The Department of Health has asked the National Institute for Health and Clinical Excellence (NICE) to produce guidance on using adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a TNF inhibitor in the NHS in England and Wales. The Appraisal Committee has considered the evidence submitted and the views of non-manufacturer consultees and commentators, and clinical specialists and patient experts.

This document has been prepared for consultation with the consultees. It summarises the evidence and views that have been considered, and sets out the draft recommendations made by the Committee. NICE invites comments from the consultees and commentators for this appraisal (see appendix B) and the public. This document should be read along with the evidence base (the evaluation report), which is available from www.nice.org.uk

The Appraisal Committee is interested in receiving comments on the following:

• Has all of the relevant evidence been taken into account?
• Are the summaries of clinical and cost effectiveness reasonable interpretations of the evidence?
• Are the provisional recommendations sound and a suitable basis for guidance to the NHS?
• Are there any aspects of the recommendations that need particular consideration to ensure we avoid unlawful discrimination against any group of people on the grounds of gender, race, disability, age, sexual orientation, religion or belief?

Note that this document is not NICE's final guidance on adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a TNF inhibitor. The recommendations in section 1 may change after consultation.

After consultation:

• The Appraisal Committee will meet again to consider the evidence, this appraisal consultation document and comments from the consultees.
• At that meeting, the Committee will also consider comments made by people who are not consultees.
• After considering these comments, the Committee will prepare the final appraisal determination (FAD).
• Subject to any appeal by consultees, the FAD may be used as the basis for NICE’s guidance on using adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a TNF inhibitor in the NHS in England and Wales.

For further details, see the ‘Guide to the technology appraisal process’ (available at www.nice.org.uk).

The key dates for this appraisal are:

Closing date for comments: 24 March 2010

Second Appraisal Committee meeting: 6 April 2010

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 is not NICE's final guidance on adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a TNF inhibitor. The recommendations in section 1 may change after consultation.

1 Appraisal Committee's preliminary recommendations

1.1 Rituximab in combination with methotrexate is recommended as an option for the treatment of adults with severe active rheumatoid arthritis:

• that has responded inadequately to other disease-modifying anti-rheumatic drugs (DMARDs), including treatment with at least one tumour necrosis factor (TNF) inhibitor, or
• who are intolerant of other DMARDs.

1.2 Treatment with rituximab in combination with methotrexate should be continued only if there is an adequate response following initiation of therapy. An adequate response is defined as an improvement in disease activity score (DAS28) of 1.2 points or more. Repeat courses of treatment with rituximab in combination with methotrexate should be given no more frequently than every 6 months.

1.3 Treatment with rituximab in combination with methotrexate should be initiated and supervised, and treatment response assessed, by specialist physicians experienced in the diagnosis and treatment of rheumatoid arthritis.

1.4 The TNF inhibitors adalimumab, etanercept, and infliximab are recommended for the treatment of rheumatoid arthritis after the failure of a previous TNF inhibitor only in the context of research. Such research (including but not limited to clinical trials) should be designed to evaluate the clinical effectiveness of adalimumab, etanercept and infliximab when used sequentially after the failure of a previous TNF inhibitor, in comparison with management strategies that do not include the use of TNF inhibitors.

1.5 Abatacept is not recommended for the treatment of rheumatoid arthritis after the failure of a TNF inhibitor.

2 Clinical need and practice

2.1 Rheumatoid arthritis is a chronic and progressive disabling condition characterised by inflammation of the synovial tissue of the joints. It causes tenderness and stiffness of joints and their progressive destruction, and other symptoms such as pain and fatigue. It is estimated that 580,000 people in England and Wales, approximately 1% of the population, have rheumatoid arthritis. Of these, approximately 15% have severe disease. Rheumatoid arthritis affects three times as many women as men and has a peak age of onset of 40–70 years.

2.2 In rheumatoid arthritis, the synovial membrane thickens because of an increased number of synovial cells, infiltration by white blood cells and formation of new blood vessels. There is an increase in synovial fluid in the joint cavity, and bone mineral density adjacent to the joint is often reduced. Erosions of the bone occur at the margin of the joint where synovial tissue meets cartilage and bone, and this leads to long-term irreversible damage to the structure and function of the joint.

2.3 Inflammatory disease involving areas other than the joints can also occur, with dryness of the eyes and mouth, and the formation of nodules (particularly over extensor surfaces, such as the backs of elbows) affecting up to a third of people with rheumatoid arthritis. More severe inflammatory manifestations may lead to fibrosis in the lungs and inflammation affecting the lining of the heart, lungs and blood vessels. Heart conditions such as ischaemic heart disease and cardiac failure are more common in people with rheumatoid arthritis than in those without rheumatoid arthritis. Osteoporosis is also more common because of reduced mobility, inflammation and/or the side effects of drugs used to treat rheumatoid arthritis (particularly corticosteroids). Corticosteroid use can also contribute to an increased risk of infection.

2.4 Internationally agreed criteria for the diagnosis of rheumatoid arthritis (American College of Rheumatology [ACR] 1987) require four of the following features:

• morning stiffness in joints exceeding 1 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
• radiographic changes typical of rheumatoid disease.

All except the last have to be present for a minimum of 6 weeks. However, clinicians may diagnose rheumatoid arthritis without reference to these criteria.

2.5 The course of rheumatoid arthritis is variable, with the following factors indicating poor prognosis:  the presence of rheumatoid factor or anti-cyclic citrullinated peptide (CCP) antibodies; high erythrocyte sedimentation rate or concentrations of C-reactive protein; early radiographic evidence of erosions; and the presence of swollen and tender joints. Within 2 years of diagnosis, people with rheumatoid arthritis usually experience moderate disability, and after 10 years 30% are severely disabled. Approximately one third stop work because of the disease. Rheumatoid arthritis also reduces life expectancy; for example, a 50-year-old woman with rheumatoid arthritis is expected to die 4 years earlier than a 50-year-old woman without rheumatoid arthritis.

2.6 The aim of treatment is to induce remission of disease, control pain and inflammation and reduce or prevent joint damage, disability and loss of function, thereby improving quality of life. Treatment involves a combination of pharmacological and non-pharmacological interventions. Pharmacological treatment relies on various combinations of non-steroidal anti-inflammatory drugs (NSAIDs), analgesics, corticosteroids and disease modifying anti-rheumatic drugs (DMARDs). DMARDs act to ameliorate symptoms and slow progression of structural damage. DMARDs may be classified as conventional (for example methotrexate or sulfasalazine) or biological.  Biological DMARDs include the TNF inhibitors adalimumab, etanercept and infliximab, as well as rituximab and abatacept. Non-pharmacological interventions include orthopaedic surgery, physiotherapy and occupational therapy.

2.7 NICE clinical guideline 79 recommends the use of a combination of conventional DMARDs (including methotrexate and at least one other DMARD plus short-term glucocorticoids) as first-line treatment, ideally beginning within 3 months of the onset of persistent symptoms. When combination therapy is not appropriate (for example, in cases of methotrexate intolerance), clinical guideline 79 recommends monotherapy with fast escalation to a clinically effective dose.

2.8 NICE technology appraisal guidance 130 recommends the TNF inhibitors adalimumab, etanercept and infliximab, each in combination with methotrexate, as options for the treatment of adults with active rheumatoid arthritis who have a disease activity score (DAS28) greater than 5.1 and whose rheumatoid arthritis has failed to respond to at least two conventional DMARDs, including methotrexate. When a person is intolerant of methotrexate or where methotrexate treatment is considered to be inappropriate, adalimumab or etanercept may be given as monotherapy. Treatment should be withdrawn if response is not adequate within 6 months (as defined by an improvement in DAS28 score of more than 1.2 points) or if response is not maintained. Response to treatment should be monitored at least every 6 months. An alternative TNF inhibitor may be considered when treatment with a first TNF inhibitor is withdrawn because of an adverse event before the initial 6-month assessment.

2.9 NICE technology appraisal guidance 126 recommends rituximab in combination with methotrexate as an option for the treatment of adults with severe active rheumatoid arthritis who have had an inadequate response to or are intolerant of other DMARDs, including treatment with at least one TNF inhibitor. Treatment should be continued only if there is an adequate response (defined as a DAS28 improvement of more than 1.2 points) following initiation of therapy. Repeat courses of rituximab should be given no more frequently than every 6 months. NICE technology appraisal guidance 141 does not recommend the use of abatacept for the treatment of rheumatoid arthritis.

2.10 Several tools have been developed to assess response to treatment in rheumatoid arthritis. The American College of Rheumatology (ACR) response criteria (ACR20, 50, and 70) require a specified improvement in the percentage (20, 50 or 70% respectively) of tender joints, swollen joints, global assessments, pain, disability and circulating inflammatory markers (for example, erythrocyte sedimentation rate). 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 indicates high disease activity, between 5.1 and 3.2 moderate disease activity and less than 3.2 low disease activity. A score of less than 2.6 indicates disease remission. An improvement in DAS28 score of 0.6 or less is considered a poor response, and improvements greater than 1.2 points indicate a good response. The European League Against Rheumatism (EULAR) response criteria are based on the DAS measure. The Stanford Health Assessment Questionnaire (HAQ) comprises one component of the ACR criteria and scores the ability to perform daily activities; it ranges from 0 (least disability) to 3 (most severe disability). The modified Sharp score measures joint damage as assessed radiographically, and is scored on joint-space narrowing and erosions. 

3 The technologies

Adalimumab

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

3.2 Common adverse events reported during adalimumab therapy include injection-site reactions and infections. Before initiating therapy, physicians should evaluate patients for both active and inactive (latent) tuberculosis infection. Adalimumab is contraindicated in patients with moderate to severe heart failure, active tuberculosis, or other active infections. For full details of undesirable 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’, edition 58 [BNF58]). 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 receptor fusion protein. It interferes with the inflammatory cascade by binding to TNF, thereby blocking its interaction with cell-surface receptors. Etanercept has a marketing authorisation for the treatment of moderate to severe active rheumatoid arthritis when the response to DMARDs, including methotrexate, has been inadequate. Etanercept is also indicated in the treatment of severe, active and progressive rheumatoid arthritis in adults not previously treated with methotrexate. The SPC states that etanercept should be given in combination with methotrexate, except where methotrexate is not tolerated or is considered inappropriate.

3.5 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 risk of sepsis and those with other active infections. There are no requirements for monitoring. For full details of undesirable 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. The net price for a 25-mg vial is £89.38 (excluding VAT; BNF58). The annual cost of etanercept using either 52 once-weekly doses of 50 mg or 104 twice-weekly doses of 25 mg is £9295. Costs may vary in different settings because of negotiated procurement discounts.

Infliximab

3.7 Infliximab (Remicade, Schering-Plough) is a chimeric monoclonal antibody that binds with high affinity to TNF, thereby neutralising its activity. Infliximab has a marketing authorisation in combination with methotrexate for the treatment of active rheumatoid arthritis when 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.

3.8 The most common adverse events reported during infliximab therapy include acute infusion-related reactions, infections, and delayed hypersensitivity reactions. Infliximab is contraindicated in people with moderate or severe heart failure or active infections. Before initiating treatment, physicians should screen people for both active and inactive tuberculosis. For full details of undesirable effects and contraindications, see the SPC.

3.9 Infliximab is administered at a dose of 3 mg/kg by intravenous infusion over 2 hours at an initial infusion (week 0) and then at weeks 2 and 6, and thereafter every 8 weeks. If there is an inadequate response or a loss of response after 12 weeks, physicians may consider increasing the dose of infliximab stepwise 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. The net price for a 100-mg vial is £419.62 (excluding VAT; BNF58). The annual drug costs associated with infliximab vary according to body weight and the number of infusions required. Assuming an average weight of 70 kg and a dose of 3 mg/kg, each dose of infliximab requires three vials at a cost of £1259. 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. Costs may vary in different settings because of negotiated procurement discounts.

Rituximab

3.10 Rituximab (MabThera, Roche Products) is a genetically engineered chimeric monoclonal antibody that depletes the B-cell population by targeting cells bearing the CD20 surface marker. Rituximab has a marketing authorisation in combination with methotrexate for the treatment of adult patients with severe active rheumatoid arthritis who have had an inadequate response or intolerance to other DMARDs including one or more TNF inhibitor therapies.

3.11 The most common adverse events associated with treatment with rituximab include infusion reactions and infection. Contraindications to the use of rituximab include active severe infections (including tuberculosis, sepsis and opportunistic infections), and severe heart failure or severe uncontrolled cardiac disease. For full details of undesirable effects and contraindications, see the SPC.

3.12 A course of rituximab consists of two 1000-mg intravenous infusions given 2 weeks apart. The SPC specifies that courses of rituximab should be given at an interval of no less than 16 weeks. The cost to the NHS of 10-ml and 50-ml vials of rituximab is £174.63 and £873.15 respectively (excluding VAT; BNF58). The cost of a single course of rituximab is £3492 (two 1000-mg intravenous infusions). Costs may vary in different settings because of negotiated procurement discounts.

Abatacept

3.13 Abatacept (Orencia, Bristol-Myers Squibb) is a selective T-cell co-stimulation modulator that blocks a key co-stimulatory signal required for T-cell activation. Abatacept has a marketing authorisation for use in combination with methotrexate for the treatment of moderate to severe active rheumatoid arthritis in adult patients who have had an insufficient response or intolerance to other DMARDs, including at least one TNF inhibitor.

3.14 The most common adverse events associated with treatment with abatacept include infections, including sepsis and pneumonia. Contraindications for the use of rituximab include severe and uncontrolled infections, such as sepsis and opportunistic infections. For full details of undesirable effects and contraindications, see the SPC.

3.15 Abatacept is administered as a 30-minute intravenous infusion. After an initial infusion (week 0), it is repeated at week 2, week 4 and every 4 weeks thereafter. Patients require a total of 14 infusions in the first year and 13 infusions in subsequent years. Abatacept is available in 250-mg vials at a cost of £242.17 per vial (excluding VAT; BNF58). The dose of abatacept depends on the body weight of the patient: those weighing less than 60 kg, 60–100 kg and over 100 kg require 500 mg, 750 mg and 1000 mg, respectively. The annual drug costs associated with abatacept vary according to body weight and the number of infusions required. For a patient weighing between 60 and 100 kg, the annual drug cost will be £10,171.14 in the first year and £9444.63 in subsequent years. 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 The Assessment Group completed a systematic review of the efficacy of the technologies for the treatment of rheumatoid arthritis after the failure of a TNF inhibitor. Thirty-five studies met the criteria for inclusion. Five of these were randomised controlled trials (RCTs), one was a non-randomised controlled study, and 29 were included in the Assessment Report as uncontrolled studies (including two long-term RCT extensions). Three of the RCTs were subsequently excluded from the review by the Assessment Group because they either considered regimens outside of their marketing authorisation, or the comparator was not considered relevant. The two included RCTs compared rituximab with placebo plus ongoing methotrexate (the REFLEX trial) and abatacept with placebo plus ongoing conventional DMARDs (the ATTAIN trial). This section summarises the outcomes for clinical effectiveness in terms of response of ACR 20, 50 and 70, and improvement in DAS28 and/or HAQ score for the studies identified in the Assessment Group’s systematic review.

Adalimumab

4.1.2 For adalimumab, the Assessment Group identified five uncontrolled studies with duration of follow-up ranging from 3 to 12 months. Four studies had small sample sizes ranging from 24 to 41. The fifth, a multicentre study, included 899 people. The results were not pooled because of substantial clinical and statistical heterogeneity between studies. Three studies reported ACR 20, 50 and 70 response rates ranging from 46% to 75%, 27% to 50% and 13% to 33% respectively. Four studies reported mean improvement in DAS28 score ranging from 1.30 to 1.90 when compared with pre-treatment values. Three studies reported mean improvement in HAQ ranging from 0.21 to 0.48 when compared with pre-treatment values. None of the studies assessed joint damage or quality of life.

Etanercept

4.1.3 For etanercept, the Assessment Group identified seven uncontrolled studies with duration of follow-up ranging from 3 months to over 9 months. Sample sizes ranged from 25 to 201. The results were not pooled because of substantial clinical and statistical heterogeneity between studies. Four studies reported ACR 20, 50 and 70 response rates ranging from 38% to 72%, 18% to 21% and 8% to 20% respectively. Four studies reported mean improvement in DAS28 score ranging from 0.47 to 1.80 when compared with pre-treatment values. Three studies reported mean improvement in HAQ score ranging from zero to 0.35 when compared with pre-treatment values. None of the studies assessed joint damage or quality of life.

Infliximab

4.1.4 For infliximab, three uncontrolled studies were identified, each with a small sample size ranging from 20 to 24. The Assessment Group could not determine the length of follow-up in the studies. None of the studies reported ACR response criteria or quantitative results of changes in DAS28 and HAQ scores, or assessed joint damage or quality of life.

TNF inhibitors as a group

4.1.5 Eight studies were identified. None provided separate outcome data for individual TNF inhibitors. One study, a non-randomised controlled study, compared TNF inhibitors with rituximab (see section 4.2.8) and 7 studies had no control group. The duration of follow-up in the studies ranged from 3 months to 4 years and sample sizes ranged from 70 to 818. One study reported ACR 20, 50 and 70 response rates of 46%, 26% and 7% respectively. A different study reported mean improvement in HAQ score of 0.11 when compared with pre-treatment values. Three studies reported mean improvements in DAS28 score of 0.88 to 1.00 when compared with pre-treatment values. No studies assessed joint damage or quality of life.

Rituximab

4.1.6 The Assessment Group identified one RCT (REFLEX, n = 517), as well as the trial’s long term extension. The REFLEX trial compared rituximab with placebo (with ongoing methotrexate in both groups) in people who had had an inadequate response to one or more TNF inhibitors. The primary outcome in the REFLEX trial was ACR 20 response rate at 6 months. The REFLEX trial reported statistically significant differences favouring the rituximab group for ACR 20, 50 and 70 response rates. For the rituximab group the values were 51%, 27% and 12%, and for the placebo group these were 18%, 5% and 1% respectively (for all comparisons p < 0.0001). A statistically significant difference in mean improvement in DAS28 was also reported (1.9 in the rituximab group in comparison with 0.4 in the placebo group, p < 0.0001). A statistically significant difference was also reported for mean improvement in HAQ score (0.40 in the rituximab group in comparison with 0.10 in the placebo group, p < 0.0001). The
long-term observational extension of the REFLEX trial included people who had received up to three courses of rituximab. This reported that patients receiving further courses of rituximab responded in terms of ACR comparably to patients who received rituximab in the randomised phase of the RCT.

4.1.7 In addition to the REFLEX trial, the Assessment Group identified one non-randomised controlled study comparing TNF inhibitors and rituximab (see section 4.2.8), five uncontrolled studies and a pooled analysis combining data from the REFLEX trial, its long-term extension and other studies. Duration of follow-up in the uncontrolled studies ranged from 6 months to 1 year and sample sizes ranged from 20 to 158. The Assessment Group could not determine how many patients the pooled analysis included. One study reported ACR 20, 50 and 70 response rates of 65%, 33% and 12% respectively. Another study reported a mean improvement in DAS of 1.61 when compared with pre-treatment values. None of the uncontrolled studies assessed improvement in HAQ score, joint damage or quality of life. The pooled analysis included people who had had up to five courses of rituximab treatment; this study showed similar clinical outcomes to those seen for rituximab in the REFLEX trial.

Abatacept

4.1.8 The Assessment Group identified one RCT (ATTAIN), and its long-term extension. The ATTAIN trial compared abatacept with placebo (with ongoing DMARDs in both groups) in people with an inadequate response to one or more TNF inhibitors. The co-primary outcomes in the ATTAIN trial were ACR 20 response rate and change in HAQ score at 6 months. The ATTAIN trial reported statistically significant differences in response rates favouring the abatacept group. The values were 50% in comparison with 20% (p < 0.001) for ACR 20, 20% in comparison with 4% (p < 0.001) for ACR 50, and 10% in comparison with 2% (p < 0.01) for ACR 70. The ATTAIN trial also reported a statistically significant improvement in mean DAS28 score favouring the abatacept group (1.98 in comparison with 0.71, p < 0.001). The ATTAIN trial also reported a statistically significant difference in mean improvement in the HAQ score favouring the abatacept group (0.45 in comparison with 0.11, p < 0.001). The long-term extension of the ATTAIN trial followed people for up to 5 years. This analysis showed that among people continuing on abatacept, clinical outcomes in terms of ACR response rates were comparable with those seen for abatacept in the randomised phase of the RCT. Further data were provided from a large prospective uncontrolled study (ARRIVE, n = 1046); this study reported an improvement in DAS28 of 2.00 when compared with pre-treatment values.

Comparative effectiveness

4.1.9 The Assessment Group did not identify any randomised controlled trials directly comparing the five technologies, or trials comparing the technologies with other biological DMARDs or previously untried conventional DMARDs. One non-randomised controlled study (n = 318) compared switching from a TNF inhibitor to rituximab with switching to an alternative TNF inhibitor. When a switch occurred because the first TNF inhibitor was not effective, the mean change in DAS28 score was reported to be significantly greater in the rituximab group (mean change -1.34) compared with the group who received an alternative TNF inhibitor (mean change -0.93) (p = 0.03).

4.1.10 The Assessment Group conducted an adjusted indirect comparison of rituximab and abatacept using data from placebo-controlled trials that included similar populations. The analysis suggested no statistically significant differences in response rates between abatacept and rituximab for ACR20 (relative risk 1.12, 95% CI 0.68 to 1.84), ACR50 (relative risk 1.00, 95% CI 0.33 to 2.98) and ACR 70 (relative risk 1.80, 95% CI 0.24 to 13.35).

Subgroup analyses

4.1.11 The Assessment Group identified evidence from two uncontrolled studies of adalimumab that showed statistically significant differences in response rates for ACR 20 (pooled estimate risk difference -0.20, 95% CI -0.37 to -0.02) and ACR 50 (pooled estimate risk difference -0.12, 95% CI -0.20 to -0.04) in favour of people who experienced a reduction in response of their first TNF inhibitor in comparison with people who experienced a primary non-response (that is to say, whose disease had never responded to treatment). Other differences between the two groups for ACR 70, EULAR response, change in DAS28 and HAQ change were not statistically significant. For etanercept, evidence from two uncontrolled studies indicated that there were no significant differences in response between these subgroups. One study reported data for the TNF inhibitors as a class. This study reported EULAR response rates at 3 months which, assuming missing observations represented non-responders, showed statistically significantly better response rates in people who switched because of primary non-response (risk difference 0.30, 95% CI 0.13 to 0.46). Other differences between groups for withdrawal, EULAR response and proportion of people with a DAS28 equal to or less than 3.2 were not statistically significant. Data for abatacept from the ATTAIN LTE showed that in a non-intention-to-treat analysis of the proportions of people experiencing a change in HAQ greater than 0.3 at 6 months, the proportion of people who had stopped their first TNF inhibitor because of a secondary loss of response was statistically significantly greater than those who had stopped because of a primary non-response (risk difference -0.15, 95% CI -0.28 to -0.02). Other differences for ACR response rates and DAS28 score between groups were not statistically significant. No data for infliximab and rituximab were identified.

4.1.12 Evidence for the influence of the presence of auto-antibodies (that is, rheumatoid factor and anti-CCP status) on effectiveness was available only for rituximab, from the REFLEX trial. The trial reported no statistically significant differences in treatment effect by rheumatoid factor status. However, absolute response rates were lower in both the rituximab and the placebo groups for people who were rheumatoid factor negative than those who were rheumatoid factor positive. When participants were stratified according to both rheumatoid factor and anti-CCP status, data suggested a greater treatment response in people who were either rheumatoid factor or anti-CCP positive than in those who were negative for both rheumatoid factor and anti-CCP. The Assessment Group noted that this retrospective analysis should be treated with caution.

4.2 Cost effectiveness

Published literature

4.2.1 The Assessment Group identified four published economic analyses – two of rituximab and two of abatacept – that met the criteria for inclusion in the systematic review, all of which used a decision analytic model. Three of the studies carried out a
cost–utility analysis and reported results in terms of costs per quality-adjusted life years (QALYs) gained. The remaining study (of abatacept) reported results in terms of costs per additional case of ‘low disease-activity state’ gained (DAS28 less than 2.6) and costs per additional remission gained (DAS28 up to 3.2). The Assessment Group could not perform a direct comparison of the incremental cost-effectiveness ratios (ICERs) because of different specifications of the models, including treatment sequence, time horizon, perspective and country of origin.

Manufacturers' submissions

4.2.2 All five manufacturers provided economic analyses to support their submissions. One model (etanercept, Wyeth Pharmaceuticals) was provided only as a narrative summary and not as a fully executable file. All submissions were based on cost–utility analyses run over a lifetime horizon and from the perspective of the healthcare provider. All but one submission (abatacept, Bristol-Myers Squibb) used conventional DMARDs as the base-case comparator.

Abbott Laboratories (adalimumab)

4.2.3 Abbott Laboratories developed a discrete-event simulation model and performed a cost–utility analysis of adalimumab, etanercept, infliximab, rituximab and abatacept (all of which were considered in combination with methotrexate) each in comparison with conventional DMARDs. The model also compared adalimumab with conventional DMARDs only, and the sequence of adalimumab followed by rituximab compared with each of the remaining biological DMARDs. The model simulates people whose profiles are based on the baseline characteristics of people in the British Society for Rheumatology Biologics Register. The model included adverse events. The base-case model included a continuation rule using ACR50 response to determine whether a person continued therapy after an initial trial period.

4.2.4 Response to treatment was based on ACR response rates mapped to a change in HAQ score. The manufacturer derived the ACR response rates from a mixed treatment comparison of 34 studies and assumed that the responses were equal across all TNF inhibitors (that is, that the response to adalimumab was not different from other TNF inhibitors). To map ACR to HAQ, the change in HAQ score associated with each ACR response category was calculated from adalimumab clinical trial data in which both HAQ and ACR were measured. The model assumed that when people discontinued treatment with a TNF inhibitor, the initial effect of treatment was lost. The model assumed that disease progressed while on treatment; disease progressed at a constant annual rate to a greater degree on conventional than on biological DMARDS. This was modelled in terms of a worsening annual HAQ score of 0.030 for biological DMARDs, 0.045 for conventional DMARDs and 0.060 for rescue therapy. To convert HAQ scores to EQ-5D scores, the manufacturer used a non-linear mapping mechanism estimated using EQ-5D data collected in trials of tocilizumab (an alternative biological DMARD).

4.2.5 Costs included drug acquisition, administration, monitoring and hospitalisation (including joint replacement surgery). The cost of administering intravenous drugs was estimated to be £462 for each infusion, based on the Healthcare Resource Group 2007/08 tariff. The manufacturer of adalimumab assumed that administering subcutaneous drugs would require 3 hours of nurse training incurring a one-off cost of £129. The manufacturer assumed retreatment with rituximab would occur every 9 months.

4.2.6 The base-case analysis showed that for rituximab in comparison with conventional DMARDs, the incremental QALY gain was 1.375 at an incremental cost of £15,100 giving an ICER of £10,986 per QALY gained. The base-case analysis showed that for adalimumab or etanercept in comparison with conventional DMARDs, the QALY gain was 1.467 at an incremental cost of £23,423, giving an incremental cost-effectiveness ratio (ICER) of £15,962 per QALY gained. For infliximab and abatacept (each in comparison with conventional DMARDs), the QALY gains were 1.451 and 1.136 respectively. The incremental costs were £31,241 and £34,188 respectively, giving ICERs of £21,529 and £30,104 per QALY gained. Univariate sensitivity analyses (altering one variable at a time) suggested that the model was most sensitive to the HAQ score at the start of treatment, change in HAQ score while on treatment (that is, underlying disease progression), HAQ rebound following stopping treatment, the way in which HAQ was mapped to EQ-5D, and the dosing schedule of rituximab.

Wyeth Pharmaceuticals (etanercept)

4.2.7 Wyeth Pharmaceuticals presented the results of a Markov model with a 6-month cycle. The model compared three strategies: treatment with two sequential TNF inhibitors, treatment with a TNF inhibitor followed by a conventional DMARD, and treatment with a TNF inhibitor followed by rituximab. The manufacturer did not include abatacept in the economic analyses. Baseline patient characteristics reflected those of the patients in the TEMPO trial (an RCT of etanercept in people whose rheumatoid arthritis had had an inadequate response to conventional DMARDs). The model included serious adverse events.

4.2.8 The manufacturer defined response to treatment in terms of mean change in HAQ score in people treated with a second TNF inhibitor after primary non-response, secondary loss of response or intolerance of their first TNF inhibitor. The data were taken from a trial of adalimumab; the values used were -0.44, -0.51 and -0.55 respectively. The manufacturer estimated the mean changes in HAQ score for those treated with rituximab (-0.40) from the REFLEX trial; all were unadjusted estimates of absolute treatment effect observed in the trial. The effect of conventional DMARDs following failure of a TNF inhibitor was assumed to be zero, based on data from the British Society for Rheumatology Biologics Register. The model included underlying disease progression while on treatment, modelled in terms of worsening HAQ score over time. The manufacturer assumed that while on treatment with biological DMARDs the HAQ score remained unchanged (that is, disease did not progress/worsen) but that while on conventional DMARDs, the HAQ score changed at a rate of 0.075 per 6-month cycle from the first 6 months up to 3 years, and then 0.10 per 6-month cycle from year 3 onwards. The manufacturer used a linear mapping mechanism to convert HAQ scores to EQ-5D scores during each model cycle.

4.2.9 Costs included drug acquisition and administration, and costs associated with hospitalisation, outpatient visits, primary care visits, investigations and monitoring. The cost of administration was unclear. Rituximab was assumed to be provided once every 6 months.

4.2.10 The manufacturer presented the base-case results for a range of assumptions regarding changes in HAQ score for both TNF inhibitors and conventional DMARDs. Total differences in costs and QALYs were presented only for people who had switched from one TNF inhibitor to another because of an adverse event. The ICER for TNF inhibitors compared with conventional DMARDs was £15,294 per QALY gained when switching as a result of primary non-response and £14,501 per QALY gained when switching as a result of secondary loss of response. The ICER for TNF inhibitors compared with rituximab was £19,077 per QALY gained and £16,225 per QALY gained following switching for primary
non-response and secondary loss of response respectively. The manufacturer presented no probabilistic sensitivity analysis results in the submission.

Schering-Plough (infliximab)

4.2.11 Schering-Plough developed a patient-level simulation model and performed a cost–utility analysis of infliximab compared with adalimumab, etanercept, rituximab, and abatacept, all of which were considered in combination with methotrexate. Comparisons were also made with conventional DMARDs only, and of the TNF inhibitors followed by rituximab. The model simulates people based on the characteristics at baseline of participants in the GO-AFTER trial (a trial of the TNF inhibitor golimumab in people with an inadequate response to a previous TNF inhibitor). The model did not include adverse events. The base-case model included a continuation rule using EULAR response to determine whether a person continued therapy after an initial trial period.

4.2.12 The manufacturer determined response to treatment by a two-step process. First, the manufacturer mapped ACR response rates (derived from a mixed treatment comparison of data from RCTs of biological DMARDs) to EULAR response rates using an algorithm derived from the GO-AFTER trial. The EULAR response categories were then mapped to EQ-5D using algorithms derived from British Society for Rheumatology Biologics Register data that indirectly calculated EQ-5D from HAQ. In addition to the initial response to treatment, the model included underlying disease progression while on treatment modelled using change in HAQ score over time. The manufacturer assumed that people treated with biological DMARDs experienced no progression in their disease, whereas the condition deteriorated at a rate of 0.042 per year when treated with conventional DMARDs.

4.2.13 Costs included drug acquisition and administration, monitoring and hospitalisation. It was assumed that in 63% of cases, sharing of vials resulted in no wastage of unused infliximab. The cost of administering infused drugs was assumed to be £162.12, based on the cost given in the assessment report for NICE technology appraisal guidance 130 and adjusted for inflation. The manufacturer presented two analyses for rituximab: one assuming re-treatment every 6 months and the other every 9 months.

4.2.14 The base-case analysis showed that for rituximab in comparison with conventional DMARDs, the incremental QALY gain was 0.65 at an incremental cost of £11,325 giving an ICER of £17,422 per QALY gained (assuming 9-month re-treatment intervals). The QALY gains for adalimumab, etanercept and infliximab were 0.66, 0.62 and 0.65 respectively. The respective incremental costs were £23,129, £22,257 and £18,628, giving ICERs of £35,138, £35,898 and £28,661 per QALY gained. The strategy comparing abatacept with conventional DMARDs resulted in an incremental QALY gain of 0.63 for an incremental cost of £28,205, producing an ICER of £44,795 per QALY gained.

Roche Products (rituximab)

4.2.15 Roche Products developed a patient-level simulation model and performed a cost–utility analysis of rituximab compared with adalimumab, etanercept, infliximab and abatacept, all of which were followed by a sequence of conventional DMARDs. The manufacturer also compared rituximab with conventional DMARDs alone. The model simulates people whose profiles are based on baseline characteristics of participants in the REFLEX trial. The manufacturer did not include adverse events.

4.2.16 Response to treatment was defined in terms of ACR response rates mapped to a change in HAQ score. ACR response rates were derived from two sources: a mixed treatment comparison of RCTs of TNF inhibitors in people whose rheumatoid arthritis had had an inadequate response to conventional DMARDs, and an indirect comparison of the abatacept ATTAIN trial and the rituximab REFLEX trial. The manufacturer then adjusted (reduced by 30%) the results of the mixed treatment comparison to reflect a lower response to treatment observed in people who had had an inadequate response to a first TNF inhibitor. The manufacturer converted ACR to HAQ using an algorithm from data in the REFLEX trial. When people discontinued treatment, the manufacturer assumed that the initial effect of treatment was lost. The model included both initial response to treatment and an underlying disease progression while on treatment, each modelled as changes in HAQ score. It was assumed that while a person was on a biological DMARD there was no change in HAQ score. For people on conventional DMARDs the change in HAQ score was 0.0225 per 6-month cycle and for people receiving palliative care the value was 0.03 per 6-month cycle. The manufacturer mapped HAQ scores to EQ-5D scores using a non-linear mapping mechanism derived from data from tocilizumab trials.

4.2.17 The costs included drug acquisition and administration, monitoring and hospitalisation. The cost of administration was assumed to be £162 per infusion and this included all premedication and monitoring costs. Subcutaneous drugs incurred monitoring and premedication costs of £1268 per year and administration costs (£136 for etanercept and £68 for adalimumab), reflecting that 10% of people will receive injections by a district nurse. Re-treatment with rituximab was assumed to occur every 8.7 months.

4.2.18 The base-case analysis showed that for rituximab in comparison with conventional DMARDs, the incremental QALY gain was 1.071 with an incremental cost of £5,685 giving an ICER of £5,311 per QALY gained. The strategies comparing rituximab with etanercept, infliximab or abatacept showed rituximab to be both more effective and less costly. The strategy comparing rituximab with adalimumab showed rituximab to be less effective and less costly, with a QALY loss of 0.044 and an incremental reduction in cost of £13,551, resulting in an ICER of £310,771.

Bristol-Myers Squibb (abatacept)

4.2.19 Bristol-Myers Squibb developed a patient-level simulation model and performed a cost–utility analysis of abatacept compared with rituximab both followed by infliximab. They also modelled abatacept compared with a basket of TNF inhibitors (reflecting the proportion of each drug’s market share) both followed by another basket of TNF inhibitors. The model simulates people whose profiles are based on the baseline characteristics of participants in the ATTAIN trial. The model included adverse events for the first 6 months of treatment.

4.2.20 The manufacturer defined response to treatment in terms of mean change in HAQ score. Estimates for rituximab (0.38) and abatacept (0.42) were based on a mixed treatment comparison of the ATTAIN and REFLEX trials. Estimates for TNF inhibitors (0.21) were taken from an analysis completed by NICE’s Decision Support Unit for TA130 of data from the British Society for Rheumatology Biologics Register. The manufacturer assumed that people who discontinued treatment lost the initial effect of treatment. Underlying progression of disease while on treatment was modelled using HAQ score. This was assumed to improve at an annual rate of 0.0729 for those treated with abatacept in analyses compared with rituximab and of 0.013 in analyses compared with TNF inhibitors. The manufacturer assumed that disease deteriorated at a rate of 0.012 for those treated either with rituximab or TNF inhibitors. A linear mapping mechanism was used to convert HAQ scores to Health Utilities Index Mark 3 scores during each model cycle.

4.2.21 Costs included drug acquisition and administration, monitoring, hospitalisation (including that for joint replacement surgery), outpatient visits, and costs associated with adverse events. Different administration costs were used for the different drugs requiring intravenous infusion. For abatacept the cost per infusion was £141.83 based on the assessment report for NICE technology appraisal guidance 130 and adjusted for inflation to 2007/2008; for rituximab and infliximab the cost was £284.73 based on NHS references costs. For subcutaneous treatments a one-off cost of £25.66 was incurred for training. Re-treatment with rituximab occurred once every 6 months.

4.2.22 The base-case analysis showed that in comparison with the basket of TNF inhibitors, the QALY gain for abatacept was 0.47 at an incremental cost of £10,888, giving an ICER of £23,019 per QALY gained. The strategy comparing abatacept with rituximab resulted in an incremental QALY gain of 0.45 for an incremental cost of £9238, producing an ICER of £20,438 per QALY gained. Sensitivity analyses showed that when it was assumed that HAQ progression rates were the same for all biological DMARDs, the ICER for abatacept was £40,534 per QALY gained compared with rituximab, and £27,871 per QALY gained compared with TNF inhibitors.

The Birmingham Rheumatoid Arthritis Model

4.2.23 The Assessment Group submitted an independent economic analysis using the Birmingham Rheumatoid Arthritis Model. The model samples patients individually and compares each of the technologies (followed by a sequence of conventional DMARDs) with one another or with conventional DMARDs alone. The model simulates people based on the baseline characteristics of people in the British Society for Rheumatology Biologics Register. It allows for two stages of stopping treatment early. The first step represents stopping treatment after 6 weeks (assumed to be because of toxicity) and the second step represents stopping treatment between 6 and 24 weeks (assumed to be because of either toxicity or lack of efficacy). The model does not allow for stopping rituximab early because it is necessary to model the full costs of each cycle of treatment.

4.2.24 The Assessment Group modelled response to treatment using HAQ, with changes in HAQ scores calculated using a multiplier that represents a proportional change from a given baseline HAQ score. The respective HAQ multipliers for rituximab and abatacept were derived from the REFLEX and ATTAIN trials. The HAQ multipliers for adalimumab and etanercept were derived from uncontrolled studies. In the absence of data, the HAQ multiplier for infliximab was assumed the same as etanercept. The Assessment Group assumed that when people discontinue treatment, they lose the initial effect of treatment. In addition to the initial response to treatment, the model assumed that underlying disease progresses during treatment. This was modelled by increases in HAQ score. In the base-case analysis, it was assumed that HAQ score remains constant for a person treated with a biological DMARD, but increases (worsens) for people treated with conventional DMARDs or palliative care. The annual rates of HAQ progression were 0.045 for conventional DMARDs and 0.06 for palliative care. The Assessment Group used a non-linear equation to convert HAQ scores to EQ-5D scores.

4.2.25 Costs included drug acquisition and administration plus monitoring. The administration cost for drugs requiring infusion was assumed to be £141.83. Costs for hospitalisation and joint replacement were estimated using a cost per unit HAQ score. Retreatment with rituximab was assumed to occur every 8.7 months.

4.2.26 The base-case analysis showed that for rituximab compared with conventional DMARDs, the incremental QALY gain was 0.96 with an incremental cost of £20,400 giving an ICER of £21,100 per QALY gained. The QALY gains for adalimumab, etanercept and infliximab were 0.75, 0.67 and 0.67 respectively. The respective incremental costs were £25,800, £26,100 and £24,000, giving ICERs (rounded to the nearest £100) of £34,300, £38,900 and £36,100 per QALY gained. The strategy comparing abatacept with conventional DMARDs resulted in an incremental QALY gain of 1.15 for an incremental cost of £44,000, producing an ICER of £38,400 per QALY gained. Compared with the TNF inhibitors, rituximab was shown to be both less costly and more effective. The ICER for abatacept in comparison with rituximab was £130,600 per QALY gained. The strategies comparing abatacept with adalimumab, etanercept and infliximab resulted in ICERs of £46,400 per QALY gained, £37,800 per QALY gained, and £41,700 per QALY gained respectively.

4.2.27 Scenario analyses were undertaken to explore the impact of varying single assumptions within the model. These included: the time on treatment with the various therapies; the rituximab treatment interval; the efficacy of conventional DMARDs after the failure of a TNF inhibitor; the change in HAQ score while on biological DMARDs; the proportion of people stopping treatment early; the inclusion of costs of adverse events and palliation; and assumptions related to the equation used to map HAQ score to EQ-5D scores. These analyses indicated that the results are subject to considerable uncertainty.

4.2.28 Assuming that there was underlying progression of disease modelled as an increase in HAQ score of 0.03 per year while on biological DMARDs increased the ICERs for the comparison with conventional DMARDs. The ICERs were £61,300 per QALY gained for adalimumab, £76,300 per QALY gained for etanercept, £68,900 per QALY gained for infliximab, £46,000 per QALY gained for rituximab and £63,300 per QALY gained for abatacept. Assuming conventional DMARDs were no more effective than placebo reduced the base-case ICERs for the comparison with conventional DMARDs to £28,100 per QALY gained for adalimumab, £31,100 per QALY gained for etanercept, £28,800 per QALY gained for infliximab, £16,300 per QALY gained for rituximab and £32,100 per QALY gained for abatacept. Using the same proportion of people stopping early as was used in the Roche model (based on failure to achieve an ACR20 response) reduced the base-case ICERs for the comparison with conventional DMARDs to £22,200 per QALY gained for adalimumab, £23,400 per QALY gained for etanercept, £26,200 per QALY gained for infliximab, £19,500 per QALY gained for rituximab, and £24,100 per QALY gained for abatacept. Results suggested that the model was additionally sensitive to changes in the equation converting HAQ to health-related quality of life; and the assumed time between treatments for comparisons involving rituximab.

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, infliximab, rituximab and abatacept after the failure of a TNF inhibitor, having considered evidence on the nature of rheumatoid arthritis and the value placed on the benefits of adalimumab, etanercept, infliximab, rituximab and abatacept by people with the condition, those who represent them and clinical specialists. It also took into account the effective use of NHS resources.

Clinical effectiveness

4.3.2 The Committee considered current clinical management of people with rheumatoid arthritis. The Committee heard from clinical specialists that the pathway of care following the failure of treatment with a TNF inhibitor depends on the individual person’s responses to therapies, the clinical experience of the physician and the person’s preference. The Committee heard from patient experts that rheumatoid arthritis has a severe impact on quality of life, with fatigue, pain and depression being common among people with the disease. Patient experts reported that rheumatoid arthritis frequently affects people’s ability to work, noting that there was considerable burden placed on the carers of people with the disease. The Committee heard that rheumatoid arthritis may not respond to a given treatment, or there may be a decline in response over time that requires a change in treatment. Clinical specialists and patient experts therefore emphasised the importance of the availability of multiple treatment options for people whose disease had not responded adequately to initial treatment with a TNF inhibitor.

4.3.3 The Committee heard from clinical specialists that rheumatoid arthritis is heterogeneous and therefore different people respond differently to different treatments. The Committee heard from clinical specialists that it is difficult to predict whose disease will respond to treatment. Experts stated that people for whom a TNF inhibitor had never produced a response may be less suitable for a second TNF inhibitor, and people with sero-negative antibody status may be less suitable for treatment with rituximab. The Committee therefore understood that response to treatments varies, and that it is not currently possible to target a specific treatment to individual patients because the response to any particular treatment cannot be predicted.

4.3.4 The Committee heard that the management of rheumatoid arthritis was changing in line with NICE guidelines for rheumatoid arthritis, with more clinicians using an approach of maximising disease control by starting DMARDs early and increasing the dose of DMARDs quickly as required. The Committee heard from clinical specialists that, as a consequence of this accelerated approach to DMARD usage, treatment with TNF inhibitors was initiated sooner after diagnosis than had previously been the case and therefore the characteristics of the people being treated with TNF inhibitors had changed over time. The Committee understood that these changes in the management of rheumatoid arthritis limited the generalisability of data from the British Society for Rheumatology Biologics Register, as it represents a cohort of people whose characteristics (including disease duration and previously received treatments) may not reflect those of the current group of people for whom the first biological DMARD has failed.

4.3.5 The Committee considered whether the TNF inhibitors exhibited a class effect and could be considered as a group with respect to clinical effectiveness. The Committee was aware that the TNF inhibitors each have a different mechanism of action. The Committee heard from clinical specialists that variations in the underlying mechanism of disease coupled with different mechanisms of action can result in a variety of responses to treatment with the TNF inhibitors. The Committee heard from clinical specialists that data from the British Society for Rheumatology Biologics Register show no statistically significant difference in effect between TNF inhibitors, but that these data reflect the effectiveness of the first use of TNF inhibitors and not effectiveness after the failure of previous TNF inhibitor. The Committee concluded that based on the clinical specialists’ evidence it would not be appropriate to assume a class effect among the TNF inhibitors.

4.3.6 The Committee discussed the clinical effectiveness of a second TNF inhibitor after the failure of a first. It noted that the review of the evidence had identified no randomised controlled trials and that the majority of the studies were uncontrolled observational or registry datasets, some of which had examined the TNF inhibitors as a group. The Committee heard from clinical specialists that for conventional DMARDs, the proportion of people whose condition responded to the sequential treatments was reduced as the number of treatments received increased. The same was considered to hold true for biological DMARDs. The clinical specialists noted that failure of a first TNF inhibitor was associated with an increased risk of failure of a second TNF inhibitor, but that the proportion with a good response was comparable. The clinical specialists therefore considered that a second TNF inhibitor was clinically effective. The Committee heard that data from the British Society for Rheumatology Biologics Register reported an improvement in HAQ score of 0.11, among people receiving a second TNF inhibitor. The Committee heard from the clinical specialists that this change was smaller than the minimum value that is considered a clinically important difference within the context of a clinical trial (0.22) and within the context of an observational study (0.14). The Committee also heard that the average change in HAQ score among people whose first TNF inhibitor had failed but who had continued to take it did not differ significantly from those who had switched to a second TNF inhibitor. The Committee noted the limitations of the British Society for Rheumatology Biologics Register data. The Committee concluded that, although the studies suggest that a second TNF inhibitor is effective after the failure of a first, the absence of any rigorously controlled data meant that it could not quantify the relative effect of a second TNF inhibitor in comparison with either conventional DMARDs or alternative biological DMARDs.

4.3.7 The Committee considered the evidence from the randomised controlled trials of rituximab (REFLEX trial) and of abatacept (ATTAIN trial). The Committee noted the results of the Assessment Group’s indirect comparison of rituximab and abatacept based on these trials, which did not show statistically significant differences between the two treatments. The Committee concluded that both treatments had been shown to be clinically effective in comparison with placebo, but that one treatment had not been shown to be more effective than the other. The Committee concluded that the data for TNF inhibitors were insufficient to quantify the relative effect of rituximab and abatacept in comparison with a TNF inhibitor when used after the failure of the first.

4.3.8 The Committee specifically considered the evidence of clinical effectiveness for the subgroup of people defined by reason for withdrawal of the first TNF inhibitor. It heard from clinical specialists that people whose disease had not responded to the first TNF inhibitor (primary failure) would be less likely to experience a response to a second than those whose disease had initially responded but who had later experienced diminishing benefit (secondary failure). However, the Committee considered evidence from the Assessment Group that showed variations in response (including less response, similar response and better response) for secondary failure in comparison with primary failure. The Committee concluded that although some evidence and clinical testimony suggested a difference in response by reason for withdrawal, there was currently insufficient evidence for the Committee to use this as a basis for making recommendations for this specific subgroup.

4.3.9 The Committee also considered subgroups based on the presence of auto-antibodies (rheumatoid factor and anti-CCP status). It discussed the impact of the presence of auto-antibodies on the clinical effectiveness of rituximab. The Committee noted that the REFLEX trial showed no statistically significant differences in relative effectiveness between subgroups defined by auto-antibody status. Furthermore, the analyses by both rheumatoid factor and anti-CCP status were post hoc. It heard from clinical specialists that current guidelines from the British Society for Rheumatology advise against the use of rituximab in people who test sero-negative, but that responses to rituximab were observed in these patients. Furthermore, the Committee also heard from the clinical specialists that the presence of auto-antibodies is not a consistent measure in that the same patient may have a positive test for auto-antibodies in one instance and negative test in another. The Committee concluded that there was insufficient evidence to make differential recommendations for subgroups based on auto-antibody status.

4.3.10 The Committee noted that no studies had been identified that compared the biological DMARDs with a newly-initiated conventional DMARD after the failure of a first TNF inhibitor. The Committee heard from clinical specialists that they considered that any treatment effect for conventional DMARDs in this situation would be very limited. The Committee was aware of evidence from the Behandel Strategieen (BeST) study, which investigated the effectiveness of different treatment sequences of biological and conventional DMARDs in patients with early rheumatoid arthritis. The Committee heard from the Assessment Group that evidence from the BeST study was not appropriate in this instance, as it did not provide clinical effectiveness evidence for individual DMARDs and the population did not represent people with established RA. Overall, the Committee concluded that, on the basis of clinical opinion, the effect of conventional DMARDs in people for whom a TNF inhibitor had failed was likely to be small, but the relative effect in comparison with biological treatments was not currently quantifiable.

4.3.11 In summary, the Committee noted that apart from the randomised controlled trials of rituximab and abatacept, the available evidence on the effectiveness of treatment with a biological DMARD after the failure of a TNF inhibitor was mainly derived from observational studies with short follow-up periods that included relatively small numbers of people. The Committee noted that many of the studies lacked a comparison group. The Committee considered that shortcomings in the design of studies of the sequential use of TNF inhibitors could affect the validity of the results. It also considered that characteristics of the included patients, changes in clinical practice, and, in some instances, small patient numbers could affect the generalisability of the results. The Committee concluded that there are significant limitations in the evidence base available for this appraisal and that more research is needed, specifically using the DAS28 outcome measure (which forms the basis for treatment continuation rules in current NICE guidance on treatments for rheumatoid arthritis). The Committee heard from clinical specialists and manufacturers about ongoing research regarding the treatment of rheumatoid arthritis after the failure of a TNF inhibitor. The Committee heard that a current clinical trial of infliximab (RESTART) is being undertaken in patients with active rheumatoid arthritis in whom treatment with etanercept or adalimumab has failed.  

Cost effectiveness

4.3.12 The Committee examined the cost-effectiveness analysis of sequential use of TNF inhibitors performed by the Assessment Group and the manufacturers of the technologies. The Committee noted that all analyses modelled a sequence of treatments, which it considered appropriate for rheumatoid arthritis. The Committee noted, however, that there were differences in the sequences modelled. The Committee was aware that one of the models (from Wyeth Pharmaceuticals) had not been provided as an executable file, and had not included abatacept. This limited the Committee’s ability to use the model to inform decision making. The Committee recognised that one of the models (from Bristol Myers Squibb), had not included a comparison with conventional DMARDs, which limited the comparability of the model with those of the other manufacturers and of the Assessment Group.

4.3.13 The Committee was presented with information about the costs used in the economic models. The Committee recognised that the costs of hospitalisation and joint replacement had been included in all of the manufacturers’ models, and that these costs were derived from a range of data sources including the British Society for Rheumatology Biologics Register and the Norfolk Arthritis Register. The Committee was aware that the Birmingham Rheumatoid Arthritis Model included an assumed cost for joint replacement and hospitalisation. The Committee recognised that the Assessment Group had carried out a series of analyses examining the sensitivity of the ICERs to changes in the cost parameters, including the removal of joint replacement and hospitalisation costs, the addition of extra costs of palliation and inclusion of the costs of adverse events. These analyses showed that the ICERs were not very sensitive to changes in costs, and that they were most sensitive to changes in the assumptions about natural history of disease, the efficacy of the treatments and the number of people stopping treatment early.

4.3.14 The Committee discussed the different sources of estimates of clinical effectiveness for the biological DMARDs had been used in the economic modelling. The Committee noted that all models had used the REFLEX and ATTAIN trials to inform the estimates of rituximab and abatacept, but that sources varied for the estimates for TNF inhibitors and conventional DMARDs. It noted that some had included RCT data from populations outside of the scope of the appraisal, or uncontrolled observational studies or registry data. The Committee was aware that no head-to-head evidence existed that compared all the biological DMARDs, and as a result some models derived relative treatment effect from indirect comparisons. The Committee noted that these had included evidence from studies in which participants had not previously been treated with a TNF inhibitor. The Assessment Group reported that it considered that the use data from populations beyond the scope of the appraisal to complete an indirect comparison was inappropriate because of the variability of the studies from which the data were taken. The Committee heard from the Assessment Group that it had modelled the rates of effectiveness for biological and conventional DMARDs as absolute rather than relative changes, even if from placebo-controlled randomised trials, because they considered that evidence did not allow them to complete a mixed treatment or indirect comparison. The Committee considered that the use of non-randomised comparisons could affect the robustness of the results. However, it accepted that the evidence base available for the sequential use of biological DMARDs did not currently allow for a robust analysis of the relative treatment effect.

4.3.15 The Committee considered the value of HAQ score as a measure of functional assessment. 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 longstanding disease the potential for improvements in HAQ score is smaller because of irreversible damage. The clinical specialists and patient experts considered that treatment might benefit individuals in ways not captured by HAQ score (such as a reduction in inflammation). The Committee recognised that the HAQ may be subject to ‘ceiling effects’ (the score could not worsen), and that it does not incorporate some aspects of rheumatoid arthritis such as pain, fatigue and sleep disturbance. The Committee concluded that patients may derive benefits from the treatment that are not reflected in HAQ score because of irreversible joint damage.

4.3.16 The Committee discussed the range of methods used to model efficacy of the treatments, including ACR response categories mapped to change in HAQ, ACR response categories mapped to EULAR response, and mean HAQ change without the use of response categories. Where HAQ had been used, the Committee was aware of its limitations, including its insensitivity to small changes within the higher range of scores and its inability to capture meaningful improvements in pain and fatigue (see section 4.3.15). Following explanation from the Assessment Group, the Committee understood that HAQ multipliers represent a proportional change from a given baseline HAQ score. This means that for a baseline HAQ score of 2.00, the use of a HAQ multiplier of 0.25 translates into a HAQ improvement of 0.50, which results in a post-treatment HAQ score of 1.50. The Committee considered that the use of such a multiplier to model changes in HAQ meant that absolute changes in the upper range of the HAQ scores were larger than those in the lower range, and that therefore people with more severe disease would have larger HAQ improvements than if the HAQ scores from the clinical studies were used directly. Bearing in mind these considerations, the Committee accepted the use of a HAQ multiplier as a reasonable way to model changes in HAQ score.

4.3.17 The Committee discussed how the models had incorporated underlying progression of disease during treatment. The Committee noted that all but two analyses had been carried out assuming that disease did not progress in people receiving TNF inhibitors, rituximab and abatacept, but that disease did progress in people taking conventional DMARDs. The Committee was aware that for the biological DMARDs, the use of no progression assumed both no underlying deterioration of physical function and no reduction in response to treatment. The Committee noted that one of the analyses (from Bristol-Myers Squibb) had assumed that abatacept delayed progression more than the other biological DMARDs. The Committee was not persuaded that this was supported by the evidence. In conclusion, the Committee was persuaded that it was appropriate to assume that biological DMARDs delayed disease more than conventional DMARDs. However, the Committee was aware that people with rheumatoid arthritis normally experience a reduction in response to treatment before stopping treatment (secondary loss of response) or a decline in physical function as they age. The Committee agreed to base its discussions on the ICERs which assumed no progression of disease for patients during treatment with the biological DMARDs, but was not persuaded that this assumption fully reflects the disease process. This is because people could experience some worsening of HAQ while on treatment, particularly in the period of time prior to stopping treatment because of secondary loss of response.

4.3.18 The Committee noted that none of the economic models included health-related quality of life measured using a generic preference-based measure, but had mapped a disease-specific measure (HAQ or DAS) to a generic measure (EQ-5D). The Committee understood that in the case where DAS was mapped to EQ-5D, the algorithm used had been developed from EQ-5D data itself derived indirectly from HAQ data. The Committee noted that the mapping of HAQ to EQ-5D allowed for the symptoms of rheumatoid arthritis to cover a broad range of values on the quality-of-life scale, from excellent health to states worse than death. The Committee noted that mapping utilities was outside the reference case, but recognised it had been used in previous NICE technology appraisals of treatments for rheumatoid arthritis. The Committee heard from the Assessment Group that the Birmingham Rheumatoid Arthritis Model incorporated HAQ because they did not consider that DAS captured all aspects of disability that one would expect to correlate with health-related quality of life. The Committee heard from clinical specialists that evidence from the British Society for Rheumatology Biologics Register suggested that for more severe HAQ scores, mapping may underestimate the change in EQ-5D. However, the Committee was mindful that all models presented had included EQ-5D data derived from HAQ, and therefore no alternative was available. The Committee noted that some of the manufacturers had mapped HAQ to EQ-5D using a linear function, while others had used a non-linear function. It heard from the Assessment Group that the use of non-linear function attaches a greater value to changes at the lower end of the HAQ scale than at the top, but that this did not significantly change the estimated ICERs. The Committee concluded that mapping HAQ to EQ-5D had shortcomings, but in the absence of an alternative was an acceptable way to derive estimates of utility, and that the use of a non-linear function was not unreasonable.

4.3.19 The Committee discussed the time intervals between treatments with rituximab. The Committee was aware of the results of the REFLEX trial, in which the average time interval between treatments was 307 days, and the SPC for rituximab, which indicates treatment intervals of no less than 16 weeks. It heard from clinical specialists that they would offer to re-treat a patient with rituximab before disease flared, and that there was wide variation in time to re-treatment with rituximab; some people require an infusion less than once a year. The Committee noted that the Birmingham Rheumatoid Arthritis Model modelled time to repeat treatment as 8.7 months in the base case, basing this estimate on Roche’s submission. It noted that similar time to re-treatment had been assumed in a number of the other manufacturers’ submissions. On the basis of the clinical specialists’ advice, the Committee assumed that treatment with rituximab would occur, on average, less frequently than every 6 months.

4.3.20 The Committee considered the use of stopping and continuation rules in the economic models. The Committee understood that current NICE guidance on the first use of TNF inhibitors (technology appraisal guidance 130) recommends that TNF inhibitors should be continued only if there is an adequate response at 6 months following initiation of therapy. An adequate response is defined as an improvement in DAS28 of 1.2 points or more. The Committee heard from the clinical specialists that data from the British Society for Rheumatology Biologics Register indicate that a number of people will continue treatment with a TNF inhibitor even in the absence of such a response, indicating that the use of stopping rules does not reflect current clinical practice. It further heard from the Assessment Group that for this reason stopping rules based on a response criterion had not been incorporated into the Birmingham Rheumatoid Arthritis Model base-case analysis. The Committee understood that the Birmingham Rheumatoid Arthritis Model was not designed in a way which could incorporate stopping rules based on a response criterion. The Committee noted, however, that a scenario analysis which included the proportions of people stopping treatment early that were used in the manufacturers’ response-based models lowered the ICERs for the TNF inhibitors and abatacept by approximately £10,000 per QALY gained. The Committee did not consider that the Assessment Group’s analysis could be used as a basis for decision making because it did not fully incorporate response criteria. In addition, the Committee questioned if the application of such response criteria would be reflective of clinical practice.

4.3.21 The Committee considered the different ways in which the manufacturers and the Assessment Group had modelled the efficacy of conventional DMARDs. The Committee noted that the Birmingham Rheumatoid Arthritis Model assumed that the conventional DMARDs used after the failure of a TNF inhibitor were 50% as effective as when used in early rheumatoid arthritis. The Committee considered that in light of the clinical experts’ testimony regarding the poor efficacy of conventional DMARDs at this point in the treatment pathway (see section 4.3.10), the Assessment Group may have overestimated the efficacy of conventional DMARDs. The Committee noted that the Assessment Group had completed a scenario analysis that assumed an efficacy of conventional DMARDs equal to that of placebo (reflecting the assumption used in the submission from Roche). This resulted in ICERs of approximately £16,000 per QALY gained for rituximab compared with conventional DMARDs, and between £28,000 and £32,000 per QALY gained for the other technologies compared with conventional DMARDs. The Assessment Group explained that the differences were not larger because the Birmingham Rheumatoid Arthritis Model assumes that TNF inhibitors are added to a sequence rather than used as an alternative treatment. Therefore, the effects of the conventional DMARDs were observed in both the intervention and comparator sequences. The Committee concluded that an analysis that assumed the effect of conventional DMARDs to be no more than that of placebo was not plausible, but accepted on the basis of clinical specialists’ testimony that the base case assumption of a reduction by 50% may be an underestimate of the reduction in effect of conventional DMARDs, therefore overestimating the ICERs in the Assessment Group’s base case analysis.

4.3.22 The Committee considered the estimates of cost effectiveness for the use of rituximab after the failure of a TNF inhibitor. It recognised that in all but one of the economic models, rituximab had been associated with the lowest ICERs of the biological DMARDs in comparison with conventional DMARDs. Rituximab was also associated with the lowest ICERs of the biological DMARDs in the Assessment Group’s scenario analysis that assumed a poorer response to conventional DMARDs than was assumed in the base case. In the model in which rituximab was not associated with the lowest ICERs, it had been assumed that rituximab was provided once every 6 months. The Committee considered the differences among the models, including both base-case and sensitivity analyses, and concluded that, on balance, the Birmingham Rheumatoid Arthritis Model reference case represented a plausible estimate of incremental cost effectiveness at £21,100 per QALY gained. The Committee then examined the Assessment Group’s scenario analysis, which assumed a time to re-treatment of 6 months. It noted this assumption increased the ICER from £21,100 to £32,600. Taking into account the considerations around the effectiveness of conventional DMARDs (see 4.3.21), the Committee concluded that rituximab could be considered a cost effective use of NHS resources, as long as treatment is not administered more frequently than every 6 months and is stopped if there is an inadequate response to treatment. 

4.3.23 The Committee discussed the cost effectiveness of the TNF inhibitors. The Committee noted that that in the absence of robust data of clinical effectiveness of the TNF inhibitors, the ICERs were uncertain. The Committee considered that most of the economic models showed that in comparison with rituximab, either the ICERs for the TNF inhibitors were very high (above £80,000 per QALY gained) or the TNF inhibitors were dominated by rituximab (that is, rituximab was both more effective and less costly). The analysis by Wyeth comparing the TNF inhibitors to rituximab produced ICERs of £19,077 per QALY gained (with primary non-response to the first TNF inhibitor) and £16,225 per QALY gained (with secondary loss of response). However, as Wyeth did not include an economic model in their submission, these results could not be validated. Rituximab dominated the TNF inhibitors in the analysis by the Assessment Group with assumed a lower efficacy of conventional DMARDs (reflecting the assumption in the Roche submission).  The Committee was not persuaded that the current evidence available and the cost-effectiveness analyses presented could support a decision to recommend adalimumab, etanercept or infliximab when used as an alternative to rituximab after the failure of a previous TNF inhibitor as an appropriate use of NHS resources.

4.3.24 The Committee discussed the cost effectiveness of abatacept. The Committee considered that most of the economic models showed that in comparison with rituximab, the ICERs for abatacept  were either very high (above £100,000 per QALY gained in the Assessment Group base case)  or abatacept was dominated by rituximab (that is, rituximab was both more effective and less costly). The analysis by Bristol-Myers Squibb which produced an ICER of £20,438 per QALY gained assumed an improvement in HAQ of 0.013 per year during treatment with abatacept. When the same rate of HAQ progression was assumed for abatacept as was for the other biological DMARDs in the base case (a worsening of 0.012 per year), the ICER increased of £40,534 per QALY gained. The Committee therefore concluded that abatacept when used as an alternative to rituximab after the failure of a previous TNF inhibitor would not be a cost-effective use of NHS resources.

4.3.25 The Committee was aware that for some people rituximab treatment may not be suitable because of intolerance of or contraindications to rituximab or methotrexate. For these people the comparison might reasonably be with conventional DMARDs. However, the Committee considered that it had not been presented with any clinical evidence regarding the use adalimumab, etanercept, infliximab or abatacept for patients for whom rituximab failed or in whom rituximab was contraindicated or not tolerated, and therefore had insufficient evidence on which to base a differential recommendation for this group of patients. The Committee therefore concluded that the current evidence available did not support a decision that adalimumab, etanercept, infliximab or abatacept used after the failure of a TNF inhibitor for the treatment of people who were intolerant of or had contraindications to rituximab or methotrexate would be an appropriate use of NHS resources.

4.3.26 The Committee considered the value of further research regarding the clinical effectiveness of TNF inhibitors used after the failure of a previous TNF inhibitor. The Committee was aware that there is direct evidence for the clinical effectiveness of abatacept after the failure of a TNF inhibitor. The Committee considered that there were limitations to the evidence available for the clinical effectiveness of the TNF inhibitors when used sequentially. The Committee agreed on the importance of further research that examined comparative efficacy of relevant options and that reflected current best practice in the clinical management of rheumatoid arthritis. The Committee expressed an interest in research in which the response to treatment is reported in terms of the outcome measure used in current NICE guidance to define response to treatment (DAS28). The Committee concluded that it would be appropriate to recommend the use of adalimumab, etanercept and infliximab after failure of a TNF inhibitor only in the context of research.

Summary of Appraisal Committee's key conclusions

TAXXX (STA)	Appraisal title: Adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a TNF inhibitor (part review of NICE technology appraisal guidance 36, review of NICE technology appraisal guidance 126 and 141)		ACD section
Key conclusion
Rituximab in combination with methotrexate is recommended as an option for the treatment of adults with rheumatoid arthritis that has responded inadequately to other disease-modifying anti-rheumatic drugs (DMARDs), including treatment with at least one tumour necrosis factor (TNF) inhibitor, or who are intolerant of other DMARDs. The key driver for this preliminary recommendation was that rituximab was considered a cost effective option across most of the models available for this appraisal. The TNF inhibitors adalimumab, etanercept, and infliximab are only recommended for the treatment of rheumatoid arthritis after the failure of a previous TNF inhibitor in the context of research. The key drivers for this preliminary recommendation were: (1) the lack of clinical effectiveness data for the TNF inhibitors compared with management strategies that do not include the use of TNF inhibitors at this stage in the treatment pathway, and the resulting uncertainty in the ICERs; and (2) that based on the evidence available, the ICERs for the TNF inhibitors compared with rituximab were either very high or the TNF inhibitors were dominated by rituximab. The research recommended should be designed to evaluate the clinical effectiveness of these TNF inhibitors when used sequentially after the failure of a previous TNF inhibitor compared with management strategies that do not include the use of TNF inhibitors. Abatacept was not recommended for the treatment of rheumatoid arthritis after the failure of a TNF inhibitor. The key driver for this preliminary recommendation was that abatacept was either dominated by treatment with rituxumab or the ICERs for abatacept compared with rituximab were very high.		1.1-1.5
Current practice
Clinical need of patients	Rheumatoid arthritis has a severe impact on quality of life, with fatigue, pain and depression being common among people with the disease. In addition, rheumatoid arthritis frequently impacts upon patients’ abilities to work, including considerable burden placed on the carers of patients with the disease. Patients may not respond to a treatment with a TNF inhibitor, or may experience a decline in initial response over time, and therefore need to change treatments.		4.3.2 4.3.2
Availability of alternative treatments	The pathway of care following the failure of treatment with a TNF inhibitor depends on individual patient responses to therapies, the clinical experience of the physician, and patient preference. Multiple treatment options are important for people whose disease had not responded adequately to initial therapy with a TNF inhibitor. It is not currently possible to target a specific treatment to individual patients because the response to any particular treatment cannot be predicted.		4.3.2 4.3.2 4.3.3
The technology
Proposed benefits of the technology from the manufacturer, clinician and patient perspective	The different mechanisms of action among the technologies mean people respond differently to different treatments.		4.3.3
How innovative is the technology	This is a review of already established technologies and indications.		N/A
Adverse events	Adverse events were not specifically discussed in the context of this appraisal.		N/A
Evidence for clinical effectiveness
Quality of the evidence	There was an absence of robust clinical data on the clinical effectiveness of the TNF inhibitors. The majority of studies were uncontrolled observational or registry datasets. Data from randomised controlled trials were only available for rituximab and abatacept. Subgroup analyses based on rheumatoid factor and anti-CCP status were post hoc.		4.3.6 4.3.7 4.3.9
Availability and nature of evidence	A second TNF inhibitor was considered effective after the failure of a first, but the absence of any rigorously controlled data meant that the relative effect of a second TNF inhibitor in comparison with either conventional DMARDs or alternative biological DMARDs could not be quantified. There were insufficient data to quantify the relative effect of rituximab and abatacept in comparison with a TNF inhibitor when used after the failure of the first. There was insufficient evidence suggesting a difference in response by reason for withdrawal of the first TNF inhibitor. There was insufficient evidence to make differential recommendations for these groups based on auto-antibody status. No clinical evidence was presented regarding the use of a second biological DMARD in people for whom rituximab may not be suitable because of intolerance or contraindications to rituximab or methotrexate. No studies were identified that compared biological DMARDs with newly-initiated conventional DMARDs. The effect of conventional DMARDs in people for whom a TNF inhibitor had failed was likely to be small, but the relative effect in comparison with biological DMARD treatments was not currently quantifiable.		4.3.6 4.3.7 4.3.8 4.3.9 4.3.10 4.3.10 4.3.10
Relevance to general  clinical practice in the NHS	Changes in clinical management including accelerated usage of DMARDs and sooner initiation of treatment with TNF inhibitors than was seen in the past limit the generalisability of some of the registry data presented. Patients may derive benefits from the treatment that would not be reflected in HAQ score because of irreversible joint damage.		4.3.4 4.3.15
Uncertainties generated by the evidence	Based on the clinical specialists’ evidence, it would not be appropriate to assume a class effect among the TNF inhibitors, but evidence was not available to enable any distinction. See also ‘Availability and nature of evidence’ above.		4.3.5
Evidence for cost effectiveness
Availability and nature of evidence	One of the models was not provided as an executable file limiting the ability to validate the modelling and ICERs. Another model did not include a comparison with conventional DMARDs, limiting the ability to compare with other models. The Assessment Group model was less sensitive to assumptions about costs and most sensitive to assumptions about natural history, clinical effectiveness and rate of stopping treatment. The sources of effectiveness evidence varied for the estimates of the TNF inhibitors and conventional DMARDs including RCT data from populations outside the scope of the appraisal, and/or uncontrolled observational studies or registry data. The Assessment Group modelled rates of effectiveness for biological DMARDs and conventional DMARDs as absolute, rather than relative, changes in disease measures, which could affect the robustness of the results. However, the Assessment Group’s rationale that the current evidence base did not allow for an appropriate mixed treatment comparison was accepted. A range of methods were used to model efficacy of treatments, including mapping response criteria to HAQ change and use of HAQ change on its own. The Committee was mindful of limitations of HAQ but accepted the use of a proportional change in HAQ from baseline as a reasonable way of modelling changes in HAQ score. A variety of assumptions were made about progression of disease while on treatment with biological DMARDs including no progression, worsening disease and continuing improvement. All models except one assumed no progression for all biological DMARDs. The Committee did not consider that the evidence supported an assumption of differential HAQ progression for the biological DMARDs. No cost effectiveness evidence was presented for use of TNF inhibitors or abatacept in people whose disease had failed, or were contraindicated to treatment with, rituximab.		4.3.12 4.3.13 4.3.14 4.3.14 4.3.16 4.3.17 4.3.25
Uncertainties around and plausibility of assumptions and inputs in the economic model	The Committee considered estimates of cost effectiveness using an assumption of no progression of disease while on treatment with biological DMARDs, but was not persuaded that this fully reflects the disease process. Based on clinical expert testimony, the Committee considered an assumed 50% reduction in the efficacy of conventional DMARDs to be an underestimate, although the assumption that they are no more effective than placebo was also considered implausible. The Committee recognised that an incorporation of response-based stopping rules into the models lowered the ICERs for the TNF inhibitors and abatacept in comparison with conventional DMARDs. It understood, however, that the Birmingham Rheumatoid Arthritis Model was not designed in a way which could incorporate response-based stopping rules, and that it is unclear based on the BSRBR data if the application of response-based stopping rules is reflective of clinical practice. On the basis of the clinical specialists’ advice, the Committee considered that treatment with rituximab would occur less frequently than every 6 months.		4.3.17 4.3.21 4.3.19 4.3.21
Incorporation of health-related quality of life benefits and utility values	All models presented EQ-5D data derived from HAQ. The mapping of HAQ to EQ-5D has shortcomings, but short of alternative approaches the mapping was considered as acceptable way to derive estimates of utility. Use of a non-linear mapping function was not unreasonable.		4.3.18
Most likely cost-effectiveness estimate (given as an ICER)	For rituximab, the Assessment Group’s base case represented a plausible estimate of rituximab’s incremental cost-effectiveness (£21,100 per QALY gained). In the absence of robust data of clinical effectiveness of the TNF inhibitors, the estimates of cost effectiveness were uncertain. Most models showed that in comparison to rituximab, the ICERs for the TNF inhibitors were either very high (above £80,000 per QALY gained) or that TNF inhibitors were dominated by rituximab. No model was provided for the analyses presented by Wyeth, so its results could not be validated. Most models suggested similar results for abatacept compared with rituximab, and showed either very high ICERs (above £40,000 per QALY gained) or that abatacept was dominated by rituximab. The only exception was the analyses from the manufacturer of abatacept which assumed HAQ improvement while on abatacept (which was an assumption that the Committee did not accept).		4.3.22 4.3.23 4.3.24
Additional factors taken into account
Equalities considerations, social value judgements	No issues were raised in the scoping or appraisal phase.		N/A

5 Implementation

5.1 The Secretary of State has issued directions to the NHS on implementing NICE technology appraisal guidance. When a NICE technology appraisal recommends use of a drug or treatment, or other technology, the NHS must provide funding and resources for it within 3 months of the guidance being published. If the Department of Health issues a variation to the 3-month funding direction, details will be available on the NICE website. The NHS is not required to fund treatments that are not recommended by NICE.

5.2 NICE has developed tools to help organisations put this guidance into practice (listed below). These are available on our website (www.nice.org.uk/guidance/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 that support this locally.
• A costing statement explaining the resource impact of this guidance.
• Audit support for monitoring local practice.

6 Proposed recommendations for further research

6.1 Further clinical trials should be undertaken to compare the clinical effectiveness of adalimumab, etanercept and infliximab when used sequentially after the failure of a TNF inhibitor in comparison with management strategies that do not include the use of TNF inhibitors, including untried DMARDs or biological DMARDs such as rituximab. This is important because there is currently no evidence on the clinical effectiveness of the TNF inhibitors at this stage in the treatment pathway compared with alternative treatment options (see section 4.3.6).

6.2 Further research should be undertaken to estimate utilities using directly observed health-related quality of life values (such as EQ−5D scores) in people with rheumatoid arthritis. This is important because currently used methods of establishing utility values do not allow for the link to be made between utility and common clinical measures such as DAS.

7 Related NICE guidance

Published

• Rheumatoid arthritis: the management of rheumatoid arthritis in adults. NICE clinical guideline 79 (2009). Available from www.nice.org.uk/guidance/CG79
• Abatacept for the treatment of rheumatoid arthritis. NICE technology appraisal guidance 141 (2008). Available from www.nice.org.uk/guidance/TA141
• Adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis. NICE technology appraisal guidance 130 (2007). Available from www.nice.org.uk/guidance/TA130
• Rituximab for the treatment of rheumatoid arthritis. NICE technology appraisal guidance 126 (2007). Available from www.nice.org.uk/guidance/TA126
• The clinical effectiveness and cost effectiveness of etanercept and infliximab for rheumatoid arthritis and juvenile poly-articular idiopathic arthritis; partially replaced by TA130. NICE technology appraisal guidance 36 (2002). Available from www.nice.org.uk/guidance/TA036

Under development

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

• Certolizumab pegol for the treatment of rheumatoid arthritis. NICE technology appraisal guidance (publication expected February 2010).
• Tocilizumab for the treatment of rheumatoid arthritis. NICE technology appraisal guidance (publication expected May 2010).

8 Proposed date for review of guidance

8.1 NICE proposes that the guidance on this technology is considered for review by the Guidance Executive in February 2013. NICE welcomes comment on this proposed date. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.

Amanda Adler
Chair, Appraisal Committee
February 2010

Appendix A: Appraisal Committee members, and NICE project team

A. Appraisal Committee members

The Appraisal Committee is one of NICE’s standing advisory committees. 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 Amanda Adler (Chair)
Consultant Physician, Addenbrooke's Hospital

Dr Ray Armstrong
Consultant Rheumatologist, Southampton General Hospital

Dr Jeff Aronson
Reader in Clinical Pharmacology, University Department of Primary Health Care, University of Oxford

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

Dr Michael Boscoe
Consultant Cardiothoracic Anaesthetist, Royal Brompton and Harefield NHS Foundation Trust

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

Dr Mark Chakravarty
External Relations Director – Pharmaceuticals and Personal Health, Oral Care Europe

Dr Fergus Gleeson
Consultant Radiologist, Churchill Hospital, Oxford

Ms Sally Gooch
Independent Nursing and Healthcare Consultant

Mrs Eleanor Grey
Lay member

Mr Sanjay Gupta
YPD Service Case Manager, Southwark Health and Social Care, Southwark Primary Care Trust

Dr Neil Iosson
General Practitioner

Mr Terence Lewis
Lay member

Dr Ruairidh Milne
Director of Strategy and Development and Director for Public Health Research NIHR Evaluation, Trials and Studies Coordinating Centre, University of Southampton

Mr Stephen Palmer
Senior Research Fellow, Centre for Health Economics, University of York

Dr John Pounsford
Consultant Physician, Frenchay Hospital, Bristol

Mr Navin Sewak
Primary Care Pharmacist, NHS Hammersmith and Fulham

Dr Lindsay Smith
General Practitioner, East Somerset Research Consortium

Mr Roderick Smith
Finance Director, West Kent Primary Care Trust

Mr Cliff Snelling
Lay member

Professor Ken Stein (Vice Chair)
Professor of Public Health, Peninsula Technology Assessment Group (PenTAG), University of Exeter

Professor Andrew Stevens
Professor of Public Health, Department of Public Health and Epidemiology, University of Birmingham

Dr Rod Taylor
Associate Professor in Health Services Research, Peninsula Medical School, Universities of Exeter and Plymouth

Mr Tom Wilson
Director of Contracting and Performance, NHS Tameside and Glossop

B. 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.

Whitney Miller
Technical Lead

Zoe Garrett
Technical Adviser

Jeremy Powell
Project Manager

Appendix B: Sources of evidence considered by the Committee

A. The assessment report for this appraisal was prepared by the West Midlands Health Technology Assessment Collaboration:

• Malottki K., Barton P., et. al. Adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a TNF inhibitor: a systematic review and economic evaluation (November 2009)

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

I. Manufacturers/sponsors:

• Abbott
• Bristol-Myers Squibb
• Roche
• Schering-Plough
• Wyeth

II. Professional/specialist and patient/carer groups:

• Arthritis & Musculoskeletal Alliance (ARMA)
• Arthritis Care
• British Health Professionals in Rheumatology
• British Society for Rheumatology
• National Rheumatoid Arthritis Society
• Primary Care Rheumatology Society
• Royal College of Nursing
• Royal College of Pathologists
• Royal College of Physicians
• South Asian Health Foundation

III. Other consultees:

• Department of Health
• Welsh Assembly Government

IV. Commentator organisations (without the right of appeal):

• Arthritis Research Campaign
• AstraZeneca UK
• Department of Health, Social Services and Public Safety for Northern Ireland
• GlaxoSmithKline
• Medac UK
• NHS Quality Improvement Scotland
• Novartis
• Pfizer
• Roche Products
• Sanofi Aventis
• Schering Plough
• UCB Pharma

C. The following individuals were selected from clinical specialist and patient expert 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, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a TNF inhibitor by attending the initial Committee discussion and/or providing written evidence to the Committee. They are invited to comment on the ACD.

• Dr Chris Deighton, Consultant Rheumatologist, Derbyshire Royal Infirmary, nominated by the British Society for Rheumatology – clinical specialist
• Dr Frank McKenna, Consultant Rheumatologist, Trafford General Hospital, nominated by the British Society for Rheumatology – clinical specialist
• Ailsa Bosworth, Chief Executive Officer, National Rheumatoid Arthritis Society, nominated by the National Rheumatoid Arthritis Society – patient expert
• Jean Burke, nominated by the National Rheumatoid Arthritis Society – patient expert

D. Representatives from the following manufacturers/sponsors attended Committee meetings. They contributed only when asked by the Committee chair to clarify specific issues and comment on factual accuracy.

• Abbott
• Bristol-Myers Squibb
• Roche
• Schering-Plough
• Wyeth