the cost-effectiveness of the Ontario UIIP by comparing the health outcomes and costs associated with its introduction with the health outcomes and costs associated with a hypothetical continuation of targeted influenza immunization.

Annual outbreaks (epidemics) of influenza—a viral disease of the nose, throat, and airways—make millions of people ill and kill about 500,000 individuals every year. In doing so, they impose a considerable economic burden on society in terms of health care costs and lost productivity. Influenza epidemics occur because small but frequent changes in the viral proteins to which the immune system responds mean that an immune response produced one year by exposure to an influenza virus provides only partial protection against influenza the next year. Annual immunization with a vaccine that contains killed influenza viruses of the major circulating strains can boost this natural immunity and greatly reduce a person's chances of catching influenza. Consequently, many countries run seasonal influenza vaccine programs. These programs usually target people at high risk of complications from influenza and individuals likely to come into close contact with them, and people who provide essential community services. So, for example, in most Canadian provinces, targeted influenza immunization programs (TIIPs) offer free influenza vaccinations to people aged 65 years or older, to people with chronic medical conditions, and to health care workers.

The cost-effectiveness of universal vaccination has not been evaluated, despite the investment of substantial financial resources. The objective of this study was to conduct an economic appraisal of Ontario's UIIP.

In 2000, the province of Ontario, Canada, initiated a universal influenza immunization program (UIIP) [12] to provide free influenza vaccines for the entire population (6 mo of age or older). Introduction of this program was associated with greater overall increases in influenza vaccination rates, particularly in children and working-age adults, and greater reductions in influenza-associated mortality and health care use in Ontario compared to other provinces that maintained targeted programs [13] , [14] .

In most jurisdictions, seasonal prophylaxis with vaccines is currently recommended for people at high risk of complications, those capable of transmitting influenza to individuals at high risk of complications, and those who provide essential community services [8] . Nevertheless, vaccine coverage rates among high-risk groups in Canada have been low in the past, substantially lower than the target coverage rate (70%) set by a national consensus conference on influenza in 1993 [9] . In response to these findings, most provinces and territories in Canada offer free influenza vaccinations for those 65 y or older, those with chronic medical conditions, and health care workers (Targeted Influenza Immunization Program, TIIP) [10] . The age-based recommendations in the United States are more broad, including individuals 50 y or older and children aged 6 mo to 18 y [11] .

Seasonal prophylaxis with vaccines is the cornerstone of influenza management. Influenza vaccines are generally safe and effective. They reduce serologically confirmed influenza cases by 73% in healthy adults [2] and 58% in the elderly [3] . Influenza vaccination in young children decreases the incidence of influenza infection [4] , acute otitis media [5] , [6] , and daycare absenteeism [7] .

Methods

An economic evaluation was performed to estimate health outcomes and costs related to universal vaccination compared to the hypothetical continuation of a targeted program for the entire population of Ontario (12.16 million).

Data All the input data are age specific (Tables S1 and S2) and used as such in the calculations. The seven age groups are 4 y and under, 5–19 y, 20–49 y, 50–64 y, 65–74 y, 75–84 y, and 85 y and older. Most results are aggregated and reported for the total program; supplementary information is available by age group (Table S3).

Effectiveness of UIIP This economic evaluation was informed by an earlier epidemiological study that compared outcomes in Ontario before and after universal immunization, using other provinces as controls [13]. Introduction of Ontario's UIIP was associated with greater overall increases in influenza vaccination rates in Ontario (from 18% in 1996 to 42% in 2005) compared to other provinces (from 13% to 28%). Therefore, there was a 9-percentage-point incremental increase in Ontario, and the relative increases were most evident among those under 65 y. A different pattern was observed among the elderly; for those aged 75 y or older, there were greater relative increases among other provinces compared to Ontario, although Ontario still maintained higher rates at all times. The impact of Ontario's UIIP on influenza-associated mortality, hospitalizations, and visits to emergency departments (EDs) and doctors' offices was estimated using data from 1997 to 2004 (3 y before and 4 y after UIIP implementation). To estimate influenza-associated outcomes, we used multivariate regression models to predict events with influenza viral activity in the model, and we subsequently removed the influenza terms (i.e., viral surveillance data) from the model to generate a baseline function that represented the hypothetical absence of influenza. To calculate influenza-associated events, we subtracted the expected baseline events from observed events during periods of influenza activity. The models controlled for age, sex, province, influenza surveillance data, and temporal trends. Influenza-associated event rates in the overall population decreased 40%–60% more in Ontario than in other provinces for all study outcomes. The relative reductions were particularly prominent among age groups younger than 65, consistent with the changes in vaccine uptake. However, despite greater increases in vaccination rates among the elderly in other provinces compared to Ontario, the reductions in influenza-associated events among the elderly were either less pronounced or the same in Ontario compared to other provinces. The robustness of these findings was confirmed by numerous sensitivity analyses [13]. For a more detailed description of the regression model and results, see Text S1 and Table S6. Side effects due to influenza vaccine were not included as they are usually mild. While there is a small risk of hospitalization because of Guillain-Barré syndrome (GBS), a population-based study found no statistically significant increase in hospital admissions because of GBS after introduction of UIIP [15].

Resource Use: Physician Services and Hospitalizations For the economic evaluation, the mean number of events per season post-UIIP implementation as observed in Ontario was compared with the expected number of events under hypothetical continuation of TIIP (Table 1; more detailed information can be found in Tables S1 and S2). To calculate the expected number of events under hypothetical continuation of TIIP for Ontario, the relative change of mean number of events pre-2000 (1997/1998 to 1999/2000) to post-2000 (2000/2001 to 2003/2004) observed in other Canadian provinces was applied to the pre-UIIP event rates in Ontario. This assumes that in Ontario vaccination coverage rates would have increased and influenza-related events decreased by the same relative magnitude as in other provinces after 2000. PPT PowerPoint slide

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larger image TIFF original image Download: Table 1. Mean annual influenza-related event rates and relative rates comparing post-UIIP to pre-UIIP event rates. https://doi.org/10.1371/journal.pmed.1000256.t001 All data were obtained for seven influenza seasons covering the years from 1997 to 2004 [13]. Physician services data were extracted from provincial datasets for Ontario (Ontario Health Insurance Plan, OHIP) and three other Canadian provinces (Quebec's Physician Claims Dataset, Alberta's Health Care Insurance Plan Dataset, and Manitoba's Medical Claims Dataset). Hospitalization data were obtained from Statistics Canada's Hospital Morbidity Database, a national hospital discharge dataset. Influenza-related events were identified using ICD 9/10 (International Statistical Classification of Diseases and Related Health Problems) service codes associated with pneumonia or influenza. These are complete datasets, covering all residents of the respective provinces. Influenza-associated events decreased more in Ontario than other provinces: 75% versus 56% for hospitalizations, 69% versus 31% for ED use, and 79% versus 48% for doctors' office visits [13].

Quality-Adjusted Life Years (QALYs) Lost from Influenza The administrative data used to estimate resource use do not yield a count of influenza cases. The number of cases of influenza requiring health care was estimated using the number of office visits and ED visits and excluding repeat visits by the same patient for the same diagnosis within a 21-d window following an initial visit. According to this approximation, 90% of all influenza-associated office visits, 85% of all influenza-associated ED visits, and all influenza-associated hospitalizations were deemed to be discrete new cases of influenza. The remainder of visits were considered to be repeat visits. Multiple visits across settings by the same patient were not removed since the number of those was expected to be small (for example, only 0.07% of all health care contacts were hospitalizations, some of which may have had an office and/or ED visit before being hospitalized). It was assumed that patients who die due to influenza had at least one health care contact before death. Therefore, these were also not separately counted as cases as they were presumed to have been accounted for. Quality weights as reported by Turner [16] were used to estimate QALYs lost per case of influenza due to morbidity. In this recent assessment by the National Institute for Health and Clinical Excellence (NICE) of antiviral treatment of influenza, utilities for influenza were estimated from patient health state valuations reported daily for 21 d in oseltamivir clinical trials. Utilities were generated by recalibrating the Likert scores as obtained in the clinical trials to mean visual analogue scale scores, which were then transformed to time trade-off scores. Quality of life data were available for “otherwise healthy adults,” “adults with co-morbidities,” and the “elderly.” In the absence of utility data for children, it was assumed that children have similar utility weights as “otherwise healthy adults” as both groups are similar in other health outcome measures, such as time to return to normal activity [17]. The utility weight for adults with co-morbidities as obtained in the clinical trials was applied to the 18.8% of the Ontario population aged 12 to 64 y deemed high risk because of chronic conditions [18]. Patients in the trials were recruited from Europe and North America. We assume that the clinical trial population is sufficiently similar to the Ontario population (high income Western countries with similar life expectancy and population health status) so that we can apply the utility estimates to the population under consideration here. The QALY gain per influenza case prevented (Table 2) was calculated by multiplying the duration of the symptomatic period by the utility decrement associated with influenza-related illness. PPT PowerPoint slide

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larger image TIFF original image Download: Table 2. Key data used in the economic evaluation. https://doi.org/10.1371/journal.pmed.1000256.t002 To calculate QALYs lost due to premature death (Table 2), we estimated influenza-associated deaths using mortality data from Statistics Canada's Mortality Database [13]. We considered deaths due to all respiratory and circulatory conditions for seven influenza seasons covering the years from 1997 to 2004. After UIIP introduction, influenza-associated mortality decreased 77% in Ontario compared to 46% in other provinces [13]. The average life expectancy was estimated by age [19] and adjusted for quality of life, using utility scores from a community-dwelling population, ranging from 0.88 to 0.94 depending on age [20]. Quality-adjusted life expectancy was discounted at 3% per year in the base case analysis [21].

Unit Costs: UIIP Program, Physician Services, and Hospitalizations All costs were obtained from Ontario sources and are expressed in 2006 Canadian dollars. Cost data are summarized in Table 2. The total program cost for the universal program was $40 million per year (approximately $3.96 per dose and $7.55 in total per dose distributed) for each year since introducing the program (Nancy Peroff-Johnston, Ministry of Health and Long-Term Care [MOHLTC], personal communication, May 11, 2007). This included the cost of the vaccine, health care provider reimbursement for vaccination, communications strategies, and direct operating expenditures for the MOHLTC including staffing. Approximately 50% of the total budget was spent on the vaccine and the remaining 50% on all other cost items. To calculate the expected targeted program (TIIP) cost if universal immunization (UIIP) had not been implemented, the relative change in vaccine coverage (pre-2000 versus post-2000) observed in other provinces was applied to Ontario's pre-2000 vaccine coverage rate. Vaccine coverage rates for the population 12 y or older more than doubled (18% to 42%) in Ontario and other provinces (13% to 28%) between 1996/1997 and 2005. The Ontario pre-2000 TIIP program cost (Nancy Peroff-Johnston, MOHLTC, personal communication, May 11, 2007) per person vaccinated was used, inflated to 2006, and applied to the population who would have been covered under a targeted program [22]. This assumes that the average cost per person (including vaccine, vaccine delivery, and other cost to the Ministry) remains the same but is applied to a larger number of persons receiving influenza immunization. For an expected TIIP coverage rate of 40%, the total program cost for targeted immunization was expected to be $20 million if TIIP had been continued. Unit costs for physician services (office visits, ED visits, and in-hospital services) were obtained from the OHIP dataset. A location code in the dataset indicates whether the services were provided in the physician office, ED, or hospital. Costs reflect the fee paid by condition type (pneumonia and influenza). Mean fees paid ($35 per office visit, $54 per ED visit) were used in the base case analysis; 95% CI defined the lower and upper limit for deterministic sensitivity analysis. For probabilistic analysis the primary data were sampled. An additional $166 per ED visit was added for non-physician costs to calculate total cost per ED visit [23]. Hospitalization costs were costed using the resource intensity weight (RIW) approach [24],[25]. The RIW is the ratio of the cost of a case in a Case Mix Group (CMG) to the average cost of all cases. The mean RIWs for pneumonia- or influenza-related hospitalizations were extracted from the acute care Discharge Abstract Database (DAD). The provincial cost per weighted case of $4,732 was applied to the mean RIW of influenza-associated hospitalizations of 1.33 [23]. Mean physician charges for hospital inpatient services for pneumonia or influenza (obtained from the OHIP database using location code) were added. On average, there were 1.65 claims for physician services per hospitalization at a cost of $66.41 each. The average length of stay for pneumonia and influenza is 6 d [26]. The total mean cost of a pneumonia- and influenza-related episode of hospitalization was therefore $6,418.