Baricitinib for moderate to severe rheumatoid arthritis

3.1 Baricitinib'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 NICE technology appraisal guidance on 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 adalimumab, certolizumab pegol, etanercept or tocilizumab may be used as monotherapy.

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 recommends the biological DMARD rituximab in combination with methotrexate for treating severe active rheumatoid arthritis. If rituximab is contraindicated or withdrawn because of an adverse event, the guidance recommends abatacept, adalimumab, etanercept or infliximab in combination with methotrexate. NICE also recommends golimumab under the same circumstances in NICE's technology appraisal guidance on golimumab. If methotrexate is contraindicated or withdrawn because of an adverse event, NICE's technology appraisal guidance on adalimumab, etanercept, infliximab, rituximab and abatacept recommends adalimumab or etanercept as monotherapy. NICE technology appraisal guidance on tocilizumab and certolizumab pegol recommend both treatments as alternatives to TNF‑alpha inhibitors in the same circumstances (that is, for people with severe rheumatoid arthritis who have already had at least 1 TNF‑alpha inhibitor that hasn't worked, in combination with methotrexate when rituximab is contraindicated or withdrawn. Certolizumab pegol is also recommended as monotherapy if methotrexate is contraindicated or withdrawn). 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, and that there are few tools available to predict response to help decide which treatment to use. 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 methotrexate because of side effects. The clinical experts emphasised that baricitinib 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 2 will affect a broad range of cytokines involved in the pathogenesis of rheumatoid arthritis. The clinical experts also noted the fast kinetic action of baricitinib compared with biological DMARDs. Both the clinical and patient experts also highlighted that baricitinib 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.

3.5 The committee was aware that the company had analysed 4 distinct subgroups in which baricitinib could be used:

3.6 The company's clinical evidence came from 4 phase III randomised controlled trials and 1 long-term safety and tolerability study. The trials included people with moderate to severe rheumatoid arthritis, as defined in section 3.2. The trials were:

3.7 The primary outcome of all the randomised controlled trials was the proportion of people achieving a 20% improvement in the American College of Rheumatology response criteria (ACR20) at week 12 or 24. Secondary outcomes included the proportion of people achieving a 50% or 70% improvement in the response criteria (ACR50 and ACR70 respectively), and the proportion of people meeting the European League Against Rheumatism (EULAR) response criteria. The committee concluded that the trials were relevant and adequate for its decision-making.

3.8 The committee considered RA‑BEAM and RA‑BUILD, which included people with moderate to severe rheumatoid arthritis which responded inadequately to conventional DMARDs. In RA‑BEAM, there was a significant increase in the proportion of people meeting the ACR20 criteria at 12 weeks with 4 mg baricitinib plus conventional DMARDs compared with conventional DMARDs alone (odds ratio [OR] 3.6; 95% confidence interval [CI] 2.7 to 4.7, p=0.001). A smaller response was seen with 4 mg baricitinib plus conventional DMARDs compared with adalimumab plus conventional DMARDs (OR 1.5; 95% CI 1.1 to 2.0, p=0.014 for ACR20). Significant improvements in ACR20 and EULAR good and moderate responses were also seen in RA‑BUILD for 4 mg baricitinib plus conventional DMARDs compared with conventional DMARDs alone (OR 2.5; 95% CI 1.7 to 3.7, p=0.001 for ACR20 and OR 3.5; 95% CI 2.3 to 5.4, p=0.001 for EULAR). The committee also noted that in RA‑BUILD, 2 mg baricitinib plus conventional DMARDs improved ACR20 and EULAR responses in this population compared with conventional DMARDs alone (OR 3.0; 95% CI 2.0 to 4.4, p=0.001 for ACR20 and OR 3.3; 95% CI 2.2 to 5.0, p=0.001 for EULAR good and moderate response). The committee concluded that 4 mg baricitinib plus conventional DMARDs has similar efficacy to adalimumab plus conventional DMARDs, and is more effective than conventional DMARDs alone in people with moderate to severe rheumatoid arthritis which has responded inadequately to conventional DMARDs.

3.9 The committee considered RA‑BEACON, which included people with moderate to severe rheumatoid arthritis which responded inadequately to TNF‑alpha inhibitors. There was a significant increase in the proportion of people meeting the ACR20 criteria and having a EULAR moderate or good response rate at 12 weeks for 4 mg baricitinib plus conventional DMARDs compared with conventional DMARDs alone (OR 3.4; 95% CI 2.2 to 5.4, p=0.001 for ACR20 and OR 3.6; 95% CI 2.3 to 5.7, p=0.001 for EULAR moderate and good response). The committee also noted that 2 mg baricitinib plus conventional DMARDs also improved ACR20 and EULAR response rates in this population compared with conventional DMARDs alone (OR 2.7; 95% CI 1.7 to 4.2, p=0.001 for ACR20 OR 2.7; 95% CI 1.8 to 4.2, p=0.001 for EULAR moderate and good response). The committee concluded that both dosages of baricitinib, when given with conventional DMARDs, are more effective than conventional DMARDs alone in people with moderate to severe rheumatoid arthritis which has responded inadequately to TNF‑alpha inhibitors.

3.10 The committee noted that across all 3 randomised controlled trials in which patients had previously had conventional or biological DMARDs (RA‑BEAM, RA‑BUILD and RA‑BEACON), the safety profile of baricitinib was similar to that of the conventional DMARDs. In addition, it noted that the safety profiles were found to be similar in the head-to-head comparison of baricitinib and adalimumab (RA‑BEAM).

3.11 The committee was aware that other than the direct comparison with adalimumab, the only evidence available on the comparative effectiveness of baricitinib and the biological DMARDs was from the company's network meta-analyses. The company did separate analyses for patients whose disease inadequately responded to either conventional or biological DMARDs, using ACR and EULAR outcome measures.

At 24 weeks' follow-up, for patients whose disease inadequately responded to conventional DMARDs, the network meta-analysis showed:

3.12 The committee heard from the ERG that there were problems with the methods used in the company's network meta-analysis. These included the conversion of ACR data to EULAR data before synthesis, the use of simultaneous models for baseline and treatment effects, the use of a random effects model for 1 population and a fixed effects model for the other, and poor model fit. In addition, the company had pooled the control data inappropriately. The ERG corrected the errors in the company's network meta-analysis. Having reviewed both analyses, the committee concluded that the results of the corrected network meta-analysis and the company's network meta-analysis were broadly comparable.

3.13 The company identified 9 UK-based cost-effectiveness studies. The committee was aware that 8 of these were associated with previous NICE technology appraisals guidance; 1 was an independent published review. The company did not identify any studies that included baricitinib, but the committee noted that the studies were nonetheless relevant and appropriate.

3.14 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 the company's network meta-analysis. The company analysed cost effectiveness for each of the subgroups described in section 3.5. The committee concluded that the model structure was appropriate for its decision-making.

3.15 The company's model included costs associated with drug acquisition, drug administration and monitoring, and hospitalisation. The committee was aware that baricitinib and several of the biological DMARDs have patient access schemes. It noted that the company had incorporated the patient access scheme prices for baricitinib, certolizumab pegol and golimumab in the model, but not the confidential patient access schemes for abatacept and tocilizumab. The incremental cost-effectiveness ratios (ICERs) that incorporated these confidential patient access schemes cannot be reported here, but the range of ICERs usually considered to be cost effective is from £20,000 to £30,000 per quality-adjusted life year (QALY) gained. The company had also calculated the average cost of drug doses using the average weight, rather than the distribution of the weight of the modelled patient population. The committee was also aware that the company overestimated the number of doses and therefore the costs of infliximab.

3.16 The company did not identify any evidence on the effectiveness of adalimumab, certolizumab pegol, etanercept or infliximab plus conventional DMARDs in patients with severe active rheumatoid arthritis which has responded inadequately to biological DMARDs when rituximab is contraindicated or not tolerated. In the absence of these data, the company used the same efficacy estimates for these treatments as those in patients with severe active rheumatoid arthritis which has responded inadequately to conventional DMARDs. The EULAR responses for all treatments were higher in these patients than in those with an inadequate response to biological DMARDs. The committee heard from the ERG that because of this, the company's base case is likely to have overestimated the efficacy of adalimumab, certolizumab pegol, etanercept and infliximab plus conventional DMARDs in patients with active rheumatoid arthritis which has responded inadequately to biological DMARDs when rituximab is contraindicated or not tolerated. The committee accepted this in the absence of any other evidence.

3.17 Health-related quality of life data were collected using a health assessment questionnaire (HAQ) in RA‑BEAM, RA‑BUILD and RA‑BEACON. Patient-level responses were converted to utility index-based EQ-5D-5L scores using the UK-specific scoring algorithm reported by Hernandez Alava et al. (2012). The committee was aware this was not in line with the analysis done during NICE's technology appraisal on adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept, but it heard from the ERG that this approach was unlikely to change the overall conclusions.

3.18 The ERG identified several issues with the company's economic analyses including:

3.19 The company carried out several scenario analyses. In one, the company assumed that patients having conventional DMARDs or palliative care had a linear increase in their HAQ scores at a yearly rate of 0.045 and 0.060 respectively (based on Malottki et al. 2011), instead of using the latent class approach. For the moderate rheumatoid arthritis population, the ICER for baricitinib plus conventional DMARDs compared with intensive conventional DMARDs alone decreased from £37,420 to £20,965 per QALY gained. In the severe rheumatoid arthritis population, the ICERs were slightly lower for the most effective drugs. The company also:

3.20 In the moderate active rheumatoid arthritis population whose disease has responded inadequately to conventional DMARDs, the company's base-case ICER for the baricitinib sequence compared with the conventional DMARD sequence was £37,420 per QALY. The committee noted that the company used a different sequence for this population to that used in the NICE technology appraisal guidance on adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept. The ERG did not correct this or the errors in the model because they were unlikely to change the conclusions, and it could use the model from the other appraisal as a reference. The ERG noted that the median ICER of biological DMARDs in the NICE appraisal of adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept was around £50,000 per QALY gained. Taking into account the cost-effectiveness evidence for baricitinib in patients with moderate active rheumatoid arthritis whose disease has responded inadequately to conventional DMARDs, the committee considered that baricitinib plus conventional DMARDs did not have plausible potential to be cost effective in this population.

3.21 In the company's base-case analysis for the severe rheumatoid arthritis population whose disease has responded inadequately to conventional DMARDs, baricitinib plus conventional DMARDs dominated all its comparators (that is, it was both less costly and more effective). The exception to this was certolizumab pegol plus conventional DMARDs, which had an ICER of £18,400 per QALY compared with baricitinib plus conventional DMARDs. The committee noted that there are confidential patient access schemes in place for subcutaneous abatacept and intravenous tocilizumab, which the company did not include in its analysis. The ERG calculated new ICERs using the confidential comparator prices. The committee noted that all the comparisons produced very similar estimates of clinical and cost effectiveness, and concluded to recommend baricitinib plus conventional DMARDs as a cost-effective use of NHS resources for people with severe rheumatoid arthritis whose disease has responded inadequately to conventional DMARDs.

3.22 In the company's base-case analysis for the severe rheumatoid arthritis population whose disease has responded inadequately to biological DMARDs and for whom rituximab is a treatment option, baricitinib plus conventional DMARDs was dominated by rituximab plus conventional DMARDs (that is, it was more costly and less effective). The committee concluded that baricitinib plus conventional DMARDs 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.

3.23 In the pairwise analysis for the severe rheumatoid arthritis population whose disease has responded inadequately to biological DMARDs and for whom rituximab is contraindicated or not tolerated, baricitinib plus conventional DMARDs was dominated by golimumab plus conventional DMARDs. Compared with all other comparators, the ICERs ranged from £16,201 to £484,782. In the full incremental analysis, baricitinib plus conventional DMARDs dominated or extendedly dominated all comparators except for certolizumab pegol plus conventional DMARDs, which had an ICER of £16,201 per QALY gained. The ICERs for biosimilar etanercept plus conventional DMARDs compared with baricitinib plus conventional DMARDs, and adalimumab plus conventional DMARDs compared with baricitinib plus conventional DMARDs, were also less than £30,000 per QALY gained. The committee again noted the confidential patient access schemes in place for subcutaneous abatacept and intravenous tocilizumab, which the company did not include in its analysis. The ERG calculated new ICERs using the confidential comparator prices. The committee noted that all the comparisons produced very similar estimates of clinical and cost effectiveness, and concluded to recommend baricitinib plus conventional DMARDs as 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.

3.24 The committee was aware that the marketing authorisation for baricitinib includes its use as a monotherapy, but that the company did not present an economic analysis for baricitinib alone for patients who cannot have methotrexate. The committee noted that the only available evidence for baricitinib alone is in people who have not had conventional DMARDs, which is outside of its marketing authorisation. The committee recognised the considerable uncertainty about the effectiveness of baricitinib alone in people whose rheumatoid arthritis has had an inadequate response to conventional or biological DMARDs. The committee heard from the ERG that data from RA-BEGIN showed that the addition of methotrexate to 4 mg baricitinib produced similar ACR scores compared with baricitinib alone. The committee agreed that baricitinib monotherapy provides similar clinical efficacy to baricitinib plus conventional DMARDs. It concluded that its recommendations for baricitinib plus conventional DMARDs should also apply to baricitinib alone.