Tocilizumab for the treatment of rheumatoid arthritis

Evidence-based recommendations on tocilizumab (RoActemra) for treating rheumatoid arthritis in adults.

# Guidance
Tocilizumab in combination with methotrexate is recommended as an option for the treatment of rheumatoid arthritis in adults if:
the disease has responded inadequately to DMARDs and a TNF inhibitor and the person cannot receive rituximab because of a contraindication to rituximab, or because rituximab is withdrawn because of an adverse event, and tocilizumab is used as described for TNF inhibitor treatments in the NICE technology appraisal guidance on adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a TNF inhibitor, specifically the recommendations on disease activity or
the disease has responded inadequately to one or more TNF inhibitor treatments and to rituximab
and the manufacturer provides tocilizumab with the discount agreed as part of the patient access scheme.
People currently receiving tocilizumab for the treatment of rheumatoid arthritis who do not meet the criteria in 1.1 should have the option to continue treatment until they and their clinicians consider it appropriate to stop.
Take into account any physical, sensory or learning disabilities, or communication difficulties that could affect the responses to the disease activity score and make any appropriate adjustments.# The technology 
Tocilizumab (RoActemra, Roche) is a humanised monoclonal antibody that inhibits cytokine interleukin6 (IL6). Reducing the activity of IL6 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 were intolerant to, previous therapy with one or more DMARDs or TNF-alpha antagonists. In these people, tocilizumab can be given as monotherapy in case of intolerance to methotrexate or if continued treatment with methotrexate is inappropriate. Tocilizumab has been shown to reduce the rate of progression of joint damage as measured by Xray and to improve physical function when given in combination with methotrexate.
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. For full details of side effects and contraindications, see the SPC.
Tocilizumab is administered as an intravenous infusion, given over 1 hour. The recommended dosage is 8 mg/kg, given once every 4 weeks. For people whose body weight is more than 100 kg, doses exceeding 800 mg per infusion are not recommended. 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 ('British national formulary'  edition 59, excluding VAT). The cost for tocilizumab as reported by the manufacturer is 9295 per year for a patient weighing approximately 70 kg. Costs may vary in different settings because of negotiated procurement discounts.
The Department of Health and the manufacturer have agreed that tocilizumab will be available to the NHS with a patient access scheme in which a discount from the list price is applied to original invoices. The level of the discount is commercial in confidence (see section 5.2). The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS. The manufacturer has agreed that the patient access scheme will remain in place until any review of this NICE technology appraisal guidance is published.# The manufacturer's submission
The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of tocilizumab, a review of this submission by the Evidence Review Group (ERG; appendix B), and two additional analyses by the Decision Support Unit (DSU; appendix B).

# Clinical effectiveness
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 but before treatment with a TNFalpha inhibitor (the 'DMARDIR' population) and people whose rheumatoid arthritis had responded inadequately to previous TNFalpha inhibitors but before treatment with rituximab (the 'TNFIR' population). 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 because 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.

## Tocilizumab plus methotrexate as a treatment option after an inadequate response to conventional DMARDs
The main clinical-effectiveness evidence for the DMARDIR population came from three randomised controlled trials (RCTs). All three RCTs were 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=398) compared with placebo plus methotrexate (n=393). The TOWARD trial assessed the effects of tocilizumab 8 mg/kg plus DMARDs (n=805) compared with placebo plus DMARDs (n=415).
The primary outcome in the RCTs was the proportion of people with an American of Rheumatology (ACR) 20 response at week 24. This was defined as at least a 20% improvement 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 rate, which was examined by logistic regression analysis. No statistically 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 8mg/kg arm compared with 25.8% in the placebo arm (p0.0001) at week 24.
Secondary outcomes of the RCTs, measured at 24 weeks, were pooled across the three 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% for ACR70 response rates (p0.0001), and 4.2% compared with 0.3% for ACR90 response rates (p0.0001), for the tocilizumab 8mg/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 participants going into remission while on tocilizumab was reported to increase during the study period. There was a greater decrease (improvement) in averaged health assessment questionnaire (HAQ) results from baseline HAQ score in the tocilizumab groups than in the placebo groups. In the pooled population at week 24, the proportion of participants with 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%).
Additionally, European quality of life (EuroQoL) health-state questionnaire (EQ5D) scores were collected in the OPTION and LITHE RCTs. In the OPTION RCT, the baseline mean EQ5D 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 EQ5D 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 manufacturer did not provide EQ5D results from the LITHE RCT separately by treatment arm.
Two single-arm extension studies assessed maintenance of clinical benefit of tocilizumab beyond 24 weeks. Overall, response rates for those remaining on tocilizumab plus DMARD treatment were maintained or continued to improve with duration of treatment, with an increasing proportion of people achieving higher ACR scores over time. The manufacturer reported that improvements in HAQ scores were observed for up to 132 weeks in the pooled tocilizumab 8 mg/kg plus DMARD arm.
No head-to-head studies were identified that provided evidence on the clinical effectiveness of tocilizumab compared with TNFalpha inhibitors and abatacept for the DMARDIR population. Therefore, the manufacturer conducted a mixed treatment comparison. A total of 18 RCTs (including OPTION, LITHE and TOWARD) 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. Participants 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 to ACR core parameters. Results for TNFalpha inhibitors were pooled, because it was assumed there was no difference in efficacy between these drugs. This assumption was reported to be informed by the guidance on adalimumab, etanercept and infliximab for rheumatoid arthritis (NICE technology appraisal guidance 130).
The mixed treatment comparison suggested that tocilizumab showed efficacy (measured by ACR20 and ACR50 response rates) comparable to all included biological treatments. For the ACR70 response rate, tocilizumab treatment was associated with a higher response rate than the TNFalpha inhibitors and abatacept (relative risks of 1.77 and 1.98 respectively). In the base-case comparison, there was a greater than 99% probability that tocilizumab was more efficacious than biological treatments (that is, etanercept, infliximab and adalimumab), as measured by ACR70 response rates. The manufacturer stated that homogeneity at each ACR response level was assessed using Cochran's Qstatistic (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 response rates, and fixed-effect methods to estimate ACR70 response rates. 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.

## Tocilizumab plus methotrexate as a treatment option after an inadequate response to a TNFalpha inhibitor
The main clinical-effectiveness evidence for the TNFIR population came from one RCT, known as RADIATE. RADIATE was a double-blind, placebo-controlled, parallel-group study in adults with moderate to severe rheumatoid arthritis. The participants' rheumatoid arthritis had responded inadequately to previous TNFalpha inhibitor therapy. RADIATE assessed the effects of tocilizumab 8 mg/kg plus methotrexate (n=170) compared with placebo plus methotrexate (n=158).
The primary outcome of the RADIATE trial was ACR20 response rate. At 24 weeks, 50% of people in the tocilizumab arm compared with 10% of people 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.
Two single-arm extension studies assessed the maintenance of clinical benefit of tocilizumab plus DMARDs beyond 24 weeks. Response rates to therapy with tocilizumab were maintained or continued to improve with duration of treatment (as in the DMARDIR population). Results similar to those for the DMARDIR 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 as a monotherapy
One RCT (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 treatment with methotrexate before or had stopped methotrexate treatment for reasons other than toxicity or lack of efficacy.
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). The manufacturer concluded that treatment with tocilizumab was non-inferior to treatment with methotrexate. The manufacturer also stated that the trial population of AMBITION was not in accordance with the SPC of tocilizumab. This was because the AMBITION trial had recruited people who had not received any previous treatment with methotrexate; the SPC states that tocilizumab can be given as monotherapy in case of intolerance to methotrexate or if continued treatment with methotrexate is inappropriate.

## Adverse events
The manufacturer reported that adverse events associated with the mechanism of IL6 receptor (IL6R) inhibition were observed in all tocilizumab treatment groups. These adverse events included transient hepatic transaminase elevations, asymptomatic elevations of indirect bilirubin, transient neutropenia, and lipid elevations that 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 with the incidence of serious infections with TNF-alpha 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 hyperlipidaemia. 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.

## Follow-up data
In addition to the original submission, the manufacturer of tocilizumab provided updated data with a maximum of 180 weeks of follow-up. The response rates of all people who received at least one dose of tocilizumab in the OPTION, AMBITION, RADIATE and TOWARD trials were analysed. A total of 3986 people were included in the long-term analyses. Approximately 14% of people discontinued tocilizumab treatment for safety reasons (including intercurrent illness). The manufacturer stated that tocilizumab increased or maintained ACR response rates in the DMARDIR, TNF-IR and tocilizumab monotherapy populations. This was demonstrated by the increased proportion of people with ACR50 and ACR70 responses and with an ACR70 response maintained for 24 consecutive weeks. The manufacturer also used the long-term follow-up data to re-estimate the HAQ progression with tocilizumab. The manufacturer stated that there was a negative trend (an improvement) in HAQ progression for both the DMARDIR and TNFIR populations.

# Cost effectiveness
The manufacturer did not identify any economic evaluations of tocilizumab and developed an 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 DMARDIR and TNFIR populations separately. No evidence on the cost effectiveness of tocilizumab monotherapy was presented.
The manufacturer's initial economic model compared a treatment sequence that included tocilizumab with the same treatment sequence without tocilizumab for two populations. For the DMARDIR population, tocilizumab plus methotrexate was the first biological treatment and if the condition did not respond or if the ACR20 response rate was no longer achieved then etanercept plus methotrexate was the next treatment. This was followed by rituximab plus methotrexate, then leflunomide, then gold, then ciclosporin until people withdrew from the last treatment (ciclosporin) and moved on to palliative care. The sequence was the same for the comparator arm, but excluded tocilizumab plus methotrexate at the beginning. For the TNFIR population, the sequence was the same as the DMARDIR population, except for the omission of etanercept plus methotrexate (that is, the first treatment in the comparator arm was rituximab plus methotrexate).
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. People 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. People whose condition responded were assumed to have a constant probability of withdrawal owing to lack of efficacy. The probability of withdrawing from treatment was the same for the biological treatments (infliximab, etanercept, adalimumab, rituximab and tocilizumab) and was calculated as the average of two withdrawal rate estimates for etanercept and infliximab. At the point of switching to the next treatment, people were assumed to experience an increase in their HAQ score (rebound) equal to the initial HAQ improvement. After the initial 24week period the HAQ score with tocilizumab plus methotrexate was assumed to decrease linearly (improve) based on the observational extensions to the RCTs. Because of substantial uncertainty in the data for weeks 132156, 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. Beyond this (3 years after initial treatment in the DMARD-IR cohort and 2.5 years after initial treatment in the TNF-IR cohort), the HAQ score was assumed to stay constant (that is, zero HAQ improvement) with tocilizumab plus methotrexate treatment. After the initial 24week treatment period, no change in HAQ score was assumed (zero HAQ improvement) for biological treatments such as etanercept and rituximab. After the initial 24week treatment period, an increase in HAQ score (that is, a worsening of physical function) was assumed for traditional DMARDs. The manufacturer also carried out sensitivity analyses using an assumption of zero HAQ progression (no improvement or worsening) while on treatment.
Tocilizumab plus methotrexate 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 (see section 3.25 for subsequent considerations of administration costs). The costs of treating any adverse events were not included in the economic model presented by the manufacturer. The manufacturer reported that EQ5D scores from the tocilizumab OPTION and LITHE trials were mapped to HAQ scores using a quadratic regression model. Alternative mapping equations as used in the guidance on adalimumab, etanercept and infliximab for rheumatoid arthritis (NICE technology appraisal guidance 130) and other submissions to NICE were examined in scenario analyses. Utility weights were derived from the EQ5D scores using the UK time trade-off tariff. Adverse events associated with tocilizumab treatment were assumed to generate an insignificant burden on people's quality of life, and therefore were not included in the model.
For the DMARDIR population, the treatment sequence including tocilizumab plus methotrexate 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 TNFIR population, the treatment sequence including tocilizumab plus methotrexate 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 and methotrexate to the treatment sequences had a 56.4% and 22.4% probability of being cost effective (for the DMARDIR and TNFIR 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. The ICERs increased to 24,905 and 24,739 per QALY gained for the DMARDIR and TNFIR populations respectively, using an assumption of no change in HAQ score (that is, no continued improvement on tocilizumab after the initial ACR response).

# Evidence Review Group comments
The ERG highlighted the following key areas of concern with the manufacturer's submission.
The selection of the studies and the pooling of the TNFalpha inhibitors in the mixed treatment comparison.
The long-term estimates of HAQ score.
Mapping HAQ scores to EQ5D 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.
The ERG explored the combined adjusted ACR response rates for TNFalpha inhibitors used in the mixed treatment comparison (DMARDIR 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 TNFalpha inhibitors was a single large trial with a very high response rate in the placebo arm (the Klareskog trial). The ERG noted that this trial only included people 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 the Klareskog trial from the analysis, etanercept appeared more efficacious than tocilizumab and all the other treatments in the comparison. The ERG then questioned the validity of assuming that all TNFalpha inhibitors had the same efficacy in the model, because this lowered the estimate of the effectiveness of the TNFalpha inhibitor used in the model.
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 DMARDIR population and 2.5 years for the TNFIR 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.
The ERG was also concerned about the way the relationship between HAQ and EQ5D was modelled. The manufacturer's submission used a quadratic equation for this. The quadratic model predicted that EQ5D scores would be lower at high HAQ scores compared with a linear model. In addition, literature has shown that EQ5D and HAQ are closely correlated at baseline and that when quality of life worsened over time the EQ5D became more variable (resulting in a weaker correlation). The ERG noted that the modelled relationship between HAQ and EQ5D scores resulted in negative utilities for health states (that is, health states that are considered to be worse than death). The ERG stated that using negative utility values is questionable because a certain amount of disability (because of irreversible characteristics such as damaged joints) may remain despite optimal control of inflammatory disease. The ERG concluded that algorithms for modelling the relationship between HAQ and EQ5D should only be used when there are no direct utility scores; however, the trials for tocilizumab (OPTION and LITHE) measured EQ5D directly.
The manufacturer assumed the cost of administering each infusion of tocilizumab was 142. This was derived by adjusting for inflation the cost of an infusion as used in the guidance on adalimumab, etanercept and infliximab for rheumatoid arthritis (NICE technology appraisal guidance 130). However, the ERG commented that this cost should have been adjusted for inflation from 2001 and not from 2004 as was presented by the manufacturer.
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 the HAQ score for people treated with tocilizumab improved over the course of treatment, but that for other treatments the HAQ score either remained the same (biological treatments) 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. The guidance on adalimumab, etanercept and infliximab for rheumatoid arthritis (NICE technology appraisal guidance 130) accepted a similar assumption that people would lose their initial HAQ improvement when treatment was withdrawn, and also that biological treatments delayed disease progression more than conventional DMARDs. However, whereas the HAQ score representing underlying disease progression for all biological treatments in the guidance on adalimumab, etanercept and infliximab for rheumatoid arthritis (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 for a lasting improvement of the condition.
In addition, the ERG considered that excluding adverse events in the manufacturer's model was questionable because biological treatments are known to be associated with adverse events. It reported that it was unclear whether the adverse-event rate is higher or lower for tocilizumab than for other biological treatments. The manufacturer's submission states that the mean and median duration of treatment with tocilizumab in the clinical trials was 1.08 years. The ERG commented that the risks of longer-term treatment with tocilizumab were unknown.

# Manufacturer's response to consultation
In response to three rounds of consultation for the original guidance on tocilizumab for rheumatoid arthritis (NICE technology appraisal guidance 198), the manufacturer presented revised ICERs for the DMARDIR and TNFIR populations incorporating some of the ERG's suggested changes. The manufacturer also provided ICERs for positioning tocilizumab after an inadequate response to rituximab, and tocilizumab for people who are intolerant to rituximab or for whom rituximab is contraindicated. The clinical-effectiveness data for tocilizumab used in these positions were taken from the RADIATE trial. All of the revised and new ICERs incorporated degraded ACR response rates for tocilizumab, etanercept and rituximab when they are used later in the treatment sequence. Estimates for etanercept were based on treatment response to a second or third TNFalpha inhibitor reported from the South Swedish Arthritis Treatment Group. These downgraded the efficacy of etanercept from 62%, 38% and 16% to 49%, 26% and 7% for ACR20, ACR50 and ACR70 response rates respectively when used after one biological treatment. For tocilizumab when used after two biological treatments, degraded rates were based on the subgroup of people from the RADIATE trial whose rheumatoid arthritis had responded inadequately to more than one TNFalpha inhibitor. Based on these data, tocilizumab response rates changed from 62%, 31% and 12% to 50%, 31% and 15% for ACR20, ACR50 and ACR70 response rates respectively. For rituximab used after two biological treatments, the manufacturer provided downgraded response rates based on a subgroup of people whose rheumatoid arthritis had responded inadequately to more than one TNFalpha inhibitor from a trial comparing rituximab plus methotrexate with placebo plus methotrexate (REFLEX). Based on these data, the rituximab response rates were downgraded from 46%, 23% and 14% to 42%, 22% and 10% respectively.
The revised ICERs were based on the adjusted ACR rates from the mixed treatment comparison, and included a long-term HAQ improvement for tocilizumab and a stable HAQ score (that is, zero HAQ progression) for all other biological treatments. This was not the case for the ICER for tocilizumab given after rituximab, for which no HAQ improvement for treatment with any biological treatment, including tocilizumab, was assumed. All of the revised ICERs were calculated using the HAQ to EQ5D mapping and included negative utilities that represented states worse than death. The ICERs were subject to the assumption that a person would experience the same adverse events during treatment as during palliative care, and that the cost of administration of tocilizumab was 154.
The manufacturer's revised ICER for the DMARDIR population increased from 19,870 to 21,733 per QALY gained and increased from 22,003 to 23,285 per QALY gained for the TNFIR population. The ICER for tocilizumab used after rituximab was 23,735 per QALY gained. The ICER for tocilizumab for people who are intolerant to rituximab or for whom rituximab is contraindicated was 20,242 per QALY gained.

# Decision Support Unit report 2010
In 2010, the DSU was asked to undertake additional cost-effectiveness analyses to validate the manufacturer's ICERs submitted following the third round of consultation, and to conduct sensitivity analyses to address the Appraisal Committee's concerns about key parameter assumptions. The 2010 report highlighted a key issue with the calculation of the ICERs presented by the manufacturer. This concerned the 'pair-wise' calculation of sequences containing tocilizumab plus methotrexate with the same sequence excluding tocilizumab rather than an 'incremental' comparison of all strategies containing tocilizumab plus methotrexate with each other and with a base-case strategy without tocilizumab. The DSU considered that the incremental approach was the most appropriate, not only to determine whether tocilizumab plus methotrexate was cost effective, but also in what circumstances, given the availability of a number of other treatments that are used sequentially. The DSU's 2010 report explained that an ICER calculated through a pair-wise comparison does not demonstrate that the sequence can be considered cost effective because there are a series of mutually exclusive sequences available and only one can be selected at any one time.
For etanercept, the mixed treatment comparison analysis combined all TNFalpha inhibitors (etanercept, infliximab and adalimumab) but excluded the Klareskog trial of etanercept that the Committee had requested to be removed because of its unusually high placebo response rate. The DSU noted in the 2010 report that the adjusted mixed treatment comparison rates were lower than the unadjusted trial ACR, or point estimate, rates for etanercept. The adjusted etanercept ACR20, ACR50 and ACR70 response rates were 62%, 38% and 16% respectively and the unadjusted ACR20, ACR50 and ACR70 response rates were 71%, 39% and 17% respectively. In 2010 the DSU reported that the unadjusted rates in the model were taken from a single etanercept trial, without justification for the sole use of this particular trial. The DSU provided an alternative set of unadjusted response rates for etanercept, which were based on the two etanercept trials from the mixed treatment comparison (rather than the single trial chosen by the manufacturer). The DSU stated in the 2010 report that this appeared to represent the most robust data. The resulting unadjusted ACR response rates were 73%, 47% and 22% for ACR20, ACR50 and ACR70 respectively. For rituximab, the adjusted mixed treatment comparison ACR response rates were also lower than the unadjusted ACR trial response rates. The percentage of people reaching an ACR20, ACR50 and ACR70 response rate was 51%, 27% and 12% respectively in the unadjusted analysis and 46%, 23% and 14% respectively in the adjusted analysis. The unadjusted data were taken from the REFLEX trial.
The DSU highlighted in the 2010 report that the opposite effect was observed with the adjusted and unadjusted ACR rates for tocilizumab, that is, the adjusted rates from the mixed treatment comparison were higher than the unadjusted rates. For tocilizumab given as the first biological treatment in the sequence, the adjusted rates were 63%, 41% and 26% for ACR20, ACR50 and ACR70 response rates respectively and the unadjusted rates for tocilizumab, which were based on a separate meta-analysis of OPTION, TOWARD and LITHE (submitted as part of the manufacturer's licence application), were 59%, 37% and 19% respectively. For tocilizumab used as the second biological treatment in a sequence (that is, after a TNFalpha inhibitor), the mixed treatment comparison had the same effect of increasing the tocilizumab ACR response rates. The adjusted rates were 62%, 31% and 12%, whereas the unadjusted rates were 50%, 29% and 12% for ACR20, ACR50 and ACR70 response rates respectively. The unadjusted rates for tocilizumab used as the second biological treatment in the sequence were taken from the RADIATE trial.
The DSU also commented on the degradation rates provided by the manufacturer. These rates were all from single data sources, without justification given for the selection of the sources. The DSU highlighted that the degraded response rates for etanercept were based on the reported ACR rates for the TNFalpha inhibitors as a group and may not have been generalisable to etanercept. The DSU also noted that the degraded ACR70 response rate for tocilizumab used after two biological treatments assumed by the manufacturer (15%) was marginally better than when used after a single biological treatment (12%). The DSU stated that this appeared to be counterintuitive and that it would be more appropriate to assume the same ACR70 response rate when tocilizumab is given after two biological treatments as for when it is given after one.
In the 2010 report the DSU considered four separate approaches that varied the ACR response rates and degradation rates used to calculate the incremental ICERs (approaches to evidence synthesis).
Approach 1 was the same as the manufacturer's revised base case and used the adjusted mixed treatment comparison results with the degradation rates supplied by the manufacturer.
Approach 2 used the unadjusted single trial ACR response rates for etanercept when used first in the treatment sequence as supplied by the manufacturer. All other estimates remained the same as in approach 1.
Approach 3 used the unadjusted trial ACR response rates for all treatments in the sequence as supplied by the manufacturer. In addition, this approach replaced the degraded effect for tocilizumab when used after two biological treatments with the same effect assumed after one biological treatment to account for the counterintuitive change in response rate assumed by the manufacturer (see section 3.34).
Approach 4 was the same as approach 3, except that the DSU used the alternative unadjusted ACR response rates for etanercept from the two trials (described in section 3.32).
For each of the four approaches to evidence synthesis, the DSU undertook four sets of sensitivity analyses to assess the robustness of the ICER results to other key parameter assumptions in the 2010 report. These were:
employing the same set of parameter assumptions employed by the manufacturer in its base case
assuming no long-term HAQ improvement with tocilizumab
assuming no long-term HAQ improvement with tocilizumab and excluding negative utilities from the HAQ to EQ-5D mapping
assuming no long-term HAQ improvement with tocilizumab and doubling the administration costs for tocilizumab to 308.60 per infusion.
The DSU in the 2010 report calculated the incremental ICERs for each approach using the four sensitivity analyses and presented the incremental results separately for each of the 16 possible analyses. In each incremental analysis, the treatment strategies compared with each other were:
etanercept followed by rituximab (strategy 1)
tocilizumab, followed by etanercept, followed by rituximab (strategy 2)
etanercept, followed by tocilizumab, followed by rituximab (strategy 3)
etanercept, followed by rituximab, followed by tocilizumab (strategy 4).
For all treatment strategies, the calculation of the ICER included the costs and QALYs associated with treatment with conventional DMARDs and palliative care at the end of the sequence. All treatment strategies were in combination with methotrexate.
Using the threshold for cost effectiveness (30,000 per QALY gained), the results of the fully incremental analysis undertaken by the DSU in the 2010 report indicated that using tocilizumab as a first-line treatment before etanercept would not be cost effective for any approach and with any set of parameter assumptions (including the manufacturer's base-case assumptions). Using tocilizumab as a second-line treatment before rituximab would only be cost effective if it is assumed that tocilizumab has long-term HAQ improvement and there is no HAQ improvement assumed with other biological treatments. However, if tocilizumab has zero HAQ improvement, then tocilizumab would only be cost effective when used as a third-line treatment after rituximab. If tocilizumab has zero HAQ improvement and the administration costs of tocilizumab are doubled, then tocilizumab is never cost effective (that is, standard care is the most cost-effective sequence). For people who have an intolerance to rituximab, or for whom rituximab is contraindicated, adding tocilizumab to the current standard care is cost effective. However, if tocilizumab does not have a different effect on long-term HAQ and the administration costs of tocilizumab are doubled, then the current standard care would be more cost effective for this population.

# Rapid review of NICE technology appraisal guidance 198: patient access scheme
In the Appraisal Committee's original guidance on tocilizumab for rheumatoid arthritis (NICE technology appraisal guidance 198) tocilizumab plus methotrexate was recommended for the treatment of rheumatoid arthritis that has not responded adequately to one or more TNFalpha inhibitors or to rituximab, or in whom rituximab is contraindicated or is withdrawn because of an adverse effect. Following publication of this guidance, the manufacturer submitted a patient access scheme in which a discount was applied to all indications for tocilizumab (see section 2.4) to be considered as a rapid review of the original guidance.
As part of the rapid review, the manufacturer did not submit any additional clinical-effectiveness data. However, the manufacturer did clarify the ACR and non-response rates for each drug for each position in the treatment sequences. This highlighted that when tocilizumab is the first biological treatment in the sequence, the non-response rate is approximately 40% compared with 27% when etanercept is the first biological treatment in the sequence.
The manufacturer submitted revised ICERs using the assumptions that the Committee agreed at the final Committee meeting before issuing NICE technology appraisal guidance 198, which included:
using approach 4 to evidence synthesis (see section 3.35)
assuming no long-term HAQ improvement with tocilizumab.
The manufacturer presented the results of an incremental analysis for the DMARDIR population in which the following treatment sequences were included:
etanercept then rituximab (baseline sequence)
tocilizumab then etanercept then rituximab
etanercept then tocilizumab then rituximab
etanercept then rituximab then tocilizumab.
The manufacturer was requested to include an additional baseline treatment sequence of tocilizumab, followed by etanercept. In this analysis the ICER for tocilizumab as the first treatment in the sequence was 5716 per QALY gained. As the second treatment in the sequence it was 30,716 per QALY gained, and as the third treatment in the sequence the ICER was 8134 per QALY gained. All ICERs incorporated the discount for tocilizumab agreed as part of the patient access scheme.
The manufacturer also responded to a request from the DSU as part of this rapid review to provide ICERs for the TNFIR population in which the following treatment sequences were included:
rituximab (baseline sequence)
tocilizumab then rituximab.
In this analysis the costs and QALYs associated with prior treatment with a TNFalpha inhibitor were assumed to be the same for both treatment strategies and were therefore not modelled. The ICER for the tocilizumab sequence compared with the baseline sequence (incorporating the discount for tocilizumab agreed as part of the patient access scheme) was 22,690 per QALY gained.

# Decision Support Unit report 2011
In 2011, the DSU was asked to undertake a review of whether the manufacturer had correctly implemented the Department of Health approved patient access scheme within their cost-effectiveness analysis. Additionally the DSU critiqued the changes to the costs of tocilizumab and ensured the Committee's agreed assumptions from the guidance on tocilizumab for rheumatoid arthritis (NICE technology appraisal guidance 198) had been used as the starting point within the economic analysis.
The DSU confirmed in the 2011 report that these conditions were met. However it raised the following issues with the manufacturer's analyses:
No results had been presented for the subgroup of people intolerant to rituximab or who have had rituximab withdrawn because of a contraindication. The ICERs were incorrect because no account had been taken of sequences that were extendedly dominated (less effective than and at least as costly as a combination of other drug sequences).
Within the TNF-IR analysis a sequence of rituximab followed by tocilizumab had not been included.
The DSU also corrected for a minor inaccuracy in the unadjusted trial rates used in NICE technology appraisal guidance 198. This changed the ACR20, ACR50 and ACR70 response rates for tocilizumab following two biologicals from 0.50, 0.31 and 0.15 to 0.50, 0.29 and 0.12 respectively.
In 2011, the DSU reported the results of their exploratory analysis for the DMARDIR population, which included the same treatment sequences in an incremental analysis as those modelled by the manufacturer (see section 3.42). All ICERs incorporated the discount for tocilizumab agreed as part of the patient access scheme. In this analysis, three sequences were extendedly dominated (first: etanercept followed by rituximab; second: tocilizumab as the first treatment; third: tocilizumab as the second treatment). The ICER for tocilizumab as the third treatment in the sequence was 28,380 per QALY gained compared with 8134 per QALY gained from the manufacturer's analysis.
The DSU provided an additional exploratory analysis in the 2011 report. This was an exploratory analysis for the rituximab-intolerant DMARD-IR population. All ICERs incorporated the discount for tocilizumab agreed as part of the patient access scheme. In this analysis etanercept alone was extendedly dominated. The ICER for tocilizumab followed by etanercept compared with tocilizumab alone was 10,698 per QALY gained, and the ICER for etanercept followed by tocilizumab compared with tocilizumab followed by etanercept was 30,121 per QALY gained.
The DSU reported the results of their exploratory analysis for the TNF-IR population, which included the same treatment sequences in an incremental analysis as those modelled by the manufacturer (see section 3.43). All ICERs incorporated the discount for tocilizumab agreed as part of the patient access scheme. In this analysis, tocilizumab followed by rituximab was dominated (was less effective than and at least as costly) by rituximab followed by tocilizumab. The ICER for rituximab followed by tocilizumab was 18,527 per QALY gained compared with the manufacturer's estimate of 22,690 per QALY gained.
Full details of all the evidence are in the manufacturer's submissions, the ERG report, and the reports from the DSU, which are available from the NICE website.# Consideration of the evidence
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.
The Committee understood that the main purpose of 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 clinical specialists and patient 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 the safety data presented by the manufacturer, which reported 27 deaths and a serious adverse event rate of 5.8%. The Committee considered that this adverse event rate was high, but heard that it was comparable with other biological treatments.
The Committee understood the guidance on adalimumab, etanercept and infliximab for rheumatoid arthritis (NICE technology appraisal guidance 130) recommends TNFalpha inhibitors adalimumab, etanercept and infliximab as options for the treatment of adults whose rheumatoid arthritis has responded inadequately to two DMARDs (unless DMARDs are contraindicated), and with a DAS28 score greater than 5.1. The Committee noted that in NICE technology appraisal guidance 130, treatment should normally be initiated with the least expensive drug (taking into account administration costs, required dose and product price per dose) and this may need to be varied in individual cases because of differences in the mode of administration and treatment schedules. It was also aware of:
Certolizumab pegol for the treatment of rheumatoid arthritis (NICE technology appraisal guidance 186) and
Golimumab for the treatment of rheumatoid arthritis after the failure of previous disease-modifying anti-rheumatic drugs (NICE technology appraisal guidance 225).
It noted the recommendations for the TNFalpha inhibitors certolizumab pegol and golimumab to be used as described in the guidance on adalimumab, etanercept and infliximab for rheumatoid arthritis (NICE technology appraisal guidance 130), including the specific considerations concerning disease activity and choice of treatment. For treatment following an inadequate response to DMARDs (including at least one TNFalpha inhibitor), the guidance on adalimumab, etanercept, infliximab, rituximab and abatacept for rheumatoid arthritis (NICE technology appraisal guidance 195) recommends rituximab plus methotrexate.
The Committee discussed the treatment options for people with moderate to severe active rheumatoid arthritis. It was aware that after an inadequate response to rituximab, additional DMARDs and best supportive care would be offered. The Committee heard from the manufacturer that it was seeking a recommendation for tocilizumab as an option along with other biological treatments in the treatment pathway. The Committee concluded that there were four possible scenarios for including tocilizumab in the treatment pathway:
Tocilizumab after two DMARDs as an alternative to TNFalpha inhibitors.
Tocilizumab after TNFalpha inhibitors as an alternative to rituximab.
Tocilizumab after TNFalpha inhibitors when a person is intolerant to rituximab or for whom rituximab is contraindicated.
Tocilizumab as an addition to the treatment pathway after rituximab.

# Clinical effectiveness
The Committee first discussed tocilizumab given as monotherapy. It noted that the only clinical evidence for tocilizumab monotherapy came from a trial that included people who had not been previously treated with methotrexate and that tocilizumab monotherapy treatment for this population was outside the licensed indication of tocilizumab. The Committee also noted that no cost-effectiveness estimates of tocilizumab given as monotherapy had been presented by the manufacturer. It concluded that no evidence for tocilizumab monotherapy within its licensed indication was available, and therefore no recommendations for tocilizumab as a monotherapy could be made.
The Committee considered the evidence on the clinical effectiveness of tocilizumab plus DMARDs compared with placebo plus DMARDs. The Committee concluded that tocilizumab plus methotrexate was clinically effective compared with placebo plus DMARDs when given before TNFalpha inhibitors and when given before rituximab.
The Committee then considered the evidence for the relative efficacy of tocilizumab compared with etanercept and compared with rituximab when all treatment strategies were in combination with methotrexate. It understood that tocilizumab had not been compared head-to-head with etanercept (or any other TNFalpha inhibitor) or rituximab, and that indirect evidence had been combined in a mixed treatment comparison for this purpose. It noted the concerns raised by the ERG and clinical specialists regarding the mixed treatment comparison. The mixed treatment comparison assumed that the TNFalpha results could be regarded as a class; however, when merged, the overall results reduced the efficacy of etanercept. The Committee noted that the manufacturers had responded to its requests to remove the Klareskog trial of etanercept from the analysis because this was a large RCT with unusually high control-arm response rates and did not correspond with the inclusion criteria of the mixed treatment comparison. With this trial removed, the Committee noted that etanercept appeared at least equal to, and possibly had higher efficacy than, tocilizumab.
The Committee further noted the concerns of the DSU in its 2010 report regarding the adjusted ACR response rates from the mixed treatment comparison compared with the 'unadjusted' point estimates from the individual trials. It understood that the proportions of people achieving ACR20, ACR50 and ACR70 response rates for etanercept and rituximab resulting from the mixed treatment comparison were lower than the corresponding unadjusted trial ACR response rates. Conversely, the proportions of people achieving ACR20, ACR50 and ACR70 response rates were higher for tocilizumab in the adjusted mixed treatment comparison analysis than the unadjusted trial rates. The 2010 DSU report clarified that the counterintuitive results of the mixed treatment comparison had possibly arisen when the comparator response rates from all of the trials had been pooled. The Committee considered that the mixed treatment comparison included a set of heterogeneous trials, which meant that the results were subject to considerable uncertainty, and that limited confidence could be placed in the adjusted ACR response rates in the manufacturer's revised base case. The Committee concluded that using the unadjusted trial estimates in the analyses was more appropriate.
The Committee considered the relative efficacy of tocilizumab compared with etanercept and also with rituximab using the unadjusted trial estimates of ACR rates. It considered that the evidence was not conclusive of a benefit of any one drug over another. The Committee concluded that no convincing evidence had been presented to demonstrate the superiority of tocilizumab over etanercept or rituximab, but that the estimates were in a similar range to etanercept and rituximab.
The Committee considered the clinical evidence for tocilizumab after treatment with rituximab. Based on previous discussions it recognised that tocilizumab plus methotrexate is clinically effective compared with placebo plus methotrexate (see section 4.7). It noted the evidence from the RADIATE trial in which a subgroup of people had rheumatoid arthritis that had responded inadequately to two TNFalpha inhibitors. It understood that this was the only available evidence to consider the effectiveness of tocilizumab after rituximab. The Committee considered that it indicated a benefit of tocilizumab after two biological treatments. In view of this evidence and considering the comments from patient experts and clinical specialists, the Committee, on balance, agreed that tocilizumab was likely to benefit people whose rheumatoid arthritis has responded inadequately to rituximab.

# Cost effectiveness
The Committee discussed the appropriate approach for determining the cost effectiveness of tocilizumab. It understood that before the 2010 DSU report the manufacturer's ICERs were based on adjusted trial response rates from the mixed treatment comparison. It also understood that the 2010 DSU report presented analyses using four different approaches to evidence synthesis (see section 3.35). The Committee considered, on the basis of previous discussions (see section 4.8), that approach 1, in which the ACR response rates came from the mixed treatment comparison, was not appropriate. The remaining three approaches to evidence synthesis used the unadjusted trial response rates for all treatments and incorporated degradation rates. The Committee understood that approaches 2 and 3 only used the unadjusted ACR response rate from a single trial for etanercept, rather than from the two available trials. The Committee had a strong preference for approach 4, which used data from both of the etanercept trials. Approach 4 also corrected the counterintuitive ACR70 response rate for tocilizumab used as a third biological treatment in the treatment sequence noted by the DSU in the 2010 report. The Committee concluded that approach 4 to evidence synthesis (see section 3.35) was the most appropriate for consideration.
The Committee also discussed the two sensitivity analyses presented by the DSU within approach 4 in the 2010 report. The first concerned evidence supplied by the manufacturer for a long-term HAQ improvement. It understood that the data for a HAQ improvement with tocilizumab treatment came from open-label extension studies in which only the HAQ scores for people who remained on treatment were available. It noted that, for the open-label extension trial assessing the benefits of tocilizumab after the failure of conventional DMARDs (that is, before etanercept), approximately 30% of people had stopped treatment. It further noted that the confidence intervals around the mean HAQ scores at each point in time were wide. The Committee therefore considered that the manufacturer's evidence was not a robust estimate of the long-term HAQ improvement on tocilizumab and was subject to uncertainty. Furthermore, the manufacturer had not provided any comparable investigation into long-term HAQ trends for the comparator biological treatments other than rituximab. The manufacturer presented a graph of a stable HAQ trend for people on rituximab from the REFLEX trial. However, no data had been supplied by the manufacturer to support the graph. The Committee questioned the comparability of the rituximab and tocilizumab HAQ trend lines, and considered that single-arm extension trial data did not provide a direct comparison of the relative benefits between the two treatments. In addition, the Committee heard from patient experts and clinical specialists that it was unlikely that tocilizumab would provide a long-term HAQ benefit over and above that of any other biological treatment. Overall, the Committee could not support the assumption that there is a long-term HAQ gain with tocilizumab (that is, a HAQ improvement with tocilizumab) compared with no HAQ improvement with other biological treatments. It concluded, on the basis of the evidence presented, that the long-term HAQ improvement on tocilizumab treatment had not been demonstrated. The Committee agreed that the analyses that assumed no long-term HAQ improvement with tocilizumab were therefore the most appropriate for consideration.
The second sensitivity analysis that the Committee considered concerned the exclusion of negative utilities (health states worse than death) from the incremental analysis. The Committee noted that the manufacturer's mapping of HAQ scores to EQ-5D utility values resulted in negative utility values. It discussed that excluding negative utility values could be considered counterintuitive and did not allow for a worsening of quality of life when a person had rheumatoid arthritis. The Committee heard from the manufacturer that it was possible that there were some people with rheumatoid arthritis who may experience negative utility values. The Committee noted that the impact of removing the negative utilities from the incremental analysis was minimal. The Committee agreed that although the exclusion of negative utility values was subject to some debate, it was not a key issue in determining the cost effectiveness of tocilizumab. The Committee therefore accepted that the calculation of some ICERs would include negative utility values but concluded that this was acceptable because of the low impact on the ICERs.
The Committee considered the administration costs of tocilizumab. It noted comments received during consultation in 2010 that, although the infusion took 1 hour, the total time taken to administer tocilizumab in an organised unit would be at least 2 hours. The Committee then discussed the 2010 DSU analysis using approach 4 with no long-term HAQ improvement and the administration costs doubled. It heard from the DSU that the decision to double the cost was not based on a robust estimate of the time taken to administer tocilizumab, but was intended to illustrate the sensitivity of the ICERs to this assumption. Although the Committee agreed that a cost based on an administration time of 1 hour represented the minimum cost to the NHS, it did not agree that the true cost would be as much as double. The Committee therefore considered that it was not appropriate to double the administration cost of tocilizumab and concluded that the manufacturer's revised estimate of 154 was acceptable.
The Committee noted that some modelling assumptions in the manufacturer's submission had not been investigated by the DSU in the 2010 report. These included, first, any difference in the adverse events that may occur on biological treatment compared with those that might occur in palliative care. Second, that despite previous requests to the manufacturer to use directly observed EQ5D data, the revised base-case ICERs from the manufacturer were still subject to a HAQ mapping algorithm. The Committee highlighted its concern with this, but acknowledged that the data had not been available to investigate these assumptions.
In summary the Committee concluded that the best estimate of cost effectiveness of tocilizumab in any position in the treatment pathway should be based on approach 4 to evidence synthesis in which the ACR response rates came from the trials rather than the mixed treatment comparison and used a corrected degradation factor for tocilizumab (see section 3.35). In addition, it concluded that no long-term HAQ improvements with tocilizumab should be assumed.
The Committee considered the cost-effectiveness analyses submitted by the manufacturer in 2011 that were based on the preferred approach (see section 4.17) and that incorporated tocilizumab at the discount agreed as part of the patient access scheme (see section 2.4). It also considered the DSU 2011 report when reviewing the manufacturer's submission. It discussed the manufacturer's analyses, which the DSU replicated including fully incremental calculations (see sections 3.45 to 3.47) for all three patient subgroups: people whose rheumatoid arthritis has responded inadequately to one or more conventional DMARDs (DMARD-IR analysis); people who are intolerant to rituximab, or for whom rituximab is contraindicated (DMARD-IR rituximab intolerant); people whose rheumatoid arthritis has responded inadequately to TNFalpha inhibitors (TNF-IR analysis). The Committee accepted the DSU separate exploratory incremental analyses. It noted the DSU's comment from the 2011 report that the manufacturer's analysis had not taken into account extended dominance (when one or more drug sequences are less effective than and at least as costly as another sequence) and that this had an impact on the ICERs. The Committee concluded that the DSU's 2011 exploratory analyses should be used as the basis for determining the cost effectiveness of tocilizumab.
The Committee also considered the straightforward inferences that could be made from its separate clinical effectiveness and costing conclusions. These were that for the DMARD-IR population (who had not received a TNFalpha inhibitor or any other biological treatment) tocilizumab was similar in clinical effectiveness (see section 4.10) to the TNFalpha inhibitors and could be considered a plausible alternative. In the case of the TNFIR population (whose condition had failed to respond to a TNFalpha inhibitor but who had not yet tried rituximab), the position was different. Although tocilizumab might be as clinically effective as rituximab, it was also more expensive and so the Committee concluded tocilizumab could not be considered an option unless rituximab was contraindicated, not tolerated or had failed.
The Committee considered the DMARD-IR ICERs in the DSU's 2011 exploratory analysis. It noted from the total costs and QALYs for the sequences that when tocilizumab was the first biological treatment rather than etanercept, it was associated with fewer QALYs and less cost. It understood that this was because of the percentage of non-responders on tocilizumab (approximately 40%) when taken as a first-line biological treatment, which resulted in reduced time on tocilizumab treatment and therefore lower cost of the sequence. The Committee noted that this improved the cost effectiveness of tocilizumab. However, on the basis of previous discussions (see section 4.10) the Committee was not convinced that the clinical effectiveness of tocilizumab would be superior to that of etanercept. The Committee concluded that the improved cost effectiveness of tocilizumab as the first biological treatment compared with etanercept was due to the cost of time on treatment, rather than any substantial differences in clinical or cost effectiveness between tocilizumab and etanercept.
The Committee further considered the DMARD-IR ICERs from the DSU's 2011 exploratory analysis. It noted that although tocilizumab appeared cost effective as the first biological treatment (5700 per QALY gained), this sequence had rituximab as the third biological treatment in the sequence, rather than the second. The Committee raised concerns that this was counterintuitive because the total drug treatment cost of rituximab is approximately half that of either tocilizumab or etanercept. On the basis of previous discussions (see section 4.11) the Committee was not convinced that the clinical effectiveness of etanercept or tocilizumab would be sufficiently superior to rituximab such that a sequence in which rituximab was third would be more cost effective than one in which rituximab was second. The Committee noted that a sequence in which tocilizumab was the first biological treatment, followed by rituximab, followed by etanercept, had not been included in either the manufacturer's or the DSU's 2011 analyses. It was aware that in clinical practice this sequence would involve off-licence use of rituximab because the marketing authorisation restricts rituximab to use after an inadequate response or intolerance to other DMARDs including one or more TNFalpha inhibitors. However the Committee considered that to understand the impact on the cost effectiveness of placing tocilizumab first in the sequence, it was important to consider all possible treatment sequences. It noted that in their exploratory incremental analysis from 2011, the DSU had incorporated an alternative baseline sequence of tocilizumab followed by rituximab. The Committee accepted this sequence as a proxy for tocilizumab, followed by rituximab, followed by etanercept. It noted that when this alternative baseline sequence was included in the exploratory analysis, three sequences were extendedly dominated (see section 3.49) leaving the baseline sequence of tocilizumab followed by rituximab, and the sequence of etanercept, followed by rituximab, followed by tocilizumab. Comparing these two sequences, tocilizumab as the third biological in the sequence had an ICER of 28,400 per QALY gained, compared with tocilizumab as the first biological treatment in the sequence. It accepted that some uncertainty around the point estimates of the ICERs was likely. However the conclusion to this analysis was consistent with the reasoning in section 4.18. The Committee concluded that tocilizumab should be recommended as an option when used in the same way as the TNFalpha inhibitors etanercept, adalimumab, infliximab, golimumab and certolizumab pegol recommended in NICE technology appraisal guidance 130, 186 and 225. The Committee understood that its recommendation would apply to people whose rheumatoid arthritis has a DAS28 score of greater than 5.1. It also understood that treatment should normally be initiated with the least expensive drug (taking into account administration costs, required dose and product price per dose) and this may need to be varied in individual cases because of differences in the mode of administration and treatment schedules.
The Committee discussed the cost effectiveness of tocilizumab when a person is intolerant to rituximab or for whom rituximab is contraindicated (that is, the DMARDIR rituximab intolerant population). The Committee again took the view that, assuming that etanercept and tocilizumab have approximately equal effectiveness (see section 4.19) and cost, it would be reasonable for either to be an option in this position. The Committee noted that the DSU's 2011 analyses broadly corroborated these conclusions. It noted that in this population the ICER from the DSU's 2011 exploratory incremental analysis was 30,100 per QALY gained for a sequence in which etanercept was followed by tocilizumab, and 10,700 per QALY gained for a sequence in which tocilizumab was followed by etanercept (see section 3.50). The Committee concluded that tocilizumab should be recommended as an option for the DMARD-IR rituximab intolerant population. It further concluded that this recommendation should be in line with the guidance on adalimumab, etanercept, infliximab, rituximab and abatacept (NICE technology appraisal guidance 195), specifically the recommendations on disease activity when a second TNFalpha inhibitor is recommended for people in whom rituximab is contraindicated or when rituximab is withdrawn because of an adverse event.
Finally, the Committee considered the DSU's 2011 exploratory analysis for the TNFIR population. It understood that in this analysis, the costs and QALYs associated with earlier treatment on a TNFalpha inhibitor were assumed to be the same and so the analysis comprised two sequences containing tocilizumab (one in which tocilizumab is followed by rituximab and one in which rituximab is followed by tocilizumab) and a baseline treatment sequence of rituximab alone. The Committee noted from this analysis that the treatment strategy that placed tocilizumab before rituximab was dominated by treating with rituximab before tocilizumab (in people who had previously only had a TNFalpha inhibitor). The Committee accepted the ICER from this analysis as the most plausible estimate of tocilizumab following rituximab in this population (that is, 18,500 per QALY gained). The Committee also compared this ICER with the manufacturer's estimate of 22,700 per QALY gained. In view of this, the Committee concluded that tocilizumab could be considered an option after an inadequate response to treatment with rituximab but should not be recommended as an alternative to rituximab.
The Committee noted that, in clinical practice and as recommended in the guidance on adalimumab, etanercept and infliximab for rheumatoid arthritis (NICE technology appraisal guidance 130), treatment should normally be initiated with the least expensive drug; this would not necessarily be the same drug in individual cases because of differences in the mode of administration and treatment schedules. The Committee therefore concluded that it was appropriate to recommend tocilizumab as an option following the same considerations as for the drugs recommended as options in NICE technology appraisal guidance 130.
The Committee concluded that it was appropriate to recommend tocilizumab plus methotrexate as an option for people whose rheumatoid arthritis has a DAS28 score greater than 5.1 and has responded inadequately to one or more previous DMARDs if used as described for TNF inhibitor treatments in NICE technology appraisal guidance 130, specifically the recommendations on disease activity and choice of treatment. It concluded that tocilizumab plus methotrexate could be recommended as an option for people whose rheumatoid arthritis has responded inadequately to treatment with DMARDs and a TNF inhibitor and in whom rituximab is contraindicated or who had rituximab withdrawn because of an adverse event. The Committee concluded that, for people whose rheumatoid arthritis has responded inadequately to previous TNF inhibitors, and for whom rituximab is an option, tocilizumab plus methotrexate could not be recommended because although it might be as effective as rituximab, it was more expensive and so could not be considered unless rituximab was contraindicated, not tolerated or had failed. The Committee also concluded that tocilizumab plus methotrexate could be recommended for people whose rheumatoid arthritis has responded inadequately to treatment with one or more previous TNF inhibitors and rituximab. It also decided that a recommendation about tocilizumab as monotherapy could not be made because there was not enough evidence of its efficacy as a monotherapy.
TA247
Appraisal title: Tocilizumab for the treatment of rheumatoid arthritis (rapid review of technology appraisal guidance 198)
Section
Key conclusion
Tocilizumab in combination with methotrexate is recommended as an option for the treatment of rheumatoid arthritis in adults if:
the disease has responded inadequately to disease-modifying anti-rheumatic drugs (DMARDs) and it is used as described for tumour necrosis factor (TNF) inhibitor treatments in Adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis (NICE technology appraisal guidance 130), specifically the recommendations on disease activity and choice of treatment or
January 2016: This bullet point has been updated by NICE technology appraisal guidance 375.
the disease has responded inadequately to DMARDs and a TNF inhibitor and the person cannot receive rituximab because of a contraindication to rituximab, or because rituximab is withdrawn because of an adverse event, and tocilizumab is used as described for TNF inhibitor treatments in NICE technology appraisal guidance on adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a TNF inhibitor, specifically the recommendations on disease activity or
the disease has responded inadequately to one or more TNF inhibitor treatments and to rituximab
and the manufacturer provides tocilizumab with the discount agreed as part of the patient access scheme.
People currently receiving tocilizumab for the treatment of rheumatoid arthritis who do not meet the criteria in 1.1 should have the option to continue treatment until they and their clinicians consider it appropriate to stop.
Current practice
Clinical need of patients, including the availability of alternative treatments
The Committee understood the guidance on adalimumab, etanercept and infliximab for rheumatoid arthritis (NICE technology appraisal guidance 130) recommends TNFalpha inhibitors adalimumab, etanercept and infliximab as options for the treatment of adults whose rheumatoid arthritis has responded inadequately to two DMARDs (unless DMARDs are contraindicated), and with a DAS28 score greater than 5.1. The Committee noted that in NICE technology appraisal guidance 130, treatment should normally be initiated with the least expensive drug (taking into account administration costs, required dose and product price per dose) and this may need to be varied in individual cases because of differences in the mode of administration and treatment schedules. It was also aware of certolizumab pegol for the treatment of rheumatoid arthritis (NICE technology appraisal guidance 186) and golimumab for the treatment of rheumatoid arthritis after the failure of previous disease-modifying anti-rheumatic drugs (NICE technology appraisal guidance 225).
For treatment following an inadequate response to DMARDs (including at least one TNFalpha inhibitor), the guidance on adalimumab, etanercept, infliximab, rituximab and abatacept for rheumatoid arthritis (NICE technology appraisal guidance 195) recommends rituximab plus methotrexate.
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?
Tocilizumab has been shown to reduce the rate of progression of joint damage as measured by X-ray and to improve physical function when given in combination with methotrexate.
What is the position of the treatment in the pathway of care for the condition?
The Committee concluded that there were four possible scenarios for including tocilizumab in the treatment pathway:
Tocilizumab after two DMARDs as an alternative to TNFalpha inhibitors.
Tocilizumab after TNFalpha inhibitors as an alternative to rituximab.
Tocilizumab after TNFalpha inhibitors when a person is intolerant to rituximab or for whom rituximab is contraindicated.
Tocilizumab as an addition to the treatment pathway after rituximab.
Adverse effects
The Committee noted the safety data presented by the manufacturer, which reported 27 deaths and a serious adverse event rate of 5.8%. The Committee considered that this adverse event rate was high, but heard that it was comparable with other biological treatments.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The Committee concluded that no evidence for tocilizumab monotherapy within its licensed indication was available, and therefore no recommendations for tocilizumab as a monotherapy could be made.
The Committee considered the evidence on the clinical effectiveness of tocilizumab plus DMARDs compared with placebo plus DMARDs. The Committee concluded that tocilizumab plus methotrexate was clinically effective compared with placebo plus DMARDs when given before TNFalpha inhibitors and when given before rituximab.
The Committee then considered the evidence for the relative efficacy of tocilizumab compared with etanercept and compared with rituximab when all treatment strategies were in combination with methotrexate. It understood that tocilizumab had not been compared head-to-head with either etanercept (or any other TNFalpha inhibitor) or rituximab, and that indirect evidence had been combined in a mixed treatment comparison for this purpose.
Relevance to general clinical practice in the NHS
The Committee did not raise any issues about the relevance of the clinical-effectiveness data to general clinical practice in the NHS.
N/A
Uncertainties generated by the evidence
The mixed treatment comparison assumed that the TNFalpha results could be regarded as a class. The Committee noted that the manufacturers had responded to requests to remove the Klareskog trial of etanercept from the analysis because this was a large RCT with unusually high control-arm response rates and did not correspond with the inclusion criteria of the mixed treatment comparison. With this trial removed, the Committee noted that etanercept appeared at least equal to, and possibly had higher efficacy than, tocilizumab.
The Committee considered that limited confidence could be placed in the adjusted ACR response rates in the manufacturer's revised base case. The Committee concluded that using the unadjusted trial estimates in the analyses was more appropriate.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
N/A
N/A
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The Committee concluded that no convincing evidence had been presented to demonstrate the superiority of tocilizumab over etanercept or rituximab, but that the estimates were in a similar range to etanercept and rituximab.
The Committee noted the evidence from the RADIATE trial and, on balance, agreed that tocilizumab was likely to benefit people whose rheumatoid arthritis has responded inadequately to rituximab.
Evidence for cost effectiveness
Availability and nature of evidence
The manufacturer did not identify any economic evaluations of tocilizumab and developed an 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.
Uncertainties around and plausibility of assumptions and inputs in the economic model
In summary the Committee concluded that the best estimate of cost effectiveness of tocilizumab in any position in the treatment pathway should be based on approach 4 to evidence synthesis in which the ACR response rates came from the trials rather than the mixed treatment comparison and used a corrected degradation factor for tocilizumab (see section 3.35). In addition, it concluded that no long-term HAQ improvements with tocilizumab should be assumed.
The economic model incorporated tocilizumab at the discount agreed as part of the patient access scheme.
The manufacturer's analysis had not taken into account extended dominance and that this had an impact on the ICERs. The Committee concluded that the DSU's 2011 exploratory analyses should be used as the basis for determining the cost effectiveness of tocilizumab.
Incorporation of health-related quality-of-life benefits and utility values
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
The Committee noted that the manufacturer's mapping of HAQ scores to EQ5D utility values resulted in negative utility values. The Committee heard from the manufacturer that it was possible that there were some people with rheumatoid arthritis who may experience negative utility values. The Committee therefore accepted that the calculation of some ICERs would include negative utility values but concluded that this was acceptable because of the low impact on the ICERs.
Are there specific groups of people for whom the technology is particularly cost effective?
The Committee heard from the manufacturer that it was seeking a recommendation for tocilizumab as an option along with other biological treatments in the treatment pathway. It therefore considered that there were four possible scenarios for including tocilizumab in the treatment pathway:
Tocilizumab after two DMARDs as an alternative to TNFalpha inhibitors.
Tocilizumab after TNFalpha inhibitors as an alternative to rituximab.
Tocilizumab after TNFalpha inhibitors when a person is intolerant to rituximab or for whom rituximab is contraindicated.
Tocilizumab as an addition to the treatment pathway after rituximab.
What are the key drivers of cost effectiveness?
The Committee concluded that the improved cost effectiveness of tocilizumab as the first biological treatment compared with etanercept was due to the cost of time on treatment, rather than any substantial differences in clinical or cost effectiveness between tocilizumab and etanercept.
Most likely cost-effectiveness estimate (given as an ICER)
For the DMARDIR population: three sequences were extendedly dominated (less effective than and at least as costly as a combination of other drug sequences). When tocilizumab is the third biological in the sequence the most plausible estimate of the ICER is 28,400 per QALY gained. The Committee accepted that some uncertainty around the point estimates of the ICERs was likely.
For the DMARDIR rituximab intolerant population: the Committee noted that the most plausible estimate for the ICER ranged from 10,700 per QALY gained for the sequence in which etanercept followed tocilizumab to 30,100 per QALY gained in the sequence where tocilizumab followed etanercept.
For the TNFIR population: the Committee accepted the ICER of 18,500 per QALY gained as the most plausible ICER estimate for tocilizumab following rituximab in this population.
Additional factors taken into account
Patient access schemes (PPRS)
The Department of Health and the manufacturer have agreed that tocilizumab will be available to the NHS with a patient access scheme in which a discount from the list price is applied to original invoices. The level of the discount is commercial in confidence.
End-of-life considerations
N/A
N/A
Equalities considerations and social value judgements
No equalities issues were raised in the appraisal.
N/A