Pulmonary arterial hypertension (adults) - drugs: appraisal consultation document

Appraisal consultation document

Epoprostenol, iloprost, bosentan, sitaxentan and sildenafil for the treatment of pulmonary arterial hypertension in adults

The Department of Health has asked the National Institute for Health and Clinical Excellence (NICE or the Institute) to conduct a multiple technology appraisal of epoprostenol, iloprost, bosentan, sitaxentan and sildenafil and provide guidance on their use to the NHS in England and Wales. The Appraisal Committee has had its first meeting to consider both the evidence submitted and the views put forward by non-manufacturer consultees and commentators, and by the clinical specialist and patient expert representatives nominated for this appraisal by non-manufacturer consultees and commentators. The Committee has developed preliminary recommendations on the use of epoprostenol, iloprost, bosentan, sitaxentan and sildenafil.

This document has been prepared for consultation with the formal consultees.It summarises the evidence and views that have been considered and sets out the preliminary recommendations developed by the Committee. The Institute is now inviting comments from the formal consultees in the appraisal process (the consultees for this appraisal are listed on the NICE website, www.nice.org.uk). This document should be read in conjunction with the evidence base for this appraisal (the evaluation report) which is available from www.nice.org.uk

Note that this document does not constitute the Institute's formal guidance on epoprostenol, iloprost, bosentan, sitaxentan and sildenafil. The recommendations made in section 1 are preliminary and may change after consultation.

  • The process the Institute will follow after the consultation period is summarised below. For further details, see the 'Guide to the technology appraisal process' (this document is available on the Institute's website, www.nice.org.uk).
  • The Appraisal Committee will meet again to consider the original evidence and this appraisal consultation document in the light of the views of the formal consultees.
  • At that meeting, the Committee will also consider comments made on the document by people who are not formal consultees in the appraisal process.
  • After considering feedback from the consultation process, the Committee will prepare the final appraisal determination (FAD) and submit it to the Institute.
  • Subject to any appeal by consultees, the FAD may be used as the basis for the Institute's guidance on the use of the appraised technology in the NHS in England and Wales.

The key dates for this appraisal are:

Closing date for comments: 20 March 2008

Second Appraisal Committee meeting: 3 April 2008

Details of membership of the Appraisal Committee are given in appendix A, and a list of the sources of evidence used in the preparation of this document is given in appendix B

Note that this document does not constitute the Institute's formal guidance on epoprostenol, iloprost, bosentan, sitaxentan and sildenafil. The recommendations made in section 1 are preliminary and may change after consultation.

1 Appraisal Committee's preliminary recommendations
1.1 Sildenafil is recommended, within its marketing authorisation, for the treatment of pulmonary arterial hypertension in adults.
1.2

Bosentan and sitaxentan, within their licensed indications, are recommended as treatment options for pulmonary arterial hypertension only for adults in whom:

  • sildenafil is contraindicated (see summary of product characteristics [SPC])
  • sildenafil, as prescribed in accordance with section 1.1, is not effective in controlling the person's symptoms or degree of pulmonary hypertension
  • sildenafil, as prescribed in accordance with section 1.1, is poorly tolerated.
1.3 Intravenous epoprostenol and inhaled iloprost are not recommended for the treatment of pulmonary arterial hypertension in adults
1.4 People who are currently receiving bosentan or sitaxentan (outside the recommendations in section 1.2), intravenous epoprostenol or inhaled iloprost should have the option to continue therapy until they and their clinicians consider it appropriate to stop.
 
2 Clinical need and practice
2.1 Pulmonary arterial hypertension (PAH) is one of five subtypes of pulmonary hypertension. PAH is a diverse group of diseases of similar pathophysiology and clinical presentation. They are characterised by a progressive increase in pulmonary vascular resistance, which leads to right ventricular heart failure and premature death.
2.2 Pulmonary hypertension is currently categorised using the Venice 2003 clinical classification system, which includes five major categories, one of which is PAH (category 1). Within the PAH category, there are a further five subcategories: idiopathic (IPAH); familial (FPAH); associated with other conditions (APAH); associated with significant venous or capillary involvement; and persistent pulmonary hypertension of the newborn (PPHN). The term primary pulmonary hypertension was widely used before the advent of the Venice 2003 classification and is regarded as interchangeable with IPAH. In addition, people with PAH are classified according to their functional capacity using the New York Heart Association (NYHA)/ World Health Organization (WHO) classification of functional status (functional class [FC] l, ll, lll and lV).
2.3 PAH is a rare condition and, as with such conditions, a lack of data prevents reliable predictions of morbidity and mortality. The estimated annual incidence of IPAH is 1-2 cases per million population, and the annual incidence of other types of PAH is a further 1-2 cases per million population. In the UK, the likely prevalence of PAH has been estimated to be 15-50 cases per million population, with suggestions that the estimate may be towards the upper end of this range. Assuming an adult population in England and Wales of 43.3 million, this would give an approximate upper estimate of 2165 adults with PAH.
2.4 Before the therapies currently under assessment became available, only supportive care (comprising treatments such as anticoagulants, diuretics, oxygen, digoxin and calcium channel blockers) was given. The prognosis for people with PAH receiving supportive care only is considered to be poor. In the 1980s, before intravenous prostenoids became available, median survival at the time of diagnosis for people with IPAH receiving supportive treatment was 2.8 years. Patient survival was estimated as 68% at 1 year, 48% at 3 years and 24% at 5 years.
2.5 Since 2001, people with PAH in the UK have been referred to and managed at specialist centres. There are currently seven centres in England designated by the Department of Health through the National Commissioning Group.
2.6 People with PAH can remain relatively asymptomatic until the underlying disease process is advanced. The key initial symptoms are breathlessness on exertion, with possible chest pain (angina) and fainting (syncope). Accurate diagnosis can be difficult, because symptoms are non-specific and there is often a long delay between the onset of symptoms and reaching a definitive diagnosis. This delay may be several years, and people can have severe disease (and possibly signs and symptoms of right ventricular heart failure) by the time appropriate treatment is started. Loss of exercise capacity and, later, the capacity for daily living are often devastating to a person's quality of life. This can also lead to depression, leading to further deterioration in quality of remaining life. PAH, and IPAH in particular, can occur at a relatively young age, increasing the impact of the disease on people with PAH and their carers.
2.7 Different measures are used to monitor the severity, progression and response to treatment of PAH. Clinically, no single measure or composite measure is utilised to measure the disease. Key measures include: the six-minute walk test/distance (6MWT/D), dyspnoea scores on the Borg or Mahler scales, pulmonary artery pressure (PAP), right atrial pressure (RAP), pulmonary capillary wedge pressure (PCWP), pulmonary vascular resistance (PVR) and cardiac output/cardiac index.
 
3 The technologies          
Epoprostenol  
3.1 Epoprostenol (Flolan, GlaxoSmithKline) belongs to a class of drugs known as prostanoids; it is a synthetic form of prostaglandin I2 (prostacyclin). Epoprostenol is licensed for the intravenous treatment of primary pulmonary hypertension in NYHA FC III and FC IV people who do not respond adequately to conventional therapy.
3.2 Epoprostenol is contraindicated in people with a known hypersensitivity to the drug, with congestive heart failure from severe left ventricular dysfunction, or who develop pulmonary oedema during dose ranging. Side effects include sepsis, anxiety, headache, tachycardia, nausea, vomiting and jaw pain. For full details of side effects and contraindications, see the SPC.
3.3 Epoprostenol is administered by continuous intravenous infusion at an initial infusion rate of 1-2 nanogram/kg/min, which is increased until maximum benefit on haemodynamic parameters is achieved and/or dose-limiting effects occur. The cost is £64.57 for a 0.5-mg vial and £130.07 for a 1.5-mg vial (excluding VAT; 'British national formulary' [BNF] edition 54). Costs may vary in different settings because of negotiated procurement discounts.
3.4 People receive initial treatment as inpatients under specialist care to enable intensive training for them and/or their carers in administering the drug. Close monitoring and emergency back-up are also needed. Patients who are well enough can return home after the initiation of treatment. A great deal of ability and commitment is required from the person and/or carer to prepare and administer the drug under sterile conditions and to maintain sterility of the permanent central venous catheter. Ongoing education and training are vital and these are delivered regularly by a specialist nurse.
Iloprost  
3.5 Iloprost (Ventavis, Bayer Schering Pharma) is a stable prostaglandin I2 analogue developed for intravenous, oral and inhaled administration. Only the formulation for inhalation is licensed for PAH; therefore the other formulations have not been included in this technology appraisal. Inhaled iloprost is licensed for the treatment of people with primary pulmonary hypertension, classified as NYHA FC III, to improve exercise capacity and symptoms.
3.6 The contraindications listed in the SPC for Iloprost include: a known hypersensitivity to the drug; severe coronary disease events (for example, severe artery disease, angina or recent myocardial infarction); recent cerebrovascular events (for example, stroke) and pulmonary hypertension caused by veno-occlusive disease. Furthermore, iloprost is not recommended for people with unstable pulmonary hypertension who have advanced right ventricular heart failure. The most common side effects include vasodilatation, hypotension, headache and increased cough. For full details of side effects and contraindications, see the SPC.
3.7 Iloprost is administered by inhalation through a nebuliser at a dosage of 2.5-5 micrograms 6-9 times daily, adjusted according to response. The cost is £424.50 for 30 x 1-ml vials (10 micrograms per vial) and £2377.20 for 168 x 1-ml vials (excluding VAT; BNF edition 54). Costs may vary in different settings because of negotiated procurement discounts.
3.8 Treatment is usually initiated under specialist care, and the person is usually admitted to hospital for about 3 days for training, education and monitoring of self-delivery. Patients can return home once stabilised and trained. Patients receive two nebulisers (one as back-up), and consumables are delivered regularly to their home. Nebulisers are replaced approximately every 2 years.
Bosentan  
3.9 Bosentan (Tracleer, Actelion Pharmaceuticals) is a dual endothelin receptor antagonist with affinity for both endothelin A and B receptors (ETA and ETB). It is licensed for the treatment of PAH to improve exercise capacity and symptoms in people with grade III functional status; efficacy has been shown in: primary PAH (IPAH and FPAH); PAH secondary to scleroderma without significant interstitial pulmonary disease; and PAH associated with congenital systemic-to-pulmonary shunts and Eisenmenger's physiology.
3.10 Bosentan is contraindicated in people with a known hypersensitivity to the drug, hepatic impairment (including aminotransferases of more than three times the upper limit of normal) and those taking ciclosporin. Bosentan is contraindicated in pregnancy because it is assumed to be teratogenic, and women with child-bearing potential should not receive bosentan unless they are using a reliable contraceptive. Side effects include headache, flushing, abnormal hepatic function, leg oedema and anaemia. For full details of side effects and contraindications, see the SPC.
3.11 Bosentan is administered orally at an initial dosage of 62.5 mg twice daily, increased after 4 weeks to 125 mg twice daily; the maximum dosage is 250 mg twice daily. The cost is £1541 for 56 x 62.5-mg tablets and £1541 for 56 x 125-mg tablets (excluding VAT; BNF edition 54). Costs may vary in different settings because of negotiated procurement discounts.
3.12 Treatment is usually initiated during admission to hospital as a day case under specialist care and patient education is provided; subsequent treatments are taken at home.
Sitaxentan  
3.13 Sitaxentan (Thelin, Encysive) is a selective receptor antagonist for ETA (but not ETB). It is indicated for the treatment of people with PAclassified as WHO FC III to improve exercise capacity; efficacy has been shown in primary pulmonary hypertension and in pulmonary hypertension associated with connective tissue disorder (CTD).
3.14 Sitaxentan has contraindications that are similar to those of bosentan (above). Common side effects include headache, peripheral oedema, nasal congestion, constipation, flushing and muscle cramp. For full details of side effects and contraindications, see the SPC.
3.15 Sitaxentan is administered orally at a dosage of 100 mg once daily. The cost is £1540.00 for 28 x 100-mg tablets (excluding VAT; BNF edition 54). Costs may vary in different settings because of negotiated procurement discounts.
3.16 Treatment is usually initiated during admission to hospital as a day case under specialist care and patient education is provided; subsequent treatments are taken at home.
Sildenafil  
3.17 Sildenafil (Revatio, Pfizer) is a specific inhibitor of phosphodiesterase-5. It is indicated for the treatment of people with PAH classified as WHO FC III to improve exercise capacity; efficacy has been shown in primary pulmonary hypertension and pulmonary hypertension associated with CTD.
3.18 Sildenafil is contraindicated in people with a hypersensitivity to the drug, severe hepatic impairment, recent history of stroke or myocardial infarction, and severe hypotension at initiation. Use with nitric oxide-producing treatment or nitrates is not recommended because sildenafil potentiates the hypotensive effects of these agents. Common side effects include headache, flushing, dyspepsia, diarrhoea, and limb pain. For full details of side effects and contraindications, see the SPC.
3.19 Sildenafil is administered orally at a dosage of 20 mg three times daily. Tablets should be taken approximately 6 to 8 hours apart with or without food. The cost is £373.50 for 90 x 20-mg tablets (excluding VAT; BNF edition 54). Costs may vary in different settings because of negotiated procurement discounts.
3.20 Treatment is usually initiated during admission to hospital as a day case under specialist care and patient education is provided; subsequent treatments are taken at home.
   
4.

Evidence and interpretation

The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B).

4.1 Clinical effectiveness
4.1.1 Randomised controlled trials (RCTs) were identified for each of the five technologies in this appraisal. Most RCTs compared one technology plus supportive care with placebo and/or supportive care. There were few head-to-head comparisons of the technologies, and few RCTs compared a single technology with combination technologies. The Assessment Group presented results of meta-analyses (or individual trial results when only one trial provided data) for all the drugs in this appraisal. The RCTs included in the appraisal were of 18 weeks' duration or less. The populations of the RCTs differed in terms of types of PAH and the FC at baseline. 
4.1.2 The inclusion criteria of the RCTs usually required patients to be stable on supportive care (usually for 4 weeks or longer) before study entry. Therefore, the trials essentially excluded unstable and potentially more severely ill patients, who are frequently seen in clinical practice. This could have implications on the generalisability of the results from the trials.
4.1.3 Epoprostenol
4.1.3.1 Three RCTs comparing epoprostenol plus supportive care with supportive care alone were identified, together with two other studies; one comparing epoprostenol with bosentan (see section 4.1.5.3), and a further, unpublished, study comparing epoprostenol with sildenafil.
4.1.3.2 In the pooled analysis of the three trials, epoprostenol plus supportive care statistically significantly improved exercise capacity (using the 6MWD measure) and haemodynamic measures compared with supportive care alone, and increased the proportion of patients with improved FC. A total of 21 deaths (5 for epoprostenol, 16 for supportive care) were reported in the three trials. A significant decrease in the risk of death was reported in one trial for patients receiving epoprostenol. The pooled relative risk also showed a trend in favour of epoprostenol although this did not reach statistical significance. Statistically significant improvements in PAH-associated dyspnoea were reported for patients receiving epoprostenol compared with supportive care in the three trials. One trial also showed significant improvements in certain quality of life measures for the epoprostenol group.
4.1.4 Iloprost
4.1.4.1 Two RCTs compared inhaled iloprost plus supportive care with supportive care alone. Two further RCTs identified by the Assessment Group compared iloprost added to ongoing bosentan therapy and supportive care with ongoing bosentan therapy and supportive care alone. The manufacturer identified and summarised further observational studies to support its clinical findings.
4.1.4.2 The RCTs comparing inhaled iloprost plus supportive care with supportive care alone were carried out in mixed populations. They included IPAH and other subtypes of PAH within category 1 of the Venice classification, as well as other types of pulmonary hypertension (mainly chronic thrombotic, Venice category 4). One of the RCTs included people with PAH in FC III and IV (AIR), and the second RCT also included people in FC II (AIR-2). The results of the AIR study showed that iloprost plus supportive care statistically significantly improved exercise capacity (6MWD) and haemodynamic measures, when measured post-inhalation, compared with supportive care alone. Statistically significant improvements in PAH-associated dyspnoea were also observed in the AIR study. Pooled results from AIR and AIR-2 showed improvement in the EuroQol visual analogue scale. The proportion of patients with improved FC was significantly higher in the iloprost groups based on pooled results of both trials.
4.1.4.3 In the RCTs that compared iloprost plus ongoing bosentan therapy and supportive care with ongoing bosentan therapy and supportive care alone, no statistically significant difference was found between the iloprost group and the control group for any of the outcome measures in a FC III IPAH population. The second RCT included a mixed PAH population (all within Venice category 1), with the majority with PAH being in FC III. In this study there was a statistically significant increase in the likelihood of FC improvement for the iloprost group compared with the control group. There was also statistically significant improvement in haemodynamic measures when measured post-inhalation. The changes in 6MWD between treatment groups were not statistically significant in either of the trials.
4.1.5 Bosentan
4.1.5.1 Bosentan was investigated in six of the included RCTs. Four of these compared bosentan plus supportive care with placebo plus supportive care; one of these trials also included a sitaxentan arm. Another trial compared the combination of epoprostenol plus bosentan with epoprostenol alone. Bosentan was compared with sildenafil in a further study; however the dose of sildenafil used in this study was higher than that recommended in the SPC.
4.1.5.2 Bosentan plus supportive care resulted in a statistically significant improvement in exercise capacity (6MWD) and haemodynamic outcomes compared with placebo plus supportive care, both in PAH populations with mixed FC (II, III and IV) and specifically in FC III. There was also a statistically significant increase in time to clinical worsening, improvement in FC and PAH-associated dyspnoea, and reduced risk of serious adverse events in bosentan-treated patients compared with placebo, in PAH populations with mixed FC.
4.1.5.3 In the RCT that compared bosentan plus epoprostenol with epoprostenol alone in mixed PAH populations (IPAH and PAH/CTD) with mixed FC (III and IV), no statistically significant difference was observed between the treatment groups for any of the outcomes assessed in the trial.
4.1.6 Sitaxentan
4.1.6.1 Sitaxentan was investigated in three of the included RCTs. All three trials compared sitaxentan, at various dosages, with placebo in patients receiving ongoing supportive care. One of these trials also included an open-label bosentan arm. The manufacturer identified three other observational long-term studies and a study evaluating the safety and efficacy of sitaxentan in patients with PAH who had previously discontinued bosentan.
4.1.6.2 Sitaxentan at its licensed dose plus supportive care statistically significantly reduced the risk of clinical worsening, increased exercise capacity (6MWD), and improved FC and haemodynamic outcomes compared with supportive care alone in PAH populations with mixed FC (II, III and IV). Improvement in FC was observed in patients with FC III but this did not reach statistical significance. Additional positive findings in physical health-related quality of life were found, but the Assessment Group noted that this posthoc analysis should be interpreted with caution.
4.1.6.3 The manufacturer provided additional data, on request, on the estimate of time to death from a pooled analysis of two trials (one RCT and one long term study).
4.1.7 Sildenafil
4.1.7.1 Sildenafil was investigated in six of the included RCTs. Four of these compared sildenafil with placebo in patients receiving ongoing supportive care. Another trial, identified through the manufacturer's submission, compared sildenafil with placebo in patients receiving ongoing epoprostenol and supportive care. Only one of these studies (called SUPER-1) included a treatment arm using the dosage of 20 mg three times daily recommended in the SPC. All the other studies used higher doses or planned escalation to higher doses. Sildenafil was compared with bosentan in a further study but the dose of sildenafil was higher than that recommended in the SPC.
4.1.7.2 Sildenafil at its licensed dose plus supportive care demonstrated statistically significant improvements in exercise capacity (6MWD), haemodynamic outcomes, and the proportion of patients in whom FC was improved in PAH populations with mixed FC (I, II, III and IV). There were also improvements in certain domains of quality of life measures compared with supportive care alone in PAH populations with mixed FC (I, II, III and IV).
4.1.8 Survival data
4.1.8.1 The National Pulmonary Vascular Disease Unit submitted a survey carried out in six of the seven designated PAH UK centres. This survey included data on the survival of people with PAH between 2001 and 2006. This data was submitted as academic in confidence and is therefore not presented here.
4.1.9 Summary of clinical evidence
4.1.9.1 The RCTs showed statistically significant improvements in FC, 6MWD and haemodynamic measures for each of the technologies compared with placebo/control, although the volume of evidence varied among the technologies. Many of the trials recruited a mixed population of different PAH subcategories and/or FC; therefore, the studies differed in the extent to which they could be generalised to the licensed indication of individual technologies. None of the RCTs for the therapies under consideration had study durations of more than 18 weeks. All five technologies (intravenous epoprostenol, inhaled iloprost and oral bosentan, sitaxentan and sildenafil), when added to supportive care and used at their licensed doses, have been shown to be more clinically effective than supportive care alone.
4.2 Cost effectiveness
Published economic evaluations  
4.2.1 The Assessment Group identified four published economic evaluations. Only one of the economic evaluations reported its results in terms of incremental cost-effectiveness ratios (ICERs). Direct comparisons between the different economic evaluations were not possible owing to different model specifications, including time horizon, perspective and country of origin. The results from the models are not generalisable to the NHS.  
Epoprostenol - the manufacturer's economic evaluation  
4.2.2 The GlaxoSmithKline submission did not include an economic evaluation.
Iloprost - the manufacturer's economic evaluation  
4.2.3 Bayer Schering Pharma submitted a Markov model with a cohort of 100 patients that evaluated the cost effectiveness of inhaled iloprost compared with epoprostenol. No comparison was made with supportive care. The manufacturer's model assumed that iloprost had a fixed price regardless of dose. A cost-utility analysis was undertaken with outcomes measured in quality-adjusted life years (QALYs). The model had a time horizon of 20 years, with a cycle length of 3 months. The patient group modelled was that with a diagnosis of primary pulmonary hypertension in FC III who had not responded to or were unable to tolerate oral therapy, and would otherwise have required intravenous epoprostenol.
4.2.4 When compared with epoprostenol in the base-case analysis, iloprost was shown to reduce costs by £348,000 per person and increase QALYs by 0.04 per person. Therefore, iloprost was dominant (more effective and less costly) compared with epoprostenol alone. One-way sensitivity analysis showed results to be most sensitive to assumptions made about the proportion of patients who improve with supportive care. Results were also sensitive to the cost of the drugs, but they were less sensitive when the costs of managing PAH were included. A probabilistic sensitivity analysis (PSA) demonstrated that if the maximum acceptable amount to pay for an additional QALY is £30,000 per QALY gained, the probability of iloprost being cost effective was 100%.
Bosentan - the manufacturer's economic evaluation  
4.2.5 Actelion submitted a Discrete Event Simulation (DES), which compared bosentan (as first-line treatment) with the following three comparators: historical care (defined as 30% of patients receiving the lowest-cost intravenous prostanoid [epoprostenol] and 70% receiving supportive care); supportive care (in which no one received intravenous prostanoids); and intravenous prostanoids. The definition of historical care was based on audit data from specialised PAH centres before the launch of bosentan. Epoprostenol's efficacy and cost were used as a proxy for all intravenous prostanoids.
4.2.6 The model considered 10,000 hypothetical people with PAH in FC III, who remained in the model until 'clinical worsening' occurred, defined as death, a change in treatment through addition of or substitution of another intervention or the need for transplantation. Thus, costs and QALYs were not counted after a person with PAH was deemed to have reached clinical worsening. If a person with PAH achieved their life expectancy age without clinical worsening, he or she was assumed to die from other causes. Two types of PAH were considered separately by the model ? IPAH and PAH/CTD.
4.2.7 When compared with historical care in the base-case analysis for IPAH, bosentan was shown to increase costs by £20,000 per person and increase QALYs by 0.96 per person. Therefore, the ICER for bosentan compared with historical care was £21,000 per QALY gained. This rose to £84,000 per QALY gained when bosentan was compared with supportive care. Bosentan was dominant (more effective and less costly) compared with intravenous prostanoids. When considered in PAH associated with CTD, bosentan was more cost effective than in IPAH: the ICER for bosentan compared with historical care was £15,000 per QALY gained, rising to £78,000 per QALY gained compared with supportive care. Again, bosentan dominated intravenous prostanoids.
4.2.8 Results of the PSA showed bosentan to have a 40% probability of being cost effective compared with historical care in people with IPAH if the maximum acceptable amount to pay for an additional QALY is £20,000, and 90% if the amount is £30,000 per additional QALY. When compared with supportive care, bosentan was not cost effective at either of the maximum acceptable amounts to pay for an additional QALY. The corresponding analysis for PAH associated with CTD care gave 90% and 100% probabilities of bosentan being cost effective compared with historical care at maximum acceptable amounts to pay for an additional QALY of £20,000 and £30,000, respectively, but again it was not cost effective at either figure when the comparator was supportive care.
Sitaxentan - the manufacturer's economic evaluation  
4.2.9 Encysive submitted a Markov model that evaluated the cost effectiveness of sitaxentan as first-line treatment when compared with supportive care and bosentan. A cost-effectiveness analysis was undertaken with outcomes measured in life years rather than QALYs. The model time horizon was 5 years, with a cycle length of 1 week. The model followed a population of adults with PAH in FC III, based on trial populations. People with PAH started in a pre-deterioration state, and they could remain in that state, deteriorate and move into a post-deterioration state, or die.
4.2.10 Base-case results showed sitaxentan to be more effective (with a gain of 3.32 life years) than supportive care (2.70 life years) or bosentan (2.45 life years) but also more expensive. The ICER for sitaxentan compared with supportive care was £94,600 per life year gained, and £19,500 per life year gained when compared with bosentan. Sensitivity analysis shows that the choice of comparator was a key issue regarding cost effectiveness. Results of the PSA showed considerable uncertainty, particularly in relation to supportive care, for which sitaxentan had only a 44% chance of being cost effective, even if the maximum acceptable amount to pay for an additional life year was £80,000 per life year gained.
Sildenafil - the manufacturer's economic evaluation  
4.2.11 Pfizer presented two types of analysis. The first was a cost-utility analysis of sildenafil compared with supportive care. The second was a cost-minimisation analysis (CMA) comparing all five interventions considered in the appraisal. The cost-utility analysis presented was a Markov model with two distinct parts. In the first year, the first three cycles were 12 weeks each, followed by one cycle of 16 weeks. From year 2 onwards, a yearly cycle was used. Base-case results were presented for a time horizon of 30 years, representing remaining lifetime, and all patients were assumed to have died by the age of 79 years.
4.2.12 Results of the base-case analyses showed that treatment with sildenafil increased costs by £22,000 and increased QALYs by 1.01 compared with supportive care. This resulted in an ICER of £22,000 per QALY gained for sildenafil compared with supportive care alone. A PSA, run for 1000 iterations, suggested that sildenafil had a 66% probability of being cost effective at a maximum acceptable amount to pay for an additional QALY of £20,000, and 84% if that figure was £30,000 per QALY. A sensitivity analysis of results over a 1-year period was considered, and the ICER for sildenafil compared with supportive care alone was lower than in the base-case (lifetime) at £15,300 per QALY gained.
4.2.13 In the CMA, QALYs were assumed to be equivalent across intervention therapies, because efficacy was assumed to be the same. Total costs and an average cost per QALY were presented for each therapy, with the lowest costs demonstrated for sildenafil.
The Assessment Group's economic evaluation  
4.2.14 The Assessment Group developed a Markov model to determine the cost effectiveness of each technology plus supportive care compared with supportive care alone. The time horizon of the model was 30 years, with a cycle length of 12 weeks. The population considered was adults with PAH (category 1 of the Venice 2003 clinical classification) in FC III for all drugs (and also FC IV for epoprostenol), for whom calcium channel blockers were inappropriate or no longer effective. One base-case analysis was conducted, using data on all Venice category 1 PAH patients. A separate analysis for the subcategory of IPAH alone was proposed but a lack of data prevented this.
4.2.15 All five technologies were considered. Only the first use of each intervention was considered, and initiation of any of the interventions after failure of another listed intervention was not considered, with the exception of epoprostenol for people with PAH FC IV. Therefore, for all treatments, the starting state was FC III with a further analysis conducted with a starting state of FC IV for epoprostenol. The analyses for iloprost, bosentan, sitaxentan and sildenafil were based on the assumption that all people with PAH switch to intravenous epoprostenol upon deterioration to FC IV with the first-line therapy discontinued. Although in clinical practice the first line therapy is unlikely to be stopped, this appraisal considered the treatments within their marketing authorisations only, therefore this was the only option considered. Data on the effectiveness of combination therapies was not available; therefore the inclusion of combination in FC IV would only have an impact on cost. The supportive care arm in these analyses included epoprostenol when FC IV was reached. In the starting state of FC IV for epoprostenol, the comparator was supportive care alone.
4.2.16 The transition probabilities between the FCs for supportive care were calculated from the pooled analyses and directly related to each intervention. For each therapy the effect of treatment was incorporated into a transition probability by applying the odds ratio for change in FC on treatment to the respective supportive care transition probability. The effect on mortality (survival) for each treatment was based on the pooled data from trials and observational studies, where available. The estimate for mortality on sildenafil was based on data for sitaxentan because the clinical trials of sildenafil did not provide adequate data on this outcome. The mortality on supportive care was also directly related to each intervention and was estimated by applying the odds ratios for change in FC to the mortality on each treatment.
4.2.17 The resource use was broadly concerned with the initiation and ongoing costs of each intervention, contacts with primary and secondary health care, adverse events, and use of wider social services including palliative care. The perspective adopted was that of the NHS and Personal Social Services, and a price year of 2006 was applied.
4.2.18 The base case for epoprostenol plus supportive care compared with supportive care alone was associated with incremental costs and QALYs of £218,000 and 0.79, respectively, resulting in an ICER of £277,000 per QALY gained for people with PAH in FC III. The base case for epoprostenol plus supportive care compared with supportive care alone for people with PAH in FC IV was associated with an incremental costs and QALYs of £403,000 and 1.17, respectively, resulting in an ICER of £343,000 per QALY gained. The base-case analysis for iloprost plus supportive care compared with supportive care alone was associated with incremental costs and QALYs of £103,000 and 1.02 respectively, resulting in an ICER of £101,000 per QALY gained. The base-case analysis for bosentan plus supportive care compared with supportive care alone was associated with incremental costs and QALYs of £93,000 and 3.49, respectively, giving an ICER of £27,000 per QALY gained. The base-case analysis for sitaxentan plus supportive care compared with supportive care alone was associated with incremental costs and QALYs of £76,000 and 3.09, respectively, resulting in an ICER of £25,000 per QALY gained. Sildenafil plus supportive care was more effective (incremental QALYs of 3.24) and less costly (£36,000) and was therefore dominant compared with supportive care alone. On request of the committee, the results of the Assessment Group's base case cost-effectiveness analyses for the oral treatments were also presented incrementally.
4.2.19 Further scenarios were considered by the Assessment Group on the request of the Appraisal Committee. One of these altered the base case to remove the assumption that patients switch to epoprostenol on progression to FC IV. All patients who progressed to FC IV were assumed to receive supportive care only. The incremental costs and QALYs for epoprostenol compared with supportive care alone were £229,000 and 0.84, respectively, resulting in an ICER for people with PAH in FC III of £273,000 per QALY gained. The incremental costs and QALYs for iloprost compared with supportive care alone were £102,000 and 1.05, respectively, resulting in an ICER of £98,000 per QALY gained. The incremental costs and QALYs for bosentan compared with supportive care alone were £155,000 and 3.68, respectively, resulting in an ICER of £42,000 per QALY gained. The incremental costs and QALYs for sitaxentan compared with supportive care alone were £142,000 and 3.25, respectively, resulting in an ICER of £44,000 per QALY gained. The incremental costs and QALYs for sildenafil compared with supportive care alone were £31,000 and 3.42, respectively, resulting in an ICER of £9000 per QALY gained.
4.2.20 A second scenario considered alternative assumptions about the mortality on oral treatment in FC III. For this analysis, the base case was modified to incorporate the assumption that mortality on oral drug treatment was the same as that used in the model for epoprostenol in FC III and the corresponding supportive care arm. The incremental costs and QALYs for bosentan plus supportive care compared with supportive care alone were £14,000 and 2.62, respectively, resulting in an ICER of £6000 per QALY gained. Sitaxentan plus supportive care compared with supportive care alone was associated with incremental costs and QALYS of £3,000 and 2.17, respectively, resulting in an ICER of £1400 per QALY gained. Sildenafil plus supportive care was more effective (incremental QALYs of 2.38) and less costly (£90,000) and was therefore dominant compared with supportive care alone.
4.3 Consideration of the evidence
4.3.1 The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of epoprostenol, iloprost, bosentan, sitaxentan and sildenafil, having considered evidence on the nature of the condition and the value placed on the benefits of epoprostenol, iloprost, bosentan, sitaxentan and sildenafil by people with PAH, those who represent them, and clinical specialists. It was also mindful of the need to take account of the effective use of NHS resources.
4.3.2 The Committee reviewed the clinical effectiveness of each of the technologies under consideration. It agreed that studies had demonstrated the efficacy of intravenous epoprostenol, inhaled iloprost and oral bosentan, sitaxentan and sildenafil in improving exercise and functional capacity and symptoms of PAH relative to supportive care alone. However, the Committee noted that the clinical effectiveness data came from short-term studies, and in some cases the studies included populations that did not completely correspond to the technologies' licensed indications, for example, in terms of the functional class or the Venice classification. The Committee noted that only the studies of intravenous epoprostenol had demonstrated a statistically significant benefit in terms of survival and that the studies of other drugs had not been of sufficient power or duration to demonstrate such a benefit. However, given that these drugs had been shown to improve FC in PAH, the Committee accepted that a survival benefit was likely with these treatments.
4.3.3 The Committee assessed the submissions on cost effectiveness from the manufacturers and the Assessment Group. All the manufacturers (except for the manufacturer of epoprostenol) submitted cost-effectiveness analyses. The comparators within the manufacturers' analyses differed, and each manufacturer used different structures and assumptions (for example, Markov models with differing time horizons, a DES model and a CMA). The Assessment Group's model compared each intervention plus supportive care with supportive care alone, using a Markov model over a 30-year time horizon. The Committee agreed that the Assessment Group's approach was most appropriate for the purpose of making its recommendations, because each intervention was compared with supportive care, and common assumptions were made across the interventions. 
4.3.4 The Committee discussed the cost-effectiveness analyses, particularly in relation to inclusion in the model of the routine use of intravenous epoprostenol in people with PAH who progressed to FC IV. It noted that the ICER for epoprostenol compared with supportive care in the Assessment Group's base-case analysis was £343,000 per additional QALY for people in FC IV. There was no alternative estimate of cost effectiveness submitted by the manufacturer. However, the Committee noted that the manufacturer had indicated that epoprostenol was available at a nationally agreed reduced price for the treatment of PAH. Using this price in the Assessment Group's model resulted in a lower ICER; however the Committee noted that the ICER remained significantly higher than that considered to be cost effective. While acknowledging that the treatment of choice for people with PAH in FC IV is an intravenous prostanoid, the Committee nevertheless felt that it could not recommend the use of epoprostenol as a cost-effective use of NHS resources, even taking into account the availability of epoprostenol at the reduced price indicated by the manufacturer.
4.3.5 The Committee considered the alternatives available to people with PAH in FC III and noted that all the drugs under consideration were licensed as options at this stage. However, the Committee heard from the experts that intravenous prostanoids were unlikely to be the initial choice for people in FC III because they require a permanent central venous catheter (Hickman line), which can be difficult to manage and requires ongoing training by a specialist nurse. Furthermore, the Committee noted that the ICER for epoprostenol relative to supportive care in FC III, although lower than that in FC IV, remained unacceptably high, even taking into account the availability of epoprostenol at a reduced price. Therefore, the Committee concluded that epoprostenol within its licensed indication is not recommended for the treatment of PAH in adults in either FC III or FC IV.
4.3.6 The Committee noted that, of the remaining treatments, sildenafil gave the lowest ICERs relative to supportive care. In the Assessment Group's base-case analysis, sildenafil dominated supportive care: that is, it was associated with both greater benefit and lower cost than supportive care. The Committee noted that the Assessment Group's base-case analysis incorporated and was dependent on the assumption that people were routinely treated with epoprostenol when their functional capacity had deteriorated to the point when they entered FC IV. However, even when it was assumed that people in FC IV received supportive care only, the ICER rose only to £9000 per additional QALY. The Committee was concerned about the estimate of effectiveness for sildenafil because only a small number of patients in the clinical trials both met the criterion of having PAH at FC III and received the dose specified in the SPC. The estimate of effectiveness was therefore based on only this small group, but the Committee nevertheless considered that the probability of the technology being cost effective was acceptably high. Furthermore, it noted that the estimate for mortality on sildenafil had been based on data for another drug, because the clinical trials of sildenafil did not provide adequate data on this outcome. The Committee was reassured by observational data from a national registry. While noting that the populations treated with sildenafil might not be comparable with those treated with other drugs in the observational data set and the differing pharmacological actions of the oral agents, the Committee accepted that the estimate of mortality on sildenafil in the model was plausible. The Committee therefore concluded that sildenafil was cost effective at its licensed dose for the treatment of PAH in adults in FC III.
4.3.7 The Committee discussed the two other oral therapies: bosentan and sitaxentan. It noted that in the Assessment Group's cost-effectiveness analysis, sitaxentan compared with supportive care was associated with lower incremental QALYs and higher incremental costs than those for sildenafil compared with supportive care. Bosentan compared with supportive care was associated with higher incremental QALYs and higher incremental costs than those for sildenafil compared with supportive care. The Committee accepted that when the Assessment Group's cost effectiveness results were presented incrementally, sildenafil was shown to dominate sitaxentan (that is, sildenafil was more effective and less costly), and the ICER for bosentan compared with sildenafil was too high to be considered cost effective. The Committee therefore concluded that these drugs could not be recommended as options for the treatment of PAH in people in FC III where sildenafil would be an appropriate alternative.   
4.3.8 The Committee then considered the use of bosentan and sitaxentan in situations when sildenafil was not an option, for example, because it was contraindicated, poorly tolerated, or had failed to control symptoms adequately. In these circumstances, the comparator for the treatments would be supportive care. The Assessment Group's base-case analyses gave ICERs of £27,000 per QALY for bosentan and £25,000 per QALY for sitaxentan, compared with supportive care. The Committee considered further scenarios and noted that when it was assumed that people with PAH in FC IV would receive supportive care only, rather than intravenous epoprostenol, the ICER increased to £42,000 per QALY gained for bosentan and £44,000 per QALY gained for sitaxentan, compared with supportive care. The Committee understood that the change in the ICERs was principally because of the delay in progression from FC III to FC IV and the associated avoidance of the routine use of intravenous epoprostenol in FC IV and the costs involved. The clinical specialists also informed the Committee that, in clinical practice, people who present with PAH in FC IV would be treated with intravenous prostanoids as first-line therapy and that unlicensed prostanoids are sometimes used in this situation. The experts stated that those who progress from FC III to FC IV might continue oral therapy, possibly moving to combination therapy rather than switching to intravenous treatment. The experts noted that there was no evidence for using oral treatments in FC IV, and their effectiveness is unknown, although they could be anticipated to have some continued benefit. The Committee acknowledged that, in clinical practice, given the severity of this disease, it was unlikely that supportive care alone would be given to all people with PAH in FC IV. Therefore, the Committee accepted that this scenario was an extreme case and that the true cost effectiveness of the two drugs would lie somewhere between the base case and the scenario where supportive care only was given in FC IV.
4.3.9 In a further analysis, the assumption in the base case was changed so that the mortality on treatment and mortality on supportive care of the oral therapies were assumed to be equal to those used for the analysis of epoprostenol in FC III. This analysis reduced the ICERs considerably for bosentan and sitaxentan compared with supportive care. The Committee heard from the clinical specialists that the survival of people with PAH in FC III initiated on intravenous prostanoids or oral therapies were thought to be similar, based on observational studies and clinical practice. The Committee concluded that, although this was an extreme scenario, it accepted that these observational data supported the argument that the ICERs for these drugs could be lower than in the scenario considered most plausible by the Committee.
4.3.10

The Committee considered that, given the uncertainty around the ICERs, bosentan and sitaxentan could not be recommended as a first-line option in parallel with sildenafil. The Committee therefore concluded that bosentan and sitaxentan, within their licensed indications, should be recommended only as treatment options for adults with PAH when sildenafil is:

  • contraindicated
  • not effective at the dose recommended in the SPC, or
  • poorly tolerated
4.3.11 The Committee discussed the cost-effectiveness results for inhaled iloprost in people in FC III. It noted that the ICER for inhaled iloprost compared with supportive care in the Assessment Group's base-case analysis was £101,000 per QALY gained. In the scenario where supportive care alone is available to FC IV patients, the ICER for inhaled iloprost reduced to £98,000 per QALY gained. The Committee heard from the clinical specialists that oral therapies would usually be the first-line treatment for patients in FC III. The Committee decided that, given the magnitude of the ICERs for inhaled iloprost, this treatment could not be considered to be a cost-effective use of NHS resources. Therefore, the Committee concluded that inhaled iloprost, within its licensed indication, should not be recommended for the treatment of PAH in adults. 
4.3.12 The Committee heard from the clinical experts that combinations of oral agents and/or prostanoids may be used in clinical practice. However, the Committee were not presented with evidence on the clinical and cost effectiveness of these combinations and noted that these were not considered in the marketing authorisations for the drugs. The Committee considered that further research on combination therapy would be valuable.
   
5 Implementation
5.1 The Healthcare Commission assesses the performance of NHS organisations in meeting core and developmental standards set by the Department of Health in 'Standards for better health' issued in July 2004. The Secretary of State has directed that the NHS provides funding and resources for medicines and treatments that have been recommended by NICE technology appraisals normally within 3 months from the date that NICE publishes the guidance. Core standard C5 states that healthcare organisations should ensure they conform to NICE technology appraisals.
5.2 'Healthcare Standards for Wales' was issued by the Welsh Assembly Government in May 2005 and provides a framework both for self-assessment by healthcare organisations and for external review and investigation by Healthcare Inspectorate Wales. Standard 12a requires healthcare organisations to ensure that patients and service users are provided with effective treatment and care that conforms to NICE technology appraisal guidance. The Assembly Minister for Health and Social Services issued a Direction in October 2003 which requires Local Health Boards and NHS Trusts to make funding available to enable the implementation of NICE technology appraisal guidance, normally within 3 months.
5.3

NICE has developed tools to help organisations implement this guidance (listed below). These are available on our website (www.nice.org.uk/TAXXX). [Note: tools will be available when the final guidance is issued]

  • Slides highlighting key messages for local discussion
  • Costing report and costing template to estimate the savings and costs associated with implementation
  • Implementation advice on how to put the guidance into practice and national initiatives which support this locally
  • Audit criteria to monitor local practice
   
6 Proposed recommendations for further research
6.1 The Committee recommends research into the long-term effects of the therapies and recommends that the survival benefit of the therapies is investigated.
6.2 The Committee recommends research into the comparative effectiveness of the oral therapies (bosentan, sitaxentan and sildenafil). Such trials would allow for direct clinical- and cost-effectiveness analyses.
6.3 The Committee recommends continuing research into dual- and triple-therapy treatments compared with monotherapy across all the technologies.
6.4 The Committee recommends research into the sequencing of technologies to assess the feasibilities of replacing an ongoing treatment that provides inadequate control of the disease with a new treatment.
   
7 Related NICE guidance
  There is no related guidance for these technologies.
   
8 Proposed date for review of guidance
8.1 The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider whether the technology should be reviewed. This decision will be taken in the light of information gathered by the Institute, and in consultation with consultees and commentators.
8.2 It is proposed that the guidance on these technologies is considered for review in July 2011. The Institute would particularly welcome comment on this proposed date.
  David Barnett
  Chair, Appraisal Committee
  February 2008
   
   
   
  Appendix A: Appraisal Committee members and NICE project team
A Appraisal Committee members
 

The Appraisal Committee is a standing advisory committee of the Institute. Its members are appointed for a 3-year term. A list of the Committee members who took part in the discussions for this appraisal appears below. The Appraisal Committee meets three times a month except in December, when there are no meetings. The Committee membership is split into three branches, each with a chair and vice-chair. Each branch considers its own list of technologies and ongoing topics are not moved between the branches.

Committee members are asked to declare any interests in the technology to be appraised. If it is considered there is a conflict of interest, the member is excluded from participating further in that appraisal.

The minutes of each Appraisal Committee meeting, which include the names of the members who attended and their declarations of interests, are posted on the NICE website.

 

Dr Ray Armstrong
Consultant Rheumatologist, Southampton General Hospital

Dr Jeffrey Aronson
Reader in Clinical Pharmacology, University Department of Primary Health Care, Oxford

Professor David Barnett (Chair of the Committee)
Professor of Clinical Pharmacology, University of Leicester

Dr Peter Barry
Consultant in Paediatric Intensive Care, Leicester Royal Infirmary

Professor Stirling Bryan
Director, Health Economics Facility, University of Birmingham

Professor John Cairns
Public Health and Policy, London School of Hygiene and Tropical Medicine

Dr Mark Chakravarty
Director - External Relations, Procter and Gamble Healthcare Europe

Professor Jack Dowie
Health Economist, London School of Hygiene

Ms Lynn Field
Nurse Director, Pan Birmingham Cancer Network

Dr Fergus Gleeson
Consultant Radiologist, The Churchill Hospital, Oxford

Mrs Barbara Greggains
Lay Member

Mr Terence Lewis
Lay Member

Professor Gary McVeigh
Professor of Cardiovascular Medicine, Queen's University Belfast

Dr Ruairidh Milne
Senior Lecturer in Health Technology Assessment, National Coordinating Centre for Health Technology

Dr Rubin Minhas
General Practitioner

Dr John Pounsford
Consultant Physician, Frenchay Hospital, Bristol

Dr Rosalind Ramsay
Consultant Psychiatrist, Adult Mental Health Services, Maudsley Hospital

Dr Stephen Saltissi
Consultant Physician, The Royal Liverpool University Hospital

Dr Lindsay Smith
General Practitioner, East Somerset Research Consortium

Mr Roderick Smith
Finance Director, West Kent PCT

Dr Ken Stein
Senior Lecturer, Peninsula Technology Assessment Group (PenTAG), University of Exeter

Professor Andrew Stevens
Professor of Public Health, University of Birmingham

Dr Rod Taylor
Associate Professor in Health Services Research, Peninsula Medical School, Universities of Exeter & Plymouth

B NICE project team
  Each technology appraisal is assigned to a team consisting of one or more health technology analysts (who act as technical leads for the appraisal), a technical adviser and a project manager.
 

Emma Pugh and Helen Knight
Technical Leads

Janet Robertson
Technical Adviser

Natalie Bemrose
Project Manager

  Appendix B: Sources of evidence considered by the Committee
A

The assessment report for this appraisal was prepared by West Midlands Health Technology Assessment Collaboration.

  • Chen YF, Jowett S, Barton P et al, Clinical and cost effectiveness of treatments for pulmonary arterial hypertension (PAH) within their licensed indications, August, 2007
B

The Addendum to the Assessment Report was prepared by West Midlands Health Technology Assessment Collaboration.

  • Chen YF, Jowett S, Barton P et al, Epoprostenol, iloprost, bosentan, sitaxentan and sildenafil for the treatment of pulmonary arterial hypertension in adults. Assessment Group Additional Work, January 2008.

Data requested by the committee to assess the effect of altering key assumptions around the clinical pathway and survival benefit in the economic analysis on the results of the cost-effectiveness.

C

Results of the request for additional survival data and incremental results of cost-effectiveness analysis were prepared by the technical lead following submissions from consultees and commentators regarding additional survival data on pulmonary arterial hypertension (PAH).

Pugh Emma, Epoprostenol, iloprost, bosentan, sitaxentan and sildenafil for the treatment of pulmonary arterial hypertension in adults ; Results of the request for additional survival data and incremental results of cost-effectiveness analysis, January 2008

D

The following organisations accepted the invitation to participate in this appraisal. They were invited to comment on the draft scope, assessment report and the appraisal consultation document (ACD). Organisations listed in I II and IV were also invited to make written submissions and have the opportunity to appeal against the final appraisal determination.

I

  • Manufacturers/sponsors:
  • Actelion Pharmaceuticals UK Ltd
  • Encysive pharmaceuticals
  • GlaxoSmithKline
  • Pfizer Ltd
  • Schering-Plough Ltd

II

  • Professional/specialist and patient/carer groups:
  • British Cardiovascular Society
  • British Heart Foundation
  • British Society for Rheumatology
  • British Thoracic Society
  • National Pulmonary Hypertension Service
  • Pulmonary Hypertension Association UK
  • Raynaud's and Scleroderma Association
  • Royal College of General Practitioners
  • Royal College of Nursing
  • Royal College of Physicians
  • Royal College of Physicians Cardiology Society
  • Scleroderma Society
  • West Midlands Specialist Services Commissioning Group

III

  • Commentator organisations (without the right of appeal):
  • British Society for Cardiovascular Research
  • Department of Health and Social Services and Public Safety for Northern Ireland
  • Medicines and Healthcare products Regulatory Agency (MHRA)
  • National Public Health Service for Wales
  • National Specialist Commissioning Advisory Group (NSCAG)
  • NHS Confederation
  • NHS Purchasing and Supplies Agency
  • NHS Quality Improvement Scotland
  • Scottish Medicines Consortium

IV

  • Other
  • Welsh Assembly Government
  • Department of Health
E

The following organisations provided additional survival data on pulmonary arterial hypertension (PAH).

  • Actelion Pharmaceuticals UK Ltd
  • Encysive pharmaceuticals
  • National Pulmonary Hypertension Service
  • The West Midlands Specialist Services Agency (WMSSA)
F

The following individuals were selected from clinical specialist and patient advocate nominations from the non-manufacturer/sponsor consultees and commentators. They participated in the Appraisal Committee discussions and provided evidence to inform the Appraisal Committee's deliberations. They gave their expert personal view on drugs for the treatment of pulmonary arterial hypertension by attending the initial Committee discussion and/or providing written evidence to the Committee. They are invited to comment on the ACD.

  • Dr Daphne Austin, Consultant in Public Health, nominated by the West Midlands Specialist Services Commissioning Group ' clinical specialist
  • Professor Paul Corris, Professor of Thoracic Medicine, nominated by the British Thoracic Society ' clinical specialist
  • Mrs Wendy Gin-Sing, Specialist Nurse Pulmonary Hypertension, nominated by the Pulmonary Hypertension Association - clinical specialist
  • Mrs Tracie Pannell, nominated by the Pulmonary Hypertension Association - patient expert
  • Mrs Sue Townsley, nominated by the Pulmonary Hypertension Association - patient expert
   

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