Roflumilast for treating chronic obstructive pulmonary disease

Evidence-based recommendations on roflumilast (Daxas) for treating chronic obstructive pulmonary disease in adults with chronic bronchitis.

# Recommendations
Roflumilast, as an add-on to bronchodilator therapy, is recommended as an option for treating severe chronic obstructive pulmonary disease in adults with chronic bronchitis, only if:
the disease is severe, defined as a forced expiratory volume in 1 second (FEV1) after a bronchodilator of less than 50% of predicted normal, and
the person has had 2 or more exacerbations in the previous 12 months despite triple inhaled therapy with a long-acting muscarinic antagonist, a long-acting beta-2 agonist and an inhaled corticosteroid.
Treatment with roflumilast should be started by a specialist in respiratory medicine.
These recommendations are not intended to affect treatment with roflumilast that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.# The technology
Description of the technology
Roflumilast (Daxas, AstraZeneca) is an orally administered long-acting selective phosphodiesterase-4 enzyme inhibitor. It targets cells and mediators believed to be important in chronic obstructive pulmonary disease (COPD).
Marketing authorisation
Roflumilast has a marketing authorisation in the UK for maintenance treatment of severe COPD (forced expiratory volume in the first second  post-bronchodilator less than 50% predicted) associated with chronic bronchitis in adult patients with a history of frequent exacerbations as add-on to bronchodilator treatment.
Adverse reactions
The most common adverse reactions associated with roflumilast include diarrhoea, weight loss, nausea, abdominal pain and headache. Roflumilast is subject to additional monitoring for weight loss. For full details of adverse reactions and contraindications, see the summary of product characteristics.
Recommended dose and schedule
The recommended dose is 500 micrograms (1 tablet) of roflumilast once daily.
Price
37.71 for 30 tablets and 113.14 for 90 tablets (excluding VAT; 'British national formulary'  edition 72). Costs may vary in different settings because of negotiated procurement discounts.# Evidence
The appraisal committee (section 6) considered evidence submitted by AstraZeneca and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.# Committee discussion
The appraisal committee reviewed the data available on the clinical and cost effectiveness of roflumilast, having considered evidence on the nature of chronic obstructive pulmonary disease (COPD) and the value placed on the benefits of roflumilast by clinical experts. No evidence was submitted by patient groups and no patient experts attended the committee meetings. The committee also took into account the effective use of NHS resources.

# Clinical need of people with COPD
The committee heard that COPD is a chronic and progressive disease characterised by obstruction of the airways, breathlessness and cough. Airflow limitation becomes worse over time, with periodic acute exacerbations. The clinical expert advised that despite treatment with optimal inhaled therapy many people with severe COPD have several exacerbations each year, which is a huge burden on patients and the NHS. Exacerbations worsen a patient's health status, reduce their quality of life, accelerate decline in lung function, lead to hospitalisation and increase mortality. The committee was disappointed that no evidence was submitted by patient groups and that no patient experts attended the committee meeting. However, it recognised that a new treatment that reduced exacerbations in people with severe COPD would be highly valued by patients and their carers, and addresses an unmet need.

# Clinical management of COPD
The committee heard from the clinical expert that COPD is treated according to NICE's clinical guideline on chronic obstructive pulmonary disease in over 16s: diagnosis and management. For severe COPD (defined as forced expiratory volume in the first second  less than 50% predicted) the guideline recommends using either an inhaled long-acting muscarinic antagonist alone, a fixed combination of an inhaled corticosteroid and a long-acting beta2 agonist (dual inhaled therapy), or a combination of all these treatments (triple inhaled therapy). The committee understood that triple inhaled therapy is the standard treatment for people who continue to have exacerbations despite treatment with monotherapy or dual therapy. It noted that the company was seeking a recommendation for the use of roflumilast as an add-on treatment to triple inhaled therapy but not for monotherapy or dual therapy, which were included in the NICE scope. The committee considered whether this was appropriate. It heard from the clinical expert that the 2017 update of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) report recommended roflumilast as an add-on therapy for people with severe COPD who continue to have exacerbations despite treatment with triple therapy, particularly if they had at least 1 hospitalisation for an exacerbation in the previous year. The committee also heard from the clinical expert that the company's proposed placement of roflumilast in the treatment pathway is consistent with clinical practice, and that around 90% of people having roflumilast will be on triple therapy. The committee concluded that the company's proposed positioning of roflumilast as an add-on to triple inhaled therapy is appropriate.

# Comparators
The committee understood that the comparators in the appraisal scope included monotherapy (a long-acting muscarinic or beta2 agonist), dual therapy (the above treatments combined with each other or with inhaled corticosteroids), triple therapy (all of the above treatments) and theophylline in combination with inhaled maintenance bronchodilator treatment. The committee noted that the company did not consider monotherapy and dual therapy to be appropriate comparators because it intended to position roflumilast as an add-on treatment to triple inhaled therapy (see section 4.2). The committee accepted that this approach is appropriate. It also noted that the company does not consider theophylline to be an appropriate comparator. The committee heard from the clinical expert that theophylline is not generally used in clinical practice because of the high risk of toxicity, lack of evidence for clinical effectiveness, and associated side effects (such as seizures and cardiac arrhythmias). The committee accepted the company's rationale for excluding theophylline and concluded that triple inhaled therapy is the appropriate comparator for this appraisal.

# Clinical effectiveness

## Source of clinical evidence
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 beta2 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 beta2 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.

## Clinical-effectiveness results
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  patients). It also noted that the ERG presented results for the same subgroup from RE2SPOND (1,094  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.

## Adverse effects
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.

# Cost effectiveness
The committee noted that the company had developed a Markov model with 3 health states (severe COPD, very severe COPD and death) and monthly cycles. The model was based on the rate of moderate and severe exacerbations for patients having roflumilast plus triple inhaled therapy, compared with triple therapy alone. The committee understood that exacerbations led to additional costs, a temporary decrease in quality of life and, in the case of a severe exacerbation, an increased risk of death. The committee agreed with the ERG that the model structure excluded some important aspects of COPD progression. For example, health states were defined by FEV1 values alone rather than incorporating other prognostic information. The model also assumed that exacerbations did not affect FEV1, previous exacerbations did not affect future risk of exacerbations and baseline characteristics such as smoking status did not affect disease progression and risk of exacerbation. The committee noted the limitations of the model but concluded that it is adequate for decision-making.

## Modelling rates of exacerbation
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.

## Incorporation of health-related quality-of-life data in the model
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).

## Incorporation of annual FEV1 decline in the model
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.

## Incorporation of post-hospitalisation excess mortality in the model
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.

## Most plausible incremental cost-effectiveness ratio
Taking into account the amendments described in section 4.8, and sections 4.104.11, 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.

# Pharmaceutical Price Regulation Scheme 2014
The committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism. It accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The committee heard nothing to suggest that there is any basis for taking a different view about the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant in considering the cost effectiveness of the technology in this appraisal.

# Summary of appraisal committee's key conclusions
TA461
Appraisal title: Roflumilast for treating chronic obstructive pulmonary disease
Section
Key conclusion
Roflumilast, as an add-on to bronchodilator therapy, is recommended as an option for treating severe chronic obstructive pulmonary disease in adults with chronic bronchitis, only if:
the disease is severe, defined as a forced expiratory volume in 1 second (FEV1) after a bronchodilator of less than 50% of predicted normal, and
the person has had 2 or more exacerbations in the previous 12 months despite triple inhaled therapy with a long-acting muscarinic antagonist, a long-acting beta-2 agonist and an inhaled corticosteroid.
The committee concluded that there is 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 concluded that the company's revised base-case incremental cost-effectiveness ratio (ICER) of 24,976 per quality-adjusted life year (QALY) gained is a plausible estimate of the cost effectiveness of roflumilast as an add-on treatment to triple inhaled therapy, and is within the range normally considered a cost-effective use of NHS resources (that is, between 20,000 and 30,000 per QALY gained).
Current practice
Clinical need of patients, including the availability of alternative treatments
The committee heard from the clinical expert that despite treatment with optimal inhaled therapy many people with severe COPD have several exacerbations each year, which is a huge burden on patients and the NHS. The committee was disappointed that no evidence had been submitted by patient groups and that no patient experts attended the committee meeting.
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?
The committee recognised that a new treatment that reduces exacerbations in people with severe COPD would be highly valued by patients and their carers and address an unmet need.
What is the position of the treatment in the pathway of care for the condition?
The committee understood that triple inhaled therapy is the standard treatment for people who continue to have exacerbations despite treatment with monotherapy or dual therapy. It concluded that the company's proposed positioning of roflumilast as an add-on to triple inhaled therapy is appropriate.
Adverse reactions
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.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The committee noted that the evidence for roflumilast submitted by the company came from REACT (a multicentre double-blind randomised controlled trial with 1,935 patients, comparing roflumilast plus inhaled combination therapy with placebo plus inhaled combination therapy) and RE2SPOND, another multicentre double-blind trial of roflumilast that included 2,352 patients.
Relevance to general clinical practice in the NHS
The committee concluded that both REACT and RE2SPOND are relevant for this appraisal.
Uncertainties generated by the evidence
The committee considered uncertainties in the clinical evidence and acknowledged the difference in duration of background inhaled therapies in REACT and RE2SPOND, but concluded that both trials are relevant for this appraisal.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
The committee considered that it was reasonable to consider the results for the subgroup of patients who were taking a concomitant long-acting muscarinic antagonist as part of their inhaled combination therapy, given the company's intention to position roflumilast as an add-on treatment to triple inhaled therapy.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
In the subgroup of patients who were taking a concomitant long-acting muscarinic antagonist as part of their inhaled combination therapy, the committee concluded that there was sufficient evidence of the clinical efficacy of roflumilast compared with placebo.
How has the new clinical evidence that has emerged since the original appraisal (TA244) influenced the current recommendations?
TA244 recommended that roflumilast should only be used as part of a clinical trial for adults with severe COPD. Since TA244 was published, 2 multicentre double-blind randomised controlled trials have been published and the results of both trials have informed the recommendations in this appraisal.
Evidence for cost effectiveness
Availability and nature of evidence
The committee noted that the company had developed a Markov model that was based on the rate of moderate and severe exacerbations for patients having roflumilast plus triple inhaled therapy, compared with triple therapy alone. The committee noted some limitations in the model but concluded that it is adequate for decision-making.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The committee noted that there is uncertainty in the estimates used for annual decline in forced expiratory volume in the first second  and post-hospitalisation mortality, but concluded that the estimates used by the company were reasonable.
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?
The committee recognised that the data source for disutilities did not have a large impact on the ICER.
Are there specific groups of people for whom the technology is particularly cost effective?
The company presented cost-effectiveness results for the subgroup of people taking a concomitant long-acting muscarinic antagonist as part of their inhaled combination therapy. The committee considered this was appropriate given the company's intention to position roflumilast as an add-on treatment to triple inhaled therapy.
What are the key drivers of cost effectiveness?
The committee recognised that post-hospitalisation mortality was a key driver of the cost-effectiveness results.
Most likely cost-effectiveness estimate (given as an ICER)
The committee concluded that the company's revised base-case estimate of 24,976 per QALY gained was a plausible estimate of the cost effectiveness of roflumilast.
How has the new cost-effectiveness evidence that has emerged since the original appraisal (TA244) influenced the current recommendations?
The current appraisal used clinical evidence from 2 randomised controlled trials (REACT and RE2SPOND) to re-model the cost effectiveness of roflumilast and this has led to a change in the recommendations.
Additional factors taken into account
Patient access schemes (PPRS)
The company did not submit a patient access scheme.
End-of-life considerations
Not applicable.
Equalities considerations and social value judgements
The committee did not note any specific equalities considerations.