Appraisal consultation document

Ustekinumab for the treatment of adults with moderate to severe psoriasis

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 ustekinumab for the treatment of moderate to severe psoriasis 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 ustekinumab for the treatment of moderate to severe psoriasis.

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: 10/06/2009

Second Appraisal Committee meeting: 24/06/2009

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  Ustekinumab is recommended as a treatment option for adults with plaque psoriasis when the following criteria are met.

• The disease is severe, as defined by a total Psoriasis Area Severity Index (PASI) score of 10 or more and a Dermatology Life Quality Index (DLQI) score of more than 10.
• The psoriasis has not responded to standard systemic therapies, includingciclosporin, methotrexate and PUVA (psoralen and long-wave ultraviolet radiation), or the person is intolerant of or has a contraindication to these treatments.
• The manufacturer provides the 90 mg dose (2 x 45 mg vials) for people who weigh more than 100 kg at the same total cost as for a single 45 mg vial.

1.2  Ustekinumab treatment should be stopped in people whose psoriasis has not responded adequately by 16 weeks after starting treatment. An adequate response is defined as either:

• a 75% reduction in the PASI score (PASI 75) from when treatment started or
• a 50% reduction in the PASI score (PASI 50) and a 5-point reduction in the DLQI score from when treatment started.

1.3  When using the DLQI, healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties, that could affect the responses to the DLQI. In such cases, healthcare professionals should ensure that the DLQI continues to be a sufficiently accurate measure.

2.  The technology

2.1  Ustekinumab (Stelara, Janssen-Cilag) is a fully human monoclonal antibody that targets interleukin-12 (IL-12) and IL-23. It binds to the p40 subunit, common to both IL-12 and IL-23, which prevents these cytokines from binding to the cell surface of T cells, thereby disrupting the inflammatory cascade implicated in psoriasis. Ustekinumab has a UK marketing authorisation for the treatment of moderate to severe plaque psoriasis in adults who have not responded to, or who have a contraindication to, or are intolerant to other systemic therapies including ciclosporin, methotrexate and psoralen and long-wave ultraviolet radiation (PUVA). The recommended dose of ustekinumab is 45 mg for people who weigh 100 kg or less, and 90 mg for people who weigh over 100 kg. An initial dose of ustekinumab is administered subcutaneously at week 0, followed by another dose at week 4, and then a further dose every 12 weeks. The summary of product characteristics (SPC) states that ustekinumab is intended for use under the guidance and supervision of a physician experienced in the diagnosis and treatment of psoriasis.

2.2  Common adverse events associated with ustekinumab, as reported in the SPC, include upper respiratory tract infection, nasopharygitis, depression, headache, dizziness, diarrhoea, pruritus, back pain, fatigue and infection site erythema. Contraindications listed in the SPC include clinically important active infection and hypersensitivity to the active substance or to any of the excipients. For full details of side effects and contraindications, see the SPC.

2.3  Ustekinumab is available in 45 mg vials. The cost per vial is £2147 (Monthly index of medical specialities (mims), April 2009). Ustekinumab is not listed in the current version of the ‘British national formulary’ (BNF; version 57). The cost of ustekinumab for the two loading doses (at 0 and 4 weeks) is £4294. The cost in the first year is £12,882, with an annual cost thereafter of £9335 (the annual cost assumes an average of 4.3 injections per year). Costs may vary in different settings because of negotiated procurement discounts.

2.4  The SPC recommends that people whose body weight exceeds 100 kg should receive a dose of 90 mg of ustekinumab. This would be double the cost of the 45 mg dose indicated for the treatment of a person who weighs 100 kg or less. The manufacturer has proposed a patient access scheme to the Department of Health. Under the scheme, people who weigh more than 100 kg and who are prescribed the 90 mg dose (2 x 45 mg vials) will receive both vials at a total cost of £2147 (the cost of a single vial). The manufacturer has proposed that this patient access scheme will be available to the NHS at least until either any review of the guidance by NICE or the introduction of any new formulations that would render the scheme obsolete. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.

3.  The manufacturer’s submission

The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of ustekinumab and a review of this submission by the Evidence Review Group (ERG; appendix B).

3.1  The decision problem in the manufacturer’s submission compared ustekinumab with adalimumab, efalizumab, etanercept, infliximab and supportive care. Three doses of etanercept were considered: 25 mg twice weekly given intermittently as recommended by NICE (see ‘Etanercept and efalizumab for the treatment of adults with psoriasis’ [NICE technology appraisal guidance 103 {TA103}]), 25 mg twice weekly given continuously, and 50 mg twice weekly given for the first 12 weeks followed by a reduction in dose to 25 mg twice weekly. Clinical outcomes in the manufacturer’s submission included improvements in PASI and DLQI scores. PASI is a measure of disease severity based on body surface area affected and the extent, scaliness, thickness and redness of plaques, with scores ranging from 0 to 72. The DLQI is a disease-specific quality-of-life measure with scores ranging from 0 to 30. Moderate to severe psoriasis was defined as a PASI score of 10 or more and a DLQI score of more than 10.

3.2  The manufacturer’s submission included evidence from three randomised controlled trials (RCTs).

• PHOENIX-1 (n = 766, 5 years duration), a phase III multicentre, parallel, randomised, double-blind, placebo-controlled trial based in the USA, Canada and Belgium.
• PHOENIX-2 (n = 1230, 5 years duration), a phase III multicentre, parallel, randomised, double-blind, placebo-controlled trial based in Europe and North America.
• ACCEPT trial (n = 903, 64 weeks duration), a phase III multicentre, parallel RCT based in Europe and North America which compared ustekinumab with etanercept (50 mg twice weekly for the first 12 weeks).

3.3  In each of the RCTs, two doses (45 mg and 90 mg) of ustekinumab were investigated and patients were randomised to groups regardless of their body weight. To reflect the licensed dosing of ustekinumab, the manufacturer presented two analyses in their submission. The first used data from all the patients enrolled in the clinical trials and included dosing outside the marketing authorisation (that is, patients weighing 100 kg or less who received ustekinumab 90 mg and patients weighing over 100 kg who received ustekinumab 45 mg). The second was a subgroup analysis that included data only for patients who received ustekinumab according to the marketing authorisation (weight-based dosing; that is, 45 mg for people who weigh 100 kg or less and 90 mg for people who weigh over 100 kg).

3.4  The results of the three RCTs using data for all patients demonstrated statistically significant differences in the percentage of patients treated with ustekinumab who achieved a 75% or greater reduction in PASI score (PASI 75; the primary endpoint in the trials) compared with those who received placebo. The percentages of patients with at least a PASI 75 response at week 12 in the ustekinumab 45 mg, ustekinumab 90 mg and placebo groups were 67%, 66% and 3% respectively in the PHOENIX-1 trial (p < 0.001 for both ustekinumab doses compared with placebo) and 67%, 76% and 4% respectively in the PHOENIX-2 trial (p < 0.001). In the ACCEPT trial the percentages of patients with at least a PASI 75 response at week 12 in the ustekinumab 45 mg, ustekinumab 90 mg and etanercept groups were 68%, 74% and 57% respectively (p = 0.012 for ustekinumab 45 mg and p < 0.001 for ustekinumab 90 mg compared with etanercept).

3.5  For secondary outcomes recorded in the RCTs, such as the physician’s global assessment (PGA) score, the DLQI score and other health-related quality-of-life scores, the ustekinumab groups showed statistically significant improvements compared with the placebo groups. In the PHOENIX-1 trial, the mean change in DLQI score at week 12 was −8.0 for ustekinumab 45 mg, −8.7 for ustekinumab 90 mg and −0.6 for placebo (p < 0.001 versus placebo for both ustekinumab doses). In the PHOENIX-2 trial, the values were −9.3, −10.0 and −0.5 respectively (p < 0.001 versus placebo for both ustekinumab doses). DLQI data were not reported in the ACCEPT trial.

3.6  Data from the clinical trials suggested that 90 mg is a more effective dose of ustekinumab than 45 mg for patients who weigh more than 100 kg. In the PHOENIX-1 trial, 69% of patients weighing more than 100 kg who received ustekinumab 90 mg achieved a PASI 75 response at 12 weeks, compared with 54% of those who received ustekinumab 45 mg. In the PHOENIX-2 trial the values were 71% and 49% respectively.

3.7  The manufacturer included longer-term data from the PHOENIX trials for the weight-based dosing subgroup analysis. These data suggested that the PASI response rates observed during the double-blind, randomised phases of the studies were maintained in the longer term. In the PHOENIX-1 trial, the percentages of patients achieving a PASI 75 response at week 24 were 83% and 80% for ustekinumab 45 mg and 90 mg respectively. In the PHOENIX-2 trial, the respective percentages were 80% and 80%.

3.8   In the PHOENIX-1 trial the percentages of patients having one or more adverse events were 57.3%, 51.4% and 47.8% in the ustekinumab 45 mg, ustekinumab 90 mg and placebo groups respectively. The percentages of patients having a serious adverse event were 0.8%, 1.6% and 0.8% respectively. Similar rates of adverse events were reported in the PHOENIX-2 trial. In the ACCEPT trial the percentages of patients having one or more adverse events were 66.0%, 68.3% and 69.5% in the ustekinumab 45 mg, ustekinumab 90 mg and etanercept groups respectively. The percentages of patients having a serious adverse event were 1.9%, 1.2% and 1.2% respectively.

3.9  The manufacturer carried out an indirect comparison of ustekinumab with other biological therapies (that is, adalimumab, efalizumab, infliximab and etanercept), using a mixed treatment comparison approach. The mixed treatment comparison compared each treatment through common links to placebo, either by means of direct comparison or through comparison with any other active agent compared with placebo. The manufacturer included data from the three ustekinumab RCTs, as well as from three RCTs comparing adalimumab with placebo, five comparing efalizumab with placebo, five comparing etanercept with placebo and four comparing infliximab with placebo. The results from the mixed treatment comparison using the ustekinumab data for all patients suggested that the mean probabilities of achieving a PASI 75 response were 69% for ustekinumab 45 mg (95% confidence interval [CI] 62% to 75%), 74% for ustekinumab 90 mg (95% CI 68% to 80%), 58% for adalimumab (95% CI 49% to 68%), 80% for infliximab (95% CI 70% to 87%), 39% for etanercept 25 mg (95% CI 30% to 48%), 52% for etanercept 50 mg (95% CI 45% to 59%), 26% for efalizumab (95% CI 21% to 32%) and 4% for supportive care (95% CI 3% to 4%). The manufacturer also included a mixed treatment comparison for the weight-based dosing subgroup analysis. However, the ustekinumab data from this comparison were provided as academic in confidence.

3.10  The manufacturer based its cost-effectiveness analysis on the economic model used in ‘Etanercept and efalizumab for the treatment of adults with psoriasis’ (NICE technology appraisal guidance 103 [TA103]) and used subsequently in ‘Infliximab for the treatment of adults with psoriasis’ (NICE technology appraisal guidance 134 [TA134]) and ‘Adalimumab for the treatment of adults with psoriasis’ (NICE technology appraisal guidance 146 [TA146]) The model was adapted by the manufacturer of ustekinumab to incorporate additional evidence, including the results of the mixed treatment comparison described in section 3.9.

3.11  In the model, each person had an initial period of treatment after which response was assessed (this was referred to as the trial period). Continuation of treatment into the next phase (referred to as the treatment period) occurred only if a PASI 75 response was achieved in the trial period. The time at which the response was assessed varied for the different drugs, depending on their dosing regimen. The assessment points were at 12 weeks (etanercept), 14 weeks (infliximab) and 16 weeks (adalimumab and ustekinumab). It was assumed that for people who responded to treatment, 20% stopped treatment each year. The mean time on treatment using this assumption was calculated to be 3.65 years. The same assumption was used for all biological therapies.

3.12  The utility data used in the model were based on an estimate of the relationship between PASI response rates and changes in DLQI score from the PHOENIX-1 and PHOENIX-2 trials mapped to EQ-5D scores. First, the mean change in the DLQI score between baseline and week 12 was estimated for patients with different levels of PASI response. Secondly, the manufacturer estimated an algorithm to map DLQI score to EQ-5D score from a scatter plot published in the assessment report of TA103. The changes in mean EQ-5D score for PASI responses of less than 50%, between 50% and 74%, between 75% and 89%, and 90% or more were estimated to be 0.04, 0.17, 0.22 and 0.25 respectively.

3.13  The costs in the economic model included drug costs, administration costs and monitoring costs, and were taken from the model in TA103, NHS Reference Costs and National Tariff and the BNF (edition 56). The Personal Social Services Research Unit (PSSRU) inflation index was used to update costs from 2006 values if current costs were not available. The model assumed that if a person had an inadequate response to treatment, they would have an inpatient admission of 21 days once a year.

3.14  The manufacturer’s base-case analysis assumed a weighted average of weight-based dosing whereby 80% of people received ustekinumab 45 mg and 20% of people received ustekinumab 90 mg. The manufacturer also provided analyses using the data from all patients in the clinical trials and the data from the weight-based dosing approach with separate estimates for ustekinumab 45 mg and 90 mg. All the analyses in the submission assumed that the patient access scheme (see section 2.4) was in place.

3.15  The base-case analysis showed that when ustekinumab was compared with supportive care, the QALY gain was 0.156 at an incremental cost of £4615, giving an incremental cost-effectiveness ratio (ICER) of £29,587 per QALY gained. The ICER for ustekinumab compared with etanercept 25 mg given intermittently (assuming 88% of the cost of continuous etanercept) was £27,105 per QALY gained. The ICER for infliximab compared with ustekinumab was £304,566. Adalimumab and etanercept given continuously rather than intermittently were dominated by ustekinumab (that is, ustekinumab had both greater effectiveness and lower costs). Probabilistic sensitivity analyses suggested that the probability of ustekinumab being cost effective at £20,000 and £30,000 per QALY gained was 7.4% and 48.5% respectively. The manufacturer’s analyses suggested that ustekinumab was the only biological therapy that was likely to be cost effective at £20,000 and £30,000 per QALY gained.

3.16  The analyses using data for all patients (that is, no weight-based dosing) presented separate ICERs for ustekinumab 45 mg and 90 mg. These analyses suggested that when ustekinumab 45 mg was compared with supportive care, the QALY gain was 0.1544 at an incremental cost of £4735, giving an ICER of £30,664 per QALY gained. The estimates for ustekinumab 90 mg suggested a QALY gain of 0.1563 and incremental costs of £4613, giving an ICER of £29,520 per QALY gained. The ICERs for ustekinumab in comparison with intermittent etanercept 25 mg were £36,938 per QALY gained for ustekinumab 45 mg and £28,633 per QALY gained for ustekinumab 90 mg. Etanercept 25 mg given continuously was dominated by ustekinumab. Adalimumab was dominated by ustekinumab 90 mg, but for ustekinumab 45 mg the ICER was £16,400 per QALY gained.

3.17  Sensitivity analyses were carried out to test assumptions in the economic model. When the manufacturer reduced the length of an inpatient stay from the base-case estimate of 21 days to 17.5 days, the ICER for ustekinumab in comparison with supportive care increased from £29,587 to £34,387 per QALY gained. When the length of stay was increased to 27.5 days, the ICER decreased to £20,672 per QALY gained. The manufacturer also changed the way in which estimates of utility were obtained: from EQ-5D data mapped from DLQI scores, to SF-6D data transformed from SF-36 values collected in the PHOENIX trials. When SF-6D data were used to estimate utilities, the ICER for ustekinumab compared with supportive care increased from £29,302 to £49,371 per QALY gained.

3.18  The manufacturer also varied the assumptions about the cost and efficacy of intermittent etanercept. The cost of intermittent compared with continuous etanercept was changed from the base-case estimate of 88% to 74% (the figure used in TA103) and to 98%. Using an assumption of 74%, the ICER for ustekinumab compared with intermittent etanercept 25 mg increased from £27,105 to £68,339 per QALY gained. When an assumption of 98% was used, ustekinumab dominated intermittent etanercept. The relative efficacy of intermittent compared with continuous etanercept was assumed to be 81% in the base case. When this assumption was changed to 71%, the ICER for ustekinumab compared with intermittent etanercept decreased to £22,634 per QALY gained. When the assumption was changed to 91% the ICER was £32,949 per QALY gained.

3.19  The ERG concluded that the manufacturer’s submission provided an unbiased estimate of the clinical effectiveness of ustekinumab at 12 weeks based on the results of the three randomised comparisons. However, it noted that there was a lack of information about the methodology used for the weight-based dosing subgroup analysis. In addition, it could not determine whether the methods used were appropriate and whether the subgroup analysis supported the weight-based categorisation presented.

3.20  The ERG commented that there appeared to be differences between the mixed treatment comparison that had been used in the appraisal of etanercept and efalizumab (TA103) and that used for the current appraisal. The ERG also noted that the manufacturer’s submission included only minimal discussion of any possible clinical heterogeneity between the trials included in the mixed treatment comparison. It further noted that in the mixed treatment comparison, data from the weight-based dosing analysis of ustekinumab were taken from a subgroup of the trial data, whereas for the comparator trials data for all patients were used. The ERG was concerned that this had affected randomisation. The ERG stated that the clinical effectiveness of ustekinumab in comparison with the other biological therapies was uncertain.

3.21  The ERG also noted that the probabilistic sensitivity analysis in the manufacturer’s submission appeared to include only variables for utilities, treatment response and the proportion of people weighing more than 100 kg. It did not include other variables to which the ICERs were sensitive, such as the number of hospital days, the effects of different inpatient costs and the effectiveness of intermittent etanercept.

3.22  The ERG completed an exploratory analysis that amended the base-case analysis to include the price for ustekinumab 90 mg as double the list price of ustekinumab 45 mg (that is, assuming that there is no patient access scheme in place). The results showed that the ICER for ustekinumab compared with supportive care increased from £29,587 to £40,952 per QALY gained. A further exploratory analysis assumed that the efficacy of intermittent etanercept 25 mg was the same as that of continuous etanercept 25 mg (as was assumed in the economic model for TA103). Using this assumption, the ICER for ustekinumab compared with intermittent etanercept 25 mg in the base-case analysis increased from £27,105 to £41,449 per QALY gained.

3.23  The ERG conducted an exploratory probabilistic sensitivity analysis that included a larger number of variables than were included by the manufacturer. The results of the analysis suggested greater uncertainty around the estimates of cost effectiveness, but the cost-effectiveness acceptability curves did not differ significantly from those of the manufacturer. When the ERG repeated the analysis assuming that the cost of ustekinumab 90 mg was twice that of ustekinumab 45 mg, the probability of ustekinumab being cost effective was zero.

3.24  Full details of all the evidence are in the manufacturer’s submission and the ERG report, which are available from www.nice.org.uk

4.  Consideration of the evidence

4.1  The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of ustekinumab, having considered evidence on the nature of the condition and the value placed on the benefits of ustekinumab by people with psoriasis, those who represent them, and clinical specialists. It was also mindful of the need to take account of the effective use of NHS resources.

Clinical effectiveness

4.2  The Committee discussed the likely place of ustekinumab in the management of severe psoriasis. It heard from the clinical specialists that there has been a substantial reduction in hospital admissions for psoriasis as a result of the increasing availability of biological therapies. However, the Committee heard from the clinical specialists that there are currently no treatments that they considered to be effective for people whose psoriasis does not respond adequately to the tumour necrosis factor (TNF) inhibitors (that is, adalimumab, infliximab and etanercept). In addition, with the withdrawal of efalizumab there are no treatment options for people in whom TNF inhibitors are contraindicated, such as people with heart failure or demyelinating disease. The Committee noted that ustekinumab has a different mechanism of action from that of the TNF inhibitors, and heard that the clinical specialists considered that its mechanism of action may be specific in the management of psoriasis. The Committee understood that ustekinumab would be considered to be of value by people with psoriasis and their clinicians.

4.3  The Committee heard from the clinical specialists and patient experts that ustekinumab may be easier to use than other biological therapies because it is administered subcutaneously only once every 12 weeks after the initial trial phase. This could enable people to be given the drug during their routine scheduled clinic visits. The Committee was informed by the patient experts that people with psoriasis do not generally have a problem with the frequency of injections, although they prefer less frequent injections. The Committee accepted that the less frequent dosing for ustekinumab during routine scheduled clinic visits may also help compliance.

4.4  The Committee heard from the clinical specialists that ustekinumab is a new drug that has been given to far fewer people than the other biological therapies, and therefore its long-term safety profile is less certain. Because of this, the specialists considered that the drug may initially be prescribed more cautiously than existing treatments. The Committee also heard from the clinical specialists and patient experts that people with severe psoriasis are often well informed about drug safety and able to consider benefits and risks before starting treatment.

4.5  The Committee considered that the RCTs identified in the manufacturer’s submission confirmed the clinical effectiveness of ustekinumab compared with placebo in people with moderate to severe plaque psoriasis. The Committee also considered that ustekinumab had been demonstrated to be more clinically effective than etanercept. It noted, however, that the dosage used for etanercept in the comparative trial was different from that currently recommended by NICE in ‘Etanercept and efalizumab for the treatment of adults with psoriasis’ (TA103). The Committee heard that the inclusion criteria used in the clinical trials were representative of people with psoriasis who are being considered for treatment with biological therapies in clinical practice

4.6  The Committee noted that the manufacturer had conducted a mixed treatment comparison to enable a comparison of ustekinumab with all alternative biological therapies currently available for the treatment of psoriasis. The Committee noted that two analyses had been completed: one analysed data from all patients according to their randomisation, whereas the other analysed data from patients according to a weight-based dosing approach. The Committee noted that the results for both analyses suggested a higher probability of a response after treatment with ustekinumab than with etanercept or adalimumab, but a lower probability of a response compared with infliximab. The Committee noted that there was some uncertainty about whether the mixed treatment comparison had used a random or fixed effects baseline. In addition, the Committee considered that there may be uncertainty in the results because randomisation may not have been maintained in the weight-based dosing analysis. Nevertheless, the Committee was persuaded that the mixed treatment comparison was appropriate for considering estimates of the cost effectiveness of ustekinumab.

4.7  The Committee considered whether the appropriate comparator for ustekinumab should be etanercept given continuously or intermittently, with the latter regimen being specified in TA103 and indicated in the marketing authorisation for etanercept. The Committee heard from the clinical specialists that biological therapies for psoriasis, including etanercept, are usually used on a continuous basis in clinical practice, although treatment may be interrupted if a person has a sustained remission. The Committee heard that treatment withdrawal was carried out cautiously because people may deteriorate rapidly and then subsequently not regain full control of their disease. The Committee heard from the clinical specialists that ustekinumab would likely to be used in a similar way to other biological therapies.

Cost effectiveness

4.8  The Committee discussed the results of the economic analysis conducted by the manufacturer. It considered that the overall approach to modelling adopted by the manufacturer was appropriate. The Committee noted the concern of the ERG that no formal subgroup analysis had been done that justified weight-based dosing. However, the Committee was mindful that weight-based dosing was included in the marketing authorisation and that there was evidence for a dose–response relationship for ustekinumab.

4.9  The Committee noted the assumption in the model that a hospital inpatient period of 21 days would be required for people for whom treatment resulted in an inadequate response. The Committee noted that this assumption had been used in the appraisals of other biological therapies for psoriasis. The Committee heard from the clinical specialists and patient experts that 21 days of inpatient treatment in a year was plausible for a person who had an inadequate response to standard treatment. The Committee also heard from the clinical specialists that the cost of £288 per day for an inpatient stay, as assumed in the model, may be too low. Costs as high as £700 per day may be incurred, but these are usually associated with shorter, more intensive inpatient admissions. Additionally, the Committee heard that the cost of supportive care may be higher than calculated in the model because people may receive methotrexate or ciclosporin even if their disease is not adequately controlled by these treatments. The Committee recognised that the costs were similar to those used in previous appraisals, but was concerned about their accuracy.

4.10  The Committee noted that the economic model assumed that the efficacy of intermittent etanercept was lower than that of continuous etanercept. The Committee was informed that this was based on an RCT showing that for the outcome measured (PGA score), intermittent etanercept was less effective than continuous etanercept. This difference in effectiveness had then been applied to the continuous etanercept PASI response data in the mixed treatment comparison in order to determine the efficacy of intermittent etanercept. The Committee considered that an assumption of reduced efficacy of intermittent etanercept may be reasonable, but it considered that the way in which this had been calculated in the model increased the uncertainty in the results.

4.11  The Committee noted that the economic model included a 20% annual dropout rate for people who responded to treatment and that this rate was assumed to be the same for all biological therapies. The Committee heard from the clinical specialists that people on biological therapies did stop treatment because of a reduction in response or adverse events, and that they considered this estimate to be reasonable.

4.12  The Committee was aware that EQ-5D data had not been obtained in the clinical trials, and noted that the manufacturer had mapped DLQI scores to EQ-5D scores to obtain estimates of utility. The Committee noted that this approach had been used in TA103. The Committee recognised that the manufacturer had also provided a secondary analysis using SF-36 values from the PHOENIX trials transformed into SF-6D scores. The Committee accepted the manufacturer’s use of mapping to determine utility estimates.

4.13  The Committee noted that in the manufacturer’s base-case analysis, ustekinumab had an ICER of £29,600 per QALY gained compared with supportive care, and an ICER of £27,100 per QALY gained compared with etanercept 25 mg given intermittently. The Committee noted that the cost-effectiveness analysis included the patient access scheme. It noted that without the patient access scheme, the ICERs for ustekinumab would be £41,000 per QALY gained compared with supportive care, £102,000 per QALY gained compared with intermittent etanercept 25 mg, and £300,000 per QALY gained compared with adalimumab. The Committee therefore considered that ustekinumab could not be considered a cost-effective use of NHS resources without the patient access scheme. The Committee was reassured that the patient access scheme would remain in place until any further review of the guidance by NICE that rendered the scheme obsolete, and that the scheme would not be withdrawn without the agreement of NICE and the Department of Health. The Committee concluded that it was reasonable to consider the estimates of cost effectiveness that included the patient access scheme.

4.14  The Committee considered how the population with severe psoriasis should be defined. It heard from the clinical specialists that a combination of DLQI and PASI scores is used routinely in clinical practice, and agreed that it would be appropriate to define severe disease as a PASI score of 10 or more and a DLQI score of more than 10, in line with TA103. Furthermore, the clinical specialists indicated that the treatment continuation rules defined in section 1.2 of TA103 remain relevant to clinical practice. However, the Committee noted that the response should be measured at 16 weeks for ustekinumab, rather than at 12 weeks as defined for etanercept in TA103.

4.15  The Committee was aware that the clinical specialists had indicated that ustekinumab may be used after a person’s psoriasis has failed to respond to TNF inhibitors. The Committee noted that the manufacturer had provided no detailed evidence of clinical effectiveness and no cost-effectiveness evidence for this subgroup. However, it was also aware that approximately 40–50% of people in the PHOENIX trials had previously tried a biological therapy such as a TNF inhibitor and therefore agreed that the estimates of clinical effectiveness were based on a population that included a reasonable proportion of people who had tried biological therapies before. However, the Committee considered that the collection of effectiveness data for biological therapies for psoriasis including ustekinumab in this patient group would be beneficial for future assessments.

4.16  The Committee was mindful of the uncertainties in the resource and cost data and the potential methodological limitations of the mixed treatment comparison. The Committee considered that it would be of value to review all of the biological therapies for psoriasis in a multiple technology appraisal. On balance, the Committee was persuaded that ustekinumab should be recommended as a treatment option for people with severe plaque psoriasis when standard systemic therapies have failed to produce an adequate response, or if a person is intolerant of or has a contraindication to these treatments.

4.17  The Committee was aware that there might be some situations when the DLQI may not be a clinically appropriate tool to inform a clinician’s conclusion about the severity of plaque psoriasis; for example, because of a person’s physical, sensory of learning disabilities or other communication difficulties. The Committee heard from the clinical specialists that the DLQI is now available in more than 50 languages and that this has improved assessment for those people for whom English is a second language. The Committee concluded that in such cases healthcare professionals should ensure that their use of the DLQI continues to be a sufficiently accurate measure.

5.  Implementation

5.1  The Secretary of State and the Welsh Assembly Minister for Health and Social Services have issued directions to the NHS on implementing NICE technology appraisal guidance. When a NICE technology appraisal recommends use of a drug or treatment, or other technology, the NHS must provide funding and resources for it within 3 months of the guidance being published. If the Department of Health issues a variation to the 3-month funding direction, details will be available on the NICE website. The NHS is not required to fund treatments that are not recommended by NICE.

5.2  NICE has developed tools to help organisations implement this guidance (listed below). These are available on our website (www.nice.org.uk/TAXXX). [NICE to amend list as needed at time of publication]

• 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.  Research recommendations

The Committee considered that the following research would be of value:

• Studies that investigate the effect of ustekinumab and the other biologic therapies when used after the failure of the first biologic therapy
• Studies that investigate resource use including frequency and length of hospitalisation and its associated costs

7.  Related NICE guidance

Published

• Adalimumab for treatment of adults with psoriasis. NICE technology appraisal guidance 146 (July 2008). Available from: www.nice.org.uk/TA146
• Infliximab for the treatment of adults with psoriasis. NICE technology appraisal guidance 134 (January 2008). Available from www.nice.org.uk/TA134
• Etanercept and efalizumab for the treatment of adults with psoriasis. NICE technology appraisal guidance 103 (July 2006). Available from www.nice.org.uk/TA103

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 together with the review of other drugs for the treatment of psoriasis ‘Etanercept and efalizumab for the treatment of adults with psoriasis (NICE technology appraisal guidance 103), ‘Infliximab for the treatment of adults with psoriasis (NICE technology appraisal guidance 134) and ’Adalimumab for the treatment of adults with psoriasis’ (NICE technology appraisal guidance 146). The Institute would particularly welcome comments on this proposal.

David Barnett
Chair, Appraisal Committee
May 2009

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

Professor Philip Home (Vice Chair)
Professor of Diabetes Medicine, Newcastle University

Dr Jane Adam
Department of Diagnostic Radiology, St George’s Hospital, London

Dr Amanda Adler
Consultant Physician, Cambridge University Hospitals Trust

Professor A E Ades
MRC Senior Scientist, MRC Health Services Research Collaboration, Department of Social Medicine, University of Bristol

Dr Matt Bradley
Value Demonstration Director, AstraZeneca

Mrs Elizabeth Brain
Lay member

Dr Robin Carlisle
Deputy Director of Public Health, Rotherham PCT

Professor Karl Claxton
Professor of Health Economics, University of York

Mrs Fiona Duncan
Clinical Nurse Specialist, Anaesthetic Department, Blackpool Victoria Hospital

Dr Paul Ewings
Statistician, Taunton & Somerset NHS Trust, Taunton

Professor John Geddes
Professor of Epidemiological Psychiatry, University of Oxford

Mr John Goulston
Chief Executive, Barking, Havering and Redbridge Hospitals NHS Trust

Dr Richard Harling
Director of Public Health, Worcestershire PCT and Worcestershire County Council

Dr Peter Heywood
Consultant Neurologist, Frenchay Hospital, Bristol

Dr Vincent Kirkbride
Consultant Neonatologist, Regional Neonatal Intensive Care Unit, Sheffield

Dr Ian Lewin
Consultant Endocrinologist, North Devon District Hospital

Dr Alec Miners
Lecturer in Health Economics, London School of Hygiene and Tropical Medicine

Dr James Moon
Consultant Cardiologist and Senior Lecturer, University College London Hospital (UCLH) and UCL

Dr David Newsham
Lecturer (Orthoptics), University of Liverpool

Mrs Angela Schofield
Chairman, Bournemouth and Poole Teaching PCT

Mr Mike Spencer
General Manager, Cardiff and Vale NHS Trust – Facilities and Clinical Support Services

Professor Iain Squire
Consultant Physician, University Hospitals of Leicester

Mr David Thomson
Lay member

Mr William Turner
Consultant Urologist, Addenbrooke's Hospital, Cambridge

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.

Raphael Yugi and Sally Gallaugher
Technical Leads

Zoe Garrett
Technical Adviser

Bijal Chandarana
Project Manager

Appendix B: Sources of evidence considered by the Committee

A  The Evidence Review Group (ERG) report for this appraisal was prepared by Southampton Health Technology Assessments Centre, The University of Southampton:

• Gospodarevskaya E, Picot J, Cooper K, et al., Ustekinumab for the treatment of moderate to severe psoriasis, March 2009

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 have the opportunity to appeal against the final appraisal determination.

I  Manufacturer/sponsor:

• Janssen-Cilag

II  Professional/specialist and patient/carer groups:

• British Association of Dermatologists
• Psoriasis and Psoriatic Arthritis Alliance
• Psoriasis Association
• Royal College of Physicians
• Royal College of Nursing

III  Other consultees

• Department of Health
• Dorset PCT
• Welsh Assembly Government
• Sandwell PCT

IV  Commentator organisations (did not provide written evidence and without the right of appeal)

• Department of Health, Social Services and Public Safety for Northern Ireland
• Southampton Health Technology Assessments Centre, The University of Southampton
• National Institute for Health Research (NIHR) Health Technology Assessment Programme (HTA Programme)
• NHS Quality Improvement Scotland
• Abbott Laboratories
• Merck Serono
• Schering-Plough
• Wyeth Pharmaceuticals

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 ustekinumab for moderate to severe psoriasis by attending the initial Committee discussion and providing written evidence to the Committee. They are invited to comment on the ACD.

• Professor Alex Anstey, Consultant Dermatologist, nominated by The British Association of Dermatologists – clinical specialist
• Professor Jonathan Barker, Consultant Dermatologist, nominated by The British Association of Dermatologists – clinical specialist
• Mr Ray Jobling, nominated by The Psoriasis Association – patient expert
• Miss Helen McAteer, nominated by The Psoriasis Association – patient expert