Roflumilast for treating chronic obstructive pulmonary disease

The evidence for roflumilast submitted by the company came from REACT, a multicentre double-blind randomised controlled trial that included 1,935 patients with severe COPD, chronic bronchitis and 2 or more exacerbations in the previous year. It compared roflumilast plus inhaled combination therapy (a long-acting beta‑2 agonist plus inhaled corticosteroids, with or without a long-acting muscarinic antagonist) with placebo plus inhaled combination therapy. The committee noted that the evidence review group (ERG) presented a pooled analysis of REACT plus another multicentre double-blind trial of roflumilast that included 2,352 patients with severe COPD, chronic bronchitis and 2 or more exacerbations and/or hospitalisations in the previous year (RE²SPOND). It understood that the company did not include detailed information on RE²SPOND in its submission because it believed that the people in the trial do not accurately reflect the target population. The company stated that fewer than half of patients in RE²SPOND were on triple therapy (47% compared with 70% in REACT), 0.5% were from Western Europe (compared with 29.5% in REACT) and pre-treatment with inhaled therapies was for a minimum of 3 months rather than 12 months as in REACT. The committee heard from the clinical expert that the duration of background inhaled therapies is an important difference between the 2 trials. Patients in REACT were more likely to have well controlled COPD because they had optimal inhaled therapy for 12 months, whereas patients in RE²SPOND were not appropriately pre-treated with inhaled therapies. The clinical expert suggested that the population in RE²SPOND had a higher risk of exacerbations compared with the population in REACT. The committee also heard from the company that RE²SPOND did not reflect current clinical practice in the UK because it used lower doses of long-acting beta‑2 agonists and inhaled corticosteroids and an alternative formulation of roflumilast. The committee discussed the characteristics of the people included in both trials and considered that there were many similarities between the trial populations. The committee also decided that any heterogeneity between the studies, including the difference in the duration of background inhaled therapy, is unlikely to have systematically biased the relative treatment estimates for roflumilast. The committee concluded that it had not heard adequate justification for not including RE²SPOND and therefore that both REACT and RE²SPOND are relevant for this appraisal.

The committee noted that the company had presented clinical-effectiveness results for the subgroup of patients in REACT who were taking a concomitant long-acting muscarinic antagonist as part of their inhaled combination therapy (1,346 [70%] patients). It also noted that the ERG presented results for the same subgroup from RE²SPOND (1,094 [47%] patients) and had pooled the relative effect of roflumilast from the 2 studies. The committee considered that it was reasonable to consider the results for this subgroup given the company's intention to position roflumilast as an add-on treatment to triple inhaled therapy (see section 3). It noted that the company's response to consultation presented pooled analyses from REACT and RE²SPOND based on individual patient-level data. The committee considered that these pooled analyses are appropriate and showed that roflumilast reduced the rate of moderate or severe exacerbations (the primary outcome in both trials) compared with placebo. The committee concluded that the company's pooled analyses provided sufficient evidence of the clinical efficacy of roflumilast compared with placebo in the subgroup of patients with severe COPD having exacerbations despite triple inhaled therapy.

The committee heard from the clinical expert that roflumilast is generally well tolerated but that weight loss and gastrointestinal adverse effects can lead to discontinuation of treatment in some people. It acknowledged that in its response to consultation, the company highlighted that there were more occurrences of weight loss, nausea and abdominal pain in patients taking roflumilast than patients taking placebo in the pooled individual patient-level data from REACT and RE²SPOND. The committee also heard from the clinical expert that there is virtually no clinical experience of using roflumilast in the UK. In addition, it was aware that roflumilast is subject to additional monitoring for weight loss and that patients are issued with a patient card for reporting side effects. The committee concluded that roflumilast appears to be generally well tolerated but that there is limited experience of using it in clinical practice in the UK.

The committee noted that in each cycle of the model, patients were at risk of moderate or severe exacerbations and that these rates were incorporated separately in the model. It noted that in response to consultation the company presented a revised base-case model, using exacerbation rate ratios derived from individual patient-level data from the pooled intention-to-treat populations of REACT and RE²SPOND (see section 4.5). The committee considered that the company's approach was appropriate.

The committee noted that in its original base case, the company derived the utility values in the model from 2 studies: Rutten van Molken (2006) for COPD severity and Rutten van Molken (2009) for disutilities for exacerbation. Rutten van Molken (2006) estimated utilities in 1,235 patients, including patients with COPD from the UK, using the UK tariff of the EQ-5D. Utility values from Rutten van Molken (2009) were from valuations of COPD health profiles (presented as vignettes) by the Dutch general public rather than EQ-5D. The committee noted that the ERG's analysis used disutilities for exacerbation from Hoogendoorn et al. (2011), because these were based on patient-reported EQ-5D values and used the UK tariff. The committee acknowledged that in its revised base case, the company incorporated disutilities for exacerbation from Hoogendoorn et al. (2011), which it considered appropriate. The committee recognised, however, that using a different data source for disutilities did not have a large impact on the incremental cost-effectiveness ratio (ICER).

The committee noted that the company's revised base case incorporated an annual FEV₁ decline of 52 ml based on a review by Tantucci and Modena (2012). The committee heard from the clinical expert that 52 ml is a reasonable estimate of FEV₁ decline, noting that the 2012 review identified studies reporting mean annual FEV₁ declines of 56 ml and 59 ml for people with severe COPD. The committee noted that changing the FEV₁ decline in the model did not have a large effect on the ICER and concluded that 52 ml was a reasonable estimate of annual FEV₁ decline in people with severe COPD.

The committee noted that the company's revised base case incorporated an increased post-discharge mortality risk associated with hospitalisation for a COPD exacerbation of 15.3% from Connolly et al. (2006). The committee was aware that the ERG considered a 12% increased risk to be more plausible, based on the UK National COPD Audit 2014. It heard from the clinical expert that it is difficult to be precise about the mortality rate because of variation each year. The committee concluded that the company's estimate was reasonable but also recognised that post-hospitalisation mortality was a key driver of the results.

The committee noted the ERG's comment that the company's method of incorporating post-hospitalisation mortality into the revised model causes double counting of deaths already accounted for while calculating standardised mortality ratios in the original model. The committee accepted that correcting this would slightly decrease the revised base-case ICER estimated by the company.

Taking into account the amendments described in section 4.8, and sections 4.10 and 4.11, the company's revised base-case ICER was £24,976 per quality-adjusted life year (QALY) gained. The committee acknowledged that this incorporated the adjustments made by the ERG to the company's original model, which the committee agreed was appropriate. The committee noted that the company had done scenario analyses that varied the estimate for post-hospitalisation mortality, resulting in ICERs between £16,293 and £30,349 per QALY gained. It appreciated that the true ICER may be slightly lower because of the double counting of deaths highlighted by the ERG (see section 4.12). The committee concluded that the company's revised base-case ICER was a plausible estimate of the cost effectiveness of roflumilast as an add-on treatment to triple inhaled therapy, and that the company's ICERs are within the range normally considered a cost-effective use of NHS resources (that is, between £20,000 and £30,000 per QALY gained).

The committee recalled that roflumilast is generally well tolerated but that there are potential adverse effects such as weight loss, for which people taking roflumilast should be monitored. It also recalled that there is a lack of clinical experience in using roflumilast in the UK. The committee concluded that roflumilast could be recommended for use in the NHS for adults with severe COPD, chronic bronchitis and frequent exacerbations (2 or more exacerbations in the previous 12 months) despite triple inhaled therapy, but that treatment should only be started by a specialist in respiratory medicine.