1 Recommendations

People with rheumatoid arthritis would welcome new treatment options for moderate disease

4.1 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, complete everyday activities and increases the need for continual NHS care. The patient experts described how this affects emotional wellbeing substantially, 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 is 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. This is because the differing nature of rheumatoid arthritis 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.

This appraisal only considers first-line biological treatments in moderate disease

4.2 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 does have a place in treating rheumatoid arthritis. But they noted that changing the treatment to a drug with a different mechanism of action may be more appropriate if the loss of response is because of the development of antidrug antibodies. 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 375. It agreed that it was appropriate to assume that after the first biological treatment has failed, NICE technology appraisal guidance for severe rheumatoid arthritis was followed.

The clinical evidence used in NICE technology appraisal 375 is appropriate for this partial review

4.3 The clinical evidence used in this review is the same as that assessed in NICE technology appraisal 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.

The cost-effectiveness model used in NICE technology appraisal 375 is appropriate for this partial review

4.4 The assessment group developed an individual patient-based discrete event simulation model for its economic evaluation in NICE technology appraisal 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. So, in the economic model, after the first biological treatment had failed, 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 to the model (see section 4.5).

The changes to the assessment group's model are appropriate for decision making and reflect current NICE guidance

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

Abbreviations: DMARDs, disease-modifying antirheumatic drugs.

The treatment sequences in the updated economic model are appropriate

4.6 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. The committee noted that this assumption was accepted in NICE technology appraisal 375. 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. The assessment group confirmed that the length of treatment sequence was the same in both arms. 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 are appropriate for decision making.

The most plausible ICERs for adalimumab and infliximab are below £20,000 per QALY gained

4.7 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 ICER 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 higher than £30,000 per QALY gained, and for abatacept (intravenous and subcutaneous formulations) was substantially higher than £30,000 per QALY gained.

The assessment group's sensitivity analyses do not change the cost-effectiveness conclusions

4.8 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 4.5). These did not affect the cost-effectiveness conclusions. Another sensitivity analysis was done to remove methotrexate after tocilizumab in the treatment sequences following progression to severe disease (in line with NICE's guidance on filgotinib for treating moderate to severe rheumatoid arthritis), which also had little impact 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 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.

Adalimumab and infliximab are cost-effective treatment options for moderate disease but etanercept and abatacept are not recommended

4.9 The committee accepted the assessment group's 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. The assessment group's base-case ICERs for etanercept and abatacept were both above the range NICE considers to be an acceptable use of NHS resources. The committee therefore did not recommend etanercept or abatacept as treatment options for moderate active rheumatoid arthritis.

Adalimumab monotherapy is also recommended for people who cannot take methotrexate

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

Healthcare professionals should consider any disabilities or communication difficulties when using the DAS28 measure

4.11 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.

No other equality issues have been identified that can be addressed in this technology appraisal

4.12 The patient experts explained that certolizumab pegol, another TNF-alpha inhibitor, is often used to treat rheumatoid arthritis in women who are planning to start a family 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.

Healthcare professionals should choose the most appropriate treatment after discussing the options with the person having treatment

4.13 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 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.

The benefits of the technologies were adequately captured in the cost-effectiveness analysis

4.14 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 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.