TITLE: Omalizumab Treatment for Adults and Children with Allergic Asthma: A Review of the Clinical Effectiveness, Cost-Effectiveness, and Guidelines

Transcription

1 TITLE: Omalizumab Treatment for Adults and Children with Allergic Asthma: A Review of the Clinical Effectiveness, Cost-Effectiveness, and Guidelines DATE: 9 March 2015 CONTEXT AND POLICY ISSUES Asthma is chronic inflammatory disease of the airways that affects 300 million individuals worldwide and is associated with significant mortality and morbidity. 1 Allergic asthma is the most common form of asthma, where exacerbations are triggered by allergens such as dust mites and pollen and are attributable to immunoglobulin E (IgE)-mediated mechanisms. 2 Asthma symptoms include wheezing, breathlessness, chest tightness, and coughing. Severe asthma is estimated to occur in about 10% of the asthma population. 2 The goal of treating acute exacerbations are to re-establish adequate airflow, elevate blood oxygen saturation, and plan for the prevention of future exacerbations. 1 Current guidelines recommend the use of low-dose inhaled corticosteroids (ICS), followed by the addition of a longacting β 2 -agonist (LABA), a leukotriene receptor antagonist (LTRA), or upward titration of ICS dose if control is not gained or maintained. 1 For individuals whose asthma remains uncontrolled, further increases in ICS dose are recommended, in addition to alternative treatment options such as leukotriene modifiers, oral corticosteroids, or omalizumab. 1 Omalizumab is a humanized, recombinant, IgG, anti-ige monoclonal antibody that binds to IgE and prevents it from binding to its high-affinity receptor on mast cells and basophils, thereby reducing mast cell and basophil degranulation and the release of histamine. 2,3 Omalizumab was approved by Health Canada in 2005 for adults and adolescents 12 years with moderate to severe persistent asthma whose symptoms are inadequately controlled with ICS. The Health Canada recommended dose of omalizumab for asthma is 150 to 375 mg administered subcutaneously every 2 to 4 weeks depending on baseline IgE levels and body weight. 4 Omalizumab was previously reviewed by the Canadian Expert Drug Advisory Committee (CEDAC) in March 2006 for the treatment of moderate to severe persistent asthma in adults and adolescents 12 years whose symptoms are inadequately controlled with ICS, and received a recommendation of do not list. 5 CADTH has previously produced a Rapid Response Summary of Abstracts in November 2011 assessing the clinical and cost-effectiveness of omalizumab for Disclaimer: The Rapid Response Service is an information service for those involved in planning and providing health care in Canada. Rapid responses are based on a limited literature search and are not comprehensive, systematic reviews. The intent is to provide a list of sources of the best evidence on the topic that CADTH could identify using all reasonable efforts within the time allowed. Rapid responses should be considered along with other types of information and health care considerations. The information included in this response is not intended to replace professional medical advice, nor should it be construed as a recommendation for or against the use of a particular health technology. Readers are also cautioned that a lack of good quality evidence does not necessarily mean a lack of effectiveness particularly in the case of new and emerging health technologies, for which little information can be found, but which may in future prove to be effective. While CADTH has taken care in the preparation of the report to ensure that its contents are accurate, complete and up to date, CADTH does not make any guarantee to that effect. CADTH is not liable for any loss or damages resulting from use of the information in the report. Copyright: This report contains CADTH copyright material and may contain material in which a third party owns copyright. This report may be used for the purposes of research or private study only. It may not be copied, posted on a web site, redistributed by or stored on an electronic system without the prior written permission of CADTH or applicable copyright owner. Links: This report may contain links to other information available on the websites of third parties on the Internet. CADTH does not have control over the content of such sites. Use of third party sites is governed by the owners own terms and conditions.

2 the treatment of allergic asthma in adults and children who are not responsive to other therapies and found that omalizumab decreased the risk of asthma exacerbations and was found by most studies to be cost-effective due to the health benefits achieved. 6 The purpose of this review is to provide an update to the 2011 CADTH Rapid Response report and provide a full summary with critical appraisal by assessing the clinical and costeffectiveness of omalizumab for the treatment of allergic asthma in adults and children who are not responsive to other therapies, and identifying evidence-based guidelines regarding the use of omalizumab in these patient populations. RESEARCH QUESTIONS 1. What is the clinical effectiveness of omalizumab for the treatment of allergic asthma in adults and children who are not responsive to other therapies? 2. What is the cost-effectiveness of omalizumab for the treatment of allergic asthma in adults and children who are not responsive to other therapies? 3. What are the international evidence-based guidelines regarding the use of omalizumab for the treatment of allergic asthma in adults and children? KEY FINDINGS Evidence from systematic reviews suggests that omalizumab treatment decreases the risk of asthma exacerbations in patients with moderate to severe allergic asthma inadequately controlled by standard therapies. There is less evidence in children. Omalizumab was found by some studies to be cost-effective, but not by other studies at current willingness to pay thresholds. One evidence-based guideline recommends omalizumab for the treatment of severe persistent confirmed allergic IgE-mediated asthma as an add-on to optimized standard therapy in people aged 6 years and older who need continuous or frequent treatment with oral corticosteroids. METHODS Literature Search Methods A limited literature search was conducted on key resources including PubMed, The Cochrane Library (2015, Issue 2), University of York Centre for Reviews and Dissemination (CRD) databases, Canadian and major international health technology agencies, as well as a focused Internet search. No filters were applied to limit the retrieval by study type. Where possible, retrieval was limited to the human population. The search was also limited to English language documents published between January 1, 2011 and February 5, Rapid Response reports are organized so that the evidence for each research question is presented separately. Selection Criteria and Methods One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed and potentially relevant articles were retrieved and assessed for Omalizumab Treatment for Adults and Children with Allergic Asthma 2

3 inclusion. The final selection of full-text articles was based on the inclusion criteria presented in Table 1. Population Intervention Comparator Outcomes Study Designs Table 1: Selection Criteria Patients with moderate to severe persistent allergic asthma whose symptoms are inadequately controlled with inhaled corticosteroids Omalizumab Any comparator Clinical improvement of allergic asthma symptoms, improved asthma exacerbation management, cost-effectiveness, guidelines and recommendations Health technology assessments, systematic reviews, meta-analyses, randomized controlled trials, non-randomized studies, economic evaluations, evidence-based guidelines Exclusion Criteria Articles were excluded if they did not meet the selection criteria outlined in Table 1, they were duplicate publications, or were published prior to Critical Appraisal of Individual Studies The included systematic reviews were critically appraised using the Assessment of Multiple Systematic Reviews (AMSTAR) tool, 7 economic studies were assessed using the Drummond checklist, 8 and guidelines were assessed with the AGREE II instrument. 9 Summary scores were not calculated for the included studies; rather, a review of the strengths and limitations of each included study were described. SUMMARY OF EVIDENCE Details of study characteristics, critical appraisal, and study findings are located in Appendices 2, 3, and 4, respectively. Quantity of Research Available A total of 309 citations were identified in the literature search. Following screening of titles and abstracts, 286 citations were excluded and 23 potentially relevant reports from the electronic search were retrieved for full-text review. Four potentially relevant publications were retrieved from the grey literature search. Of these potentially relevant articles, 18 publications were excluded for various reasons, while nine publications met the inclusion criteria and were included in this report. Appendix 1 describes the PRISMA flowchart of the study selection. Three systematic reviews, four economic evaluations, and two evidence-based guidelines were identified. Summary of Study Characteristics Systematic Reviews One systematic review and meta-analysis 10 conducted in China included six long-term RCTs published between 2003 and 2011 (52 to 62 weeks in duration) that compared omalizumab at Omalizumab Treatment for Adults and Children with Allergic Asthma 3

4 any dose or route of administration as an adjunctive therapy to inhaled or oral corticosteroids to placebo in patients with persistent, uncontrolled, moderate to severe allergic asthma despite high-dose ICS or ICS + LABA. Clinical outcomes included asthma exacerbations, reduced ICS doses, asthma symptom scores, and safety. One systematic review and meta-analysis 11 conducted in the UK included 25 double-blind RCTs published between 1999 and 2012 (duration 8 to 60 weeks) that compared omalizumab at any dose or route of administration to placebo in adults and children with chronic asthma with or without background steroid therapy. Clinical outcomes included asthma exacerbations, reduction or termination of ICS use, asthma symptoms, hospitalizations, mortality, and safety. One systematic review 12 that was part of a health technology assessment included 11 RCTs published between 2004 and 2012 that compared subcutaneous omalizumab dosed every 2 to 4 weeks to placebo or optimized standard therapy in a patient group that fell within the licensed indication in the UK, which is adults and adolescents 12 years and children 6 to 11 years with severe persistent allergic asthma and exacerbations despite daily high-dose ICS + LABA. Optimized standard therapy was defined as daily high-dose ICS + LABA with the possible addition of a LTRA, theophyllines, or slow-releasing β 2 -agonist tablets plus frequent or continuous oral corticosteroids. Clinical outcomes included asthma exacerbations, reduction or termination of ICS use, asthma symptoms, hospitalizations, mortality, and safety. Economic Evaluations Four economic evaluations were included One economic evaluation each was from the UK, 13 Spain, 14 the Netherlands, 15 and Japan. 16 The economic evaluation from the UK was part of a health technology assessment 12,13 that determined the cost-effectiveness of omalizumab as add-on therapy to standard care in a patient group that fell within the licensed indication in the UK, which is adults and adolescents 12 years and children 6 to 11 years with severe persistent allergic asthma and exacerbations despite daily high-dose ICS + LABA. The analysis was conducted from the perspective of the National Health Service, and efficacy data comparing omalizumab to placebo or standard of care were taken from INNOVATE, EXALT, and IA-05. Costs of exacerbations, routine visits, initiation of therapy, standard therapy costs, omalizumab treatment costs, and administration and monitoring costs were based on 2010 prices and expressed in UK pounds sterling. The omalizumab list price in 2010 was for a 150 mg prefilled syringe and for 75 mg. The discounted patient access scheme price was not disclosed. The economic evaluation from Spain determined the cost-effectiveness of omalizumab as addon therapy to previous standard treatment (treatment indicated by clinical guidelines) compared to routine clinical practice in real-life practice from the perspective of the Spanish National Health System. 14 Efficacy data was taken from a single Severe Asthma Unit in Spain of 79 patients diagnosed with severe persistent asthma that is not controlled after over one year of follow-up. Costs of emergency room visits for exacerbations and additional use of omalizumab, were based on 2012 prices and expressed in euros. Costs of standard treatments and medical visits were not taken into account as they were assumed to be the same for both pre-treatment and post-treatment periods. The cost of treatment with omalizumab was 2.46 per mg. This study was funded by industry. Omalizumab Treatment for Adults and Children with Allergic Asthma 4

5 The economic evaluation from the Netherlands performed a cost-effectiveness analysis of omalizumab as add-on to standard to care compared to standard of care alone from a societal perspective. 15 Efficacy data was taken from observational data in the experience registry from 154 Dutch patients 12 years old with uncontrolled allergic asthma despite treatment with highdose ICS + LABA. Costs of exacerbations, standard therapy, and omalizumab therapy were taken from Dutch sources and inflated to The model assumed that doses and proportion of patients on therapy remained constant during the model and was the same for the standard of care and omalizumab groups. The annual cost of omalizumab was 16,766 based on dosing on a per mg basis. This study was funded by industry. The economic evaluation from Japan performed a cost-effectiveness analysis of omalizumab as add-on to standard therapy compared to standard therapy alone from a societal perspective. 16 Efficacy data was taken from an RCT conducted in Japan in patients 20 to 75 years with moderate to severe persistent asthma despite high-dose ICS. Costs of exacerbations, standard therapy, omalizumab therapy, and direct non-health care costs of transportation were based on 2010 prices and expressed as USD. Standard therapy costs were obtained assuming patients would receive high-dose ICS, LABA, theophylline, and LTRAs. In addition, the model assumed that a patient with a severe exacerbation made one visit to the emergency department and that emergency department visits and hospitalizations required transportation costs. The cost of omalizumab used was $635 for a 150 mg prefilled syringe. Generic drugs were not considered. Guidelines Two evidence-based guidelines from the UK were included in this review. 17,18 The Scottish Intercollegiate Guidelines Network (SIGN, 2014) provided recommendations on pharmacological and non-pharmacological asthma management. 17 The National Institute for Health and Clinical Excellence (NICE, 2013) provided recommendations based on a technology appraisal of omalizumab in adults and adolescents 12 years and children 6 to 11 years. 18 Summary of Critical Appraisal All of the included systematic reviews were based on clearly defined objectives and included a summary of included study characteristics with scientific quality and risk of bias assessed and documented. The literature search strategy was not clearly reported in in one systematic review and it was not clear whether duplicate study selection and data extraction was performed. 10 The generalizability of all the systematic reviews may be limited due to studies being included that used a range of different omalizumab dosing and heterogeneity due to different inclusion criteria and outcome measures. All of the included economic evaluations had clearly stated objectives and reported the source of efficacy and cost data. Relevant costs were considered in the included economic evaluations including costs of exacerbations, standard of therapy, and omalizumab therapy. The assumptions made were generally valid. The main limitation of the economic evaluations was the source of data used to inform the economic models. Clinical inputs were based on a single trial in three studies specific to the country the study was conducted in, which may limit generalizability of findings to other contexts The included guidelines did not report if patients preferences and views were taken into consideration. 17,18 Both guidelines were based on a systematic review of the literature and methodology used to formulate the recommendations were reported. Costs-effectiveness data Omalizumab Treatment for Adults and Children with Allergic Asthma 5

6 was considered in one guideline. 18 Both guidelines assembled an appropriate panel of experts from relevant professional groups for guideline development. Summary of Findings What is the clinical effectiveness of omalizumab for the treatment of allergic asthma in adults and children who are not responsive to other therapies? The systematic review by Lai et al. identified six RCTs (five in adults, one in children) that looked at long-term efficacy and safety of omalizumab compared to placebo and performed a meta-analysis of the studies. 10 The analysis found that omalizumab-treated patients experienced statistically significantly lower rates of clinically significant asthma exacerbations compared to patients who received placebo during the steroid-stable phase of the trials (Relative Risk [RR] 0.69; 95% Confidence Interval [CI] 0.53 to 0.90), and this reduction remained statistically significant over a period of 52 weeks (RR 0.63; 95% CI 0.55 to 0.71). The reduction in ICS dose was statistically significantly decreased in omalizumab-treated patients compared with the placebo group (RR 1.86; 95% CI 1.51 to 2.29). Two of the RCTs demonstrated greater reductions in asthma symptom scores with omalizumab than placebo. Patients reporting adverse events were similar in both treatment groups (RR 0.97; 95% CI 0.93 to 1.01). There were fewer serious adverse events reported among omalizumab-treated patients than patients who received placebo (RR 0.55; 95% CI 0.37 to 0.82). The systematic review and meta-analysis by Normansell et al. identified 25 double-blind RCTs that compared omalizumab to placebo in adults and children with chronic asthma. 11 Twenty-one RCTs were included in the main analyses as they used the subcutaneous route of administration. This review found that treatment with omalizumab resulted in a statistically significant reduction in the odds of having one or more exacerbations compared to placebo in the steroid-stable phase (10 studies, N = 3261; Odds Ratio [OR] 0.55; 95% CI to 0.65) and the steroid-tapering phase (4 studies, N = 1631; OR 0.46; 95% CI 0.36 to 0.59). This statistically significant difference was seen in the subgroup of studies looking at patients with moderate to severe asthma (7 studies; N = 1889; OR 0.50; 95% CI 0.42 to 0.60), but not in the subgroup looking at patients with severe asthma alone (2 studies, N = 277; OR 1.00; 95% CI 0.50 to 1.99). Treatment with omalizumab was found to result in a statistically significant reduction in the odds or experiencing one or more hospitalization in patients with moderate to severe asthma (4 studies, N = 1824; OR 0.16; 95% CI 0.06 to 0.42). Patients with moderate to severe asthma treated with omalizumab were statistically significantly more likely to be able to withdraw from their ICS completely than those treated with placebo (4 studies, N = 529; OR 2.50; 95% CI 2.00 to 3.13). There was a small but statistically significant reduction in daily steroid dose seen among omalizumab-treated patients compared with placebo-treated patients, but there was a high degree of heterogeneity among the three studies that looked at this outcome. Due to heterogeneity among the seven studies reporting on asthma symptoms, no statistical aggregation was performed. However, there was a statistically significant difference favouring omalizumab in end of the treatment symptom scores for patients with moderate to severe asthma in four of seven studies reporting data on this outcome. Statistically significantly fewer serious adverse events occurred in patients treated with omalizumab than those treated with placebo (15 studies, N = 5713; OR 0.72; 95% CI 0.57 to 0.91). There was no statistically significant difference between omalizumab and placebo with respect to any adverse event (14 studies, N = 5167; OR 0.92; 95% CI 0.81 to 1.06). Omalizumab Treatment for Adults and Children with Allergic Asthma 6

7 The systematic review by Norman et al (part of a NICE technology appraisal) identified 11 RCTs and that compared subcutaneous omalizumab every 2 to 4 weeks to placebo or optimized standard therapy in adults and children with severe persistent allergic asthma. 12 Due to the heterogeneity between included studies, no meta-analyses were performed and results were presented narratively. The studies INNOVATE, EXALT, and the IA-04 European Union Population (EUP) subgroup all found that treatment with omalizumab resulted in a statistically significant reduction in the rate of exacerbations in the follow-up period compared to placebo or optimized standard therapy in adult patients. Data in children was limited to a post-hoc subgroup analysis from the IA-05 EUP subgroup that found a statistically significant benefit for omalizumab in reducing exacerbation rate. Hospitalization data for adult populations were reported in three trials. Relative treatment effect for hospitalization rate favoured omalizumab in INNOVATE and EXALT, but was statistically significant only in EXALT. In children, the IA-05 EUP showed no evidence of a difference in hospitalization rates between the groups or in the number of patients with zero hospitalizations. There was limited evidence from the included RCTs on the oral steroid-sparing effect of omalizumab and the results were mixed. There was no data reported on the effect of omalizumab on ICS withdrawal and reduction. There was heterogeneity in the assessment of asthma symptoms in the included studies, a wide range of scales and individual symptom measures were used to assess response to therapy. Statistically significant benefits were seen in change from baseline in symptom scores in the INNOVATE, IA-04 EUP and the EXALT studies with omalizumab in adult patients. In children, the IA-05 EUP subgroup found no statistically significant changes from baseline in total asthma clinical symptom score in children at either 24 or 52 weeks. In the included trials, adverse event rates and serious adverse events were generally similar between treatment groups. What is the cost-effectiveness of omalizumab for the treatment of allergic asthma in adults and children who are not responsive to other therapies? One economic evaluation conducted in the UK was identified as an individual publication 13 and included as part of the NICE technology appraisal. 12 The study determined the costeffectiveness of omalizumab as an add-on to standard care versus standard care alone from the perspective of the National Health Service using a decision-analytic and Markov model using clinical inputs from RCTs identified in the systematic review and a lifetime horizon. Analyses were performed using the omalizumab list price and a patient access scheme (PAS) discounted price. Costs were expressed in 2010 UK pound sterling. Using the list price under the base case scenario, the incremental cost-effectiveness ratio (ICER) for adults and adolescents 12 years was 83,822/quality-adjusted life year (QALY), and that for children 6 to 11 years was 78,009/QALY. Using the PAS discount under the base case scenario, the ICER for adults and adolescents 12 years was 57,557/QALY, and that for children 6 to 11 years was 53,348/QALY. The ICERs were lower in subgroup analyses of patients that were hospitalized in the year prior to trial entry, and in patients receiving maintenance oral corticosteroids at trial baseline due to a greater improvement in health-related quality of life. The probability that omalizumab was cost-effective at a threshold value of 20,000 and 30,000/QALY was zero for all base case analyses except for the hospitalization subgroup analysis with the PAS discount. An economic evaluation conducted in Spain determined the cost-effectiveness of omalizumab as an add-on to previous standard treatment from the perspective of the Spanish National Health System using data from a single center 10 months before and after initiation of treatment with omalizumab. 14 Patients were asked about their history of exacerbations in the three months before omalizumab treatment and this data was linearly extrapolated to 10 months prior to treatment. Direct healthcare costs were derived from the recorded number of emergency room Omalizumab Treatment for Adults and Children with Allergic Asthma 7

8 visits for exacerbations and additional use of omalizumab. Costs were expressed in euros at 2012 values. The ICER between the two periods (10 months before and 10 months after omalizumab treatment) was determined to be 26,864.89/QALY, with the cost per exacerbation avoided being One-way sensitivity analyses found that the ICER was sensitive to the change in ER visit unit costs and change in extrapolation multiplication factor of exacerbations for the pre-omalizumab treatment period. An economic evaluation conducted in the Netherlands determined the cost-effectiveness of omalizumab as add-on to standard of care from a societal perspective using a Markov model and lifetime horizon with clinical inputs from a registry where only data from Dutch patients were extracted. 15 Costs were taken from Dutch sources and inflated to 2010 in euros. Under the base case scenario, the ICER was 38,528/QALY. Sensitivity analyses found that the economic model was sensitive to time horizon, the cost of an exacerbation, and exacerbation-related mortality. Probabilistic sensitivity analyses found that the ICER was less than 44,000/QALY 75% of the time, which was considered to be relatively good value for the Dutch healthcare system, according to the authors. An economic evaluation conducted in Japan determined the cost-effectiveness of omalizumab as add-on to standard therapy from a societal perspective using a Markov model with a lifetime horizon. 16 Costs were taken from 2010 prices and expressed as USD. Under the base case scenario, the ICER was $755,200/QALY. A subgroup analysis using responders alone calculated an ICER of $590,100/QALY. One-way sensitivity analyses found that the ICER was sensitive to the risk of death from hospitalization, rate ratio for hospitalization, utility value used for symptom-free asthma, rate ratio for symptom-free asthma, discount rate, utility for day-today asthma, and omalizumab cost. The authors concluded that omalizumab was not costeffective in Japan given a willingness-to-pay threshold of $45,000/QALY and that the costeffectiveness could be improved if omalizumab therapy could be confined to previously predicted responders. What are the international evidence-based guidelines regarding the use of omalizumab for the treatment of allergic asthma in adults and children? The Scottish Intercollegiate Guidelines Network (SIGN, 2014) recommends that omalizumab treatment should only be initiated in specialist centres with experience of evaluation and management of patients with severe and difficult asthma. 17 [Recommended best practice based on the clinical experience of the guideline development group] The National Institute for Health and Care Excellence (NICE, 2013) recommends omalizumab as an option for treating severe persistent confirmed allergic IgE-mediated asthma as an add-on to optimized standard therapy in people aged 6 years and older who need continuous or frequent treatment with oral corticosteroids (defined as 4 or more courses in the previous year). 18 This guidance was based on a NICE technology assessment. 12 Limitations There was an overlap in the studies included in the three systematic reviews, which limits the amount of novel information in this review. No economic evaluations were identified that evaluated the cost-effectiveness of omalizumab from the Canadian healthcare perspective, which may limit generalizability due to the clinical and cost inputs used to generate the economic models. In addition, half the included economic evaluations were sponsored by Omalizumab Treatment for Adults and Children with Allergic Asthma 8

9 industry. All of the economic models were based on the rate of asthma exacerbations instead of the number of patients who experienced an exacerbation, which could potentially overestimate the clinical effectiveness of omalizumab. No guidelines were published by a Canadian professional society. The NICE guideline used the technology appraisal process developed by NICE, in which grading of recommendations and levels of evidence were not clearly specified. Not all of the included studies had inclusion criteria or used clinical inputs that were in line with the Health Canada-approved indication, which may limit generalizability of findings to how omalizumab would be used in a Canadian context. There was a lack of information on the use of omalizumab in children. CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING The systematic reviews demonstrated that omalizumab was associated with a reduction of clinically significant asthma exacerbations and hospitalizations compared to placebo or standard of care in adults and adolescents. In addition, omalizumab was found to be associated with a reduction in inhaled corticosteroid use and improved asthma symptoms compared to placebo in adults and adolescents. One systematic review analyzed children 6 to 11 years old separately and found limited data demonstrating reduction in exacerbation rate with omalizumab compared to placebo in this population, but no difference in other clinical outcomes. Results from the economic evaluations did not find omalizumab to be cost-effective as an addon to standard of care using current willingness to pay thresholds in the UK and Japan. 13,16 Cost-effectiveness was improved in certain subgroup analyses of patients with more severe disease. 13 Two economic evaluations found that omalizumab was cost-effective within the Dutch and Spanish healthcare settings. 14,15 There was a lack of economic evaluations conducted from the perspective of the Canadian healthcare system, limiting generalizability of these economic findings to the Canadian context. SIGN recommends that omalizumab treatment only be initiated in specialist centers that have experience with managing patients with severe and difficult asthma, but provided no recommendation on the specific patient population to whom this should be administered. 17 NICE recommends omalizumab for the treatment of severe persistent confirmed allergic IgE-mediated asthma as an add-on to optimized standard therapy in people aged 6 years and older who need continuous or frequent treatment with oral corticosteroids. The Health Canada-approved indication for omalizumab is for the treatment of adults and adolescents 12 years of age and above with moderate to severe persistent asthma who have a positive skin test or in vitro reactivity to a perennial aeroallergen and whose symptoms are inadequately controlled with inhaled corticosteroids. In Canada, omalizumab is not indicated for children below 12 years of age. PREPARED BY: Canadian Agency for Drugs and Technologies in Health Tel: Omalizumab Treatment for Adults and Children with Allergic Asthma 9

10 REFERENCES 1. Graham LM, Eid N. The impact of asthma exacerbations and preventive strategies. Curr Med Res Opin Dec 22; McKeage K. Omalizumab: a review of its use in patients with severe persistent allergic asthma. Drugs Jul;73(11): Solèr M. Omalizumab for severe allergic asthma: 7 years and open questions. Respiration. 2014;88(2): Pr Xolair (omalizumab): sterile powder for reconstitution 150 mg vial IgE-neutralizing antibody (anti-ige) [product monograph]. Dorval (QC): Novartis Pharmaceuticals Canada Inc.; 2014 Aug Canadian Agency for Drugs and Technologies in Health. CEDAC final recommendation on reconsideration and reason for recommendation. Omalizumab (Xolair - Novartis Pharmaceuticals Canada Inc.) [Internet]. Ottawa: The Agency; 2006 Mar 7. [cited 2015 Feb 20]. Available from: 6. Canadian Agency for Drugs and Technologies in Health. Omalizumab treatment for adults and children with allergic asthma: clinical effectiveness, cost-effectiveness, and guidelines [Internet]. Ottawa: The Agency; 2011 Nov 21. [cited 2015 Feb 24]. Available from: 7. Shea BJ, Grimshaw JM, Wells GA, Boers M, Andersson N, Hamel C, et al. Development of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews. BMC Med Res Methodol [Internet] [cited 2015 Mar 9];7:10. Available from: 8. Higgins JPT, editors. Cochrane handbook for systematic reviews of interventions [Internet]. Version Drummond. Oxford (U.K.): The Cochrane Collaboration; Figure 15.5.a: Drummond checklist. [cited 2015 Mar 9]. Available from: d_1996.htm 9. Brouwers M, Kho ME, Browman GP, Burgers JS, Cluzeau F, Feder G, et al. AGREE II: advancing guideline development, reporting and evaluation in healthcare. CMAJ [Internet] Dec [cited 2014 Apr 9];182(18):E839-E842. Available from: Lai T, Wang S, Xu Z, Zhang C, Zhao Y, Hu Y, et al. Long-term efficacy and safety of omalizumab in patients with persistent uncontrolled allergic asthma: a systematic review and meta-analysis. Sci Rep. 2015;5: Normansell R, Walker S, Milan SJ, Walters EH, Nair P. Omalizumab for asthma in adults and children. Cochrane Database Syst Rev. 2014;1:CD Omalizumab Treatment for Adults and Children with Allergic Asthma 10

11 12. Norman G, Faria R, Paton F, Llewellyn A, Fox D, Palmer S, et al. Omalizumab for the treatment of severe persistent allergic asthma: a systematic review and economic evaluation. Health Technol Assess [Internet] Nov [cited 2015 Feb 9];17(52): Available from: data/assets/pdf_file/0011/93197/fullreporthta17520.pdf 13. Faria R, McKenna C, Palmer S. Optimizing the position and use of omalizumab for severe persistent allergic asthma using cost-effectiveness analysis. Value Health Dec;17(8): Levy AN, García a Ruiz A, García-Agua Soler N, Sanjuan MV. Cost-effectiveness of omalizumab in severe persistent asthma in Spain: a real-life perspective. J Asthma Nov 24; van Nooten F, Stern S, Braunstahl GJ, Thompson C, Groot M, Brown RE. Costeffectiveness of omalizumab for uncontrolled allergic asthma in the Netherlands. J Med Econ. 2013;16(3): Morishima T, Ikai H, Imanaka Y. Cost-effectiveness analysis of omalizumab for the treatment of severe asthma in Japan and the value of responder prediction methods based on a multinational trial. Value in Health Regional Issues [Internet] May [cited 2015 Feb 24];2(1): Available from: British Thoracic Society, Scottish Intercollegiate Guidelines Network. British guideline on the management of asthma: a national clinical guideline [Internet]. Edinburgh: Healthcare Improvement Scotland; 2014 Oct. SIGN 141. [cited 2015 Feb 24]. Available from: National Institute for Health and Care Excellence. Omalizumab for treating severe persistent allergic asthma (review of technology appraisal guidance 133 and 201) [Internet].NICE; 2013 Apr. London, England. [cited 2015 Feb 24]. (NICE technology appraisal guidance 278). Available from: severe-persistent-allergic-asthma-review-of-technology-appraisal-guidance-133-and-201- pdf Omalizumab Treatment for Adults and Children with Allergic Asthma 11

12 APPENDIX 1: Selection of Included Studies 309 citations identified from electronic literature search and screened 286 citations excluded 23 potentially relevant articles retrieved for scrutiny (full text, if available) 4 potentially relevant reports retrieved from other sources (grey literature, hand search) 27 potentially relevant reports 18 reports excluded: -no comparator (6) -irrelevant outcomes (1) -already included in at least one of the selected systematic reviews (6) -duplicate (1) -study design (1) -other (review articles, editorials)(3) 9 reports included in review Omalizumab Treatment for Adults and Children with Allergic Asthma 12

13 APPENDIX 2: Characteristics of Included Publications Table A1: Characteristics of Included Systematic Reviews and Meta-Analyses First Author, Population Publication Characteristics Year, Country Lai (2015) 10 China Normansell (2014) 11 UK Norman (2013) 12 UK Types and numbers of primary studies included 6 RCTs (duration 52 to 62 weeks) N = double-blind, parallel-group RCTs (duration 8 to 60 weeks) 11 RCTs (9 adults, 1 children, 1 adults and children) duration 16 to 60 weeks 13 observational studies (supportive evidence) Patients with persistent, uncontrolled, moderate to severe allergic asthma despite high-dose ICS or ICS + LABA Adults and children with chronic asthma Adults and adolescents ( 12 years) and children (6 to 11 years) with severe persistent allergic asthma and: - A positive skin test or in vitro reactivity to a perennial aeroallergen - Frequent daytime symptoms or night-time awakenings - Exacerbations despite daily high-dose ICS + LABA - Reduced lung function (FEV 1 < 80% - adults and adolescents only) Intervention Comparator(s) Clinical Outcomes, Length of Follow-Up Omalizumab as an adjunctive therapy to inhaled or oral corticosteroids (16 to 28 weeks) Steroid reduction phase (12 to 28 weeks) Anti-IgE therapy at any dose or route (omalizumab) 21 RCTs used subcutaneous route, 3 used IV, 1 used inhaled Subcutaneous omalizumab every 2 to 4 weeks Placebo with background therapy of inhaled or oral corticosteroids Placebo with or without background corticosteroid use Placebo Optimized standard therapy ICS = inhaled corticosteroids; LABA = long-acting beta 2-agonist; OMA = omalizumab; RCT = randomized controlled trial Long-term efficacy (asthma exacerbations, reduced ICS doses, asthma symptom scores), safety Asthma exacerbations, reduction or termination of ICS use, asthma symptoms, hospitalizations, mortality, safety Clinically significant exacerbations, reduction or termination of ICS use, asthma symptoms, hospitalizations, mortality, safety Omalizumab Treatment for Adults and Children with Allergic Asthma 13

14 Table A2: Characteristics of Included Cost Studies First author, Publication Year, Country Type of Analysis, Perspective Intervention, Comparator Faria (2014) 13 / Norman (2013) 12 cost effectiveness analysis UK Levy (2014) 14 Spain Costeffectiveness analysis Health care perspective: National Health Service Costeffectiveness analysis Health care perspective: Spanish National Health System Omalizumab Omalizumab add-on to previous standard treatment Routine clinical practice Study Population UK licensed indication: Adults and adolescents ( 12 years) and children (6 to 11 years) with severe persistent allergic asthma and: - A positive skin test or in vitro reactivity to a perennial aeroallergen - Frequent daytime symptoms or night-time awakenings - Exacerbations despite daily high-dose ICS + LABA - Reduced lung function (FEV 1 < 80% - adults and adolescents only) 79 patients >14 years in a single Severe Asthma Unit in Spain diagnosed with severe persistent asthma not controlled after >1 year of follow-up Time Horizon Lifetime horizon 10 months before and after initiation of treatment with omalizumab Comments Decision-analytic and Markov model Effectiveness and safety evidence were taken from systematic reviews Model inputs were mostly based on INNOVATE, EXALT, and IA-05 Costs were expressed in UK pound sterling at a 2010 price base from the perspective of the NHS omalizumab list price for 150 mg prefilled syringe and for 75 mg Both costs and QALYs were discounted at 3.5% per annum as per NICE recommendations. Industry sponsored 2012 costs were used cost of treatment with omalizumab was 2.46 per mg. Utilities were calculated from Mini Asthma Quality of Life Questionnaire (miniaqlq) scores Direct healthcare costs derived from the recorded number of ER visits (using Omalizumab Treatment for Adults and Children with Allergic Asthma 14

15 First author, Publication Year, Country Type of Analysis, Perspective Intervention, Comparator Study Population Time Horizon Comments hospital data) for exacerbations and additional use of omalizumab Univariate sensitivity analyses Van Nooten(2013) 15 The Netherlands Costeffectiveness analysis Societal perspective in the Netherlands Omalizumab + standard of care Standard of care Patients in the observational experience registry 12 years with uncontrolled allergic asthma despite treatment with high-dose ICS + LABA one year interim data from 154 Dutch patients were used Lifetime horizon Industry sponsored Resources were costed using Dutch sources and inflated to annual cost of omalizumab was 16,766 based on dosing on a per mg basis The model assumed that doses and proportion of patients on therapy remained constant during the model and was the same for the standard of care and omalizumab groups Markov model Utility values were taken from PERSIST (observational study) Morishima (2013) 16 Japan Costeffectiveness analysis Societal perspective in Japan Omalizumab + standard therapy Standard therapy 315 patients from a 16-week RCT conducted in Japan in patients 20 to 75 years with moderate-to- Lifetime horizon 5-year omalizumab add-on therapy was followed by standard Discount rates for effect and costs were 1.5% and 4%, respectively Markov model A response rate of 60.5 % was incorporated in the model as responder rates Omalizumab Treatment for Adults and Children with Allergic Asthma 15

16 First author, Publication Year, Country Type of Analysis, Perspective Intervention, Comparator Study Population severe persistent asthma despite high-dose ICS Time Horizon therapy alone Comments were not reported in the RCT 2010 costs were used and expressed as USD - $635 for 150 mg prefilled syringe and $318 for 75 mg Costs were discounted at 3% per year Utility values obtained from a different study As no deaths were recorded in the RCT, mortality risk was calculated using Japan s official database of hospitalized asthmatic patients Probabilistic sensitivity analysis using Monte Carlo simulation A responder subgroup analysis was performed using only responders receiving 5-year omalizumab therapy Omalizumab Treatment for Adults and Children with Allergic Asthma 16

17 Table A3: Characteristics of Included Guidelines Intended users/ Target population Intervention and Practice Considered Major Outcomes Considered Scottish Intercollegiate Guidelines Network (SIGN), Healthcare professionals involved in the care of people with asthma, people with asthma, parents/ carers Asthma management (nonpharmacological and pharmacological) Asthma exacerbations National Institute for Health and Clinical Excellence (NICE), Healthcare Omalizumab Asthma professionals exacerbations involved in the care of people with asthma Evidence collection, Selection and Synthesis Systematic review, recommendations assessed by GRADE Based on a technology appraisal (systematic review and economic evaluation) Recommendations development and Evaluation Guideline development group and systematic review of the evidence Appraisal committee Omalizumab Treatment for Adults and Children with Allergic Asthma 17

18 APPENDIX 3: Critical Appraisal of Included Publications Table A1: Strengths and Limitations of Systematic Reviews and Meta-Analyses using AMSTAR 7 Strengths Limitations Lai (2015) 10 Objectives clearly defined Summary of study characteristics provided Scientific quality and risk of bias of included studies assessed and documented Risk of publication bias assessed Normansell (2014) 11 Comprehensive literature search based on clearly defined objectives Summary of study characteristics and list of included and excluded studies provided Scientific quality and risk of bias of included studies assessed and documented Subgroup analyses performed to assess heterogeneity (asthma severity, age) Risk of publication bias assessed Norman (2013) 12 Comprehensive literature search based on clearly defined objectives Summary of study characteristics and list of included and excluded studies provided Scientific quality and risk of bias of included studies assessed and documented Literature search strategy unclear Unclear if duplicate study selection and data extraction was performed List of excluded studies not provided Specific inclusion criteria not reported Some a priori subgroups analyses were not possible due to trials identified (e.g., age). Studies used a range of omalizumab doses, some of which may not be Health Canada-approved doses, limiting generalizability of findings Included studies ranged in duration, but no subgroup analysis was performed for duration of treatment Unclear if risk of publication bias assessed Included studies were specific to UK licensing criteria, which may not be as generalizable to Canadian criteria No meta-analysis was performed Table A2: Strengths and Limitations of Economic Studies using Drummond 8 Strengths Limitations Faria (2014) 13 / Norman (2013) 12 cost effectiveness analysis The research question was clearly stated The sources of effectiveness data was reported Sources of data came from a systematic review and multiple trials Levy (2014) 14 The research question was clearly stated The source of effectiveness data was reported Van Nooten(2013) 15 The research question was clearly stated The source of effectiveness data was reported (expierience) Morishima (2013) 16 The research question was clearly stated The source of effectiveness data was reported and appropriate to the setting (Japan RCT) Subgroup analyses were defined post-hoc Data was based on a single-center trial in Spain, limiting generalizability of clinical inputs Time horizon was limited to 10 months before and after treatment Data was based on a single trial registry that looked specifically at the results from the Dutch population, limiting generalizability of results Data was based on a single study conducted in Japan, limiting generalizability of clinical inputs Utility values and responder data were taken from alternate sources Omalizumab Treatment for Adults and Children with Allergic Asthma 18

19 Table A3: Strengths and Limitations of Guidelines using AGREE II 9 Strengths Limitations Scottish Intercollegiate Guidelines Network (SIGN), Objectives and patient population clearly described Patient preference and views not taken into account Selection criteria and methodologies and evaluation criteria clearly described Costs and barriers of guidance implementation not evaluated Included studies were appraised for quality Recommendations were graded according to a defined grading system Guidelines were peer reviewed National Institute for Health and Clinical Excellence (NICE), Objectives and patient population clearly described Patient preference and views not taken into account Selection criteria and methodologies and evaluation criteria clearly described Included studies were appraised for quality Guidelines were peer reviewed Costs and barriers of guidance implementation not evaluated Omalizumab Treatment for Adults and Children with Allergic Asthma 19

20 APPENDIX 4: Main Study Findings and Author s Conclusions Table A1: Summary of Findings of Included Systematic Reviews and Meta-Analyses Main Study Findings Author s Conclusions Lai (2015) 10 Exacerbations Omalizumab-treated patients experienced statistically significantly lower rates of clinically significant asthma exacerbations compared to patients who received placebo during the stable phase (RR 0.69; 95% CI 0.53 to 0.90). This reduction in exacerbation rates remained statistically significant over a period of 52 weeks (RR 0.63; 95% CI 0.55 to 0.71). ICS reduction ICS doses were statistically significantly decreased in omalizumabtreated patients compared with the placebo group (RR 1.86; 95% CI 1.51 to 2.29). Asthma symptoms Two RCTs demonstrated greater reductions in asthma symptom scores with omalizumab than placebo. Based on the pooled analyses, we found that omalizumab significantly reduced the incidence of asthma exacerbations and ICS use...additionally, omalizumab was well tolerated and demonstrated an acceptable safety profile. (pp. 4-5) Safety Patients reporting adverse events were similar in both treatment groups (RR 0.97; 95% CI 0.93 to 1.01). There were fewer serious adverse events reported among omalizumab-treated patients than patients who received placebo (RR 0.55; 95% CI 0.37 to 0.82). Normansell (2014) 11 Exacerbations Treatment with omalizumab resulted in a significant reduction in the odds of having one of more exacerbations compared to placebo in all groups except for the subgroup analysis in studies looking at patients with severe asthma. Steroid-stable (10 studies, N = 3261): OR 0.55; 95% CI to 0.65 Steroid-tapering (4 studies, N = 1631): OR 0.46; 95% CI 0.36 to 0.59 Moderate/severe asthma (7 studies; N = 1889): OR 0.50; 95% CI 0.42 to 0.60 Severe asthma (2 studies, N = 277): OR 1.00; 95% CI 0.50 to 1.99 Data from the included trials have shown that omalizumab is both effective and safe in patients with moderate to severe asthma that is uncontrolled on moderate to high doses of inhaled steroids with or without long-acting beta 2-agonists. Insufficient evidence of benefit has been found in participants specifically with severe OCS-dependent asthma. Very few studies have explored efficacy in children with moderate to severe asthma. (p. 28) Hospitalizations Treatment with omalizumab resulted in a significant reduction in the odds of experiencing one or more hospitalization. Moderate/severe asthma (4 studies, N = 1824): OR 0.16; 95% CI 0.06 to 0.42 ICS withdrawal and reduction Patients treated with omalizumab were statistically significantly more likely to be able to withdraw from their ICS completely than those treated with placebo. Moderate/severe asthma (4 studies, N = 529): OR 2.50; 95% CI 2.00 to 3.13 There was a small but statistically significant reduction in daily steroid dose seen among omalizumab-treated patients compared with placebo-treated patients (3 studies, N = 1188): WMD -118 mcg BDP equivalent per day; 95% CI -154 to -84). A high degree of heterogeneity was observed. Asthma symptoms A significant difference favouring omalizumab was observed with Omalizumab Treatment for Adults and Children with Allergic Asthma 20