Upadacitinib for treating moderate 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. A range of biological and targeted synthetic DMARDs are available for moderate rheumatoid arthritis (see NICE technology appraisal guidance on filgotinib [TA676], and NICE's technology appraisal guidance on adalimumab, etanercept, infliximab and abatacept [TA715]). But these were not recommended at the time of the committee's discussion, so these treatments were not considered comparators. At the first committee meeting, patient experts explained that people with moderate disease that has not responded adequately to conventional DMARDs had few effective treatment options. The committee concluded that it is important for people with moderate rheumatoid arthritis to have a range of treatment options.

3.2 Disease severity is assessed using the disease activity score (DAS28). A DAS28 above 5.1 indicates severe disease and a DAS28 between 3.2 to 5.1 indicates moderate disease. Upadacitinib's marketing authorisation and the company's evidence submission covers its use at 2 points in the treatment pathway, specifically in adults with:

3.3 The company presented results for upadacitinib at 2 positions in the moderate rheumatoid arthritis treatment pathway (see section 3.2). A clinical expert stated that it was more likely that upadacitinib would be used after 2 conventional DMARDs. Also, the European League Against Rheumatism (EULAR) guidelines state that 2 conventional DMARDs should be tried before considering a biological DMARD. But the guidelines recommend considering a biological DMARD after 1 conventional DMARD when poor prognostic factors are present. These include the presence of rheumatoid factor, antibodies against cyclic citrullinated peptide, high disease activity and early joint damage. The ERG explained that the company's network meta-analysis did not give separate results for people with a poor prognosis. Analyses done by the ERG showed that positioning upadacitinib after 1 conventional DMARD was more likely to lead to a cost-effectiveness estimate much higher than £30,000 per quality‑adjusted life year (QALY) gained than positioning it after 2 or more conventional DMARDs. The committee concluded that the most appropriate position for upadacitinib was after treatment with 2 or more conventional DMARDs. It also concluded that, if methotrexate was tolerated, upadacitinib plus methotrexate was preferred to upadacitinib alone. The committee noted that these conclusions were in line with previous NICE technology appraisals for rheumatoid arthritis.

3.4 In the company and ERG analysis, after 2 conventional DMARDs, there were 2 potential comparators: further conventional DMARD treatment or best supportive care. The clinical expert explained that at this position, further treatment with conventional DMARDs was not expected to give a EULAR response. Despite this, patients are usually offered continued treatment with a combination of conventional DMARDs that have not been used previously, and corticosteroids are also a treatment option. The clinical expert also highlighted that after disease progression with methotrexate, it is unlikely to be used again except as part of combination therapy. The company explained that best supportive care after 2 conventional DMARDs included some continued conventional DMARDs, particularly methotrexate. The committee concluded that after 2 conventional DMARDs, best supportive care is the conventional DMARDs that had been used before, with optional corticosteroids. This was the most appropriate comparator in this group because it reflects clinical practice. The committee also concluded that best supportive care is unlikely to give a response measured using EULAR criteria but noted this was difficult to account for (see section 3.8).

3.5 The company's clinical evidence came from 4 phase 3 randomised controlled trials. The trials included people with moderate to severe rheumatoid arthritis (defined in section 3.2). The trials were:

3.6 In the full population of SELECT-NEXT, upadacitinib with conventional DMARDs showed a statistically significant improvement in American College of Rheumatology response (ACR20) at 12 weeks, compared with placebo plus 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). Similar results were seen for the moderate subgroups in both trials (exact data is confidential and cannot be reported here). The ERG and company considered that upadacitinib's safety profile is similar to that of other biological DMARDs. The committee concluded that upadacitinib plus conventional DMARDs (including methotrexate) is more clinically effective than placebo plus conventional DMARDs (including methotrexate) for moderate disease. Also, it concluded that upadacitinib alone was more clinically effective than methotrexate alone for moderate rheumatoid arthritis that has responded inadequately to conventional DMARDs.

3.7 A network meta-analysis was used for decision making for people with severe disease in NICE's technology appraisal guidance of upadacitinib for treating severe rheumatoid arthritis. However, the ERG explained that for moderate disease, it may be more appropriate to use the SELECT trials because:

3.8 The ERG modelled the efficacy of best supportive care based on the response rates seen in the placebo plus conventional DMARDs arm of the SELECT-NEXT trial (the SELECT-MONOTHERAPY trial was used to model cost effectiveness for people who could not tolerate methotrexate; see section 3.5). Best supportive care was the committee's preferred comparator and was not expected to give a EULAR response in clinical practice. However, the committee noted that a considerable response rate was seen in the placebo arms of the SELECT trials, as well as in other clinical trials in rheumatoid arthritis. It noted that this response could have been caused by several factors, including a placebo effect, disease resolving naturally over time, regression to the mean, response bias and variation in symptoms. Some of these factors might have also contributed to the response to upadacitinib in the SELECT trials. Therefore, the committee agreed it would not be appropriate to assume full clinical efficacy for upadacitinib while assuming no response to best supportive care. The ERG provided analyses that used SELECT-NEXT response rates for upadacitinib plus methotrexate and for placebo plus conventional DMARDs (a proxy for best supportive care) because it retained the relative treatment effect seen in the clinical evidence. In line with clinical expert opinion, the committee stated that it preferred to compare upadacitinib (with or without methotrexate) with methotrexate plus placebo (best supportive care) using data from the SELECT trials. After this, patients in both treatment arms would have conventional DMARDs with or without corticosteroids and no EULAR response would be expected in clinical practice. The committee concluded that the ERG's analyses had limitations because the trials did not fully reflect what is expected to happen in clinical practice, but were acceptable.

3.9 The committee was aware that since this appraisal began, TA715 had published. This was a partial review of NICE technology appraisal guidance 375 (TA375). In TA375, the efficacy of methotrexate from a network meta‑analysis was used to estimate the efficacy of best supportive care in the comparator arm of the model. In TA715, the committee agreed that because no new evidence was being considered in that appraisal, there was no strong reason to deviate from the assumptions in TA375. In its response to the second consultation, the company considered that applying the efficacy estimate from TA375 was the most consistent and transparent approach and there was no robust justification to change it. The committee noted that the treatment sequence in TA375 included methotrexate monotherapy before best supportive care. This was not consistent with clinical expert advice that methotrexate would only be used as part of combination therapy. It also noted that the network meta‑analysis in TA375 showed a moderate or good EULAR response in a significant number of patients on methotrexate, but clinical advice was that a EULAR response would not be expected at this point in the treatment pathway. The committee concluded that using estimates from the TA375 network meta‑analysis had limitations but may be acceptable. It agreed to consider this analysis as well as the analysis using the placebo arm of the SELECT trials (see section 3.8) in its decision making.

3.10 The company's model included treatment for moderate disease that had progressed to severe disease. This was consistent with recent NICE technology appraisals on treating rheumatoid arthritis. The company modelled progression by estimating the relationship between the DAS28 and health assessment questionnaire (HAQ) results from the clinical evidence. HAQ is 1 component of the ACR20 response criteria. It scores physical disability and pain from 0 (least disability) to 3 (most severe disability). The ERG noted that the company's original model did not apply this estimated relationship. After the first consultation, the company submitted 2 scenario analyses assuming that 11% and 19% of people with moderate disease have disease progression to severe disease after 2 years. The ERG explained that this was in line with the figure predicted by the UK Early Rheumatoid Arthritis Network database (19%). The committee noted that in the company's scenario analyses, most people's disease progressed to severe after 12 years, which produced lower cost-effectiveness estimates for upadacitinib. The clinical expert estimated that in clinical practice around 30% of people with moderate disease were likely to have disease progression to severe disease by 12 years. However, at the second consultation, consultees explained that rheumatoid arthritis disease activity tends to be fairly stable over time and that analysis of the Early Rheumatoid Arthritis Study did not provide any evidence that a larger number of patients (than 19%) would have an increased DAS28 score over a longer period of time. The committee was aware that this estimate may no longer be correct because of the introduction of biologic DMARDs recommended in TA715 and TA676 but noted that in this analysis varying the rate of progression did not have a large impact on the cost-effectiveness results. It concluded that it was appropriate to assume that 19% of people with moderate disease have disease progression to severe disease after 2 years.

3.11 The committee considered the treatment sequences for the populations with moderate disease and whether it was appropriate to include a clinical effect for methotrexate after upadacitinib, and before best supportive care (which had no efficacy). The committee was aware that the original ERG report criticised this approach for allowing the upadacitinib arm of the model to count the placebo effect twice, while the comparator arm only counted it once. In the second consultation, the company noted that for moderate disease, TA375 assumed that methotrexate would be given after biological treatment and that this was associated with a response. The same assumption was used in TA715, and a similar assumption was made in NICE's technology appraisal guidance on baricitinib, tofacitinib and sarilumab, which did not make positive recommendations for moderate rheumatoid arthritis. A clinical expert considered that methotrexate would not be used as monotherapy again when it had already been used earlier in the pathway. They explained that methotrexate would be continued only as part of combination treatment. The committee considered it debatable whether methotrexate monotherapy would be used at this point in the treatment pathway or what size of response would be expected, if any. On balance, the committee agreed that although it was debatable, it would consider analyses that included an effect of methotrexate after upadacitinib in its decision making.

3.12 The committee understood that using upadacitinib to treat moderate disease could change the treatment pathway for severe disease. The ERG explored 3 alternative treatment sequences for severe disease: scenario 1, scenario 2 and a preferred scenario. These included people who could and could not tolerate methotrexate. For people who could tolerate methotrexate, all treatments were taken in combination with methotrexate. Table 1 describes the treatment options in each scenario at first, second and third line for severe disease. The ERG's clinical expert explained that for people whose disease progresses to severe, adalimumab would generally be used first because it is the cheapest biological DMARD. If there was an inadequate response, rituximab is likely to be used next, even for people who cannot tolerate methotrexate. The ERG's clinical expert explained that in the first scenario analysis, people who have had upadacitinib could have abatacept instead of sarilumab because it works in a different way to upadacitinib. The ERG's second scenario explored using upadacitinib instead of sarilumab because people tend to prefer oral treatments to subcutaneous injections. The clinical expert agreed that abatacept, sarilumab and upadacitinib could be used as third‑line treatment options. Fourth‑line treatment was best supportive care in all the scenarios. The clinical expert clarified that the decision to use a particular treatment would depend on several factors including infection risk, liver function and cost of treatment. Given the multiple factors used to decide the appropriate treatment, the committee agreed that it was difficult to know with certainty if upadacitinib should be included in the treatment sequences for severe disease in the comparator arm before it had been used in routine clinical practice. It agreed that sequences in both arms should reflect clinical practice. Sequences for both arms may include different treatment options depending on what patients have previously received at an earlier disease stage. The committee understood that TA375 and the summary of product characteristics for rituximab recommend it only in combination with methotrexate. It was concerned that the ERG's analyses may not reflect treatment sequences for people who cannot tolerate methotrexate, because rituximab is not licensed as a monotherapy. It understood that this was a small population and may reflect clinical practice but noted that treatment sequences may vary in the NHS in England. The committee concluded that the ERG's alternative treatment sequences for severe disease were plausible.

3.13 In the company's base-case analysis, health-related quality of life data was calculated using a mapping function to work out a person's pain score from their HAQ score. The mapping algorithm used data from the SELECT trials to estimate EQ‑5D values. The ERG noted that TA375 used data from the National Databank for Rheumatic Diseases dataset to map pain scores from HAQ scores. It explained that the company's approach may be acceptable, but it preferred mapping based on the National Databank for Rheumatic Diseases dataset. This was because the dataset contained over 100,000 observations. After the first consultation, the company suggested that mapping based on the National Databank for Rheumatic Diseases dataset produced some counterintuitive results. Some of the lowest functionality was associated with a reduction in pain. The company noted that this did not happen using its preferred method of mapping using data from the clinical trials. The committee noted that the choice of mapping did not have a large effect on the cost‑effectiveness estimates for severe disease, because health‑related quality of life was similar across the different comparators. But it noted that for moderate disease, the company's method gave lower cost‑effectiveness estimates for upadacitinib compared with best supportive care. The committee concluded that both mapping approaches were plausible, but noted that the ERG's approach was used in TA375 and was based on a much larger dataset.

3.14 In the ERG's preferred base-case analysis, people whose disease responded to best supportive care were assumed to have the same long‑term HAQ results as those whose disease responded to biological DMARDs. The ERG explained that a large amount of the upadacitinib response was likely to have been caused by a placebo effect. This was also present in the trial control arms, so it may be inappropriate to make different assumptions about long-term HAQ results in the model. The clinical and patient experts advised that natural recovery from symptoms is rare, and it would not be sustained for a long time. The committee agreed that applying the long‑term HAQ results associated with biological DMARDs to best supportive care was likely to be an overly optimistic assumption. In response to technical engagement, the company provided an alternative scenario analysis. In this, people whose disease responded to best supportive care were assumed to have the same long‑term HAQ results as those whose disease responded to conventional DMARDs. The committee concluded that it was appropriate to assume that people whose disease responded to best supportive care had the same decreasing long‑term HAQ results as people whose disease responded to conventional DMARDs. This was consistent with previous NICE technology appraisals in rheumatoid arthritis.

3.15 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 QALY gains for biological DMARDs compared with conventional DMARDs. It explained that this mostly affects 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 TA375 model. After the first consultation, the company submitted further validation results that included corrections of 4 errors. The ERG noted that after consultation the company's results were reasonably aligned with TA375. The committee concluded that the company's model is reasonably consistent with the model used in TA375, which was considered acceptable for decision making.

3.16 The committee evaluated the cost effectiveness of upadacitinib for moderate disease considering the following conclusions:

3.17 The committee noted that the cost-effectiveness estimates for upadacitinib monotherapy would be higher than for upadacitinib plus methotrexate, because methotrexate could not be included in the treatment sequence. This would have the most impact when removing methotrexate from the treatment sequence from its position after upadacitinib in moderate disease (see section 3.11). However, the committee noted that this population is much smaller than the population who can have methotrexate. In line with previous appraisals for rheumatoid arthritis, it agreed that the small number of people who could not tolerate methotrexate should not be disadvantaged compared with other people with moderate disease, as far as possible. Therefore, the committee recommended upadacitinib monotherapy when methotrexate is contraindicated or if people cannot tolerate it.

3.18 The committee noted that the treatment pathway for moderate rheumatoid arthritis was now substantially different from the assumptions used in TA715 and TA676. Committees considering technologies for rheumatoid arthritis in the future may need to reconsider cost-effectiveness modelling assumptions in the following areas:

3.19 During the scoping process a potential equality issue was raised 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 appropriate adjustments.

3.20 Upadacitinib, like several other biological DMARDs, is taken orally. This is valued by patients. The committee noted that there are other oral treatments with a similar mechanism of action available for rheumatoid arthritis. It concluded that all the benefits of upadacitinib were captured in the model.