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Keywords:

  • asthma;
  • burden of disease;
  • cost-effectiveness;
  • omalizumab

Abstract

  1. Top of page
  2. Abstract
  3. The human impact of severe asthma
  4. The financial impact of severe asthma
  5. Treatment options for severe persistent asthma
  6. Efficacy of omalizumab in clinical trials
  7. Cost-effectiveness of omalizumab in severe persistent asthma
  8. Cost-effectiveness of other biological agents
  9. Discussion
  10. Concluding remarks
  11. Acknowledgments
  12. References

Omalizumab is the first licensed anti-immunoglobulin (Ig) E antibody shown to be effective for treatment of allergic (IgE-mediated) asthma. Recent international guidelines recommend omalizumab as add-on treatment to fixed dose inhaled corticosteroid (ICS) and long-acting β2-agonist (LABA) combination therapy. However, omalizumab is more expensive than other current asthma treatments and health and reimbursement authorities are increasingly demanding evidence of economic benefit to support pricing and formulary listing. The aims of this article are to (i) summarize data on the human and economic burden of severe asthma, (ii) summarize the efficacy data obtained for omalizumab in clinical trials in patients with inadequately controlled severe persistent allergic asthma despite high-dose ICS plus a LABA, and (iii) discuss the cost-effectiveness evidence published for omalizumab in this patient population. A wealth of evidence exists highlighting that the health, economic and societal burden of asthma is considerable and is highly skewed towards patients with severe asthma, particularly when asthma is inadequately controlled. Omalizumab is clinically beneficial in patients with severe persistent allergic asthma despite high-dose ICS plus a LABA, particularly in a subgroup of patients who respond to therapy. In patients who respond to therapy, the cost-effectiveness of omalizumab compares well with other biologic treatments for chronic illness.

Asthma affects an estimated 300 million people worldwide and causes substantial mortality and morbidity (1). There are approximately 239 000 asthma-related deaths per year (0.4% of all deaths due to disease) (2) and morbidity is of a similar magnitude to osteoarthritis and diabetes (1). In addition, asthma significantly impairs physical, emotional and social aspects of daily living (3, 4) and increases psychological distress (5). The economic impact of asthma is also considerable (6–8). Total direct and indirect annual costs are approximately €18 billion in Europe (6) and US$13 billion in the USA (7, 8).

Asthma control is far from optimal (9–14). Despite best available treatment, it is recognized that control is not always possible in patients with more severe asthma (12). Such patients are seriously debilitated by their asthma symptoms and often experience multiple hospital visits (15). Approximately 2% of all asthma patients have inadequately controlled severe persistent asthma, whose symptoms are associated with allergy (10, 11, 16). These patients lack therapeutic options once standard treatments have been exhausted.

The aim of this article is to (i) provide an overview of emerging data on the human and economic burden of severe asthma, (ii) summarize the efficacy data obtained for omalizumab in clinical trials in patients with inadequately controlled severe persistent allergic [immunoglobulin (Ig)E-mediated] asthma despite high-dose inhaled corticosteroid (ICS) plus a long-acting β2-agonist (LABA), and (iii) following a literature search for cost-effectiveness studies of omalizumab therapy in severe asthma, discuss the cost-effectiveness evidence for omalizumab in this patient population.

The human impact of severe asthma

  1. Top of page
  2. Abstract
  3. The human impact of severe asthma
  4. The financial impact of severe asthma
  5. Treatment options for severe persistent asthma
  6. Efficacy of omalizumab in clinical trials
  7. Cost-effectiveness of omalizumab in severe persistent asthma
  8. Cost-effectiveness of other biological agents
  9. Discussion
  10. Concluding remarks
  11. Acknowledgments
  12. References

Asthma mortality and emergency healthcare utilization

Patients with severe asthma have a significantly higher risk of asthma-related hospitalization or death than patients with less severe asthma. The relationship between increasing asthma severity and asthma mortality and hospitalization is well established (17, 18). Studies across the world have shown that severe asthma or factors indicative of severe asthma (e.g. hospital admission) significantly increase the risk of asthma mortality (17–23). In Canadian studies, previous hospital admission has been shown to increase the risk of asthma mortality 10-fold (20) and patients with the most severe disease have the highest incidence of recurrent hospital admission or death within 1 year of an initial hospital visit (21). Similar findings were reported in a Brazilian study (22). Although patients with severe uncontrolled asthma account for only a small proportion of the total asthma patient population, confidential enquiries into asthma-related deaths in England and Wales show that approximately 50–60% of all deaths from asthma occur in those with severe chronic disease (24, 25). A recent analysis of asthma data from the CHKS database (2000–2005) in the UK found that asthma mortality is still a significant problem, with both acute and nonacute asthma events associated with risk of fatal asthma (26). Mortality rate was 848/100 000 in patients having an acute severe asthma event and 343/100 000 in patients classified as having a general asthma event, with a 10-fold increase in mortality rates in asthma patients requiring critical care compared with other types of asthma admission (26).

Impact of severe asthma on quality of life

The impact of asthma on patients’ quality of life is most marked in patients with severe asthma (27–29). A large cross-sectional observational study has been conducted to assess the effect of asthma control and asthma severity on quality of life (30–31). In total, 965 patients from France, Germany, Italy, Spain and the UK were recruited by primary care physicians and respiratory specialists and their severity classified according to the Global Initiative for Asthma (GINA) 2002 guidelines (9) based on clinical features and current treatment. The impairment in quality of life was significantly greater in patients with inadequately controlled severe persistent asthma compared with patients with severe controlled asthma [0.46-point reduction in Mini Asthma Quality of Life Questionnaire (Mini-AQLQ) overall score] (Fig. 1A). The cumulative frequency of Mini-AQLQ overall scores showed that quality of life was poorer in patients with severe inadequately controlled asthma than in patients with severe controlled asthma for each centile (Fig. 1B). In addition, as severity increased from moderate to severe asthma, quality of life was significantly reduced both in terms of Mini-AQLQ overall score (0.86-point) and individual domain scores (Fig. 1C).

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Figure 1.  The effect of asthma control on quality of life in patients with severe persistent asthma (A), the distribution of Mini-AQLQ overall scores in patients with severe and severe inadequately controlled asthma (B), and the effect of severity on quality of life (C) (30–31).

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A recent survey by the European Federation of Allergy and Airways Diseases Patients’ Associations has also shown that severe asthma has considerable detrimental effect on patients’ lives and well being (32). A total of 1300 patients from the UK, France, Germany, Spain and Sweden who reported a previous diagnosis of asthma and reported receiving asthma medication took part in the survey. Most patients reported having limitations to their lifestyles as a consequence of the symptoms of severe asthma. Almost 70% of patients reported that physical activity was restricted, 50% were restricted from having pets, 30% from taking holidays, and many felt their job prospects were limited. In addition, 50% of this population of patients were not convinced that guideline goals were being achieved.

High levels of anxiety and depression are reported in patients with severe uncontrolled asthma. In one study, a psychiatric evaluation (chest physician opinion and Hospital Anxiety Questionnaire) was undertaken in a cohort of patients (n = 65) with poorly controlled asthma and related to asthma outcomes (33). A high prevalence (49%) of psychiatric morbidity was identified in the cohort, with just 9% previously recognized. The most common diagnosis was depressive illness (29%).

The financial impact of severe asthma

  1. Top of page
  2. Abstract
  3. The human impact of severe asthma
  4. The financial impact of severe asthma
  5. Treatment options for severe persistent asthma
  6. Efficacy of omalizumab in clinical trials
  7. Cost-effectiveness of omalizumab in severe persistent asthma
  8. Cost-effectiveness of other biological agents
  9. Discussion
  10. Concluding remarks
  11. Acknowledgments
  12. References

It is well established that asthma-related costs increase as asthma severity increases. Studies in France, Spain, Germany, Italy, USA and Canada have shown that patients with severe persistent asthma accounted for more than double the annual costs of patients with less severe disease (34–38). In an Italian survey, total costs of asthma were the greatest in patients with severe persistent asthma (GINA 2002), accounting for >50% of total asthma costs (37). It is also notable that in the Italian study, direct costs accounted for 48% of total costs, whereas indirect costs (e.g. work days lost) accounted for the remaining 52% of total costs. The relationship between costs and asthma severity (GINA 2002) was also assessed using data from Italy, France and Spain (39). This study also found that patients with severe persistent asthma accounted for the majority of total asthma-related costs (approximately 60%) (39).

The costs of asthma are the greatest in patients with inadequately controlled asthma. In a study of 13 241 asthma patients with varying degrees of severity within general practices in the UK, it was estimated that 5–9% of patients had inadequately controlled asthma but these patients accounted for 26–33% of medical costs (40). Overall, patients with inadequately controlled asthma (defined as ≥ 1 hospitalization in past 12 months) were 4–5 times more costly than patients with controlled asthma. In a separate analysis of these data, patients with inadequately controlled asthma lost a substantial number of work days (indirect costs), possibly up to 25 days more than controlled patients (41). The cost of exacerbations is an important component of overall costs. McCowan et al. (42) reported that treatment costs were three times greater in patients with severe asthma (GINA 2002 treatment step 4) with frequent (≥ 4) exacerbations compared with patients with severe asthma who had no exacerbations. Similar findings were reported in a retrospective chart-based study of 422 Swiss asthma patients (43). Higher direct costs were seen in patients with severe persistent asthma compared with patients with less severe asthma, with costs 2.5 times higher if there were no exacerbations and 5.7 times higher if exacerbations were present (43). A review of a French Medical database of 1038 patients with persistent asthma found that medical resource utilization costs were three times greater in patients with inadequately controlled asthma than in patients with controlled asthma (44). Similarly, 2-year data for almost 4000 patients enrolled in The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study in the USA, showed that the cost of uncontrolled asthma was more than double that of controlled asthma (45). Throughout the study the majority of patients had uncontrolled asthma (83% uncontrolled; 16% inconsistent control; 1.3% controlled). In patients who displayed consistent control status at baseline, and 12- and 24-month follow-up, total mean cost for patients with controlled asthma over the 24-month study period was $6452 compared with $14 212 for patients with uncontrolled asthma (45).

The cost of exacerbations also increases with exacerbation severity (46, 47). A prospective study conducted in 15 countries (Cost of Exacerbations [COAX] study) found that exacerbation costs and secondary care costs significantly increased with exacerbation severity (46). In a study of patients with severe persistent allergic asthma, the mean exacerbation-related resource cost of a severe exacerbation was approximately 50% greater than the cost of a mild exacerbation (47).

In the cross-sectional observational study by Turk et al. (31), the economic impact of inadequately controlled severe persistent asthma was also evaluated. Patients with inadequately controlled severe persistent asthma had significantly more asthma exacerbations requiring a primary care visit or emergency hospital treatment and spent significantly more time in hospital than patients with controlled severe asthma. The expected percentage (95% confidence interval) of additional resource utilization in patients with inadequately controlled severe persistent asthma vs controlled severe asthma were: primary care treatment 146 (65, 267), < 0.001; emergency hospital visit 381 (112, 992), < 0.001; hospitalization 196 (−9, 868), P = 0.07; days spent in hospital 837 (80, 4771), = 0.008 (31).

Treatment options for severe persistent asthma

  1. Top of page
  2. Abstract
  3. The human impact of severe asthma
  4. The financial impact of severe asthma
  5. Treatment options for severe persistent asthma
  6. Efficacy of omalizumab in clinical trials
  7. Cost-effectiveness of omalizumab in severe persistent asthma
  8. Cost-effectiveness of other biological agents
  9. Discussion
  10. Concluding remarks
  11. Acknowledgments
  12. References

The severity of asthma varies and was classified into four severity levels in the GINA 2002 guidelines (9): intermittent, mild persistent, moderate persistent or severe persistent. Classification of asthma severity was based on both clinical features and current treatment. Although GINA classification of asthma by severity based on clinical features (Table 1) is still considered useful when decisions are being made about management at the initial assessment of a patient, the focus of treatment decisions in the GINA 2007 guidelines has moved towards the patient’s current level of asthma control and current treatment (14).

Table 1.   GINA 2007 guidelines for the classification of asthma severity based on clinical features (14)
  1. FEV1, forced expiratory volume in 1 s; PEF, peak expiratory flow.

Intermittent
Symptoms less than once a week
Brief exacerbations
Nocturnal symptoms not more than twice a month
 FEV1 or PEF ≥ 80% predicted
 PEF or FEV1 variability < 20%
Mild persistent
Symptoms more than once a week but less than once a day
Exacerbations may affect activity and sleep
Nocturnal symptoms more than twice a month
 FEV1 or PEF ≥ 80% predicted
 PEF or FEV1 variability < 20–30%
Moderate persistent
Symptoms daily
Exacerbations may affect activity and sleep
Nocturnal symptoms more than once a week
Daily use of inhaled short-acting β2-agonist
 FEV1 or PEF 60–80% predicted
 PEF or FEV1 variability > 30%
Severe persistent
Symptoms daily
Frequent exacerbations
Frequent nocturnal asthma symptoms
Limitation of physical activities
 FEV1 or PEF ≤60% predicted
 PEF or FEV1 variability > 30%

According to the GINA 2007 guidelines, treatment should be tailored to each patient’s asthma control and current treatment (step 1–5), progressing to the next step if control is not achieved (14). Rapid-acting β2-agonists are recommended at step 1, low-dose ICS and, if needed, LABAs are recommended at steps 2 and 3. Daily medium- or high-dose ICS plus a LABA is recommended at treatment step 4, with additional controller medication if needed (sustained release theophyllines and/or leukotriene modifiers). Anti-IgE (omalizumab) and oral corticosteroids (OCS) are included at step 5 (Fig. 2). In the European Union (EU), omalizumab is indicated for the treatment of inadequately controlled severe persistent allergic asthma despite high-dose ICS plus a LABA, which corresponds to GINA treatment steps 4 and 5. In the USA, omalizumab is indicated for patients with inadequately controlled moderate-to-severe allergic asthma despite receiving ICS.

image

Figure 2.  GINA 2007 guidelines for asthma treatment (14). ICS, inhaled corticosteroid; LABA, long-acting β2-agonist.

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The Gaining Optimal Asthma Control (GOAL) study investigated whether treatment with ICS (fluticasone propionate) or ICS plus a LABA (fluticasone/salmeterol combination therapy) could achieve guideline-based asthma control in patients with uncontrolled asthma (12). In patients with the most severe asthma, according to baseline ICS use, 38% remained inadequately controlled despite optimized treatment with fluticasone/salmeterol. When a course of OCS was added to fluticasone/salmeterol at the end of this 1-year study, only a further 7% of patients’ asthma was well controlled, i.e. 31% remained inadequately controlled. These findings are consistent with results from the International Asthma Patient Insight Research (INSPIRE) study (13). The INSPIRE study included 3145 patients (≥ 16 years) with asthma and who were receiving regular maintenance therapy with ICS (30% of patients) or ICS plus LABA (70% of patients), and found that 52% of patients were classified by the Asthma Control Questionnaire (ACQ) as having uncontrolled asthma and 74% of patients used short-acting β2-agonists daily. The INSPIRE study also highlighted differences in how physicians and patients perceive asthma control. Of the patients whose asthma was not well controlled according to the ACQ, 87% rated their asthma control as relatively good and 55% of patients classified as having uncontrolled asthma rated their asthma control as relatively good.

Efficacy of omalizumab in clinical trials

  1. Top of page
  2. Abstract
  3. The human impact of severe asthma
  4. The financial impact of severe asthma
  5. Treatment options for severe persistent asthma
  6. Efficacy of omalizumab in clinical trials
  7. Cost-effectiveness of omalizumab in severe persistent asthma
  8. Cost-effectiveness of other biological agents
  9. Discussion
  10. Concluding remarks
  11. Acknowledgments
  12. References

The efficacy of omalizumab has been extensively evaluated in seven clinical studies in patients with predominantly severe persistent allergic asthma (48–57). Here we focus on data for patients with inadequately controlled severe persistent asthma despite high-dose ICS plus a LABA from the INNOVATE (48) and ETOPA (49) studies, which have been used in cost-effectiveness analyses of omalizumab in this patient population (58–60). The INNOVATE study was a 28-week, randomized, double-blind, placebo-controlled study in patients with inadequately controlled severe persistent allergic asthma despite high-dose ICS plus a LABA (plus additional controller medication as required) [GINA 2002 treatment step 4 (9); GINA 2007 treatment steps 4/5 (14)] (48). The ETOPA study was a 1-year, randomized, controlled, open-label study that enrolled patients with poorly controlled moderate-to-severe allergic asthma (94% GINA 2002 severe persistent asthma) and compared omalizumab plus current asthma therapy (CAT) with CAT alone (49).

Omalizumab has proven effective over a wide range of outcome measures including asthma exacerbation rates and total emergency visit rates (48–57). However, it is also important to recognize that patients with asthma can be seen as being in two different health states, one relating to exacerbations (experiencing exacerbations or exacerbation free) and one relating to symptoms (degree of symptoms over time). Although reductions in asthma exacerbations and exacerbation-related healthcare resource use seen with omalizumab are important efficacy outcomes, these events occur relatively infrequently. It is therefore also important to assess the efficacy of omalizumab in terms of quality of life and day-to-day symptoms, for which data are also provided.

It is also important to note that not all patients eligible for omalizumab in the EU (severe persistent allergic asthma despite high-dose ICS plus a LABA) respond to treatment (61) and physicians should judge response to omalizumab therapy at 16 weeks, as specified in the EU labeling for omalizumab. Treatment should only be continued if the physician judges that the patient has achieved a marked improvement in overall asthma control at week 16. The evaluation of treatment response is particularly important as analysis of data from the seven clinical trials has shown that it is difficult to reliably predict which patients will achieve greatest benefits with omalizumab based on pretreatment clinical characteristics (61). Efficacy data for omalizumab-treated patients who responded to therapy according to a physician’s overall assessment (INNOVATE study) (61) or a ≥ 0.5-point improvement in overall Mini-AQLQ overall score (ETOPA study) (62) are described here.

Asthma exacerbations and total emergency visits

In the INNOVATE study, adding omalizumab to high-dose ICS plus a LABA resulted in a significant 26.2% reduction in the rate of clinically significant exacerbations (asthma worsening requiring systemic corticosteroids) vs placebo (0.68 vs 0.91, = 0.042) (48), after a post hoc adjustment to account for an unexpected between group difference in pretreatment exacerbations (unadjusted reduction 19%, = 0.153). The rate of severe exacerbations [forced expiratory volume in 1 s (FEV1) or peak expiratory flow <60% of personal best and requiring treatment with systemic corticosteroids] was reduced by 50% (0.24 vs 0.48, = 0.002) and the total emergency visit rate was reduced by 44% (0.24 vs 0.43, = 0.038) compared with placebo (48). In the 1-year open-label ETOPA study (49), adding omalizumab to CAT significantly reduced annual exacerbation rates by 59% compared with CAT alone (1.26 vs 3.06; < 0.001) in the subgroup of patients receiving high-dose ICS plus a LABA (62).

In the INNOVATE study, 61% of patients were classified as omalizumab responders (61). In omalizumab-treated responders, clinically significant exacerbation rates were reduced by 60%, severe exacerbation rate was reduced by 76% and total emergency visit rate by 76%vs placebo (63). Annualized rates for all omalizumab-treated patients, omalizumab-treated responders and placebo are shown in Fig. 3 (63). In the ETOPA study, 70% of patients receiving high-dose ICS plus a LABA were classified as omalizumab responders (62). In these patients, annual exacerbation rates were reduced by 64%vs CAT (1.12 vs 3.07, < 0.001).

image

Figure 3.  Adding omalizumab significantly reduces severe exacerbation and total emergency visit rates in patients with inadequately controlled severe persistent allergic asthma despite high-dose inhaled corticosteroid and a long-acting β2-agonist (62). *< 0.05; **< 0.01; ***< 0.001 vs placebo.

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Quality of life and day-to-day symptoms

As mentioned previously, asthma exacerbations and exacerbation-related healthcare resource use seen with omalizumab are important efficacy outcomes, but these events occur relatively infrequently. It is therefore also important to assess the efficacy of omalizumab in terms of quality of life and day-to-day symptoms.

In the INNOVATE study, add-on omalizumab treatment provided significant quality of life improvements for patients (48). Change from baseline in AQLQ overall score was 0.91 in the omalizumab group compared with 0.46 in the placebo group (< 0.001). A significantly greater proportion of omalizumab-treated patients achieved a clinically meaningful (≥ 0.5-point) improvement in AQLQ overall score compared with placebo (60.8%vs 47.8%, = 0.008). In omalizumab-treated responders in the INNOVATE study, 79% of patients achieved a ≥ 0.5-point improvement in AQLQ overall score compared with 35% of placebo patients (61). Similarly, patients receiving high-dose ICS plus a LABA in the ETOPA trial (62) showed significant improvement in change from baseline in the Mini-AQLQ for omalizumab-treated patients compared with control (1.32 vs 0.17, < 0.001), and more omalizumab-treated patients achieved a clinically meaningful (≥ 0.5-point) improvement from baseline in the Mini-AQLQ overall score at 52 weeks (76.5%vs 41.7%, < 0.001). The proportion of responders showing this improvement was 91.2%.

Omalizumab significantly improved total asthma symptoms in the INNOVATE study over the 28-week treatment period in the overall omalizumab-treated population (= 0.039 vs placebo). In omalizumab-treated responders, there were significant (< 0.001) improvements in the percentage of patients with symptom free days in terms of total (46%vs 23%), morning (70%vs 54%), daytime (50%vs 27%) and night-time (66%vs 52%) symptoms compared with placebo at week 26–28 (64) (Fig. 4).

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Figure 4.  Total symptom-free days (A), morning period (B), daytime period (C), night-time period (D) (omalizumab responders vs placebo) from baseline to the last observed interval (week 26–28) (64).

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Cost-effectiveness of omalizumab in severe persistent asthma

  1. Top of page
  2. Abstract
  3. The human impact of severe asthma
  4. The financial impact of severe asthma
  5. Treatment options for severe persistent asthma
  6. Efficacy of omalizumab in clinical trials
  7. Cost-effectiveness of omalizumab in severe persistent asthma
  8. Cost-effectiveness of other biological agents
  9. Discussion
  10. Concluding remarks
  11. Acknowledgments
  12. References

In previous sections, we described the significant burden of severe asthma and the efficacy of omalizumab in terms of significantly reduced exacerbation and emergency visit rates and significantly improved quality of life and day-to-day symptoms. The incremental therapeutic value of omalizumab, which is the sum of the effect on day-to-day asthma, clinically significant exacerbations, ER visits, risk of fatal asthma and resource utilization, has also been assessed against the incremental costs of therapy. The incremental cost per quality-adjusted life year (QALY) gained is a well accepted and widely used measure of the cost-effectiveness of therapies and can capture the overall treatment effect on the patient (65).

To date, the cost-effectiveness of omalizumab add-on therapy has been assessed in several analyses (58–60, 66, 67). Four analyses assessed cost-effectiveness in patients with inadequately controlled severe persistent asthma despite high-dose ICS plus a LABA (58–60). The analysis by Dewilde et al. (58) was based on the efficacy data from the INNOVATE study (48) (reference country Sweden). One analysis by Brown et al. (59) was based on the efficacy data from the ETOPA study (49, 62) (reference country Canada), and a second (containing two base-case analyses) (60) was based on data from INNOVATE and ETOPA (reference country the Netherlands). The analysis by Oba and Salzman (66) was based on data from two randomized, placebo-controlled trials in patients with inadequately controlled moderate-to-severe allergic asthma despite receiving ICS (51–54) (reference country: USA). The analysis by Wu et al. (67) was based on the medical care component of the US Consumer Price Index (68). The funding source of a cost-effectiveness analysis is also of interest when interpreting results. Indeed, the pharmaceutical industry must provide cost-effectiveness data to secure reimbursement from health authorities. In this review, three cost-effectiveness analyses were industry sponsored (58–60) and two were investigator sponsored (66, 67).

Cost-effectiveness models

In the cost-effectiveness analyses of omalizumab in patients with inadequately controlled severe persistent allergic asthma despite high-dose ICS plus a LABA (58–60), the same Markov cohort model was used to estimate the cost-effectiveness of adding omalizumab to standard therapy. The Markov model has been described in detail by Dewilde et al. (58). Lifetime costs were determined by comparing lifelong standard therapy costs with 5 years of omalizumab add-on therapy followed by standard therapy. As only patients who are judged by physicians to have responded to omalizumab after 16 weeks of therapy should continue with treatment (EU label), nonresponders to omalizumab revert to standard therapy at 16 weeks. In the INNOVATE study, responders were defined as those patients with at least a marked improvement in asthma control (physician’s overall assessment). In the ETOPA study, responders were defined as those patients with ≥ 0.5-point improvement in Mini-AQLQ overall score. The benefits of treatment were expressed as QALYs gained and the cost-effectiveness of omalizumab was expressed as an incremental cost-effectiveness ratio (ICER). The ICER was calculated as the difference in total costs between the omalizumab and standard treatment arms per QALY (cost/QALY). Probabilistic analyses of cost-effectiveness over a range of willingness-to-pay values were also performed. The acceptance by the UK National Institute for Health and Clinical Excellence (NICE) of the submission from the manufacturers of omalizumab, which used this model and data from the INNOVATE primary-intention-to-treat population and a high-risk hospitalization subgroup, along with an additional analysis using ETOPA study data supports the validity of this model (69).

The analyses presented in the Oba and Salzman report (66) differed in several substantive ways from the research described above. The investigators constructed efficacy outcomes to assess cost-effectiveness, which was expressed as the daily cost to achieve an additional successfully controlled day or as the daily cost to achieve a >0.5-point improvement in AQLQ overall score. These outcomes, while important clinically, are of lower importance to resource decision makers who require estimates of the incremental cost/QALY. Importantly, the analyses did not account for whether or not a patient responded to omalizumab and used clinical data from a less severe patient population.

The most recent paper by Wu et al. (67) used data from the Asthma Policy Model (70) to estimate the 10-year cost-effectiveness of omalizumab added to ICS controller medication [with short-acting β2-agonist (SABAs) relievers when required] compared with ICS controller medication alone (with SABA relievers) in a severe adult asthma population. These results suggest that omalizumab, in combination with ICS, is not a cost-effective treatment strategy. Several concerns regarding the findings from this research should be noted. First, the analytic engine underlying the Wu et al. model relies heavily on the relationship between health care utilization and lung function parameters (FEV1). Omalizumab is known to exert its clinical benefits in asthma patients by reducing the risk of exacerbation and improving asthma-specific quality of life, not by improving lung function perse. Second, the analysis reports cost/QALY findings for an average cohort of severe patients. Omalizumab is recommended in the GINA guidelines as add-on treatment to combination therapy with ICS and LABA. A more relevant scenario for Wu et al. to have explored would have been to compute cost-effectiveness of omalizumab when used according to guidelines. That is, when omalizumab is added to a combination of ICS and LABA for patients who failed ICS and LABA combination. Finally, the clinical and economic value of omalizumab is seen most clearly in patients who respond to initial treatment. We describe this research in more detail below.

Cost-effectiveness results

In the reference case scenario using INNOVATE data (Sweden), estimated total lifetime discounted costs were €52 702 for 11.6 QALYs for standard therapy (58). Add-on omalizumab therapy had an additional lifetime cost of €42 754 for an additional 0.762 QALYs (ICER of €56 091) (Table 2A). Using ETOPA data (Canada), total lifetime discounted costs and QALYs for patients on standard therapy were €27 403 and 6.49 (59). Add-on omalizumab therapy had an additional lifetime cost of €33 854 for 1.08 additional QALYs (ICER of €31 209) (Table 2A). INNOVATE data (the Netherlands) produced an estimated total lifetime discounted cost of €29 476 for 11.2 QALYs (60) for standard therapy and an additional lifetime cost of €44 641 for 1.0 QALY (ICER of €44 910) for add-on omalizumab (Table 2B). ETOPA data (the Netherlands) gave a total lifetime discounted cost of €30 144 for 9.7 QALYs (60) for standard therapy and an additional lifetime cost of €32 044 for 1.2 QALYs (ICER of €26 694) for add-on omalizumab (Table 2B).

Table 2A.   One-way sensitivity analyses of omalizumab add-on vs standard therapy for severe persistent allergic asthma (58, 59)
Analyses descriptionINNOVATE (reference country - Sweden)ETOPA (reference country - Canada)
Incremental cost, €Incremental QALYICER, €Incremental cost, €Incremental QALYICER, €
  1. ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life year.

Base case42 7540.76256 09133 8541.0831 209
No discounting48 3401.07844 85840 0961.6923 762
Mortality = 0%43 8810.335131 13031 4950.4766 443
Mortality = upper range41 6340.90046 26833 5461.0033 578
Table 2B.   One-way sensitivity analyses of omalizumab add-on vs standard therapy for severe persistent allergic asthma (60)
Analyses descriptionINNOVATE (reference country - the Netherlands)ETOPA (reference country - the Netherlands)
Incremental cost, €Incremental QALYICER, €Incremental cost, €Incremental QALYICER, €
  1. ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life year.

Base case44 6411.044 91032 0441.226 694
No discounting50 1261.242 62936 5071.426 262
Mortality = 2.478%43 7150.3127 28630 6910.560 650
Mortality = upper range44 5420.944 39531 9111.128 647

The ICER range for one-way sensitivity analyses using INNOVATE data (Sweden) was €39 762 without discounting to €131 130 without inclusion of asthma-related mortality (Table 2A). The ICER range for one-way sensitivity analyses using ETOPA data (Canada) ranged from €23 762 without discounting to €66 443 without inclusion of asthma-related mortality (Table 2A). Using INNOVATE data (the Netherlands) the ICER range for one-way sensitivity analyses ranged from €42 629 without discounting to €127 286 without inclusion of asthma-related mortality (Table 2B). Using ETOPA data (the Netherlands), the ICER range for one-way sensitivity analyses ranged from €26 262 without discounting to €60 650 without inclusion of asthma-related mortality (Table 2B). The probabilistic cost-effectiveness planes for omalizumab add-on therapy vs standard therapy for INNOVATE (Sweden), ETOPA (Canada) and ETOPA (the Netherlands) data are shown in Fig. 5A–C, respectively. 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.

image

Figure 5.  Cost-effectiveness plane for omalizumab add-on therapy vs standard therapy; using (A) INNOVATE data (reference country - Sweden) (58), (B) ETOPA data (reference country - Canada) (59) and (C) ETOPA data (reference country - the Netherlands) (60).

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The potential of input parameters to influence the results of the model should be considered in analyses of this kind. The analyses using the Markov model (58–60) relied on several assumptions. For example, it was assumed that future events (hospitalizations, exacerbations) are independent of previous events. Numerous published studies have shown that previous exacerbations or hospitalizations are positively correlated with future exacerbations or hospitalizations (17–23, 71). An 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 (72). Also, the INNOVATE trial had an 8-week run-in period during which asthma therapy was optimized (48). While the optimization on therapy in the INNOVATE trial may not always reflect the case in clinical practice, it is worth noting that optimization of therapy should be an ongoing treatment goal to maximize the benefits of standard therapy before more expensive options are considered. Both analyses assumed adherence to therapy although adherence in long-term illness is generally accepted to be poor. Dewilde et al. suggested that adherence to therapy was likely to be higher in omalizumab-treated patients given the increased physician contact for purposes of omalizumab administration (58). Brown et al. acknowledged that the assumption of adherence was optimistic, but considered it not to unduly favor one treatment group over the other (59). The analyses did not include any adverse event (AE) costs or utility decrements for either treatment group as AE rates were not statistically significantly different. AEs associated with long-term use of OCS in standard therapy were not considered, as no comparable long-term data for omalizumab exist.

Brown et al. (59) highlighted the extrapolation of 1-year trial data to lifetime and the lowering of the resulting ICER as a study limitation, but argued that this extrapolation is justified, given that severe persistent allergic asthma is a chronic condition. They also used non-trial data to estimate the risk of asthma-related mortality associated with clinically significant severe exacerbations, and assumed a mortality risk from severe exacerbations despite the fact that there were no deaths in the placebo arm of the 1-year ETOPA trial (there was one death in the Xolair-treated group, but post hoc analyses showed that it was unrelated to treatment). The authors considered the inclusion of the possibility of asthma-related death to be appropriate in a lifetime analysis of severe allergic asthma patients as asthma-related fatalities are known to occur, and the subgroup of patients included in this study was at a high-risk of asthma-related mortality based on prior medical history (14, 73). This inclusion of non-trial data may be seen as a potential study limitation, and the appropriateness of its source [a small observational study (74), which was not designed to examine the relationship between severe asthma exacerbations and death] has been questioned (75). However, the clinical trial environment is an exceptional one, with greater levels of patient care and medication compliance than is standard, and sudden deteriorations are more likely to be rapidly treated, thereby reducing the risk of death. Therefore estimates based on ‘real-world’ mortality data as reported by Lowhagen et al. (74) may be justified. Other published mortality data (76, 77) support the estimates used in the model. It should also be noted that the authors conservatively assumed that no risk of fatal events is associated with clinically significant exacerbations, and a range of estimated fatality rates were presented in the results for comparison. During the NICE assessment of the HTA submission from the manufacturers of omalizumab, the Committee was of the opinion that the mortality risk in the submission was overestimated. However they also considered that the high-risk hospitalization subgroup from the INNOVATE trial would plausibly have a higher risk of asthma mortality (78). Both the risk of mortality associated with severe asthma and the considerable uncertainty in estimating that risk are documented. The results of a confidential inquiry indicated that disease severity was usually a major factor in deaths attributed to asthma (25). The problems inherent in using currently available data to estimate asthma mortality are illustrated by a review of asthma-related deaths, which concluded that relying on underlying cause-of-death data may underestimate the actual number of deaths due to asthma (79). The review found that only 45% of over 135 000 investigator-identified asthma-related deaths had asthma recorded as the underlying cause of death. Another study into mortality in hospitalized patients in the US found the overall in-hospital mortality to be 0.5%, and this represented approximately one third of all asthma deaths reported in the US (80). Noting that research data on fatal asthma are limited, a study to determine the feasibility of creating a US national fatal asthma registry concluded that, as fairly consistent demographic and clinical data were available across states, the creation of a national fatal asthma registry could be feasible if legislative barriers could be overcome (81).

In Canada, the omalizumab label is not restricted to those with severe asthma (82). Therefore, the consistency of using Canada as the reference country in the analysis by Brown et al. (59) examining a severe population may be questioned. However, as a subgroup profile that mirrors the European omalizumab label population can be applied to any database regardless of country label specifics, this approach is acceptable. Dewilde et al. (58) also pointed out that data from a multi-country trial is adaptable to the Swedish database because of the wide acceptance of GINA treatment guidelines and the severe patient populations at GINA 2002 step 4 therapy are similar in their inability to achieve asthma control despite best standard care.

The definition of treatment response in Brown et al. (59) was based on improvements in the Mini-AQLQ, which was also used in the mapping algorithm to generate the utility values. Unsurprisingly, omalizumab responders by definition have markedly higher utility values than the standard therapy arm, and the question of whether results using the overall omalizumab group should be presented is raised. The authors argue that using the overall omalizumab group response after 16 weeks would not reflect the fact that only responders continue with therapy. The AQLQ, has been shown to correlate well with the physician’s 16-week evaluation of treatment (61) included in the model and was adequate to mimic responder identification in the ETOPA trial (data relating to the physician’s 16-week assessment were not collected). The model used the overall omalizumab group Mini-AQLQ scores and clinically significant exacerbation rates for the first 16 weeks. After this, when only responders would continue with treatment, responders had exacerbation rates and utility values based upon the responder Mini-AQLQ scores, while nonresponders (who stop omalizumab) were assumed to have those of the placebo group.

Utility values for day-to-day symptoms were obtained from AQLQ (Dewilde et al.) and Mini-AQLQ (Brown et al.) data from the clinical trials, but as there were insufficient observations of clinically significant and severe exacerbations in trials, utility values relating to these states were taken from a prospective four-centre study (74). The cost estimates included by Dewilde et al. in their model were yearly drug costs (standard therapy, based on patient usage in INNOVATE) and the additional weighted average cost of omalizumab therapy including administration costs, an assumed 3-monthly GP visit for asthma, and 16-week assessment. Exacerbation and severe exacerbation costs were based on INNOVATE data. Nonhealthcare related costs in added years of life were included as recommended by the Swedish Pharmaceutical Benefits Board. The effect of excluding this would have increased the calculated ICER. Brown et al. included drug costs and significant exacerbation costs based on ETOPA data and severe exacerbation costs based on INNOVATE. Administration costs were not included in the base case (as these are supported by Novartis in Canada), and only direct medical costs were included.

The analysis by Oba and Salzman reported a daily cost of $523 to achieve an additional symptom free day with omalizumab and a daily cost of $378 to achieve a ≥ 0.5-point improvement in AQLQ overall score in patients with moderate-to-severe allergic asthma (66). The authors concluded that omalizumab may be cost saving if given to nonsmoking patients who are hospitalized five or more times or 20 or more days or longer per year despite maximal therapy.

Wu et al. estimated a cost-effectiveness ratio of $821 000 per QALY gained for patients with acute event rates at baseline. A sensitivity analysis allowing the acute event rate to increase to five times that at baseline, they estimated a cost-effectiveness ratio of $491 000 per QALY gained. Other scenarios included in sensitivity analyses were efficacy of omalizumab (in terms of exacerbation rate, varied between 33% and 92%) which produced costs per QALY of $853 000 and $727 000 respectively; QoL improvement (health-related quality of life [HRQoL] improvement from 0% to 7.2%) which produced costs per QALY of $1.42 million and $207 000 respectively; and cost of omalizumab (monthly drug costs of $200) producing a cost per QALY of $100 000. The authors concluded that, at its current price, omalizumab is not cost-effective for patients with severe asthma in the US.

Given a willingness-to-pay of €60 000, the studies using country-specific data in the Markov model (58–60) support an indication that omalizumab is cost-effective in patients with severe persistent allergic asthma despite high-dose ICS plus LABA. Using ETOPA data applied to Canada gave an ICER of €31 209 for omalizumab (59), which was lower than that reported using data from the INNOVATE study applied to Sweden (€56 091) (58). Similarly, ETOPA data applied to The Netherlands gave in ICER of €26 694 which is lower than the €44 910 ICER from INNOVATE data applied to the same country (60). 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 likely that the ETOPA data may be more representative of what would be expected in clinical practice. Data reported by Oba and Salzman (66) are more difficult to interpret as these data were based on patients with less severe asthma, artificial endpoints were used to measure cost-effectiveness, and response to omalizumab was not evaluated. Although Wu et al. (67) based their estimate on a severe population, the Asthma Policy Model they used was developed with data from patients with mild-to-severe asthma and has not been validated in patients who are more severe. Improvement in HRQoL is one of the key drivers in their model and is based on a FEV1 prediction equation. However, as omalizumab has little impact on FEV1, and FEV1 does not relate to QALYs particularly well, in this context, the model does not fully reflect the important effects of Xolair. It is therefore not surprising that the authors found that omalizumab had a very low impact on HRQoL (0.9%) and that the estimated ICER increased accordingly. When HRQoL improvement is assumed to be 7.2% in the sensitivity analysis, the ICER is reduced significantly. Responders to omalizumab were not identified in this analysis which means that all patients receive omalizumab treatment for 10 years regardless of response status. While this is acceptable as the US label does not require the identification of responders, it should be noted that this has implications on the results, particularly where omalizumab is used according to the EU label. Some level of discontinuation based on nonresponse should have been assumed in the sensitivity analysis, based on the likelihood that clinicians would not let patients continue with treatment if there is no response. Additionally, in some cases, patients would not continue with treatment if they are not experiencing benefit. Drug costs for omalizumab are therefore overestimated, as in clinical practice nonresponders are likely to have treatment discontinued.

Cost-effectiveness of other biological agents

  1. Top of page
  2. Abstract
  3. The human impact of severe asthma
  4. The financial impact of severe asthma
  5. Treatment options for severe persistent asthma
  6. Efficacy of omalizumab in clinical trials
  7. Cost-effectiveness of omalizumab in severe persistent asthma
  8. Cost-effectiveness of other biological agents
  9. Discussion
  10. Concluding remarks
  11. Acknowledgments
  12. References

Reimbursement of biologicals in other therapeutic areas may provide reference points of the willingness to pay. The results of economic analyses (cost per QALY) for other biologicals in other disease areas are summarized in Table 3 (83–97). Within each disease area, the ICER can vary widely between different therapies, and also over the range of therapeutic doses for individual therapies. Comparing the ICERs of published omalizumab cost-effectiveness studies with those of other biologicals suggests that omalizumab add-on therapy in patients with severe persistent allergic asthma despite high dose ICS plus a LABA is comparable to or more favorable than other uses of scarce healthcare resources for these agents in different disease areas.

Table 3.   Economic evaluations of biologics for rheumatoid arthritis, Crohn’s disease and multiple sclerosis
AuthorsBiologic and costs evaluated (year)Findings*
  1. Can$, Canadian dollar; GBP, British pound; QALY, quality-adjusted life year.

  2. *Results are expressed as 2003 US dollars in parentheses.

Rheumatoid arthritis
 Clark et al. (2004) (83)Anakinra Direct costs only (2002 GBP)£105 000–604 000/QALY ($164 000–942 000)
 Jobanputra et al. (2002) (84) Etanercept, infliximab Drug-related costs only (2000 GBP)£72 000–83 000/QALY ($116 000–134 000)
 Barton et al. (2004) (85) Etanercept, infliximab Direct costs only (2000 GBP)Etanercept: £40 000–51 000/QALY vs standard care ($64 400–82 110) Infliximab: £53 000–69 000/QALY vs standard care ($85 300–111 000)
 Kobelt et al. (2004) (86)Etanercept, infliximab Direct and indirect costs (2002 Euros)Direct and indirect costs: €43 500/QALY, etanercept and infliximab combined ($44 000) Direct costs only: €44 500/QALY, etanercept and infliximab combined ($45 000)
 Brennan et al. (2004) (87) Etanercept Direct costs only (2000 GBP)£16 000/QALY ($25 800)
 Kobelt et al. (2003) (88) Infliximab Direct and indirect costs (2001 Euros)Sweden: €16 000/QALY all costs ($14 100), €45 000/QALY direct costs ($39 600) UK: €48 000/QALY all costs ($42 400), €56 000/QALY direct costs ($49 300)
Crohn’s disease
 Marshall et al. (2002) (89) Infliximab Direct costs only (2001 Can$)Can$181 000–696 000/QALY ($125 000–480 000)
 Clark et al. (2003) (90) Infliximab Direct costs only (2002 GBP)£62 000–135 000/QALY ($96 700–211 000)
 Jaisson-Hot et al. (2004) (91) Infliximab Direct costs only (2002 Euros)€64 000–784 000/QALY ($64 600–792 000)
Multiple sclerosis*
 Otten et al. (1998) (92)Interferon β1a Direct costs only (1995 Can$)Can$406 000/QALY ($357 000)
 Kendrick & Johnson (2000) (93) Interferon β1a Direct and societal costs (1995 GBP)Direct cost: £27 000–38 000/QALY ($52 100–73 300)
 Chilcott et al. (2003) (94)Interferon β1a, Interferon β1b Direct costs only (2001 GBP)Interferon β1a: £42 000–72 000/QALY depending on dose ($61 300–105 000) Interferon β1b: £44 000–50 000/QALY ($64 200–73 000)
 Forbes et al. (1999) (95) Interferon β1b Direct costs only (1995 GBP)£1 000 000/QALY ($1 970 000)
 Parkin et al. (2000) (96) Interferon β1b Direct costs only (1998 GBP)£810 000/QALY ($1 510 000)
 Nuijten & Hutton (2002) (97) Interferon β1b Direct and indirect costs (1998 GBP)Public-payer perspective: £52 000/QALY ($97 200) Societal perspective: £46 000/QALY ($86 000)

Discussion

  1. Top of page
  2. Abstract
  3. The human impact of severe asthma
  4. The financial impact of severe asthma
  5. Treatment options for severe persistent asthma
  6. Efficacy of omalizumab in clinical trials
  7. Cost-effectiveness of omalizumab in severe persistent asthma
  8. Cost-effectiveness of other biological agents
  9. Discussion
  10. Concluding remarks
  11. Acknowledgments
  12. References

Decisions to adopt, reimburse or issue guidance on the use of health technologies are increasingly being informed by an explicit cost-effectiveness analysis of the alternative interventions. However, difficulties exist in how the results of economic evaluations should be interpreted and used by healthcare decision makers. This is particularly apparent for add-on therapies if there are no alternative treatment options and if innovative therapies (e.g. biologicals) enter disease areas that are characterized by a low invention intensity and therefore comparably low costs. Here the importance of the margin and the comparison with similar technologies in other disease areas is paramount. Marginal changes in the ICER take place at the ‘clinical margin’ that is, as the same intervention is expanded to cover individuals with different treatment benefit or therapeutic need. This emphasizes the importance of highly targeted patient selection for these therapies. For example, the omalizumab EU label indication specifies uncontrolled severe persistent allergic (IgE-mediated) asthma, positive skin test or serum IgE to a perennial aeroallergen, reduced lung function (FEV1 < 80%), frequent daytime symptoms or night-time awakenings, and multiple severe asthma exacerbations despite high-dose ICS plus a LABA and stringent assessment of response to therapy. In August 2007, the UK NICE gave its final appraisal determination for NHS public reimbursement of omalizumab. Describing the highly targeted population, omalizumab is recommended as add-on to optimized standard therapy (ICS plus a LABA with other controller medications where clinically appropriate) for the treatment of severe persistent allergic (IgE-mediated) asthma in adults and adolescents. IgE-mediated allergy to a perennial allergen should be confirmed, with two or more severe exacerbations requiring hospitalization within the previous year, or three or more severe exacerbations within the previous year, one requiring hospitalization, and two requiring treatment or monitoring in an accident and emergency unit (69). Differences in treatment response or risk factors can be seen at the clinical margins.

Six analyses are considered in this review. Four appeared to provide evidence of the cost-effectiveness of add-on omalizumab in patients with inadequately controlled severe persistent allergic (IgE-mediated) asthma despite high-dose ICS plus a LABA. Using data from the INNOVATE study (48) applied to Sweden, Dewilde et al. reported a reference case ICER for add-on omalizmab of €56 091 (58). Data from the naturalistic ETOPA study (49, 62) gave an ICER of €31 209 (59). Data from INNOVATE and ETOPA (60) gave ICERs of €44 910 and €26 694 respectively. These ICERs indicate that omalizumab is probably cost-effective in the label population at a willingness-to-pay value of €60 000. One analysis in moderate-to-severe patients estimates a daily cost of $523 per additional symptom free day with omalizumab, and a daily cost of $378 to achieve a ≥ 0.5-point improvement in AQLQ overall score. While concluding that omalizumab is not cost-effective, the authors of this analysis note that omalizumab may be cost saving in severe patients at high risk of hospitalization (66). One analysis calculates a base case cost per QALY of $821 000 and concludes that omalizumab is not cost-effective in the US (67).

Concluding remarks

  1. Top of page
  2. Abstract
  3. The human impact of severe asthma
  4. The financial impact of severe asthma
  5. Treatment options for severe persistent asthma
  6. Efficacy of omalizumab in clinical trials
  7. Cost-effectiveness of omalizumab in severe persistent asthma
  8. Cost-effectiveness of other biological agents
  9. Discussion
  10. Concluding remarks
  11. Acknowledgments
  12. References

Severe asthma is associated with considerable mortality, healthcare utilization and costs. Omalizumab, a novel therapeutic agent has proven efficacy in severe asthma. The weighing of the cost-effectiveness models assumptions, inputs, and the validity of the results is ultimately in the hands of healthcare decision makers. While the findings of some economic analyses of omalizumab are unfavorable, there are published cost-effectiveness analyses which indicate that omalizumab is cost-effective in patients with uncontrolled severe allergic (IgE-mediated) asthma despite other controller medications with a history of severe exacerbations and hospitalization.

Acknowledgments

  1. Top of page
  2. Abstract
  3. The human impact of severe asthma
  4. The financial impact of severe asthma
  5. Treatment options for severe persistent asthma
  6. Efficacy of omalizumab in clinical trials
  7. Cost-effectiveness of omalizumab in severe persistent asthma
  8. Cost-effectiveness of other biological agents
  9. Discussion
  10. Concluding remarks
  11. Acknowledgments
  12. References

The authors wish to thank professional medical writers Tom McMurray (ACUMED) and Dr Dominic Hague (contracted writer) for editorial assistance with the manuscript and Jon Campbell, MS for his comments on an earlier version of the paper. This support was funded by Novartis Pharma AG.

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  1. Top of page
  2. Abstract
  3. The human impact of severe asthma
  4. The financial impact of severe asthma
  5. Treatment options for severe persistent asthma
  6. Efficacy of omalizumab in clinical trials
  7. Cost-effectiveness of omalizumab in severe persistent asthma
  8. Cost-effectiveness of other biological agents
  9. Discussion
  10. Concluding remarks
  11. Acknowledgments
  12. References
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