PUBLIC SUMMARY DOCUMENT

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1 PUBLIC SUMMARY DOCUMENT Product: Budesonide with eformoterol fumarate dihydrate, powder for oral inhalation, fixed dose combination, 400 micrograms-12 micrograms per dose, Symbicort Turbuhaler 400/12 Sponsor: AstraZeneca Pty Ltd Date of PBAC Consideration: November Purpose of Application The submission sought a Restricted Benefit listing for the symptomatic treatment of patients with chronic obstructive pulmonary disease (COPD) who meet certain criteria. 2. Background The PBAC recommended the restricted benefit listings of budesonide with eformoterol Turbuhaler 200 micrograms/6 micrograms (March 2002 meeting) and 400 micrograms/12 micrograms (March 2004 meeting), on a cost-minimisation basis compared with the individual components, for the treatment of asthma in patients who meet certain criteria. Listing was effective 1 February 2003 and 1 August 2004, respectively. At the November 2004 meeting, the PBAC recommended the listing of budesonide with eformoterol Turbuhaler 100 micrograms/6 micrograms strength, and to broaden the restriction to include those patients with frequent episodes of asthma who are receiving treatment with optimal doses of budesonide. Listing was effective 1 April At the March 2007 meeting, the PBAC recommended amending the current restricted benefit listing for the 200/6 and 100/6 strengths to include single maintenance and reliever therapy (SMART) in patients who had frequent asthma symptoms while taking oral or inhaled corticosteroids. Full details in the March 2007 (PSD) available at: 3. Registration Status As at 15 October 2010, budesonide with eformoterol 400/12 Turbuhaler was TGA registered for the symptomatic treatment of moderate to severe COPD (FEV 1 less than or equal to 50% predicted normal) in adults with frequent symptoms despite long-acting bronchodilator use and/or a history of recurrent exacerbations. Symbicort Turbuhaler is not indicated for the initiation of bronchodilator therapy in COPD. It is also TGA registered for the treatment of asthma where use of a combination (inhaled corticosteroid and long acting beta-agonist) is appropriate. This includes patients who are symptomatic on inhaled corticosteroid therapy and patients who are established on regular long acting beta-agonist and inhaled corticosteroid therapy. Symbicort 400/12 should only be used in patients aged 18 years and over. The 400/12 strength should not be used for the Symbicort maintenance and reliever therapy regimen. 4. Listing Requested and PBAC s View Restricted Benefit The symptomatic treatment of moderate to severe chronic obstructive pulmonary disease (COPD) where the FEV 1 is less than or equal to 50% predicted normal in adults with frequent symptoms despite long acting bronchodilator use and/or a history of recurrent exacerbations. Page 1 of 8

2 NOTE: Budesonide with eformoterol is not indicated for the initiation of bronchodilator therapy in COPD For PBAC s view, see Recommendation and Reasons. 5. Clinical Place for the Proposed Therapy COPD is a progressive disease and lung function is expected to worsen over time. As such, treatment tends to be cumulative with more medications being required as the disease state worsens. Combined therapy with inhaled corticosteroids and long-acting beta 2-adrenoceptor agonists is used in patients with COPD who experience repeated exacerbations. The submission claimed that budesonide with eformoterol would provide an alternative therapy to fluticasone with salmeterol. 6. Comparator The submission nominated fluticasone with salmeterol (Seretide ) as the comparator. This was considered appropriate by the PBAC and is consistent with current guidelines where a long-acting beta 2-adrenoceptor agonists (LABA) is usually given with an inhaled corticosteroid (ICS). 7. Clinical Trials The submission presented an indirect comparison including a meta-analysis of four randomised trials comparing Symbicort with placebo in patients with COPD (Calverley et al 2003, SHINE, SUN, and Szafranski et al 2003), and a meta-analysis of seven randomised trials (Barnes et al 2006, Mahler et al 2002, SCO104925, SFCT01, TORCH, TRISTAN, and Zheng et al 2006) comparing Seretide with placebo in patients with COPD. The submission also presented a second indirect comparison including one randomised trial comparing Symbicort plus tiotropium with tiotropium monotherapy (CLIMB) and a metaanalysis of two randomised trials comparing Seretide plus tiotropium with tiotropium monotherapy in patients with COPD (Aaron et al 2007, Cazzola et al 2007). Publication details of the studies presented in the submission are in the table below. Trial ID / First Protocol title / Publication title author Common reference: placebo Symbicort vs placebo Calverly et al Maintenance therapy with budesonide and formoterol in chronic obstructive pulmonary disease Publication citation Eur Respir J, 2003, Dec; 22(6): SHINE Tashkin et al Efficacy and safety of budesonide and formoterol in one pressurized metered-dose inhaler in patients with moderate to very severe chronic obstructive pulmonary disease: results of a 6- month randomized clinical trial Drugs, 2008; 68(14): Page 2 of 8

3 SUN Rennard et al Szafranski et al Calverley et al Efficacy and tolerability of budesonide/formoterol in one hydrofluoroalkane pressurized metereddose inhaler in patients with chronic obstructive pulmonary disease: results from a 1-year randomized controlled clinical trial Efficacy and safety of budesonide/formoterol in the management of chronic obstructive pulmonary disease. Relationship between respiratory symptoms and medical treatment in exacerbations of COPD Drugs, 2009; 69(5): Eur Respir J, 2003, 21: Eur Respir J, 2005, 26: Seretide vs placebo Barnes et al Antiinflammatory effects of salmeterol/fluticasone propionate in chronic obstructive lung disease Mahler et al Effectiveness of Fluticasone Propionate and salmeterol Combination Delivered via the Diskus Device in the Treatment of Chronic Obstructive Pulmonary Disease Am J Crit Care Med, 2006, 173: Am J Crit Care Med, 2002, 166: TORCH Calverley et al Celli et al Crim et al Ferguson et al Jenkins et al McGarvey et al 2007 Vestbo et al Vestbo et al TRISTAN Calverley et al Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease Effect of pharmacotherapy on rate of decline of lung function in chronic obstructive pulmonary disease: results from the TORCH study Pneumonia risk in COPD patients receiving inhaled corticosteroids alone or in combination: TORCH study results Prevalence and progression of osteoporosis in patients with COPD: results from the TOwards a Revolution in COPD Health study Efficacy of salmeterol/fluticasone propionate by GOLD stage of chronic obstructive pulmonary disease: analysis from the randomised, placebocontrolled TORCH study TORCH Clinical Endpoint C. Ascertainment of cause-specific mortality in COPD: operations of the TORCH Clinical Endpoint Committee The TORCH (towards a revolution in COPD health) survival study protocol Adherence to inhaled therapy, mortality and hospital admission in COPD Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial N Engl J Med, 2007, Feb 22;356(8): Am J Respir Crit Care Med, 2008, Aug 15;178(4): Eur Respir J, 2009, Sep; 34(3): Chest, 2009, Dec; 136(6): Respir Res, 2009;10:59 Thorax, 2007, May; 62(5): Eur Respir J, 2004, Aug; 24(2): Thorax, 2009, Nov; 64(11): Lancet, 2003, Feb 8;361(9356): Page 3 of 8

4 Calverley et al Keene et al Keene et al Vestbo et al Vestbo et al Zheng et al The severity of airways obstruction as a determinant of treatment response in COPD Statistical analysis of exacerbation rates in COPD: TRISTAN and ISOLDE revisited. Analysis of exacerbation rates in asthma and chronic obstructive pulmonary disease: example from the TRISTAN study TRISTAN study g. Early onset of effect of salmeterol and fluticasone propionate in chronic obstructive pulmonary disease Gender does not influence the response to the combination of salmeterol and fluticasone propionate in COPD The efficacy and safety of combination salmeterol (50 microg)/fluticasone propionate (500 microg) inhalation twice daily via accuhaler in Chinese patients with COPD Int J Chron Obstruct Pulmon Dis, 2006; 1(3): European Respiratory Journal, 2008, July; 32(1):17-24 Pharm Stat, 2007, Apr- Jun; 6(2):89-97 Thorax, 2005, Apr; 60(4): Respir Med, 2004, Nov; 98(11): Chest, 2007, Dec; 132(6): Common reference: tiotropium; co-treatment with tiotropium Symbicort plus tiotropium vs tiotropium monotherapy CLIMB Welte et al 2009 Efficacy and tolerability of budesonide/formoterol added to tiotropium in patients with chronic obstructive pulmonary disease Seretide plus tiotropium vs tiotropium monotherapy Aaron et al Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial Am J Respir Crit Care Med, 2009, Oct 15; 180(8): Ann Intern Med, 2007, Apr 17;146(8): Aaron et al Cazzola et al The Canadian Optimal Therapy of COPD Trial: design, organization and patient recruitment A pilot study to assess the effects of combining fluticasone propionate/salmeterol and tiotropium on the airflow obstruction of patients with severeto-very severe COPD Can Respir J, 2004, Nov- Dec; 11(8): Pulm, Pharmacol, Ther, 2007; 20(5): Results of Trials The key outcomes presented in the submission were the rate of COPD exacerbations, mean change from baseline as measured by St George Respiratory Questionnaire (SGRQ) and mean change from baseline for pre- and post-dose Forced Expiratory Volume in one second (FEV 1 ). The results of the indirect comparisons are presented below. The results of the indirect comparison should be interpreted with caution due to the heterogeneity between the trials included in the analyses. Page 4 of 8

5 Rate of exacerbations The meta-analysis of rate ratios for Symbicort versus placebo showed a statistically significant reduction in the rate of COPD exacerbations in favour of Symbicort (0.72, 95% CI: 0.64 to 0.81). Similarly, meta-analysis of rate ratios for Seretide versus placebo showed a statistically significant reduction in the rate of COPD exacerbations compared to placebo (0.75, 95% CI: 0.70 to 0.80). The indirect comparison using placebo as common reference showed no statistically significant difference between Symbicort and Seretide (0.96, 95% CI: 0.84 to 1.10), and the upper 95% CI of the indirect comparison did not cross the Minimal Clinically Important Difference (MCID) of Symbicort plus tiotropium resulted in a statistically significantly lower rate of exacerbations compared to tiotropium alone (0.38, 95% CI: 0.25 to 0.57), while Seretide plus tiotropium did not result in a statistically significant lower rate of exacerbation compared to tiotropium alone (0.85, 95% CI: 0.65 to 1.11). The indirect comparison using tiotropium as the common reference suggested that Symbicort might be superior to Seretide, when used in combination with tiotropium (0.46, 95% CI: 0.27 to 0.73), however, the submission considered that the analysis needed to be interpreted with caution, as the trials were of different duration and patients enrolled in the Aaron trial were able to initiate pulmonary rehabilitation programs during the trial as well as oxygen therapy. St George Respiratory Questionnaire (SGRQ) The St George s Respiratory Questionnaire is a standardised self-completed questionnaire for measuring impaired health and perceived well-being ( quality of life ) in patients with disease of the airways. The submission presented indirect comparisons based on the change in SGRQ from baseline using placebo and tiotropium as common references. There was no statistically significant difference in change in SGRQ from baseline between Symbicort (with or without tiotropium) and Seretide (with or without tiotropium) in either indirect comparison (indirect mean difference [95% CI] [-1.5, 1.5] using placebo as common reference and 1.8 [-0.9, 4.6] using tiotropium as common reference). The treatments appeared to confer an average improvement which was less than the 4-unit difference considered in clinical guidelines to be the MCID, i.e. the trials do not provide evidence that either Symbicort or Seretide results in a clinically important improvement in SGRQ score, as monotherapy compared to placebo, or in combination with tiotropium compared to tiotropium alone. Pre and post dose FEV 1 The magnitude of change observed in FEV 1 from baseline depends on a number of factors including baseline lung function and severity of disease. The absolute change observed is less marked in patients with lower baseline lung function. The PBS listing for Seretide restricts use to patients with baseline FEV 1 less than 50% predicted normal; however unlike the Symbicort trials, the Seretide trial population included patients with baseline FEV 1 greater than 50% predicted normal. As such, to facilitate comparability, analysis of both pre Page 5 of 8

6 and post-dose FEV 1 only included those patients with baseline FEV 1 less than 50% predicted normal. Symbicort resulted in a statistically significant increase in pre-dose FEV 1 from baseline compared to placebo treatment; however, this increase of 0.09 L was below 0.12 L, which the submission considered the MCID. Similarly, Seretide resulted in a statistically significant increase in pre-dose FEV 1 (0.11 L), which was also below the MCID. There was no statistically significant difference between Symbicort and Seretide using placebo as common reference. When used in combination with tiotropium, neither Symbicort nor Seretide showed a statistically significant difference in pre-dose FEV 1 compared to tiotropium alone. There was no statistically significant difference between Symbicort plus tiotropium and Seretide plus tiotropium, using tiotropium as the common reference. Results from the indirect comparison based on change in post-dose FEV 1 from baseline showed that Symbicort resulted in statistically and clinically significant increases in postdose FEV 1, compared to placebo treatment. Seretide treatment resulted in statistically significant, but not clinically significant, differences in post-dose FEV 1. The submission claimed that there was a statistically significant difference with regard to the change in postdose FEV 1 in favour of Symbicort compared to Seretide, using placebo as common reference (indirect mean difference 0.10: 95% CI 0.07 to 0.13). The submission claimed that as the upper confidence interval crosses the upper threshold of the MCID of 0.12 L, Symbicort may result in a clinically relevant improvement compared to Seretide treatment. For PBAC s view of these results, see Recommendations and Reasons. The submission claimed that while there was an increase in adverse events when Symbicort was compared to placebo treatment, there were no statistically significant difference between Symbicort and Seretide, when the TORCH trial was excluded. The submission justified the exclusion of the TORCH trial, as this trial was of longer duration than the other studies included in the safety analyses. The submission claimed that there were no other differences in safety outcomes between Symbicort and placebo or Symbicort plus tiotropium and tiotropium as well as between Symbicort (with or without tiotropium) and Seretide (with or without tiotropium) as demonstrated by the indirect comparisons using either placebo or tiotropium as the common reference. The assessment of extended comparative harm did not reveal additional safety concerns. 9. Clinical Claim The submission claimed Symbicort as non-inferior in terms of comparative effectiveness and at least as effective in terms of comparative safety over Seretide. The PBAC considered that this was reasonable, despite the uncertainties raised with the indirect comparisons. 10. Economic Analysis The submission presented a cost minimisation analysis. The equi-effective doses were estimated as Symbicort 400/12 micrograms twice daily and Seretide 500/50 micrograms Page 6 of 8

7 twice daily, based on the recommended dose in the Australian Product Information (PI). The doses used for the claim of equi-effectiveness were similar to the doses used in the clinical trials. Each prescription of eformoterol with budesonide provides two months supply of this combination compared to the salmeterol with fluticasone combination currently PBS listed for COPD, which provides one month s supply. The submission claimed an incremental dispensed price for maximum quantity (DPMQ) saving per 2 months to the Government of $6.42 per prescription (equivalent to one pharmacy dispensing fee), as a result of the listing. 11. Estimated PBS Usage and Financial Implications The likely number of patients per year was estimated in the submission to be in the range of 10,000 to 50,000 in Year 4. This was considered to be uncertain. The submission estimated financial savings per year to the PBS of less than $10 million in Year 5 based on a weighted price. Upon request from the ESC, revised financial estimates based on the COPD price were provided in the sponsor s Pre-PBAC Response. This analysis estimated an overall net cost to the PBS of less than $10 million in Year 5 which resulted from a reduction in patient co-payments associated with Symbicort. For PBAC s view, see Recommendation and Reasons. 12. Recommendation and Reasons The PBAC recommended listing on a cost minimisation basis with equi-effective doses being salmeterol 50 micrograms with fluticasone 500 micrograms and eformoterol 12 micrograms with budesonide 400 micrograms, both agents administered twice daily. The PBAC stated that there should be no additional cost associated with this recommendation for the listing of budesonide with eformoterol on the PBS. The PBAC noted the results of the indirect comparison presented in the submission, agreeing with the concerns raised by ESC around the comparability of the clinical trials used in the indirect comparison. The PBAC noted that the pooled results for the change from baseline for the St George Respiratory Questionnaire and the pre-dose FEV 1 were not statistically significantly different from the reference therapy and that the point estimates were not greater than the Minimum Clinical Important Difference. The indirect comparison for post-dose FEV 1 showed a statistically significant difference in favour of budesonide with eformoterol, but these results may be uncertain because of the differences in the trials. Overall, on the totality of the evidence, the PBAC considered that the claim of non-inferiority of budesonide with eformoterol compared to fluticasone with salmeterol was reasonable. The PBAC noted that budesonide with eformoterol for COPD should be included in the PBS medicines for prescribing by nurse practitioners within collaborative arrangements. Recommendation: BUDESONIDE WITH EFORMOTEROL FUMARATE DIHYDRATE, powder for oral inhalation in breath actuated devices 400 micrograms-12 micrograms per dose (60 doses), 2 Extend the current restriction to include: Page 7 of 8

8 Restriction: Restricted Benefit Symptomatic treatment of chronic obstructive pulmonary disease (COPD), where the FEV 1 is less than 50% predicted normal and there is a history of repeated exacerbations with significant symptoms despite regular beta-2 agonist bronchodilator therapy. Maximum quantity: 1 Repeats: 5 NOTE: Budesonide with eformoterol fumarate dihydrate is not indicated for the initiation of bronchodilator therapy in COPD. 13. Context for Decision The PBAC helps decide whether and, if so, how medicines should be subsidised in Australia. It considers submissions in this context. A PBAC decision not to recommend listing or not to recommend changing a listing does not represent a final PBAC view about the merits of the medicine. A company can resubmit to the PBAC or seek independent review of the PBAC decision. 14. Sponsor s Comment AstraZeneca welcomes the recommendation by the PBAC to extend the listing for Symbicort, to provide access to an additional treatment option for patients with chronic obstructive pulmonary disease. Page 8 of 8