Institute of Health Policy and Management, Erasmus University Rotterdam, Rotterdam, Netherlands 3

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1 This paper presents a summary of the Evidence Review Group report for the single technology appraisal entitled Roflumilast for the management of severe chronic obstructive pulmonary disease Riemsma R, 1 * Lhachimi SK, 2 Armstrong N, 1 van Asselt ADI, 3 Allen A, 1 Manning N, 1 Harker J, 1 Tushabe DA, 1 Severens JL 2 and Kleijnen J 1,4 1 Kleijnen Systematic Reviews Ltd, York, UK 2 Institute of Health Policy and Management, Erasmus University Rotterdam, Rotterdam, Netherlands 3 Department of Clinical Epidemiology and Medical Technology Assessment, Maastricht University Medical Centre, Maastricht, Netherlands 4 School for Public Health and Primary Care (CAPHRI), Maastricht University, Maastricht, Netherlands *Corresponding author Declared competing interests of authors: none This report should be referenced as follows: Riemsma R, Lhachimi SK, Armstrong N, van Asselt ADI, Allen A, Manning N, et al. Roflumilast for the management of severe chronic obstructive pulmonary disease. Southampton: NETSCC; 2012.

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3 Single Technology Appraisal Roflumilast for the management of severe chronic obstructive pulmonary disease Riemsma R, 1 * Lhachimi SK, 2 Armstrong N, 1 van Asselt ADI, 3 Allen A, 1 Manning N, 1 Harker J, 1 Tushabe DA, 1 Severens JL 2 and Kleijnen J 1,4 1 Kleijnen Systematic Reviews Ltd, York, UK 2 Institute of Health Policy and Management, Erasmus University Rotterdam, Rotterdam, Netherlands 3 Department of Clinical Epidemiology and Medical Technology Assessment, Maastricht University Medical Centre, Maastricht, Netherlands 4 School for Public Health and Primary Care (CAPHRI), Maastricht University, Maastricht, Netherlands *Corresponding author HTA 10/06/01 Date of ERG submission: 20 July 2011 TAR Centre(s): Kleijnen Systematic Reviews Ltd in collaboration with Erasmus University Rotterdam and Maastricht University List of authors: R Riemsma, SK Lhachimi, N Armstrong, T van Asselt, A Allen, N Manning, J Harker, DA Tushabe, JL Severens and J Kleijnen Contact details: Rob Riemsma, Kleijnen Systematic Reviews Ltd, Unit 6, Escrick Business Park, Riccall Road, Escrick, York YO19 6FD, UK rob@systematic-reviews.com The research reported in this article of the journal supplement was commissioned and funded by the HTA programme on behalf of NICE as project number 10/06/01. The assessment report began editorial review in August 2011 and was accepted for publication in March See the HTA programme website for further project information ( This summary of the ERG report was compiled after the Appraisal Committee s review. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Department of Health. Discussion of Evidence Review Group reports is invited. Visit the HTA website correspondence forum ( ac.uk/correspond). Abstract This paper presents a summary of the Evidence Review Group (ERG) report into roflumilast (Daxas, MSD) for the management of severe chronic obstructive pulmonary disease (COPD). The ERG commented on the clinical effectiveness and cost-effectiveness of the phosphodiesterase-4 inhibitor drug roflumilast for the management of COPD, a chronic, progressive inflammatory disease characterised by airflow obstruction that is not fully reversible. The National Institute for Health and Clinical Excellence scope defined the population as those with severe COPD [forced expiratory volume in 1 second (FEV 1 ) post bronchodilator 50% predicted]. However, the manufacturer presented a full mixed-treatment comparison (MTC) Queen s Printer and Controller of HMSO This work was produced by Riemsma et al. under the terms of a commissioning contract issued by the Secretary of State for Health. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to NETSCC.

4 2 Roflumilast for the management of severe chronic obstructive pulmonary disease analysis in patients with moderate to severe (rather than severe) COPD. The manufacturer also presented an additive MTC analysis to provide data for other treatments including roflumilast, and the cost-effectiveness analysis (CEA) based on it, but the ERG did not comment on this second analysis as the assumptions underlying it were not met. The ERG conducted a MTC analysis on the same set of trials, limited to severe COPD, from 10 trials that included seven treatments. An additional MTC analysis was carried out by the ERG using slightly wider inclusion criteria (FEV 1 post bronchodilator 65% predicted), from 16 trials that included nine treatments. The ERG also carried out an assessment and critique of the manufacturer s CEA, which was a full incremental deterministic analysis of the treatment options and probabilistic sensitivity analysis. The ERG did not validate the economic model utilised in the manufacturer s CEA, which was found to be convoluted and lacking necessary transparency. The method used to derive the clinical evidence to model the treatment of effects was judged by the ERG as invalid and it could not be used to draw inference about the cost-effectiveness of treatments under assessment. The ERG MTC analyses for efficacy show that in patients with severe COPD (FEV 1 50%), in terms of the mean annual rate of exacerbations, roflumilast alone is not statistically superior when compared with any of the other active treatments. However, a long-acting β 2 -agonist (LABA) in combination with inhaled corticosteroid (ICS) is significantly superior to roflumilast alone [relative risk (RR) = 0.84, 95% credible interval (Crl) 0.72 to 0.98]. When compared with other active treatments, roflumilast plus LABA is significantly superior to LABA alone (RR = 0.78, 95% Crl 0.67 to 0.91). However, compared with a long-acting muscarinic antagonist (LAMA), ICS and LABA/ICS, there are no significant differences. In the wider population (FEV 1 65%), when compared with placebo, the annual rate ratios for the three most effective treatments are RR = 0.70 (95% Crl 0.52 to 0.90) for LABA/ICS plus LAMA; RR = 0.73 (95% Crl 0.67 to 0.80) for LABA/ICS; and RR = 0.76 (95% Crl 0.61 to 0.94) for roflumilast plus LABA. The ERG incremental cost-effectiveness analyses included, in total, four different model configurations. For all but one case, the options including roflumilast are dominated or dominated by extension. In only one case in the wider population (FEV 1 65%), that is using the relaxed inclusion criterion, for the ICS-intolerant population LABA plus roflumilast is on the cost-effectiveness frontier with an incremental cost-effectiveness ratio of approximately 41,000 per quality-adjusted life-year gained. Introduction The National Institute for Health and Clinical Excellence (NICE) is an independent organisation within the NHS that is responsible for providing national guidance on the treatment and care of people using the NHS in England and Wales. One of the responsibilities of NICE is to provide guidance to the NHS on the use of selected new and established health technologies, based on an appraisal of those technologies. NICE s single technology appraisal (STA) process is specifically designed for the appraisal of a single product, device or other technology, with a single indication, where most of the relevant evidence lies with one manufacturer or sponsor. 1 Typically, it is used for new pharmaceutical products close to launch. The principal evidence for an STA is derived from a submission by the manufacturer/sponsor of the technology. In addition, a report reviewing the evidence submission is submitted by the evidence review group (ERG); an external organisation independent of the NICE. This paper presents a summary of the ERG report for the STA Roflumilast for the management of severe chronic obstructive pulmonary disease. 2

5 Single Technology Appraisal Description of the underlying health problem Chronic obstructive pulmonary disease (COPD) is a chronic, progressive inflammatory disease characterised by airflow obstruction that is not fully reversible. 3 COPD is primarily caused by cigarette smoking, although other factors, particularly occupational exposures, may also contribute to its development. The term COPD encompasses chronic bronchitis, emphysema or a combination of both, 4,5 with sufferers typically experiencing a prolonged decline in lung function punctuated by acute exacerbations of symptoms. The subset of patients with chronic bronchitis are readily characterised by the presenting signs of chronic cough and sputum production. There are approximately 900,000 people diagnosed with COPD in the UK and a further 2 million are estimated to have the disease, but remain undiagnosed. 3 The prevalence of COPD increases with age, socioeconomic disparities and disease severity. It is most common in people aged 35 years. In the UK, the mean age at diagnosis is 67 years. 6 COPD affects more men than women. However, the prevalence of diagnosed COPD in women is increasing, and diagnosis in men has plateaued since the mid-1990s, a factor associated with sex differences in smoking in recent years. COPD is associated mainly with the cigarette smoking population, of whom nearly half develop some sort of airflow obstruction and around 10 20% develop COPD over time. 6 Besides smoking, other factors do play a role. COPD can develop in non-smokers too, especially those affected with alpha-1-antitrypsin deficiency and asthma. Other factors include passive smoking, air pollution, oxidative stress, nutrition and occupation. The prognosis of COPD is associated with lung inflammation over time, which causes permanent lung damage. Inflammation thickens the airway walls, leading to increased mucus production. This reduces the lung elasticity, making it very difficult to breathe, causing breathlessness, phlegm and cough. This course of lung damage is irreversible, but lifestyle changes can help reduce the extent of the damage. 7 Current treatment and intervention Current guidelines for the treatment of patients with COPD recommend the addition of therapies in a stepwise manner according to patients needs, with the aim of controlling symptoms and preventing exacerbations. 3,7 NICE has recently updated the COPD Clinical Guideline (CG101), 3 which stressed the importance of multidimensional assessment of the disease, as opposed to simple categorisation of disease severity through measure of lung function (section 6.9 of CG101). The guideline recommends that patients with severe COPD [forced expiratory volume in 1 second (FEV 1 ) < 50% predicted] receive a long-acting bronchodilator, either a long-acting β 2 -agonist (LABA) [with or without an inhaled corticosteroid (ICS)] or a long-acting muscarinic antagonist (LAMA). If patients continue to deteriorate or remain breathless, it is recommended that they progress to triple therapy with LAMA plus LABA/ICS. In patients who cannot tolerate or decline ICS, a combination of the two bronchodilators is recommended (LABA plus LAMA). Roflumilast (Daxas, MSD) is a highly selective phosphodiesterase-4 inhibitor designed to target both the systemic and pulmonary inflammation specifically associated with COPD. 8 Roflumilast is the first in this new class of COPD treatments to be granted a licence that specifically includes data on reduction in the frequency of COPD exacerbations and, thus, represents a step-change in the clinical management of the disease. Roflumilast is a once-daily oral therapy that is licensed for use as maintenance therapy within a well-defined subgroup of COPD patients, specifically those with severe COPD (FEV 1 post bronchodilator < 50% predicted) that is associated with chronic bronchitis and who have a history of frequent exacerbations despite maintenance bronchodilator treatment. 8 Queen s Printer and Controller of HMSO This work was produced by Riemsma et al. under the terms of a commissioning contract issued by the Secretary of State for Health. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to NETSCC.

6 4 Roflumilast for the management of severe chronic obstructive pulmonary disease Scope of the Evidence Review Group report The scope of the ERG report was to comment on the clinical effectiveness evidence and costeffectiveness of roflumilast for the management of severe COPD relative to other comparators as presented in the manufacturer s submission (MS) to NICE. The NICE scope 9 defines the population as Adults with severe chronic obstructive pulmonary disease [FEV 1 post bronchodilator less than or equal to ( ) 50% predicted] associated with chronic bronchitis in adult patients with a history of frequent exacerbations. The ERG report 2 focused on the population as defined in the NICE scope, which differed from the MS that presented roflumilast studies and a full mixed-treatment comparison (MTC) in patients with either moderate or severe (rather than severe) COPD. A secondary analysis was presented by the ERG using an inclusion criterion that was slightly wider, but still included severe COPD (FEV 1 65%). The ERG report did not comment on the results of the MS s additive MTC analysis to provide data for other treatments including roflumilast, and the cost-effective analysis (CEA) based on it, as the assumptions underlying this analysis were not met. The MS presented evidence from trials in severe COPD for only four relevant comparators: LABA, LAMA, ICS and LABA/ICS. The secondary ERG analysis also allows comparisons between roflumilast and LABA plus LAMA and LABA/ICS plus LAMA. Theophylline (stated by the MS as not thought to be an appropriate comparator for roflumilast, but mentioned in the NICE scope 9 ) was not analysed for efficacy or cost-effectiveness compared with roflumilast as the ERG did not have adequate time or resources to find relevant evidence. The ERG analyses and data extraction are based on the same set of trials as included in the MS, but limited to severe COPD only. The ERG presented results for two sets of data: 1. Data for adults with severe COPD (FEV 1 post bronchodilator 50% predicted) from nine trials, including seven treatments. 2. Data for adults with moderate to severe COPD (FEV 1 post bronchodilator 65% predicted) from 16 trials, including nine treatments. In addition, the ERG conducted a full, incremental deterministic analysis and probabilistic sensitivity analysis 2 following the critique of the MS CEA. Details for this are included in Methods. Methods The ERG 2 appraised the MS s searches for both efficacy and CEA and identified several consequential errors. The ERG also appraised and critiqued the review methodology including inclusion/exclusion criteria. Quality/validity assessments of included randomised controlled trials (RCTs) in the ERG analyses were appraised using Centre for Reviews and Dissemination guidelines 10 for critical appraisal of RCTs. The method of synthesis and statistical methods of the MS MTC analyses were also critiqued and the ERG conducted two additional analyses with (1) data from adults with severe COPD as defined in the NICE scope (FEV 1 post bronchodilator 50% predicted) and (2) data for adults with moderate-to-severe COPD (FEV 1

7 Single Technology Appraisal post bronchodilator 65% predicted). Furthermore, the ERG conducted a literature search to find more substantiated evidence for a number of crucial clinical parameters used in the cost-effectiveness model. Methods of statistical analysis of all included RCTs in both new MTC analyses were critiqued by the ERG and data extracted for patient withdrawals to facilitate the assessment of how missing data were handled. The MS also contained an additive MTC, which was broadly assessed by the ERG as having not met underlying assumptions, therefore no further critique/analysis of this particular MTC was undertaken. The ERG critiqued the cost-effectiveness analysis submitted by the MS and reran the economic evaluation based on the electronic model as provided by the manufacturer and, as a result of this critique, defined a new base-case scenario based on the narrow inclusion criterion (FEV 1 50%) for the MTC for both the ICS-tolerant and ICS-intolerant populations. In addition, an alternative scenario was defined based on the wide inclusion criterion (FEV 1 65%) for the MTC for both the ICS-tolerant and the ICS-intolerant populations. For these four different model configurations, a full incremental deterministic analysis and probabilistic sensitivity analysis were undertaken by the ERG. Further sensitivity analyses were also conducted. The ERG s economic evaluation used only the treatment options for which the standard (not the additive) MTC provided evidence; this applied both for the narrow (FEV 1 50%) and for the wider (FEV 1 65%) inclusion criterion populations. Therefore, not all treatment options as presented by the manufacturer were in the ERG analyses. Results Summary of submitted clinical evidence Twenty-six publications met the inclusion criteria for the MTC in the MS. Combined, these publications reported on 29 clinical trials. However, only 8 out of 29 included trials were in patients with severe COPD (FEV 1 50%). The study by Calverley et al. 11 (trials M2-124 and M2-125) is described as roflumilast compared with placebo, although about 50% of patients in both trials received concomitant LABA. Therefore, this trial should be treated as partly roflumilast compared with placebo and partly roflumilast plus LABA compared with LABA. In addition, the MS did not include trial M in its MTC, although this trial fulfilled the inclusion criteria according to the MS. The ERG included the eight trials in severe COPD with separate data for the two comparisons in trials M2-124 and M2-125, 10 making nine trials and M This resulted in a network of 10 trials, including seven treatments for the MTC. The ERG focused on these 10 trials for their primary analyses. Table 1 shows the trials used in the MS for each of the interventions included in the analyses presented in the MS. Clearly, four out of seven interventions have no underlying evidence from trials. The analyses are purely based on the additive analyses. Two out of seven interventions (roflumilast plus LABA and roflumilast plus LAMA) are based on evidence in the wrong population (not severe COPD, but mainly moderate COPD). The remaining intervention (roflumilast alone) is based on evidence from three trials, one of which is, again, in the wrong population and another combines evidence from roflumilast versus placebo with roflumilast plus LABA versus LABA plus placebo. The MS presented evidence for comparisons between roflumilast and most comparators. However, most evidence was based on trials in moderate to severe COPD or based on additive analyses. Evidence from trials in severe COPD was available for only four relevant comparators: LABA, LAMA, ICS and LABA/ICS. One of the inclusion criteria for the MTC was that trials had to report data on the total number of exacerbations and/or the mean annual rate of exacerbations; therefore, trials reporting other relevant outcomes (as mentioned in the NICE scope) were excluded in the MS. Queen s Printer and Controller of HMSO This work was produced by Riemsma et al. under the terms of a commissioning contract issued by the Secretary of State for Health. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to NETSCC.

8 6 Roflumilast for the management of severe chronic obstructive pulmonary disease TABLE 1 Evidence for roflumilast treatments in the MS model Treatment Comparator Trials Comment Roflumilast alone Placebo M2-124 and M2-125 combined (Calverley et al. 2009) 11 M2-112 (Calverley et al. 2007) 13 FEV 1 50% M2-107 (Rabe et al. 2005) 14 FEV % Roflumilast + LABA LABA M2-127 (Fabbri et al. 2009) 15 FEV % Roflumilast + LAMA LAMA M2-128 (Fabbri et al. 2009) 15 FEV % Roflumilast + ICS No evidence Used additive MTC Roflumilast + LABA + LAMA No evidence Used additive MTC Roflumilast + LABA/ICS No evidence Used additive MTC Roflumilast + LABA/ICS + LAMA No evidence Used additive MTC FEV 1 50%, 50% received concomitant LABA but all were treated as if roflumilast vs placebo FEV 1, forced expiratory volume in 1 second; ICS, inhaled corticosteroid; LABA, long-acting β 2 -agonist; LAMA, long-acting muscarinic antagonist; MS, manufacturer s submission; MTC, mixed-treatment comparison. Summary of submitted cost-effectiveness evidence Owing to the lack of published cost-effectiveness studies, as demonstrated by the manufacturer s literature review, the manufacturer conducted a de novo economic analysis. For the economic evaluation, the manufacturer presented results for two populations, an ICS-tolerant population and an ICS-intolerant population, including 10 and 6 first-line treatment options, respectively. Second-line treatment was the same for all options within each population. The manufacturer used a parsimonious but adequate Markov model distinguishing health states that reflect disease severity and line of treatment. In a deterministic cost-effectiveness analysis, all treatment options were compared. Based on these results it was stated that for each population a comparison of only two options, one including roflumilast, was subject for decision uncertainty analyses. The costs and resource use of COPD patients were grouped into three categories: the cost of COPD regimens (medication costs); the cost of maintenance of a COPD patient (mostly outpatient costs and additional medication/therapy); and, finally, the costs of exacerbations, further divided into moderate (community treated) and severe (hospital treated) exacerbations. The values for the health-related quality of life were empirically derived from COPD patients, whereas the values for the utility decrements were obtained from a preference study in the general population. Adverse events were not accounted for in the utility estimates. Commentary on the robustness of submitted evidence Strengths The manufacturer searched the required databases, with the exception of The Cochrane Library, for indirect and mixed-treatment comparisons and provided sufficient detail for the ERG to appraise the searches. The ERG considers that the standard MTC model (without the additive model) was methodologically correct and of high quality. The Markov-type model used for the cost-effectiveness analysis is parsimonious but in principle adequate for purpose.

9 Single Technology Appraisal Weaknesses and areas of uncertainty The inclusion criteria for the MTC were considerably wider than the scope. Instead of limiting the search to severe COPD (FEV 1 50%), studies with baseline FEV 1 up to 90% were included. In addition, the analyses relied on an additive model for which the underlying assumptions were not met. In general, the searches were not constructed in a systematic fashion. Redundant search terms and misuse of Boolean logic created ambiguity as to what search terms actually made it to the final set. Two of the chapters contained searches with significant structural problems, and searches across all chapters failed to make good use of COPD synonyms, truncation and controlled vocabulary. Although the manufacturer claimed the economic model has been used in prior applications of this nature and the model has been validated by experts in the field, no documentation of this is presented in the submission. The implementation of the model, that is the electronic version, is convoluted and lacks the necessary transparency. Furthermore, errors in the implementation, when uncorrected, lead to invalid results when conducting a probabilistic sensitivity analysis. More importantly, the method used to derive the clinical evidence to model the treatment effects (the reduction in the number of exacerbations an average patient can expect) of each medication is judged by the ERG as invalid and cannot be used to draw inference about cost-effectiveness of the treatments under assessment. Furthermore, a number of clinical parameters used to model a patient s course of disease, such as average number of exacerbations of untreated patients or proportion of exacerbations requiring hospital treatment, were not sufficiently justified by evidence but based on the subgroup of a single clinical trial. The use of improper clinical evidence concerning the treatment effects and some assumptions concerning the modelling of the patient s disease course, in particular the assumption of equal length of time on treatment, make the cost-effectiveness evidence as presented by the manufacturer invalid and unacceptable. Conclusions The ERG MTC analyses for efficacy show that in patients with severe COPD (FEV 1 50%), in terms of the mean annual rate of exacerbations, roflumilast alone is not statistically superior when compared with any of the other active treatments. However, LABA/ICS is significantly superior to roflumilast alone (RR = 0.84, 95% CrI 0.72 to 0.98). When compared with other active treatments, roflumilast plus LABA is significantly superior to LABA alone (RR = 0.78, 95% CrI 0.67 to 0.91). However, compared with LAMA, ICS and LABA/ICS, there are no significant differences (Table 2). Results are similar in the wider population (FEV 1 65%). Looking at the results in comparison with placebo, LABA/ICS plus LAMA seems to be the best treatment in terms of reducing the annual rate of exacerbations; LABA/ICS seems to be second best, and roflumilast plus LABA third best. In comparison with placebo, the annual rate ratios are RR = 0.70 (95% CrI 0.52 to 0.90) for LABA/ICS plus LAMA; RR = 0.73 (95% CrI 0.67 to 0.80) for LABA/ICS; and RR = 0.76 (95% CrI 0.61 to 0.94) for roflumilast plus LABA. In the ERG base-case analysis for ICS-tolerant patients, the cost-effectiveness frontier consists of the first-line treatment options ICS, LAMA, and LABA/ICS. For the change from ICS (26.48 exacerbations in 30 years) to LAMA (26.23 exacerbations in 30 years), the ICER is 14,199 per quality-adjusted life-year (QALY) gained. For the change from LAMA to LABA/ICS (26.18 exacerbations) the ICER is 22,409. For the alternative scenario, the treatment options on Queen s Printer and Controller of HMSO This work was produced by Riemsma et al. under the terms of a commissioning contract issued by the Secretary of State for Health. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to NETSCC.

10 8 Roflumilast for the management of severe chronic obstructive pulmonary disease TABLE 2 Incremental cost-effectiveness in ERG analysis (dominated and extendedly dominated options excluded): treatment options in hierarchy of costs First-line treatment option Cost ( ) QALY Incremental costs Incremental QALYs ICER ERG base-case analysis for ICS-tolerant patients ICS 22, LAMA 22, ,199 LABA/ICS 22, ,409 ERG base-case analysis for ICS-intolerant patients LABA 21, LAMA 21, ERG alternative analysis for ICS-tolerant patients ICS 22, LABA/ICS 22, ,560 LAMA + LABA/ICS 23, ,243 ERG alternative analysis for ICS-intolerant patients LABA 21, LAMA 21, LABA + roflumilast 22, ,112 ERG, Evidence Review Group; ICER, incremental cost-effectiveness ratio; ICS, inhaled corticosteroid; LABA, long-acting β 2 -agonist; LAMA, longacting muscarinic antagonist; QALY, quality-adjusted life-year. the frontier are ICS, LABA/ICS and LAMA plus LABA/ICS. For the change from ICS (26.38 exacerbations in 30 years) to LABA/ICS (26.12 exacerbations) the ICER is 18,560 per QALY gained. For the change from LABA/ICS to LAMA plus LABA/ICS (26.04 exacerbations) the ICER is 51,243. For the ICS-intolerant population, the change from LABA (32.08 exacerbations in 30 years) to LAMA (31.51 exacerbations) implies an ICER of 141 per QALY gained. In the alternative scenario, however, this ICER is 581 (based on and exacerbations, respectively), with LABA plus roflumilast as a third option on the cost-effectiveness frontier (31.51 exacerbations), which has an ICER of 41,112 per QALY gained. When the assumption about the baseline number of annual exacerbations is set from 2 to 3, this ICER goes down to 29,791. Extensive sensitivity analyses and different scenarios did not alter these findings substantially. Summary of NICE guidance issued as a result of the single technology appraisal At the time of writing, the Final Appraisal Document issued by NICE on 25 January 2012 states that: 1.1. Roflumilast is recommended only in the context of research as part of a clinical trial for adults with severe COPD (for the purposes of this guidance defined as FEV 1 postbronchodilator < 50% predicted) associated with chronic bronchitis with a history of frequent exacerbations as an add-on to bronchodilator treatment.

11 Single Technology Appraisal Such research should be designed to generate robust evidence about the benefits of roflumilast as an add-on to LAMA plus LABA plus ICS, or LAMA plus LABA for people who are intolerant to ICS People receiving roflumilast should have the option to continue treatment until they and their clinicians consider it appropriate to stop. Key references 1. National Institute for Health and Clinical Excellence (NICE). Guide to the single technology (STA) process URL: (accessed May 2012). 2. Riemsma R, Lhachimi SK, Armstrong N, Van Asselt ADI, Allen A, Manning N, et al. Roflumilast for the management of severe chronic obstructive pulmonary disease: a Single Technology Appraisal. York: Kleijnen Systematic Reviews Ltd; National Institute for Health and Clinical Excellence (NICE). NICE clinical guideline 101. Chronic obstructive pulmonary disease: management of chronic obstructive pulmonary disease in adults in primary and secondary care. London: National Clinic Guideline Centre; URL: (accessed July 2011). 4. British Lung Foundation. Invisible lives. Chronic Obstructive Pulmonary Disease (COPD) finding the missing millions URL: Foundation/Migrated%20Resources/Documents/I/Invisible%20Lives%20report.pdf (accessed July 2011). 5. Healthcare Commission. Cleaning the air: a national study of chronic obstructive pulmonary disease. URL: (accessed May 2012). 6. Devereux G. ABC of chronic obstructive pulmonary disease definition, epidemiology, and risk factors. BMJ 2006;332: GOLD Strategy Group. GOLD. Global strategy for diagnosis, management and prevention of chronic obstructive pulmonary disease. URL: html (accessed July 2011). 8. EMC. Roflumilast summary of product characteristics URL: emc/ (accessed March 2012). 9. National Institute for Health and Clinical Excellence (NICE). Single Technology Appraisal, Roflumilast for the management of chronic obstructive pulmonary disease. Appendix B Final Scope. Finalised October London: NICE; Centre for Reviews and Dissemination (CRD). CRD s guidance for undertaking reviews in health care. York: University of York; Calverley PMA, Rabe KF, Goehring U-M, Kristiansen S, Fabbri LM, Martinez FJ, et al. Roflumilast in symptomatic chronic obstructive pulmonary disease; two randomised clinical trials. Lancet 2009;374: Fichtner K. Clinical study report No. 134: effect of roflumilast on exacerbation rate in patients with chronic obstructive pulmonary disease (M2-111). Konstanz: Nycomed GmbH; Calverley PMA, Sanchez-Toril F, McIvor A, Teichmann P, Bredenbroeker D, Fabbri LM. Effect of 1-year treatment with roflumilast in severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007;176: Queen s Printer and Controller of HMSO This work was produced by Riemsma et al. under the terms of a commissioning contract issued by the Secretary of State for Health. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to NETSCC.

12 10 Roflumilast for the management of severe chronic obstructive pulmonary disease 14. Rabe KF, Bateman ED, O Donnell D, Witte S, Bredenbroker D, Bethke TD. Roflumilast an oral anti-inflammatory treatment for chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 2005;366: Fabbri LM, Calverley PMA, Izquierdo-Alonso JL, Bundschuh DS, Brose M, Martinez FJ, et al. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials. Lancet 2009;374: