Economic Evaluation of 5-Grass Pollen Tablets Versus Placebo in the Treatment of Allergic Rhinitis in Adults
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Allergen immunotherapy (AIT) is aimed at modifying the immune response to a causative allergen, thereby reducing clinical symptoms and symptomatic medication intake and improving quality of life. Long-term AIT research has led to the development of 5-grass pollen tablets, currently indicated for the treatment of grass pollen-induced allergic rhinitis (AR).
A post-hoc analysis was conducted using the Average Adjusted Symptom Score (AAdSS) to compare the effect of treatment of AR with 5-grass pollen tablets versus placebo treatment. Using the results of the VO34.04 and VO53.06 trials and economic data, cost-effectiveness analysis of 5-grass pollen tablet treatment was performed from the Italian third-party payer perspective with cost data derived from a study of 2008 updated to 2011. Also a societal perspective was considered by using the costs related to the losses of productivity by following the human capital approach. Using the results of the analysis, the estimated receiver-operating characteristic curve was plotted to evaluate medication effectiveness in terms of quality-adjusted life years (QALYs) and a decision tree constructed to model the possible outcomes and costs for adults and paediatric patients with a low, medium, and high AAdSS. Finally, probabilistic sensitivity analysis was conducted to test the robustness of the results as well as their consistency at an assumed cost-effectiveness threshold of € 30,000/QALY.
The results indicate that compared to the placebo, the 5-grass pollen tablet treatment provides a benefit of 0.127 QALYs in medium AAdSS patients and of 0.143 QALYs in high AAdSS patients. The 5-grass pollen tablet treatment was found to cost € 1,024/QALY for patients with a medium AAdSS and € 1,035/QALY for patients with a high AAdSS. Of all the simulations performed in the probabilistic sensitivity analysis, 99 % indicated that the incremental cost-effectiveness ratio of the 5-grass pollen tablet treatment was below the threshold of € 30,000/QALY in patients with medium and high AAdSS, whereas it was found to be dominated in 67 % of simulations related to patients with low AAdSS.
The 5-grass pollen tablet is a cost-effective treatment for adult AR patients with a medium or high AAdSS. This finding should be carefully considered when deciding the management strategy for these patients.
Allergic rhinitis (AR) is a significant health problem that the World Health Organization (WHO) estimates affects approximately 20 % of the world’s adult population . The severity of AR may vary considerably, depending on both individual and environmental factors. In severe cases, treatment of AR requires a high consumption of pharmaceutical agents, such as antihistamines or corticosteroids, and can cause temporary inability to work or to carry out routine activities, leading to an overall temporary decline in quality of life (QoL). As indicated by the pharmacoeconomic literature on allergy to grass pollen, sublingual immunotherapy (SLIT) and subcutaneous immunotherapy (SCIT) have a more favourable cost-effectiveness profile than traditional treatments aimed only at treating the symptoms of allergy (rhinitis and asthma) in both adults and children [2, 3, 4, 5, 6, 7, 8, 9, 10]. Recent studies that have directly compared the costs of SCIT and SLIT have also indicated that treatment with the latter is more cost effective because of the cost reduction in terms of medical intervention needed for SCIT [9, 10].
In Italy, a multicentre study was conducted in 2006 to collect cost data for sublingual treatment with the grass pollen extract Staloral . Comparison of these data with the data regarding the cost of traditional treatment provided to symptomatic patients showed that although the average annual cost of SLIT was greater (€ 311 vs. € 180), the use of SLIT led to a decrease in the amount expended on symptomatic drugs of between 22 % (in cases of rhinitis) and 34 % (in cases of rhinitis and asthma) . As additional efficacy data [12, 13] indicate that treatment with the newly available 5-grass pollen tablets provides further clinical benefit, investigation of whether this benefit represents not only a clinical but also a pharmacoeconomic improvement would be very useful.
2.1 Structure of the Model
The model was populated with effectiveness and cost indicators, with the latter reflecting the Italian National Health Service (SSN—Servizio Sanitario Nazionale) perspective. To consider the results from a societal perspective in terms of the impact of AR on QoL and the performance of daily activities, including work tasks, productivity losses in terms of lost work days were evaluated using the human capital approach .
2.3 Effectiveness Estimate
The ΔQoL indicator was used to adjust the 4-year time horizon of the model, thus obtaining incremental quality-adjusted life years (QALYs) produced by a 5-grass pollen tablet compared with placebo.
2.4 Cost Estimate
We used the results of the previous SIMAP study on Staloral , which was published in 2008, to estimate the cost parameters of AR in terms of allergy testing, spirometry, specialist medical examinations, intraocular drugs, corticosteroids drugs, and working days lost. These costs were assumed to be representative of the placebo groups of patients resulting from the VO34.04 and VO53.06 trials and were assigned prices and tariffs in accordance with the values reported in the outpatient specialist service list (year 2006), the Italian pharmaceutical formulary, and figures obtained from Italian National Institute of Statistics (ISTAT) employment market surveys in 2011 [16, 17, 18].
Finally, the 5-grass pollen tablet was priced at € 3 per tablet, under the assumption that the patients in the 5-grass pollen tablet treatment group would consume 150 tablets per year for 3 years. The expected treatment compliance rate of AR patients was assumed 70 % at baseline .
2.5 Discount Rate
The model covers a period of 4 years, which is consistent with prior studies conducted to evaluate the effectiveness of sublingual treatments, in which 3 years of administration were followed by a year of follow-up. The discount rate applied to the cost and effectiveness was 3 % per year.
2.6 Presentation of Results
The results are presented in the form of the incremental cost-effectiveness ratio (ICER), which considers the cost per ΔQoL obtained with 5-grass pollen tablet treatment in comparison with placebo treatment and is characterised by the AAdSS.
2.7 Sensitivity Analysis
In order to test the statistical consistency of the results, probabilistic sensitivity analysis was conducted . On the basis of the clinical data obtained from the VO34.04 and VO53.06 studies, we considered the standard deviations, and we estimated the parameters (alpha and beta) of a gamma random distribution to simulate the variability of the AAdSS and of the incremental costs. Other parameters whose variability was investigated were: compliance, discount rate, incremental QoL, and probability of the AAdSS to overcome the discrimination threshold (1.45) resulting from the ROC curve. The sensitivity analysis was conducted from the societal perspective.
5-Grass pollen tablets AAdSS score [mean (SD)]
Placebo AAdSS score [mean (SD)]
No. of subjects treated by 5-grass pollen tablet
No. of subjects treated by placebo
Incremental quality of life
Annual incremental costs or savings in patients with an Average Adjusted Symptom Score (AAdSS) greater than 1.45 after 5-grass pollen tablet treatment
Difference in cost compared to placebo (€)
Skin allergy testing
Test for IgE dosage
Sublingual treatment with 5-grass pollen tablets
Days off work
Table 2 shows the additional costs (or savings) obtained by providing 5-grass pollen tablet treatment to AR patients in a manner that led to an increase in their AAdSS of least 1.45 points, the threshold value that corresponds to an improvement in QoL. These findings reflect the results of the SIMAP study , whose values were modified and updated to reflect outpatient service tariffs, and the costs indicated in the pharmaceutical formulary and ISTAT market surveys in 2011. For AR patients with a low AAdSS, incremental cost values are observed, as there was no improvement in their QoL, and as the increase in their AAdSS remained below the threshold, the 5-grass pollen tablet treatment represents a cost (in terms of the cost of the drug, diagnostic testing, etc.) that provides no significant benefits. From a NHS perspective and including patients with an AAdSS below the threshold for whom there is no improvement in QoL and considering all symptoms, the 5-grass pollen tablet treatment represents an increased cost of € 208 for patients with a low AAdSS, € 130 for patients with a medium AAdSS, and € 148 for patients with a high AAdSS. If productivity losses are also included in the analysis, the incremental costs decrease to € 87 for patients with a medium AAdSS and € 119 for patients with a high AAdSS but increase to € 232 for patients with a low AAdSS.
3.3 Cost-Effectiveness Ratio
Cost-effectiveness ratio of 5-grass pollen tablets versus placebo treatment by the Average Adjusted Symptom Score (AAdSS)
3.4 Sensitivity Analysis
This study estimated the cost-effectiveness ratio of the 5-grass pollen tablet treatment by comparison of the 5-grass pollen tablets treatment with placebo treatment based on a decision tree populated with hypothetical data. This assessment produced results that can be considered favourable from a sustainability point of view. The cost-effectiveness ratio acceptability curve based on the multivariate probabilistic sensitivity analysis shows that the cost-effectiveness ratio remains below the ‘critical’ threshold of € 30,000/QALY in nearly all scenarios simulated. This study has several strengths that contribute to the robustness of these findings. First, the effectiveness data that were used to constitute the structure of the model were taken from a double-blind randomised controlled trial [12, 13]. Second, the use of the AAdSS as an effectiveness indicator permitted identification of a direct relationship between the outcome and the decrease in the consumption of resources (e.g. corticosteroids, diagnostic testing, etc.), which in part offsets the cost of 5-grass pollen tablets and thus makes a decisive contribution to the sustainability of NHS resources. Nevertheless, this study also faced several limitations. Although it used data derived from randomised controlled clinical trials, the model fits hypothetical scenarios. However, previous model-based studies of economic evaluation of AIT have provided significant findings in the understanding of the cost effectiveness of this treatment [10, 21]. Despite being estimated on the basis of the existence of a direct relationship between symptoms and the consumption of resources, the reliability of the cost-related part could be significantly improved if it were based on the resources actually consumed by patients using the microcosting method. Similarly, the utility coefficients, which were extrapolated using the ROC curve, could be measured directly by administering a questionnaire, such as the Euroqol (EQ 5D) , to AR patients. In fact, the EQ5D appears to be particularly appropriate for assessing AR, as severe or moderate AR may be presumed to have an impact on the patient’s ability to perform everyday activities (e.g. sport, work, etc.) and his/her psychological condition. It is also true that the multivariate probabilistic sensitivity analysis conducted on the deterministic results of the study gives a sufficient safety margin as to the sustainability of the cost-effectiveness ratio, which would presumably remain below the threshold of € 30,000/QALY in any case, even if the model was populated with real data and different discount rates (varied between 1.5 and 5 % in the sensitivity analysis) were used. In particular, the discount rate potentially appears be one of the most sensitive parameters as the time horizon is limited to 4 years. In this sense, this study provides added value with respect to the previous economic assessments of the use of SLIT vaccines to treat AR [8, 9, 10, 11]. Of note, the finding that the cost effectiveness of 5-grass pollen tablet treatment increases with the severity of AR symptoms agrees with the findings of a recent report regarding the higher clinical efficacy of the 5-grass pollen tablet treatment in patients with more severe AR . In this analysis, the study centres were grouped into tertiles (low, middle, and high tertiles) according to the symptom severity scores observed in the placebo patients at each centre to assess the difference in the average score between the treatment and placebo groups in each tertile. The results indicated an increased treatment effect in the most severe patients, independent of the symptom score used, during pollen season. Of note, a recent study showed that the 5-grass pollen tablet is more cost-effective than the tablet containing only one grass, i.e. Phleum pratense . This could be related to the fact that a 5-grass pollen preparation fits better with patient’s sensitisation profile, as shown by laboratory studies  and botanical observations , and thus may result in higher clinical effectiveness.
Lastly, attention should be drawn to the need to examine the administration of SLIT from an organisational point of view. The results of the clinical trials [12, 13] used in the model show that the treatment is, in all cases, effective only when at a compliance rate of 75 % or greater. However, sensitivity analysis showed that increased levels of compliance result in an increase of the ICER which, anyway, remains under the € 30,000/QALY threshold even though a 100 % compliance is assumed. This percentage is clearly of fundamental importance for the NHS when considering the level of investment that will be remunerative in terms of health gains. Thus, awareness that treatment effectiveness depends on a high level of patient compliance and adherence, which could be achieved with adequate education both at the specialist allergy centres  and by general practitioners when providing SLIT, must be a primary consideration.
This analysis, performed using the optimal tools to estimate the cost effectiveness of a medical treatment, shows that the 5-grass pollen tablet is cost effective in adult patients with grass pollen-induced seasonal allergic rhinitis who have a medium or high average adjusted symptom score compared to standard drug treatment. This finding should be carefully considered when deciding the management strategy in patients with seasonal allergic rhinitis, who, in contrast, are generally treated by symptomatic drugs.
We thank Prof. Americo Cicchetti, Dr Matteo Ruggeri, and Dr Marco Oradei for all analyses performed.
Declaration of funding
Stallergenes Italy sponsored the present study.
Declaration of financial/other relationships
Ilaria Dell’Albani, Franco Frati and Paola Puccinelli are employees of Stallergenes Italy. Cristina Romao is employee of Stallergenes SA. Cristoforo Incorvaia is a scientific consultant for Stallergenes Italy. The other authors have no conflicts of interest that are directly relevant to the content of the study.
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