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 aspects of the recommendations that need particular consideration to ensure we avoid unlawful discrimination against any group of people on the grounds of gender, race, disability, age, sexual orientation, religion or belief?

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: 12 November 2010

Second Appraisal Committee meeting: 25 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 The Committee is minded not to recommend golimumab as a treatment option for rheumatoid arthritis in people who have had therapy with conventional disease-modifying anti-rheumatic drugs (DMARDs) only.

1.2 Golimumab is not recommended for the treatment of rheumatoid arthritis in people who have had therapy with a tumour necrosis factor (TNF) inhibitor and for whom rituximab is appropriate.

1.3 The Committee is minded not to recommend golimumab as a treatment option for rheumatoid arthritis in people who have had therapy with a TNF inhibitor and for whom rituximab is contraindicated or is withdrawn because of an adverse event.

1.4 The Committee recommends that NICE asks the manufacturer of golimumab for more information about the clinical and cost effectiveness of golimumab in the populations in 1.1 and 1.3. This information should be made available for the second Appraisal Committee meeting, and should include the following:

• incorporation of ACR70 data in the economic model
• provision of SF-36 data from the GO-FORWARD and GO-AFTER trials and a sensitivity analysis in which these data are included in the economic model using SF-6D and/or mapping approaches to EQ-5D
• data including the proportion of people who will receive 100 mg golimumab (that is, people who weigh more than 100 kg and whose disease has not responded after three or four doses) and inclusion of this proportion in the economic model
• a sensitivity analysis in which disease progression on palliative treatment is reflected as an increase in HAQ score of 0.06 per year
• cost-effectiveness results for the population in 1.3 for golimumab compared with adalimumab, etanercept, infliximab, abatacept and tocilizumab.

These data should be subject to deterministic and probabilistic sensitivity analysis.

2 The technology

2.1 Golimumab (Simponi, Schering Plough) is a human monoclonal antibody that prevents the binding of TNF to its receptors, thereby neutralising its activity. Golimumab, in combination with methotrexate, has a marketing authorisation for the treatment of moderate to severe active rheumatoid arthritis in adults when the response to disease-modifying anti-rheumatic drug (DMARD) therapy including methotrexate 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 dosage 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 rheumatoid arthritis does not show an adequate clinical response after three or four doses, the dosage 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 vial, 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 and a review of this submission by the Evidence Review Group (ERG; appendix B).

Clinical effectiveness

3.1 The submission considered people who had never received a TNF inhibitor (the DMARD-experienced population) separately from people who had had previous therapy with a TNF inhibitor (the TNF inhibitor-experienced population).

DMARD-experienced population

3.2 Two trials with DMARD-experienced participants were included in the submission – a phase III randomised controlled trial (RCT) with four groups (GO‑FORWARD) and a phase II dose-ranging trial with five groups (Kay et al. 2008). The trials investigated the efficacy and the dose effect of golimumab. The manufacturer’s submission focused on the groups who had received the licensed dose of 50 mg golimumab every 4 weeks.

3.3 GO-FORWARD was a multicentre randomised double-blind trial that compared 50 mg golimumab every 4 weeks plus methotrexate (15 mg or more every week) (n = 89) with placebo plus methotrexate (15 mg or more every week) (n = 133). The trial participants had had active rheumatoid arthritis (defined as persistent disease activity with at least four swollen joints and four tender joints) for at least 3 months and had received methotrexate for at least 3 months. The trial included a controlled phase to 24 weeks and an open-label extension to 5 years.

3.4 The primary outcome measures were the proportion of participants with an ACR20 response at 14 weeks and an improvement from baseline in the Health Assessment Questionnaire – Disability Index (HAQ-DI) score at 24 weeks. Secondary outcome measures included ACR20 response at 24 weeks, ACR50 response at 14 and 24 weeks, ACR70 response at 14 and 24 weeks, Disease Activity Score (DAS) 28 at 14 and 24 weeks and improvement from baseline HAQ-DI score at 14 weeks. Health-related quality of life was measured using SF-36.

3.5 A significantly greater proportion of participants who received 50 mg golimumab plus methotrexate had an ACR20 response at 14 weeks than participants who received placebo plus methotrexate (55.1% and 33.1% respectively; p = 0.001). Improvement in HAQ-DI score at 24 weeks was significantly greater in the 50 mg golimumab plus methotrexate group compared with the placebo plus methotrexate group (median: 0.375 and 0.125 respectively; p < 0.001).

3.6 The manufacturer also reported that for key secondary endpoints a significantly greater proportion of participants in the 50 mg golimumab plus methotrexate group had a response compared with the placebo plus methotrexate group. An ACR20 response at 24 weeks was seen in 59.6% of the participants who received 50 mg golimumab plus methotrexate compared with 27.8% of the participants who received placebo plus methotrexate (p < 0.001). More patients in the 50 mg golimumab plus methotrexate group had an ACR50 response at 24 weeks than in the placebo plus methotrexate group (37.1% and 13.5% respectively; p < 0.001). An ACR70 response at 24 weeks was seen in 20.2% of the 50 mg golimumab plus methotrexate group compared with 5.3% of the placebo plus methotrexate group (p < 0.001).

3.7 The manufacturer reported similar rates of adverse events at 16 weeks in the 50 mg golimumab plus methotrexate and the placebo plus methotrexate groups (68.5% and 60.9% respectively). The incidence of serious adverse events at 16 weeks in the 50 mg golimumab plus methotrexate group was 5.6% and in the placebo plus methotrexate group 2.3%.

3.8 The second trial (Kay et al. 2008) was a multicentre randomised double-blind study that compared 50 mg golimumab (every 4 weeks) plus methotrexate (10 mg or more every week) (n = 35) with placebo plus methotrexate (10 mg or more every week) (n = 35). The trial participants had had active rheumatoid arthritis (defined as persistent disease activity with at least six swollen joints and six tender joints) for at least 3 months and had been treated with methotrexate for at least 3 months. The primary outcome was the proportion of participants who had an ACR20 response at 16 weeks. Secondary outcomes included ACR20, 50 and 70 responses over time until 52 weeks, numeric index of the ACR response at 16 weeks and DAS28 at 16 weeks.

3.9 Primary outcome data were not presented for the 50 mg golimumab group in the manufacturer’s submission. However, they were available from a published paper which showed that an ACR20 response at 16 weeks was seen in 60.0% of the participants who received 50 mg golimumab plus methotrexate and 37.1% of the participants who received placebo plus methotrexate.

3.10 An ACR20 response at 24 weeks was seen in 74.3% of participants in the 50 mg golimumab plus methotrexate group and 45.7% of participants in the placebo plus methotrexate group. More participants in the 50 mg golimumab plus methotrexate group had an ACR50 response at 24 weeks than participants in the placebo plus methotrexate group (40.0% and 11.4% respectively). An ACR70 response at 24 weeks was seen in 20.0% of participants in the 50 mg golimumab plus methotrexate group and 5.7% of those in the placebo plus methotrexate group. The ACR20 and 50 responses for the golimumab plus methotrexate group were statistically significantly different from the placebo plus methotrexate group. However the ACR70 responses were not statistically significantly different between the treatment arms.

3.11 In the second trial the proportion of participants who experienced at least one adverse event was slightly higher in the 50 mg golimumab plus methotrexate group than in the placebo plus methotrexate group (91.9% and 85.3% respectively).

TNF inhibitor-experienced population

3.12 The manufacturer’s submission included a single phase III randomised double-blind placebo-controlled trial (GO-AFTER) for the TNF inhibitor-experienced population. The trial had three groups and the manufacturer’s submission focused on the placebo group (n = 155) and the group who received 50 mg golimumab (n = 153). The trial participants had had active rheumatoid arthritis (defined as persistent disease activity with at least four swollen joints and four tender joints) for at least 3 months and had been treated with at least one dose of a TNF inhibitor (etanercept, adalimumab or infliximab). Participants in the trial did not need to take golimumab in combination with another DMARD. Approximately 66% took golimumab in combination with methotrexate.

3.13 The primary outcome was the proportion of participants with ACR20 response at 14 weeks. The duration of follow up was 24 weeks. The secondary outcomes included ACR50, 70 and 90 at 14 weeks, ACR20, 50, 70 and 90 at 24 weeks and change from baseline in HAQ score at 24 weeks. Health-related quality of life was measured using SF-36.

3.14 A significantly higher proportion of the participants who received 50 mg golimumab had an ACR20 response at 14 weeks compared with placebo (35.3% and 18.1% respectively; p < 0.001). An ACR20 response at 24 weeks was seen in 34.0% of participants in the 50 mg golimumab group compared with 16.8% of participants in the placebo group (p < 0.001). An ACR50 response at 24 weeks was seen in more participants in the 50 mg golimumab group than in the placebo group (18.3% and 5.2% respectively; p < 0.001). An ACR70 response at 24 weeks was seen in 11.8% of participants in the 50 mg golimumab group and 3.2% of those in the placebo group (p = 0.004). Change in HAQ-DI from baseline was assessed at 24 weeks. For the 50 mg golimumab group there was a median improvement in HAQ of 0.25. For the placebo group there was no change in the median HAQ score.

3.15 No major differences in reported adverse events were evident in the GO-AFTER study at 24 weeks. The number of serious adverse events at 24 weeks was slightly lower in the 50 mg golimumab group than in the placebo group.

Mixed treatment comparison and indirect comparison

3.16 No head-to-head trials analysing the efficacy of golimumab compared with other active treatment options were available. Therefore the manufacturer searched for trials of comparator interventions and completed mixed treatment and indirect comparison analyses to estimate the relative effect of golimumab versus the comparators. The manufacturer included comparators for which there were positive NICE recommendations at the time of submission. For the DMARD-experienced population comparisons were made with placebo, adalimumab, certolizumab pegol, etanercept and infliximab and for the TNF inhibitor-experienced population comparisons were made with placebo and rituximab.

DMARD-experienced population

3.17 Twenty trials were included in the mixed treatment comparison for the DMARD-experienced population. The results from the random effects model showed that for each ACR response, golimumab was statistically significantly superior to placebo (median relative risk 2.17; 95% credibility interval 1.27 to 3.00). In comparison with adalimumab, certolizumab pegol, etanercept or infliximab there were no statistically significant differences in ACR20, ACR50 or ACR70 response rates. However, the point estimates favoured the other TNF inhibitors, except in the comparison with infliximab. For ACR20 the median relative risks and 95% credibility intervals for golimumab were 0.98 (0.55 to 1.46) compared with adalimumab, 0.72 (0.41 to 1.06) compared with certolizumab pegol, 0.93 (0.51 to 1.43) compared with etanercept and 1.05 (0.57 to 1.65) compared with infliximab. For ACR50, the median relative risks and 95% credibility intervals for golimumab were 0.90 (0.40 to 1.76) compared with adalimumab, 0.63 (0.27 to 1.31) compared with certolizumab pegol, 0.98 (0.40 to 1.99) compared with etanercept and 0.99 (0.42 to 2.04) compared with infliximab. For ACR70, the median relative risks and 95% credibility intervals for golimumab were 0.75 (0.28 to 1.86) compared with adalimumab, 0.47 (0.16 to 1.35) compared with certolizumab pegol, 0.32 (0.09 to 1.15) compared with etanercept and 1.16 (0.40 to 3.00) compared with infliximab.

3.18 Sensitivity analyses were performed for ACR20 and ACR50 responses in which the TEMPO etanercept trial was excluded because of a greater response within its placebo arm compared with other studies. The exclusion of the TEMPO trial resulted in raised relative risks for ACR20 and ACR50, indicating increased efficacy for etanercept in comparison with golimumab. However, these results were statistically significant only in the fixed effects model for the ACR20 response. Exclusion of the TEMPO trial also altered the relative estimates for golimumab in comparison with the other treatments. When golimumab was compared with certolizumab pegol, the differences were statistically significant in the fixed effects model and for ACR20 in the random effects model, with both favouring certolizumab pegol.

3.19 A mixed treatment comparison was carried out for selected safety outcomes. Golimumab was estimated to be associated with a greater number of more serious adverse events than all comparators except certolizumab pegol. However, none of the differences was statistically significant, and all were uncertain, as shown by wide credibility intervals. The estimated rate of serious infections for golimumab was similar to the rates for infliximab and etanercept, and lower than those for adalimumab and certolizumab pegol. These differences reached statistical significance for the comparison of golimumab and certolizumab pegol. However, all had wide credibility intervals. Golimumab was estimated to have fewer discontinuations because of adverse events. However, this only reached statistical significance in the comparison of golimumab with certolizumab pegol.

TNF inhibitor-experienced population

3.20 Two trials were used in the indirect comparison analyses of golimumab (GO-AFTER) and rituximab (REFLEX) for the TNF inhibitor-experienced population. In these analyses (based on the methods developed by Bucher et al. 1997), golimumab and rituximab were indirectly compared with placebo as the comparator. Although the estimates of ACR response favoured rituximab, there were no statistically significant differences between golimumab and rituximab. For ACR20 the relative risk was 0.71 (95% confidence interval [CI] 0.42 to 1.20). For ACR50 and ACR70 the corresponding figures were 0.66 (95% CI 0.25 to 1.76) and 0.30 (95% CI 0.05 to 1.66).

3.21 The indirect comparison suggested that the relative risks of serious adverse events were similar for golimumab and rituximab, although these were associated with wide confidence intervals. The relative risk estimate for serious infections was slightly lower for golimumab compared with rituximab but this difference was not statistically significant. Golimumab was associated with statistically significantly lower rates of discontinuation due to adverse events.

Comments from the Evidence Review Group

3.22 The ERG considered the clinical effectiveness review methods and results to be reasonably clearly presented, with adequate systematic searches conducted. The ERG stated that all the relevant RCTs for golimumab and the comparators appeared to have been included and the golimumab trials were of reasonable methodological quality. The ERG considered that the mixed treatment comparisons and indirect comparisons used appropriate trials to inform the networks of evidence.

3.23 The ERG commented that the populations in GO-FORWARD and Kay et al. (2008) were generally representative of the UK population with rheumatoid arthritis, although in the GO-FORWARD trial the proportion of people who received glucocorticoid therapy was higher than the UK average. Similarly, steroid use in the GO-AFTER population may have been higher than the average in the UK population with rheumatoid arthritis.

3.24 The ERG noted that the evidence did not include some of the comparators listed in the final scope, and that health-related quality of life and fatigue were not adequately addressed in the clinical evidence section of the submission.

3.25 The ERG noted inconsistencies between the data presented for ACR20 and ACR50 responses in Kay et al. (2008). Different values were presented in the original study publication (week 16) and in the efficacy meta-analyses in the manufacturer’s submission. The ERG was unclear how the original efficacy data from Kay et al. (2008) have been derived and handled in the meta-analyses.

3.26 The ERG commented on the complexities involved in comparing data across the interventions in the mixed treatment and indirect comparison analyses because response rates can be influenced by changes in patient populations over time. It noted that the certolizumab pegol trials had a higher ratio of ACR responses on active treatment compared with placebo, and these trials may not be comparable with the trials of other TNF inhibitors. The ERG suggested that one factor contributing to the results observed in the certolizumab pegol trials may be that participants stopped receiving treatment at 12 weeks if there was no response, and thus slower responses in the placebo group were not detected.

3.27 The ERG noted that the manufacturer’s original submission did not include any evidence of the effect of golimumab on the radiological progression of rheumatoid arthritis. This outcome measure had been specified in the scope of this appraisal. Evidence on radiological progression was subsequently provided in the form of a research abstract but was marked commercial in confidence. The ERG also noted that SF-36 data were not provided in the manufacturer’s submission or following a clarification request.

Cost effectiveness

3.28 The manufacturer submitted two decision-analytic Markov models, each with a life time horizon. Both models evaluated golimumab as part of a sequence of treatments: one evaluated golimumab in a DMARD-experienced population (comparing golimumab with TNF inhibitors and methotrexate in people whose disease had had an inadequate response to two DMARDs) and the other evaluated golimumab in a TNF inhibitor-experienced population (comparing golimumab with rituximab and methotrexate in people whose disease had had an inadequate response to two DMARDs and a TNF inhibitor). All treatments were given in combination with methotrexate. Methotrexate monotherapy was included as a comparator in each model because it represented the placebo arm in the indirect comparison and mixed treatment analysis. The manufacturer did not include technologies being appraised by NICE at the time of the manufacturer’s submission (tocilizumab, abatacept and the use of etanercept, infliximab and adalimumab after the failure of a first TNF inhibitor) as comparators.

3.29 On starting treatment people could have either an ACR20 response, ACR50 response or no response. The probability of response for golimumab and methotrexate monotherapy was derived from the GO-FORWARD and GO-AFTER trials. To derive the efficacy for the other comparators the response for golimumab was adjusted using the relative effects estimated from the mixed treatment and indirect comparison analyses. For each ACR response criterion the corresponding change in HAQ-DI was calculated based on data from the GO-FORWARD and GO-AFTER clinical trials. The HAQ-DI was in turn mapped to EQ-5D using an equation used in NICE technology appraisal guidance 130 (‘Adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis’). People progressed to the next treatment if they did not have at least an ACR20 response at 6 months, or if they stopped treatment because of a lack of efficacy or an adverse event. In both models, people progressed to leflunomide, gold, azathioprine, ciclosporin and then palliative care.

3.30 At the start of the models people were aged 50 years in the DMARD-experienced population and 54 years in the TNF inhibitor‑experienced population. HAQ scores for people entering the model were derived from the baseline characteristics of the GO‑FORWARD and GO-AFTER trials: 1.41 and 1.58 respectively. While people were receiving a treatment, it was assumed that their disease severity increased over time. This was modelled with an annual worsening of HAQ score (that is, a HAQ progression rate). The HAQ progression rate was 0.045 for a person being treated with DMARDs, 0.00 for TNF inhibitors, 0.045 for rituximab and 0.09 for palliative care.

3.31 Costs relating to treatment, administration, monitoring and hospitalisation were included in the economic models using 2006 reference costs and 2008 unit costs. Following a clarification request, the manufacturer incorporated 2008 reference costs and 2009 unit costs. It was assumed that a course of rituximab was given once every 6 months. Joint replacement was not included in the model. Costs and quality-adjusted life years (QALYs) were discounted at a rate of 3.5%.

3.32 The impact of parameter uncertainty was estimated in a probabilistic sensitivity analysis. Scenario analyses were run on key parameters. An incremental analysis was performed within each population, but not between the two populations.

3.33 The results from the economic model were presented incrementally with all treatments compared with each other, and for each treatment individually in comparison with methotrexate. The deterministic results for the DMARD-experienced population showed that the incremental cost-effectiveness ratios (ICERs) were £31,464 (£34,030 additional costs and 1.082 additional QALYs) and £31,444 (£37,702 additional costs and 1.199 additional QALYs) per QALY gained for infliximab and certolizumab pegol respectively in comparison with methotrexate, and £25,346 (£31,878 additional costs and 1.258 additional QALYs) per QALY gained for golimumab in comparison with methotrexate. The ICERs for adalimumab and etanercept in comparison with methotrexate were £25,353 (£31,006 additional costs and 1.223 additional QALYs) and £24,514 (£38,339 additional costs and 1.564 additional QALYs) per QALY gained respectively. The incremental analysis showed that infliximab and certolizumab pegol are both dominated by golimumab because golimumab is more effective and less costly. However, adalimumab and golimumab are both extendedly dominated by etanercept. Etanercept generates the most QALYs of any strategy, at a lower cost per QALY ratio (£24,514 per QALY gained in comparison with methotrexate).

3.34 For the DMARD-experienced population, the cost-effectiveness results based on the mean costs and QALYs from the probabilistic sensitivity analysis are consistent with the deterministic analysis. At £20,000 per QALY gained, golimumab is the most cost-effective intervention in 5% of probabilistic sensitivity analysis samples, methotrexate is the most cost effective in 56% and etanercept is the most cost effective in 17%. At £30,000 per QALY gained, golimumab is the most cost-effective intervention in 8% of samples, etanercept is the most cost effective in 32% and methotrexate is the most cost effective in 24%.

3.35 The results for the deterministic base-case analysis of golimumab in a TNF inhibitor-experienced population show that rituximab is dominated by golimumab because golimumab is less costly and more effective (£31 fewer costs and 0.189 additional QALYs). Golimumab compared with methotrexate has an ICER of £28,286 (£16,502 additional costs and 0.583 additional QALYs) per QALY gained whereas rituximab compared with methotrexate has an ICER of £41,935 (£16,533 additional costs and 0.394 additional QALYs) per QALY gained.

3.36 The results from the probabilistic sensitivity analysis show that in the TNF inhibitor-experienced population, rituximab is extendedly dominated by golimumab based on the mean costs and QALYs. Golimumab has an ICER of £29,100 per QALY gained compared with methotrexate. At £20,000 per QALY gained, golimumab is the most cost effective in 5% of probabilistic sensitivity analysis samples and methotrexate is the most cost effective in 90%. At £30,000 per QALY gained, golimumab and methotrexate have similar probability of being most cost effective (46% and 44% respectively).

3.37 The manufacturer undertook a scenario analysis to examine the impact on the ICER when alternative assumptions are made about what happens when a person withdraws from treatment. The base-case analysis assumes that on stopping treatment the loss of effect is equal to the initial gain. The manufacturer undertook a sensitivity analysis in which the loss of effect on stopping treatment was equivalent to a return to the population natural history level. This assumption suggests that there are no long-term benefits of treatment with DMARDs. In the DMARD-experienced population, the incremental analysis shows that infliximab and etanercept are dominated strategies, and golimumab and adalimumab are extendedly dominated by certolizumab pegol. The ICERs for all the treatments compared with methotrexate increase to above £30,000 per QALY gained. In the TNF inhibitor-experienced population rituximab is dominated by golimumab but the ICER for golimumab compared with methotrexate rises to over £42,000 per QALY gained.

Comments from the Evidence Review Group

3.38 The ERG noted that the model results (total costs and QALYs, time in states, HAQ scores and incremental costs and QALYS) appeared plausible given the parameter inputs. It commented that the model was generally of a high quality. The ERG identified some programming errors in the model that it corrected. However, these errors did not change the conclusion in the manufacturer’s submission that compared with methotrexate, golimumab has an ICER that is comparable to other TNF inhibitors but golimumab is never the most cost-effective TNF inhibitor treatment.

3.39 The ERG considered that it would have been appropriate to include ACR70 response data in the model so that all the available clinical evidence is used to evaluate golimumab. The manufacturer justified the exclusion of these data by stating that there was not a statistically significant difference between golimumab and the comparators and that incorporating this outcome would only add an element of uncertainty to the model inputs. The ERG noted that this reason was not justified because there was no statistically significant difference in the ACR20 and ACR50 response data for golimumab and the comparators.

3.40 The ERG stated that for the TNF inhibitor-experienced population there was considerable uncertainty in the HAQ progression rate estimates and the re-administration frequency of rituximab. The ERG commented that the manufacturer assumed a HAQ progression rate equal to the rate for DMARDs rather than for TNF inhibitors, which may underestimate the benefit of rituximab. The ERG also commented that the model assumes that rituximab is re-administered every 6 months but it considered that 9 months would be more reflective of current clinical practice.

3.41 The ERG undertook a number of exploratory analyses to address some of its concerns. The original model used 2006 reference case costs and 2008 unit costs. However, after clarification, the manufacturer incorporated 2008 reference costs and 2009 unit costs. The ERG used the updated unit and reference costs and they found that they had little impact on the incremental costs for the different treatments in the DMARD-experienced population, and so the resulting ICERs did not change substantially.

3.42 The ERG identified an error in the model for infliximab in the DMARD-experienced population, which resulted in a cost being allocated when a person dies. There was also an error in the modelling of HAQ decrements for certolizumab pegol. The method used was different from that used for comparator drugs; however, there was no difference in the methods reported in the submission. Because each of these errors only affects a single comparator, both were corrected. Correcting the infliximab costs reduces the total cost of infliximab treatment, and it was no longer dominated by adalimumab. Correcting the HAQ decrements in the certolizumab pegol arm means that it is the optimal intervention instead of etanercept.

3.43 The economic model used the response rates from the GO-FOWARD trial to estimate the probability of ACR response and the probability of stopping treatment because of an adverse event at 6 months in the golimumab and placebo arms. However, the model used the mixed treatment comparison to estimate the rates of these events for the comparators; this approach excludes the evidence from Kay et al. (2008). In the exploratory analysis the ERG used the mixed treatment comparison, incorporating the evidence from Kay et al. (2008), to estimate the probability of these outcomes in the placebo group, which is used to populate the methotrexate arm of the economic model. Using the mixed treatment comparison rather than the GO-FORWARD study alone to inform the golimumab versus methotrexate comparison did not substantially alter the results.

3.44 The cumulative impact of the changes described in sections 3.38–3.40 reduced all the ICERs for all TNF inhibitors in comparison with methotrexate. The ICERs for infliximab and certolizumab pegol in comparison with methotrexate were £24,137 and £20,800 per QALY gained. The ICER for golimumab compared with methotrexate was £24,794 per QALY gained. The ICERs for adalimumab and etanercept in comparison with methotrexate were £24,800 and £23,990 per QALY gained. The incremental analysis suggested that certolizumab pegol including its Patient Access Scheme is the optimal treatment strategy, dominating etanercept and extendedly dominating golimumab, adalimumab and infliximab.

3.45 For the TNF inhibitor-experienced population the costs were updated as described for the DMARD-experienced population. The ERG also amended the model so that rituximab has a zero HAQ progression rate (equal to that of TNF inhibitors) rather than the 0.045 that was assumed in the base-case analysis. The ERG also amended the model so that each person received two infusions in the first 6 months and then one infusion every 9 months.

3.46 The cumulative impact of the changes described in 3.42 and 3.44 reduced the ICERs for golimumab and rituximab in comparison with methotrexate (£28,115 and £10,088 per QALY gained, respectively). The incremental analysis showed that rituximab dominated golimumab.

3.47 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 rheumatoid 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 discussed the clinical management of rheumatoid arthritis. The clinical specialists explained that ideally DMARD therapy should be started as early as possible after diagnosis to reduce joint damage, and that for the majority of people therapy with conventional DMARDs is sufficient. However, they explained that for a small proportion of people conventional DMARDs do not adequately control disease, and for this group of people biological DMARDs such as TNF inhibitors are needed. The Committee heard from the patient experts and clinical specialists that it is not possible to predict which TNF inhibitor will produce the best effect for each person. Therefore patients prefer to have a choice of treatments and another treatment option would be welcome. The clinical specialists explained that they discuss with patients the different options for treatment and the choice of treatment is a joint decision between the clinician and the patient. The Committee heard from the clinical specialists and the patient experts that golimumab is administered once per month and this may be an advantage for people who have difficulty injecting themselves because of the joint damage caused by the disease and for people who have a fear of injections. The patient experts said that once-monthly administration may be more convenient if they want to travel, as trips could more easily be planned around once-a-month administration. However, the Committee heard from the clinical specialists that the length of the half-life of golimumab may make it difficult if a person needs to stop treatment quickly, for example because of unplanned surgery, since it would take time for the treatment effects (on immunity, for example) to wear off. The Committee understood that the provision of a range of treatments was valued by clinicians and patients, and that golimumab may provide some additional benefits because of its once-monthly administration.

Clinical effectiveness

4.3 The Committee considered the evidence on the clinical effectiveness of golimumab in combination with methotrexate and noted that the manufacturer’s submission considered golimumab at two positions in the treatment pathway – after treatment with conventional DMARDs only, and after therapy with both conventional DMARDs and a TNF inhibitor. The Committee heard from clinical specialists how golimumab would fit into the current treatment pathway. It heard that golimumab may be used either as a first TNF inhibitor therapy in people whose disease has not responded to conventional DMARD therapy, or as a second TNF inhibitor therapy in people who have had previous therapy with a TNF inhibitor. The Committee concluded that these two positions in the treatment pathway as included in the manufacturer’s submission were appropriate to be considered in this appraisal.

4.4 For people who had previously received only conventional DMARDs, the Committee considered the evidence from the two placebo-controlled trials of golimumab in combination with methotrexate. It noted that golimumab in combination with methotrexate had greater clinical effectiveness than placebo in combination with methotrexate. The Committee then discussed the mixed treatment comparison presented by the manufacturer in the absence of head‑to-head trials comparing the efficacy of golimumab and the other available TNF inhibitors. It accepted that the mixed treatment comparison showed that there were no significant differences in ACR20, ACR50 and ACR70 response rates between golimumab and the other TNF inhibitors. The Committee noted that the credibility intervals around the estimates were wide, indicating that there was a high degree of uncertainty about the effectiveness point estimates. The Committee heard from clinical specialists that they considered that the different TNF inhibitors have broadly similar efficacy but that they do have some differences depending on the type of biological agent they are. The Committee concluded that golimumab had been demonstrated to be more effective than placebo but had not been shown to be more effective than the other TNF inhibitors.

4.5 The Committee considered the evidence for the clinical effectiveness of golimumab compared with placebo for the people who had had previous treatment with both conventional DMARDs and a TNF inhibitor. It noted that there was a single trial (GO‑AFTER) comparing golimumab with placebo and this trial showed that golimumab had greater clinical effectiveness than placebo. The Committee discussed the indirect comparison of golimumab and rituximab performed in the absence of head-to-head trials comparing the efficacy of golimumab and rituximab. It agreed that rituximab was an appropriate comparator for this population, although it was aware that since the manufacturer’s submission NICE has published further guidance recommending the use of tocilizumab, abatacept and a second TNF inhibitor in certain people who have had previous treatment with a TNF inhibitor. The Committee concluded that although the point estimates favoured rituximab, the indirect comparison did not demonstrate any statistically significant differences in clinical efficacy between golimumab and rituximab.

4.6 The Committee discussed the data on health-related quality of life in the manufacturer’s submission. It expressed concerns regarding the lack of data on quality of life in the clinical effectiveness comparisons and noted that SF-36 data had been collected in both the GO-FORWARD and GO-AFTER trials, but not included in the submission. It agreed that the inclusion of these data would have helped assess the impact on quality of life of golimumab. The Committee was aware that SF-36 data had been requested by the ERG, but had not been provided by the manufacturer. It concluded that these data should again be requested from the manufacturer.

4.7 The Committee discussed the adverse events seen in the golimumab RCTs and the results from the mixed treatment comparison and the indirect comparison of golimumab and the comparators in both populations. It noted that the data from the mixed treatment and indirect comparisons suggested few statistically significant differences between the treatments but that these were associated with considerable uncertainty. It heard from the clinical specialists that there are no long-term adverse event data for golimumab but that they expected the adverse event profile of golimumab to be no different from that of other TNF inhibitors. It suggested that since golimumab is administered once a month, there might be fewer adverse events compared with other TNF inhibitors as a result of the reduced frequency of administration. The Committee concluded that there was uncertainty surrounding the adverse event profile of golimumab, particularly in the absence of long-term data, but that golimumab’s adverse event profile had not been shown to be different from that of other TNF inhibitors.

Cost effectiveness

4.8 The Committee considered the economic model that evaluated golimumab as part of a sequence of treatments in people who had had previous treatment with conventional DMARDs only and who had not had a previous TNF inhibitor. It noted that, on the whole, the model had similar assumptions to other models submitted in previous appraisals of TNF inhibitors in rheumatoid arthritis but that there were some differences from the other models. For example ACR70 response data, rates of disease progression while on treatment and the methods for deriving estimates of utility. The Committee considered these to be key factors in determining the cost effectiveness of golimumab.

4.9 The Committee discussed the omission of ACR70 response data in the model. The Committee heard from the ERG that the exclusion of ACR70 response rate meant that the model did not make use of all available data and that since the point estimates for the ACR70 response tended to favour the comparators, the ERG considered that the omission of ACR70 response data from the model would favour golimumab. The Committee discussed the importance of ACR70 response rates in clinical management and heard from the clinical specialists that because the aim of treatment is to reduce disease activity as much as possible they prefer to see an ACR70 response as an indication of the degree of therapeutic effect. The Committee heard from patient experts that they agreed that an ACR70 response was important. However, the patient experts also considered that ACR20 and ACR50 would provide benefits to patients. The Committee concluded that the omission of ACR70 response rates from the model meant that the model failed to fully characterise the comparison of treatment benefit and was a significant limitation in considering the cost effectiveness of golimumab. For this reason, the Committee recommended that further analyses should be requested from the manufacturer that incorporates ACR70 response rates in the economic model.

4.10 The Committee considered the utility estimates incorporated in the model, and noted that the utility formula was derived from the ACR response, which was converted to a change in HAQ score and then mapped to EQ-5D. The Committee recognised that a similar approach to mapping had been used in previous appraisals. However, it discussed how this was different from the NICE reference case, which recommends inclusion of directly collected utility data. The Committee noted that SF-36 was included as an outcome in both the GO-FORWARD and GO-AFTER trials. The Committee agreed that a cost-effectiveness analysis that had used these data would have been valuable in determining the face validity of the mapping approach used. The Committee concluded that further analyses of the SF-36 data and their inclusion in the economic model would have enabled a more robust consideration of the cost effectiveness of golimumab.

4.11 The Committee discussed the 100 mg dose which is indicated for patients who weigh more than 100 kg and whose rheumatoid arthritis has not responded after three or four doses of golimumab. It noted that evidence for the clinical and cost effectiveness of this dose was not included in the submission. The Committee understood that even though the proportion of people who received this dose might be quite small, if the acquisition cost was included in the model the ICER for golimumab would be expected to be higher than that estimated in the base-case presented by the manufacturer. The Committee concluded that the costs of the 100 mg golimumab dose should have been considered in the economic model. Therefore the Committee requested that data about the proportion of people who will receive the 100 mg golimumab dose should be provided and incorporated in the economic model.

4.12 The Committee discussed the progression of disease while on treatment with TNF inhibitors for the population of people who had had therapy with conventional DMARDs only. The Committee noted that the economic analysis from the manufacturer had assumed that there was no progression of disease while on treatment with a TNF inhibitor, but that there was progression while on treatment with conventional DMARDs and palliative treatment. The Committee considered that an assumption of no progression while on treatment with a TNF inhibitor could be over-optimistic. However, it heard from clinical specialists that while no progression on treatment may be over-optimistic, findings from long-term studies suggest that it was a reasonable assumption for those patients that respond to treatment. The Committee recognised that similar assumptions had been made in other appraisals of TNF inhibitor treatments for rheumatoid arthritis. However, it noted that a higher rate of progression while on palliative treatment (that is, a worsening of HAQ score of 0.09 a year) had been assumed in this appraisal than had previously been used (that is, a worsening of HAQ score of 0.06 a year). The Committee was persuaded to consider the estimate of cost effectiveness that included no progression while on treatment with a TNF inhibitor. However, it noted that this may not fully reflect the progress of disease. Further it concluded that a rate of progression for palliative treatment consistent with previous appraisals should be included as a sensitivity analysis in the assessment of cost effectiveness. The Committee agreed that a sensitivity analysis in which disease progression on palliative treatment is reflected as an increase in HAQ score of 0.06 per year should be requested from the manufacturer.

4.13 The Committee considered the results of the manufacturer’s base‑case analysis for the group of people who had had previous treatment with conventional DMARDs only, which compared golimumab with the other TNF inhibitors and with methotrexate. It noted that a small number of amendments had been made by the ERG and that the combined impact of these changes was to reduce the estimates of cost effectiveness for golimumab and the other TNF inhibitors in the manufacturer’s submission from a range of £25,000 to £30,000 per QALY gained to £20,000 to £25,000 per QALY gained in comparison with methotrexate. The Committee accepted these amendments as appropriate. However, it discussed the omission of the data on ACR70 response and considered that this may have led to overestimation of the QALY gain for golimumab in comparison with the other TNF inhibitors. It further considered that the omission of the 100 mg dose may have underestimated the costs of golimumab. The Committee considered that it is not possible to conclude that golimumab is a cost-effective use of NHS resources and that the economic model for the group of people who had had previous treatment with conventional DMARDs only should be revised to include ACR70 response data and costs for the 100 mg golimumab dose. The Committee concluded that a sensitivity analysis in which disease progression on palliative treatment is reflected as an increase in HAQ score of 0.06 per year should be requested from the manufacturer. The Committee also concluded that the SF-36 data from the GO-FORWARD clinical trial should be provided to enable a more robust consideration of the HAQ-utility mapping.

4.14 The Committee considered the economic model for the group of people who had had previous treatment with both conventional DMARDs and a TNF inhibitor. It noted that the model assumed that rituximab is re-administered every 6 months and heard from the ERG that they considered that re-administration of rituximab every 9 months would be more reflective of clinical practice. The Committee further heard from clinical specialists that for people responding to rituximab treatment the re-treatment intervals would be greater than 6 months. The Committed heard from the ERG about the costs for the first year of rituximab treatment that were included in the model. For the first 6 months of treatment, 1.5 courses of rituximab were included and 1 course of rituximab was included for the second 6 months. The Committee heard that it was unclear why a greater number of courses were required in the first 6 months than in subsequent 6-month periods. The Committee concluded that the rituximab costs had been overestimated in the economic model, and that a re-treatment interval of 9 months was more appropriate.

4.15 The Committee discussed the progression of disease while on treatment for people who have had previous treatment with conventional DMARDs and a TNF inhibitor. It noted that the manufacturer had assumed that the TNF inhibitors all stopped progression of disease while on treatment, but that for rituximab it was assumed that the disease continued to worsen while on treatment by an increase of 0.045 per year in HAQ score. It noted that this was the same as the rate used for conventional DMARDs. The Committee heard from the ERG and clinical specialists that this underestimates the benefits of rituximab, and that a more appropriate assumption would have been to assume that, for people whose disease responds to treatment, rituximab reduces the progression of disease to the same extent as the TNF inhibitors. The Committee was not persuaded that it is appropriate to assume a differential rate of underlying progression of disease between rituximab and golimumab, and that this assumption had overestimated the cost-effectiveness of golimumab compared with rituximab.

4.16 The Committee discussed the results of the manufacturer’s base‑case analysis and the ERG’s exploratory analyses for the group of people who had had previous treatment with both conventional DMARDs and a TNF inhibitor, which compared golimumab and rituximab. It agreed that the ERG amendments to increase the time between treatment intervals for rituximab and remove the assumption of a differential rate of underlying progression of disease were appropriate. The Committee noted that when these assumptions were changed the estimate of cost effectiveness went from golimumab being associated with fewer costs and more QALYs than rituximab, to rituximab being associated with fewer costs and more QALYs than golimumab. The Committee therefore concluded that golimumab would not be a cost-effective use of NHS resources in people who have had previous treatment with conventional DMARDs and a TNF inhibitor and for whom rituximab is an appropriate treatment option.

4.17 The Committee recognised that in August 2010 NICE published guidance recommending the TNF inhibitors adalimumab, etanercept, infliximab, as well as abatacept and tocilizumab for people with rheumatoid arthritis who are unable to have rituximab therapy because of contraindications or if rituximab is withdrawn because of an adverse event (‘Adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a TNF inhibitor’ [NICE technology appraisal guidance 195] and ‘Tocilizumab for the treatment of rheumatoid arthritis’ [NICE technology appraisal guidance 198]). The Committee agreed that it was appropriate to consider this group of people and the treatment options now available for these patients. The Committee noted that the ICER for golimumab in comparison with methotrexate is £28,000 per QALY gained. The Committee considered that this is likely to be an underestimate because of the omission of ACR70 response data and the costs of the 100 mg dose. However, mindful of NICE guidance on the other TNF inhibitors, it agreed that this additional evidence should be requested from the manufacturer. The Committee concluded that it could not recommend the use of golimumab as an appropriate use of NHS resources and that the manufacturer should be requested to revise the economic model for the group of people unable to have rituximab therapy, to make appropriate comparisons with golimumab and other available treatment options and to include ACR70 response data, costs for the 100 mg golimumab dose and the disease progression reflected as an increase in HAQ of 0.06 a year for palliative care. In addition, the SF-36 data from the GO-AFTER clinical trial should be provided to enable a more robust consideration of the HAQ-utility mapping.

TAXXX		Golimumab for the treatment of rheumatoid arthritis after the failure of previous disease-modifying anti-rheumatic drugs	Section
Key conclusions
The Committee is minded not to recommend golimumab as a treatment option for rheumatoid arthritis in people who have had therapy with conventional DMARDs only, and who have had therapy with a TNF inhibitor and for whom rituximab is contraindicated or is withdrawn because of an adverse event. The Committee concluded that it could not recommend the use of golimumab as an appropriate use of NHS resources for the above two populations because it had not yet received sufficient information related to the inclusion of ACR70 response and SF-36 data, alternative assumptions for disease progression while on palliative treatment, costs for the 100 mg golimumab dose and comparisons with other comparators for the population of people for whom rituximab is contraindicated or is withdrawn because of an adverse event. The Committee recommends that this information should be requested from the manufacturer of golimumab Golimumab is not recommended for the treatment of rheumatoid arthritis in people who have had therapy with a TNF inhibitor and for whom rituximab is appropriate. The reason for this recommendation is that golimumab was associated with greater costs and fewer QALYs than rituximab.			1.1 1.3 1.4 1.2
Current practice
Clinical need of patients including the availability of alternative treatments	The clinical specialists explained that ideally DMARD therapy should be started as early as possible after diagnosis to reduce joint damage. For the majority of people therapy with conventional DMARDs is sufficient. However, for a small proportion of people conventional DMARDs do not adequately control disease, and for this group of people biological DMARDs such as TNF inhibitors are needed. It is not possible to predict which TNF inhibitor will produce the best effect for each person. Therefore clinicians and patients prefer a choice of treatments and another treatment option would be welcome.		4.2
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?	Golimumab is administered once per month and this may be an advantage for people who have difficulty injecting themselves because of the joint damage caused by the disease and for people who have a fear of injections. Once-monthly administration may be more convenient for people who travel.		4.2
What is the position of the treatment in the pathway of care for the condition?	Both the marketing authorisation and clinician opinion indicates that golimumab may be used either as first TNF inhibitor therapy in people whose disease has not responded to conventional DMARD therapy, or as second TNF inhibitor therapy in people who have had previous therapy with a TNF inhibitor.		4.3
Adverse effects	There is uncertainty about the adverse event profile of golimumab in the absence of long-term data. However, the clinical specialists expected the adverse event profile of golimumab to be no different from that of other TNF inhibitors.		4.7
Evidence for clinical effectiveness
Availability, nature and quality of evidence	The manufacturer’s submission considered golimumab at two positions in the treatment pathway – after treatment with conventional DMARDs and not a TNF inhibitor, and after therapy with both conventional DMARDs and a TNF inhibitor. For people who had previously received only conventional DMARDs, there were two clinical trials but there were no head-to-head trials between golimumab and other available TNF inhibitors. As a result, the manufacturer had conducted a mixed treatment comparison and an indirect comparison. For the people who had had previous treatment with both conventional DMARDs and a TNF inhibitor, there was a single trial comparing golimumab with placebo. In the absence of head-to-head trials the manufacturer carried out an indirect comparison of golimumab and rituximab.		4.3 4.4 4.5
Relevance to general clinical practice in the NHS	The relevance of the evidence to the UK population in clinical practice was not identified as an issue.
Uncertainties generated by the evidence	For both populations, there were no statistically significant differences in ACR20, ACR50 and ACR70 response rates between golimumab and the active comparators in the mixed treatment and indirect comparisons. However, the credibility intervals around the point estimates were wide, indicating uncertainty.		4.4
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?	N/A
Estimate of the size of the clinical effectiveness including strength of supporting evidence	The Committee concluded that for people who had previously received only conventional DMARDs golimumab had been demonstrated to be more effective than placebo but had not been shown to be more effective than the other TNF inhibitors. For people who had previously received both conventional DMARDs and a TNF inhibitor, the Committee considered that golimumab had greater clinical effectiveness than placebo. It noted that the point estimates for the comparison of rituximab and golimumab favoured rituximab but that there were no statistically significant differences in clinical efficacy between golimumab and rituximab		4.4 4.5
Evidence for cost effectiveness
Availability and nature of evidence	The economic model evaluated golimumab as part of a sequence of treatments. One model evaluated golimumab in people who had had previous treatment with conventional DMARDs only, and the other in people who had had treatment with both conventional DMARDs and a TNF inhibitor.		4.8
Uncertainties around and plausibility of assumptions and inputs in the economic model	The Committee concluded that the omission of ACR70 response rates from the model meant that the model failed to fully characterise the comparison of treatment benefit and was a significant limitation in considering the cost effectiveness of golimumab. The Committee concluded that a sensitivity analysis in which disease progression on palliative treatment is reflected as an increase in HAQ score of 0.06 per year should be requested from the manufacturer. It also concluded that further analyses of the SF-36 data and their inclusion in the economic model would have enabled a more robust consideration of the cost effectiveness of golimumab. The Committee concluded that the omission of the costs of the 100 mg golimumab dose may have underestimated the costs of golimumab. The Committee concluded that the rituximab costs had been overestimated in the economic model, and that a re-treatment interval of 9 months was more appropriate. The Committee was not persuaded that it is appropriate to assume a differential rate of underlying progression of disease between rituximab and golimumab.		4.9 4.12 4.10 4.11 4.14 4.15
Incorporation of health-related quality of life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?	The Committee considered the utility estimates incorporated in the model, and noted that the utility formula was derived from the ACR response, which was converted to a change in HAQ score and then mapped to EQ-5D. The Committee noted that SF-36 was included as an outcome in both the GO-FORWARD and GO-AFTER trials. The Committee agreed that a cost-effectiveness analysis that had used these data would have been valuable in determining the face validity of the mapping approach used.		4.10
Are there specific groups of people for whom the technology is particularly cost effective?	N/A
Most likely cost-effectiveness estimate (given as an ICER)	The Committee noted that following a small number of amendments made by the ERG, the estimates of cost effectiveness for golimumab and the other TNF inhibitors for people who had previously received conventional DMARDs only ranged from £20,000 to £25,000 per QALY gained in comparison with methotrexate. For the group of people who had had previous treatment with both conventional DMARDs and a TNF inhibitor and for whom rituximab is contraindicated or withdrawn because of an adverse event, the ICER for golimumab in comparison with methotrexate was £28,000 per QALY gained. However, the Committee was concerned that these ICERs were likely to be underestimates because of the omission of ACR70 response data and the costs of the 100 mg dose. For the group of people who had had both conventional DMARDs and a TNF inhibitor, and for whom rituximab is appropriate, the Committee considered the amendments made by the ERG which included its preferred assumptions about disease progression and the rituximab re-treatment interval, and noted that that rituximab was associated with fewer costs and more QALYs than golimumab.		4.13 4.17 4.16
Additional factors taken into account
Patient access schemes (Pharmaceutical Price Regulation Scheme [PPRS])	No patient access scheme was submitted for the technology being appraised.
End-of-life considerations	The supplementary advice was not relevant to this appraisal.
Equalities considerations, social value judgements	No equalities issues were raised in the appraisal.

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 Related NICE guidance

Published

• Tocilizumab for the treatment of rheumatoid arthritis. NICE technology appraisal guidance 198 (2010). Available from www.nice.org.uk/guidance/TA198
• Adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a TNF inhibitor. NICE technology appraisal guidance 195 (2010). Available from www.nice.org.uk/guidance/TA195
• Certolizumab pegol for the treatment of rheumatoid arthritis in adults. NICE technology appraisal guidance 186 (2010). Available from www.nice.org.uk/guidance/TA186
• Rheumatoid arthritis: the management of rheumatoid arthritis in adults. NICE clinical guideline 79 (2009). Available from www.nice.org.uk/guidance/CG79
• Adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis. NICE technology appraisal guidance 130 (2007). Available from www.nice.org.uk/guidance/TA130

 

7 Proposed date for review of guidance

7.1 NICE proposes that the guidance on this technology is considered for review together with the review of NICE technology appraisal guidance 130 and 186 in 2011. NICE welcomes comment on this proposal. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.

Peter Clark
Chair, Appraisal Committee
October 2010

Appendix A: Appraisal Committee members, guideline representatives 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.

Professor Darren Ashcroft

Professor of Pharmacoepidemiology, School of Pharmacy and Pharmaceutical Sciences, University of Manchester

Dr Matthew Bradley

Value Demonstration Director, AstraZeneca

Dr Brian Buckley

Lay member

Professor Usha Chakravarthy

Professor of Ophthalmology and Vision Sciences, The Queen’s University of Belfast

Professor Peter Clark

Consultant Medical Oncologist, Clatterbridge Centre for Oncology

Dr Ian Davidson

Lecturer in Rehabilitation, University of Manchester

Professor Simon Dixon

Senior Lecturer in Health Economics, University of Sheffield

Dr Martin Duerden

Medical Director, Conwy Local Health Board

Dr Alexander Dyker

Consultant Physician, Wolfson Unit of Clinical Pharmacology

Dr Jon Fear

Consultant in Public Health Medicine, Head of Healthcare Effectiveness NHS Leeds

Paula Ghaneh

Senior Lecturer and Honorary Consultant, University of Liverpool

Susan Griffin

Research Fellow, University of York

Professor Carol Haigh

Professor in Nursing, Manchester Metropolitan University

Alison Hawdale

Lay Member

Professor John Hutton

Professor of Health Economics, University of York

Professor Peter Jones

Pro Vice Chancellor for Research & Enterprise, Keele University
Professor of Statistics, Keele University

Dr Steven Julious

Senior Lecturer in Medical Statistics, University of Sheffield

Dr Vincent Kirkbride

Consultant Neonatologist, Regional Neonatal Intensive Care Unit, Sheffield

Dr Rachel Lewis

Doctoral Researcher

Professor Jonathan Michaels

Professor of Vascular Surgery, University of Sheffield

Dr John Radford

Director of Public Health, Rotherham Primary Care Trust

Dr Phillip Rutledge

GP and Consultant in Medicines Management, NHS Lothian

Dr Brian Shine

Consultant Chemical Pathologist, John Radcliffe Hospital

Paddy Storrie

Lay Member

Dr Lok Yap

Consultant in Acute Medicine & Clinical Pharmacology, Whittington Hospitals NHS Trust

B Guideline representatives

The following individual, representing the Guideline Development Group responsible for developing NICE’s clinical guideline related to this topic, was invited to attend the meeting to observe and to contribute as an adviser to the Committee.

• Dr Chris Deighton, Rheumatoid Arthritis Management Guideline Development Group

C 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.

Sally Doss

Technical Lead

Zoe Garrett

Technical Adviser

Kate Moore

Project Manager

Appendix B: Sources of evidence considered by the Committee

A The Evidence Review Group (ERG) report for this appraisal was prepared by the School of Health and Related Research (ScHARR), University of Sheffield:

• Jackson R et al. Golimumab for the treatment of rheumatoid arthritis after failure of previous disease-modifying antirheumatic drugs: a single technology appraisal, September 2010

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:

• Schering Plough (part of MSD)

II Professional/specialist and patient/carer groups:

• National Rheumatoid Arthritis Society
• 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
• Northumberland Care Trust
• Torbay Care Trust
• Welsh Assembly Government

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

• Commissioning Support Appraisals Service
• NHS Quality Improvement Scotland
• Abbott Laboratories (adalimumab)
• AstraZeneca UK
• Bristol Myers Squibb
• Pfizer
• Roche Products
• Sanofi Aventis
• MSD
• UCB Pharma
• National Institute for Health Research Health Technology Assessment Programme
• School of Health & Related Research Sheffield (ScHARR)
• National Clinical Guideline Centre (NCGC)

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 rheumatoid arthritis after failure of previous disease-modifying antirheumatic drugs by attending the initial Committee discussion and providing written evidence to the Committee. They are invited to comment on the ACD.

• Dr Chris Deighton, Consultant Rheumatologist, nominated by National Clinical Guideline Centre – clinical specialist
• Professor Rob Moots, Professor of Rheumatology, nominated by British Society for Rheumatology
• Jean Burke, nominated by National Rheumatoid Arthritis Society – patient expert
• Adrienne Yarwood, nominated by National Rheumatoid Arthritis Society – patient expert

D 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