To cite this article: Brüggenjürgen B, Ezzat N, Kardos P, Buhl R. Economic evaluation of BDP/formoterol fixed vs two single inhalers in asthma treatment. Allergy 2010; 65: 1108–1115.
Background: Asthma treatment costs are substantial, the largest proportion being incurred by medications. Combination therapy with inhaled corticosteroids (ICS) and long-acting beta2-agonists (LABA) is recommended in patients not adequately controlled by ICS alone. Aim of this study was to compare costs and health outcomes of a fixed ICS–LABA combination of beclomethasone dipropionate (BDP) and formoterol fumarate (FF) vs the same drugs delivered via separate inhalers in Germany.
Methods: A cost-minimization analysis, a cost-effectiveness analysis, as well as a threshold analysis were undertaken. Efficacy results were obtained from a recent clinical trial. Cost inputs include medical costs, physician costs, and hospital admission costs. Medical costs, health outcomes, and treatment costs were also varied to assess their impact on results.
Results: Beclomethasone dipropionate/FF fixed combination was less costly compared to BDP + FF delivered as separate inhalers, costs totaling €525 and €637, respectively, over a 24-week treatment period. The incremental cost-effectiveness ratio was €−9.77 per additional day free of asthma symptoms. Equal cost-effectiveness ratios would still be obtained at a price of the fixed combination increased by 3.4-fold.
Conclusion: A cost-minimization analysis as well as a cost-effectiveness analysis for Germany based on different product price calculations show that BDP/FF fixed combination is superior to BDP + FF delivered via separate inhalers.
Asthma is a chronic inflammatory disease characterized by reversible airway obstruction, airway remodeling, and nonspecific airway hyperresponsiveness (1, 2). The main goals of current asthma treatment are to achieve and maintain control of asthma symptoms, to maintain normal activity levels, and to maintain pulmonary function as close to normal as possible, while reducing the potential for adverse effects and/or exacerbations (3). Combination therapy with inhaled corticosteroids (ICS) and long-acting beta2-agonists (LABA) is currently recommended in patients uncontrolled with ICS alone (3). Combination therapy is available in a single inhaler or in two separate inhalers.
Asthma is a very common chronic disease, affecting about 10% of children and 5% of adults. Prevalence is increasing worldwide, especially in children and adolescents (4). Costs of the disease are substantial. In Germany, the total annual cost of asthma is estimated to range from 2.1 to 2.74 billion € (4, 5). Only about 50% of costs is reimbursed by the Statutory Health Insurances (SHI), while remaining costs must be covered by patients, insurance companies, employers or other third party payers (4). For children and adults suffering from moderate allergic asthma, the total annual cost (including direct and indirect costs) of asthma has been estimated at €2200 and €2700 respectively, with the annual cost of severe allergic asthma and nonallergic forms of the disease being even higher (6, 7). Costs for evidence-based pharmaceutical treatment covered by the SHI would result in annual costs of €642 and €1040 per patient for moderate (step 3) and severe (step 4) asthma, respectively (8). Because of increasing cost pressure in health care systems and a large patient population, choosing cost-effective treatment is of increasing importance.
As a result of recent attention placed on cost-benefit assessment in Germany, a higher awareness has emerged for both clinical and economic aspects (9). The analysis was designed to determine the cost-effectiveness of a fixed combination of ICS and LABA compared to ICS and LABA delivered by separate inhalers from a health insurance point of view. The research was conducted by applying German cost data to the results of a large, randomized, double-blind, double-dummy, 6-month trial (10). The study was conducted in Belgium, France, Hungary, Poland, Romania, and Russia. Although no German study centers participated in this trial, it was assumed that the clinical trial results could be transferred to Germany.
Foster® (Chiesi Farmaceutici S.p.A., Parma, Italy) is an ICS–LABA combination that has been available in Germany since 2006. It is a fixed, extra-fine formulation of the combination of beclomethasone dipropionate (BDP) 100 μg and formoterol fumarate (FF) 6 μg, delivered via a pressurized metered dose inhaler (pMDI) driven by a hydrofluoroalkane (HFA) propellant. As the generated aerosol of Foster® is extra-fine, the nominal dose of BDP in the combination is reduced from 250 μg [conventional BDP dose delivered through chlorofluorocarbon (CFC)-containing pMDI] to 100 μg, while maintaining the same respirable fraction (11). In asthmatic patients, 100 μg BDP extra-fine has been shown to be as effective as CFC BDP 250 μg (12, 13). As for the formoterol component, both the fine particle dose and the clinical equivalence in terms of lung function improvement between extra-fine formoterol HFA pMDI and formoterol dry powder inhaler (DPI) (Foradil Aerolizer, Novartis Pharma GmbH, Nürnberg, Germany) at equivalent doses have been demonstrated (11).
Foster® was compared with BDP and FF delivered via separate inhalers in a recent clinical study. Full details of the study are reported elsewhere and are summarized here (10). The 24-week study was conducted on patients between the ages of 18 and 70 with moderate to severe asthma. Inclusion criteria included 1-s forced expiratory volume (FEV1) ≥40% and ≤80% of the predicted normal value and a documented positive response to the reversibility test. Patients previously treated with ICS (750–1000 μg CFC BDP or equivalent) either alone or in combination with a LABA were included if they still had asthma symptoms >3 times/week. The use of short-acting beta2-agonist (SABA) on an as-needed basis was allowed. Patients were randomized to either:
- 1 Beclomethasone dipropionate/FF fixed combination: pMDI containing BDP 100 μg + FF 6 μg with HFA-134a as a propellant (Foster®), two actuations twice daily (total daily dose: BDP 400 μg + FF 24 μg).
- 2 Beclomethasone dipropionate + FF: CFC pMDI containing BDP 250 μg (Becloforte®; Allen & Hanburys, Dublin, Ireland), two actuations twice daily + DPI containing FF 12 μg (Foradil® Aerolizer®; Novartis Pharma GmbH, Nürnberg, Germany), twice daily, given separately (total daily dose: BDP 1000 μg + FF 24 μg).
- 3 Beclomethasone dipropionate alone: CFC pMDI containing BDP 250 μg (Becloforte®), two actuations twice daily (total daily dose: BDP 1000 μg).
Primary study endpoint was mean morning peak expiratory flow (PEF) as measured by patients on a portable peak flow meter (Spirotel™, MIR – Medical International Research, Rome, Italy) in the last 14 days of the treatment period. Secondary outcomes included standard pulmonary function tests measured at clinics; morning and evening asthma symptom scores; percent of asthma symptom-free days, nights and/or full days (asthma symptoms over 24 h); daily use of SABA; mild, moderate, and severe asthma exacerbations as reported in the clinical study (13).
A simple model was developed in Excel (Excel 2003 for Microsoft Windows®), analysing costs and cost-effectiveness of both Foster®, the BDP/FF fixed combination, and conventional BDP + FF in two separate inhalers for Germany. The clinical trial arm of BDP alone was not included in the economic analysis.
For cost-effectiveness analysis, the selected outcome parameter should be representative of the study findings and relevant from an economic point of view, reflecting for example both reduction in resource utilization and improved health status. Ideally, it should display similar trends with other outcomes for the treatment of interest (14). Hence, despite PEF being the primary study endpoint, the following secondary efficacy parameters were chosen for the economic analysis: percent asthma symptom-free days, percent asthma symptom-free nights, percent asthma symptom-free full days (24-h period) and percent asthma-controlled days. For economic interpretation reasons, in this analysis these variables were converted into absolute ‘additional asthma-free days, nights, full days’ and ‘additional asthma-controlled days’. This was achieved by calculating the difference in values between baseline and study end and multiplying by the number of study days. In contrast to the primary endpoint PEF, all the selected endpoints are patient-relevant, as they all have an impact on morbidity, satisfaction with treatment, and quality of life (15).
The model allows for the analysis of three different model scenarios. The first scenario is a priori cost analysis, assuming the same efficacy of the two treatment alternatives. The second scenario incorporates patient-relevant outcomes of the study, and in the third scenario, the threshold of equal cost-effectiveness ratios was calculated by varying the price of BDP/FF fixed combination at given efficacy results.
The time frame of the model is the clinical trial period of 24 weeks. The chosen perspective is the payers’ perspective, including only direct costs paid by the SHI.
The cost input parameters include medical costs, as well as outpatient physician care and hospitalization costs. Unit costs are reported in 2008 Euros.
The drug prices are based on the Lauer Taxe ex pharmacy price as of July 2008 (16) including VAT and considering patient co-payment, as well as SHI rebates. To obtain SHI-borne drug costs, pharmacy prices were reduced by both the SHI-claimed rebate of €2.30 per package and the patient’s co-payment, now 10% of the market price (not more than €10 and at least €5) per package (17). In the base case, BDP/FF fixed combination was compared to BDP + FF (Foradil Aerolizer 12 μg plus branded BDP HFA 250 μg nonextra-fine), as per protocol weighted with IMS HEALTH data according volumes and standard units to approximate the German market situation (18).
The outpatient care costs, i.e., office-based physician treatment costs, are based on the Uniform Value Scale (EBM –Einheitlicher Bewertungsmaßstab) 2008 (19). Assumptions on frequency of visits and type of treatment of an asthma patient, verified by experts, did not differ among treatment alternatives but were included to reflect realistic resource utilization of an asthmatic patient. Treatments given by both general practitioners and specialists were included in the analysis.
Hospital admission costs include only treatment costs of severe exacerbations, as this was the only resource utilization parameter powered in the clinical trial. Hence, neither other asthma related nor side-effect related hospitalization costs were applied. Hospitalization costs correspond with the German Diagnosis Related Groups (DRG) system (20). Costs were based on the three most frequent DRGs for status asthmaticus (verified by experts) and were weighted with the proportion of patients hospitalized because of severe exacerbations in the study.
No attempt was made to extrapolate beyond the clinical trial period in the scenarios; consequently, discounting was not applied.
In a sensitivity analysis, several parameters were varied separately in a univariate sensitivity analysis or simultaneously in a multivariate sensitivity analysis.
A univariate sensitivity analysis was conducted for the costs of BDP + FF in separate inhalers including weighting based on IMS HEALTH data to approximate the German market situation:
- • Formoterol Aerolizer 12 μg + BDP HFA 250 μg nonextra-fine (branded + generics)
- • Formoterol 6 μg + BDP HFA 100 μg extra-fine with same composition as BDP/FF fixed combination (branded + generics)
- • Formoterol Aerolizer 12 μg + BDP HFA 250 μg non-extra-fine (generics) (18)
In a multivariate sensitivity analysis at the given drug costs, outpatient care and hospital costs, as well as the proportion of patients admitted to hospital because of severe exacerbations were varied by ±10%. Additionally, variation of efficacy parameters was incorporated by including the standard error according to the phase III study results for BDP/FF fixed combination and BDP + FF delivered separately.
A complete description of the efficacy and safety results has been presented elsewhere and is summarized as follows (10). The three groups (BDP/FF fixed combination, N = 212; BDP + FF, N = 220 and BDP, N = 213, respectively) were well balanced with respect to age, weight, and height. There were a higher percentage of women (65.1; 65.0 and 62.9, respectively) than men but the proportion of women and men in each group was comparable. Mean values for FEV1 were similar across the three treatment groups and are shown in Table 1.
|BDP/FF fixed combination (n = 212)||BDP + FF (n = 220)||BDP (n = 213)|
|Age (years)||47.3 (18–69)||47.4 (18–70)||47.3 (18–70)|
|Sex n (%)|
|Male||74 (34.9)||77 (35.0)||79 (37.1)|
|Female||138 (65.1)||143 (65.0)||134 (62.9)|
|Weight (kg)||74.41 (42.0–125.0)||75.54 (41.0–127.4)||74.87 (40.0–128.0)|
|Height (cm)||167.11 (145.0–194.0)||166.97 (149.0–200.0)||167.28 (148.0–199.0)|
|FEV1 (% predicted)||1.95 (0.88–3.64)||1.99 (0.91–4.26)||1.97 (0.95–3.94)|
Primary outcome results demonstrated that BDP/FF fixed combination was significantly superior to BDP monotherapy. For both the intention-to-treat and per-protocol populations, non-inferiority of BDP/FF fixed combination over BDP + FF was demonstrated. Secondary outcome results, percent asthma symptom-free days, nights, full days, were unchanged on BDP monotherapy, increased from baseline on both BDP/FF fixed combination and BDP + FF and were significantly higher in the BDP/FF fixed combination group compared to the BDP + FF group at the end of the study. Furthermore, a significantly higher percentage of asthma-controlled days were recorded in the fixed combination group compared to BDP + FF and BDP monotherapy (10) (Table 2). The number of asthma exacerbations requiring unscheduled medical intervention, such as hospitalization and those that led to loss of asthma control for two consecutive days or more, was lower in the BDP/FF fixed combination treatment group compared to the BDP + FF and BDP treatment group (P = 0.103).
|Percent days free of asthma||Percent nights free of asthma||Percent complete days free of asthma||Percent days asthma was controlled|
|BDP/FF fixed combination (n = 211)|
|End of treatment (LS mean) [±SE] (difference)||35.80 [2.31] (14.60)||38.10 [2.30] (14.40)||26.90 [2.01] (16.10)||30.45 [1.97] (4.15)|
|BDP + FF (n = 220)|
|End of treatment (LS mean) [±SE] (difference)||29.70 [2.25] (7.80)||30.50 [2.23] (3.60)||20.00 [1.95] (8.10)||24.04 [1.91] (−2.18)|
In the economic analysis, only results of BDP/FF fixed combination and BDP + FF were included. German drug costs were as follows: with the market price of €1.88 per day for BDP/FF fixed combination, the SHI has to bear €1.62, accounting for rebates and co-payments. At a market price of €2.37 per day, SHI has to bear €2.10 daily for the single comparator medication components. The sum of drug costs over the entire study period was €272 for the BDP/FF fixed combination and €353 for BDP + FF. General physician and specialist outpatient care costs were estimated at €70.35 and €81.88 per quarter, respectively. According to the expert panel, it may be assumed that all patients are seen by their general practitioner every quarter. Additionally, 75% of patients are treated by a specialist every quarter; 12.5% every second quarter. The sum of total physician costs, therefore, was €253 in the trial period. In the clinical study, only 1.36% of patients were hospitalized because of severe exacerbations in the BDP + FF group and none in the BDP/FF group. Hospital costs totaled €31 and €0, respectively. All calculated unit costs for resources are presented in Tables 3 and 4.
|BDP/FF fixed combination||BDP + FF|
|Drug costs study medication|
|Study medication costs per day (€)||1.62||2.10|
|Total study medication costs (€)||272.46||353.24|
|Per quarter at general practitioner (€)||70.35||70.35|
|Per quarter at specialist (€)||81.88||81.88|
|Total costs (€)||252.69||252.69|
|Costs per hospitalization (€)||2287.48||2287.48|
|Percentage of patients hospitalized||0||1.36|
|Costs weighted with percentage of patients hospitalized (€)||0||31.19|
|Weighted SHI costs per day||Weighted SHI costs per day||Total SHI costs per day (€)|
|Study medication||€0.72||Study medication||€1.38||2.10|
|BDP 250 μg nonextra-fine weighted||€0.66||Aerolizer weighted (CT-Arzneimittel GmbH, Berlin, Germany)||€1.10||1.76|
|BDP 100 μg extra-fine weighted||€0.45||Formoterol 6 μg weighted||€1.58||2.03|
In the first a priori model scenario, assuming same efficacy of the two treatment alternatives, total costs incurred for treatment with BDP/FF were €525.15 compared with €637.12 for BDP + FF. Efficacy results of the phase III study were included in the second scenario. The cost-effectiveness ratio for BDP/FF fixed combination was €21.34 per additional day free of asthma symptoms and that for separate intake was €48.45 per additional day free of asthma symptoms. Hence, the fixed combination was the dominant strategy (incremental cost-effectiveness ratio (ICER) −€9.77 in favor of fixed combination). Results of all efficacy parameter are presented in Table 5 and Fig. 1. In the third model arm, the price of BDP/FF fixed combination was calculated where the cost-effectiveness ratios of the two treatment alternatives correspond. As a result, the price of BDP/FF fixed combination could increase by at least 3.4-fold depending on the efficacy parameter.
|BDP/FF fixed combination||BDP + FF||Difference||ICER (€ per efficacy parameter)|
|Additional days free of asthma symptoms||24.61||13.15||11.46||−9.77|
|Additional nights free of asthma symptoms||24.28||6.07||18.21||−6.15|
|Additional complete days free of asthma symptoms||27.14||13.65||13.49||−8.30|
|Additional days asthma was controlled||7.00||−3.67||10.67||−10.49|
In the univariate sensitivity analysis, prices for BDP + FF were varied, as presented in Table 4. Drug costs of Formoterol Aerolizer 12 μg + BDP HFA 250 μg nonextra-fine are €1.76 per day and result in a cost-effectiveness ratio of €44.15 per additional day free of asthma symptoms. Drug costs of Formoterol 6 μg + BDP HFA 100 μg extra-fine are €2.03 per day and result in a cost-effectiveness ratio of €47.63 per additional day free of asthma symptoms. Accordingly, although costs of BDP + FF include branded and generic products, reflecting the actual market situation by weighting with IMS HEALTH data, the fixed combination with €1.62 per day is the less expensive alternative. Considering a hypothetical situation where the single agents market is totally made up of only generic products, the daily drug costs for BDP + FF result in €1.46. However, total costs of €530.71 remain higher than the fixed combination. The cost-effectiveness ratio is €40.36 per additional day free of asthma symptoms for BDP + FF compared with the €21.34 for the fixed combination. Hence, with a negative ICER of €−0.48, the fixed combination remains the dominant strategy.
In the multivariate sensitivity analysis, physician care, hospitalization costs and efficacy parameters were varied at the given medical costs. Results of the cost-effectiveness analysis based on study medication and efficacy parameter ‘additional asthma symptom-free days’ are presented in Fig. 2.
Cost-effectiveness analyses are used to demonstrate the relationship between the cost and effectiveness of intervention. In this economic analysis for Germany, we used treatment and outcome data of an international multicentre trial. We compared costs and outcomes using BDP/FF fixed combination in a single inhaler as maintenance therapy for asthma vs BDP + FF administered via separate inhalers. The cost analysis favored BDP/FF fixed combination over the separate administration of BDP + FF (BDP/FF fixed combination €525.15 vs BDP + FF €637.12). The cost-effectiveness analysis also favored the fixed combination, showing it to be less costly and more effective. Additionally, a threshold analysis demonstrated that the price of the BDP/FF fixed combination could be over three times the current price before the cost-effectiveness ratios of the alternative free combinations would be offset. Taking into account different cost calculations for the separate administration of BDP + FF including branded and generic products, BDP/FF fixed remains the dominant strategy. Therewith, this analysis confirms the results of Shepherd et al. 2008 (21), analysing among others cost-effectiveness of combination and separate inhalers.
As detailed resource utilization data were not collected in the underlying clinical study, we assumed outpatient care costs to be identical for both comparators. Hence, this analysis only accounted for the economically relevant difference in severe exacerbations. Furthermore, this approach meets the requirement that protocol-driven costs should be excluded (22).
As a further potential cost contributor, the inclusion of concomitant medication would also be of great interest. However, the underlying study reported no differing trends in the distribution of concomitant medications across the two treatment groups. During the study period, 97.6% and 96.8% of patients required concomitant medication in the BDP/FF and BDP + FF group, respectively, including inhaled nasal corticosteroids, short courses of oral corticosteroids for asthma exacerbations as well as inhaled short-acting β2-adrenoreceptor agonists. As information about the quantity of concomitant medication was not collected in the study, it was not possible to include cost estimations in the economic analysis. Additionally, both treatment groups had a reduction from baseline in mean SABA consumption, which was similar at the end of treatment with 0.33 puffs/day in both the BDP/FF and BDP + FF treatment groups. German guidelines recommend among others salbutamol as SABA, with an actual price of €0.074 per puff (200 puffs €14.80) (23). Because of the marginality of costs, SABA consumption was not included in the calculations.
Annual costs calculated for Germany in our analysis (BDP/FF fixed combination €1138 vs BDP + FF €1344) correspond well with published cost of illness analyses. Derived from a cross-sectional German study, Schramm et al. (7) reported about €830 direct annual costs of moderate asthma and about €1400 of severe asthma in 2000 (extrapolated from Fig. 3 in their publication). A top–down analysis of published German drug utilization data estimated costs at €642 and €1040, respectively, for step 3 (moderate) and step 4 (severe) of asthma treatment (8).
This analysis was based on a clinical trial using the additional rigor of a double-blind design. However, using clinical trial results bears some limitations:
First, no German patients were enrolled in this phase III clinical study, even though approximately 15% of study centers were in countries with health care systems comparable to Germany (i.e. France, Belgium) and the remaining being in Eastern European countries. In this model, it was assumed that patients in Europe do not differ in their drug response. Moreover, all comparator study medications used were available in Germany. Furthermore, the indications for hospitalizations might differ between Germany and the participating countries; however, they were assumed to be comparable because of lacking data.
Second, BDP/FF fixed combination was administered using a pMDI driven by an HFA-134a propellant, whereby BDP in a single inhaler was given via a CFC-containing pMDI. This difference can be ignored for the purpose of a pharmaco-economic evaluation, considering that clinically equivalent doses of BDP were used (12, 13). Because of the ban on CFC-containing devices in 2003, corresponding HFA costs had to be employed.
Third, although our economic evaluation applied patient-relevant outcomes as effectiveness parameters, they were derived from secondary study endpoints only, whereas ideally endpoints used in economic analysis should both be primary and patient-relevant (15).
Fourth, no relevant resource utilization data, with the exception of hospital admissions because of severe exacerbations, were collected in the phase III study. However, as hospitalizations can be rare, and may not be captured by a short-term study, true costs because of severe exacerbations may therefore be underestimated (24). Given the small number of severe exacerbations leading to hospital admission in this clinical trial, the impact on costs is very limited but was included to adhere to principles of completeness. In this setting, the main difference in resource utilization relates merely to drug costs. To reflect a total cost level of the treatment alternatives, costs for outpatient physician care, which may or may not differ between the two alternatives, were also included with the same value.
Patient study and/or treatment compliance is greater during clinical trials compared to routine clinical practice. As surveys on current management of asthma indicate, even in severe asthma patients, only 26% are treated adequately with an anti-inflammatory maintenance medication (25). Hence, in real life an economic benefit might result from more appropriate treatment according to guidelines by simplification of the treatment scheme and the guaranteed ICS exposure (26). This is of particular clinical relevance, considering that single-inhaler combinations have also been preferentially recommended to avoid treating asthma with a LABA monotherapy (27), and thus reducing adverse effects described with chronic use of this class of bronchodilators (28, 29). The direct costs reported in this analysis might overestimate the true costs borne by SHI in Germany, as adherence in real practice even with a fixed combination is lower than in a clinical trial setting. This is supported by a randomized, open label trial conducted in Germany, where treatment with budesonide and formoterol administered separately resulted in an annual direct cost of €292 under real practice conditions and 2001 Euros (30).
When considering different cost calculations including branded and generic products, BDP/FF fixed combination is the cost-effective alternative and remains the dominant strategy compared with BDP + FF given in separate inhalers. In addition, BDP/FF fixed combination improves patient safety.
The study was funded by by an unconditional grant from Chiesi Farmaceutici Spa, Parma, Italy. We thank Raffaella Monno, Carsten Demgensky, and Cecilia Merli for the critical review of the paper.