Hyperuricaemia - febuxostat: appraisal consultation document
Appraisal consultation document
Febuxostat for the management of hyperuricaemia in patients with gout
The Department of Health has asked the National Institute for Health and Clinical Excellence (NICE or the Institute) to conduct a single technology appraisal (STA) of febuxostat for the management of hyperuricaemia in patients with gout and provide guidance on its use to the NHS in England and Wales. The Appraisal Committee has had its first meeting to consider both the evidence submitted by the manufacturer 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 febuxostat.
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 this technology. 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 single 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: 17 June 2008
Second Appraisal Committee meeting: 2 July 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 this technology. The recommendations made in section 1 are preliminary and may change after consultation.
1 Appraisal Committee's preliminary recommendations
1.1 Febuxostat is not recommended for the management of chronic hyperuricaemia in people with gout.
1.2 People currently receiving febuxostat should have the option to continue therapy until they and their clinicians consider it appropriate to stop.
2 The technology
2.1 Febuxostat (Adenuric, Ipsen) is a non-purine selective inhibitor of xanthine oxidase that achieves its therapeutic effects by decreasing the serum uric acid concentration. Febuxostat has a marketing authorisation for the treatment of chronic hyperuricaemia in conditions where urate/uric acid deposition has already occurred (including a history or the presence of tophus and/or gouty arthritis.
2.2 The most common side effects associated with febuxostat include diarrhoea, nausea, headache, liver function test abnormalities and rash. Uncommon side effects include fatigue, oedema, dizziness, altered sense of taste, increase in blood amylase, decrease in platelet count, increase in blood creatinine and arthralgia. Rare side effects include nervousness, insomnia, asthenia and renal insufficiency. The summary of product characteristics states that treatment with febuxostat in patients with ischaemic heart disease or congestive heart failure is not recommended. For full details of side effects and contraindications, see the summary of product characteristics (SPC).
2.3 The proposed recommended dose of febuxostat is 80 mg once daily. If the serum uric acid concentration is above 6 mg/100 ml (360 µmol/l) after 2-4 weeks, febuxostat 120 mg once daily may be considered. The price for febuxostat 80 mg and 120 mg is £0.87. Annual treatment costs will be approximately £318. Costs may vary in different settings because of negotiated procurement discounts.
3 The manufacturer's submission
The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of febuxostat and a review of this submission by the Evidence Review Group (ERG; appendix B).
3.1 The manufacturer's decision problem specified febuxostat (80 mg or 120 mg once daily) as the intervention of interest in a population of adults with hyperuricaemia in gout. The comparator specified by the manufacturer was fixed-dose allopurinol (300 mg once daily). The manufacturer did not present comparisons with alternative comparators such as sulphinpyrazone, benzbromarone, probenecid or combinations of these treatments. The health outcomes considered included serum uric acid concentration, gout flares, reduction in size of tophi, tolerance and health-related quality of life. Results of the economic evaluation were expressed as incremental cost per quality-adjusted life year (QALY) over a time horizon of 2 years.
3.2 The manufacturer presented evidence on the clinical effectiveness of febuxostat from three randomised controlled trials (RCTs): the FACT trial, the APEX trial and the TM-00-004 study. The FACT trial was a 52-week phase III multi-arm randomised double-blind parallel-group trial that compared febuxostat 80 mg/day (n = 257), febuxostat 120 mg/day (n = 251) and allopurinol 300 mg/day (n = 254). The APEX trial was a 28-week phase III multi-arm randomised double-blind trial that compared febuxostat 80 mg/day (n = 267), febuxostat 120 mg/day (n = 269), febuxostat 240 mg/day (n = 134), allopurinol 300 or 100 mg/day (n = 268) and placebo (n = 134). The reduced dose of allopurinol (100 mg/day) in the APEX trial was used for 10 patients with renal impairment. In the APEX, FACT and EXCEL trials, colchicine and naproxen (a non-steroidal anti-inflammatory drug [NSAID]) were given as prophylaxis for treatment-initiated gout flares before week 8 visits. The TM-00-004 study was a 4-week phase II (dose-response) multicentre randomised double-blind parallel-group trial that compared febuxostat 40 mg/day (n = 37), febuxostat 80 mg/day (n = 40), febuxostat 120 mg/day (n = 38) and placebo (n = 38). A meta-analysis of the RCT data requested by the ERG from the manufacturer was not provided.
3.3 Supplementary data were provided by the manufacturer from two open-label extension studies in support of the clinical effectiveness of febuxostat. The EXCEL trial is an ongoing open-label extension study that enrolled a subset of patients (n = 735) from the APEX and FACT trials. The EXCEL study compared febuxostat 80 mg/day (n = 299), febuxostat 120 mg/day (n = 291) and allopurinol 300 or 100 mg/day (n = 145). The FOCUS trial was a 5-year open-label non-controlled extension study that enrolled patients (n = 116) who completed the TM-00-004 study. The FOCUS study evaluated febuxostat 80 mg/day, with dose titration to lower (40 mg/day) or higher (120 mg/day) doses permitted between weeks 4 and 28. Although summaries of the clinical evidence from the respective trials were provided by the manufacturer, the main evidence presented in support of the clinical effectiveness of febuxostat was based on pooled data from the APEX, FACT and TM-00-004 trials. This was not carried out as a meta-analysis of the separate studies and consisted of adding the number of events observed for each treatment group across the trials and dividing the results by the total number of patients in the treatment group.
3.4 The pooled analysis suggested that febuxostat 80 mg/day and 120 mg/day was significantly more effective (p = 0.05) than fixed-dose allopurinol (300 or 100 mg/day) at lowering serum uric acid concentrations either to target therapeutic levels (of below 6 mg/100 ml) or from baseline levels at the last three visits or the final visit. No statistically significant changes were observed with febuxostat 80 mg/day compared to allopurinol (300 or 100 mg/day) in the proportion of patients requiring treatment for gout flares. In contrast, the proportion of patients requiring treatment for gout flares was statistically significantly higher (p = 0.05) with febuxostat 120 mg/day than with allopurinol (300 or 100 mg/day), both during (weeks 1-8) and after (weeks 9-52) prophylaxis. The difference was more marked during the initial weeks of treatment. No statistically significant differences were found between groups in the percentage reduction in tophus area except at week 28. At week 28, significantly greater reductions were observed in primary tophus size from baseline with febuxostat 120 mg/day than with allopurinol.
3.5 Post-hoc subgroup analysis of the pooled data showed that febuxostat was more effective (p = 0.05) than allopurinol in lowering serum uric acid concentration to below 6 mg/100 ml in three subgroups of patients defined according to baseline serum acid concentrations of below 9 mg/100 ml, between 9 and 10 mg/100 ml and above 10 mg/100 ml. The proportion of patients receiving febuxostat who achieved a target serum uric acid concentration of below 5 mg/100 ml was higher (p = 0.05) than among those receiving fixed-dose allopurinol. No subgroup analyses were conducted for patients with renal impairment and non-responders to allopurinol.
3.6 Results from the EXCEL extension study showed that more patients receiving febuxostat (80 mg/day or 120 mg/day) remained on initial treatment than among those receiving fixed-dose allopurinol (300 or 100 mg/day) after more than 24 months of follow-up. For each year of febuxostat treatment in the EXCEL trial, the number of gout flares decreased over time. However, the ERG considered that this evidence should be treated with caution, since statistical comparisons between treatment groups were not reported; nor were data provided on withdrawals due to gout flares, adverse events or non-response to treatment.
3.7 The ERG considered that the evidence presented in support of the clinical effectiveness of febuxostat in comparison with allopurinol may not be adequate. This is because guidelines for gout management by the British Society of Rheumatology and British Health Professionals in Rheumatology (BSR) and the European League Against Rheumatism (EULAR), and the SPC for allopurinol, recommend dose titration for allopurinol according to therapeutic targets. It is possible that dose-titrated allopurinol may be more effective than fixed-dose allopurinol, and that the additional clinical benefits of febuxostat may not be as great in routine practice as is suggested by the results from RCT comparisons with fixed-dose allopurinol. However, the ERG noted that dose titration of allopurinol is rarely carried out in routine clinical practice.
3.8 The ERG expressed concerns about the analysis of clinical efficacy based on pooling data across trials because this approach fails to preserve randomisation in the RCT evidence, which may introduce bias. The ERG carried out a corrected meta-analysis (based on both fixed- and random-effects modelling) using the RCT data and evidence presented by the manufacturer. The results of the meta-analysis showed that the probability of reaching therapeutic targets for serum uric acid concentration was statistically significantly higher for patients receiving febuxostat (80 or 120 mg/day) than for those receiving fixed-dose allopurinol (300 mg/day). The ERG's meta-analysis also showed that a higher proportion of people receiving febuxostat needed treatment for gout flares (both during prophylaxis [weeks 1-8] and after prophylaxis [weeks 9-52]) compared with those receiving fixed-dose allopurinol. For the febuxostat 80 mg/day group this difference was not statistically significant (p > 0.18), but for the 120 mg/day febuxostat group it was (p < 0.05).
3.9 The manufacturer's submission presented an analysis of the cost effectiveness of febuxostat in comparison with fixed-dose allopurinol. A decision-tree model was provided to estimate the cost and health outcomes for patients with gout after initiation of urate-lowering therapy with febuxostat 80 mg or 120 mg daily, or allopurinol 300 mg daily. The model had a time horizon of up to 2 years. The time horizon was based on 1-year trial data and a further 1 year of extrapolation, which was extended to 5 years in sensitivity analyses. A mixed cohort of men and women with gout and a baseline serum uric acid concentration of 80 mg/100 ml or above entered the model after initiation of urate-lowering therapy. The model was split into two time periods: an initial period of 3 months, during which patients may or may not experience a treatment-initiated flare, and a treatment maintenance period from 4 to 24 months.
3.10 The results of the economic analysis were presented as incremental costs per QALY gained for febuxostat in comparison with fixed-dose allopurinol. The base-case economic analysis using pooled clinical data over a 1-year time horizon comparing febuxostat (80 mg and 120 mg) with fixed-dose allopurinol 300 mg produced an incremental cost-effectiveness ratio (ICER) of £16,574 per QALY. An alternative base-case analysis based on a 2-year time horizon produced an ICER of £15,565 per QALY. The manufacturer presented results of a probabilistic sensitivity analysis that produced a mean ICER of £16,324 per QALY (95% CI £6281 to £239,928 per QALY). The cost-effectiveness acceptability curve reported that the probability that febuxostat 80 mg/day (titrated to 120 mg/day where appropriate) had an ICER lower than £20,000 per QALY gained compared with fixed-dose allopurinol was 63%.
3.11 The manufacturer presented a number of univariate sensitivity analyses to evaluate the impacts of: changing the time horizon of the model; the protective effect of colchicine prophylaxis; discount rates; the assumed cost of febuxostat; the disutility associated with increments in serum uric acid concentration; and the proportion of patients with a serum uric acid concentration below 360 µmol/l (6 mg/100 ml) between 4 and 24 months of treatment with febuxostat. The results of these sensitivity analyses showed that the key drivers of the economic model were: (1) the assumed cost of febuxostat, (2) the disutility associated with each increment in serum uric acid concentration and (3) the proportion of patients with a serum uric acid concentration below 360 µmol/l (6 mg/100 ml) between 4 and 24 months of treatment with febuxostat. The base-case ICER remained stable over time when extrapolating to a 5-year time horizon. In the base case analysis, gout flare rates were reduced by 78% in the first three months by assuming patients received three months of prophylaxis with colchicine. Setting the reduction in gout flares due to prophylaxis to 0% increased the ICER to £18,826. Discounting had only a marginal effect on the ICER.
3.12 The ERG noted a number of areas of uncertainty around the cost-effectiveness analyses undertaken in the manufacturer's submission. The ERG noted that the natural history of hyperuricaemic patients with gout who did not receive treatment was not modelled, and hence no inference could be made as to the cost effectiveness of febuxostat in comparison with no treatment. The ERG requested that a sequence of strategies where patients progress to an alternative intervention (allopurinol, febuxostat or no treatment) following lack of response should be evaluated. The manufacturer declined the request, arguing that estimation of a sequential strategy was not feasible because of a lack of clinical data. In addition the manufacturer argued that it was unethical to consider febuxostat as second-line therapy when it is cost effective as first-line therapy, and that the only appropriate comparison was that investigated in the pivotal RCTs; that is, at first-line therapy. The ERG asserted that appropriate modelling assumptions could have been made to allow some exploratory analysis.
3.13 The ERG noted that no data were provided on the likely serum uric acid concentration of patients who receive no treatment, and that the model assumes full treatment adherence and usage over the time horizon modelled. However, evidence from the FACT and APEX trials showed that treatment continuation rates were lower for febuxostat than for allopurinol. Contradictory evidence from the open-label EXCEL trial reports gave treatment continuation rates of 35% for 80 mg daily febuxostat, 10% for 120 mg daily febuxostat but only 5% for allopurinol. Additional evidence presented by the manufacturer suggested that in a randomised subset of the EXCEL trial, 76% of patients receiving 80 mg/day febuxostat, 71% of patients receiving 120 mg/day febuxostat and 40% of patients receiving allopurinol remained on initial treatment after more than 24 months. The ERG stated that the lack of data on the likely serum uric acid concentrations of patients who receive no treatment made it difficult to accurately account for treatment discontinuation rates in the manufacturer's economic model. An assumption of full treatment adherence and usage over the time horizon could potentially bias the economic results in favour of febuxostat.
3.14 The ERG noted that in the manufacturer's economic model, data on the number of gout flares within the initial 3 months of treatment were taken from the pooled analysis of the results from the APEX trials. The flare rates were reduced by 78% by assuming that patients received 3 months of colchicine prophylaxis. However, this reduction may be an overestimate, since in the APEX and FACT trials colchicine prophylaxis was given for only 8 weeks. After the first 3 months of treatment, the proportion of gout flares was assumed to be related to serum uric acid concentration on the basis of a multivariate analysis of data provided in confidence by the manufacturer. The significance of the correlation between serum uric acid concentration and the number of gout flares disappears in the manufacturer's 'multivariate analysis' when other significant covariates are included. However, the manufacturer's 'multivariate analysis' appears to be the same as a bivariate analysis of the relationship between serum uric acid concentration and the odds of gout flares occurring (the p values for both analyses were identical). The ERG argued that a proper multivariate analysis, in which a backward stepwise analysis is carried out, should be presented. The ERG further expressed concerns about discarded data points from the datasets used in the analysis showing a relationship between serum uric acid concentration and gout flares. The ERG stated that a relationship, not necessarily linear, between serum uric acid concentration and number of gout flares may still be found with more appropriate analysis and larger or different datasets.
3.15 The ERG noted that the relationship between serum uric acid concentration and the expected number of gout flares (with a 'chronic utility gain' associated with lower serum uric acid concentrations and decreased utility associated with gout flares) is a key driver of the economic results presented by the manufacturer. Therefore uncertainty about this relationship translates into uncertainty about the ICER estimates presented by the manufacturer. The ERG considered that this uncertainty has not been adequately investigated. In an exploratory analysis provided by the ERG, removing the 'chronic utility gain' associated with lower serum uric acid concentrations, the base case ICER increased to £81,000 per QALY over a 2-year time horizon. A similar analysis over a 1-year time horizon gave an ICER of £696,000 per QALY and over a 5-year time horizon, the analysis gave an ICER of £150,000 per QALY.
3.16 Full details of all the evidence are in the manufacturer's submission and the ERG report, which are available from www.nice.org.uk/TAxxx
4 Consideration of the evidence
4.1 The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of febuxostat for the management of hyperuricaemia in patients with gout, having considered evidence on the nature of the condition and the value placed on the benefits of febuxostat by people with chronic hyperuricaemia in conditions where uric acid deposition has already occurred (including a history or the presence of tophi and/or gouty arthritis), those who represent them, and clinical specialists. It was also mindful of the need to take account of the effective use of NHS resources.
4.2 The Committee discussed the decision problem presented in the manufacturer's submission. It noted that the manufacturer had presented evidence for the clinical and cost effectiveness of febuxostat only as a first-line therapy, whereas the marketing authorisation does not make this restriction. It heard from the clinical specialists that in current clinical practice allopurinol is used as standard first-line therapy, and that febuxostat was a plausible improvement on current second-line options. These options are considered where allopurinol is not appropriate (for example due to intolerance or lack of response), and include benzbromarone, sulphinpyrazone and probenecid, all which have limitations such as limited availability, adverse effects and poor effectiveness. The Committee concluded that other second-line therapies should be considered as comparators for febuxostat.
4.3 The Committee discussed first-line use of febuxostat and identified the following issues. Firstly, it has been established (as set out in BSR and EULAR guidelines) that allopurinol could be most effective when given in a titrated regimen depending on serum uric acid concentrations. The Committee concluded that up-titrated allopurinol (to a maximum of 900 mg) should be considered as a comparator for febuxostat. Secondly, the Committee considered the outcomes in the decision problem, and in doing so explored the relationship between hyperuricaemia and the clinical manifestations of gout. In particular, it discussed the surrogate outcome of serum uric acid concentration. It heard from the clinical specialists that a significant proportion of the population have high serum uric acid concentrations but that comparatively few people present with clinical symptoms related to gout. The relationship between serum uric acid concentration and symptoms is complex and not completely understood. The Committee understood from patient experts that quality of life is affected by the symptoms experienced and not by serum uric acid concentration itself. The Committee was persuaded that reduction of the serum uric acid concentration below the 'saturation point' (approximately 6 mg/100 ml) was necessary to avoid precipitation of uric acid crystals in tissues in the long term. However, it concluded that there was uncertainty regarding the relationship between serum uric acid concentration above this level and clinical benefits, such as gout flare control and reduction in tophi size and number.
4.4 The Committee discussed the evidence for the clinical effectiveness of febuxostat, and specifically the randomised controlled trials (RCTs and extension studies in which febuxostat was compared with fixed-dose allopurinol. It noted the ERG critique of the efficacy results from the pooled analysis of data from the APEX and FACT trials and agreed that the approach was methodologically inappropriate, in that it failed to preserve randomisation in the RCT evidence. The Committee noted that the manufacturer was asked to conduct a meta-analysis of the RCT data but this was not provided. The Committee noted, however, that an appropriately conducted meta-analysis from the ERG showed very similar results, demonstrating that febuxostat is more effective than allopurinol in lowering serum uric acid concentration.
4.5 The Committee discussed the observation that the proportion of people with recurrent gout flares needing treatment was higher in the febuxostat arm of the APEX and FACT RCTs although the number of gout flares declined over time. It heard from the clinical specialists that this phenomenon is seen with all uric acid-lowering therapies. Although the mechanism is not completely understood, it is believed to relate to the rate of change in serum uric acid concentration, with treatments that reduce serum uric acid concentration more effectively and rapidly giving a more pronounced effect. The Committee accepted this explanation, noting that an initial rise in clinical flares can be prevented with the use of an NSAID or colchicine prophylaxis, although the use of such treatments varies in clinical practice.
4.6 The Committee accepted that febuxostat is more effective at reducing the serum uric acid concentration than fixed-dose allopurinol. However, it concluded that the benefits of febuxostat compared with allopurinol in improving clinical outcomes, such as flare control, reduction in tophi size and number and avoidance of joint and organ damage due to urate deposition, in the longer term had not been clearly demonstrated. In addition, it queried the generalisability of the RCT results to UK clinical practice. The Committee heard from the clinical specialists that the patient population in the APEX and FACT trials had more 'severe' manifestations of the disease (for example, the presence of tophi) than might be seen in UK general practice. Moreover, there was a lack of evidence about the clinical effectiveness of febuxostat compared with up-titrated allopurinol or second-line therapies.
4.7 The Committee considered the adverse effects associated with febuxostat in comparison with fixed-dose allopurinol. In particular, it noted that there was a higher incidence of cardiovascular events and deaths across the febuxostat arms of the APEX, FACT and EXCEL studies. It noted that the manufacturer had reported such differences as not being statistically significant, but that the ERG had found a lack of clarity in reporting, despite requests for clarification. It concluded that consideration of these adverse effects, however uncertain, was an essential part of comparing relative clinical outcomes of the intervention and comparator and this should have been included in the economic modelling.
4.8 The Committee discussed the economic model presented by the manufacturer and the ERG's subsequent critique. It had a number of concerns with the model structure and parameter assumptions in the model. It thought that the evidence base was incomplete because the comparison presented by the manufacturer was limited to a suboptimal (that is, fixed-dose) regimen of allopurinol. The Committee noted that no estimate had been made of the cost effectiveness of febuxostat in cases of non-response or intolerance or contraindicated to allopurinol. It heard from clinical specialists that new and relatively unfamiliar drugs are often used, initially at least, when current drugs are inappropriate or have failed to achieve a response. The Committee was mindful that the ERG had made a request for modelling of sequential use when patients progress to alternative treatments or no-treatment options, and that the manufacturer had declined the request on the basis of lack of evidence. The Committee concluded that without evidence that febuxostat is cost effective either when compared with up-titrated allopurinol or in sequential comparisons, it could not recommend its use either as an alternative to up-titrated allopurinol or as a second-line therapy.
4.9 The Committee discussed the linear relationship assumed in the cost-effectiveness model between serum uric acid concentration and frequency of gout flares, and how this may translate into improvements in health-related quality of life. Firstly, the Committee considered the ERG's concerns about the validity of the 'multivariate analysis' conducted to inform the assumption of a linear relationship between serum uric acid concentration and frequency of gout flares. It noted the ERG's critique that this was based on a dataset from which some data points had been selectively excluded. It agreed with the ERG that there had not been adequate explanation of this data selection. The Committee further considered the statements from the clinical specialists that although a relationship between serum uric acid concentration above the saturation point and frequency of gout flares is plausible, it is unlikely to be linear. The Committee concluded that the relationship between serum uric acid concentration and frequency of flares was implausible and was likely to lead to overestimation of the incremental QALYs gained.
4.10 The Committee then considered how improvements in health-related quality of life obtained with febuxostat had been estimated. The Committee noted that estimates reported in the manufacturer's submission had been based on utility decrements associated with gout flares and on a 'chronic utility gain' associated with lower serum uric acid concentrations. It noted that this had been reported in the manufacturer's submission on the basis of a separate analysis in which a linear relationship between utility and serum uric acid concentration had been assumed. The Committee considered that the evidence supporting this linear relationship was uncertain and speculative. In particular, it considered the exploratory ERG analysis that showed the incremental QALY gain associated with the effect of lowering serum uric acid concentration (0.032), which includes the incremental QALY gain from avoidance of gout flares, as compared with the incremental QALY gain from avoidance of gout flares alone (0.006), was very high and the impact of this factor on the final ICER proportionately substantial. The Committee noted that removing the component of incremental QALY gain associated with only serum uric acid concentrations, increased the ICER from the base case of £15,000 per QALY gained to £81,000 per QALY gained over a 2-year time horizon.
4.11 The Committee also considered that the difference in quality of life between experiencing a flare or not might have been overestimated because of bias in the research used to inform this parameter, since individuals had been asked to recall or imagine states they were not currently in. While it understood that the pain of flares can be extreme, it thought that the reported difference in EQ-5D scores for experiencing a gout flare of 1 week duration was an overestimate. On the other hand, it heard from a patient expert that the assumption that gout flares lasted for 1 week might be a significant underestimate. Overall, the Committee thought that there was considerable uncertainty over the estimation of disutility associated with gout flares. The Committee noted that there were a number of anomalous responses, such as better overall health when experiencing a flare than when not, and perfect health during a flare.
4.12 The Committee discussed the time horizons used in the manufacturer's model. It thought that for this chronic illness requiring life-long therapy, a lifetime time horizon would have been appropriate. The Committee took into account evidence from the open-label EXCEL extension study showing that a higher percentage of patients receiving febuxostat discontinued treatment compared with those receiving allopurinol. The Committee believed that the assumption over the 2-year time horizon that patients would remain on treatment, even if only a partial treatment effect was achieved, potentially biased the economic results in favour of febuxostat. It also noted that there could potentially be long-term benefits associated with febuxostat, such as avoidance of adverse renal events in comparison with other therapies. The Committee considered the univariate sensitivity analysis, which showed that an extension of the manufacturer's economic model to 5 years had marginal impacts on the base-case ICER. However, it noted that this simply reflects the assumption that patients continue to accrue treatment benefits beyond the 2-year time horizon.
4.13 The Committee discussed cost assumptions in the model. It considered it plausible that the main drivers of incremental cost would be the drug cost (noting the 13-fold difference between febuxostat and allopurinol), and the costs saved by avoiding treatment costs associated with any flares. It concluded that the total cost avoided by reduction in flares may have been overstated because the difference in expected number of flares may have been overestimated, as discussed above.
4.14 Overall, the Committee concluded that, on the basis of the evidence presented, febuxostat had not been shown to be clinically effective or cost effective compared with the appropriate comparators, which are up-titrated allopurinol and second-line therapies. It agreed that febuxostat had been shown to be more effective than fixed-dose allopurinol in lowering serum uric acid concentrations. It concluded that recommending febuxostat for the management of chronic hyperuricaemia in patients with gout would not be a cost-effective use of NHS resources.
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 that 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).
- 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 support for monitoring local practice.
6 Proposed recommendations for further research
6.1 None identified.
7 Related NICE guidance
There is no related guidance for this technology.
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 this technology is considered for review in May 2011. The Institute would particularly welcome comment on this proposed date.
Chair, Appraisal Committee
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.
Professor Keith Abrams
Professor of Medical Statistics, University of Leicester
Dr Jeff Aronson
Reader in Clinical Pharmacology, University Department of Primary Health Care, University of Oxford
Dr Darren Ashcroft
Reader in Medicines Usage and Safety, School of Pharmacy and Pharmaceutical Sciences, University of Manchester
Professor David Barnett (Chair)
Professor of Clinical Pharmacology, University of Leicester
Dr Peter Barry
Consultant in Paediatric Intensive Care, Leicester Royal Infirmary
Professor Stirling Bryan
Head, Department of Health Economics, University of Birmingham
Professor John Cairns
Public Health and Policy, London School of Hygiene and Tropical Medicine
Dr Mark Charkravarty
Director, External Relations, Procter and Gamble Health Care, Europe
Professor Jack Dowie
Heatlh Economist, London School of Hygiene and Tropical Medicine
Ms Lynn Field
Nurse Director, Pan Birmingham Cancer Network
Ms Sally Gooch
Independent Nursing and Healthcare Consultant
Mrs Barbara Greggains
Mr Sanjay Gupta
Former Service Manager in Stroke, Gastroenterology, Diabetes and Endocrinology, Basildon and Thurrock University Hospitals Foundation NHS Trust
Dr Ruairidh Milne
Senior Lecturer in Public Health, National Coordinating Centre for Health Technology, University of Southampton
Dr Neil Milner
General Medical Practitioner, Tramways Medical Centre, Sheffield
Dr Rubin Minhas
General Practitioner, CHD Clinical Lead, Medway PCT
Dr John Pounsford
Consultant Physician, Frenchay Hospital, Bristol
Dr Rosalind Ramsay
Consultant Psychiatrist, Adult Mental Health Services, Maudsley Hospital, London
Dr Stephen Saltissi
Consultant Cardiologist, Royal Liverpool University Hospital
Mr Roderick Smith
Finance Director, West Kent PCT
Mr Cliff Snelling
Professor Ken Stein (Vice Chair)
Professor of Public Health, Peninsula College of Medicine and Dentistry, University of Exeter
Professor Andrew Stevens
Professor of Public Health, Department of Public Health and Epidemiology, University of Birmingham
Dr Rod Taylor
Associate Professor in Health Services Research, Peninsula Medical School, Universities of Exeter and 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.
Appendix B: Sources of evidence considered by the Committee
A The Evidence Review Group (ERG) report for this appraisal was prepared by the School of Health and Related Research (ScHARR), The University of Sheffield:
- Stevenson M, Pandor A, Febuxostat for the management of Hyperuricaemia in patients with gout, March 2008
B The following organisations accepted the invitation to participate in this appraisal. They were invited to comment on the draft scope, the ERG report and the appraisal consultation document (ACD). Organisations listed in I were also invited to make written submissions. Organisations listed in II and III had the opportunity to give their expert views. Organisations listed in I II and III also had the opportunity to appeal against the final appraisal determination.
II Professional/specialist and patient/carer groups:
- Arthritis Care
- Kidney Research UK
- South Asian Health Foundation
- Royal College of Physicians
- Royal College of Pathologists
- Royal College of Nursing
- Royal College of General Practitioners
- Primary Care Rheumatology Society
- British Society for Rheumatology
III Other consultees:
- Welsh Assembly Government Department of Health
IV Commentator organisations (did not provide written evidence and without the right of appeal):
- NHS Quality Improvement Scotland
C The following individuals were selected from clinical specialist and patient advocate nominations from the non-manufacturer/sponsor consultees and commentators. They gave their expert personal view on febuxostat by attending the initial Committee discussion and providing written evidence to the Committee. They are invited to comment on the ACD.
- Dr Paramit Chowdhury, Consultant Nephrologist, Guy's and St Thomas' (nominated by the Royal College of Physicians) - clinical specialist
- Dr Paul Collinson, Consultant Chemical Pathologist, St George's Hospital, London (nominated by the Royal College of Pathologists) - clinical specialist
- Professor Michael Doherty, Professor of Rheumatology, University of Nottingham (nominated by the British Society for Rheumatology) - clinical specialist
- Mr Iain Phillips (nominated by the UK Gout Society) - patient expert
This page was last updated: 30 March 2010