Pharmacoeconomics 2011; 29 (2): 133-140

1170-7690/11/0002-0133/$49.95/0

REVIEW ARTICLE

2011 Adis Data Information BV. All rights reserved.

Febuxostat for the Management of

Hyperuricaemia in Patients with Gout
A NICE Single Technology Appraisal
Matt Stevenson and Abdullah Pandor
School of Health and Related Research, University of Sheffield, Sheffield, UK

Contents
Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. The Decision Problem. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2. The Independent Evidence Review Group (ERG) Review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1 Clinical Evidence Provided by the Manufacturer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1.1 Critique of Clinical Evidence and Interpretation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2 Cost-Effectiveness Evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.1 Critique of Cost-Effectiveness Evidence and Interpretation . . . . . . . . . . . . . . . . . . . . . . . . .
2.3 Conclusions of the ERG Report . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3. Key Methodological Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4. National Institute for Health and Clinical Excellence Guidance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1 Consideration of Clinical and Cost-Effectiveness Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1.1 Titration of Allopurinol and Sequential Therapies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1.2 Sequential Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1.3 The Relationship between Serum Uric Acid Levels and Clinical Outcomes. . . . . . . . . . . . .
4.1.4 The Exploratory Modelling Presented Following the Appraisal Consultation Document . .
4.2 Outcome of Appraisal Committee Meetings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Abstract

133
135
135
136
136
137
137
138
138
138
138
138
139
139
139
139
139

As part of the National Institute for Health and Clinical Excellence

(NICE) single technology appraisal (STA) process, the manufacturer of febuxostat (Adenuric; Ipsen, UK) was invited to submit evidence for the
clinical and cost effectiveness of febuxostat for the management of hyperuricaemia in patients with gout. The School of Health and Related Research
Technology Appraisal Group (ScHARR-TAG) at the University of Sheffield
were commissioned to act as the independent Evidence Review Group
(ERG).
This article provides details of the companys initial submission, the ERGs
clarification questions and the ERG report submitted to NICE. The decision
made by NICE is provided alongside a brief comment on additional results
produced by a substantially different model, which were presented by the
manufacturer after the production of the appraisal consultation document.
The ERG produced a critical review of the evidence for the clinical evidence and cost effectiveness of the technology based upon the manufacturers
submission to NICE.

Stevenson & Pandor

134

The clinical evidence was derived from two head-to-head, phase III, multiarm, randomized, double blind, controlled trials comparing the efficacy and
safety of febuxostat with fixed-dose allopurinol (300/100 mg/day) in patients
with hyperuricaemia and gout. The ERG considered that the trials were of
reasonable methodological quality and measured a clinically relevant range
of outcomes. Although a simple pooled analysis of the individual patientlevel data from the two trials was undertaken, the statistical approach for
combining the data was considered inappropriate by the ERG as it failed to
preserve randomization and introduced bias and confounding. There was
substantial uncertainty in the relationships reported by the manufacturer
regarding serum uric acid levels and the incidence of gout flares and underlying patient utility. The mathematical model developed was flawed and was
not corrected despite ERG comments. It focused only on patients receiving
febuxostat (80 mg/day titrated to 120 mg/day if necessary) with fixed-dose
allopurinol (300/100 mg/day). Sequential treatment was not modeled, nor was
titrating allopurinol to 900 mg/day, which is regarded as best practice. Numerous other errors were identified, which included the uncertain price of
febuxostat being sampled within the probabilistic sensitivity analyses. Supplementary exploratory modelling addressing the position of febuxostat
where patients were intolerant or contraindicated to allopurinol was provided
to the NICE Appraisal Committee following the release of the appraisal
consultation document.
The NICE Appraisal Committee concluded that febuxostat be recommended as an option for the management of chronic hyperuricaemia in gout
only for people who are intolerant to allopurinol or for whom allopurinol is
contraindicated.

The UK National Institute for Health and

Clinical Excellence (NICE) is an independent
organization whose responsibilities include providing national guidance to the NHS in England
and Wales on the use of selected new and established health technologies. One aspect of this is
the single technology appraisal (STA) process,
which is specifically designed for the appraisal
of a single health technology, with a single indication, where most of the relevant evidence
lies with one manufacturer or sponsor.[1] Typically, it is used for new pharmaceutical products
recently launched. The evidence for an STA is
principally derived from a submission by the
manufacturer/sponsor of the technology, which
should be based on a specification developed by
NICE. A report reviewing this evidence submission is then produced by an external organization
independent of NICE: the evidence review group
(ERG).
2011 Adis Data Information BV. All rights reserved.

The NICE Appraisal Committee (AC) then

considers the submissions from the manufacturer
or sponsor and the ERG alongside testimony
from experts and other stakeholders to develop
provisional (Appraisal Consultation Document
[ACD]) or final (Final Appraisal Determination
[FAD]) recommendations. Normally, an ACD
is produced only if the recommendations from
the AC are restrictive or if the manufacturer or
sponsor is requested to provide further clarification on their evidence submission. Otherwise,
formal consultation does not take place and an
FAD is agreed. If an ACD is produced, all stakeholders have an opportunity to comment on it
and the NICE AC meets again to consider the
ACD in light of the comments received and produce the FAD. This article presents a summary
of the ERG report for the STA of febuxostat
(Adenuric) for the management of hyperuricaemia in patients with gout and the subsequent
Pharmacoeconomics 2011; 29 (2)

NICE STA for Febuxostat

development of NICE guidance for the use of this

drug.
1. The Decision Problem
Gout is a chronic, progressive and destructive
condition that erodes and degrades cartilage and
muscle tissue. The disease is heterogeneous, resulting from the deposition of urate crystals (tophi).
Symptomatic disease is manifested in gout flares,
which result in severe pain and restricted movement
in the affected joint(s), commonly the toes and
fingers.[2] The overall prevalence rate of gout in the
UK is in the region of 1.4%, although the prevalence increases with age and is more common in
males than females;[3,4] the prevalence of gout in
males aged 6575 years is reported as being 7.3%.[3]
There is evidence to suggest that the risk of a
gout flare is related to the level of serum uric acid
(sUA) within a patient.[5] Research has shown
that the lowering of sUA levels is associated with
a reduction in the incidence of gout flares.[6,7]
Accordingly, there are guidelines to reduce sUA
levels; the European League Against Rheumatism expert consensus guidelines[8] recommend
a target sUA level of 360 mmol/L (6 mg/100 mL)
to eliminate gout flares and to resolve tophi, whilst
the British Society for Rheumatology (BSR) expert consensus guidelines[9] recommend lowering
and maintaining sUA levels to below 300 mmol/L
(5 mg/100 mL).
The treatment algorithm proposed for the UK
is contained in the BSR guidelines.[9] For the
long-term management of recurrent, intercritical and chronic gout, the guidelines recommend
first-line treatment with allopurinol with the dose
titrated from 50 to 100 mg/day up to a maximum of 900 mg/day, until sUA levels are below
300 mmol/L. Colchicine is recommended for up to
6 months, following initiation of allopurinol.
Patients contraindicated to allopurinol can be
prescribed uricosuric agents (sulfinpyrazone with
normal renal function and benzbromarone with
mild or moderate renal insufficiency); patients
contraindicated to colchicine can be treated with
an NSAID or cyclo-oxygenase (COX)-2 inhibitor, although the treatment duration should be
limited to 6 weeks.
2011 Adis Data Information BV. All rights reserved.

135

Febuxostat is a 2-arylthiazole derivative that

achieves the therapeutic effect of decreasing sUA
levels by selectively inhibiting xanthine oxidase
and, at doses of 80 mg or 120 mg per day, is indicated for the treatment of hyperuricaemia
(sUA levels 8 mg/100 mL) and gout. Febuxostat
received marketing approval from the European
Medicines Agency in 2008. NICE, in accordance
with the reference case, developed a scope for the
assessment of febuxostat[10] compared with allopurinol or alternate standard care for adults with
hyperuricaemia in whom urate deposition has already occurred.[11] Outcome measures to be specifically reported included sUA levels, incidence
of gout flares, adverse effects of treatment and
health-related quality of life (QOL).
2. The Independent Evidence Review
Group (ERG) Review
The manufacturer (Ipsen, UK) provided a submission to NICE regarding the clinical and cost effectiveness of febuxostat compared with fixed-dose
allopurinol only.[12] The ERG report[13] comprised a
critical review of the clinical and cost-effectiveness
evidence from the manufacturers submission, assessing whether the manufacturers interpretation
and analysis of the evidence were appropriate.
In accordance with the process for STAs, the
ERG had the opportunity to obtain clarification
on specific points in the manufacturers submission, resulting in the manufacturer providing additional evidence on a subset of the issues raised.
Often in an STA, the ERG would undertake exploratory analysis (either by modifying the model
structure or altering parameters included in the
model) to provide the NICE AC with further
evidence on which to base their decision. In this
instance, no such work was undertaken as the
ERG deemed that the model was so fundamentally flawed that an appropriate estimation of the
cost effectiveness could not be achieved within the
time from receipt of the response to the clarification letter and the submission of the final ERG
report (2 weeks).
This section summarizes the evidence presented in the manufacturers submission and the
ERGs review of that evidence.
Pharmacoeconomics 2011; 29 (2)

Stevenson & Pandor

136

2.1 Clinical Evidence Provided by the

Manufacturer

The main evidence provided in the submission

was derived from two head-to-head, phase III,
multi-arm, randomized, double-blind, controlled
trials (the 52-week FACT [Febuxostat versus
Allopurinol Control Trial][14] and 28-week APEX
[Allopurinol and Placebo-Controlled Efficacy
Study of Febuxostat] trials[15]) comparing the efficacy and safety of febuxostat with fixed-dose
allopurinol (300/100 mg/day) with the dose dependent on serum creatine levels in patients with
hyperuricaemia and gout. Supplementary data
from an ongoing long-term, open-label extension
study of the two head-to-head trials (EXCEL
[febuxostat/allopurinol comparative extension longterm study]) were provided to assess the clinical
efficacy of febuxostat over a period of 2 years.
The pooled (not meta-analysed) clinical efficacy
analysis of the FACT and APEX trials (representing 1689 patients) showed that febuxostat
(80 mg/day and 120 mg/day) was significantly
more effective than fixed-dose allopurinol (300/
100 mg/day) at reducing sUA levels to <6 mg/
100 mL. However, a large percentage of patients
receiving febuxostat did not achieve this target.
Post hoc subgroup analyses showed that febuxostat was more effective than allopurinol in decreasing sUA levels to <6 mg/100 mL in all of the
subgroups analysed (<9 mg/100 mL; between 9 and
10 mg/100 mL and >10 mg/100 mL). In addition,
significantly more febuxostat recipients achieved
sUA levels lower than therapeutic targets (<5 mg/
100 mL) than fixed-dose allopurinol recipients. No
subgroup analyses were conducted for patients with
renal impairment, non-responders to allopurinol or
patients with severe disease.
Although the adverse event profile was similar
in those receiving febuxostat to those receiving
allopurinol, more febuxostat recipients discontinued treatment prematurely. Reasons for withdrawal included gout flares and adverse events
such as liver function test abnormalities.
The manufacturer estimated the relationship
between changes in sUA levels and changes in the
incidence of gout flares from a statistical analysis
of individual patient-level data (n = 213) contain 2011 Adis Data Information BV. All rights reserved.

ed within a database held by a third-party consultancy. sUA levels were categorized into four
groups: sUA 360 mmol/L; sUA >360 mmol/L and
480 mmol/L; sUA >480 mmol/L and 600 mmol/L;
and sUA >600 mmol/L.
2.1.1 Critique of Clinical Evidence and
Interpretation

The ERG considered that the two identified

trials, which represent the main clinical efficacy evidence, were of reasonable methodological quality
(with some limitations), and measured a range of
outcomes that were as appropriate and clinically
relevant as possible. The ERG had five key concerns
regarding the clinical evidence and interpretation.
1. A simple pooled analysis of the patient-level
data from the two head-to-head trials was undertaken. Although the methods for this type of data
pooling were not explicitly described in the manufacurers submission, the statistical approach
for combining the data appeared to be inappropriate as it failed to preserve randomization and
introduced bias and confounding. The resulting
pooled data should therefore be treated with
caution; however, a meta-analysis performed by
the ERG indicated that the results of the pooled
analysis were similar to the values produced by
the meta-analysis.
2. The ERG was concerned that the submitted
model did not allow for the titration of allopurinol, which can be dose-escalated to a maximum
of 900 mg/day.[8,9] However, the manufacturer
suggested that dose escalation is rarely used by
most clinicians in clinical practice.
3. Whilst measures such as gout flares and
tophi resolution were secondary outcomes in
the trials, these are more clinically important.
Randomized controlled trial evidence shows
that, even though more febuxostat recipients
experienced the recommended biochemical goal
(<6 mg/100 mL), this did not translate into an
advantage over allopurinol in clinically important outcomes.
4. The ERG had serious concerns regarding the
data selected to estimate the relationship between
sUA levels and the number of gout flares expected.
A large portion of the data that were collected to
develop this linkage were excluded (accounting for
Pharmacoeconomics 2011; 29 (2)

NICE STA for Febuxostat

51% of all patients and 77% for UK patients), with

less than robust reasoning for favouring the data
contained in the third-party database. Full commentary on this issue is provided in the ERG
report.[13]
5. The ERG had serious concerns about the
interpretation of the multivariate analyses. This
analysis indicated that there was no significant
association between sUA levels and the number
of gout flares reported. This analysis was overlooked in favour of a bivariate analysis that did
not include other confounders. Note that, whilst
no statistically significant relationship was found
within this data set, this does not mean that such
a relationship does not exist, as is indicated in
clinical guidelines.[9,10]
2.2 Cost-Effectiveness Evidence

The manufacturer submitted a model constructed in Microsoft Excel, which compared

the cost effectiveness of febuxostat (at 80 mg/day
titrated to 120 mg/day where appropriate) with
fixed-dose (300/100 mg/day) allopurinol. A mixed
cohort of men and women with gout and baseline
sUA concentration of 80 mg/100 mL entered the
model after initiation of urate-lowering therapy.
The model had two components: an initial
3-month period in which flares were estimated
from pooled data from the FACT and APEX
trials,[14,15] with an assumption that prophylactic
colchicine treatment reduced the incidence of flares
by 78%;[16] and a longer term period (21 months)
during which the patients experiences would be
estimated based on sUA categorization levels as
previously described. QOL gains were assumed to
be achieved through the reduction of flares and in
a long-term increase in utility associated with
improved sUA categorization. The manufacturer
reported a deterministic cost per QALY gained
of d15 565, which comprised an incremental cost
of d540 per patient and an incremental QALY
gain of 0.035 over a 2-year time horizon. The
manufacturer presented the results of a probabilistic sensitivity analysis (PSA) that gave a
mean ICER of d16 324 per QALY gained (95%
CI 6281, 239 928). It was further reported that the
probability that febuxostat 80 mg/day (titrated to
120 mg/day where appropriate) had an ICER
2011 Adis Data Information BV. All rights reserved.

137

lower than d20 000 per QALY gained compared

with fixed-dose allopurinol was 63%.
2.2.1 Critique of Cost-Effectiveness Evidence
and Interpretation

The ERG assessment identified a number of

areas of uncertainty around the cost-effectiveness
analyses undertaken by the manufacturer and
deemed that there were major shortcomings in
the structure of the decision analytic model,
model population and model interpretation. The
key limitations, in addition to those raised in the
clinical section are described.
1. The ERG was extremely concerned regarding
the cost-effectiveness analyses undertaken, primarily due to the model structure and the strategies compared. The analyses presented compared only two strategies, the provision of allopurinol
for the entire time horizon and the provision of
febuxostat for the entire time horizon. For both
interventions, treatment was assumed to persist
regardless of the patient response. In the clarification letter sent to the manufacturer, the ERG
suggested that the following strategies, where
patients progress to the next intervention following lack of response, should be evaluated as a
minimum: allopurinol febuxostat no treatment; febuxostat allopurinol no treatment;
allopurinol no treatment; and febuxostat no
treatment. Assumptions regarding the efficacies
of second-line interventions would be necessary,
with the base case assuming that the effect
on sUA levels and gout flares remained at the
level seen in first-line treatments. These strategies
allow the option for patients to be prescribed the cheaper, generic intervention (allopurinol)
and to only progress to the more expensive, nongeneric treatment (febuxostat) if a lack of response was identified. The manufacturer declined
to assess these strategies within the initial STA
process, stating that it would be unethical to consider febuxostat as a second-line therapy when it
is cost effective as a first-line therapy, and that the
only appropriate comparison was that investigated in the pivotal randomized controlled trials,
that is, first-line therapy.
2. The ERG was concerned regarding the assumption that lower sUA levels would produce
Pharmacoeconomics 2011; 29 (2)

Stevenson & Pandor

138

utility gains independently of the incidence of gout

flares. The clinical experts advising the ERG did
not believe that this was plausible as gout is
generally considered asymptomatic unless a flare
occurs. The ERG noted that the reported EQ-5D
values from some patients were not plausible,
with some without a flare rating their utility as
worse than death. Furthermore, potential confounders such as the presence of hypertension
were omitted, which could have influenced the
results.
3. The prophylactic effects of colchicine were
incorrectly calculated. Colchicine was provided for the first 8 weeks of the FACT and APEX
trials, and thus applying the 78% reduction in
flares assumed in the model was inappropriate.
4. A number of errors were identified by the
ERG, which were relayed to the manufacturer
during the clarification process; however, these
were not corrected. The errors included, but were
not limited to, the following: the incorporation
of the price (undetermined at the time of the
submission) of febuxostat within the PSA; the
incorrect price used for allopurinol; and the
omission of many variables from the PSA.
2.3 Conclusions of the ERG Report

The ERG concluded that the results presented

by the manufacturer could not be taken as a reliable indicator of the cost effectiveness of febuxostat in the management of hyperuricaemia
in patients with gout. The ERG considered the
mathematical model to be substantially flawed
and, as such, no modifications were made to address the reported limitations.
3. Key Methodological Issues
The ERG believed that only a new model and
analysis of the parameter values could resolve the
limitations contained within the manufacturers
submission. Evidence regarding the comparative
effectiveness of febuxostat when compared with
an allopurinol dose that could be escalated is required, as is a better understanding of the relationship between sUA levels and incidence of
gout flares and underlying patient utility.
2011 Adis Data Information BV. All rights reserved.

4. National Institute for Health and

Clinical Excellence Guidance
In April 2008, based on the evidence available
(including verbal testimony of invited clinical experts and patient representatives), the AC produced preliminary advice that febuxostat should
not be recommended for NHS use for the management of hyperuricaemia in patients with gout.
Patients already receiving this treatment for this
indication should have the option of continuing
treatment until they and their clinician considered it appropriate to stop.[17]
Following the Committees preliminary recommendations on the use of febuxostat (the ACD),
comments were invited from consultees and commentators in the appraisal process and the public.
In the manufacturers response, some of the limitations of the previous modelling were addressed, and
an exploratory model allowing sequential therapy
was provided. The model explicitly included a
comparison of febuxostat versus placebo in a population contraindicated to allopurinol. The estimated cost per QALY reported for this scenario
was d3727. Although not part of the standard
STA process, the process does allow new evidence
to be accepted if it is likely to affect the provisional
recommendations; however, the process timelines
for this appraisal did not permit an assessment by
the ERG.[18]
4.1 Consideration of Clinical and
Cost-Effectiveness Issues

This section discusses the key issues considered

by the AC. The full list can be found in the FAD.[18]
4.1.1 Titration of Allopurinol and Sequential
Therapies

Clinical experts indicated to the AC that allopurinol was widely used as a first-line treatment
option and that best practice would allow dose
titration to 900 mg/day, where necessary. The AC
concluded that omitting the possibility that allopurinol could be titrated would be significantly
favourable to febuxostat. During the appeal it
was iterated that the decision not to recommend
febuxostat as a second-line treatment was deliberate as there was no evidence to suggest that
Pharmacoeconomics 2011; 29 (2)

NICE STA for Febuxostat

gout controlled with a properly titrated dose of

allopurinol would be better controlled with febuxostat.[18]
4.1.2 Sequential Therapies

The AC considered the model structure and

was mindful that the ERG had requested sequential modelling and that the manufacturer had
declined. It was commented that the preferred
place of febuxostat was for second-line treatment
and that the cost effectiveness of febuxostat in this
position had not been estimated.
4.1.3 The Relationship between Serum Uric Acid
Levels and Clinical Outcomes

The AC discussed the uncertainty in the relationship between sUA levels and the incidence
of gout flares. It was concluded that the relationship was not fully understood, but it was accepted
that as sUA concentration levels increased above
6 mg/100 mL it was likely that symptoms would
be more frequent.
At the request of the AC, the ERG calculated
the proportion of overall QALY gain reported for
febuxostat in the manufacturers submission that
was associated with a reduction in the incidence of
gout flares and the proportion of overall QALY
gain associated with a long-term utility gain due to
being in a lower sUA category.[19] This analysis
indicated that, in the manufacturers submission,
the QALY gain associated with a long-term utility
gain due to reduced sUA levels was over five times
greater than the QALY gain associated with a reduced number of gout flares.
The uncertainty in the relationship between
sUA levels and long-term utility was discussed, in
conjunction with the fact that the modelled
QALY gain was largely driven by this value. The
AC was concerned that although a relationship
may be plausible this was not clearly established.
The AC was persuaded that, if all of the longterm utility gain associated with lower sUA levels
was removed, then the cost-effectiveness ratio
would underestimate the long-term benefit of
treatment; however, the AC noted that the basecase cost-effectiveness ratio against fixed-dose
allopurinol would be likely to be within the range
of d15 00081 000 per QALY gained.
2011 Adis Data Information BV. All rights reserved.

139

4.1.4 The Exploratory Modelling Presented Following

the Appraisal Consultation Document

The AC considered the exploratory modelling

submitted by the manufacturer. The AC concluded that, whilst the reported value of d3727
was subject to substantial uncertainty, it was very
likely to be at an acceptable level in those patients
who are intolerant of allopurinol or for whom
allopurinol is contraindicated.
4.2 Outcome of Appraisal Committee
Meetings

Following this process, the preliminary guidance

was replaced with a FAD and NICE guidance,[20]
which indicated that febuxostat was recommended
as an option for the management of chronic hyperuricaemia in gout only for people who are intolerant of allopurinol (as defined in section 1.2 of the
FAD) or for whom allopurinol is contraindicated.
An important point highlighted by this technology
appraisal was that the comparator treatment should
be in accordance with best practice (dose escalation
of allopurinol in accordance with national guidelines.[8,9]) rather than current clinical (suboptimal)
practice, and healthcare professionals should be
encouraged to dose titrate where necessary. The
manufacturer appealed this decision; however, this
was dismissed on all points, with the appeal panel
declaring that the committee had acted reasonably
in reaching its conclusion.
5. Conclusions
The STA described here is atypical of those
seen by the authors in that the model submitted
both initially and following the clarification process was not considered fit for purpose by the
ERG and could not be used to accurately assess
the cost effectiveness of febuxostat in the management of hyperuricaemia in patients with gout.
Following the ACs preliminary recommendations on the use of febuxostat, the manufacturer
acknowledged the limitations and provided an
exploratory attempt to address the concerns of the
AC and the ERG. An important point highlighted
by this technology appraisal was that the comparator should be best practice (dose escalation of
Pharmacoeconomics 2011; 29 (2)

Stevenson & Pandor

140

allopurinol in accordance with national guidelines) rather than current clinical practice, and
healthcare professionals should be encouraged to
dose titrate where necessary.
Acknowledgements
This project was funded by the National Institute for
Health Research (NIHR) Health Technology Assessment
Programme (project number 07/69/01) and will be published
as part of a compendium of ERG articles in Health Technology Assessment. See the HTA programme website for further
project information (http://www.hta.ac.uk). This summary of
the ERG report was compiled after the ACs review.
The authors acknowledge the clinical advice provided by
Dr Kelsey Jordan and Dr Michael Snaith, who are consultant
rheumatologists. The views and opinions expressed therein
are those of the authors and do not necessarily reflect those of
NICE or the Department of Health.
The authors have no conflicts of interest that are directly
relevant to the content of this review.

References
1. National Institute for Health and Clinical Excellence. Guide
to the single technology appraisal (STA) process. London:
NICE, 2006 Sep [online]. Available from URL: http://
www.nice.org.uk/nicemedia/pdf/STA_Process_Guide.pdf
[Accessed 2010 Apr 1]
2. Teng GG, Nair R, Saag KG. Pathophysiology, clinical presentation and treatment of gout. Drugs 2006; 66: 1547-63
3. Mikuls TR, Farrar JT, Bilker WB, et al. Gout epidemiology:
results from the UK General Practice Research Database,
19901999. Ann Rheum Dis 2005; 64: 267-72
4. Annemans L, Spaepen E, Gaskin M, et al. Gout in the UK and
Germany: prevalence, comorbidities and management in general practice 20002005. Ann Rheum Dis 2008; 67 (7): 960-6
5. Falasca GF. Metabolic diseases: gout. Clin Dermatol 2006;
24: 498-508
6. Yamanaka H, Togashi R, Hakoda M, et al. Optimal range
of serum urate concentrations to minimize risk of gouty
attacks during anti-hyperuricemic treatment. Adv Exp
Med Biol 1998; 431: 13-8
7. Shoji A, Yamanaka H, Kamatani N. A retrospective study
of the relationship between serum urate level and recurrent
attacks of gouty arthritis: evidence for reduction of recurrent gouty arthritis with antihyperuricemic therapy.
Arthritis Rheum 2004; 51 (3): 321-5
8. Zhang W, Doherty M, Bardin T, et al. EULAR evidence
based recommendations for gout: part II. Management:
report of a task force of the EULAR Standing Committee
for International Clinical Studies Including Therapeutics
(ESCISIT). Ann Rheum Dis 2006; 65: 1312-24
9. Jordan KM, Cameron JS, Snaith M, et al., on behalf of the
British Society for Rheumatology. British Society for
Rheumatology and British Health Professionals in Rheumatology guideline for the management of gout. Rheumatology (Oxford) 2007; 46: 1372-4

2011 Adis Data Information BV. All rights reserved.

10. National Institute for Health and Clinical Excellence.

Health technology appraisal: febuxostat for the management of hyperuricaemia in patients with gout. Final scope.
London: NICE, 2007 Aug [online]. Available from URL:
http://www.nice.org.uk/nicemedia/live/11830/36209/36209.
pdf [Accessed 2010 Apr 1]
11. National Institute for Health and Clinical Excellence. Guide
to the methods of technology appraisals. London: NICE,
2008 Jun [online]. Available from URL: http://www.nice.
org.uk/media/B52/A7/TAMethodsGuideUpdatedJune2008.
pdf [Accessed 2010 Apr 1]
12. Ipsen UK. Febuxostat for the treatment of gout. Single
technology appraisal submission to the National Institute
for Health and Clinical Excellence. Final 15 January 2008
revised 14 May 2008. London: Ipsen, 2008 [online]. Available
from URL: http://www.nice.org.uk/nicemedia/live/11830/40731/
40731.pdf [Accessed 2010 Apr 1]
13. Stevenson M, Pandor A. Febuxostat for the management of
hyperuricaemia in patients with gout. Sheffield: University
of Sheffield, 2008 Mar 31 [online]. Available from URL:
http://www.nice.org.uk/nicemedia/live/11830/40721/40721.
pdf [Accessed 2010 Apr 1]
14. Becker MA, Schumacher R, Wortmann RL, et al. Febuxostat compared with allopurinol in patients with hyperuricaemia and gout. N Engl J Med 2005; 353: 2450-61
15. Schumacher HR, Becker MA, Wortmann RL, et al. Febuxostat vs allopurinol and placebo in subjects with hyperuricaemia and gout: the 28-week APEX study [poster].
The Annual Scientific meeting of the American College of
Rheumatology; 2005 Nov 1617; San Diego (CA)
16. Borstad GC, Bryant LR, Abel MP, et al. Colchicine for
prophylaxis of acute flares when initiating allopurinol for
chronic gouty arthritis. J Rheumatol 2004; 31: 2429-32
17. National Institute for Health and Clinical Excellence.
Hyperuricaemia febuxostat: appraisal consultation
document. London: NICE, 2010 Mar 30 [online]. Available
from URL: http://www.nice.org.uk/guidance/index.jsp?
action=article&o=40696 [Accessed 2010 Apr 1]
18. National Institute for Health and Clinical Excellence. Appeal hearing: febuxostat for the management of hyperuricaemia in patients with gout. London: NICE, 2008 Oct
[online]. Available from URL: http://www.nice.org.uk/
nicemedia/live/11830/42724/42724.pdf [Accessed 2010 Apr 1]
19. Stevenson M. NICE single technology appraisal of febuxostat for the treatment of hyperuricaemia. London: NICE,
2008 May 12 [online]. Available from URL: http://www.
nice.org.uk/nicemedia/live/11830/40722/40722.pdf [Accessed
2010 Apr 1]
20. National Institute for Health and Clinical Excellence. Final
appraisal determination: febuxostat for the management of
hyperuricaemia in people with gout. London: NICE, 2008
Aug [online]. Available from URL: http://www.nice.org.
uk/nicemedia/live/11830/41648/41648.pdf. [Accessed 2010
Apr 1]

Correspondence: Dr Matt Stevenson, School of Health and

Related Research, University of Sheffield, Regent Court,
30 Regent Street, Sheffield, South Yorkshire, S1 4DA, UK.
E-mail: m.d.stevenson@shef.ac.uk

Pharmacoeconomics 2011; 29 (2)

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.