The Department of Health has asked the National Institute for Health and Clinical Excellence (NICE) to produce guidance on using golimumab in the NHS in England and Wales. The Appraisal Committee has considered the evidence submitted by the manufacturer and the views of non-manufacturer consultees and commentators, and clinical specialists and patient experts.

This document has been prepared for consultation with the consultees. It summarises the evidence and views that have been considered, and sets out the draft recommendations made by the Committee. NICE invites comments from the consultees and commentators for this appraisal (see appendix B) and the public. This document should be read along with the evidence base (the evaluation report), which is available from www.nice.org.uk

The Appraisal Committee is interested in receiving comments on the following:

• Has all of the relevant evidence been taken into account?
• Are the summaries of clinical and cost effectiveness reasonable interpretations of the evidence?
• Are the provisional recommendations sound and a suitable basis for guidance to the NHS?
• Are there any equality-related issues that need special consideration and that are not covered in the appraisal consultation document?

Note that this document is not NICE's final guidance on this technology. The recommendations in section 1 may change after consultation.

After consultation:

• The Appraisal Committee will meet again to consider the evidence, this appraisal consultation document and comments from the consultees.
• At that meeting, the Committee will also consider comments made by people who are not consultees.
• After considering these comments, the Committee will prepare the final appraisal determination (FAD).
• Subject to any appeal by consultees, the FAD may be used as the basis for NICE’s guidance on using golimumab in the NHS in England and Wales.

For further details, see the ‘Guide to the technology appraisal process’ (available at www.nice.org.uk).

The key dates for this appraisal are:

Closing date for comments: 27 October 2010

Second Appraisal Committee meeting: 10 November 2010

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 is not NICE's final guidance on this technology. The recommendations in section 1 may change after consultation.

1. Appraisal Committee's preliminary recommendations

1.1 Golimumab is not recommended for the treatment of active and progressive psoriatic arthritis in adults when the response to previous disease-modifying anti-rheumatic drug therapy has been inadequate.

2. The technology

2.1 Golimumab (Simponi) is a human monoclonal antibody that prevents the binding of tumour necrosis factor (TNF) to its receptors, thereby neutralising its activity. Golimumab has a marketing authorisation for the treatment of active and progressive psoriatic arthritis (alone or in combination with methotrexate) in adults when the response to previous disease-modifying anti-rheumatic drug (DMARD) therapy has been inadequate. The summary of product characteristics (SPC) notes that golimumab has also been shown to improve physical function in this population.

2.2 Golimumab is contraindicated in people with moderate to severe heart failure, hereditary problems of fructose intolerance, active tuberculosis and other severe infections. Before initiating therapy, physicians should evaluate people for prior evidence of hepatitis B virus infection, and both active and inactive (latent) tuberculosis infection. The SPC reports that the most common adverse reactions are upper respiratory tract infections, including nasopharyngitis, pharyngitis, laryngitis and rhinitis. For full details of adverse effects, contraindications, special warnings and precautions for use, see the SPC.

2.3 Golimumab is injected subcutaneously via a pre-filled injection pen. The recommended dose is 50 mg given once a month, on the same date each month. The SPC states that in people who weigh more than 100 kg whose psoriatic arthritis does not show an adequate clinical response after three or four doses, the dose of golimumab may be increased to 100 mg once a month. The manufacturer’s submission states that the cost of golimumab is £774.58 for a 50 mg pre-filled injection pen, and estimates an annual cost of £9294.96. 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 golimumab (Schering-Plough/Centocor) and a review of this submission by the Evidence Review Group (ERG; appendix B).

3.1 The main clinical effectiveness data were derived from a single phase III randomised controlled trial (RCT) – GO-REVEAL. The trial compared golimumab with placebo for the treatment of active and progressive psoriatic arthritis in people who had symptoms despite the use of current or previous DMARDs or non-steroidal anti-inflammatory drugs. Of the 405 trial participants, 113 were randomised to placebo, 146 were randomised to a 50 mg dose of golimumab and 146 were randomised to a 100 mg dose of golimumab. Randomisation was maintained for 24 weeks. Upward titration was allowed at week 16, such that the participants in the placebo group could switch to 50 mg golimumab and those in the 50 mg golimumab group could have their dose increased to 100 mg if their disease had failed to respond. In the placebo group 50% of participants crossed over to golimumab 50 mg treatment and in the golimumab 50 mg group 20% crossed over to golimumab 100 mg treatment. Outcomes were assessed at 14 and 24 weeks.

3.2 The primary outcomes in GO-REVEAL were American College of Rheumatology (ACR) 20 response at week 14 and the change from baseline in the psoriatic arthritis modified van der Heijde-Sharp (vdH-S) score at week 24. Secondary outcomes included ACR 20 response at week 24, Psoriatic Arthritis Response Criteria (PsARC) response at weeks 14 and 24, and Psoriasis Area and Severity Index (PASI) 75 improvement at week 14 in participants with psoriasis that affected 3% or more of their body surface area at baseline. Physical functional status was measured by Health Assessment Questionnaire (HAQ) score at week 24. Health-related quality of life was measured by the Short Form 36 Health Survey (SF-36) at week 14.

3.3 The week 14 results of GO-REVEAL indicated that, compared with placebo, golimumab showed a statistically significant improvement in joint disease. An ACR 20 response was seen in 50.7% of participants in the 50 mg treatment arm compared with 8.8% in the placebo arm (relative risk [RR] 5.727, 95% confidence interval [CI] 3.24 to 10.56). A PsARC response was seen in 73.3% of participants in the 50 mg treatment arm compared with 21.2% in the placebo arm (RR 3.451, 95% CI 2.46 to 4.87). Golimumab also showed a statistically significant improvement in skin disease as measured by PASI 75 at both 14 and 24 weeks. A PASI 75 response was seen in 40.4% of participants in the 50 mg treatment arm compared with 2.5% in the placebo arm (RR 15.945, 95% CI 4.62 to 59.11) at 14 weeks, and in 55.9% of participants in the 50 mg treatment arm compared with 1.4% in the placebo arm (RR 40.794, 95% CI 7.86 to 232.88) at 24 weeks. There was also a statistically significant improvement in functional status (HAQ) at 24 weeks. A mean HAQ score change from baseline of 0.33 (standard deviation [SD] 0.55, p < 0.001) was observed in the golimumab 50 mg arm compared with −0.01 (SD 0.49) in the placebo arm. Data on HAQ score change from baseline were not available for the 14-week time point.

3.4 The manufacturer reported that golimumab 50 mg produced a statistically significant reduction from baseline in vdH-S score of 0.16 (p = 0.01) at 24 weeks compared with placebo. The reduction from baseline in vdH-S score was not statistically significant in the golimumab 100 mg group (p = 0.09). The manufacturer did not report vdH-S scores at the 14 week time point.

3.5 The Evidence Review Group (ERG) reported that the main limitation of the efficacy evaluation of golimumab was that the analyses of efficacy outcomes were restricted to the GO-REVEAL trial, which had a limited sample size and was of limited duration (see section 3.1).

3.6 The manufacturer stated that the most frequently reported adverse events associated with golimumab therapy were infections and infestations, including upper respiratory tract infections and nasopharyngitis. The manufacturer reported that the safety profile of golimumab was comparable to that of the other TNF inhibitors adalimumab, etanercept and infliximab.

3.7 The ERG reported concerns about the adverse event data presented for golimumab. It noted that no long-term adverse event data had been presented, and that the manufacturer had not included adverse event data on golimumab from controlled studies of its use in other conditions such as rheumatoid arthritis or ankylosing spondylitis. The ERG reported that the manufacturer’s conclusion that golimumab has a safety profile comparable to that of the other TNF inhibitors may be premature.

3.8 In the absence of head-to-head comparisons between golimumab and the other TNF inhibitors, the manufacturer conducted a mixed treatment comparison. The mixed treatment comparison included seven trials: the GO-REVEAL trial (golimumab versus placebo); two RCTs comparing etanercept with placebo; two RCTs comparing infliximab with placebo; and two RCTs comparing adalimumab with placebo. All of the TNF inhibitors have marketing authorisations for the treatment of active and progressive psoriatic arthritis that has responded inadequately to previous DMARDs.

3.9 The trials included in the mixed treatment comparison were similar in terms of joint disease severity at baseline (for example, mean tender joint count and mean swollen joint count). There were differences, however, in the proportions of trial participants who could be evaluated for psoriasis endpoints at baseline. Most participants had received treatment with one prior DMARD, although no trial specified non-response to at least two DMARDs.

3.10 The outcomes included in the mixed treatment comparison analyses were PsARC response, change in HAQ score given PsARC response to treatment, change in HAQ score given no PsARC response, and change in PASI in people with psoriasis that affected 3% or more of their body surface area at baseline. The manufacturer selected absolute changes as the main outcomes, stating that this was the most appropriate outcome for economic modelling. No analysis of the ACR outcomes was included in the mixed treatment comparison.

3.11 The results of the mixed treatment comparison indicated that of the four TNF inhibitors golimumab was associated with the third highest PsARC response and absolute change in PASI from baseline. Of the four TNF inhibitors, golimumab had the lowest HAQ score change from baseline, both in participants whose disease responded to treatment based on PsARC score and those whose disease did not respond. The numerical values for each outcome derived from the mixed treatment comparison were marked as confidential and therefore cannot be reported.

3.12 The ERG reported that the network of trials included in the mixed treatment comparison was appropriately constructed, but that there were differences among the trial populations in disease severity and number of previously tried DMARDs (with many participants having received only one previous DMARD). The ERG commented that the trial populations were not precisely representative of the population with active and progressive psoriatic arthritis for whom TNF inhibitors are recommended in current British Society for Rheumatology guidelines and in ‘Etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis’ (NICE technology appraisal (TA) guidance 199).

3.13 The manufacturer developed its own economic evaluation, which comprised a patient cohort model. The model compared the effects of treatment with golimumab (50 mg) in adults with active and progressive psoriatic arthritis whose disease had responded inadequately to DMARDs with the effects of treatment with infliximab, adalimumab and etanercept and with palliative care. All participants entered the model with the same baseline characteristics as participants in the GO-REVEAL trial and left the model at death, irrespective of the treatment regimen. The model used a 12-week cycle for the first two cycles and annual cycles thereafter. The model captured response to treatment using HAQ score (conditional on PsARC response) as the arthritis measure and PASI score as the psoriasis measure. If there was no response to treatment at 12 weeks it was discontinued. The price year used for costs was not reported in the manufacturer’s submission. Costs and benefits were discounted at 3.5% per annum over 40 years.

3.14 The manufacturer reported that estimates of treatment effectiveness – including PsARC response, HAQ score changes from baseline for participants whose disease had responded to treatment according to PsARC at 12 weeks, HAQ score changes from baseline for those whose disease had not responded to treatment according to PsARC at 12 weeks, and PASI change from baseline in patients with measurable psoriasis – were derived from the mixed treatment comparison.

3.15 The model assumed that people who continue treatment with a TNF inhibitor maintain their initial improvement in HAQ score. The same ongoing rate of withdrawal from treatment was used for all the TNF inhibitors (16.5% per annum) and represented withdrawal because of treatment failure or adverse events.

3.16 The manufacturer combined data from IMPACT2 (a study of infliximab) and GO-REVEAL using the ‘Gray’ algorithm to estimate utility values. The Gray algorithm converts Short Form 36 (SF-36) data to EuroQol (EQ-5D) estimates and then to utilities. The disutility of adverse events was not modelled.

3.17 The manufacturer reported that resource use associated with treatment, administration and monitoring of infliximab, etanercept and adalimumab was taken from the Assessment Group’s model for TA 199. Only the costs of the 50 mg dose of golimumab, and not the 100 mg dose, were included. The model contained an additional 4 hours of staff nurse costs for training people to self-administer subcutaneous TNF inhibitors. The costs of infliximab were initially calculated on the assumption that vial sharing was allowed (using an average of 3.5 vials per infusion, although this assumption was later removed following a request from the ERG). The costs associated with adverse events were not included.

3.18 The manufacturer revised its original base-case estimates in response to a request from the ERG for clarification about the way utilities were calculated and for the removal of the infliximab vial sharing assumption (see section 3.16). The revised base-case results produced total costs, total quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs, compared with palliative care) as follows:

• palliative care: total costs of £62,224 and total QALYs of 6.61
• golimumab: total costs of £94,151 and total QALYs of 8.21, resulting in an ICER of £19,993 per QALY gained
• adalimumab: total costs of £86,410 and total QALYs of 7.89, resulting in an ICER of £18,824 per QALY gained
• etanercept: total costs of £94,578 and total QALYs of 8.49, resulting in an ICER of £17,177 per QALY gained
• infliximab: total costs of £106,620 and total QALYs of 8.49, resulting in an ICER of £23,578 per QALY.

3.19 The ERG reported that the manufacturer had not provided an incremental analysis in which dominated and extendedly dominated options were excluded. An option is 'dominated' if there is another option that is less costly and more effective. An option is ‘extendedly dominated’ when its ICER is higher than that of the next, more effective, option when compared with a common baseline (that is, it is dominated by a combination of two other alternatives). The ERG recalculated the manufacturer’s base-case results by incrementally comparing each treatment with the next, more effective, option and excluding those that were extendedly dominated. The recalculated base-case results showed that both adalimumab and golimumab were extendedly dominated by a combination of etanercept and palliative care. Etanercept in comparison with palliative care had an ICER of £17,209. Infliximab was dominated by etanercept.

3.20 The manufacturer conducted subgroup analyses of the populations with ‘predominantly’ rheumatic disease and those with ‘significant’ psoriasis. The ERG recalculated the results of these analyses as described in section 3.18. The results of the recalculated subgroup analyses show adalimumab and golimumab to be extendedly dominated by a combination of etanercept and palliative care. Etanercept in comparison with palliative care produced an ICER of £15,607 per QALY gained in the rheumatic disease subgroup and £14,028 per QALY gained in the psoriasis subgroup. Infliximab was dominated by etanercept in the rheumatic disease subgroup and produced an ICER of £570,200 per QALY gained in comparison with etanercept in the psoriasis subgroup.

3.21 The ERG commented that the model structure was reasonable. The ERG stated that the inclusion of costs to cover time for training in self-injection may have been unnecessary, but reported that all other included costs were appropriate. The ERG considered that it may have been appropriate to account for the possibility of dose escalation to 100 mg (as per the marketing authorisation; see section 2.3). The ERG reported that the subgroup analyses were appropriate.

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

4. Consideration of the evidence

4.1 The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of golimumab, having considered evidence on the nature of psoriatic arthritis and the value placed on the benefits of golimumab by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.

4.2 The Committee understood that psoriatic arthritis can cause significant distress and psychological impact on the person’s life, employment and social activities. The Committee heard from a patient expert that TNF inhibitors are valued options for the treatment of psoriatic arthritis and have a positive impact on quality of life. It understood that people with the condition may prefer the option of a treatment that is self-injectable and/or has a longer retreatment interval. The Committee understood that people value having a choice of TNF inhibitors and that another treatment option will always be welcome.

4.3 The Committee considered current clinical practice for the treatment of psoriatic arthritis. It understood that TA 199 recommended adalimumab, etanercept and infliximab for the treatment of psoriatic arthritis in people who have peripheral arthritis with three or more tender joints and three or more swollen joints, and when the psoriatic arthritis has not responded to adequate trials of at least two standard DMARDs (administered either individually or in combination). The Committee also noted that TA 199 specified that treatment should be started with the least expensive drug, taking into account drug administration costs, required dose and product price per dose. It heard from the clinical specialists that they considered there to be little demonstrable difference between the TNF inhibitors in terms of their clinical effectiveness. The clinical experts did, however, point to slight differences among the TNF inhibitors in the extent to which efficacy was likely to be lost. The Committee heard from the commissioning expert that subtle differences in cost and administration, particularly with regard to dose escalation (as included in the marketing authorisation for infliximab) and hospitalisation, can make a big cost difference. The Committee concluded that adalimumab, etanercept and infliximab were the appropriate comparators for golimumab.

4.4 The Committee heard from the clinical specialists and patient expert that people often prefer a less frequent dosing schedule. It understood that people with psoriatic arthritis and their clinicians may therefore value the once-monthly, self-injectable administration of golimumab. However, the Committee noted the 12-day half-life of golimumab and the possibility that a longer retreatment interval with golimumab may result in longer periods of discomfort because of waning efficacy before retreatment. It also noted that the longer half-life of golimumab may make it difficult if a person needs to stop treatment quickly, for example because of an adverse event, as it would take longer for the treatment effect to wear off.

4.5 The Committee considered the evidence on the clinical effectiveness of golimumab. It understood that the main clinical effectiveness data were derived from a single phase III, randomised controlled trial. It noted statistically significant outcomes for the 50 mg dose compared with placebo in terms of improvements in joint disease, skin disease and functional status. The Committee concluded that golimumab was clinically effective compared with placebo. It noted that there had been no head-to-head trials between golimumab and any of the other TNF inhibitors, and that, as a result, the manufacturer had conducted a mixed treatment comparison.

4.6 The Committee noted that neither the 100 mg arm nor dose escalation to 100 mg in the 50 mg arm in the GO-REVEAL trial was limited to people who weighed more than 100 kg, and therefore did not reflect the licensed population for the 100 mg dose. The Committee heard from clinical specialists that they would probably be more likely to switch to a different TNF inhibitor than to increase the dose if the 50 mg dose of golimumab failed to produce a response. The Committee concluded that it was uncertain of the extent to which the 100 mg dose would be used in clinical practice.

4.7 The Committee considered the results of the trials of the other TNF inhibitors and of the mixed treatment comparison presented by the manufacturer. The Committee understood from the clinical specialists and the patient expert that pain and disability caused by arthritis (as captured by HAQ score and reflected in the manufacturer’s economic model) often has a significant impact on the person’s quality of life. The Committee therefore took particular account of outcomes related to this disease component, in particular the estimates of changes in HAQ score from baseline (with a negative score indicating improvement) in people whose disease responded to treatment at 12 weeks (according the PsARC) as estimated by the mixed treatment comparison. The Committee noted that the change in HAQ score in people whose disease responded to treatment appeared much lower for golimumab than for etanercept. The Committee inferred that, based on the changes in HAQ score, golimumab and etanercept could not be assumed to be of equal efficacy.

4.8 The Committee considered the evidence on the adverse event rates associated with the use of golimumab. It noted a number of reported ‘serious’ adverse events, but understood that GO-REVEAL was not powered to detect statistically significant differences in adverse event outcomes. The Committee heard from clinical specialists that there are long-term registry data (including adverse event outcomes) available for adalimumab, etanercept and infliximab, but not for golimumab. The clinical specialists did not consider that there are definite signals to indicate that there would be safety differences between golimumab and the other TNF inhibitors. However, the Committee understood from the manufacturer that the long-term follow-up of the GO-REVEAL trial has yet to be completed and that data on adverse events are being collected. It also understood that the manufacturer had not provided any adverse event data derived from the use of golimumab for other indications (rheumatoid arthritis and ankylosing spondylitis). The Committee concluded that there remains uncertainty about the long-term adverse event profile of golimumab.

4.9 The Committee considered the economic model presented by the manufacturer. The Committee noted that the model assumed people continuing on therapy maintained their initial improvement in HAQ score. The Committee considered the utility estimates incorporated in the model, and noted that the utility formula was derived from the HAQ score and the PASI response. The HAQ score response had a greater effect on utility than the PASI response did, indicating that the calculated utility benefit was driven more by the reduction in joint symptoms than the reduction in skin disease. The Committee concluded that this was appropriate (see section 4.7).

4.10 The Committee considered the results of the manufacturer’s
base-case analysis, which compared each of the TNF inhibitors (including golimumab) with palliative care. The Committee heard from the ERG that the pair-wise comparisons with palliative care needed to be reworked into an incremental analysis comparing each treatment with the next most effective alternative. The ERG re-presented these results. The Committee noted that all alternatives to etanercept were either dominated (infliximab was more expensive but no better than etanercept) or extendedly dominated (adalimumab and golimumab were, in effect, less cost effective than etanercept; see section 3.19).

4.11 The Committee considered the 100 mg dose of golimumab. The Committee was aware that the SPC for golimumab states that for people who weigh more than 100 kg whose disease does not show an adequate clinical response after three or four doses, the dose of golimumab may be increased to 100 mg once a month. It noted that the cost of golimumab for people having the 100 mg dose would be double that for those having the 50 mg dose. Although the exact proportion of people who would be eligible for the higher dose is not known, the Committee estimated that this proportion would be significant. The Committee concluded that if the acquisition cost was averaged across the population to account for the expected proportion eligible for the 100 mg dose, the ICER for golimumab would be expected to be higher than that estimated in the base case.

4.12 The Committee was aware of registries that collect data on the long-term outcomes of treatment with TNF inhibitors for rheumatoid arthritis. The Committee noted the importance of registries in gathering data and supported the inclusion of outcomes specific to psoriatic arthritis in a suitable registry so that specific information about treatments and treatment-related adverse events in psoriatic arthritis can be collected.

4.13 In summary, the Committee considered the clinical and cost effectiveness of golimumab in the light of the submitted evidence and the comments of the clinical specialists, the commissioning expert and the patient expert. The Committee noted that golimumab was not found to be as effective as the key comparator, etanercept. The Committee further noted that if the expected cost of treatment with the 100 mg dose was included, the cost of golimumab would be higher than estimated in the economics analysis. The Committee was also mindful of considerable uncertainty about the long-term adverse event profile of golimumab. The Committee therefore concluded that golimumab for the treatment of active and progressive psoriatic arthritis in adults when the response to previous DMARD therapy has been inadequate would not be a cost-effective use of NHS resources.

4.13

Summary of the Appraisal Committee’s key conclusions

TAXXX (STA)	Appraisal Title: Golimumab for the treatment of psoriatic arthritis	ACD section
Key conclusion
Golimumab is not recommended for the treatment of active and progressive psoriatic arthritis in adults when the response to previous disease-modifying anti-rheumatic therapy has been inadequate. The key driver for this preliminary recommendation was that based on the evidence available, golimumab was not found to be as effective as the key comparator etanercept and was expected to be more costly than estimated in the economic model.		1.1 4.13
Current practice
Clinical need of patients	Psoriatic arthritis can cause significant distress and psychological impact on a patient’s life. Patients value a choice among treatments, and may prefer the option of a treatment that is self-injectable and/or has a longer re-treatment interval. The Committee noted that the pain and disability of the arthritis component of the disease often has a greater impact on the patient than the skin component.	4.2 4.7
Availability of alternative treatments	NICE technology appraisal 199 recommends adalimumab, etanercept and infliximab for the treatment of psoriatic arthritis when the person has peripheral arthritis with three or more tender joints and three or more swollen joints, and when the psoriatic arthritis has not responded to adequate trials of at least two standard DMARDs (administered either individually or in combination). NICE technology appraisal 199 specifies that treatment should be started with the least expensive drug, taking into account drug administration costs, required dose and product price per dose.	4.3
The technology
Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits and how it might improve the way that current need is met (i.e., is this a ‘step-change’ in the management of the condition)?	Clinical specialists and the patient expert emphasised that patients often prefer a less frequent dosing schedule. The Committee understood that patients and clinicians may therefore value the once-monthly, self-injectable administration of golimumab.	4.4
What is the position of the treatment in the pathway of care for the condition?	The Committee concluded that adalimumab, etanercept and infliximab were the appropriate comparators for golimumab.	4.3
Adverse effects	There were a number of serious adverse events associated with the use of golimumab. However, the pivotal trial was not powered to detect statistically significant differences in safety outcomes. The Committee concluded that there was uncertainty around the long-term safety profile of golimumab.	4.8
Evidence for clinical effectiveness
Availability, nature and quality of evidence	The main clinical effectiveness data were derived from a single phase III, randomised controlled trial. The Committee noted statistically significant outcomes for the 50 mg dose of golimumab compared with placebo for improvements in joint disease, skin disease and functional status. The Committee concluded that golimumab was clinically effective compared with placebo. It noted there had been no head-to-head trials between golimumab and any of the other TNF inhibitors. As a result, the manufacturer had conducted a mixed treatment comparison. The Committee noted that the change in HAQ score in people whose disease responded to treatment from the mixed treatment comparison appeared much lower for golimumab than for etanercept. The Committee inferred that, based on the changes in HAQ score, golimumab and etanercept could not be assumed to be of equal efficacy.	4.5 4.7
Relevance to general clinical practice in the NHS	Clinical specialists noted that they would probably be more likely to switch a patient to a different TNF inhibitor if the 50 mg dose of golimumab failed to produce a response than to increase the dose.	4.6
Uncertainties generated by the evidence	The main clinical trial evidence was derived from a single phase III, randomised controlled study. Because there had been no head-to-head trials between golimumab and any of the other TNF inhibitors, the manufacturer had conducted a mixed treatment comparison. The 100 mg dose in the pivotal trial was not limited to patients weighing over 100 kg, and was therefore not reflective of the licensed population for that dose. There was uncertainty around the long-term adverse event profile of golimumab (see ‘Availability, nature and quality of the evidence’),	4.7 4.6 4.6
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?	No subgroups were identified for which there is evidence of differential effectiveness.	N/A
Estimate of the size of the clinical effectiveness including strength of supporting evidence	Based on the results of the mixed treatment comparison, the Committee inferred that golimumab could not be assumed to be as effective as etanercept.	4.7
Evidence for cost effectiveness
Availability and nature of evidence	The Committee heard from the ERG that the pair-wise comparisons of each of the TNF inhibitors with palliative care needed to be reworked into an incremental analysis, comparing each treatment with the next most effective alternative. The ERG re-presented these results.	4.10
Uncertainties around and plausibility of assumptions and inputs in the economic model	The Committee concluded that if the acquisition cost was averaged across the population to account for the proportion eligible for the 100 mg dose, the ICER for golimumab would be expected to be higher than that estimated in the base case.	4.11
Incorporation of health-related quality of life benefits and utility values	The utility formula was derived from the HAQ score and the PASI response. The HAQ response had a greater effect on utility than did the PASI response, indicating that the utility benefit was driven mainly by the response in joint symptoms, rather than on skin disease. The Committee concluded that this was appropriate.	4.9
Have any potential significant and substantial health-related benefits been identified that were not included in the QALY calculation, and how have these been separately evaluated and what is the impact (if any) on the judgement of the most plausible ICER?	There were no material claims made by the manufacturer regarding any health-related benefits of the technology that were not included in the QALY calculation. None were identified or considered by the Committee.	N/A
Are there specific groups of people for whom the technology is particularly cost effective?	No subgroups were identified for whom golimumab is particularly cost effective.	N/A
What are the key drivers of cost effectiveness?	The changes in HAQ score from baseline (in people whose disease had responded to treatment at 12 weeks, according to PsARC) were much lower for golimumab that for etanercept. The Committee inferred that, based on the changes in HAQ score, golimumab and etanercept could not be assumed to be of equal efficacy.	4.7
Most likely cost-effectiveness estimate (given as an ICER)	When each TNF inhibitor was compared to the next most effective alternative, all alternatives to etanercept were either dominated (infliximab) or extendedly-dominated (adalimumab and golimumab). The Committee concluded that golimumab was, in effect, less cost effective than etanercept.	4.10
Additional factors taken into account
Patient Access Schemes (PPRS)	No patient access scheme was submitted for the technology being appraised.	N/A
End-of-life considerations (Supplementary advice on end-of-life)	The supplementary advice was not relevant to this appraisal.	N/A
Equalities considerations	No equalities issues were raised in the appraisal.	N/A

5. Implementation

5.1 The Secretary of State and the Welsh Assembly Minister for Health and Social Services have issued directions to the NHS in England and Wales on implementing NICE technology appraisal guidance. When a NICE technology appraisal recommends use of a drug or treatment, or other technology, the NHS must usually 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. When there is no NICE technology appraisal guidance on a drug, treatment or other technology, decisions on funding should be made locally.

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

• Slides highlighting key messages for local discussion.
• Costing template and report to estimate the national and local savings and costs associated with implementation.
• Implementation advice on how to put the guidance into practice and national initiatives that support this locally.
• A costing statement explaining the resource impact of this guidance.
• Audit support for monitoring local practice.

6. Proposed recommendations for further research

6.1 The Committee highlighted the importance of collecting further data within registries of patients receiving biological treatments for psoriatic arthritis to obtain information on long-term outcomes, including adverse events.

7. Related NICE guidance

Published

• Etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis. NICE technology appraisal guidance 199 (August 2010). Available from www.nice.org.uk/guidance/TA199

8. Proposed date for review of guidance

8.1 NICE proposes that the guidance on this technology is considered for review by the Guidance Executive alongside technology appraisal 199 (‘Etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis’, review date June 2013). NICE welcomes comment on this proposed date. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.

Andrew Stevens
Chair, Appraisal Committee
September 2010

Appendix A: Appraisal Committee members and NICE project team

A. Appraisal Committee members

The Appraisal Committees are standing advisory committees of NICE. 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. There are four Appraisal Committees, each with a chair and vice chair. Each Appraisal Committee meets once a month, except in December when there are no meetings. Each Committee considers its own list of technologies, and ongoing topics are not moved between Committees.

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

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

Dr Kathryn Abel
Reader and Consultant Psychiatrist/Director of Centre for Women's Mental Health, University of Manchester

Dr David Black
Director of Public Health, Derbyshire County Primary Care Trust

Dr Mary Cooke
Lecturer, School of Nursing, Midwifery and Social Work, University of Manchester

Dr Chris Cooper
General Practitioner, London

Professor Peter Crome
Consultant Physician, Bucknall Hospital, Stoke-on-Trent

Dr Christine Davey
Senior Researcher, North Yorkshire Alliance Research and Development Unit, North Yorkshire

Dr Wasim Hanif
Consultant Physician and Honorary Senior Lecturer, University Hospital Birmingham

Dr Peter Jackson
Clinical Pharmacologist, University of Sheffield

Professor Gary McVeigh
Professor of Cardiovascular Medicine, Queens University Belfast and Consultant Physician, Belfast City Hospital

Dr Eugene Milne
Deputy Medical Director, North East Strategic Health Authority, Newcastle upon Tyne

Dr Neil Myers
General Practitioner, Glasgow

Dr Richard Nakielny
Consultant Radiologist, Sheffield Teaching Hospitals Foundation Trust

Dr Katherine Payne
Health Economics Research Fellow, University of Manchester

Dr Danielle Preedy
Lay member

Dr Peter Selby
Consultant Physician, Central Manchester University Hospitals NHS Foundation Trust

Dr Surinder Sethi
Consultant in Public Health Medicine, North West Specialised Services Commissioning Team, Warrington

Professor Andrew Stevens
Chair of Appraisal Committee C, Professor of Public Health, University of Birmingham

Dr Matt Stevenson
Technical Director, School of Health and Related Research, University of Sheffield

Professor Paul Trueman
Health Economics Research Group, Brunel University

Dr Judith Wardle
Lay member

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.

Whitney Miller
Technical Lead

Helen Knight
Technical Adviser

Lori Farrar
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 NHS Centre for Reviews and Dissemination and Centre for Health Economics:

• Yang H, Epstein D, Bojke L, Craig D et al. (August 2010), Golimumab for the treatment of psoriatic arthritis. York: NHS Centre for Reviews and Dissemination and Centre for Health Economics, University of York.

B. The following organisations accepted the invitation to participate in this appraisal as consultees and commentators. 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:

• Centocor/Schering-Plough

II Professional/specialist and patient/carer groups:

• Psoriasis and Psoriatic Arthritis Alliance
• Psoriasis Association
• British Association of Dermatologists
• British Health Professionals in Rheumatology
• British Society for Rheumatology
• Primary Care Rheumatology Society
• Royal College of Nursing
• Royal College of Pathologists
• Royal College of Physicians

III Other consultees:

• Department of Health
• NHS Haringey
• NHS Havering
• Welsh Assembly Government

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

• British National Formulary
• Commissioning Support Appraisals Service
• Department of Health, Social Services and Public Safety for Northern Ireland
• NHS Quality Improvement Scotland
• Abbott (adalimumab)
• Pfizer (methotrexate, sulfasalazine)
• Sanofi-Aventis (leflunomide)
• National Institute for Health Research Health Technology Assessment Programme
• NHS Centre for Reviews & Dissemination and Centre for Health Economics – York

C. The following individuals were selected from clinical specialist and patient expert nominations from the non-manufacturer/sponsor consultees and commentators. They gave their expert personal view on golimumab for the treatment of psoriatic arthritis by attending the initial Committee discussion and providing written evidence to the Committee. They are invited to comment on the ACD.

• Eleanor Korendowych, Consultant Rheumatologist, nominated by British Society for Rheumatology – clinical specialist
• Alex Anstey, Consultant Dermatologist, nominated by British Association of Dermatologists – clinical specialist
• Philip Helliwell, nominated by British Society of Rheumatology – clinical specialist
• Jana James, nominated by Psoriasis and Psoriatic Arthritis Alliance – patient expert

D. The following individual was nominated as NHS Commissioning expert by the selected NHS trust allocated to this appraisal. She gave her NHS commissioning personal view on golimumab for the treatment of psoriatic arthritis by attending the initial Committee discussion and providing written evidence to the Committee. She is invited to comment on the ACD.

• Sue Ashwell, Chief Pharmacist, NHS Cambridgeshire selected by NHS Havering – NHS Commissioning expert

E. Representatives from the following manufacturer/sponsor attended Committee meetings. They contributed only when asked by the Committee chair to clarify specific issues and comment on factual accuracy:

• Schering-Plough