Ruth E. Brown Health Care Analytics Group United BioSource Corporation 20 Bloomsbury Square London WC1A 2NS UK
Background: The health, economic and societal burden of asthma is considerable, and is greatest in patients with severe asthma, particularly when inadequately controlled. Real-life studies that assess the effectiveness of treatment are of particular interest.
Methods: We determined the incremental cost-effectiveness ratio (ICER) of adding omalizumab to standard therapy using data from the real-life 1-year randomized open-label study (ETOPA) and using Canada as a reference country. Only patients receiving high-dose ICS plus LABA were included in the analysis, reflecting the EU label for omalizumab. Costs and quality-adjusted life years (QALYs) gained were used to calculate the ICER for omalizumab (cost/QALY). Probabilistic sensitivity analysis was performed to determine the 95% confidence interval and one-sided sensitivity analyses were performed.
Results: The base case lifetime analysis of standard therapy vs standard therapy plus add-on omalizumab for the first 5 years, gave an ICER of €31 209. Probabilistic sensitivity analysis indicated that the 95% confidence interval around the ICER was €27 739–€40 840. The ICER range for one-way sensitivity analyses was €23 762 without discounting to €66 443 without inclusion of asthma-related mortality.
Conclusions: This study demonstrates that add-on omalizumab therapy is cost-effective in patients with severe persistent allergic asthma.
Asthma is a major public health problem (1) and its economic impact is considerable (2–4), with direct and indirect costs totalling approximately US$13 billion in the United States in 1998 (2) and €18 billion in Europe in 2003 (3). In Canada, the urgent care costs of uncontrolled asthma are estimated to be CAD$162 million (Canadian dollars; CAD$1 = €0.7) (4). Asthma-related costs increase as asthma severity increases (5–8), particularly when asthma is inadequately controlled (7, 8).
In the UK, the National Institute for Clinical Excellence (NICE) has published guidelines for economic evaluations to assess whether new healthcare technologies contribute to the efficient use of National Health Service resources. Although there may be some limitations (9, 10), the analytical basis of the guidelines is a comparison of the costs and consequences of new and existing methods for dealing with particular conditions using the incremental cost-effectiveness ratio [ICER; the difference in total costs between treatment A and treatment B per quality-adjusted life year (QALY), with a lower ICER value indicating greater cost-effectiveness for treatment A] (11), which has been used in asthma cost-effectiveness studies (12, 13).
Omalizumab, an anti-IgE antibody, is effective and has a good safety and tolerability profile in patients with severe persistent allergic (IgE-mediated) asthma that remains inadequately controlled despite optimal pharmacological treatment (14, 15). The cost-effectiveness of omalizumab in severe persistent asthma has been assessed using efficacy data from the INNOVATE study (14) and using a Markov cohort model to estimate the cost-effectiveness of adding omalizumab to standard therapy (reference country Sweden) (13). The benefits of treatment were expressed as QALYs gained and the cost-effectiveness of omalizumab was expressed as an ICER. The analysis by Dewilde et al. (13) showed that omalizumab has an attractive ICER (€56 091) in the treatment of patients with inadequately controlled severe persistent allergic asthma who responded to omalizumab therapy. However, cost-effectiveness analyses generated from randomized controlled trials represent results obtained under ideal experimental conditions and their applicability to real-world settings (effectiveness) may be questionable (16).
The aim of this study was to assess the cost-effectiveness of omalizumab in a naturalistic setting to attain a closer approximation of expected real-life outcomes. This study uses the Markov model from Dewilde et al. (13) with data from a 1-year, randomized open-label trial of omalizumab (ETOPA study) (17) in a corresponding subgroup of patients with severe persistent allergic asthma despite high-dose ICS plus LABA [reference country Canada; ICER threshold €35 000 (CAD$50 000)] (18).
To attain a closer approximation of expected real-life outcomes an economic analysis was conducted using data from the 1-year open-label ETOPA study (17) using Canada as a reference country, chosen because economic analyses are widely used to inform health resource allocation here. Exacerbation rates, resource use, utility values and omalizumab dosing patterns from ETOPA were used in the cost-effectiveness analysis to provide evidence of the potential cost-effectiveness of omalizumab in a real-world setting. Only patients who were receiving high-dose ICS plus a LABA (plus additional controller medication if required) were included in the cost-effectiveness analysis. This subpopulation corresponds closely to the European label population of severe persistent allergic asthma and comprised 52.6% of the total trial population.
The Markov model used to evaluate the economic value of omalizumab has been described in detail by Dewilde et al. (13). The model has three health states: day-to-day asthma (periods with no clinically significant nonsevere or severe exacerbations); clinically significant nonsevere exacerbation; and clinically significant severe exacerbation. Death from all causes, and asthma-related death due to severe exacerbations are also included in the model.
The costs and QALYs gained were used to calculate the ICER for omalizumab, which corresponds to the difference in total costs of omalizumab and standard therapy divided by the difference in total QALYs providing a cost/QALY. Probabilistic sensitivity analysis was performed to determine the 95% confidence interval for the ICER. In addition, one-way sensitivity analyses were performed on key variables. Costs are given in Euros.
Exacerbation rates and exacerbation-related risk of fatality
In the ETOPA study, clinically significant exacerbations were defined as asthma worsening requiring treatment with systemic corticosteroids. As severe exacerbations were not specifically recorded in the ETOPA trial we assumed the same distribution to that seen in the INNOVATE study (14), which defined severe exacerbations as peak expiratory flow/forced expiratory volume in 1 s <60% of personal best in addition to requiring rescue treatment with systemic corticosteroids. It was assumed that future exacerbations were independent of events that occurred in previous cycles. Exacerbation rates for omalizumab-treated responders [defined as those patients having ≥0.5 point improvement in Mini Asthma Quality of Life Questionnaire (MiniAQLQ) overall score from baseline to end of treatment] and patients who received standard therapy in the ETOPA study are shown in Table 1A.
Table 1. Exacerbations rates and utility values used in the cost-effectiveness model for omalizumab-treated responders and patients receiving standard therapy in the ETOPA study (17)
*Based on distribution seen in the INNOVATE study (14).
Clinically significant nonsevere exacerbations, value (SD)
Clinically significant severe exacerbations, value (SD)
The risk of exacerbation-related fatality from clinically significant severe exacerbations was based on data from a community-based study by Lowhagen et al. (19) because there were no deaths in the ETOPA study. The mortality risk associated with each clinically significant severe exacerbation was estimated to be 3.108%. The estimated risk was the same regardless of treatment; however, the annual mortality risk for omalizumab patients would be expected to be lower due to the lower frequency of clinically significant severe exacerbations. This estimate was examined in sensitivity analyses using a 2.48% likelihood of death from a clinically significant severe asthma exacerbation, based upon an analysis of asthma deaths among patients hospitalized in the UK for acute, severe asthma aged 45 and over (20) and excluding other asthma-related mortality. The risk of death from all causes was based on the data from Statistics Canada (21). All-cause mortality for the Canadian general population was 0.12%.
Utility values for the model were obtained from two sources, depending on the Markov disease state. For the ‘day-to-day asthma’ state, utilities were obtained from Mini-AQLQ values collected during the ETOPA trial (17). These values were mapped onto the EQ5D, separated by disease state and responder status, using a specially created mapping function and then transforming them into utilities (22). AQLQ data at the end of the 1-year study were selected for this analysis. Utilities for the ‘clinically significant nonsevere and severe exacerbation’ states were obtained using data from a prospective study conducted in the UK at four speciality asthma centres (23) as trial data had insufficient patient quality of life data during exacerbations (measurements not taken at that time). In the UK study, patients had moderate-to-severe asthma treated with ICS, LABA or leukotriene modifiers (23). Average utilities for the ‘day-to-day asthma’ state and ‘exacerbation’ state within each group are shown in Table 1B.
The model included costs for exacerbations, drug costs and routine visit costs with all costs discounted at 5%. Exacerbation-related costs were obtained by pooling data on exacerbation-related resource use from the two treatment arms of the ETOPA study. The resource use for clinically significant severe exacerbations and nonsevere exacerbations was derived from the INNOVATE study (14). The average cost per clinically significant severe exacerbation and nonsevere exacerbation was estimated to be €260.90 and €177.40 respectively.
Average resource costs were estimated using published unit costs from the Ontario Schedule of Benefits and fees (24) and hospitalization costs were determined according to Canadian Institute of Health Information (25). The administration costs of omalizumab were not included in the base case scenario. In Canada, these costs are supported by Novartis through a comprehensive support program (Xolair Healthcare Assistance and Link to Education, XHALETM) that assists patients and healthcare professionals. In a sensitivity analysis, administration costs for omalizumab were included. Where possible, the costs of generic drugs were used to calculate annual drug costs with the assumption that patients were fully compliant. Costs were not assigned to patient days lost from school or work. Only direct medical costs were included in the calculations. Annual routine visit costs (e.g. prescription renewal or check up) were €153.
Drug costs were estimated according to medication use in the ETOPA study (17). Adherence to therapy was assumed to be the same in both treatment groups. Annual drug costs for omalizumab (based on an average 27.7 vials over the 52-week trial) were €11 634. The annual cost of standard therapy was €1938.
In the base case lifetime analysis of standard therapy compared with standard therapy plus omalizumab add-on therapy for the first 5 years, the results give an ICER of €31 209. Total lifetime discounted costs and QALYs for patients on standard therapy were €27 403 and 6.49. The additional cost of add-on omalizumab was €33 854 for 1.08 additional QALYs. The probabilistic sensitivity analysis indicated that the 95% confidence interval around the ICER was €27 739–€40 840.
The probability that omalizumab is cost-effective over a range of willingness-to-pay values is shown in Fig. 1. For a threshold value of €35 000 [CAD$50 000 (20)], the probability that omalizumab is cost-effective is 69.7%. The ICER range for one-way sensitivity analyses was from €23 762 when future costs and outcomes were not discounted to €66 443 when asthma-related mortality was excluded (Table 2). Adding the costs of administration by a healthcare provider to the omalizumab cost increased the ICER due to higher costs for that treatment group compared with standard therapy alone. The shorter time horizon has a lower incremental cost, but the longer term benefits of avoided exacerbations and mortality result in less QALYs and an increased ICER. The probabilistic cost-effectiveness plane for omalizumab add-on therapy vs standard therapy is shown in Fig. 2. Each point is defined on the horizontal axis by the incremental difference in QALYs for omalizumab relative to standard therapy alone and the vertical axis depicts the incremental difference in cost. The horizontal dispersion is a reflection of the variation in QALYs.
Table 2. One-way sensitivity analyses of omalizumab add-on vs standard therapy for severe persistent allergic asthma
Incremental cost (€)
QALY, quality-adjusted life year.
Discount rate at 3% for costs and outcomes
Time horizon = 5 years (without follow-up)
Administration costs included
Mortality = 0%
Mortality = 2.48%
Cost-effectiveness analysis has been advocated in the health economics literature and increasingly adopted as an evidence base for decision makers charged with maximizing health gains from available resources. The ICER is widely used to assess cost-effectiveness of therapies (9). The results presented here using ETOPA data calculate the ICER for omalizumab add-on therapy to be €31 209. This is considerably lower than the ICER reported using data from the INNOVATE study (14) applied to Sweden, which reported an ICER for add-on omalizumab of €56 091. As the ETOPA study was a 1-year randomized open-label trial in a naturalistic setting and INNOVATE was a 28-week, randomized placebo-controlled trial, it is possible that the ETOPA data may be more representative of what would be expected in clinical practice. Similar findings were reported with etanercept in the treatment of rheumatoid arthritis where the ICER varied depending on the type of clinical setting used for the analysis (16).
Our economic analysis has a number of assumptions and limitations. The 1-year trial was extrapolated to life-time, and nontrial data were used to estimate asthma-related mortality associated with clinically significant severe exacerbations. Excluding the risk of asthma-related mortality or shortening the time frame of the analysis results in a much higher ICER. Because severe persistent allergic asthma is a chronic condition and because asthma-related fatalities are known to occur, we believe that the long-term analysis including possible mortality is justified.
It was also assumed that patients would be adherent to both therapies and that patients would not discontinue treatment. While these assumptions are optimistic, their application to both treatment groups does not unduly favour one over the other.
Thirdly, we assumed that future events (hospitalizations, exacerbations) are independent of previous events, which is more likely to favour standard therapy over omalizumab. Numerous published studies have shown that previous exacerbations or hospitalizations are strongly correlated with future exacerbations or hospitalizations (26, 27). Indeed, analysis of INNOVATE data found that a history of clinically significant exacerbations in the year prior to the study was highly predictive of exacerbations during the study (28).
The burden of asthma is greatest in patients with inadequately controlled severe persistent asthma. These patients are at high risk of life-threatening exacerbation, hospitalization, mortality (29–31), and are most affected in terms of quality of life (7, 32). Similarly, the economic burden of asthma increases with asthma severity (5–8) and is greatest in this patient group (7, 8). Despite treatment in accordance with current guidelines, many patients with severe asthma remain inadequately controlled (33, 34).
Comparison of effectiveness of different biological treatments is difficult as studies use a modelled estimation of effectiveness which may vary between countries, healthcare systems and outcome measures. However, the effectiveness of omalizumab assessed in this study compares favourably with other biologics in rheumatoid arthritis (10), hepatitis B (35) or cancer (36).
The present study demonstrates that omalizumab add-on therapy in patients with severe persistent allergic asthma results in a cost-per-QALY ratio that compares favourably with other uses of scarce healthcare resources that are recommended by national reimbursement bodies and could be considered cost-effective. In the current climate of scarce healthcare resources, it is important to demonstrate economic value as well as therapeutic value. Omalizumab offers both therapeutic and economic value and represents a major advance for the treatment of patients with inadequately controlled severe persistent allergic asthma.
The authors acknowledge all investigators and study coordinators who participated in the ETOPA study and all patients for their commitment to the study, which was supported by Novartis Pharma AG, Basel, Switzerland. The authors would like to thank medical writer, Dr Dominic Hague, for assistance in drafting this manuscript and Helen Venables for editorial assistance.