Rheumatoid arthritis - adalimumab, etanercept and infliximab (sequential use): appraisal consultation document

NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE
Appraisal consultation document
Adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis after failure of a TNF-alpha inhibitor

The Department of Health and the Welsh Assembly Government have asked the National Institute for Health and Clinical Excellence (NICE or the Institute) to conduct a multiple technology appraisal of adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis after the failure of a TNF-alpha inhibitor and provide guidance on their use to the NHS in England and Wales. The Appraisal Committee has had its first meeting to consider both the evidence submitted and the views put forward by non-manufacturer consultees and commentators, and by the clinical specialist and patient expert representatives nominated for this appraisal by non-manufacturer consultees and commentators. The Committee has developed preliminary recommendations on the use of adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis after the failure of a TNF-alpha inhibitor.

This document has been prepared for consultation with the formal consultees. It summarises the evidence and views that have been considered and sets out the preliminary recommendations developed by the Committee. The Institute is now inviting comments from the formal consultees in the appraisal process (the consultees for this appraisal are listed on the NICE website, www.nice.org.uk). This document should be read in conjunction with the evidence base for this appraisal (the evaluation report) which is available from www.nice.org.uk

Note that this document does not constitute the Institute's formal guidance on adalimumab, etanercept and infliximab. The recommendations made in section 1 are preliminary and may change after consultation.

The process the Institute will follow after the consultation period is summarised below. For further details, see the 'Guide to the technology appraisal process' (this document is available on the Institute's website, www.nice.org.uk).

  • The Appraisal Committee will meet again to consider the original evidence and this appraisal consultation document in the light of the views of the formal consultees.
  • At that meeting, the Committee will also consider comments made on the document by people who are not formal consultees in the appraisal process.
  • After considering feedback from the consultation process, the Committee will prepare the final appraisal determination (FAD) and submit it to the Institute.
  • Subject to any appeal by consultees, the FAD may be used as the basis for the Institute?s guidance on the use of the appraised technology in the NHS in England and Wales.

The key dates for this appraisal are:

Closing date for comments: 20 May 2008

Second Appraisal Committee meeting: 03 June 2008

Details of membership of the Appraisal Committee are given in appendix A, and a list of the sources of evidence used in the preparation of this document is given in appendix B.

Note that this document does not constitute the Institute's formal guidance on adalimumab, etanercept and infliximab. The recommendations made in section 1 are preliminary and may change after consultation.

 

1 Appraisal Committee's preliminary recommendations

This guidance should be read in conjunction with 'Adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis' (NICE technology appraisal guidance 130).

1.1 Adalimumab, etanercept and infliximab, within their licensed indications, are not recommended for the treatment of rheumatoid arthritis after the failure of a tumour necrosis factor alpha (TNF-alpha) inhibitor.

1.2 People with rheumatoid arthritis currently receiving adalimumab, etanercept or infliximab after the failure of a TNF-alpha inhibitor should have the option to continue therapy until they and their clinicians consider it appropriate to stop.

 

2 Clinical need and practice

2.1 Rheumatoid arthritis (RA) is a chronic and progressive disabling condition characterised by inflammation of the synovial tissue of the joints. It causes tenderness, stiffness and progressive destruction of joints, and other symptoms such as pain and fatigue. It affects between 0.5% and 1% of the population, or approximately 400,000 people, in England and Wales. Of these, approximately 15% have severe disease. RA affects three times as many women as men and has a peak age of onset of 40-70 years.

2.2 In RA, the synovium becomes enlarged because of an increase in the number of synovial cells (hyperplasia), infiltration by white blood cells and formation of new blood vessels. There is an increase in fluid-containing inflammatory cells in the joint cavity (effusion) and, secondary to this, thinning of the bone around the joint (periarticular osteoporosis). Erosions of the bone occur where synovial tissue meets cartilage and bone, and these, together with the periarticular bone thinning, lead to irreversible damage to the structure and function of the joint.

2.3 Internationally agreed criteria (American College of Rheumatology [ACR] criteria of 1987) for the diagnosis of RA require four of the following features to be present: morning stiffness in joints exceeding an hour; physician-observed arthritis of three or more areas with soft tissue swelling; arthritis involving hand joints; symmetrical arthritis; rheumatoid skin nodules; a positive blood test for rheumatoid factor; and radiographic changes typical of rheumatoid disease. However, clinicians may diagnose RA without reference to these criteria and patients might not meet formal disease classification criteria early on in their disease.

2.4 The course of RA is heterogeneous and variable. However, a number of factors have been identified as being associated with poor prognosis. These include the presence of rheumatoid factor or anti-cyclic citrullinated peptide (CCP) antibodies, high erythrocyte sedimentation rate or C-reactive protein (CRP) levels, early radiographic evidence of erosions, and the presence of swollen and tender joints. Within 2 years of diagnosis, patients usually experience moderate disability and after 10 years 30% are severely disabled. Approximately a third of patients cease work because of the disease. Life expectancy in patients with RA is also reduced. For example, a 50-year-old woman with RA is expected to die 4 years earlier than a woman without RA.

2.5 There is no cure for RA; conventional treatment aims to control pain and inflammation, and to reduce joint damage, disability and loss of function, thereby improving quality of life. Treatment involves a combination of pharmacological and non-pharmacological interventions. Conventional drug therapy relies on various combinations of non-steroidal anti-inflammatory drugs (NSAIDs), analgesics, corticosteroids and disease-modifying anti-rheumatic drugs (DMARDs). DMARDs act to reduce symptoms and slow progression of structural damage; they are used as monotherapy or in combination, often with steroids. DMARD treatment is started soon after diagnosis, with the aim of trying to achieve remission. Methotrexate and sulfasalazine are DMARDs often used as initial therapy. Non-drug therapies include surgery, physiotherapy and occupational therapy.

2.6 Not all people respond to all DMARDs and, where there is a response to treatment, the response may reduce over time. This means that people with RA usually require a series of treatments. NICE technology appraisal guidance 130 (TA130) recommends the use of one of the TNF-alpha inhibitors adalimumab, etanercept or infliximab after the failure of two conventional DMARDs, including methotrexate. If the first TNF-a inhibitor has to be stopped because of an adverse event in the first 6 months, NICE recommends that a second TNF-alpha inhibitor may be tried. NICE technology appraisal guidance 126 ('Rituximab for the treatment of rheumatoid arthritis') recommends the use of rituximab, a treatment that depletes B cells, which is licensed for people for whom a TNF-alpha inhibitor has failed.

2.7 Several measures have been developed to assess response to treatment in RA. For example, the ACR response criteria (ACR20, 50 and 70) require a specified percentage improvement (20, 50 or 70%, respectively) in tender joint count, swollen joint count, global assessments, pain, disability and circulating inflammatory markers (for example, erythrocyte sedimentation rate or CRP). The disease activity score (DAS) is an alternative scoring system developed in Europe. It is calculated using a formula that includes counts for tender and swollen joints (53 and 44 joints, respectively), an evaluation of general health by the patient (on a scale of 0 to 100) and a measure of circulating inflammatory markers. DAS28 is similar to DAS above but uses only 28 joints for assessment. A DAS28 score greater than 5.1 is considered to be indicative of high disease activity, between 5.1 and 3.2 of moderate disease activity and less than 3.2 of low disease activity. A patient scoring less than 2.6 is defined as being in remission. The European League Against Rheumatism (EULAR) response criteria are based on the DAS measure. A decrease in DAS28 score of 0.6 or less is considered to show a poor response, while decreases greater than 1.2 points indicate a moderate or good response, dependent on whether an individual?s DAS28 score at the end point is above or below 3.2, respectively. The Stanford Health Assessment Questionnaire (HAQ) scores ability to perform daily activities from 0 (least disability) to 3 (most severe disability).

 

3 The technologies

Adalimumab

3.1 Adalimumab (Humira, Abbott Laboratories) is a human-sequence antibody that binds specifically to TNF-alpha and neutralises its biological function by blocking its interaction with cell-surface
TNF-alpha receptors. It also modulates biological responses that are induced or regulated by TNF-alpha, including changes in the levels of adhesion molecules responsible for leukocyte migration. Adalimumab is licensed for the treatment of moderate to severe, active RA in adults when the response to DMARDs, including methotrexate, has been inadequate, and for the treatment of severe, active and progressive RA in adults not previously treated with methotrexate. The summary of product characteristics (SPC) states that adalimumab should be given in combination with methotrexate, except where methotrexate is not tolerated or is considered inappropriate.

3.2 According to the SPC, common adverse events reported during adalimumab therapy include injection site reactions and infections. Before initiation of therapy, all patients must be evaluated for both active and inactive (latent) tuberculosis infection. Adalimumab is contraindicated in people with moderate to severe heart failure, active tuberculosis or other active infections. For full details of side effects and contraindications, see the SPC.

3.3 Adalimumab is administered at a dose of 40 mg every other week via subcutaneous injection. In monotherapy, if patients experience a decrease in response the dose may be increased to 40 mg every week. The net price for a 40-mg prefilled syringe is £357.50 (excluding VAT; 'British National Formulary' [BNF] edition 55). The annual cost of adalimumab for 26 doses at a dose of 40 mg every other week is £9295. Costs may vary in different settings because of negotiated procurement discounts.

Etanercept

3.4 Etanercept (Enbrel, Wyeth Pharmaceuticals) is a recombinant human TNF-alpha-receptor fusion protein. It interferes with the inflammatory cascade by binding to TNF-alpha, thereby blocking its interaction with cell-surface receptors. Etanercept is licensed for use in adults with active RA whose response to DMARDs, including methotrexate, has been inadequate. Etanercept is also licensed for the treatment of severe, active and progressive RA in adults not previously treated with methotrexate. The SPC states that, for people who have had an inadequate response to conventional DMARDs, etanercept should be given in combination with methotrexate, except where methotrexate is not tolerated or is considered inappropriate.

3.5 According to the SPC, the most frequent adverse events reported during etanercept therapy include injection-site reactions, infections and allergic reactions. Etanercept is contraindicated in patients with sepsis or at risk of sepsis and in those with other active infections. For full details of side effects and contraindications, see the SPC.

3.6 Etanercept is administered by subcutaneous injection at a dose of 25 mg twice weekly. Alternatively, the SPC allows for a dose of 50 mg once weekly. Etanercept is available either in vials as powder for reconstitution or in prefilled syringes. The net price for both a 25-mg vial and a 25-mg prefilled syringe is £89.38 (excluding VAT; BNF edition 55). The annual cost of etanercept using either 52 once-weekly doses or 104 twice-weekly doses is £9295. Costs may vary in different settings because of negotiated procurement discounts.

Infliximab

3.7 Infliximab (Remicade, Schering-Plough Ltd) is a chimeric monoclonal antibody that binds with high affinity to TNF-alpha, thereby neutralising its activity. Infliximab is licensed for the treatment of active RA where the response to DMARDs, including methotrexate, has been inadequate, and for patients with severe, active and progressive disease not previously treated with methotrexate or other DMARDs. The SPC specifies that infliximab must be used in combination with methotrexate.

3.8 According to the SPC, the most common adverse events reported during infliximab therapy include acute infusion-related reactions and infections. Infliximab is contraindicated in people with moderate or severe heart failure and active infections. Before treatment is initiated, people must be screened for both active and inactive tuberculosis. For full details of side effects and contraindications, see the SPC.

3.9 The starting dose for infliximab is 3 mg/kg administered by intravenous infusion over 2 hours at weeks 0, 2 and 6, and thereafter every 8 weeks. If a person has an inadequate response, or response is reduced, consideration may be given to increasing the dose step-wise by approximately 1.5 mg/kg, up to a maximum of 7.5 mg/kg every 8 weeks. Alternatively, administration of 3 mg/kg as often as every 4 weeks may be considered. If an adequate response is achieved, the person should be continued on the selected dose or dose frequency. The net price for a 100-mg vial is £419.62 (excluding VAT; BNF edition 55). The dosing of infliximab depends on the weight of the person to be infused. If a person weighs 70 kg, each dose of infliximab, at the licensed starting dose, requires three vials at a cost of £1259, assuming vial wastage. The three loading doses cost £3777, with an annual cost following the loading doses of between £7553 and £8812, depending on whether six or seven doses are required, and assuming that only 3 mg/kg is required once every 8 weeks. Costs may vary in different settings because of negotiated procurement discounts.

 

4 Evidence and interpretation

The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B).

4.1 Clinical effectiveness

4.1.1 Evidence for the clinical effectiveness of the use of a second TNF-alpha inhibitor, and of comparator treatments, was taken from a systematic review completed by the Institute's Decision Support Unit (DSU). Twenty nine studies were identified that investigated the efficacy of the use of a second TNF-alpha inhibitor after the first TNF-alpha inhibitor had failed. Data for one or more specified outcomes (ACR response, DAS28 score, EULAR response and HAQ score change) could be extracted from 19 of these studies, with a further four studies reporting these outcomes for the TNF-alpha inhibitors as a group rather than for the individual drugs. These 23 studies are reported in the following sections. Only one of the studies was a randomised controlled trial. In this study (n = 28), people with an inadequate response to etanercept were randomised to switch to infliximab or to continue with etanercept. The results of the studies could not be combined in meta-analysis. Therefore, only the range of responses observed in studies of a second TNF-alpha inhibitor is reported in the following clinical effectiveness sections.

Adalimumab

4.1.2 Ten studies investigated the effectiveness of adalimumab used after the failure of either etanercept or infliximab, nine of which provided data for the review. Six studies compared the effect seen in first-time users of a TNF-alpha inhibitor with the effect seen in people who had previously used a TNF inhibitor. One study compared the response of the same person to their first and second TNF-alpha inhibitor. The remaining two studies reported the response to a second TNF-alpha inhibitor but did not draw comparisons with response to the first. The follow up in the studies ranged from 12 to 52 weeks. Five studies reported ACR response rates. The ACR20 response rates for adalimumab as a second TNF-alpha inhibitor ranged from 49% to 89%, ACR50 response rates ranged from 26% to 56% and ACR70 response rates ranged from 13% to 33%. Eight studies reported decreases in DAS28 score, which ranged from 0.9 to 2.7. EULAR response rates were reported in six studies. Non-response rates ranged from 22% to 62%, moderate response rates ranged from 25% to 62% and good response rates ranged from 7% to 25%. Three studies reported improvements in HAQ score, which ranged from 0.22 to 0.51.

4.1.3 The largest of the comparative studies was the Research in Active Rheumatoid Arthritis (ReACT) study, which investigated the response to adalimumab after the failure of a different TNF-alpha inhibitor in 899 people, compared with the response in 5711 people who had not previously had a TNF-alpha inhibitor. This study suggested that the response to adalimumab was lower in people who had previously had a different TNF-alpha inhibitor than in those who were TNF-alpha inhibitor naïve. It also suggested that the response rate to adalimumab was lowest among people who were non-responders to their first TNF-a inhibitor, rather than people who had had a reduction in the response to their first TNF-a inhibitor. These findings were supported by the other comparative studies.

Etanercept

4.1.4 Fourteen studies investigated the effectiveness of etanercept used after the failure of either infliximab or adalimumab, ten of which provided data for the review. One study compared the effect seen in first-time users of a TNF-alpha inhibitor with the effect seen in people who had previously used a TNF-alpha inhibitor. One study compared the response of the same person to their first and second TNF-alpha inhibitor. One study compared the effect seen in people who switched to etanercept with that seen in people who switched to infliximab and one study compared the effect seen in people who switched TNF-alpha inhibitor with that seen in people who stayed on the same TNF-alpha inhibitor. A further five studies only reported response to a second TNF-alpha inhibitor without drawing comparisons with the response to the first TNF-alpha inhibitor, and one study included no numerical data for the comparator. Follow up in the studies ranged from 12 to 26 weeks. Five studies reported ACR response rates. ACR20 response rates for etanercept as a second TNF-a inhibitor ranged from 38% to 90%, ACR50 response rates ranged from 23% to 66% and ACR70 response rates ranged from 5% to 33%. Six studies reported decreases in DAS28 score, which ranged from 1.2 to 2.4. EULAR response rate was reported in five studies. EULAR non-response rates ranged from 17% to 46%, moderate response rates ranged from 16% to 67% and good response rates ranged from 12% to 58%. Two studies reported improvements in HAQ score, one of 0.41 and the other of 0.45.

4.1.5 In the study that compared the second use with the first use of etanercept in different groups of people, the response rate to a second TNF-alpha inhibitor was lower. In the study that compared response rates for a second TNF-alpha inhibitor with the same person's response to their first TNF-alpha inhibitor, response rates were similar. A study that compared switching TNF-alpha inhibitors with staying on the same TNF-a inhibitor suggested higher response rates if a person changed TNF-alpha inhibitor. Another study, which compared people who switched from etanercept to infliximab with those who switched from infliximab to etanercept, suggested that switching to etanercept was associated with higher response rates than switching to infliximab.

Infliximab

4.1.6 Nine studies investigated the effectiveness of infliximab used after the failure of either etanercept or adalimumab, five of which provided data for the review. One randomised controlled trial compared switching to infliximab with staying on etanercept. One study compared the effect seen in first-time users of a TNF-a inhibitor with the effect seen in people who had previously used a TNF-alpha inhibitor. One study compared the effect seen in people who switched to etanercept with that seen in people who switched to infliximab. One study only reported response to a second TNF-alpha inhibitor without drawing comparisons with the response to the first, and one study included no numerical data for the comparator. The follow up in the studies ranged from 12 weeks to 26 weeks. Two studies reported ACR20 response rates for a second TNF-alpha inhibitor of 62% and 67%, one study reported an ACR50 response rate of 31%, but no studies reported ACR70 response rates. Four studies reported decreases in DAS28 score, which ranged from 0.9 to 2.2. Two studies reported EULAR responses rates, one of which had two groups. EULAR non-response rates ranged from 25% to 33%, moderate response rates ranged from 33% to 75% and good response rates ranged from 25% to 33%. One study reported an improvement in HAQ score of 0.13.

4.1.7 In a study that compared response rates for first and second TNF-alpha inhibitor in the same group of people, results were inconsistent across outcomes. A study that compared switching to a different TNF-a inhibitor with staying on the same TNF-alpha inhibitor suggested that switching was more effective. A final study, which compared people who switched from etanercept to infliximab with those who switched from infliximab to etanercept, suggested that switching to infliximab was less effective than switching to etanercept.

TNF-alpha inhibitors as a group

4.1.8 Five studies investigated the effect of sequential use of TNF-alpha inhibitors but reported results for TNF-alpha inhibitors only as a group. Four of these studies provided data for the review. Two of these studies compared switching to a second TNF-alpha inhibitor with switching to rituximab, and two made no comparisons. The follow up in the two comparative studies was 12 weeks, one study included 20 people switching to a second TNF-alpha inhibitor and 10 people switching to rituximab, the other included 66 and 50 people, respectively. Both studies reported similar results: decreases in DAS28 score of 0.8 for the TNF-alpha inhibitor groups, and of 1.48 in one study and 1.28 in the second study for the groups switching to rituximab.

4.1.9 Data for the effectiveness of TNF-a inhibitors as a group are also available from two observational registries. The first, the British Society for Rheumatology Biologics Register (BSRBR), has data from 308 people who switched to a second TNF-alpha inhibitor. For people who had been followed up for at least 6 months, the data suggested an unadjusted improvement in HAQ score for a second TNF-alpha inhibitor of 0.15 (unadjusted) and 0.21 (adjusted for confounders). In comparison, for people starting their first TNF-alpha inhibitor, the BSRBR shows an improvement in HAQ score of 0.30 (unadjusted) after 6 months. In addition, a regression analysis of data from the BSRBR suggested that the likelihood of response for an 'average' person to a second TNF-alpha inhibitor was lower than for the first TNF-alpha inhibitor. The second observational registry is the US National Databank for Rheumatic Diseases. This register has data for 284 people who switched TNF-alpha inhibitors. These data suggest an improvement in HAQ score of 0.04 after a year's follow up. No comparative data for first use of a TNF-alpha inhibitor were available.

Conventional DMARDs

4.1.10 None of the studies identified in the systematic review enabled direct comparisons to be made between switching to a second TNF-alpha inhibitor and returning to conventional DMARDs. A separate review of the literature identified no studies that had investigated the effect of conventional DMARDs in a group of people for whom TNF-alpha inhibitors had failed. Four studies were identified that investigated the effect of conventional DMARDs in people with established RA (on average greater than 3 years). However, none of these studies included people for whom a TNF-alpha inhibitor had failed. The study that included people with the longest disease duration was an analysis of data from the control group in the BSRBR. This study suggests that for conventional DMARDs the probability of EULAR response is reduced slightly as the disease duration and the number of prior treatments increases.

4.1.11 Two further studies were identified that investigated the use of novel treatments, in people for whom TNF-alpha inhibitors had failed, in comparison with placebo when added to an ongoing DMARD regimen. Although not measuring the effect of an individual DMARD, these studies may provide an indication of the effect (mean improvement in HAQ score of 0.11) of conventional DMARDs when used in people for whom TNF-alpha inhibitors have failed. Unpublished data were also identified from the US National Databank of Rheumatic Diseases. These data suggest no change in HAQ score after follow up of year for people who had switched to conventional DMARDs after having had a TNF-alpha inhibitor.

4.2 Cost effectiveness

4.2.1 Two manufacturers (Abbott Laboratories and Wyeth Pharmaceuticals) included analyses of sequential use of TNF-alpha inhibitors in their submissions for TA130. Both assumed no reduction in effectiveness when a TNF-alpha inhibitor was used after the failure of another. Analyses from the manufacturer of adalimumab suggested that providing adalimumab as a fifth-line therapy after infliximab had failed gave an estimate of incremental cost effectiveness of £19,800 per additional quality-adjusted life year (QALY) gained. Analyses from the manufacturer of etanercept provided estimates of incremental cost effectiveness of between £15,000 to almost £25,500 per additional QALY gained, depending on the exact sequence of TNF-alpha inhibitors used. In addition, sequential analyses were provided by the Arthritis Musculoskeletal Alliance based on data from the BSRBR. These suggested that providing two TNF-alpha inhibitors sequentially in comparison with a single TNF-alpha inhibitor gave an estimate of incremental cost effectiveness of £27,000 per additional QALY gained. All these analyses were carried out using discount rates of 6% for costs and 1.5% for benefits.

4.2.2 Additional analyses of the cost effectiveness of the sequential use of TNF-alpha inhibitors were carried out using the economic model developed for TA130. The Birmingham Rheumatoid Arthritis Model (BRAM) is an individual sampling model, which assesses the cost effectiveness of adding a TNF-alpha inhibitor to a sequence of DMARDs when compared with the same sequence of DMARDs without a TNF-alpha inhibitor. In this model, the initial age and sex distributions, as well as the starting distribution of HAQ scores, were based on observational data from the Norfolk Arthritis Register, a primary-care-based cohort of patients with inflammatory polyarthritis. Change in HAQ score was modelled as a multiplier of the starting HAQ score, both were sampled from distributions rather than being constant. Utilities were estimated based on a mapping process whereby HAQ scores in the trial were mapped via an algorithm to EQ-5D scores in order to derive estimates of utility. The model included a proportion of people stopping treatment at 24 weeks due to toxicity and lack of efficacy. Joint replacement and associated costs were included in sensitivity analyses.

4.2.3 Analyses were carried out comparing TNF-alpha inhibitors both with rituximab and with conventional DMARDs. For each of these, two sets of analyses were completed each using effectiveness data for TNF-alpha inhibitors from a different source. The first source was the BSRBR, which suggested a mean improvement in HAQ score, on starting treatment, of 0.21, following adjustment for confounding variables. The second source was an adalimumab study (ReACT), which suggested an improvement in HAQ score of between 0.33 and 0.51 depending on the previous treatment used and the reasons for its failure. Each set of analyses was completed twice using effectiveness data for conventional DMARDs after the use of the first TNF-? inhibitors from two different sources. The first source reflected that used in TA130 and was mainly derived from studies of people with early RA rather than people for whom a TNF-alpha inhibitor had failed. The second source was data from the placebo arm of a clinical trial that examined the effectiveness of abatacept for RA in a population for whom a TNF-alpha inhibitor had failed. This study reported an improvement in HAQ score of 0.11 in the placebo arm.

4.2.4 Disease progression was modelled as a constant increase in HAQ score indicating worsening functional ability. On starting treatment, people on a TNF-alpha inhibitor were assumed to have no disease progression until treatment was stopped. People on palliative therapy were assumed to have underlying disease progression twice that of the general population (HAQ score increase of 0.06 a year), while those on conventional DMARDs had an HAQ score increase of 0.045 a year. These assumptions are more favourable to TNF-alpha inhibitors than those that were previously modelled as the base case in TA130, where it was assumed that people on TNF-alpha inhibitors have underlying disease progression commensurate with the general population (HAQ score increase of 0.03 a year). The discount rates for costs and benefits were 3.5% and 3.5% rather than 1.5% and 6%, which were used in TA130.4.2.5 For the comparison of TNF-alpha inhibitors with conventional DMARDs, the cost effectiveness analyses using TNF-alpha inhibitor data from the BSRBR and the data for conventional DMARDs, as had been used in TA130, gave a range of estimates of incremental cost effectiveness of £136,000 to £164,000 per additional QALY gained. Substituting the TNF-alpha inhibitor data with that from the ReACT study reduced the estimate of incremental cost effectiveness to £56,000 to £94,500 per additional QALY gained. Using data for conventional DMARDs from the placebo arm of the abatacept trial and the TNF-alpha inhibitor data from the BSRBR reduced the estimate of incremental cost effectiveness to £44,500 to £47,500 per additional QALY gained. In a scenario that used both the abatacept placebo data and the TNF-alpha inhibitor data from the ReACT study, the estimate of incremental cost effectiveness was £31,000 to £38,700 per additional QALY gained. A threshold analysis demonstrated that for TNF-alpha inhibitors to be cost effective at a threshold of £30,000, the effectiveness had to be slightly greater than that observed in the ReACT study.

4.2.6 Cost-effectiveness analyses were carried out comparing the use of a second TNF-alpha inhibitor with the use of rituximab. These analyses were carried out using the same combinations of TNF-alpha inhibitor and conventional DMARD data, as described in the previous analyses, but also included rituximab in the treatment sequence. The improvement in HAQ score on starting treatment with rituximab was 0.4 based on the results of the Randomised Evaluation of Long-Term Efficacy of Rituximab (REFLEX) trial. In these analyses, it was assumed that people on rituximab had underlying disease progression modelled as an increase in HAQ score of 0.03 per annum, but that people on TNF-alpha inhibitors had no underlying disease progression while on treatment.

4.2.7 For the comparison of switching to a second TNF-alpha inhibitor with switching to rituximab, the cost effectiveness analyses using TNF-alpha inhibitor data from the BSRBR and data for conventional DMARDs, as had been used in TA130, produced a range of estimates of incremental cost effectiveness of £255,000 to £919,000 per additional QALY gained. Substituting the BSRBR TNF-alpha inhibitor data with that from the ReACT study reduced the estimate of incremental cost effectiveness to £56,900 to £138,000 per additional QALY gained. Using alternative data for conventional DMARDs from the placebo arm of the abatacept clinical trial and the TNF-alpha inhibitor data from the BSRBR reduced the estimate of incremental cost effectiveness to £56,400 to £74,800 per additional QALY gained. In a scenario that used placebo data from the abatacept trial to reflect conventional DMARDs and TNF-alpha inhibitor data from the ReACT study, the estimate of incremental cost effectiveness was £32,200 to £50,500 per additional QALY gained.

4.2.8 New cost-effectiveness analyses were carried out examining the impact on cost effectiveness of assuming no vial wastage for infliximab, that is, assuming that any infliximab left over in the vial after withdrawing the appropriate dose for one person can be used for someone else. Using data for TNF-alpha inhibitors from the BSRBR and data for conventional DMARDs, as had been used in TA130, suggested an estimate of incremental cost effectiveness of approximately £100,000 per additional QALY gained if no infliximab is wasted. Using the TNF-alpha inhibitor data from the ReACT study reduced the estimate of incremental cost effectiveness to approximately £40,000 per additional QALY gained. Using alternative data for conventional DMARDs from the placebo arm of the abatacept clinical trial and the TNF-alpha inhibitor data from the BSRBR reduced the estimate of incremental cost effectiveness to approximately £32,000 per additional QALY gained. In a scenario that used placebo data from the abatacept trial to reflect conventional DMARDs and TNF-alpha inhibitor data from the ReACT study, the estimate of incremental cost effectiveness was approximately £22,000 per additional QALY gained.

4.2.9 Additional analyses were also carried out examining the cost effectiveness of infliximab in comparison with conventional DMARDs for those people who required either an increase in the dose of infliximab or an increase in the frequency of dosing either to maintain or to generate a response to treatment. The estimates of incremental cost effectiveness ranged from approximately £40,000 to £211,000 and £60,000 to £314,000 per additional QALY gained for 5 mg/kg and 7.5 mg/kg, respectively. The estimates of incremental cost effectiveness ranged from approximately £41,000 to £224,000 and £61,000 to £320,000 per additional QALY gained when the time between 3 mg/kg doses was reduced to 6 weeks and 4 weeks, respectively. The estimates varied depending on the source of data used for TNF-alpha inhibitors and conventional DMARDs.

4.3 Consideration of the evidence

4.3.1 The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of adalimumab, etanercept and infliximab, having considered evidence on the nature of the condition and the value placed on the benefits of adalimumab, etanercept and infliximab by people with RA, those who represent them, and clinical specialists. It was also mindful of the need to take account of the effective use of NHS resources.

4.3.2 The Committee heard from clinical specialists and patient experts about the clinical management of people with RA. The Committee heard that the management of RA was changing, with more clinicians using an approach of maximising disease control by starting DMARDs early and increasing the dose of DMARDs quickly if control of disease was not achieved. The Committee heard from clinical specialists that, as a consequence of this accelerated approach to DMARD usage, the TNF-alpha inhibitors were initiated sooner after diagnosis than had previously been the case and therefore the characteristics of the people being treated with TNF-alpha inhibitors had changed over time. The Committee considered that these changes to the management of RA needed to be taken into account while it examined the evidence that was available in the appraisal.

4.3.3 The Committee considered the studies of the clinical effectiveness of TNF-alpha inhibitors when used sequentially. The Committee noted that the available evidence was mainly from observational studies that included relatively small numbers of people. The Committee examined registry data from the BSRBR, which showed that the proportion of people responding (that is, the response rate) to a second a TNF-alpha inhibitor as well as the average size of the treatment effect, was lower than the response to a first TNF-alpha inhibitor. The Committee heard from clinical specialists that this was plausible and that the response to a second TNF-alpha inhibitor might be expected to be lower than when a TNF-alpha inhibitor is used for the first time. The Committee concluded that, based on current evidence, a second TNF-alpha inhibitor was clinically effective but likely to be less effective than when TNF-alpha inhibitors were used for the first time. In reaching this conclusion, the Committee noted that while BSRBR data suggested that the response in terms of treatment effect to the second TNF-alpha inhibitor may be about 70% of that to the first, data from a US National Databank for Rheumatic Diseases showed only a very small treatment effect of a second TNF-alpha inhibitor when used after the failure of the first TNF-alpha inhibitor.

4.3.4 The Committee noted that some differences in effectiveness of sequential TNF-alpha inhibitors had been observed between people who had never had a response to the first treatment with a TNF-alpha inhibitor and people who had had a response to treatment that had reduced over time. The Committee also noted observational data that suggested that some sequences of TNF-alpha inhibitors had been shown to be more effective than others with regard to the response to the second. The Committee heard from clinical specialists that differences in response to different treatments may be due to the development of antibodies to specific TNF-alpha inhibitors. However, these may vary and may not be the only mechanism responsible, so differences in response are not predictable. The Committee concluded that there was currently insufficient data to support a conclusion of differential effectiveness for different sequences of TNF-alpha inhibitors. The Committee also concluded that there was insufficient evidence to distinguish between the clinical effectiveness of the second TNF-alpha inhibitor when used in people who did not achieve any response to their first TNF-alpha inhibitor (that is, primary failure) and people who, after an initial response to their first TNF-alpha inhibitor, had experienced a reduction in response (that is, secondary failure).

4.3.5 The Committee was persuaded of the importance of considering specifically the evidence of the effectiveness of conventional DMARDs after the failure of TNF-alpha inhibitors, as this would be an important comparator for a second TNF-alpha inhibitor after failure of the first. The Committee noted that a review of the evidence had identified no studies of the effectiveness of conventional DMARDs after the failure of a TNF-alpha inhibitor. The Committee noted that, although some evidence had been identified for the effectiveness of conventional DMARDs in people with disease of long duration, the relevance of these data to the current appraisal were limited because of the differences in the population characteristics. However, the Committee concluded that the data suggested a decrease in the response to conventional DMARDs with increasing duration of disease and number of prior treatments.

4.3.6 The Committee noted that data had also been provided from the US National Databank for Rheumatic Diseases, which showed that after the failure of a TNF-alpha inhibitor, no change in HAQ score was observed on switching treatment to a conventional DMARD. The Committee heard from clinical specialists that any treatment effect for conventional DMARDs in this situation would be very limited. The Committee heard that the reduced treatment effect for DMARDs was supported by data from the BSRBR, which showed no change in HAQ for people who had stopped TNF-alpha inhibitors, although this was based on an assumption that these people had switched to conventional DMARDs. In addition, the Committee heard from clinical specialists that if people had received appropriate clinical management early in the disease that included rapid escalation of conventional DMARDs, particularly methotrexate, it was less likely that conventional DMARDs would subsequently be effective. However, the Committee considered that the data from the BSRBR and US National Databank for Rheumatic Diseases were consistent with the possibility that conventional DMARDs used after the failure of the first TNF-alpha inhibitor were having a positive effect by preventing further HAQ deterioration. The Committee concluded that the effect of conventional DMARDs in people for whom a TNF-? inhibitor had failed was likely to be small, but that an assumption of zero effect was not supported by the evidence before them.

4.3.7 The Committee examined the cost-effectiveness analysis of sequential use of TNF-alpha inhibitors and considered those carried out using the BRAM, as well as analyses that were available from the BSRBR. The Committee was aware that HAQ score had been used as the basis for the modelling in the BRAM. The Committee heard from clinical specialists that HAQ score was affected by both reversible and irreversible components of the disease process and that for people with long-standing disease the potential for improvements in HAQ may be reduced because of irreversible damage. In addition, as inflammation could be improved by treatment even though HAQ score did not change appreciably, the clinical specialists considered that there could still be an important benefit from treatment in this situation that would not be captured by the HAQ score. The Committee considered that the important factor in the modelling was how HAQ mapped to EQ-5D to produce utility values rather than the HAQ scale itself. The Committee noted that analyses from the BSRBR had used DAS28 response and EQ 5D that had been measured directly from the people with RA that were enrolled in the BSRBR. The Committee noted that the BRAM and BSRBR analyses had used different discount rates, and considered that had the same discount rates been applied to both analyses then the estimates of cost effectiveness would have been similar. The Committee concluded that the different methods of analysis led to similar estimates of cost effectiveness and it was appropriate to use the BRAM as a basis for the consideration of the cost effectiveness of the sequential use of TNF-alpha inhibitors.

4.3.8 The Committee noted that the cost-effectiveness analyses had been carried out assuming no progression of disease while on treatment with TNF-alpha inhibitors, but assuming some progression of disease while on conventional DMARDs and rituximab. The Committee was aware that for TNF-alpha inhibitors this assumed both no underlying deterioration of physical function and no reduction in response to treatment. The Committee was aware that people with RA could experience a reduction in response to treatment and that people without RA experienced some decline in physical function as they aged. Therefore the Committee concluded that the assumption of no deterioration in HAQ score whilst on treatment reflected a favourable modelling scenario for the use the TNF-alpha inhibitors.

4.3.9 The Committee then considered the different sources of clinical effectiveness data that had been used in the economic modelling. The Committee heard that it had not been possible to use data from randomised comparisons in the economic modelling, and that this could affect the robustness of the results. The Committee considered, on the basis of the evidence for this appraisal and the testimony of the clinical specialists, that the values for the clinical effectiveness of conventional DMARDs used in the original assessment report could over estimate the clinical effectiveness of DMARDs used after the failure of a first TNF-alpha inhibitor. However, the Committee noted that the other data source used for the treatment effect of conventional DMARDs in this situation was based on the placebo arm of a clinical trial of abatacept and did not directly measure the effect of a conventional DMARD. The Committee was aware that similar data had been used to represent the effectiveness of conventional DMARDs in the appraisals of rituximab and abatacept. The Committee were mindful of the comments from clinical specialists about the reduced treatment effect of conventional DMARDs at this stage of the disease. Therefore the Committee accepted that it was more appropriate to examine the estimates that had used the placebo data. However, it was not persuaded that the effect of conventional DMARDs could be expected to be substantially less than the placebo arm in the abatacept clinical trial, and considered that the effect was unlikely to be zero.

4.3.10 The Committee considered the sources of clinical effectiveness estimates for TNF-alphainhibitors that had been used in the economic model. The Committee noted that using clinical effectiveness data from the BSRBR produced less favourable estimates of cost effectiveness than using clinical effectiveness data from an adalimumab study (the ReACT study). The Committee heard from clinical specialists that, because of changes in clinical management and differences in clinical practice in other countries, neither source of data necessarily reflected current UK practice or the full implementation of the current NICE guidance. The Committee noted that an analysis to identify the minimum effectiveness required for TNF-alpha inhibitors to be cost effective at a willingness to pay of £30,000 per QALY suggested that the imputed clinical effectiveness would need to be higher than that shown in the ReACT study. The Committee was mindful that if the willingness to pay was £20,000 per additional QALY gained, then TNF-alpha inhibitors would have to be about twice as effective as the current estimates suggested. The Committee concluded that the data available did not support greater clinical effectiveness of TNF-alpha inhibitors than was observed in the ReACT study, and noted that a number of databases suggested estimates that were lower than those in the ReACT study.

4.3.11 In considering the estimates of cost effectiveness, the Committee recognised that infliximab was dosed according to weight and therefore drug costs differed according to the weight of the person. The Committee was aware that this could alter the estimate of cost effectiveness for people of different weights. The Committee was also mindful that the analyses of the cost effectiveness of infliximab assumed no sharing of vial contents between people and that if it was possible to minimise vial wastage then the cost effectiveness would be improved. The Committee considered that it could not be assumed that there would be no vial wastage and that the original estimates of cost effectiveness that assumed that infliximab vials were not shared were appropriate. The Committee appreciated that adjustments to the dosing of infliximab would affect the calculation of cost effectiveness, but did not consider that it would change their view of the underlying estimates of clinical effectiveness.

4.3.12 The Committee noted changes to the licensed indication for infliximab that allowed for an increased dose of infliximab or increased frequency of administration. The Committee noted that the SPC stated that this should be considered for those people who were either not responding to infliximab or for whom the response to infliximab was reduced. The Committee considered on the basis of this information that the assumption in the economic analyses of no additional benefit for the extra cost of increasing the dose of infliximab was appropriate. The Committee concluded that the costs of increasing the dose or frequency of administration of infliximab in order to maintain the same effect would increase the incremental cost effectiveness ratio to the extent that the Committee could not recommend dose escalation or increased frequency of administration of infliximab.

4.3.13 The Committee considered the current NICE guidance on the use of rituximab. It noted that rituximab could be used at the same point in the treatment pathway as a second TNF-alpha inhibitor and could therefore be considered an appropriate comparator for the second use of a TNF-alpha inhibitor. The Committee noted that the estimates of incremental cost effectiveness for a second TNF-alpha inhibitor compared with rituximab using the lower estimates of efficacy for conventional DMARDs were £32,000 (with clinical effectiveness data from the ReACT study) to £75,000 (with clinical effectiveness data from the BSRBR) per additional QALY gained. The Committee was mindful of the issues in interpreting the clinical effectiveness data (discussed in 4.3.9 and 4.3.10), as well as the assumptions about HAQ progression for TNF-alpha inhibitors (discussed in 4.3.8). The Committee therefore concluded that adalimumab, etanercept and infliximab used after the failure of a TNF-alpha inhibitor would not be a cost-effective use of NHS resources in comparison with the use of rituximab.

4.3.14 The Committee was aware that for some people rituximab treatment may not be suitable because of intolerance or contraindications to rituximab or methotrexate. Therefore, the Committee examined the estimates of cost effectiveness for the comparison of use of a second TNF-alpha inhibitor with conventional DMARDs that:

  • assumed no progression of disease while on treatment
  • used data from the placebo arm of an abatacept clinical trial to reflect the treatment effect of conventional DMARDs, and
  • used data from the ReACT study for the effectiveness of a TNF-alpha inhibitor.

The Committee noted that in this scenario the estimates of incremental cost effectiveness were £31,000 to £39,000 per additional QALY gained, but in an alternative scenario with clinical effectiveness data from the BSRBR the estimates were approximately £45,000 per additional QALY gained. The Committee, on balance, was not persuaded that the current evidence available supported the cost effectiveness of TNF-alpha inhibitors when used after the failure of a TNF-alpha inhibitor in comparison with conventional DMARDs. The Committee concluded that adalimumab, etanercept and infliximab used after the failure of a TNF-alpha inhibitor would not be a cost-effective use of NHS resources.

 

5 Implementation

5.1 The Healthcare Commission assesses the performance of NHS organisations in meeting core and developmental standards set by the Department of Health in 'Standards for better health' issued in July 2004. The Secretary of State has directed that the NHS provides funding and resources for medicines and treatments that have been recommended by NICE technology appraisals normally within 3 months from the date that NICE publishes the guidance. Core standard C5 states that healthcare organisations should ensure they conform to NICE technology appraisals.

5.2 'Healthcare standards for Wales' was issued by the Welsh Assembly Government in May 2005 and provides a framework both for self-assessment by healthcare organisations and for external review and investigation by Healthcare Inspectorate Wales. Standard 12a requires healthcare organisations to ensure that patients and service users are provided with effective treatment and care that conforms to NICE technology appraisal guidance. The Assembly Minister for Health and Social Services issued a Direction in October 2003 that requires local health boards and NHS trusts to make funding available to enable the implementation of NICE technology appraisal guidance, normally within 3 months.

5.3 NICE has developed tools to help organisations implement this guidance (listed below). These are available on our website (www.nice.org.uk/TAXXX). [NICE to amend list as needed at time of publication]

  • Slides highlighting key messages for local discussion.
  • Costing report and costing template to estimate the savings and costs associated with implementation.
  • Implementation advice on how to put the guidance into practice and national initiatives which support this locally.
  • Audit support for monitoring local practice.

 

6 Proposed recommendations for further research

6.1 The Committee considered that the following further research would be of value:

  • the clinical effectiveness of the different TNF-alpha inhibitors when used sequentially
  • comparisons of the effectiveness of TNF-alpha inhibitors when used sequentially with previously untried conventional DMARDs
  • investigations of the natural history of RA
  • factors predicting who will respond to treatment with a second TNF-alpha inhibitor.

 

7 Related NICE guidance

Published

  • Abatacept for the treatment of rheumatoid arthritis. NICE technology appraisal guidance 141 (April 2008). Available from www.nice.org.uk/TA141
  • Adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis. NICE technology appraisal guidance 130 (October 2007). Available from www.nice.org.uk/TA130
  • Rituximab for the treatment of rheumatoid arthritis. NICE technology appraisal guidance 126 (August 2007). Available from www.nice.org.uk/TA126
  • Anakinra for rheumatoid arthritis. NICE technology appraisal guidance 72 (November 2003). Available from www.nice.org.uk/TA072

Under development

NICE is developing the following guidance (details available from www.nice.org.uk):

  • Rheumatoid arthritis in adults. NICE clinical guideline (publication expected February 2009).

 

8 Proposed date for review of guidance

8.1 The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider whether the technology should be reviewed. This decision will be taken in the light of information gathered by the Institute, and in consultation with consultees and commentators.

8.2 It is proposed that the guidance on this technology is considered for review in July 2010. This is to coincide with the review date for 'Rituximab for the treatment of rheumatoid arthritis' (NICE technology appraisal guidance 126). The Institute would particularly welcome comment on this proposed date.

David Barnett
Chair, Appraisal Committee
April 2008

 

Appendix A: Appraisal Committee members, guideline representatives and NICE project team

A Appraisal Committee members
The Appraisal Committee is a standing advisory committee of the Institute. Its members are appointed for a 3-year term. A list of the Committee members who took part in the discussions for this appraisal appears below. The Appraisal Committee meets three times a month except in December, when there are no meetings. The Committee membership is split into three branches, each with a chair and vice-chair. Each branch considers its own list of technologies and ongoing topics are not moved between the branches.

Committee members are asked to declare any interests in the technology to be appraised. If it is considered there is a conflict of interest, the member is excluded from participating further in that appraisal.

The minutes of each Appraisal Committee meeting, which include the names of the members who attended and their declarations of interests, are posted on the NICE website.

Dr Ray Armstrong
Consultant Rheumatologist, Southampton General Hospital

Dr Jeff Aronson
Reader in Clinical Pharmacology, University Department of Primary Health Care, University of Oxford
Professor David Barnett (Chair)
Professor of Clinical Pharmacology, University of Leicester

Dr Peter Barry
Consultant in Paediatric Intensive Care, Leicester Royal Infirmary

Professor Stirling Bryan
Head, Department of Health Economics, University of Birmingham

Professor John Cairns
Public Health and Policy, London School of Hygiene and Tropical Medicine

Dr Mark Charkravarty
Director, External Relations, Procter and Gamble Health Care, Europe

Professor Jack Dowie
Health Economist, London School of Hygiene and Tropical Medicine

Ms Lynn Field
Nurse Director, Pan Birmingham Cancer Network

Dr Fergus Gleeson
Consultant Radiologist, Churchill Hospital, Oxford

Ms Sally Gooch
Independent Nursing and Healthcare Consultant

Mr Sanjay Gupta
Former Service Manager in Stroke, Gastroenterology, Diabetes and Endocrinology, Basildon and Thurrock University Hospitals Foundation NHS Trust

Dr Mike Laker (2005-2008)
Medical Director, Newcastle Hospitals NHS Trust

Professor Gary McVeigh
Professor of Cardiovascular Medicine, Queens University, Belfast and Consultant Physician, Belfast Trust

Dr Ruairidh Milne
Senior Lecturer in Public Health, National Coordinating Centre for Health Technology, University of Southampton

Dr Neil Milner
General Medical Practitioner, Tramways Medical Centre, Sheffield

Dr Rubin Minhas
General Practitioner, Coronary Heart Disease Clinical Lead, Medway PCT

Dr John Pounsford
Consultant Physician, Frenchay Hospital, Bristol

Dr Stephen Saltissi
Consultant Cardiologist, Royal Liverpool University Hospital

Dr Lindsay Smith
General Practitioner, East Somerset Research Consortium

Mr Roderick Smith
Finance Director. West Kent PCT

Mr Cliff Snelling
Lay member

Professor Ken Stein (Vice Chair)
Professor of Public Health, Peninsula College of Medicine and Dentistry, University of Exeter

B Guideline representatives

The following individuals, representing the Guideline Development Group responsible for developing the Institute?s clinical guideline related to this topic, were invited to attend the meeting to observe and to contribute as advisers to the Committee.

  • Jill Parnham, Manager, National Collaborating Centre for Chronic Conditions
  • Dr Christopher Deighton, Consultant Rheumatologist, Derbyshire Royal Infirmary

C NICE project team

Each technology appraisal is assigned to a team consisting of one or more health technology analysts (who act as technical leads for the appraisal), a technical adviser and a project manager.

Zoe Garrett
Technical Lead

Janet Robertson
Technical Adviser

Natalie Bemrose
Project Manager


Appendix B: Sources of evidence considered by the Committee

A The assessment report for this appraisal was prepared by West Midlands Health Technology Assessment (HTA) Collaboration, University of Birmingham.

  • Chen Y-F, Jobanputra P, Barton P et al. A systematic review of the effectiveness of adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis in adults and an economic evaluation of their cost-effectiveness, Health Technology Assessment 2006; 10(42).

Extra analysis reports were prepared by the Decision Support Unit, The University of Sheffield, School of Health and Related Research (ScHARR).

  • Wailoo A, Tosh J, The effectiveness of non biologic DMARDS after anti TNF alpha inhibitor failure, January 2008.
  • Wailoo A, The sequential use of TNF alpha inhibitors, January 2008.

Extra analysis report prepared by West Midlands HTA Collaboration, University of Birmingham.

  • Barton P, Further cost-effectiveness analysis of sequential TNF inhibitors for rheumatoid arthritis patients, January 2008.

B The following organisations accepted the invitation to participate in this appraisal. They were invited to comment on the draft scope, assessment report and the appraisal consultation document (ACD). Organisations listed in I, III and III were also invited to make written submissions and have the opportunity to appeal against the final appraisal determination.

I Manufacturer/sponsors:

  • Abbot Laboratories Ltd
  • Wyeth Pharmaceuticals
  • Schering-Plough Ltd

II Professional/specialist and patient/carer groups:

  • Arthritis and Musculoskeletal Alliance
  • Arthritis Care
  • BackCare
  • British Association of Spine Surgeons
  • British Health Professionals in Rheumatology
  • British Institute of Musculoskeletal Medicine
  • British Orthopaedic Association
  • British Society for Rheumatology
  • Department of Health
  • Eastern Hull Primary Care Trust
  • National Rheumatoid Arthritis Society
  • Primary Care Rheumatology Society
  • Royal College of Nursing
  • Royal College of Physicians
  • Royal Pharmaceutical Society of Great Britain

III Other consultees

  • Somerset Coast Primary Care Trust
  • Welsh Assembly Government

IV Commentator organisations (without the right of appeal):

  • Arthritis Research Campaign
  • Board of Community Health Councils in Wales
  • British National Formulary
  • National Public Health Service for Wales
  • NHS Quality Improvement Scotland

C The following individuals were selected from clinical specialist and patient advocate nominations from the non-manufacturer/sponsor consultees and commentators. They participated in the Appraisal Committee discussions and provided evidence to inform the Appraisal Committee's deliberations. They gave their expert personal view on adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis after failure of a different TNF-alpha inhibitor by attending the initial Committee discussion and/or providing written evidence to the Committee. They are invited to comment on the ACD.

  • Dr Robin Butler, Consultant Rheumatologist, Robert Jones and Agnes Hunt Orthopaedic Hospital nominated by British Health Professionals in Rheumatology and British Society for Rheumatology - clinical specialist
  • Dr Frank McKenna, Consultant Physician and Rheumatologist, Trafford General Hospital nominated by the British Society for Rheumatology - clinical specialist
  • Mrs Ailsa Bosworth, Chair of the National Rheumatoid Arthritis Society nominated by the National Rheumatoid Arthritis Society - patient expert
  • Ms Homaira Khan nominated by Arthritis Care - patient expert

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Copyright 2014 National Institute for Health and Care Excellence. All rights reserved.