Asthma (uncontrolled) - omalizumab

3. The manufacturer’s submission

The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of omalizumab and a review of this submission by the Evidence Review Group (ERG; appendix B).

3.1. The manufacturer approached the decision problem by looking at adults and adolescents (12 years and older) with severe persistent (IgE mediated) allergic asthma in accordance with the marketing authorisation. Omalizumab as add-on therapy to standard therapy was compared with standard therapy alone, which included inhaled corticosteroids, long-acting beta-2 agonists, short-acting beta-2 agonists, oral corticosteroids, leukotriene antagonists and where appropriate, theophylline. Health outcome measures included the rate of clinically significant asthma exacerbations, the rate of clinically significant severe exacerbations and the rate of emergency visits for asthma. In the manufacturer’s submission, clinically significant exacerbations were defined as a worsening of asthma symptoms requiring treatment with systemic corticosteroids. Clinically significant severe exacerbations were defined as a peak expiratory flow rate or FEV ₁  < 60% of personal best, requiring treatment with systemic corticosteroids.

3.2. The manufacturer’s submission presented evidence on the clinical effectiveness of omalizumab add-on therapy based on the results of the pivotal INNOVATE randomised controlled trial (RCT). Following amendments to the INNOVATE trial protocol, partly to reflect revisions of the Global Initiative on Asthma (GINA) guidelines, the manufacturer presented results on a primary intention-to-treat (PITT) population that excluded 13% of randomised patients prior to the implementation of the protocol amendments. The patient population in the INNOVATE RCT underwent a 7-day screening period for evaluating eligibility, followed by an 8-week run-in phase during which asthma management was reviewed and optimised to include advice on allergen avoidance, theophylline monitoring (if applicable) and inhaler technique in order to achieve best control. Efficacy analyses of the PITT population showed that the rate of clinically significant exacerbations in the omalizumab arm (0.74) was lower than in the standard therapy (placebo) arm (0.92) but this difference was not statistically significant (rate ratio 0.806; 95% confidence interval [CI] 0.600 to 1.083, p = 0.153). When post hoc statistical adjustments for baseline asthma exacerbations were made, clinically significant exacerbations were less frequent in the omalizumab arm (0.68) compared with the standard therapy (placebo) arm (0.91). This difference was statistically significant (rate ratio 0.738; 95% CI 0.552 to 0.988, p = 0.042). Clinically significant severe exacerbations were also lower in the omalizumab arm of the trial (0.24) than in the placebo arm (0.48) and this was statistically significant (rate ratio 0.499; 95% CI 0.321 to 0.777, p = 0.002). Omalizumab-treated patients showed statistically significant improvements from baseline in their asthma quality of life questionnaire (AQLQ) scores: 91% versus 46% in the placebo arm (p < 0.001).

3.3. The manufacturer’s submission also presented post hoc efficacy analyses of a high-risk subgroup, consisting of 39% of patients in the INNOVATE RCT, who had asthma exacerbations requiring hospital admission in the year prior to enrolling in the trial. There was a lower rate of clinically significant exacerbations in the omalizumab arm (0.78) compared to the standard therapy (placebo) arm (1.19; rate ratio 0.656; 95% CI 0.427 to 1.009, p = 0.153). Post hoc statistical adjustments to reflect differences in baseline asthma exacerbations which the manufacturer described as clinically relevant, but which were not statistically significant, resulted in a rate ratio of 0.714 (95% CI 0.481 to 1.062, p = 0.096). Clinically significant severe exacerbations were also lower in the omalizumab arm of the trial (0.361) versus 0.658 in the placebo arm (rate ratio 0.55; 95% CI not reported, p = 0.155). Omalizumab-treated patients showed statistically significant improvements from baseline in their AQLQ scores (94% versus 36% in the placebo arm, p = 0.002). The manufacturer’s submission also referred to a study which suggested a correlation between hospitalisation and asthma-related mortality.

3.4. The manufacturer’s submission presented another post hoc subgroup analysis versus standard therapy, identifying omalizumab responders in both the PITT population and the high risk hospitalisation subgroup according to a rating of excellent or good on the physician global evaluation of treatment effectiveness (GETE) scale at the end of the study. The results were presented to indicate greater treatment effect experienced by patients continuing omalizumab therapy beyond 16 weeks. No p values were given.

3.5. The manufacturer specifically presented additional clinical evidence from an open label trial, ETOPA (IA-04), to support the clinical efficacy and safety results from the INNOVATE study. However, patients recruited to ETOPA (IA-04) had moderate to severe asthma and only 52.6% of randomised patients met the inclusion criteria for the INNOVATE study. The rationale for including ETOPA (IA-04) was that it represented ‘real life’ clinical practice because randomised patients in both arms of the trial did not receive optimised standard therapy. The clinical results from the ETOPA (IA-04) subpopulation who met the INNOVATE inclusion criteria were used to inform the economic analysis as an alternative base-case.

3.6. The manufacturer’s submission presented an economic analysis comparing omalizumab add-on therapy to standard therapy with standard therapy alone using a Markov transition model with a lifetime horizon of 40 years. The economic model had five health states: day-to-day symptoms, clinically significant non-severe exacerbations, clinically significant severe exacerbations, asthma death and non-asthma death. In the manufacturer’s model it was assumed that the population cohort are assessed at 16 weeks for response to omalizumab treatment, after which omalizumab non-responders switch back to standard therapy and have similar responses and exacerbation rates as the standard therapy group in the model.

3.7. The economic analysis was performed for the INNOVATE PITT population and the high-risk hospitalisation subgroup. Base-case analysis for the INNOVATE PITT population produced an incremental cost effectiveness ratio (ICER) of £30,600 per QALY gained and an ICER of £26,500 per QALY gained for the high-risk hospitalisation subgroup. The manufacturer also presented an alternative base-case analysis using subpopulation data from the ETOPA (IA-04) trial that gave an ICER of £21,700 per QALY gained.

3.8. One-way sensitivity analyses presented in the manufacturer’s submission suggested that the key drivers of the economic model were asthma mortality rate from clinically significant severe exacerbations, omalizumab treatment duration and time horizon. Notably, assuming an asthma mortality rate of 0% from clinically significant severe exacerbations, the base-case ICER increases to £73,200 per QALY gained. Assuming the asthma-related mortality rate is 2.478% gives an ICER of £33,500 per QALY gained. The manufacturer’s submission presented a probabilistic sensitivity analysis that showed a mean ICER of £31,700 per QALY gained (95% CI, £23,200 to £48,200 per QALY). No probabilistic sensitivity analysis was performed for the high-risk hospitalisation subgroup.

3.9. The ERG identified a number of issues with the parameters used in the economic model and uncertainties relating to the economic analyses presented in the manufacturer’s submission. The ERG commented that the one-way sensitivity analysis in the manufacturer’s submission was performed on a limited number of parameters and that the ranges of parameter values investigated were inappropriate. The ERG carried out an amended one-way sensitivity analysis that showed that the key drivers of the economic model were utility values assigned to omalizumab responders, the costs of omalizumab and asthma mortality rate.

3.10. The ERG in particular noted uncertainties surrounding the following parameter assumptions: costing of omalizumab on a per mg basis, utility values assigned to non-severe clinically significant exacerbations, clinically significant severe exacerbations and asthma mortality rate. The ERG therefore explored a number of scenario analyses on alternative assumptions for these parameters. The scenario analyses for the INNOVATE PITT population ranged from £33,300 to £40,900 per QALY gained while the scenario analyses for the high-risk hospitalisation subgroup ranged from £29,800 to £34,300 per QALY gained. The ERG performed an amended probabilistic sensitivity analysis that showed greater uncertainty around the ICERs for the INNOVATE PITT population than suggested in the manufacturer’s economic analyses. The ERG’s amended probabilistic sensitivity analysis showed a mean ICER of £38,900 per QALY gained. At a threshold willingness to pay of £30,000 per QALY, omalizumab add-on therapy was estimated to have a 23.6% probability of being cost effective. No probabilistic sensitivity analysis was performed for the high-risk hospitalisation subgroup.

3.11. Full details of all the evidence are in the manufacturer’s submission and the ERG report, which are available from www.nice.org.uk/TA133 .