Adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for rheumatoid arthritis not previously treated with DMARDs or after conventional DMARDs only have failed

Sixty randomised controlled trials were identified by the Assessment Group as meeting the criteria for inclusion in the systematic review:

• 6 trials were head‑to‑head comparisons that compared 1 biological disease‑modifying antirheumatic drug (DMARD) with another biological DMARD

• 1 trial compared tumour necrosis factor (TNF)‑alpha inhibitors (as a group) with combination conventional DMARDs (TACIT trial)

• 53 trials compared a biological DMARD with placebo or conventional DMARDs.

The Assessment Group reported that many of the trials included in the systematic review were of good quality, and had a reasonably low risk of bias. The Assessment Group noted that there may be issues with generalisability to the UK, because some of the trials done in Japan used low‑dose methotrexate treatment before randomisation, which could affect the rate of methotrexate response among the trial populations. The Assessment Group also noted that the strict trial inclusion criteria applied resulted in study populations who may not fully reflect the range of patients seen in clinical practice in England, and that randomised controlled trials may not capture rare adverse events. For the Assessment Group the primary outcomes of interest were American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) response data.

The Assessment Group included 30 studies in their systematic review of the literature. Twenty‑three studies evaluated biological DMARDs in people who had previously had DMARDs, 6 studies evaluated biological DMARDs in people who had not previously had DMARDs, and 1 study evaluated people in both groups. Most studies were of etanercept, infliximab and adalimumab, with no studies found for certolizumab pegol or golimumab. The studies had a wide range of model methods, time horizons, price years, currencies and discount rates. The Assessment Group stated that a detailed analysis of the parameters used in each study was not feasible, and that drawing strong conclusions on the cost effectiveness of individual therapies was not possible. The results of the Assessment Group's systematic review indicated that, in people who had previously had DMARD therapy, many biological DMARDs had incremental cost‑effectiveness ratios (ICERs) close to £30,000 per quality‑adjusted life year (QALY) gained in both directions, and that the ICERs were often higher for those people not previously treated with DMARDs. No individual biological DMARD was seen to be consistently more cost effective than any other biological DMARD. The Assessment Group noted that 3 studies (Jobanputra 2002; Barton 2004; Chen 2006) had been used in previous NICE technology appraisal guidance on adalimumab, etanercept and infliximab (TA130) and adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis.

The Assessment Group developed an individual patient‑based discrete event simulation model for their economic evaluation. The model incorporated a response criterion based on EULAR response at 6 months to reflect UK clinical practice. The Assessment Group modelled:

• people with severe active disease previously treated with methotrexate

• people with moderate active disease previously treated with methotrexate

• people with severe active disease not previously treated with methotrexate.
  
  Technologies were assessed both in combination with methotrexate and as monotherapy in the 3 populations.

The model approach meant that there were no time cycles. The model had a lifetime time horizon similar to those in the companies' submissions. The Assessment Group used an NHS and personal social services perspective and a discount rate of 3.5% for both costs and benefits.

The initial response to treatment was modelled using the EULAR response data from the Assessment Group network meta‑analysis. Because a smaller number of trials included EULAR response data compared with ACR response data and not all interventions could be included in the EULAR network, a separate analysis was also done in which ACR data were mapped to EULAR response using individual patient level data from the Veterans Affairs Rheumatoid Arthritis (VARA) database. The Assessment Group also did scenario analyses in which it extended the network of evidence to include the 12 trials that had been excluded from the systematic review and network meta‑analysis.

The Assessment Group analysed 24 combinations of factors – the 3 populations (the severe active and moderate active disease populations who had been previously treated with methotrexate, and the severe active population who had not been previously treated with methotrexate), whether the treatment was provided as monotherapy or with methotrexate, whether EULAR or ACR mapped to EULAR response data were used in the model, and whether the HAQ trajectory for conventional DMARDs was taken from ERAS or from previous NICE technology appraisal guidance. EULAR response in people who had not previously had methotrexate was not analysed because no data were available. The Assessment Group also did sensitivity analyses assessing the effect of including different randomised controlled trials in the network meta‑analysis, using different mapping functions of HAQ to utility, using the discount rates in NICE technology appraisal guidance 130 on adalimumab, etanercept and infliximab, increasing the effect of adverse events and using a different assumed relationship between HAQ and pain.

The Assessment Group presented the median ICERs for biological DMARDs for the 3 different populations. For the population who had not had methotrexate before, no results were presented for a model based on EULAR response because of lack of data. The results provided use ACR data mapped to EULAR response. The incremental costs and QALYs are not presented in this document because some of the patient access schemes are commercial in confidence. However, the Assessment Group noted that there were only small differences in costs and QALYs between the different biological DMARDs. On this basis it noted that the fully incremental cost‑effectiveness analyses may be misleading.

The Assessment Group compared the results of their model with those of the companies and also with the ICERs presented in the NICE technology appraisal guidance 130 on adalimumab, etanercept and infliximab. Using the assumption of linear HAQ progression as used in the companies' models and in previous NICE appraisals, the ICERs were between £35,000 and £40,000 per QALY gained. Using the discount rates applied in the NICE technology appraisal guidance on adalimumab, etanercept and infliximab (that is, the discount rates of 6% for costs and 1.5% for benefits) the ICERs reduced further to approximately £25,000 per QALY gained. The Assessment Group considered that these results demonstrated that their model, using similar inputs, produced comparable ICERs to those of the economic models that had been used in previous appraisals.

The Committee discussed the impact of rheumatoid arthritis on people with the condition, and how this was affected by the current use of DMARDs. The Committee was aware that rheumatoid arthritis can affect parts of the body other than the joints and that it has a significant effect on social life, employment and mental health. It heard from the patient expert that biological DMARDs can enable patients to continue working. It also heard that when treatment has to be temporarily stopped before surgery, deterioration in mobility could mean that a wheelchair is needed, with a significant effect on daily activities. The Committee concluded that rheumatoid arthritis can have a significant effect on the lives of patients and their families.

The Committee discussed clinical practice in early rheumatoid arthritis. It heard from clinical experts about the importance of early diagnosis and treatment to prevent irreversible joint damage. The Committee heard that NICE's guideline on rheumatoid arthritis recommends combination DMARD therapy, which in clinical practice would be intensive therapy with a combination of conventional DMARDs or stepped‑up conventional DMARD therapy, normally including methotrexate, hydroxychloroquine, sulfasalazine and a glucocorticoid. The Committee heard from the clinical experts that after starting treatment, clinical management aims to adjust conventional DMARD therapy to achieve tight disease control, that is, low disease activity or remission. The clinical experts stated that intensive conventional DMARD therapy is effective in preventing permanent joint damage and that most people would have methotrexate before biological DMARD therapy was considered. The Committee understood that for treating early rheumatoid arthritis conventional DMARDs were an effective treatment and that the main clinical interest in using biological DMARDs was after conventional DMARDs had failed.

The Committee discussed the management of established rheumatoid arthritis. The Committee heard from clinical experts that patients whose disease does not respond to intensive combination therapy with conventional DMARDs are likely to have disease that progresses more quickly with worse outcomes. The clinical experts estimated that this was the case for approximately 15% of patients with rheumatoid arthritis, and that it is these people who currently have biological DMARDs. The Committee understood that most people have biological DMARDs in combination with methotrexate, but heard from clinical experts that there is a small minority of people who cannot take methotrexate (because it is contraindicated or because of intolerance) for whom biological DMARDs are used as monotherapy. The Committee heard from both the clinical experts and the patient expert that it was not possible to predict which biological DMARDs the disease will respond to before starting treatment. Therefore having a variety of biological DMARDs available was important. The Committee heard that, if there are no contraindications, clinicians may prefer to use a TNF‑alpha inhibitor because of its established use. However in other people, such as those with systemic disease, tocilizumab may be preferred, and in people with prior malignancy or with uveitis, particular biological DMARDs may be chosen in preference to others. The Committee understood the importance that clinicians placed on having a selection of biological DMARDs available.

The Committee discussed unmet need in clinical practice. The Committee heard from clinical experts that the NICE guidance being reviewed in this appraisal restricts the use of biological DMARDs to people with a disease activity score (DAS28) greater than 5.1. However, there is a group of people with lower levels of disease activity whose disease is not controlled on conventional DMARDs, and who need glucocorticoids to maintain disease control. For these people the availability of biological DMARDs would be welcomed, because currently the only way they can be offered biological DMARDs is if their glucocorticoids are withdrawn and their disease worsens to become severe active disease. The clinical experts noted that when disease responds badly to conventional DMARD therapy, there is less chance that it will respond well to other treatments. This is the case regardless of DAS. The Committee understood that there was clinical interest in the use of biological DMARDs in people with moderate active disease (that is, with a DAS28 of less than 5.1) whose disease was not controlled on conventional DMARDs.

The Committee discussed the different measures of response used in clinical practice and in the clinical trials. The Committee understood from clinical experts that although ACR20 was used in the clinical trials, it did not represent a significant clinical improvement; although people would have relief from some symptoms, they would still have disability. ACR70, however represented a significant improvement in symptoms (similar to that seen in remission), and was closer to the current aim of clinical management. The Committee also discussed how disease status is determined in UK clinical practice. It heard from clinical experts that the most commonly used measures of disease response are DAS and EULAR response, rather than ACR response. This is because DAS is a continuous measurement, unlike ACR response which is categorical. The Committee heard from the clinical experts that the cut‑off points for DAS being low, moderate or severe disease activity are arbitrary and that there are not necessarily significant clinical distinctions on either side of the boundaries of the cut‑off points. The Committee, while noting the limitations of the DAS and EULAR response measures, concluded that these are the most commonly used measures of disease response in the NHS in England.

The Committee noted comments from consultation that DAS does not define patients with rapid disease progression, and that rather than using only DAS to identify people suitable for treatment with biological DMARDs, treatment can be targeted at people likely to have rapid disease progression. These people can be identified based on persistent synovitis and failure of the disease to respond to combination therapy with conventional DMARDs, plus:

• persistent elevation of inflammatory markers (such as C‑reactive protein [CRP]) and

• presence of erosions on X‑ray and

• positive for anti‑citrullinated protein antibodies (ACPA).
  
  The Committee discussed whether it is possible to use these criteria to identify a group of patients with rapid disease progression. The clinical experts explained that each of these measures had been validated individually, and that they are all used in clinical practice in the NHS. Clinical experts considered that disease which has not responded to combination therapy, in people who have these criteria, would progress faster than in people who do not have these criteria. The Committee also heard from one of the company representatives that there is evidence to show that these criteria, taken together, can predict rapid progression in people with rheumatoid arthritis. The Committee supported the concept of identifying people likely to have rapid disease progression in order to target treatment with biological DMARDs. However, it noted that some of the criteria proposed are already used in rheumatoid arthritis diagnosis (for example, ACPA positivity) and that clinical experts suggested that, taken together, the measures would identify approximately one third to one half of patients with moderate active disease. The Committee was not persuaded of the sensitivity of the measures for identifying people with the fastest disease progression. The Committee also noted that, although individually validated, the measures were not necessarily independent of each other, and different thresholds for presence or absence can be applied. It also noted that the effect of these different thresholds on speed of progression, when combined with thresholds applied for the other measures, was unclear. It also noted that no economic modelling had been provided for this group, and that it had not been provided with any clinical evidence to support the assumption that disease with these characteristics would respond well to biological DMARDs. The Committee concluded that further research is needed on the use of these criteria in combination with each other to identify patients with rapid disease progression, and the clinical effectiveness of treatment in the presence of these criteria. However, currently these criteria cannot be used in decision‑making.

The Committee considered the clinical evidence presented by the Assessment Group and noted that the network meta‑analysis had been updated after consultation on the assessment report and economic model. The Committee heard from the companies that they had concerns with some trials that were included in the Assessment Group's analyses, in particular Swefot, in which a small proportion of people had switched to etanercept. The Committee also noted concerns from the companies that some trial data were not included in the Assessment Group's base‑case analyses, notably RAPID 1, RAPID 2, JRAPID, FAST4WARD and HIKARI. The Committee heard from the Assessment Group that they considered the proportion of people in Swefot who switched to etanercept be sufficiently small (5 in approximately 100) to be unlikely to affect the overall results. The Committee also heard that the Assessment Group had excluded trials that included people who had previously had biological treatments; this approach was supported by some stakeholders, but it meant that the RAPID trials for certolizumab pegol were excluded. The Assessment Group clarified that these had been included in both clinical and cost‑effectiveness sensitivity analyses, so that the effect on the ICERs of the inclusion and exclusion criteria of the systematic review could be seen. The Committee understood that the Assessment Group's systematic review had excluded some certolizumab pegol monotherapy data, but that this had been provided by the company. The Assessment Group noted that the ICERs were not sensitive to the estimates of initial treatment response. The Committee accepted the Assessment Group's explanation. It concluded that it was appropriate to consider the main analysis presented by the Assessment Group and also their sensitivity analyses using the wider set of clinical trials.

The Committee discussed the results of the network meta‑analyses done by the Assessment Group. It noted that for the analysis of rheumatoid arthritis not previously treated with methotrexate, intensive combination DMARDs appeared to have a similar probability of response as the biological DMARDs. However, for rheumatoid arthritis previously treated with methotrexate, analyses showed a bigger difference in the probability of response between conventional DMARDs and biological DMARDs. The Committee discussed whether the clinical evidence suggested that 1 biological DMARD might be more effective than the others. It considered that for all of the biological DMARDs there were similar results for both ACR and EULAR response, and that the overlapping credible intervals were often wide, indicating uncertainty in the true estimate of effect. The Committee concluded that the evidence of greater clinical effectiveness for biological DMARDs compared with conventional DMARDs was more compelling in disease previously treated with methotrexate and that the evidence did not suggest differential effectiveness between the biological DMARDs. The clinical experts confirmed that this was their view too.

The Committee considered the economic models submitted by the companies. The Committee noted that most of the companies' models had used ACR response criteria, which, although reflecting the measure often used in the clinical trials, did not reflect the measures used in UK clinical practice. It noted that none of the models submitted by the companies used EULAR response data for all of the populations and interventions specified in the scope, whereas the model developed by the Assessment Group did. The Committee concluded that the use of the EULAR response measure was appropriate and that the Assessment Group's model most accurately reflected rheumatoid arthritis care in the UK. The Committee understood that using EULAR response had meant that a smaller number of trials could be taken into account, but noted that the effect of the full set of trials was considered, by mapping ACR response data to EULAR scores when necessary.

The Committee noted that the Assessment Group completed a series of analyses to make the assumptions used in their model more similar to those used in the companies' models and the models used in the previous NICE technology appraisals. The Committee understood from the Assessment Group that these analyses – using the rates of underlying disease progression and discount rates used in previous appraisals – produced ICERs that were not dissimilar to those seen in previous appraisals. The Committee was aware of comments from consultation that the Assessment Group model did not associate increases in HAQ with increases in expected mortality, as had been modelled in previous appraisals. It heard from the Assessment Group that the evidence they identified reported that baseline HAQ was associated with mortality risk, and change in HAQ did not improve predictive accuracy. The Committee concluded that the Assessment Group model was appropriate to use for decision‑making purposes.

The Committee understood that infliximab biosimilars were now available in the NHS and that the scope of the appraisal had been updated to include these. It heard from the clinical experts that policies differ, but in their trusts people starting treatment may have a biosimilar. However, if a person is already on a treatment and their disease is responding, they would not be switched to a biosimilar. The clinical experts noted that few people start treatment with infliximab because it is given by infusion rather than subcutaneous injection and is associated with greater administration costs than other TNF‑alpha inhibitors. The Committee discussed comments from consultation that biosimilar products should not be considered interchangeable with the originator products. It understood that the approach adopted by NICE in this appraisal was consistent with the NICE position statement on biosimilars and that the regulatory authorities had concluded that infliximab biosimilars were sufficiently similar to the originator product to be granted marketing authorisation. The Committee noted that the NHS contract price for infliximab biosimilars was lower than the list price because of tendering by the NHS Commercial Medicines Unit. It noted that the prices from the NHS Commercial Medicines Unit had been included in sensitivity analyses completed by the Assessment Group (see section 4.88). The Committee concluded that the ICERs for the infliximab biosimilars were a relevant consideration.

The Committee discussed the sensitivity analyses done by the Assessment Group to identify the key drivers of the cost‑effectiveness results. It noted that including or excluding trials (for example, trials that included previous biological DMARD use) and including adverse events had relatively modest effects on the ICERs, compared with the assumptions about mapping of HAQ to utility, discount rates and underlying disease progression while having treatment with conventional DMARDs. The Committee, while noting concerns about the studies included by the Assessment Group in the network meta‑analysis, concluded that the effect of including or excluding the trials on the ICERs was not large enough to affect decision‑making in this appraisal, and that the assumptions about the progression of disease and its effect on health‑related quality of life were key drivers for decision‑making.

The Committee initially discussed the assumptions about underlying disease progression used in the companies' submissions and in previous NICE technology appraisal guidance. These assumptions were a worsening in HAQ score of 0.00 per year for biological DMARDs, 0.045 for conventional DMARDs and 0.06 for palliative care for people with disease that was not responding to treatment. These changes were assumed to accrue each year until the person reached an HAQ score of 3 (that is, the worst HAQ score). The Committee heard from the Assessment Group that these assumptions were made based on a study in Finland that showed the annual change in HAQ score for the general rheumatoid arthritis population was 0.03. The Assessment Group for previous NICE technology appraisals had assumed that HAQ score during palliative care changes at twice the rate of the general population, and that for conventional DMARDs it was halfway between 0.03 and 0.06, which was 0.045. The Committee, although aware of the use of these values in previous appraisals, concluded that there was limited evidence to support these assumptions.

The Committee discussed the assumptions made by the Assessment Group about underlying disease progression for people having biological DMARDs. The Committee noted that the Assessment Group assumed a 0.00 change in HAQ score for people having biological DMARDs, which was the same as that used by the companies. The Committee noted that the Assessment Group did not rely on the assumptions from previous NICE technology appraisal guidance to obtain this value; rather, it had analysed data from the BSRBR that confirmed there was no change in HAQ score while on treatment. The Committee accepted the Assessment Group's assumption that there was no disease progression while people were having biological DMARDs.

The Committee then considered the assumptions made by the Assessment Group about underlying disease progression for people having conventional DMARDs. It noted that an initial error had been corrected in the model, and that the model now included disease progression for patients with disease that had not responded at the start of treatment. It also noted that although the Assessment Group's report referred to this parameter as progression while on conventional DMARDs, the parameter more accurately reflected progression while on all non‑biological treatments (for example, conventional DMARDs, surgery and glucocorticoids). The Committee noted that the estimate of disease progression had been obtained from an alternative source to that of the biological DMARDs; the ERAS dataset. This dataset suggested an initial decrease (improvement) in HAQ score for the first 2 years, followed by an increase (worsening) in HAQ score for the following 5 years, with a slowing down in worsening approximately 7 to 10 years after diagnosis. The Committee heard from the Assessment Group that their estimate of the rate of disease progression was higher in the first 7 years than the assumption of 0.045 made by the companies, but that it reduced after this. The Assessment Group commented that this avoided the assumption that a large proportion of patients progress to an HAQ score of 3 before death, which is not supported by observational data. The Assessment Group also stated that the original analyses from ERAS (showing the slowing down of worsening) were also supported by its analyses of the NOAR and ERAN datasets. The Committee heard from the clinical experts that, although they accepted that there was no perfect dataset available, they had concerns about the use of these data because ERAS was a general rheumatoid arthritis cohort and would not be representative of people who would be likely to use biological DMARDs. The Committee heard from the Assessment Group that it recognised that ERAS was a mixed cohort and that, rather than using the ERAS dataset as it existed, a model was developed that included patient characteristics as covariates, so that patients with characteristics similar to those likely to have biological DMARDs were sampled. This meant that overall the Assessment Group sample had a larger proportion of people with more rapid progression of disease than in the ERAS dataset as a whole. The Committee accepted that there were limitations with the model developed by the Assessment Group for estimating the underlying progression of disease while on conventional DMARDs. However, any limitations also needed to be balanced with the limitations of the methods used for obtaining the estimates used in previous NICE technology appraisals.

The Committee considered both of the approaches used to model the underlying progression of disease while having conventional DMARDs. The Committee noted that the previous approach to modelling HAQ trajectory with conventional DMARD therapy was based on a series of assumptions that had limited evidence to support them. The Committee also noted that the Assessment Group's approach to modelling the progression of disease was informed by more evidence, but there may be limitations with using the ERAS dataset. However, the Committee considered that the Assessment Group's analysis (showing a decrease over time of the rate of underlying disease progression) had greater clinical plausibility than the linear estimates of the rate of disease progression, because observational studies do not show large proportions of people in the worst HAQ score states. The Committee accepted the Assessment Group's method for modelling disease progression while having conventional DMARDs. It concluded that the Assessment Group's model more accurately represented disease progression with conventional DMARDs than the assumptions used in previous NICE technology appraisals.

The Committee examined the different methods that had been used to obtain EQ‑5D from HAQ scores. It understood that the Assessment Group had used a function from a mixture model developed using the NDB and ERAS datasets. This estimated EQ‑5D using both HAQ score and pain score. The Committee noted that in response to comments on the assessment report the function had been updated, and that the model fit had been improved. It heard from the Assessment Group that it had used an alternative approach and dataset (the NDB dataset) to that used in previous appraisals and in some of the company models (Malottki et al. 2011). This was because the use of linear regression in Malottki et al. to estimate EQ‑5D was not appropriate, because EQ‑5D scores are not normally distributed. Further, the ERAS and NDB datasets are also larger than that used in Malottki et al. and have a higher number of patients at the severe end of the HAQ scale, which is the population of greatest relevance to the appraisal. Finally, the Committee heard from the Assessment Group that the function in Malottki et al. was associated with the biggest range of EQ‑5D estimated from HAQ compared with other available equations, and therefore they considered it to be an outlier. The Committee concluded that the Assessment Group's method of estimating EQ‑5D from HAQ was appropriate to use in decision‑making.

The Committee noted that the original NICE technology appraisal guidance had used a different set of discount rates to the appraisal review. The original guidance used discount rates of 6% for costs and 1.5% for benefits, whereas the analyses in the review used a 3.5% discount rate for both costs and benefits, as specified in NICE's guide to the methods of technology appraisal. The Committee was aware that sensitivity analyses using the previous discount rates significantly reduced the ICER. The Committee discussed the fact that the discount rates were inconsistent between the original guidance and the review, but it considered that for recommendations being made at the same point in time the same discount rates should be used. The Committee was also aware of the economic rationale for equal discount rates for costs and benefits. The Committee also noted consultation comments and discussed whether the alternative discount rates described in section 6.2.19 of NICE's guide to the methods of technology appraisal would apply to rheumatoid arthritis. It understood that the criteria in the methods guide were for use when the costs of a treatment were accrued at the beginning of treatment, but the benefits only accrued in the long term. It concluded that the circumstances described in the methods guide did not apply to ongoing treatment. The Committee concluded that using a 3.5% discount rate for both costs and benefits, in line with the current NICE methods guide, was appropriate.

The Committee noted that the Assessment Group had done an analysis using the rates of HAQ progression for people with rapid disease progression, and that this reduced the base‑case ICERs for the severe active population who can have methotrexate from £41,600 to £25,300 per QALY gained. For the severe active population having monotherapy, the ICER changed from £48,300 to £29,000 per QALY gained. The Committee noted that this analysis was not based on a patient subgroup defined by a pre‑specified set of characteristics; rather, it used the fastest rates of disease progression observed in each of the latent classes in the Assessment Group's analysis of HAQ progression for conventional DMARDs. The Committee discussed whether this analysis could be used as the basis for decision‑making. The Committee considered that there was uncertainty in the analysis because it was not based on a set of patients defined by their characteristics. The Committee concluded that it had not been presented with sufficient clinical evidence about the characteristics of patients with rapid disease progression to be able to use the Assessment Group's exploratory analysis as the basis for decision‑making (see section 4.94). However, it considered that such patients would be a subset of those currently having biological DMARDs (see section 4.91) and concluded that the Assessment Group's ICER for the severe active subgroup may be overestimated.

The Committee considered the most appropriate ICERs for the population with severe active rheumatoid arthritis that has not been treated with methotrexate. Based on the clinical expert comments, the Committee considered that intensive therapy with combination DMARDs was the appropriate comparator. The Committee noted that AbbVie had submitted an ICER for adalimumab plus methotrexate compared with methotrexate plus hydroxychloroquine of £70,000 per QALY gained, and that Pfizer's analysis suggested that the ICER for etanercept plus methotrexate compared with combination conventional DMARDs was £34,400 per QALY gained. The Committee noted that the Assessment Group's base‑case ICER for the population who have not had methotrexate before, but who could have it, was £68,300 per QALY gained. For the population who have not had methotrexate before and who cannot have it, the ICER was £77,500 per QALY gained. The Committee, noting the clinical expert comments that there was limited clinical interest in using biological DMARDs before methotrexate, concluded that biological DMARDs were not cost effective for people who had severe active rheumatoid arthritis not previously treated with methotrexate.

The Committee considered the most appropriate ICERs for the population with severe active rheumatoid arthritis previously treated with methotrexate. The Committee accepted the use of the ERAS dataset to estimate underlying disease progression for conventional DMARDs, the Assessment Group's HAQ‑to‑utility mapping function, and discount rates of 3.5%. It considered that the most plausible ICER for biological DMARDs used in severe active rheumatoid arthritis was likely to lie between the Assessment Group's base‑case ICER (that is, £41,600 per QALY gained) and the Assessment Group's ICER for the exploratory analysis for the severe group with the fastest HAQ progression (that is, £25,300 per QALY gained). Noting that the upper end of this range was higher than the range of ICERs normally considered a cost‑effective use of NHS resources (£20,000 to £30,000 per QALY gained) the Committee discussed whether there were other factors that should be taken into account in its decision‑making. It noted that the biological DMARDs have significantly changed the management of rheumatoid arthritis, affecting surgery rates and hospitalisation. The Committee agreed that the biological DMARDs should be considered an innovative class of drugs. It also noted the comments from patient experts that biological DMARDs provide extensive benefits for people with rheumatoid arthritis and their families, in terms of both physical and mental health. It understood that the physical health benefits associated with biological DMARDs may encompass improvements in pain and cardiovascular health as well as benefits to the musculoskeletal system. On balance, based on the range of the most plausible ICERs, the Committee concluded that biological DMARDs in combination with methotrexate were a cost‑effective use of NHS resources for people with severe active rheumatoid arthritis previously treated with methotrexate.

The Committee discussed criteria for starting and stopping treatment with biological DMARDs. It noted data from the BSRBR that not all patients having treatment with biological DMARDs are recorded as having a response to treatment. It heard from the clinical expert that stopping rules should be applied, so that patients whose disease is not responding stop having an ineffective treatment that is not controlling disease and could potentially be causing adverse effects. The Committee understood from clinical experts that, before starting treatment with biological DMARDs, patients should have had intensive combination therapy with conventional DMARDs. It also noted that the basis of the ICERs in the Assessment Group's modelling was DAS28 and a moderate EULAR response. The Committee, although aware of the limitations of the DAS score, concluded that it was appropriate to base starting and stopping criteria on DAS28 and moderate EULAR response (because of their use in the calculation of the ICERs) plus the failure of intensive combination treatment with conventional DMARDs.

The Committee discussed the most plausible ICERs for the population with moderate active rheumatoid arthritis. It noted that the ICERs for this group were higher than those for the severe active group for the analyses presented by the Assessment Group. For the biological DMARDs used in moderate active rheumatoid arthritis, the most plausible ICER was the median, £51,100 per QALY gained (using the EULAR main analysis), approximately £10,000 higher than the upper end of the range for the severe active population. The Committee noted that the ICER reduced to the lowest bound of the ICER range of £28,500 per QALY gained when using the exploratory analysis for the moderate active group with the fastest HAQ progression. The Committee was not persuaded that the exploratory analysis for the moderate active group was as applicable to this group as to the severe active group. It noted that the analysis was retrospective and was not based on pre‑identifiable patient characteristics which could inform a decision about whether or not a treatment should be offered. The assumptions were also highly uncertain and none of them were directly linked with the work done by the DSU. It also noted that the assumptions were very favourable, such as all patients would have the worst possible trajectory. Furthermore, the Committee did not find it plausible that the £28,500 ICER would apply to approximately one third to one half of patients with moderate active disease that the measures in section 4.94 would identify. The Committee accepted that current clinical management includes treating severe active disease that is progressing rapidly (see section 4.91), therefore the Assessment Group's base‑case ICER would be an overestimate. However, the Committee was not persuaded that expanding treatment to include moderate disease activity would also target those patients whose disease was progressing rapidly. It was not persuaded that the alternative treatment criteria proposed could be currently used in decision‑making (see section 4.94). The Committee noted the reduction in the ICER to £37,600 per QALY gained for infliximab biosimilars, but was aware of statements from clinical experts that infliximab was not frequently used in the NHS because of its mode of administration. The availability of infliximab biosimilars did not change its decision. It also understood that the benefits to physical and mental health for patients with rheumatoid arthritis and their families (see sections 4.89 and 4.109) would also apply to moderate active disease, but noting the higher base‑case ICER for the moderate active population compared with the severe active population, the Committee was not persuaded that these factors changed its decision. The Committee concluded that at current prices the biological therapies could not be considered a cost‑effective use of NHS resources for patients with moderate active disease.

The Committee discussed the ICERs for biological monotherapy, noting that these were higher than those for combination therapy. The Committee heard from the Assessment Group that the higher ICERs were mainly driven by the costs of treatments given after the failure of the first biological DMARD, and less costly rituximab not being available to people who cannot take methotrexate (because it has to be given in combination with methotrexate). The Committee noted the results of the exploratory analyses of the Assessment Group, which included rituximab in the monotherapy treatment sequence. The Committee noted that these ICERs were comparable to those for combination therapy. It also noted comments from consultation that rituximab may be used in clinical practice as monotherapy, even though it is not licensed. The Committee concluded that the base‑case ICERs for monotherapy were higher than those for combination therapy. However, it accepted that this was mainly because of the costs of later treatments rather than the costs or benefits associated with the first biological DMARD. It also 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 concluded that biological DMARDs, for which the marketing authorisation allows, should be recommended as a cost‑effective use of NHS resources when used as monotherapy for severe active disease previously treated with DMARDs.

The Committee considered whether it should take into account the consequences of the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism, when appraising adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept. The Appraisal Committee noted NICE's position statement about this, and accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The Committee heard nothing to suggest that there is any basis for taking a different view with regard to the relevance of the PPRS to this appraisal of adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept. It therefore concluded that the PPRS payment mechanism was irrelevant for the consideration of the cost effectiveness of adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept.

There were no equality issues raised during the Committee discussion.