TA276
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Appraisal title: Colistimethate sodium and tobramycin dry powders for inhalation for treating pseudomonas lung infection in cystic fibrosis
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Section
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Key conclusions
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The Committee concluded that it could only draw conclusions based on the evidence described in the 2 key trials and that it had no clinical evidence comparing colistimethate sodium DPI with the appropriate comparator, nebulised colistimethate sodium.
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4.3.12
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The Committee agreed that despite the limitations of all the clinical- and cost-effectiveness evidence and hence the uncertainty inherent in the Assessment Group model, it was reasonable to conclude that tobramycin DPI was a cost-effective use of NHS resources. The Committee recommended tobramycin DPI as a treatment option only when nebulised tobramycin is considered an appropriate treatment; that is, when colistimethate sodium is contraindicated, is not tolerated, or has not produced an adequate clinical response. This is provided that the patient access scheme is operational in primary, secondary and tertiary settings of care.
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4.3.18
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Given the available evidence and the current treatment pathway, the Committee could only recommend colistimethate sodium DPI as a treatment option for people who would clinically benefit from continued colistimethate sodium but cannot tolerate it in its nebulised form. This is provided that the patient access scheme is operational in primary, secondary and tertiary settings of care.
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4.3.19
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Current practice
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Clinical need of patients, including the availability of alternative treatments
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The most important outcomes for the patient that influence treatment decisions are the person's quality of life, treatment burden, maintaining good lung function and reducing the incidence of exacerbations.
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4.3.2
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Current treatment options include the use of inhaled antibiotics effective against P. aeruginosa (such as nebulised colistimethate sodium or tobramycin) and oral or intravenous antibiotics to eradicate initial or intermittent P. aeruginosa colonisation or acute exacerbations of chronic infection. Azithromycin may be given in combination with these antibiotics to act on the biofilms.
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2.5
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First-line treatment for chronic P. aeruginosa lung infection routinely starts with nebulised colistimethate sodium (unless it is contraindicated), this choice being largely based on cost. If there is no response, an unacceptable adverse event profile, an excessive number of acute exacerbations or a loss of lung function, then treatment is switched routinely to nebulised tobramycin.
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4.3.2
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The technology
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Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?
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The Committee recognised that the strict routine and amount of time spent receiving treatment have a significant impact on the daily activities of people with cystic fibrosis and their families. The Committee concluded that reducing the time that people with cystic fibrosis spend receiving treatment would be beneficial in improving the quality of life of people with cystic fibrosis and their families.
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4.3.5
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The Committee concluded that in clinical practice (rather than in clinical trials), people with cystic fibrosis may be more likely to adhere to a dry powder for inhalation treatment than a nebulised treatment in view of the speed and convenience of drug delivery.
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4.3.6
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What is the position of the treatment in the pathway of care for the condition?
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The Committee heard from the manufacturer of colistimethate sodium DPI that the EMA had indicated that the most appropriate comparator at the time of the study design for its pivotal trial would be nebulised tobramycin because this was the only licensed comparator in all of the study site countries. The Committee agreed that given the current clinical pathway, ideally it would have liked to have seen effectiveness evidence comparing colistimethate sodium DPI with nebulised colistimethate sodium and also whether there was evidence of any clinical benefit of colistimethate sodium DPI in people being switched from nebulised colistimethate sodium because of lack of efficacy. Given the current treatment pathway in the UK, the Committee concluded that the most appropriate comparator for colistimethate sodium DPI would be nebulised colistimethate sodium and the most appropriate comparator for tobramycin DPI would be nebulised tobramycin.
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4.3.4
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Adverse reactions
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The Committee was unsure whether the adverse events associated with either tobramycin DPI or colistimethate sodium DPI were significantly different from those associated with nebulised tobramycin.
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4.3.10
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Evidence for clinical effectiveness
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Availability, nature and quality of evidence
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The Committee discussed the quality of the 2 key trials that compared colistimethate sodium DPI with nebulised tobramycin and tobramycin DPI with nebulised tobramycin. It noted the Assessment Group's critique of the trials, in particular the fact that the manufacturers had not commented in their submissions on the quality of the trials in light of the current EMA research guidelines for the development of medicinal products for the treatment of cystic fibrosis. The Committee supported the Assessment Group's comments on the methodological limitations of both trials, such as a lack of blinding, and agreed that this could have introduced selection and reporting bias for subjective outcomes such as adverse events and might limit the generalisability of the findings. The Committee concluded that the evidence base for assessing the clinical effectiveness of colistimethate sodium and tobramycin DPIs was of, at best, modest quality but that it was the best available.
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4.3.8
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The Committee noted that there was no clinical trial comparing the effectiveness of colistimethate sodium DPI with that of the preferred comparator, nebulised colistimethate sodium.
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4.3.7
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The Committee noted that both trials were non-inferiority in design and therefore only assessed whether the interventions were not worse than nebulised tobramycin.
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4.3.7
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Relevance to general clinical practice in the NHS
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The Committee acknowledged that both nebulised colistimethate sodium and nebulised tobramycin were embedded as treatment options in current clinical practice and thus judged to be clinically effective in treating chronic P. aeruginosa lung infection. The Committee therefore accepted that a change in the mode of delivery of these drugs would be unlikely to adversely affect their clinical effectiveness compared with nebulised formulations of the drugs.
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4.3.13
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Uncertainties generated by the evidence
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There is uncertainty about the clinical relevance of the findings of the 2 key trials given the short-term nature of these trials.
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4.3.9
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The Committee concluded that it was uncertain as to how it should interpret the exacerbation results. Because there were limited data on quality of life and uncertainty around the evidence for exacerbations, the Committee could not draw definitive conclusions as to whether either dry powder offered any clinical benefit over nebulised tobramycin for clinically relevant outcomes.
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4.3.11
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Whilst the Committee would have much preferred trials that were designed for equivalence and had continued for at least the 12 months specified in the current EMA research guidelines for such agents, it accepted that the evidence presented in terms of FEV1% was the best available and it had to make its judgements accordingly.
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4.3.9
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Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
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Not applicable
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Estimate of the size of the clinical effectiveness including strength of supporting evidence
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For the primary end point of mean difference in change in FEV1% predicted after 24 weeks of treatment, the result from the ANCOVA analysis on the ITT population using LOCF data was −1.16% (95% CI −3.15% to 0.84%) suggesting that colistimethate sodium DPI was marginally less efficacious than tobramycin nebuliser solution (because the non-inferiority criterion was not met). The results of the log-transformed and non-parametric ITT population LOCF data analyses were −0.98% (95% CI −2.74% to 0.86%) and −0.56% (95% CI −2.16% to 1.00%) respectively, suggesting in both cases that colistimethate sodium DPI was non-inferior to nebulised tobramycin. For the PP population the ANCOVA, log-transformed and non-parametric analyses using LOCF data indicated that the non-inferiority hypothesis was satisfied for non-parametric analysis only (ANCOVA −1.49% [95% CI −3.79% to 0.81%], log-transformed −1.10% [95% CI −3.08% to 0.97%] and non-parametric −0.67% [95% CI −2.57% to 1.16%]).
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4.1.4
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Tobramycin DPI was associated with an improved mean FEV1% predicted compared with nebulised tobramycin at 20 weeks of +0.59% (SE 0.92). The manufacturer reported non-inferiority (supported by least squares mean difference relative change of 1.1% [SE 1.75] which has a lower limit of the one-sided 85% confidence interval within the predicted 6% margin for non-inferiority).
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4.1.9
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The Committee concluded that it only had evidence exploring whether either dry powder formulation was no worse than nebulised tobramycin and no evidence to prove that either was more effective than or equivalent to nebulised tobramycin.
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4.3.7
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The Committee concluded that the COLO/DPI/02/06 and EAGER trials may have demonstrated that colistimethate sodium DPI and tobramycin DPI were non-inferior to nebulised tobramycin with respect to change in FEV1% within the populations tested and in the manner conducted within each trial, but remained concerned with the uncertain clinical relevance of these findings given the short-term nature of these trials.
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4.3.9
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Evidence for cost effectiveness
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Availability and nature of evidence
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The manufacturer of colistimethate sodium DPI used a cohort-based decision analysis to compare colistimethate sodium DPI with nebulised tobramycin in people aged 6 years or older with documented cystic fibrosis who had chronic pseudomonas lung infection.
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4.2.3
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The Committee concluded that the manufacturer's (Forest's) model lacked credibility and therefore they would not consider it or its results plausible.
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4.3.14
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The Committee discussed the Assessment Group's de novo model which compared colistimethate sodium DPI with nebulised tobramycin and tobramycin DPI with nebulised tobramycin. The Committee noted that the model had a lifetime time horizon. The Committee agreed that the use of a lifetime horizon was appropriate, but acknowledged the limitation of extrapolating short-term trial results over long time horizons. Additionally the Committee noted other limitations of the Assessment Group model, including the fact that it did not recognise that, in the current treatment pathway, some people would move from one drug to another (for example from colistimethate sodium to tobramycin).
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4.3.15
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The Committee concluded, however, that despite these limitations the Assessment Group's de novo model was the best available framework for assessing the cost effectiveness of colistimethate sodium DPI compared with nebulised tobramycin and of tobramycin DPI compared with nebulised tobramycin.
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4.3.15
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The Assessment Group also carried out additional analyses in response to the patient access schemes submitted by the manufacturers of colistimethate sodium DPI and tobramycin DPI.
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4.2.15–4.2.25
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Uncertainties around and plausibility of assumptions and inputs in the economic model
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Colistimethate sodium DPI: The Committee had particular concerns about the inconsistent time horizons used in the Forest model for costs and health outcomes and the validity of using mortality benefits associated with 24 weeks of treatment and extrapolating over a lifetime.
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4.3.14
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The Committee had particular concerns about limitations of the Assessment Group's model. The Committee agreed that the use of a lifetime horizon was appropriate, but acknowledged the limitation of extrapolating short-term trial results over long time horizons. Additionally it noted that the model did not recognise that, in the current treatment pathway, some people would move from one drug to another (for example from colistimethate sodium to tobramycin). The Committee also noted that treatment duration is assumed to be equivalent between the 2 treatments. It agreed that it was also plausible that some people on nebulised tobramycin would receive some form of treatment on a continuous basis (either as continuous nebulised reduced-dose tobramycin or as nebulised colistimethate sodium in off-months from tobramycin) but there was no evidence on which to base any cost-effectiveness estimate.
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4.3.15
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Tobramycin DPI: The Committee was aware that for the Assessment Group model for tobramycin DPI uncertainty was generated because the analyses were based on the inclusion of aggregate lung disorder data as a proxy measure for exacerbations because data on major and minor exacerbations had not been collected in the EAGER trial.
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4.3.18
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The QALY gain for tobramycin DPI was uncertain because quality-of-life data were not collected in the EAGER trial.
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4.3.18
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Incorporation of health-related quality-of-life benefits and utility values
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
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The Committee discussed the additional benefits of the mode of delivery of the dry powder formulations over nebulised alternatives. The Committee noted that both technologies aimed to give people with cystic fibrosis and chronic P. aeruginosa lung infection quality-of-life benefits in terms of ease of use and convenience.
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4.3.13
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The Committee acknowledged that the small QALY gain for tobramycin DPI was uncertain because quality-of-life data were not collected in the EAGER trial. However, it agreed it was reasonable to assume that there would be some QALY gain for tobramycin DPI over nebulised tobramycin in clinical practice in view of the reported benefits to patients in terms of ease of use and convenience although it acknowledged that the number of withdrawals from the EAGER trial did not indicate this relationship.
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4.3.18
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The Committee noted the small QALY loss for colistimethate sodium DPI compared with nebulised tobramycin but also the substantial saving (£38,000 with the list price for nebulised tobramycin). The Committee further observed that adherence might be greater with the use of a dry powder inhaler in such a population.
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4.3.19
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Are there specific groups of people for whom the technology is particularly cost effective?
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Not applicable
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What are the key drivers of cost effectiveness?
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The key drivers of cost effectiveness were the cost of interventions and comparators when the most recent patient access schemes were included, and the small QALY gains for tobramycin DPI compared with nebulised tobramycin and for colistimethate sodium compared with nebulised tobramycin.
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4.2.24, 4.2.25
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Most likely cost-effectiveness estimate (given as an ICER)
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Tobramycin DPI consistently dominated nebulised tobramycin with inclusion of the patient access scheme, that is, there was a cost saving and QALY gain for tobramycin DPI compared to nebulised tobramycin.
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4.3.18
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The Committee noted the small QALY loss for colistimethate sodium DPI compared with nebulised tobramycin but also the substantial cost saving (£38,000 with the list price for nebulised tobramycin).
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4.3.19
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Additional factors taken into account
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Patient access schemes (PPRS)
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A patient access scheme has been agreed with the Department of Health for colistimethate sodium DPI, details of which are confidential.
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3.3
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A patient access scheme has been agreed with the Department of Health for tobramycin DPI, details of which are confidential.
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3.6
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The Committee noted the approved patient access scheme for colistimethate sodium DPI and based its decisions on the cost-effectiveness results from analyses involving the patient access scheme price.
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4.3.16
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The Committee based its discussions on the cost-effectiveness analysis of tobramycin DPI carried out by the Assessment Group incorporating the patient access scheme.
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4.3.18
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End-of-life considerations
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Not applicable
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Equalities considerations and social value judgements
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The Committee discussed NICE's duties under the equalities legislation and concluded that its recommendations would not affect any of the groups whose interests are protected by the legislation and that there was no need to alter or add to its recommendations.
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4.3.20
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