Adalimumab, etanercept, infliximab and abatacept for treating moderate rheumatoid arthritis after conventional DMARDs have failed

3.1 The patient experts explained that people with moderate active rheumatoid arthritis have significant disability and reduced quality of life if their disease is not adequately controlled. This can affect a person's ability to work and do everyday activities. It also increases the need for continual NHS care. The patient experts described how this substantially affects emotional wellbeing, causing stress and anxiety, which can trigger further flare-ups of the disease. Although there are a range of advanced treatment options for severe rheumatoid arthritis, only filgotinib is recommended for treating moderate disease after failure of 2 or more conventional disease-modifying antirheumatic drugs (DMARDs; such as methotrexate, leflunomide, sulfasalazine and hydroxychloroquine; see NICE's technology appraisal guidance on filgotinib). The committee noted that when this partial update started, the appraisal of filgotinib had not concluded. Therefore, filgotinib was not included in the scope as a comparator. The patient experts explained that it is important that there is a wide range of treatment options available for rheumatoid arthritis. This is because the differing nature of the disease means that a treatment may work well for one person but not another. The clinical experts explained that although the medicines appraised are similarly beneficial for treating the articular features of rheumatoid arthritis, they differ in their effectiveness in preventing particular comorbidities. This means that it is important for people with rheumatoid arthritis to have a range of different medicines available, even within the same drug class. The clinical experts explained that earlier access to advanced treatments in moderate disease would reduce disease progression and increase the likelihood of remission. The committee concluded that people with moderate rheumatoid arthritis would welcome a range of advanced treatment options.

3.2 A company representative explained that the moderate treatment sequences modelled by the assessment group did not consider cycling of tumour necrosis factor (TNF)-alpha inhibitors (taking another TNF-alpha inhibitor after a first one). This would happen if a person does not tolerate the first treatment, or if their disease either does not respond or responds inadequately after an initial response. The clinical experts explained that because the technologies are protein-based drugs, there is a risk of developing antidrug antibodies, which reduces the treatment benefit over time. They noted that around 50% of people will stop treatment within 3 years because of loss of efficacy. The clinical experts explained that the cycling of TNF-alpha inhibitors has a place in treating rheumatoid arthritis. They explained that, for this reason, having a variety of therapeutic choices for moderate disease would benefit people. The committee noted that the scope for the appraisal includes only first-line use of biological DMARDs (after a person's disease has responded inadequately to 2 or more conventional DMARDs) as in NICE technology appraisal guidance 375. It agreed that it was appropriate to assume that after the first biological treatment has failed, if the disease progresses to severe, NICE technology appraisal guidance for severe rheumatoid arthritis would be followed.

3.3 The clinical evidence used in this review is the same as that assessed in NICE technology appraisal guidance 375. So, the treatment efficacy of the interventions and comparators (adalimumab, etanercept, infliximab, abatacept all with methotrexate, and methotrexate alone) and subsequent treatments (rituximab and tocilizumab both with methotrexate) were informed by the results of the network meta-analysis done by the assessment group in NICE technology appraisal 375. The trials in the network meta-analysis included people with moderate and severe disease, so the efficacy of treatments was assumed to be the same in both populations. The committee considered the uncertainty around the midpoint estimates used when making its recommendations for treatments used in severe disease in NICE technology appraisal 375. The clinical experts explained that there is long-term clinical trial evidence and real-world evidence that strongly supports using biological DMARDs for treating moderate active disease. The committee concluded that the efficacy data accepted in the original guidance was appropriate to assess the cost effectiveness of adalimumab, etanercept, infliximab and abatacept for people with moderate active disease as part of this partial review.

3.4 The assessment group developed an individual patient-based discrete event simulation model for its economic evaluation in NICE technology appraisal guidance 375. The scope for this appraisal included only the first-line use of biological DMARDs after an inadequate disease response to 2 or more conventional DMARDs. In the economic model, after the first biological treatment had failed, if disease progresses to severe, NICE technology appraisal guidance for severe rheumatoid arthritis was followed. For all analyses it was assumed that methotrexate was used in combination with the biological DMARD, and that the results for combination therapy could be generalised to biological DMARD monotherapy (if monotherapy use was included in the marketing authorisation). This assumption was also made in NICE technology appraisal 375. The model incorporated a response criterion based on European League Against Rheumatism (EULAR) response at 6 months to reflect UK clinical practice. If there was no EULAR response to a biological DMARD after 6 months then the next treatment in the strategy was used. Further details about the assessment group's original economic model can be found in the final guidance for NICE technology appraisal 375. The committee concluded that the cost-effectiveness model accepted in the original guidance was appropriate to use in this partial review, with some updates (see section 3.5).

3.5 The assessment group's analyses included the assumptions preferred by the committee in NICE technology appraisal guidance 375. There were several updates to its original model:

3.6 The trials included in the network meta-analysis showed people's disease responded to methotrexate (a conventional DMARD) when it is used as the first treatment. Therefore, the assessment group included a response to methotrexate when used as a first treatment in the comparator arm of the model (for people with moderate disease who had had 2 conventional DMARDs) but did not include a response to methotrexate after a biological DMARD in the treatment arm of the model. The trials also showed a response with methotrexate following treatment with tocilizumab (in both treatment arms) and this efficacy was also included in the model in the treatment sequence for severe disease. The efficacy of conventional DMARDs when used later in the treatment pathway for moderate disease and at the end of the pathway in severe disease was assumed to be zero for both arms. In response to consultation, one consultee noted that in NICE technology appraisal guidance 375, in moderate disease, it was assumed that after biological treatments people would have methotrexate, which was associated with a response. A similar assumption was also made in NICE's technology appraisal guidance on baricitinib, tofacitinib and sarilumab. The committee noted that none of these appraisals had made positive recommendations for moderate disease. So, it did not consider that this point had been fully accepted by the committee in these appraisals. Also, it noted that it was debatable whether methotrexate would be used at this point in the treatment pathway or what size of response would be expected. However, because no new clinical evidence was being considered in this appraisal, it agreed there was no strong reason to deviate from the assumption put forward in NICE technology appraisal 375 and subsequent appraisals. The committee concluded that the assessment group's model was previously considered acceptable in NICE technology appraisal 375 and that the updates made to reflect current NICE guidance and consultation responses are appropriate for decision making (see table 2).

Abbreviations: DMARDs, disease-modifying antirheumatic drugs

3.7 NICE's guide to the methods of technology appraisal notes that above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per quality-adjusted life year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee agreed that an acceptable ICER would be within the range NICE normally considers a cost-effective use of NHS resources (£20,000 to £30,000 per QALY gained). Because of the confidential discounts for the treatments and some of the subsequent therapies, the exact ICERs are confidential and cannot be reported here. The assessment group's base-case analyses used the cheapest formulation of each intervention and prices included homecare support (when available). The assessment group's base-case ICERs for adalimumab and infliximab compared with conventional DMARDs were both substantially lower than £20,000 per QALY gained. The assessment group's base-case ICER for etanercept compared with conventional DMARDs was lower than £30,000 per QALY gained. For abatacept (intravenous and subcutaneous formulations) the ICER was substantially higher than £30,000 per QALY gained.

3.8 The assessment group did several sensitivity analyses including using lower (the exact figure is confidential and cannot be reported here) and higher values (0.70) for change in DAS28 score when HAQ score increases (see section 3.5). These had a small effect on the ICERs. Another sensitivity analysis was done to remove methotrexate after tocilizumab in the treatment sequences following progression to severe disease (in line with NICE's technology appraisal guidance on filgotinib), which also had little effect on the ICERs. The committee understood that there was some uncertainty about the efficacy estimates used in the model, which may have influenced the cost-effectiveness results. However, it agreed that these estimates were considered acceptable by the committee in NICE technology appraisal guidance 375. The committee discussed that there are multiple biosimilars for adalimumab, and the availability of these differs regionally in England, unlike etanercept and infliximab biosimilars, which are nationally available. The committee considered a further sensitivity analysis using the highest price that any region would need to pay for adalimumab. It was reassured that this did not change the cost-effectiveness conclusions for adalimumab.

3.9 The committee accepted the assessment group's updated base-case analyses. The assessment group's base-case ICERs for adalimumab and infliximab were both below the range NICE considers to be an acceptable use of NHS resources. Therefore, the committee recommended adalimumab and infliximab as first-line biological treatments for moderate active rheumatoid arthritis that has had an inadequate response to intensive therapy with 2 or more conventional DMARDs. Although the assessment group's ICER for etanercept was higher than those for adalimumab and infliximab, it was below £30,000 per QALY gained. In response to consultation, it was highlighted that there are some people for whom etanercept would be a particularly useful treatment option. For example, etanercept has a much lower risk of reactivating latent tuberculosis, which has a higher prevalence in people with a South Asian family background. In addition, compared with some of the other biologicals, etanercept does not need to be stopped as far in advance by people wishing to conceive. The committee recognised that these groups would likely only represent a small number of people with moderate rheumatoid arthritis. The committee noted that the recommendations state that if more than 1 biological is an appropriate treatment option, treatment should start with the least expensive. So it also recommended etanercept as an option. The assessment group's base-case ICER for abatacept was above the range NICE considers to be an acceptable use of NHS resources. The committee therefore did not recommend abatacept as a treatment option for moderate active rheumatoid arthritis.

3.10 The committee agreed that people with moderate rheumatoid arthritis who cannot tolerate methotrexate should not be disadvantaged compared with other people with moderate disease, as far as possible. The committee concluded that, based on the marketing authorisation and the cost-effectiveness estimates, adalimumab and etanercept could be recommended as monotherapy for moderate active disease previously treated with conventional DMARDs.

3.11 A potential equality issue was raised in NICE's technology appraisal guidance on upadacitinib for treating severe rheumatoid arthritis, 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 agreed that this equality issue was also important to consider for this appraisal. 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.

3.12 Some of the people for whom etanercept may be particularly beneficial have protected characteristics. The committee took this into account in its decision making about etanercept (see section 3.9).

3.13 The patient experts explained that certolizumab pegol, another TNF-alpha inhibitor, is often used to treat rheumatoid arthritis in women who are planning to become pregnant or who are pregnant. They described how not having this as a treatment option for people with moderate disease could potentially discriminate against women of childbearing age. The clinical experts explained that certolizumab pegol does not easily cross the placenta so is usually the preferred treatment choice during pregnancy. However, they explained that other TNF-alpha inhibitors can be used in different stages of pregnancy but that there is a risk of active transport across the placenta, which often means that treatment is stopped. The committee concluded that this issue could not be addressed in this technology appraisal, because the company manufacturing certolizumab pegol decided not to participate in this partial review. So, the committee could not make recommendations on its use for moderate disease.

3.14 The committee understood that having a range of treatment options is important in treating moderate rheumatoid arthritis. It understood that NICE recommended filgotinib for treating moderate to severe rheumatoid arthritis (see NICE's technology appraisal guidance on filgotinib) and noted NICE's ongoing technology appraisal on upadacitinib for previously treated moderate active rheumatoid arthritis. The committee concluded that healthcare professionals should choose the most appropriate treatment after discussing the advantages and disadvantages of the treatments available with the person having treatment. If more than 1 treatment is suitable, they should start treatment with the least expensive drug (taking into account administration costs, dose needed and product price per dose). This may vary because of differences in how the drugs are used and treatment schedules.

3.15 The patient and clinical experts explained that biological DMARDs are highly effective in reducing disease progression and improving quality of life in people with rheumatoid arthritis. The committee noted that biological DMARDs were considered to be innovative in NICE technology appraisal guidance 375 for people with severe disease. It discussed that while filgotinib is the only advanced treatment option currently available for people with moderate disease, its mechanism of action is different to the biological DMARDs, of which none are currently available for people with moderate disease. The committee agreed that the technologies are important treatment options for these people. It concluded that all the benefits of the technologies were adequately captured in the model.