Rheumatoid arthritis - tocilizumab: appraisal consultation document

Appraisal consultation document

Tocilizumab for the treatment of rheumatoid arthritis

The Department of Health asked the National Institute for Health and Clinical Excellence (NICE) to produce guidance on using tocilizumab for the treatment of rheumatoid arthritis in the NHS in England and Wales. The Appraisal Committee considered the evidence submitted by the manufacturer and the views of non-manufacturer consultees and commentators, and clinical specialist 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

Note that this document is not NICE’s final guidance on this technology. 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 tocilizumab for treating rheumatoid arthritis 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: 22nd October 2009

Second Appraisal Committee meeting: 11th November 2009

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 this technology. The recommendations in section 1 may change after consultation.

1 Appraisal Committee’s preliminary recommendations

1.1 Tocilizumab is not recommended for the treatment of moderate to severe active rheumatoid arthritis.

1.2 People who are currently receiving tocilizumab for the treatment of rheumatoid arthritis should have the option to continue treatment until they and their clinicians consider it appropriate to stop.

2 The technology

2.1 Tocilizumab (RoActemra, Roche) is a humanised monoclonal antibody that inhibits cytokine interleukin-6 (IL-6). Reducing the activity of IL-6 may reduce inflammation in the joints, prevent long‑term damage, improve quality of life and function and relieve certain systemic effects of rheumatoid arthritis. Tocilizumab, in combination with methotrexate, has a UK marketing authorisation for the treatment of moderate to severe active rheumatoid arthritis in adults whose disease has not responded adequately to, or who are intolerant of, previous therapy with one or more disease‑modifying anti-rheumatic drugs (DMARDs) or tumour necrosis factor-α (TNF-α) antagonists. In these patients, tocilizumab can be given as monotherapy in case of intolerance to methotrexate or if continued treatment with methotrexate is inappropriate.

2.2 Tocilizumab is contraindicated in people with active, severe infections. The summary of product characteristics (SPC) lists the following as the most commonly reported adverse drug reactions associated with tocilizumab treatment: upper respiratory tract infections, nasopharyngitis, headache, hypertension and increased alanine transaminase (ALT). For full details of side effects and contraindications, see the SPC.

2.3 Tocilizumab is administered as an intravenous infusion, given over 1 hour. The recommended dosage is 8 mg/kg, but no lower than 480 mg, given once every 4 weeks. The cost for tocilizumab as reported by the manufacturer is £1.28/mg, or £9295/year for a patient weighing approximately 70 kg. Tocilizumab is available in three vial sizes, which are priced at £102.40 for an 80-mg vial, £256 for a 200-mg vial and £512 for a 400-mg vial. Costs may vary in different settings because of negotiated procurement discounts.

3 The manufacturer’s submission

The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of tocilizumab and a review of this submission by the Evidence Review Group (ERG; appendix B).

Clinical effectiveness

3.1 In the submission, the manufacturer presented evidence on the clinical effectiveness of tocilizumab in combination with DMARDs for two populations: people whose rheumatoid arthritis had responded inadequately to previous DMARDs (DMARD-IR) and people whose rheumatoid arthritis had responded inadequately to previous TNF-α inhibitors (TNF-IR). The manufacturer also presented evidence on the clinical effectiveness of tocilizumab as monotherapy. The submission focused on the tocilizumab 8-mg/kg treatment arms of the included studies as this is the recommended dose in the SPC. Some of the studies also included doses other than the licensed dose. Results for doses other than the licensed dose are not considered in this appraisal.

DMARD-IR population

3.2 The main clinical-effectiveness evidence for the DMARD-IR population came from three randomised controlled trials (RCTs). All three RCTs were randomised, double-blind, placebo-controlled parallel-group studies in adults with moderate to severe active rheumatoid arthritis whose condition had responded inadequately to treatment with methotrexate (OPTION and LITHE) or traditional DMARDs (TOWARD). The OPTION trial, assessed the effects of tocilizumab 8 mg/kg plus methotrexate (n = 205) compared with placebo plus methotrexate (n = 204). The LITHE trial, assessed the effects of tocilizumab 8 mg/kg plus methotrexate (n = 401) compared with placebo plus methotrexate (n = 394). The TOWARD trial, assessed the effects of tocilizumab 8 mg/kg plus DMARDs (n = 805) compared with placebo plus DMARDs (n = 415).

3.3 The primary outcome in the RCTs was the proportion of people with an American College of Rheumatology (ACR) 20 response at week 24. This was defined as at least 20% improvements in both the tender joint count and the swollen joint count and at least a 20% improvement in three of the other five core set measures included in the ACR score. In all three RCTs, the same outcome measure and data collection instruments were used. The manufacturer stated that the RCTs had similar patient populations. This was demonstrated by general demographics and the effect of various factors on the ACR20 response, which was examined by logistic regression analysis. No significant differences were found in treatment effects between studies and the manufacturer inferred that pooling the results of the three RCTs for the primary outcome was appropriate. The manufacturer’s submission stated that the adjusted odds ratio for the ACR20 response of tocilizumab 8 mg/kg plus DMARD compared with placebo plus DMARD was approximately 4.2. Averaged ACR20 response rates, described as pooled results, were 59.2% in the tocilizumab 8 mg/kg arm compared with 25.8% in the placebo arm (p ≤ 0.0001) at week 24.

3.4 Secondary outcomes of the RCTs, measured at 24 weeks, were pooled across the 3 RCTs by the manufacturer. Pooled ACR response rates were: 37.0% compared with 9.6% for ACR50 response rates (p < 0.0001), 18.5% compared with 2.4% (p ≤ 0.0001) for ACR70 response rates, and 4.2% compared with 0.3% (p ≤ 0.0001) for the ACR90 response rates, for the tocilizumab 8 mg/kg plus DMARD arms and placebo plus DMARD arms, respectively. The manufacturer also presented averaged disease activity score 28 (DAS28) results from the three RCTs. Approximately half of all people in the RCTs reached low disease activity, defined as DAS28 of less than 3.2. Approximately one third of people in the RCTs went into remission, defined as DAS28 of less than 2.6. The proportion of patients going into remission while on tocilizumab was reported to increase during the study period. There was a greater decrease in averaged health assessment questionnaire‑disability index (HAQ) results from baseline HAQ score in the tocilizumab groups compared with placebo. In the pooled population at week 24, the proportion of patients achieving a clinically relevant improvement in HAQ (defined as a decrease of at least 0.25 in an individual’s total score) was higher in the tocilizumab groups (68%) than in the placebo groups (52%).

3.5 Additionally, European quality of life (EuroQoL) health-state questionnaire (EQ-5D) scores were collected in the OPTION and LITHE RCTs. In the OPTION RCT, the baseline mean EQ-5D was 0.393 (standard deviation 0.327) in the tocilizumab 8 mg/kg plus methotrexate arm, and 0.391 (standard deviation 0.329) in the placebo plus methotrexate arm. At follow-up, the mean EQ-5D was 0.671 (standard deviation 0.237) in the tocilizumab 8 mg/kg arm and 0.534 (standard deviation 0.318) in the placebo arm. The EQ‑5D results from the LITHE RCT were not provided separately by treatment arm by the manufacturer.

3.6 Two single-arm extension studies assessed maintenance of clinical benefit of tocilizumab beyond 24 weeks. Overall, response rates to therapy with tocilizumab plus DMARD were maintained or continued to improve with duration of treatment, with increasing numbers of people achieving higher ACR scores over time. The manufacturer reported that this pattern for HAQ scores was observed for up to 132 weeks in the pooled tocilizumab 8 mg/kg plus DMARD arm.

3.7 No head-to-head studies were identified that provided evidence on the clinical effectiveness of tocilizumab compared with TNF-α inhibitors, abatacept or rituximab for the DMARD-IR population. Therefore, the manufacturer conducted a mixed treatment comparison. A total of 18 RCTs (including the OPTION, LITHE and TOWARD trials) were identified for inclusion. All studies were randomised, placebo-controlled, double-blind trials and all had a follow-up period of either 24 or 30 weeks. Patients included were predominantly female (approximately 80%), older than 50 years, had experienced more than 6 years’ duration of rheumatoid arthritis, were previously treated with an average of two or more DMARDs, and more than half had used non‑steroidal anti-inflammatory drugs or glucocorticoids concomitantly. The manufacturer reported that the baseline characteristics across the trials were comparable with respect to ACR core parameters. Results for TNF-α inhibitors were pooled, because it was assumed there was no difference in efficacy between these drugs. This assumption was reported to be informed by ‘Adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis’ (NICE technology appraisal guidance 130).

3.8 The mixed treatment comparison suggested that tocilizumab showed comparable efficacy (measured by ACR20 and ACR50 responses) to all included biological treatments. However, for the ACR70 response rate, tocilizumab resulted in a higher response rate than the TNF-α inhibitors and abatacept (relative risks of 1.77 and 1.98 respectively) and a comparable response to rituximab. In the base‑case comparison, there was a greater than 99% probability that tocilizumab was more efficacious than biological treatments, as measured with ACR70 response rates. The manufacturer stated that homogeneity at each ACR response level was assessed using Cochran’s Q-statistic (ACR20: 44.1857, p = 0.0002; ACR50: 41.6878, p = 0.0004; ACR70: 25.5752, p = 0.0603). Based on these results, the manufacturer used random effects methods to estimate ACR20 and ACR50 responses, and fixed effects methods to estimate ACR70 responses. The manufacturer also reported that tocilizumab provided a 27% increase in remission rates (remission defined as DAS28 less than 2.6) compared with placebo. The next most effective TNF-α inhibitor (infliximab) provided a 17% increase in remission rates compared with placebo. As well as the base‑case mixed treatment comparison, the manufacturer also presented three scenario analyses, which included or excluded data from certain trials included in the base case. The manufacturer stated that overall the results from these alternative scenarios were consistent with the initial findings.

TNF-IR population

3.9 The main clinical-effectiveness evidence for the TNF-IR population came from one RCT, known as RADIATE. RADIATE was a randomised, double-blind, placebo-controlled, parallel-group study in adults with moderate to severe rheumatoid arthritis. The participants’ rheumatoid arthritis had responded inadequately to previous TNF-α inhibitor therapy. RADIATE assessed the effects of tocilizumab 8 mg/kg plus methotrexate (n = 175) compared with placebo plus methotrexate (n = 160).

3.10 The primary outcome of RADIATE trial was ACR20 response rate. At 24 weeks, 50% of patients in the tocilizumab arm compared with 10% of patients in the placebo arm had experienced an ACR20 response (p < 0.0001). Additionally, at 24 weeks, 28.8% compared with 3.8% had experienced an ACR50 response (p < 0.0001), and 12.4% compared with 1.3% had experienced an ACR70 response (p < 0.0002), for the tocilizumab arm and the placebo arm, respectively. At week 24, the mean change from baseline in DAS28 was –3.16 for tocilizumab and −0.95 for placebo. The manufacturer stated that the remission rates were similar to those seen in the DMARD-IR population at 24 weeks. The mean decrease in HAQ from baseline at 24 weeks for the tocilizumab group was 0.39, compared with 0.05 for the placebo group.

3.11 Two single-arm extension studies assessed the maintenance of clinical benefit of tocilizumab beyond 24 weeks. Response rates to therapy with tocilizumab were maintained or continued to improve with duration of treatment (as in the DMARD-IR population). Similar results to the DMARD-IR population were reported and the manufacturer noted that the pattern of improvement in mean HAQ score was also observed for up to 132 weeks.

Tocilizumab monotherapy

3.12 One RCT, known as AMBITION, assessed the effects of tocilizumab 8 mg/kg alone (n = 288) compared with methotrexate alone (n = 284). This was a double-blind, placebo-controlled trial that included a sub-study tocilizumab arm in which placebo was given first for 8 weeks and then tocilizumab was given for 16 weeks. Most of the people in the AMBITION RCT had not received prior treatment with methotrexate or had stopped methotrexate treatment for reasons other than toxicity or lack of efficacy.

3.13 The ACR20 response rate at 24 weeks in the intention-to-treat population was 69.9% in the tocilizumab arm compared with 52.5% in the methotrexate arm. The weighted difference in ACR20 response was 0.19 (95% confidence interval 0.11 to 0.27). It was concluded that treatment with tocilizumab was non inferior to treatment with methotrexate.

Adverse events

3.14 The manufacturer reported that adverse effects associated with the mechanism of IL-6R inhibition were observed in all tocilizumab treatment groups. These adverse effects include transient hepatic transaminase elevations (IL-6R expressed on hepatocytes), asymptomatic elevations of indirect bilirubin, transient neutropenia (IL‑6R expressed on neutrophils), and lipid elevations which appear to occur in association with marked decreases in acute phase proteins. In addition, serious infections associated with the immunomodulatory effects of tocilizumab were comparable to the incidence of serious infections with TNF-α inhibitors. Adverse events reported more frequently with tocilizumab 8 mg/kg monotherapy than in the methotrexate group were abdominal pain and discomfort, headache, dizziness, rash, pruritis and elevated blood pressure, neutropenia, leukopenia and hyperlipidemia events. Most of these events were mild and transient. The manufacturer reported that there was no increase in the severity or frequency of adverse events with prolonged exposure to the tocilizumab 8 mg/kg dose.

Cost effectiveness

3.15 The manufacturer did not identify any economic evaluations of tocilizumab and developed a de novo economic model for the submission. This was an individual sampling model with a hypothetical homogenous cohort. The model used a lifetime horizon for costs and benefits. It considered the DMARD-IR and TNF-IR populations separately. No evidence on the cost effectiveness of tocilizumab monotherapy was presented.

3.16 In the manufacturer’s economic model, people with rheumatoid arthritis followed a specified treatment sequence. For the DMARD-IR population, tocilizumab with methotrexate was the first treatment and if the condition did not respond or if efficacy was lost after 24 weeks, etanercept with methotrexate was the next treatment. This was followed by rituximab with methotrexate, then leflunomide, then gold, then ciclosporin until people withdrew from the last treatment (ciclosporin) and moved onto palliative care. The sequence was the same for the comparator arm, but excluded tocilizumab at the beginning. For the TNF-IR population, the sequence was the same as the DMARD-IR population, except for the omission of etanercept plus methotrexate (that is, the first treatment in the comparator arm was rituximab).

3.17 The probabilities of response were derived from the adjusted ACR response rates (adjusted for placebo differences across trials) from the base-case mixed treatment comparison. There were four categories of response: non-response; ACR20 response; ACR50 response; and ACR70 response. Patients were assigned a predefined drop in HAQ score (that is, an improvement in physical function) based on their ACR responses. Data from four RCTs (OPTION, TOWARD, LITHE and RADIATE) were analysed to estimate the relationship between ACR response and HAQ score in the first 24 weeks. Those patients whose condition responded were assumed to have a constant probability of withdrawal due to lack of efficacy. At the point of switching to the next treatment, patients were assumed to experience an increase in their HAQ score (rebound) equal to the initial HAQ improvement. After the initial 24-week period the HAQ score was assumed to decrease linearly based on the medium-term observational extensions to the RCTs. Because of substantial uncertainty in the data for weeks 132–156, this continued improvement was only assumed for the first 3 years in the DMARD‑IR cohort and 2.5 years in the TNF‑IR cohort. For the long-term analysis (post-3 years after initial treatment in the DMARD-IR cohort and post-2.5 years after initial treatment in the TNF-IR cohort), the HAQ score was assumed to stay constant (that is zero HAQ progression) with tocilizumab treatment. After the initial 24‑week treatment period, no change in HAQ score was assumed (zero HAQ progression) for biologics like etanercept and rituximab. After the initial 24‑week treatment period, an increase in HAQ score (that is, a worsening of physical function) was assumed for traditional DMARDs.

3.18 Tocilizumab was assumed to be given for a minimum of 6 months and the administration cost of each infusion of tocilizumab was assumed to be £142. The costs of treating any adverse events were not included in the economic model presented by the manufacturer. The manufacturer reported that EQ-5D scores from the tocilizumab OPTION and LITHE trials were mapped to HAQ scores using a quadratic regression model. Alternative mapping equations as used in NICE technology appraisal guidance 130 and other submissions to NICE were examined in scenario analyses. Utility weights were derived from the EQ-5D scores using the UK time trade-off tariff. Adverse events associated with tocilizumab treatment were assumed to generate an insignificant burden in the quality of life of the patients, and therefore were not included in the model.

3.19 For the DMARD-IR population, the treatment sequence including tocilizumab compared with the sequence without tocilizumab produced incremental costs of £23,253 and incremental quality‑adjusted life years (QALYs) of 1.17. This resulted in a base‑case incremental cost effectiveness ratio (ICER) of £19,870 per QALY gained. For the TNF-IR population, the treatment sequence including tocilizumab compared with the sequence without tocilizumab produced incremental costs of £26,640 and incremental QALYs of 1.21. This resulted in a base-case ICER of £22,003 per QALY gained. Probabilistic sensitivity analyses suggested that the addition of tocilizumab to the treatment sequences had a 56.4% and 22.4% probability of being cost effective (for the DMARD-IR and TNF-IR populations, respectively) if the maximum acceptable amount to pay for a QALY gained is £20,000. All scenario analyses presented by the manufacturer resulted in ICERs of less than £30,000 per QALY gained.

Evidence Review Group comments

3.20 The ERG stated that the manufacturer’s submission identified all relevant published studies of tocilizumab in a population appropriate for the decision problem and that critical appraisal of the included studies was reasonably thorough. The ERG commented that the general approach to the modelling framework chosen was appropriate to the decision problem and that the broad structural assumptions used in modelling were appropriate and similar to previous models used to evaluate the cost effectiveness of biological DMARDs. However, the ERG considered that the decision problem addressed only one of a number of possible treatment sequences that could be used in rheumatoid arthritis. Therefore the ERG considered that several possible treatment options were omitted in both the DMARD‑IR and TNF-IR populations.

3.21 The ERG highlighted the following key areas of concern with the manufacturer’s submission:

  • The inclusion of the studies and the pooling of the TNF-α inhibitors in the mixed treatment comparison.
  • The long-term estimates of HAQ score.
  • Mapping HAQ scores to EQ-5D in order to derive utility estimates for the economic model.
  • The rebound effect on discontinuation (defined as an increase in a person’s HAQ score when treatment is withdrawn).
  • The non-inclusion of adverse events in the economic model.

3.22 The ERG explored the combined adjusted ACR response rates for TNF-α inhibitors used in the mixed treatment comparison (DMARD‑IR population) and considered that etanercept appeared less efficacious in the comparison than the literature suggested. The ERG commented that the reason for the apparent low efficacy of etanercept compared with both tocilizumab and the other TNF-α inhibitors was a single large trial with a very high response rate in the placebo arm. The ERG noted that this trial only included patients who were likely to benefit from methotrexate and had an aggressive dosing schedule of methotrexate if the signs and symptoms of rheumatoid arthritis reappeared. When the ERG removed this trial from the analysis, etanercept appeared more efficacious than tocilizumab. The ERG then questioned the validity of assuming that all TNF-α inhibitors had the same efficacy in the model, as this lowered the estimate of the effectiveness of the TNF-α inhibitor used in the model. When the ERG investigated the use of unpooled parameters in the economic model for the DMARD-IR population (that is, the withdrawal rate of etanercept was reduced from 10% to 8%, then the incremental costs were reduced to £22,887 and incremental QALYs were reduced to 1.13. This resulted in an increase in the ICER from £19,870 to £20,166 per QALY gained.

3.23 The ERG commented that the follow-up period of 24 weeks in the five included tocilizumab studies could be considered too short. It noted that the longer-term data on tocilizumab came from single‑arm studies with no comparator of placebo, conventional DMARDs or biological agents, so the long-term effectiveness of tocilizumab was unclear. The manufacturer estimated the medium‑term HAQ progression (up to 3 years for the DMARD-IR population and 2.5 years for the TNF-IR population) using linear functions. However, the ERG suggested that an exponential function was equally plausible. The ERG noted that any functions fitted to the data needed to be constructed carefully because even small changes to the predictions would have a significant impact on the ICER.

3.24 The ERG was also concerned about the way the relationship between HAQ and EQ-5D was modelled. The manufacturer’s submission used a quadratic equation for this. The quadratic model predicted that EQ-5D scores would be lower at high HAQ scores compared with a linear model. In addition, literature has shown that EQ-5D and HAQ are closely correlated at baseline and that when quality of life worsened over time the EQ-5D became more variable (resulting in a weaker correlation). The ERG noted that the entire scale of the EQ-5D might have been used, as suggested by negative utility values that were removed in the scenario analysis. Using the entire EQ-5D scale is questionable because a certain amount of disability may remain despite optimal control of inflammatory disease, due to irreversible characteristics such as damaged joints. The ERG concluded that algorithms for modelling the relationship between HAQ and EQ-5D should only be used when there are no direct utility scores; however, the trials for tocilizumab (OPTION and LITHE) measured EQ-5D directly. When the ERG removed negative EQ-5D utility scores from the model for the DMARD-IR population, the ICER increased from £19,870 to £20,214 per QALY gained. The effect on the base‑case ICER for the TNF-IR population was not modelled, but the ERG stated that it was likely to also be increased.

3.25 The cost of £142 for an infusion was based on a 0.5 day day-case admission cost from the 2001 version of the Personal Social Services Research Unit’s (PSSRU) Unit Costs of Health and Social Care of £124. This figure was used in NICE technology appraisal guidance 130 and was subsequently adjusted for inflation by the manufacturer to 2008 prices resulting in £142. The ERG commented that this cost should have been adjusted for inflation from 2001 and not from 2004 as was presented by the manufacturer.

3.26 The manufacturer’s submission assumed that the rebound after withdrawal from treatment was equal to the initial HAQ improvement only. The manufacturer’s submission also assumed that HAQ score for patients treated with tocilizumab improved over the course of treatment, but that for other treatments HAQ score either remained the same (biological DMARDs) or worsened (conventional DMARDs and palliative care). Therefore, it was assumed that the short to medium term HAQ benefit was retained in the long term. NICE technology appraisal guidance 130 accepted a similar assumption that patients would lose their initial HAQ improvement when treatment was withdrawn, and also that biological DMARDs delayed disease progression more than conventional DMARDs. However, whereas the HAQ score representing underlying disease progression for all biological DMARDs in NICE technology appraisal guidance 130 remained the same or worsened only slightly while on treatment, the manufacturer assumed that HAQ score improvement was possible for tocilizumab only. The ERG commented that the assumptions about rebound effect and HAQ progression disproportionately favoured tocilizumab by not only allowing the drug to delay disease progression, but also by allowing the possibility for the patient to obtain a lasting improvement in their condition. When the ERG investigated the use of a different rebound effect following withdrawal from treatment (as was used in the economic model for technology appraisal guidance 130) for the DMARD-IR population, the incremental costs were unchanged from the base case and the incremental QALYs were reduced to 0.96. This resulted in the ICER increasing from £19,870 to £24,252 per QALY gained. The ERG stated that, although not modelled, the respective cost-effectiveness estimates for the TNF‑IR population would be likely to be increased further.

3.27 In addition, the ERG considered that excluding adverse events in the manufacturer’s model was questionable because biological DMARDs were known to be associated with adverse events. The ERG noted that the manufacturer’s submission compared the adverse events for tocilizumab with those of methotrexate. It reported that it was unclear whether the adverse event rate is higher or lower for tocilizumab than for other biological DMARDs. The manufacturer’s submission states that the mean and median duration of tocilizumab exposure was 1.08 years. The ERG commented that the risks of longer-term treatment with tocilizumab were unknown. The ERG incorporated a QALY loss of 0.05 for every cycle that a person is on any DMARD treatment (except for palliative care) for the DMARD-IR population to estimate the effects of adverse events. The incremental costs were unchanged from the base case and the incremental QALYs were reduced to 0.94. This resulted in the ICER increasing from £19,870 to £24,629 per QALY gained. The ERG stated that the respective cost‑effectiveness estimates for the TNF-IR population would be likely to be increased further, although this was not modelled.

3.28 Full details of all the evidence are in the manufacturer’s submission and the ERG report, which are available from www.nice.org.uk/TAxxx

4 Consideration of the evidence

4.1 The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of tocilizumab, having considered evidence on the nature of rheumatoid arthritis and the value placed on the benefits of tocilizumab by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.

4.2 The Committee understood that the main purpose of biological treatment for rheumatoid arthritis is to suppress inflammation, which in turn can slow disease progression and prevent irreversible joint damage. The Committee heard from the experts that the primary concern with tocilizumab treatment was the potential for infectious complications, but that trial data suggested that most adverse events were relatively minor, and, in most cases, did not limit treatment use. The Committee noted that treatment with tocilizumab would be delivered in secondary care, within existing care structures.

4.3 The Committee considered the evidence on the clinical effectiveness of tocilizumab in the DMARD-IR population. It noted that there were statistically significant improvements in all ACR response rates at 24 weeks with tocilizumab plus DMARDs (mainly methotrexate) compared with DMARDs plus placebo. The Committee noted that there were also improvements in HAQ and DAS28 scores in the three RCTs of people receiving tocilizumab plus DMARDs. It heard from clinical specialists and patient experts that the observed benefits in these three RCTs were clinically meaningful. It also noted that adverse effects of tocilizumab were not considered to be worse than those associated with other biologic treatments for rheumatoid arthritis. The Committee therefore concluded that tocilizumab plus methotrexate was clinically effective compared with placebo plus DMARDs.

4.4 The Committee then considered the mixed treatment comparison for the DMARD-IR population as presented by the manufacturer. It noted the concerns raised by the ERG and clinical specialists that the inclusion criteria of the trials that were incorporated into the mixed treatment comparison varied. The Committee heard from clinical specialists that the dose of methotrexate used as a comparator in the RCTs varied and that the dose used in clinical practice has increased over time; meaning that the comparator arms of the earlier trials received a different dose of methotrexate than the comparator arms of the most recent trials. Consequently the Committee concluded that the mixed treatment comparison included a heterogeneous set of RCTs. The ERG also highlighted concerns with the inclusion of one large RCT which compared etanercept with methotrexate that was included in the mixed treatment comparison. It noted that this trial was conducted in people who were still able to benefit from methotrexate treatment and hence had high response rates in the comparator arm. The Committee accepted the ERG comments that this RCT should not have been included because the inclusion criteria of the RCT did not meet the stated inclusion criteria for the mixed treatment comparison. The Committee noted that when this RCT was removed from the mixed treatment comparison then tocilizumab was not more clinically effective than etanercept. The Committee was also concerned that some relevant RCTs (included in previous technology appraisals of treatments for rheumatoid arthritis) were missing from the mixed treatment comparison. The Committee therefore concluded that the superiority of tocilizumab over etanercept had not been demonstrated in the DMARD-IR population.

4.5 The Committee then considered the clinical-effectiveness evidence in the TNF-IR population. It noted that there were statistically significant improvements in all ACR response rates at 24 weeks with tocilizumab plus DMARDs compared with DMARDs plus placebo. The Committee noted that there were also improvements in HAQ and DAS28 scores in the three RCTs for people receiving tocilizumab plus DMARDs. The Committee heard from clinical specialists and patient experts that the observed benefits in these three RCTs were clinically meaningful. It also noted that the adverse effects of tocilizumab were not considered to be worse than those associated with other treatments for rheumatoid arthritis. The Committee therefore concluded that tocilizumab plus methotrexate was clinically effective compared with placebo plus methotrexate in the TNF-IR population.

4.6 The Committee discussed the cost-effectiveness estimates of tocilizumab plus methotrexate for the DMARD-IR and TNF-IR populations. It noted that no cost‑effectiveness estimates of tocilizumab given as monotherapy had been presented by the manufacturer. The Committee understood that the economic model developed by the manufacturer considered only one possible treatment sequence of many. It noted the comments from the ERG that the submission did not explore the cost effectiveness of tocilizumab given after a person’s condition has failed to respond to rituximab or a second TNF-α inhibitor.

4.7 The Committee considered the cost‑effectiveness estimates for tocilizumab in combination with methotrexate in the DMARD-IR population. It noted that the base-case ICER was estimated by the manufacturer as £19,900 per QALY gained. The Committee understood that the effectiveness estimates in the model had been derived from the mixed treatment comparison. The Committee noted that it was plausible that tocilizumab could be less clinically effective than etanercept in the DMARD-IR population, and concluded that the results of the mixed treatment comparison should be viewed with caution. The Committee understood that the acquisition costs of tocilizumab were similar to those for etanercept; however it noted that tocilizumab is given as an intravenous infusion whereas etanercept is given as a subcutaneous injection and therefore can be given at home with lower administration and monitoring costs than tocilizumab. The Committee further noted that the administration costs of tocilizumab (that is, the administration costs of each infusion) may have been underestimated in the base-case analysis. The Committee considered that tocilizumab was likely to be more costly overall and to be no more clinically effective than etanercept, and therefore in the DMARD-IR population, etanercept would be expected to dominate tocilizumab. The Committee therefore concluded that for people whose rheumatoid arthritis had responded inadequately to previous DMARDs, tocilizumab would not be a cost-effective use of NHS resources and could therefore not be recommended.

4.8 The Committee then considered the cost‑effectiveness estimates for the TNF-IR population. It noted that the base-case ICER was estimated to be £22,000 per QALY gained. The Committee understood that the model developed by the manufacturer compared a sequence including tocilizumab plus methotrexate given after failure of DMARDs and etanercept. The Committee noted that it would have been appropriate and plausible to conduct an indirect comparison of rituximab with tocilizumab, both given after DMARD and etanercept failure. The Committee also noted that no subgroup analyses had been presented by the manufacturer, for example, according to rheumatoid factor status, which it understood may influence response to rituximab.

4.9 The Committee discussed the assumptions used in the economic model presented by the manufacturer for the TNF-IR population. The Committee considered how the utility values used in the manufacturer’s economic model had been derived and noted the ERG’s concerns about the use of mapping when EQ-5D had been directly assessed in the tocilizumab studies. The Committee agreed that this approach was not consistent with the reference case as outlined by NICE and noted that the full EQ-5D data that were collected in the trials had not been presented by the manufacturer. The Committee understood that the manufacturer had used a quadratic regression function to map onto EQ-5D scores for consistency with previous appraisals. However, the mapping technique used by the manufacturer differed from the approach used in previous appraisals. The ERG was also not able to fully appraise the mapping technique used as it had been presented in abstract form only, and stated that other, more common, mapping techniques (as used in previous appraisals) might have been more appropriate. The Committee concluded that other mapping techniques were likely to increase the ICER for tocilizumab.

4.10 The Committee noted the ERG’s concerns over the linearly decreasing HAQ score with tocilizumab for up to 2.5 or 3 years, based on observational follow-up from extension trials. No comparable improvement in HAQ scores were assumed for etanercept or rituximab treatment over this medium-term period. The Committee heard from clinical specialists that it was unlikely that the medium-term progression of HAQ score with tocilizumab would be any different from etanercept or rituximab, and assuming zero HAQ progression after the initial improvement while on treatment for tocilizumab and other biological treatments was more plausible (see 3.17 and 3.26). The Committee considered that the assumptions made on HAQ progression in the medium to long-term from the previous appraisals were more plausible and agreed with the ERG that the ICER from the manufacturer’s base-case would be expected to increase if no change in HAQ score was assumed while patients were on treatment. The ERG stated that the ICER was sensitive to variations in the extrapolation and mapping methods used and that the most plausible ICER, although uncertain, would be substantially higher than the base-case ICER as presented by the manufacturer.

4.11 The Committee proceeded to discuss the ‘rebound’ assumption used in the economic model presented by the manufacturer. It understood that in the model a ‘rebound’ effect after treatment withdrawal equal to the initial improvement in quality of life (as measured by HAQ score) was assumed. The Committee heard from clinical specialists that where treatment has been discontinued, the most plausible assumption would be one similar to that used in the economic model underpinning previous NICE technology appraisal guidance 130. The evidence that formed the basis of NICE technology appraisal guidance 130 assumed that the HAQ score for all biological DMARDs remained the same or worsened only slightly while on treatment rather than improving. Therefore, there was an assumed rebound that was equal to gain in initial HAQ score (rebound to baseline). The economic model for tocilizumab assumed a rebound effect that was equal to the initial benefit, similar to NICE technology appraisal guidance 130; however patients did not rebound to baseline because the economic model also assumed a decrease in the HAQ score while on treatment (see 4.10). Therefore when treatment was withdrawn patients in the economic model used to support NICE technology appraisal guidance 130 would ‘rebound’ to baseline whereas patients in the tocilizumab economic model would ‘rebound’ to a state that is better than baseline.  The Committee agreed with the ERG’s conclusions that the ICER would be expected to increase further from the base case if the assumption used to support NICE technology appraisal guidance 130 was used.

4.12 The Committee discussed the ERG’s concerns that the adverse effects of treatment had not been included in the manufacturer’s economic model. The Committee understood that the economic model compared two similar treatment pathways; the only difference being that people in the tocilizumab arm received tocilizumab as an initial treatment as an addition to the treatment pathway. The Committee considered that for people in the tocilizumab arm (who were receiving one more biologic treatment than people in the non-tocilizumab arm) it was plausible that there would be additional associated adverse effects. The Committee concluded that the effects of adverse events associated with tocilizumab treatment on health-related quality of life should have been incorporated into the economic model. The ERG stated that the ICER would be expected to increase from the base case if such effects were incorporated.

4.13 The Committee considered the cost-effectiveness estimate for tocilizumab for the TNF-IR population of £22,000 per QALY gained, in light of the issues and concerns raised by the ERG, clinical specialists and patient experts. The Committee agreed that the plausible adjustments to the key model inputs discussed would increase the base-case ICER substantially and were associated with a great deal of uncertainty. The Committee therefore concluded that the use of tocilizumab in combination with methotrexate in this population could not be recommended as a cost-effective use of NHS resources.

5 Implementation

5.1 The Secretary of State and the Welsh Assembly Minister for Health and Social Services have 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 implement this guidance (listed below). These are available on our website (www.nice.org.uk/TAXXX). [NICE to amend list as needed at time of publication]

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

6 Proposed recommendations for further research

6.1 The Committee recommended that a head-to-head trial of tocilizumab compared with rituximab should be done.

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/CG79
  • Abatacept for the treatment of rheumatoid arthritis. NICE technology appraisal guidance 141 (2008). Available from www.nice.org.uk/TA141
  • Adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis. NICE technology appraisal guidance 130 (2007). Available from www.nice.org.uk/TA130
  • Rituximab for the treatment of rheumatoid arthritis. NICE technology appraisal guidance 126 (2007). Available from www.nice.org.uk/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/TA036

Under development

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

  • Certolizumab pegol for rheumatoid arthritis. NICE technology appraisal guidance (publication expected February 2010).
  • Adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a TNF inhibitor. NICE technology appraisal guidance (publication expected June 2010).
  • Golimumab for rheumatoid arthritis (after failure of previous antirheumatic drugs). NICE technology appraisal guidance (appraisal suspended).
  • Golimumab for rheumatoid arthritis (methotrexate-naive). NICE technology appraisal guidance (appraisal suspended).
  • Sequential use of adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis (terminated appraisal).

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 September 2012. 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.

Jonathan Michaels
Chair, Appraisal Committee
September 2009

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 Kathryn Abel
Reader and Consultant Psychiatrist, University of Manchester

Professor David Barnett
Professor of Clinical Pharmacology, University of Leicester

Dr David W Black
Director of Public Health, Derbyshire County Primary Care Trust

Mr Brian Buckley
Lay Member

Mr David Chandler
Lay member

Dr Christine Davey
Senior Researcher, North Yorkshire Alliance R & D Unit

Professor Rachel Elliot
Senior clinical lecturer, School of Pharmacy and Pharmaceutical Sciences, University of Manchester

Dr Dyfrig Hughes
Senior Research Fellow, University of Wales Bangor

Dr Peter Jackson
Clinical Pharmacologist, University of Sheffield

Professor Peter Jones
Pro Vice Chancellor for Research & Enterprise, Keele University
Professor of Statistics, Keele University

Mr Henry Marsh
Consultant Neurosurgeon, St George’s Hospital London

Professor Jonathan Michaels (Chair)
Professor of Vascular Surgery, University of Sheffield

Dr Simon Mitchell
Consultant Neonatal Paediatrician, St Mary’s Hospital, Manchester

Dr Richard Alexander Nakielny
Consultant Radiologist, Royal Hallamshire Hospital, Sheffield

Mrs Ruth Oliver-Williams
Head of Nursing, Quality Improvement Lead Surgical Services, Royal Derby Hospital, Derby

Dr Danielle Preedy
Lay Member

Professor Andrew Stevens
Chair of Appraisal Committee C

Dr Matt Stevenson
Technical Director School or Health and Related Research, University of Sheffield

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.

Carina Righetti
Technical Lead

Rebecca Trowman
Technical Adviser

Laura Malone
Project Manager

Appendix B: Sources of evidence considered by the Committee

A The Evidence Review Group (ERG) report for this appraisal was prepared by:

  • West Midlands Health Technology Assessment Collaboration, Meads Cet al., Tocilizumab for the treatment of rheumatoid arthritis, April 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, the ERG report and the appraisal consultation document (ACD). Organisations listed in I were also invited to make written submissions. Organisations listed in II and III had the opportunity to give their expert views. Organisations listed in I, II and III also have the opportunity to appeal against the final appraisal determination.

I Manufacturer/sponsor:

  • Roche Products (Tocilizumab)

II Professional/specialist and patient/carer groups:

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

III Other consultees:

  • Department of Health
  • Welsh Assembly Government

IV Commentator organisations (did not provide written evidence and without the right of appeal):

  • Department of Health, Social Services and Public Safety for Northern Ireland
  • NHS Quality Improvement Scotland
  • Abbott Laboratories (adalimumab)
  • AstraZeneca UK (chloroquine)
  • GlaxoSmith Kline (azathioprine)
  • Novartis (ciclosporin)
  • Pfizer (methotrexate, sulfasalazine)
  • Roche Products (rituximab)
  • Sanofi – Aventis (hydroxychloquine, leflunomide, sodium aurothiomalate
  • Schering – Plough (infliximab)
  • Wyeth Pharamceuticals (etanercept)
  • West Midlands Health Technology Assessment Collaboration
  • National Institute for Health Research (NIHR) Health Technology Assessment Programme (HTA Programme)

C The following individuals were selected from clinical specialist and patient expert nominations from the non-manufacturer/sponsor consultees and commentators. They gave their expert personal view on tocilizumab for the treatment of rheumatoid arthritis by attending the initial Committee discussion and providing written evidence to the Committee. They are invited to comment on the ACD.

  • Dr Pavaladurai Vijayadurai, Consultant Immunologist, nominated by Royal College of Pathologists – clinical specialist
  • Professor Peter C Taylor, Professor of Experimental Rheumatology and Honorary Consultant Rheumatologist, nominated by The British Society for Rheumatology – clinical specialist
  • Dr Andrew J K Oster, Consultant Rheumatologist & Associate Lecturer School of Clinical Medicine University of Cambridge Director, Rheumatology Clinical Research Unit, nominated by The British Society for Rheumatology – clinical specialist
  • Ms Ailsa Bosworth, Chief Executive National Rheumatoid Arthritis Society (NRAS), nominated by the National Rheumatoid Arthritis Society (NRAS) – patient expert
  • Ms Jean Burke, Management Consultant Comma Consulting, nominated by the National Rheumatoid Arthritis Society (NRAS) – patient expert

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