Tofacitinib for moderate to severe rheumatoid arthritis

3.1 Tofacitinib's marketing authorisation covers its use at 4 points in the treatment pathway, specifically in adults with:

3.2 NICE currently recommends the use of the biological DMARDs in its technology appraisal guidance on baricitinib, adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept (of which adalimumab, certolizumab pegol, etanercept, golimumab and infliximab are TNF‑alpha inhibitors), in combination with methotrexate, in people with severe rheumatoid arthritis that has not responded to intensive treatment with combinations of conventional DMARDs. Disease severity is assessed using the disease activity score (DAS28). A DAS28 of more than 5.1 indicates severe disease (between 3.2 and 5.1 indicates moderate disease, less than 3.2 but more than 2.6 indicates mild disease and less than 2.6 indicates disease remission). For people who meet these criteria but cannot take methotrexate, the guidance recommends that baricitinib, adalimumab, certolizumab pegol, etanercept or tocilizumab may be used as monotherapy. The guidance recommends treatment should start with the least expensive drug (taking into account administration costs, dose needed and product price per dose) and should only be continued according to European League Against Rheumatism (EULAR) response at 6 months.

3.3 For people with severe rheumatoid arthritis who have already had at least 1 TNF‑alpha inhibitor that hasn't worked, NICE technology appraisal guidance on adalimumab, etanercept, infliximab, rituximab and abatacept and golimumab recommends the biological DMARD rituximab in combination with methotrexate for treating severe active rheumatoid arthritis. But, if rituximab is contraindicated or withdrawn because of an adverse event, NICE technology appraisal guidance recommends tocilizumab, certolizumab pegol, baricitinib, abatacept, adalimumab, etanercept, infliximab or golimumab, in combination with methotrexate. If methotrexate is contraindicated or withdrawn because of an adverse event, NICE's guidance on abatacept, adalimumab, etanercept, infliximab, golimumab, tocilizumab, certolizumab pegol or baricitinib recommends adalimumab, etanercept, tocilizumab, certolizumab pegol or baricitinib as monotherapy. NICE technology appraisal guidance also recommends tocilizumab in combination with methotrexate when neither TNF‑alpha inhibitors nor rituximab have worked.

3.4 The committee heard from the patient experts that rheumatoid arthritis is a lifetime condition that can severely reduce quality of life. The clinical experts stated that conventional DMARDs such as methotrexate are inadequate for many people. They added that the disease sometimes does not respond adequately to the first biological DMARD prescribed. Both the clinical and patient experts said it would be helpful to have new treatments that can be used at various points in the treatment pathway, alongside biological DMARDs after failure of conventional DMARDs. The clinical and patient experts agreed that methotrexate is often not well tolerated; the clinical experts noted that up to a third of people who are prescribed methotrexate with biological DMARDs do not take the drug because of side effects. The committee concluded that a range of treatment options is important in rheumatoid arthritis.

3.5 The clinical experts emphasised that tofacitinib is a novel treatment with a different mode of action to the biological DMARDs. They noted that the selective inhibition of Janus kinase 1 and 3 will affect a broad range of cytokines involved in the pathogenesis of rheumatoid arthritis. The clinical experts noted that there are subtly different adverse effects across the different classes of drugs for rheumatoid arthritis, but the adverse effects associated with Janus kinase inhibitors are unlikely to influence their desire to prescribe the drug. The patient experts noted that the potential benefits of treatment with Janus kinase inhibitors are likely to outweigh the adverse effects. The clinical experts also noted the similar kinetic action of tofacitinib compared with biological DMARDs, specifically TNF‑alpha inhibitors. Both the clinical and patient experts also highlighted that tofacitinib is given orally, which has major benefits for both patients and the health system. The patient experts emphasised that this is an important factor for people who have difficulty injecting themselves because of the disease affecting their hands. The patient experts also noted that some current treatments have to be stopped if the person gets an infection, and that some treatments may cause injection site reactions. The committee recognised that rheumatoid arthritis significantly affects quality of life. It concluded that there is a need for new treatment options, particularly when there is an inadequate response to conventional or biological DMARDs.

3.6 The committee was aware that the company had analysed 5 distinct subgroups for whom tofacitinib could be used:

3.7 The company's clinical evidence came mainly from 4 phase III randomised controlled trials. The trials included people with moderate to severe rheumatoid arthritis, as defined in section 3.6. The trials were:

Additional clinical evidence came from ORAL Strategy, a phase III/IVb randomised controlled trial. It included people with moderate to severe rheumatoid arthritis, and measured ACR50 at month 6, as its primary outcome. The committee concluded that the trials were adequate and suitable for decision-making.

3.8 The committee noted that because the ORAL trials did not collect the EULAR response criteria, EULAR response was derived from the DAS28 scores for each trial, at month 3 or 6. The EULAR response criteria use the individual change in DAS28 and the absolute DAS28 score to classify a EULAR response as good, moderate, or none. The committee accepted the company's estimation of the EULAR response and concluded that the trials were relevant and adequate for its decision-making.

3.9 The committee noted that the design of the ORAL trials allowed all the patients having placebo or all patients whose condition did not respond to placebo to have tofacitinib after month 3 (response was defined as a 20% reduction in the number of tender and swollen joints). The committee heard from the ERG that, to adjust for crossover, 2 approaches were applied. The first approach estimated the treatment effect (estimate 1) by imputing the number of patients from the placebo arm whose condition did not respond at month 3 (also known as non-responder imputation without advancement penalty). The second approach estimated the treatment effect (estimate 2) by imputing the number of patients from the placebo arm whose condition did not respond at month 3 as well as the patients from the tofacitinib arm whose condition did not respond (also known as non-responder imputation with advancement penalty). The committee noted that the primary analysis for the ORAL Standard, Scan and Sync trials was based on non-responder imputation with advancement penalty (estimate 2) and therefore clinical results are reported for a combined placebo group (that is, the group who crossed over to have either 5 mg or 10 mg of tofacitinib, because the results were not provided separately for the licensed 5 mg dose). Because fewer patients from the placebo arm whose condition did not respond at month 3 later developed a response at month 6 compared with patients from the tofacitinib arm, the ERG agreed that the true treatment effect was likely to lie between these 2 estimates, but closer to estimate 1 than to estimate 2. The committee was satisfied with the approaches used to adjust for crossover and agreed with the ERG on their estimation of the true treatment effect.

Tofacitinib with methotrexate is more clinically effective than conventional DMARDs for moderate to severe disease that has responded inadequately to conventional DMARDs

3.10 The committee considered ORAL Standard and ORAL Scan, which included people with moderate to severe rheumatoid arthritis whose disease responded inadequately to conventional DMARDs. In both trials, there was a statistically significant increase in the proportion of people having tofacitinib who met the ACR20 criteria at month 6 compared with the combined placebo group (see section 3.9): ORAL Standard 51.5% compared with 28.3% respectively, p<0.001; ORAL Scan 51.5% compared with 25.3% respectively, p<0.001. In ORAL Standard, there was also a statistically significant increase in the proportion of people having adalimumab who met the ACR20 criteria at month 6 compared with the combined placebo group: 47.2% compared with 28.3% respectively, p<0.001. Statistically significant improvements in the mean change from baseline in HAQ-DI scores and the proportion of patients achieving a DAS28 of less than 2.6 were also seen in ORAL Standard for tofacitinib compared with the combined placebo group (−0.55 compared with −0.24, p<0.001; 6.2% compared with 1.1%, p value is confidential). For ORAL Scan, no statements about statistical significance could be made for the HAQ‑DI score or DAS28 outcomes. The committee considered ORAL Strategy, which included people with moderate to severe rheumatoid arthritis that responded inadequately to conventional DMARDs. For the proportion of people meeting the ACR50 criteria at 6 months, tofacitinib plus conventional DMARDs was non-inferior to adalimumab plus conventional DMARDs, and tofacitinib monotherapy was less effective than both tofacitinib and adalimumab, both in combination with conventional DMARDs. The committee concluded that in people with moderate to severe rheumatoid arthritis whose disease has responded inadequately to conventional DMARDs, tofacitinib plus conventional DMARDs is not worse in effectiveness than adalimumab plus conventional DMARDs, and is more effective than conventional DMARDs alone.

Tofacitinib alone and with methotrexate is more clinically effective than conventional DMARDs for moderate to severe disease that has responded inadequately to conventional or biological DMARDs

3.11 The committee considered ORAL Sync (combination therapy) and ORAL Solo (monotherapy), which included people with moderate to severe rheumatoid arthritis whose disease responded inadequately to conventional or biological DMARDs. For ORAL Sync, in the tofacitinib plus methotrexate group compared with the combined placebo group, there was a statistically significant increase in the proportion of people meeting the ACR20 criteria at 6 months (52.7% compared with 31.2%, p<0.001) and in the mean change from baseline in HAQ-DI scores at 3 months (−0.46 compared with −0.21, p<0.01) respectively. The proportion achieving remission using a DAS28 less than 2.6 response at 3 months was 9.1% compared with 2.7% for tofacitinib plus methotrexate compared with combined placebo (p=0.0038). In ORAL Solo, the proportion of people meeting the ACR20 criteria and the mean change from baseline in HAQ-DI scores at 3 months was statistically significantly higher for tofacitinib monotherapy compared with combined placebo at 3 months (ACR20 59.8% compared with 26.7%, p<0.001; HAQ-DI −0.50 compared with −0.19, p<0.001). The proportion of patients in the tofacitinib monotherapy group compared with the combined placebo group who went into remission, based on a DAS28 response of less than 2.6 at 3 months, was not statistically significantly different (5.6% compared with 4.4%; p=0.62). The committee concluded that tofacitinib plus conventional DMARDs is more effective than conventional DMARDs alone, and tofacitinib alone is more effective than placebo in people with moderate to severe rheumatoid arthritis whose disease has responded inadequately to conventional or biological DMARDs.

3.12 The committee noted that the safety profiles of tofacitinib and conventional DMARDs were similar. It heard from the ERG that a safety review by Curtis et al. (2016) showed that the incidence of herpes zoster was significantly higher in people who had previously had tofacitinib than those who had previously had biological DMARDs. The committee heard from clinical experts that this adverse effect was specific to the class of Janus kinase inhibitors rather than tofacitinib. It also heard that the higher incidence of herpes zoster in the review was not associated with a higher rate of patients stopping treatment with tofacitinib because it is considered as a manageable infection. The committee concluded that tofacitinib's safety profile was acceptable and similar to that of conventional DMARDs.

3.13 The committee was aware that other than the direct comparison with adalimumab, the only evidence available on the comparative effectiveness of tofacitinib and the biological DMARDs was from the company's network meta-analyses. The company did separate analyses for patients whose disease responded inadequately to either conventional or biological DMARDs, using change in HAQ-DI from baseline and EULAR response outcome measures, together with estimate 1 (see section 3.9) in the base case.

At the 20- to 30‑week follow-up, for patients whose disease responded inadequately to conventional DMARDs, the network meta-analysis showed that:

3.14 The committee heard from the ERG that there were problems with the methods used in the company's network meta-analysis. These included:

3.15 The company used an individual patient-based discrete event simulation model for its economic evaluation. The model simulates patients' disease progression through the sequences of treatments being compared. It was based on the model used by the assessment group during the production of NICE technology appraisal guidance on adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for rheumatoid arthritis. The model categorised patients based on their EULAR response (good, moderate or no response) at 6 months. Response rates were based on a regression model using ORAL trial data (for tofacitinib and tofacitinib plus methotrexate) and the company's network meta-analysis (for the comparators). The treatment stopped if the patient did not have at least a moderate EULAR response at 6 months. The company analysed cost effectiveness for each of the subgroups described in section 3.6. The committee concluded that the model structure was appropriate for its decision-making.

3.16 After corrections by the company (at the clarification stage and a later correction of an error in the company submission), the ERG identified several issues with the company's economic analyses including:

3.17 In the moderate active rheumatoid arthritis population whose disease has responded inadequately to conventional DMARDs, the ERG's incremental cost-effectiveness ratio (ICER) for the tofacitinib sequence compared with the conventional DMARD sequence, including the confidential comparator patient access scheme, was above £30,000 per quality-adjusted life year (QALY) gained. The committee considered that tofacitinib plus conventional DMARDs was not cost effective in people with moderate rheumatoid arthritis whose disease has responded inadequately to conventional DMARDs.

3.18 In the ERG's analysis for the severe rheumatoid arthritis population whose disease has responded inadequately to conventional DMARDs, the clinical and cost-effectiveness estimates for tofacitinib plus conventional DMARDs were very similar to what had previously been seen in rheumatoid arthritis. The committee concluded that it could recommend tofacitinib plus methotrexate as a cost-effective use of NHS resources for people with severe rheumatoid arthritis whose disease has responded inadequately to conventional DMARDs, in line with the NICE recommendations on adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept.

3.19 In the ERG's analysis for the severe rheumatoid arthritis population whose disease has responded inadequately to conventional DMARDs, tofacitinib monotherapy produced very similar clinical and cost-effectiveness estimates compared with what had previously been seen in rheumatoid arthritis. The committee concluded that it could recommend tofacitinib monotherapy as a cost-effective use of NHS resources for people with severe rheumatoid arthritis whose disease has responded inadequately to conventional DMARDs, in line with the NICE recommendations on adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept.

3.20 For the severe rheumatoid arthritis population whose disease has responded inadequately to biological DMARDs and for whom rituximab is a treatment option, the only sequence recommended by NICE is rituximab followed by tocilizumab. In the ERG's analysis, ICERs were presented for alternative sequences compared with the recommended sequence. It showed that when using estimate 1, tofacitinib followed by tocilizumab was dominated by rituximab followed by tocilizumab, whereas the sequence of rituximab followed by tofacitinib gives cost savings but also loss of QALYs, resulting in ICERs that reflect 'savings per QALY lost'. For example, in the ERG's analysis, when comparing the sequence starting with rituximab followed by tofacitinib with the sequence starting with rituximab followed by tocilizumab, there was a cost saving of £15,284 in the tofacitinib sequence, but a QALY loss of −0.19, resulting in an ICER of £80,442 saved per QALY lost. When using estimate 2, the sequence of tofacitinib followed by tocilizumab was dominated by rituximab followed by tocilizumab (less costly and more effective) whereas rituximab followed by tofacitinib resulted in cost savings but also loss of QALYs (£137,483 saved per QALY lost). The committee noted that a confidential patient access scheme is in place for tocilizumab, which was not included in this analysis. The committee considered the ICERs that incorporated confidential patient access schemes for tocilizumab and tofacitinib, but the results are confidential and cannot be reported here (to protect the confidentiality of the discounts in the patient access schemes). The committee noted that when using estimate 1, the sequence of tofacitinib followed by tocilizumab remained dominated by NICE's recommended sequence, and although the ICER for rituximab followed by tofacitinib was lower, the cost savings were at a less acceptable level given the QALYs that would be lost. When using estimate 2, the sequence of tofacitinib followed by tocilizumab resulted in cost savings and loss of QALYs. The ICER for rituximab followed by tofacitinib no longer resulted in cost savings and was dominated by the recommended sequence. Therefore there was a high degree of uncertainty around the cost-effectiveness estimates in this population. Taking into account all of the information presented, the committee concluded that tofacitinib was not a cost-effective use of NHS resources for people with severe rheumatoid arthritis whose disease has responded inadequately to biological DMARDs if rituximab is a treatment option.

3.21 The committee noted that adalimumab, infliximab and certolizumab pegol, all in combination with methotrexate, have not been included in the analyses despite this being recommended by NICE. The committee noted that all the comparisons produced very similar estimates of clinical and cost effectiveness compared with those previously seen in appraisals of rheumatoid arthritis. It concluded that tofacitinib plus methotrexate was a cost-effective use of NHS resources for people with severe rheumatoid arthritis whose disease has responded inadequately to biological DMARDs and for whom rituximab is not a treatment option.

3.22 The committee was aware that the marketing authorisation for tofacitinib includes its use as a monotherapy. But the company did not present an economic analysis for tofacitinib alone for severe disease, after biological DMARDs, in patients who cannot have methotrexate. The committee recognised the considerable uncertainty about the effectiveness of tofacitinib alone in people whose disease has responded inadequately to conventional or biological DMARDs. The committee was aware that in the appraisal of baricitinib, the committee concluded that baricitinib monotherapy has similar clinical effectiveness to baricitinib plus conventional DMARDs. The committee heard from the clinical experts that, although the preference is to give tofacitinib plus methotrexate, if a person cannot take methotrexate, tofacitinib will be given alone. The clinical experts also noted that Janus kinase inhibitors seem to have similar clinical effectiveness. The committee concluded that its recommendations for tofacitinib plus conventional DMARDs should also apply to tofacitinib alone for people with severe rheumatoid arthritis whose disease has responded inadequately to biological DMARDs and who cannot take methotrexate because it is contraindicated or not tolerated.