Suffolk PCT Drug & Therapeutics Committee New Medicine Report (Adopted by the CCG until review and further notice)

Suffolk PCT Drug & Therapeutics Committee New Medicine Report (Adopted by the CCG until review and further notice) This drug has been reviewed because it is a product that may be prescribed in primary care. Medicine Roflumilast (Daxas, Nycomed) Document status Reviewed at NHS Suffolk Drug and Therapeutics Committee meeting July 15 th 2010 Date of last revision September 2010 Traffic light decision Blue initiated in Primary Care Clinical priorities Double Red- not to be prescribed in NHS Suffolk. group decision Prescribers rating Judgement reserved-the committee postpones its judgement until better data and a more thorough evaluation of the drug are available Mechanism of action Licensed indication Roflumilast is a long-acting selective phosphodiesterase-4 (PDE4) inhibitor which relieves the underlying symptoms of Chronic Obstructive Pulmonary Disease (COPD) through an anti-inflammatory effect. It acts by inhibiting the synthesis of leukotriene B4 and reactive oxygen species in neutrophils, as well as inhibition of TNF-α release by mononuclear cells. Roflumilast also inhibits T-cell proliferation, cytokine production, and cell infiltration of the lungs. (1,2) Roflumilast has been submitted for an EU license for the treatment of COPD. In April 2010, the committee for Medicinal Products for Human Use (CHMP) recommended that roflumilast be granted marketing authorisation for the maintenance treatment of severe COPD (FEV1 post-bronchodilator <50% predicted) associated with chronic bronchitis in adult patients as an add-on to bronchodilator treatment. (3) In the USA in April 2010, an advisory panel to the FDA voted 10-5 against recommending the approval of roflumilast for COPD see points for consideration section. (4) Dosage 500mcg orally ONCE a day (1,2,3) Treatment alternatives Inhaled bronchodilator therapy - Short-acting beta 2 agonist e.g.salbutamol - Short acting antimuscarinic e.g. ipratropium - Long-acting beta 2 agonist e.g. salmeterol - Long acting antimuscarinic e.g. tiotropium Theophylline slow release formulations

Place in therapy Future alternatives Evidence for use Corticosteroids - Inhaled corticosteroid (ICS) e.g. beclometasone dipropionate not licensed for use alone in COPD Or a combination of the above. (1) The place of roflumilast in the management of patients with COPD is uncertain. Further studies are required to establish whether roflumilast (in addition to inhaled bronchodilator treatment) offers any meaningful advantages as an alternative, or in addition, to an ICS. (1) Roflumilast has not been considered in the updated NICE COPD clinical guideline, due for publication in June 2010, but is included in the list of proposed technology appraisals. (2) None known at present There have been 4 key clinical trials (see appendix 1 for details). (5,6) AURA and HERMES were one-year randomised, double-blind clinical trials (total N=3,091), in symptomatic patients with mainly severe or very severe COPD. Roflumilast reduced the number of moderate-to severe exacerbations compared to placebo and improved lung function (increasing FEV1 by 48mL). Long-acting anti-cholinergics and inhaled corticosteroids (ICS) were not allowed during these trials. (5) In two 24-week randomised, double blind trials (EOS N=933, and HELIOS N=742) of patients with moderate to severe COPD, roflumilast combined with either salmeterol or tiotropium improved FEV1 compared to placebo plus either salmeterol or tiotropium (by 49mL and 80mL, respectively). (6) Critical Appraisal (2) The focused selection criteria of the patients enrolled in the studies restricts the generalisability of the results of these studies. The functional benefits of the improvements in lung function or the patients' health status were not addressed in either paper. The design of the studies (i.e. addition of roflumilast to salmeterol or tiotropium), does not allow a direct comparison of the two long-acting bronchodilators when administered with roflumilast. There is no information available about the efficacy of

roflumilast when added to inhaled corticosteroids and longacting bronchodilators. Cautions / side effects NNT/NNH Costs Costs of alternatives for 28 days treatment (MIMS, June 2010) Potential number of patients in NHS Suffolk If roflumilast is not more efficacious than inhaled corticosteroids (when added to long-acting inhaled bronchodilators) in reducing COPD exacerbations, the side-effect profile will need to be weighed against the increased risk of pneumonia when inhaled corticosteroids are used in patients with COPD. From the pooled AURA/HERMES trial results, more roflumilast patients reported adverse events, compared to placebo (67% vs. 62%, p value not quoted). Diarrhoea and weight loss were more common in roflumilast patients 14% of roflumilast and 11% of placebo patients withdrew from treatment due to adverse events (mainly diarrhoea, nausea and headache). These were more likely to occur in roflumilast patients in the first 12 weeks. (2,5) In EOS, adverse events were reported by 63% of patients in the salmeterol plus roflumilast arm compared to 59% of patients in the salmeterol plus placebo arm. In HELIOS, 46% of tiotropium plus roflumilast patients patients and 41% of tiotropium plus placebo patients reported adverse events (p values not quoted). (5) Weight loss, nausea and diarrhoea were more common in patients who received roflumilast. The NNH for withdrawal due to an adverse event was approximately 15 in EOS and 29 in HELIOS, over 24 weeks. (2, 6) NNT=5 to prevent one exacerbation over one year NNH 35 over one year for withdrawal due to an adverse event. The cost of roflumilast is not yet known but expected to be similar to the cost of tiotropium. (2) Drug / device (dose) Cost (30 days) Salmeterol (Serevent Accuhaler) 29.26 50 µg twice daily Tiotropium (Spiriva Handihaler) 18µg once daily (Respimat) 5mcg 34.87 Refill 31.89 36.27 11.88-24.80 Fomoterol 12mcg twice daily (dry powder or aerosol) An average GP practice of 6,600 patients is likely to have about 100 patients on its COPD disease register. The manufacturer of roflumilast estimates that approximately 25% of COPD patients would meet the anticipated licence criteria. (2) With approximately 600,000 people in NHS Suffolk, there may be about 9000 people with COPD. Of these 2250 people may be eligible for treatment with roflumilast.

Points for consideration (1) The manufacturer estimate a budget impact of 4,491 per 100,000 in 2010 and 8,981 in 2011. Therefore given the population of NHS Suffolk of 581,797, the budget impact is estimated to be 26,129 in 2010 and 52,251 in 2011. The proposed indication for roflumilast is the maintenance treatment of severe COPD (FEV1 <50% predicted) associated with chronic bronchitis in adult patients with a history of frequent exacerbations as add on to bronchodilator treatment. In the trials 'bronchotic symptoms' referred to chronic cough and sputum production. Therefore, only these specific patients should be considered if roflumilast reaches the market. There is no standard definition of an exacerbation. Change in FEV1 should be a minimum of 120ml to be clinically significant These studies do not inform about whether roflumilast (in addition to inhaled bronchodilator treatment) provides any significant benefit when used instead of, or in addition to, an ICS [inhaled corticosteroid] the current NICE recommended treatment option. It is not possible to extrapolate the results of these trials to patients in the real world. Many patients in the trials were already receiving an ICS prior to enrolment, which was discontinued. Trials of longer duration are necessary to assess long-term efficacy and safety. Oral, once daily, treatment may have advantages in terms of ease of use and compliance. Further studies are required to establish whether roflumilast offers any meaningful advantages as an alternative, or in addition to an inhaled steroid. There is insufficient evidence to justify the use of roflumilast ahead or instead of inhaled corticosteroids, for those people who remain symptomatic or suffer exacerbations on optimal bronchodilator therapy (long acting beta-agonists and or tiotropium). Any possible benefits of roflumilast have to be balanced against the possibility of adverse effects. An advisory panel to the FDA voted in April 2010 against recommending approval of roflumilast for COPD. They did

Decisions sought from other bodies Decision review date acknowledge that the drug appears safe and effective but concluded the company had provided insufficient evidence to support approval of the drug in the US. The FDA reviewers said roflumilast produced only a modest improvement in lung function and urged the panel to weigh that against concerns about severe diarrhoea, weight loss, cancer, psychiatric problems and suicides among people who took roflumilast in studies. The company said there was no evidence that the drug caused the suicides or raised the risk of cancer and the other risks were manageable. (4) Cambridgeshire JPG not assessed Norfolk TAG not assessed IHT not assessed WSH not assessed SMC not assessed AWMSG not assessed TBC This review is based on the NPC Review published in March 2010 (2) References 1. National Horizon Scanning Centre, University of Birmingham, August 2009. Roflumilast (Daxa) for chronic obstructive pulmonary disease. Available via http://www.haps.bham.ac.uk/publichealth/horizon/outputs/documents/2009/mayaug/roflumilast.pdf 2. Roflumilast for chronic obstructive pulmonary disease (COPD). On the Horizon Future Medicines, March 2010. Available via http://www.npc.nhs.uk/secure/ebt/new_medicines/resp/copd/oth_roflumilast.htm 3. Daxas. Roflumilast. Summary of positive opinion. European Medicines Agency 22 April 2010 EMA/CHMP/159861/2010 Committee for medicinal products for human use (CHMP). Available via http://www.ema.europa.eu/pdfs/human/opinion/daxas_15986110en.pdf 4. Advisory panel votes against approving roflumilast for COPD in the United States: PharmaTimes, Reuters Health. Available via http://reuters.com/article/idcnn0713717420100407?rpc=44 5. Calverly P at al. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet 2009;374:685-94 6. Fabbri L et al. For the M2-127 and M2-128 study groups. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with long acting bronchodialtors: two randomised clinical trials. Lancet 2009:374:685-703 7. Prescribing Impact Resource Template for Roflumilast (Daxas) for Chronic Pulmonary Disease (COPD). A resource for NHS Budget Holders. Received from Nycomed Medical Information June 2010

Appendix 1; Key Clinical Trials Trial Trial Design Trial Population M2-124 HERMES (HERMES) N=772 M2-125 roflumilast (AURA) (5) 2 Phase II international, multi-centre, randomised, placebo-controlled trials of 52 weeks duration. Identical designs in 2 different geographical locations. Analysis was by intention to treat and allocation was concealed. Stratified according to smoking status and treatment with long acting beta 2 agonists. N= 796 placebo AURA N=765 roflumilast N= 758 placebo Patients were aged over 40 years, with severe airflow limitation, bronchotic symptoms, and a history of exacerbations. Treatment Roflumilast 500µg daily or placebo Primary Outcomes The primary endpoints were change in pre-bronchodilator forced expiratory volume in 1 second (FEV1) and the rate of exacerbations that were moderate (glucocorticosteroid-treated) or severe. The primary outcomes; effects on exacerbation rates and pulmonary function (FEV1) were achieved. In pooled analysis, pre-bronchodilator FEV1 increased by a modest 48mL with roflumilast vs. placebo ([95% CI 35mL to 62mL] (p<0.0001). Individual results for AURA and HERMES were 39mL and 58mL respectively. There was a mean reduction in the rate of moderate (i.e. requiring oral corticosteroids or parenteral corticosteroids) or severe (i.e. resulting in hospital admissions or death) from 1.37 per year to 1.14 per year (rate ratio RR 0.83; 95% CI 0.75 to 0.92; p = 0.0003) with roflumilast a reduction of 0.23 exacerbations per year. (NNT 5 to prevent 1 exacerbation in a year). The rate of exacerbations that were moderate or severe per patient year was 1.14 with roflumilast and 1.37 with placebo (reduction 17% [8-25]; p<0.003). AEs were more common with roflumilast (1040 [67%]) than with placebo (963 [62%]). 219 (14%) patients on roflumilast vs. 177

(12%) on placebo discontinued treatment because of AEs. M2-127 (EOS) M2-128 (HELIOS) (6) 2 supporting randomised controlled trials of 24 weeks duration. Patients were randomised after a 4 week run in. N = 933 (M2-127) N = 742 (M2-128) Patients were aged over 40 years, with moderate to severe COPD already being treated with salmeterol or tiotropium Roflumilast 500mcg daily or placebo This was in addition to salmeterol (M2-127) or tiotropium (M2-128). The difference in weight change during the study between the roflumilast and placebo group was -2.17 kg. The primary outcome was change in pre-bronchodilator FEV1 and rates of exacerbations in order to confirm the efficacy of roflumilast when used with standard bronchodilator therapies. Compared with placebo, roflumilast consistently improved mean prebronchodialtor FEV1 by 49 ml (95% CI 27 71; p<0.0001) in patients treated with salmeterol, and 80ml (95% CI 51-110; p<0.0001) in those treated with tioproium. Similar improvement in post-bronchodilator FEV1 was noted in both groups. Patients in the HELIOS study were more symptomatic than in EOS, and used more as-needed medication. The salmeterol plus roflumilast trial involved 466 patients on roflumilast and 467 on placebo; in the tiotropium plus roflumilast trial, 371 patients received Nausea, diarrhoea, weight loss and to a lesser extent, headache were more frequent in patients in the roflumilast group. Discontinuations due to adverse events were more common with roflumilast than placebo (significant in AURA HERMES and EOS).

roflumilast and 372 placebo. Grids used to assist the NHS Suffolk PCT Drug & Therapeutics Committee in reaching a decision about new medications For many years scientists have recognised two types of research: Primary: original studies, based on observation or experimentation on subjects. Secondary: reviews of published research, drawing together the findings of two or more primary studies. In biomedical science there is general agreement over a hierarchy: the higher up a methodology is ranked, the more robust and closer to objective truth it is assumed to be. The orthodox hierarchy looks something like this- Rank: Methodology Description 1 Systematic reviews and meta-analyses Systematic review: review of a body of data that uses explicit methods to locate primary studies, and explicit criteria to assess their quality. Meta-analysis: A statistical analysis that combines or integrates the results of several independent clinical trials considered by the analyst to be "combinable" usually to the level of re-analysing the original data, also sometimes called: pooling, quantitative synthesis. Both are sometimes called "overviews." 2 Randomised controlled trials (finer distinctions may be drawn within this group based on statistical parameters like the confidence intervals) Individuals are randomly allocated to a control group and a group who receive a specific intervention. Otherwise the two groups are identical for any significant variables. They are followed up for specific end points. 3 Cohort studies Groups of people are selected on the basis of their exposure to a particular agent and followed up for specific outcomes.

4 Case-control studies "Cases" with the condition are matched with "controls" without, and a retrospective analysis used to look for differences between the two groups. 5 Cross sectional surveys Survey or interview of a sample of the population of interest at one point in time 6 Case reports. A report based on a single patient or subject; sometimes collected together into a short series 7 Expert opinion A consensus of experience from the good and the great. 8 Anecdotal Something a bloke told you after a meeting or in the bar. Adapted from Systematic reviews, What are they and why are they useful? ScHARR 2008 To Decide if a Medication Is To Be Used In Suffolk Criterion to be measured Tends to poor 2 Medium 4 Tends to good Quality of evidence in the papers reviewed 7-8 5-6 3 4 2 1 Magnitude of effect inferred from trials reviewed Low x Medium High Are trial end-points surrogate markers or clinical outcomes? Clinical outcomes Clinical usefulness of trial end-points x Known Side Effect Profile High Medium Low Known Interactions High Medium Low Concern re Possible Side Effects Not Yet Uncovered High x Medium Low Balance of Benefit To Harm (side effects toxicity interactions etc) Poor Medium Good NNT High x Medium Low Comparison Of Effectiveness With Other Medicines In Use For The Poor Medium Good Same Condition Severity of Condition to be Treated Trivial Medium Severe Novel drug or member of existing class Uptake (estimated proportion of people with this condition likely to be prescribed the medication under consideration maximum and minimum uptake) Is the drug to be used in Suffolk? Member of existing class 10 to 20% of COPD patients yes

Prescriber s Rating Definitions Bravo! -The drug is a major therapeutic advance in an area where previously no treatment was available. A real advance - The product is an important therapeutic innovation but has certain limitations. Offers an advantage - The product has some value but does not fundamentally change present therapeutic practice. Possibly Helpful - The product has minimal additional value, and should not change prescribing habits except in rare circumstances. Judgement reserved - The Committee postpones its judgement until better data and a more thorough evaluation of the drug are available. Nothing New - The product may be a new substance but is superfluous because it does not add to the clinical possibilities offered by previous products available. In most cases these are me-too products. Not acceptable - Product without evident benefit over others but with potential or real disadvantages. (With acknowledgement to Prescrire) To Decide Where A Medication Is To Be Used In Suffolk Skills of the prescriber Criterion Red Amber Green Blue Experience Of The Condition Specific Specific Specific General Diagnosis Specific Specific Specific General Monitoring Progress Of Treatment Difficult Specific General General Therapy Patient Selection Difficult Specific Specific Easy Initiation Of Treatment Difficult Difficult Easy Easy Dose Titration Difficult Specific Easy Easy Monitoring Of Side Effects Complex Easy Easy Easy Method Of Administration Complex Normal Normal Normal Discontinuation Of Treatment Complex Complex Easy Easy References Jonsen A. Bentham in a box: Technology assessment and health care allocation. Law Med. Health Care. 1986;14:172-174 1 Suffolk Drug & Therapeutics Committee Responsibility for prescribing, Hospital Trust or GP Attached as Appendix 1 & Appendix 2 Grids used to assist the NHS Suffolk PCT Drug & Therapeutics Committee in reaching a decision about new medications

For many years scientists have recognised two types of research: Primary: original studies, based on observation or experimentation on subjects. Secondary: reviews of published research, drawing together the findings of two or more primary studies. In biomedical science there is general agreement over a hierarchy: the higher up a methodology is ranked, the more robust and closer to objective truth it is assumed to be. The orthodox hierarchy looks something like this-