Upadacitinib for treating severe rheumatoid arthritis

3.1 The patient expert explained that rheumatoid arthritis is a lifetime condition that can severely reduce quality of life. The clinical experts stated that conventional disease-modifying antirheumatic drugs (DMARDs) such as methotrexate are inadequate for many people with active rheumatoid arthritis. The expert also added that for a significant proportion of people who are eligible for treatment with biological DMARDs, their disease inadequately responds to these treatments. Both the clinical and patient experts said it would be helpful to have new treatments for various points in the treatment pathway. The committee concluded that a range of treatment options was important in rheumatoid arthritis and that upadacitinib would be a welcome additional option.

3.2 NICE technology appraisal guidance currently recommends the following DMARDs for severe rheumatoid arthritis:

3.3 Upadacitinib's marketing authorisation and the company's submission covers its use at 4 points in the treatment pathway, specifically in adults with:

3.4 The company's clinical evidence came from 4 randomised controlled trials. The trials included people with moderate to severe rheumatoid arthritis (see section 3.2). The trials were:

3.5 In SELECT-COMPARE, upadacitinib with methotrexate showed a statistically significant improvement in American College of Rheumatology response (ACR20) at 12 weeks compared with adalimumab with methotrexate or placebo with methotrexate (upadacitinib 71%, adalimumab 63%, p≤0.050; placebo 36%, p≤0.001). In SELECT-NEXT, upadacitinib with conventional DMARDs showed a statistically significant improvement in ACR20 at 12 weeks compared with placebo with conventional DMARDs (upadacitinib 64%, placebo 36%, p≤0.001). In SELECT-MONOTHERAPY, upadacitinib alone showed a statistically significant improvement in ACR20 at 12 weeks compared with methotrexate alone (upadacitinib 68%, methotrexate 41%, p≤0.001). The committee also noted that the ERG and company considered that the safety profile for upadacitinib was similar to other biological DMARDs. The committee concluded that upadacitinib with methotrexate was more clinically effective than adalimumab, placebo with methotrexate or placebo with conventional DMARDs. Also, upadacitinib alone was more clinically effective than methotrexate for moderate to severe rheumatoid arthritis that had responded inadequately to conventional DMARDs.

3.6 In SELECT-BEYOND, upadacitinib with conventional DMARDs showed a statistically significant improvement in ACR20 at 12 weeks compared with placebo with conventional DMARDs (upadacitinib 65%, placebo 28%, p≤0.001). The committee concluded that upadacitinib with conventional DMARDs was more clinically effective than placebo with conventional DMARDs for moderate to severe rheumatoid arthritis that had responded inadequately to biological DMARDs.

3.7 Other than the direct comparison with adalimumab, there was no other comparative trial evidence of upadacitinib compared with biological DMARDs. To compare with other biological DMARDs, the company did a network meta-analysis. It did separate analyses for people whose disease responded inadequately to either conventional or biological DMARDs. It also changed ACR responses to EULAR responses to inform treatment-effectiveness estimates used in the economic model. The company used 12- to 14-week data from the clinical trials to estimate EULAR response at week 24. For those whose disease responded inadequately to conventional DMARDs, the network meta-analyses at week 24 showed that:

3.8 In the company's base case, health-related quality-of-life data were calculated using a mapping function to work out a person's pain score from their Stanford Health Assessment Questionnaire (HAQ) score. HAQ is 1 component of the ACR criteria and scores physical disability and pain from 0 (least disability) to 3 (most severe disability). The mapping function used SELECT trial data, to estimate EQ‑5D values. The ERG noted that NICE's technology appraisal guidance on adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for rheumatoid arthritis not previously treated with DMARDs or after conventional DMARDs only have failed (from now on referred to as TA375) used data from the National Databank for Rheumatic Diseases dataset to map from HAQ-to-pain score. The ERG explained that while the company's approach may be acceptable, the ERG preferred the mapping based on the National Databank for Rheumatic Diseases dataset. This was because the dataset contained over 100,000 observations. After consultation, the company suggested that the mapping based on the National Databank for Rheumatic Diseases dataset gave some counter-intuitive results. This was because some of the lowest functionality was associated with reduced pain. The company confirmed that this was not seen in its preferred method based on mapping using the clinical trials. The committee was aware that the choice of mapping did not have a large effect on severe disease because health-related quality of life was similar across the different comparators. It noted that the company's method led to lower cost-effectiveness estimates compared with conventional DMARDs. The committee concluded that both the company and ERG approaches were plausible, but noted that the ERG's approach was used in TA375 and was based on a much larger dataset.

3.9 The company based its model on the model developed by the assessment group for TA375. The company provided a validation analysis comparing the outputs of its model with those from the model used in TA375 for several treatment sequences. The ERG suggested that the results of this analysis appeared to show that the company's model overestimated quality-adjusted life year (QALY) gains for biological DMARDs compared with conventional DMARDs. It explained that this primarily impacts the cost-effectiveness analysis for moderate disease, when upadacitinib is compared with conventional DMARDs. At the committee meeting, the company advised that it had found errors in the ERG's validation analysis and that its own model produced similar results to the model from TA375. After consultation, the company submitted further validation results that included corrections of 4 errors. The ERG noted that after consultation, the company's results reasonably aligned with TA375. The committee concluded that the company's model was reasonably consistent with the model used in TA375.

3.10 The ERG did analyses for people with severe disease whose disease had responded inadequately to conventional DMARDs. The clinical- and cost-effectiveness estimates for upadacitinib compared with conventional DMARDs were similar to what was previously seen in other technology appraisals for rheumatoid arthritis. Upadacitinib dominated (that is, it was cheaper and more effective than the comparator) or gave an incremental cost-effectiveness ratio (ICER) under £30,000 per QALY gained when confidential comparator discounts were applied. The committee concluded that it could recommend upadacitinib with methotrexate as a cost-effective use of NHS resources for people with severe rheumatoid arthritis whose disease had responded inadequately to conventional DMARDs. This was in line with TA375.

3.11 The ERG did an analysis for people with severe disease that has responded inadequately to biological DMARDs when rituximab is a treatment option. In this, upadacitinib with conventional DMARDs was dominated by rituximab with conventional DMARDs (that is, upadacitinib was more expensive and less effective). The committee concluded that upadacitinib with conventional DMARDs was not a cost-effective use of NHS resources for people with severe rheumatoid arthritis whose disease had responded inadequately to biological DMARDs if rituximab was a treatment option. Therefore, it was not recommended at this position in the pathway.

3.12 The ERG did analyses for people with severe disease that had not responded adequately to rituximab and other biological DMARDs. In this, the cost-effectiveness estimates for intravenous or subcutaneous tocilizumab with methotrexate compared with upadacitinib with methotrexate were over £100,000 per QALY gained. Sarilumab with methotrexate was dominated by upadacitinib with methotrexate (that is, upadacitinib was less expensive and more effective). The committee therefore recommended upadacitinib with conventional DMARDs for people with severe rheumatoid arthritis whose disease has not responded adequately to rituximab and other biological DMARDs.

3.13 The marketing authorisation for upadacitinib includes its use as a monotherapy. The committee noted that the clinical- and cost-effectiveness results for upadacitinib monotherapy were similar to those for upadacitinib with methotrexate. It was aware that the available evidence for upadacitinib monotherapy was from people whose disease responded inadequately to methotrexate. The clinical expert explained that methotrexate is not tolerated by some patients or it is contraindicated. In line with TA375, the committee agreed that the minority of people with severe active rheumatoid arthritis who could not tolerate methotrexate should not be treated differently from other people with severe disease, as far as possible. The committee agreed that upadacitinib monotherapy was cost effective for severe active rheumatoid arthritis after conventional DMARDs if methotrexate was not suitable.

3.14 A potential equality issue was raised during the scoping process, about people with rheumatoid arthritis who have difficulty communicating. For these people, it may be more difficult to assess outcomes when using the DAS28 measure. The committee concluded that healthcare professionals should consider any physical, psychological, sensory or learning disabilities, or communication difficulties that could affect the responses to the DAS28 and make any adjustments they consider appropriate.

3.15 Upadacitinib, like other targeted synthetic DMARDs, is taken orally. This is valued by patients. The committee noted that there are also other treatments with a similar mechanism of action available for rheumatoid arthritis. Therefore the committee concluded that all the benefits of upadacitinib can be captured in the model.