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1、Technology Assessment Report commissioned by the NHS R&D HTA Programme on behalf of the National Institute for Health and Clinical Excellence Drugs for the treatment of pulmonary arterial hypertensionFinal protocol (19 February 2007, submitted to NCCHTA/NICE)1. Title of the projectClinical and cost
2、effectiveness of epoprostenol, iloprost, bosentan, sitaxentan, and sildenafil for the treatment of pulmonary arterial hypertension in adults: a systematic review and economic evaluation2. Name of the TAR team and leadWest Midlands Health Technology Assessment Collaboration (WMHTAC)Dr David MooreSeni
3、or Research AnalystDepartment of Public Health and EpidemiologyUniversity of BirminghamEdgbastonBirmingham B15 2TTTel: 0121 4147449Fax: 0121 4147878E-mail: D.J.Moorebham.ac.uk3. Plain English SummaryPulmonary arterial hypertension (PAH) is a rare, progressive but severe condition. It involves elevat
4、ed pressure in the arteries that carry blood from right heart to the lung. PAH may occur without any identifiable reasons (idiopathic PAH). It may also be associated with a diverse group of diseases such as certain diseases of the collagen tissues and congenital heart disease. If not treated, PAH le
5、ads to heart failure and eventually death.Various interventions have been used to treat patients with PAH. Some of them are for treating symptoms and conditions that are frequently associated with PAH, such as diuretics (water tablets) for swelling of limbs, anticoagulants for preventing clots in th
6、e blood vessels, inhaled oxygen to increase oxygen level in the blood, and digoxin to strengthen heart beats. As these treatments do not alter the elevated blood pressure in the lung, they are regarded as supportive treatments. In addition, a group of drugs called calcium channel blockers, which are
7、 used to treat hypertension, have been found to work in a minority of patients with PAH.More recently, newer drugs have been developed that target at different potential mechanisms underlying the development of PAH. Five of these drugs have been licensed in the UK; epoprostenol, iloprost, bosentan,
8、sitaxentan and sildenafil.The aim of this technology assessment is to evaluate whether these five drugs are effective for treating PAH, and whether the use of these drugs in addition to supportive treatments is cost-effective (good value for money) for the National Health Services (NHS). The key com
9、ponents of the report are: A systematic review of randomised controlled trials (RCTs) that investigated the effectiveness of these drugs in PAH. Variations in the effectiveness between the drugs and/or between different PAH populations will be explore if evidence from RCTs permits. A systematic revi
10、ew of published studies on the costs and cost-effectiveness of these drugs in PAH. A review of the dossiers submitted to the National Institute for Health and Clinical Excellence (NICE) by the manufacturers (GlaxoSmithKline, Schering Health Care, Actelion Pharmaceuticals, Encysive and Pfizer). A foc
11、used, model-based economic evaluation. This involves the use of mathematical and statistical methods to synthesise information on treatment costs and the impact of the treatments on patients quality and duration of life. 4. Decision problem4.1 Decision to be madeAccording to the final scope issued b
12、y the National Institute for Health and Clinical Excellence (NICE) for this technology appraisal, the decisions to be made are: Whether epoprostenol, iloprost, bosentan, sitaxentan and sildenafil, when used within their licensed indications, are clinically effective and cost effective compared to su
13、pportive treatments (see section 4.4) in adults with PAH for whom calcium channel blockers are inappropriate or no longer effective. Whether the interventions being considered are clinically more effective, or more cost-effective, in patients with certain subcategories of pulmonary arterial hyperten
14、sion according to Venice 2003 clinical classification (see Appendix 1). Whether significant differences in clinical and cost effectiveness exist between the interventions being considered (either used alone or in combination) when compared to each other and/or intravenous iloprost. It is likely that
15、 the assessment report will be able to address only some of the issues surrounding these decision problems for the following reasons:(1) While the Venice 2003 clinical classification provides a significantly improved framework for the diagnosis and management of PAH, it is worth highlighting that pa
16、tients with PAH represent diverse populations that vary greatly in aetiology, disease progression, and prognosis. Cases being grouped under each of the Venice subcategories can still be heterogeneous in term of severity, the choice and response to treatment and prognosis. For example, within the Ven
17、ice subcategory 1.3.1, scleroderma has distinct features that may warrant it being considered separately from other forms of connective tissue diseases.(2) The five interventions being considered in this technology appraisal have different routes of administration, demand on patients self-management
18、, speediness of action, adverse effect profile and contraindications. The selection of treatments is highly dependent on the nature of the underlying condition, clinical circumstances and patient ability and acceptance. The choice of treatment and appropriate comparators will therefore be dependent
19、on these factors.(3) PAH is a rare condition. The number of patients included in clinical studies is relatively small. There is unlikely to be sufficient data to allow meaningful comparison between many of the subcategories of PAH and between different treatments (or combinations of treatments).Bear
20、ing these in mind, the assessment group intends to undertake a systematic review of randomised controlled trials (RCTs) and a review of industry submissions to establish the underlying evidence base that is available to answer the above decision problems and to highlight issues that are unlikely to
21、be addressed due to paucity of evidence. A model-based economic evaluation will then be carried out to address refined and focused decision problem(s) that take into account the availability of evidence, the appropriateness of combining different populations of PAH in terms of underlying cause (e.g.
22、 whether the model can include all PAH populations or the modelling can be reasonably done only for a specific population according to the evidence), disease severity (e.g. it may be necessary to model patients in functional class III and IV separately), and the most appropriate place in the treatme
23、nt pathway for each of the interventions being considered (e.g. oral treatments would not be considered as alternative, competing interventions against intravenous epoprostenol for patients in NYHA/WHO functional class IV).4.2 Population and relevant subgroupsThe population being considered is adult
24、s with pulmonary arterial hypertension (Category 1 of the Venice 2003 clinical classification, see Appendix 1) in NYHA/WHO functional classes III (and also functional class IV for epoprostenol) for whom calcium channel blockers are inappropriate or no longer effective.Potentially relevant subgroups
25、include: PAH associated with specific disease conditions (e.g. scleroderma) or subcategories of PAH (e.g. idiopathic PAH) under Category 1 of the Venice 2003 clinical classification. These are better perceived as different patient populations that share similar clinical manifestations of PAH than su
26、bgroups of a well characterised disease. NYHA/WHO functional classes.As suggested earlier, the identification of specific subgroups to be examined (e.g. patients with idiopathic PAH in functional class III) will be undertaken in light of current treatment guidelines and consultation with our clinica
27、l advisors, taking into account the volume of available evidence and resources available for this technology assessment. 4.3 Definition of the interventionsFor patients in functional class III, interventions being considered are: Epoprostenol (Folan, GlaxoSmithKline), administered by continuous intr
28、avenous infusion Iloprost (Ventavis, Schering Health Care), administered by inhalation through a nebuliser, 2.5 micrograms to 5.0 micrograms as delivered at the mouthpiece per inhalation session) Bosentan (Tracleer, Actelion Pharmaceuticals), administered orally, 62.5 mg to 250 mg twice daily Sitaxe
29、ntan (Thelin, Encysive), administered orally, 100 mg once daily Sildenafil (Revatio, Pfizer), administered orally, 20 mg three times daily Clarification is required with regard to whether Viagra can be regarded as an intervention instead of Revatio for the purpose of cost reduction.Epoprostenol admi
30、nistered by continuous intravenous infusion is the only intervention being considered for patients in functional class IV.4.4 Relevant comparators Supportive treatments: these include digoxin, diuretics, anticoagulants and oxygen. Placebo or no treatment: whilst the above supportive treatments are u
31、sed for preventing/treating conditions and symptoms associated with PAH, the goals and mechanisms of these treatments are generally different from those of the interventions being considered here. As these supportive treatments usually start earlier in the treatment pathway and are usually continued
32、 when introducing the newer interventions, studies in which the interventions were compared to placebo or no treatment are clinically relevant provided that supportive treatments were continued in all study arms. The interventions being considered, either used alone or in combination, will be compar
33、ed with each other if evidence is available from randomised controlled trials (RCTs). Intravenous iloprost may be considered as a comparator if evidence is available from RCTs.4.5 Place of the intervention in the treatment pathway(s)Based on the final scope, the interventions being considered are to
34、 be used when conventional supportive treatments and calcium channel blockers are either inappropriate or have failed to control symptoms and maintain functional capacity.For this technology assessment, only the first use of listed interventions will be considered. Use of any of the interventions af
35、ter failure of another listed intervention will not be considered (epoprostenol for patients in functional class IV may be an exception).4.6 Key factors to be addressed (e.g. clinical and cost outcomes, further considerations, problematic factors)Key outcomesThe key outcomes, among other outcomes to
36、 be examined (see section 5.3), for the technology assessment include improvement in survival and quality of life with treatments; time to clinical deterioration (including switch of drug therapy and lung transplantation); adverse events associated with treatment withdrawal; and incremental cost-eff
37、ectiveness ratios (ICERs) for the interventions compared with supportive treatments.Potentially problematic factors Trials including patients with mixed functional classes: given that none of the interventions are licensed for functional class II and only one of them (epoprostenol) is licensed for f
38、unctional class IV, the main focus of the technology assessment will be on patients in functional class III. Nevertheless, existing trials may have included patients of various functional classes (for example, functional classes II-IV). Data for the specific subgroup of patients in functional class
39、III may not be available and will need to be obtained from the sponsors/investigators of the trials. Trials including patients with mixed categories of PAH: existing trials may include PAH of very different nature (as described in section 4.1). Separate data for specific patient groups may not be av
40、ailable and will need to be obtained from the sponsors/investigators of the trials. Insufficiency of data for subgroup analysis: as described in section 4.1, the volume of existing evidence may not be sufficient for the exploration of treatment effects in subcategories of PAH or PAH associated with
41、specific conditions. Lack of long-term survival data from RCTs: survival is likely to be one of the key outcomes that affect the cost effectiveness of the interventions, but it is envisaged that data from RCTs would not allow direct assessment of benefit in survival due to the short duration of the
42、trials. Economic modelling based on comparisons involving historical controls or data from non-randomised studies seems inevitable. Prediction of survival based on patients risk factors and/or surrogate outcomes such as haemodynamic assessment may also be needed. Rapid and continuing development of
43、treatment algorithm and patient pathway: different treatment guidelines have been drawn by various organisations, and are being updated rapidly. For example, we are aware that the guidelines issued by the European Society of Cardiology are being updated and new guidelines will be issued in 2008. Co-
44、morbidity and functional capacity can affect treatment choice: for example, bosentan and sitaxentan cannot be considered in patients with moderate to severe hepatic impairment; epoprostenol cannot be considered in outpatients who are unable to closely follow the procedure to reconstitute the prepara
45、tion.Request of data from manufacturers/sponsorsA complete list of relevant randomised controlled trials sponsored by the manufacturers and reports for any unpublished trials identified within the list will be requested from individual sponsors to minimise the potential impact of publication bias.Be
46、cause of the discrepancies between the patient groups included in clinical trials and the patient groups for whom the interventions are licensed, it is expected that additional data that may not be available in the published literature will need to be obtained in order to perform analyses that is pe
47、rtinent to the final scope. The data required are baseline values (where appropriate) and outcomes at latest follow-up for all the items listed under Outcomes within section 5.2 below. Areas that are considered outside the scope of the appraisalThe assessment group is aware of the emerging evidence
48、that suggests potential benefit of early treatment in patients with PAH who have mild symptoms and functional limitation. This group of patients, however, is excluded from the final scope as none of the interventions being considered are currently licensed for PAH patients of functional class II. The availability of trial evidence in relation to this group of patients will be highlighted in the assessment report although the data will not be included in the primary analysis (see Section 5.3).Drugs and preparations that are not currently licensed for tr