Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK 2

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1 This paper presents a summary of the Evidence Review Group report for the single technology appraisal entitled Tocilizumab for the treatment of rheumatoid arthritis C Meads, 1 * M Jit, 2 A Tsourapas, 2 K Ashfaq, 3 M Connock, 3 A Fry-Smith 3 and P Jobanputra 4 1 Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK 2 Unit of Health Economics, University of Birmingham, Birmingham, UK 3 Unit of Public Health, Epidemiology and Biostatistics, University of Birmingham, Birmingham, UK 4 Department of Rheumatology, Selly Oak Hospital, University Hospital Birmingham NHS Foundation Trust, Birmingham, UK *Corresponding author Declared competing interests of authors: PJ was invited to be part of Roche s advisory board for a preparatory meeting for its submission to the National Institute of Health and Clinical Excellence, before the start of the single technology appraisal. This was a paid consultancy for a day in the latter half of This report should be referenced as follows: Meads C, Jit M, Tsourapas A, Ashfaq K, Connock M, Fry-Smith A, et al. Tocilizumab for the treatment of rheumatoid arthritis. Southampton: NETSCC; 2012.

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3 Single Technology Appraisal Tocilizumab for the treatment of rheumatoid arthritis C Meads, 1 * M Jit, 2 A Tsourapas, 2 K Ashfaq, 3 M Connock, 3 A Fry-Smith 3 and P Jobanputra 4 1 Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK 2 Unit of Health Economics, University of Birmingham, Birmingham, UK 3 Unit of Public Health, Epidemiology and Biostatistics, University of Birmingham, Birmingham, UK 4 Department of Rheumatology, Selly Oak Hospital, University Hospital Birmingham NHS Foundation Trust, Birmingham, UK *Corresponding author HTA 08/90/01 Date of ERG submission: 6 April 2009 TAR Centre(s): West Midlands Health Technology Assessment Collaboration List of authors: C Meads, M Jit, A Tsourapas, K Ashfaq, M Connock, A Fry-Smith and P Jobanputra Contact details: C Meads, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK c.meads@qmul.ac.uk The research reported in this article was commissioned and funded by the HTA programme on behalf of NICE as project number 08/90/01. The assessment report began editorial review in June 2009 and was accepted for publication in December See the HTA programme website for further project information ( This summary of the ERG report was compiled after the Appraisal Committee s review. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Department of Health. Discussion of Evidence Review Group reports is invited. Visit the HTA website correspondence forum ( ac.uk/correspond). Abstract This paper presents a summary of the Evidence Review Group (ERG) report into the clinical effectiveness and cost-effectiveness of tocilizumab for the treatment of rheumatoid arthritis (RA), based on the evidence submission from the manufacturer/sponsor to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal process. Outcomes measures in the NICE scope were disease activity, physical function, joint damage/radiographic progression, joint replacement, pain, mortality, fatigue, health-related quality of life and adverse effects of treatment. The outcomes used in tocilizumab randomised controlled trials (RCTs) included American College of Rheumatology (ACR) 20, ACR50 and ACR70, mean change in the disease activity score (DAS28), radiographic changes, and Short Form questionnaire-36 items (SF-36) and European Quality of Life-5 Dimensions (EQ-5D) Queen s Printer and Controller of HMSO This work was produced by Meads et al. under the terms of a commissioning contract issued by the Secretary of State for Health.

4 2 Tocilizumab for the treatment of rheumatoid arthritis quality-of-life measures. The submission provided evidence from four RCTs of tocilizumab versus placebo, one RCT of tocilizumab versus methotrexate (MTX) and two longer-term singlearm extension studies following patients up to 3 or 5 years. Evidence from the mixed-treatment comparison (MTC) gave information on the relative effectiveness of tocilizumab compared with other biologic disease-modifying antirheumatic drugs (DMARDs: adalimumab, etanercept, infliximab, abatacept, rituximab). In addition, a de novo individual sampling model was included, with a hypothetical cohort of patients with moderate-to-severe RA and an inadequate response to traditional DMARDs or to one or more tumour necrosis factor alpha (TNF-α) inhibitors in addition. The intervention in the model was tocilizumab 8 mg/kg added to a sequence of biologic and conventional DMARDs compared with the same sequence without tocilizumab. The outcomes were ACR scores from the MTC to obtain Health Assessment Questionnaire (HAQ) scores and then to calculate EQ-5D using a quadratic equation derived from work published in a conference abstract. Results from the RCTs suggested that tocilizumab was more effective than placebo and more effective than MTX for ACR20, ACR50 and ACR70 and other outcome measures. Results from the MTC suggested that tocilizumab had higher relative effectiveness than rituximab and than data for three TNF-α inhibitors combined (adalimumab, etanercept, infliximab). The cost of tocilizumab was similar to etanercept at a dose of 8 mg/kg and so any decision on which drug to use would be based on ease of use, administration costs and adverse effects. Rituximab was costed in the submission to be less expensive than tocilizumab ( 4980 vs 9295) but it was unclear whether or not the estimated additional effectiveness of tocilizumab would be worth the additional cost. However, the economic model made a number of questionable assumptions that were likely to be highly influential and the probabilistic sensitivity analysis gave a remarkable lack of variation around cost. The effectiveness of tocilizumab relative to other biologic DMARDs is therefore uncertain and at present it is highly unlikely that tocilizumab would replace conventional DMARDs, such as MTX, in the treatment pathway for RA. The guidance issued by NICE in August 2010 states that for people whose RA has responded inadequately to one or more previous DMARDs, tocilizumab plus MTX is not recommended for the treatment of moderate-to-severe active RA before, or as an alternative to, treatment with TNF-α inhibitors. For people whose RA has responded inadequately to one or more previous TNF-α inhibitors, tocilizumab plus MTX is not recommended for the treatment of moderate-tosevere active RA before, or as an alternative to, treatment with rituximab. Introduction The National Institute for Health and Clinical Excellence (NICE) is an independent organisation within the NHS that is responsible for providing national guidance on the treatment and care of people using the NHS in England and Wales. One of responsibilities of NICE is to provide guidance to the NHS on the use of selected new and established health technologies, based on an appraisal of those technologies. NICE s single technology appraisal (STA) process is specifically designed for the appraisal of a single product, device or other technology, with a single indication, where most of the relevant evidence lies with one manufacturer or sponsor. 1 Typically, it is used for new pharmaceutical products close to launch. The principal evidence for a STA is derived from a submission by the manufacturer/sponsor of the technology. In addition a report reviewing the evidence submission is submitted by the Evidence Review Group (ERG); an external organisation independent of the Institute. This paper presents a summary of the ERG report for the STA Tocilizumab for the treatment of rheumatoid arthritis. 2

5 Single Technology Appraisal Description of the underlying health problem Rheumatoid arthritis (RA) is a chronic, multisystem, disabling condition characterised by inflammation of the joints, causing pain, swelling, stiffness and progressive joint destruction as well as premature mortality. At a prevalence rate of 0.5 1% in the general population, it is believed to affect approximately 400,000 people in England and Wales. Of these, approximately 30 40% have moderate-to-severe disease despite treatment with conventional disease-modifying antirheumatic drugs (DMARDs). Treatment of RA involves a combination of pharmacological and non-pharmacological interventions, aiming to control pain and inflammation and to reduce joint damage, disability and loss of function, thereby improving quality of life. Non-pharmacological therapies include surgery, physiotherapy and occupational therapy. Pharmacological interventions currently used include non-steroidal anti-inflammatory drugs, corticosteroids, analgesics and a variety of DMARDs, such as methotrexate (MTX) or sulfasalazine. Scope of the Evidence Review Group report The remit was to appraise the clinical effectiveness and cost-effectiveness of tocilizumab (RoActemra, Roche), a humanised immunoglobulin G1 (IgG1) monoclonal antibody against the human interleukin 6 (IL-6) receptor, within its licensed indication for the treatment of RA. Tocilizumab is intended to reduce inflammation seen in RA by inhibiting IL-6 in the inflammatory pathway. Tocilizumab, in combination with MTX, is licensed for the treatment of moderate-to-severe RA in adult patients who either responded inadequately or were intolerant to previous therapy with one or more DMARDs or tumour necrosis factor alpha (TNF-α) antagonists. The stated outcome measures in the NICE scope were disease activity, physical function, joint damage/radiographic progression, joint replacement, pain, mortality, fatigue, health-related quality of life and adverse effects of treatment. The outcomes used in tocilizumab RCTs included ACR20, ACR50 and ACR70 ( ACR is American College of Rheumatology for interpretation, see below), mean change in the Disease Activity Score (DAS28), radiographic changes, and Short Form questionnaire-36 items (SF-36) and European Quality of Life-5 Dimensions (EQ-5D) quality-of-life measures. The ACR20 is a change score that counts the percentage of patients who have improved by 20% in a combination of measures: (1) tender and swollen joint counts and (2) improvement in three of the following five parameters: acute-phase reactant patient assessment physician assessment pain scale [as measured by a 100-mm visual analogue scale (VAS)] disability/functional questionnaire [often the Stanford Health Assessment Questionnaire Disease Index (HAQ or HAQ-DI)]. The selection of three out of five parameters in each patient will vary over time because at each visit the best three are selected, so the HAQ score may not contribute to the ACR20 at each follow-up point. Queen s Printer and Controller of HMSO This work was produced by Meads et al. under the terms of a commissioning contract issued by the Secretary of State for Health.

6 4 Tocilizumab for the treatment of rheumatoid arthritis Methods The ERG report comprised a critical review of the evidence for the clinical evidence and costeffectiveness of the technology based upon the manufacturer s/sponsor s submission to NICE as part of the STA process. Additional work undertaken by the ERG included the following: considerable sifting through trial reports to find information that should have been made explicit in the submission checking of search strategies and searches to ensure that no studies were missed redrawing of a key meta-analysis because of several errors in the submission meta-analysis critical appraisal of a key paper 3 in the mixed-treatment comparison (MTC) of TNF-α DMARDs to establish whether it should have been omitted or not rerunning the MTC to establish the relative effectiveness of each of the TNF-α antagonist DMARDs separately (adalimumab, etanercept, infliximab) with and without the key paper 3 rerunning the economic model to vary some of the assumptions made in the existing model. Results Summary of submitted clinical evidence The submission provided evidence from four RCTs of tocilizumab versus placebo, one RCT of tocilizumab versus MTX and two longer-term single-arm extension studies following patients up to 3 or 5 years. There were no head-to-head comparisons of tocilizumab versus other biologic DMARDs. Evidence from the MTC gave information on the relative effectiveness of tocilizumab compared with other biologic DMARDs (adalimumab, etanercept, infliximab, abatacept, rituximab). Results from the RCTs suggested that tocilizumab was more effective than placebo and more effective than MTX for ACR20, ACR50 and ACR70 and other outcome measures. Results from the MTC suggested that tocilizumab had higher relative effectiveness than rituximab and than data for three TNF-α inhibitors combined (adalimumab, etanercept, infliximab). Summary of submitted cost-effectiveness evidence No evaluations of the cost-effectiveness of tocilizumab were found from literature searches. The submission included a de novo individual sampling model with a hypothetical cohort of 10,000 patients with moderate-to-severe RA and an inadequate response to traditional DMARDs or to one or more TNF-α inhibitors in addition. The intervention in the model was tocilizumab 8 mg/kg added to a sequence of biologic and conventional DMARDs compared with the same sequence without tocilizumab (Figure 1). The outcomes were ACR scores from the MTC to obtain HAQ scores and then to calculate EQ-5D using a quadratic equation derived from work published in a conference abstract. The manufacturers did not use the EQ-5D results from two of the tocilizumab RCTs that were included in the submission. EQ-5D results from one RCT were found in the trial report (Table 1). The costs were largely driven by the high treatment costs for requested clinical biologic DMARDs. The perspective was NHS, a lifetime horizon was used, and the discount rate was 3.5% per year for costs and utilities. Scenario and some probabilistic sensitivity analyses were undertaken. The model was constructed in Visual Basic for Applications within Microsoft Excel (Microsoft Corporation, Redmond, WA, USA).

7 Single Technology Appraisal Initial tdmard Some combination of sulfasalazine, methotrexate, hydroxychloroquine, but NOT leflunomide, gold or ciclosporin Second, third(?), etc. tdmard Some combination of sulfasalazine, methotrexate, hydroxychloroquine, but NOT leflunomide, gold or ciclosporin Strategy 1 Strategy 2 Tocilizumab + MTX Etanercept Etanercept Tocilizumab + MTX Rituximab Rituximab Leflunomide Leflunomide Gold Gold Ciclosporin Ciclosporin Palliative care DMARD-IR indication sequence Palliative care TNF-IR indication sequence FIGURE 1 Comparison of the two tocilizumab strategies used in the economic model. The two arms of the figure (strategy 1 and strategy 2) indicate the treatment sequence under the two indications (DMARD-IR and TNF-IR); the comparator is the same sequence with tocilizumab + MTX removed. DMARD-IR, disease-modifying antirheumatic drug inadequate responder; MTX, methotrexate; tdmard, traditional disease-modifying antirheumatic drug; TNF-IR, tumour necrosis factor inadequate responder. TABLE 1 European Quality of Life-5 Dimensions results from Option RCT (WA17822) (single index utility score intention to treat by visit) TCZ (8 mg/kg) + MTX Placebo + MTX No. of patients Mean (SD) No. of patients Mean (SD) Baseline (0.32) (0.32) Week (0.28) (0.31) Week (0.30) (0.34) Week (0.23) (0.32) MTX, methotrexate; SD, standard deviation; TCZ, tocilizumab. Commentary on the robustness of submitted evidence The NICE specification for manufacturer/sponsor submission states that A submission should be as succinct and informative as possible. It is expected that the main body of the submission will not usually exceed 75 pages. The submission for this STA was 263 pages long, plus an embedded file with the MTC of 111 pages. The submission was repetitive, difficult to understand and very complicated. Queen s Printer and Controller of HMSO This work was produced by Meads et al. under the terms of a commissioning contract issued by the Secretary of State for Health.

8 6 Tocilizumab for the treatment of rheumatoid arthritis Strengths The submission made a convincing case of the superior effectiveness of tocilizumab against placebo in European patients with moderate-to-severe RA who had an inadequate response to MTX and other conventional DMARDs in three RCTs, and who had an inadequate response to TNF inhibitors or were intolerant of these drugs in one RCT. In addition, a single, head-to-head, trial against MTX in European patients was reported and showed better efficacy for tocilizumab. The trials were sufficiently large to obtain statistically significant results. It is unlikely that any RCT evidence was missed. Weaknesses There were no RCTs of tocilizumab against any other biologic DMARDs. Owing to the lack of relevant clinical evidence, a MTC was conducted against the three TNF-α inhibitors, rituximab and abatacept. The MTC combined the effectiveness of etanercept, adalimumab and infliximab and included a RCT on etanercept 3 that should have been excluded according to the submission description of the decision problem. The de novo economic model made a number of questionable assumptions, particularly in terms of the rebound effect following withdrawal of treatment, HAQ score progression on long-term treatment and the relationship between HAQ and EQ-5D scores, which are likely to be highly influential. The probabilistic sensitivity analysis gave a remarkable lack of variation around cost. Areas of uncertainty The effectiveness of tocilizumab relative to other biologic DMARDs is uncertain. The economic model investigated sequences of treatment with or without tocilizumab. Only two of many possible sequences that could be used to treat RA are considered. Currently, NICE allows use of a TNF inhibitor in patients who have had an inadequate response to two DMARDs including MTX. Therefore, a sequence of subsequent therapies could include sulfasalazine, hydroxychloroquine and azathioprine, assuming, for example, that a patient had had an inadequate response to MTX alone. The sequences described in the model exclude some reasonable treatment options. The impact of doing so on cost-effectiveness analyses is uncertain. Similarly, some of the assumptions made in cost-effectiveness analyses can be challenged and the impact of these assumptions on costs is unclear. An important assumption in the considered DMARD sequences is that a second TNF inhibitor would not be used, based on previous NICE guidance. This guidance, however, has been challenged recently and use of two consecutive TNF inhibitors is common in practice. 4 It is uncertain whether or not the inclusion of more than one TNF inhibitor in treatment sequences could influence cost-effectiveness of tocilizumab. A summary of the impact of different assumptions on cost-effectiveness of the DMARD inadequate responder version of the model (DMARD-IR) is shown in Table 2. These show that plausible variation in several of the assumptions made in the model results in increased incremental cost-effectiveness ratios (ICERs). Cumulatively, the impact these could make would be to raise the ICER above the threshold of 30,000 per quality-adjusted life year. Preliminary estimates of cost-effectiveness using EQ-5D results from the OPTION trial gave an estimate of more than 32,000 compared with rituximab. Conclusions Currently, it is highly unlikely that tocilizumab would replace conventional DMARDs such as MTX in the treatment pathway. Therefore, the main clinical decisions could be whether or not tocilizumab: 1. could be an alternative to a TNF-α inhibitor (etanercept, adalimumab or infliximab) as the first biologic DMARD to try after two or more conventional DMARDs have failed to control

9 Single Technology Appraisal TABLE 2 Impact of assumptions on ICER (for DMARD-IR) General issue Details for this submission Effect on ICER ( ) (Roche base-case DMARD-IR) 19,870 Measurement of Use of MTX unpooled parameters of TNF-α inhibitors 20,166 effectiveness The treatment sequence for the TCZ arm always has one more DMARD in it Makes TCZ seem more effective ACR results directly from RCTs rather than from MTC Unknown Allowing for long-term TCZ effects from single-arm studies where placebo and Unknown TCZ arm RCT patients all now given TCZ Use of EQ-5D results from Option RCT Conversion to utility Use of an exponential fit to HAQ progression graph Large impact increase ICER Removal of negative utility scores (submission scenario 1 DMARD-IR) 20,214 Model structure Conversion to BRAM model-like rebound 24,252 Adverse events Incorporating comparison of adverse events of TCZ to palliative care 24,629 TCZ costs Use of a 400-mg and a 200-mg vial (likely in practice) costing 9984 rather Increase ICER than current 9295 if a 400-mg and two 80-mg vials were used Other costs Increased administration costs Increase ICERs compared with etanercept, adalimumab Removal of high estimates of monitoring costs for gold, ciclosporin, etc. Likely little effect Combination Using MTX unpooled parameters of TNF-α inhibitors plus BRAM model-like rebound plus adverse events compared with palliative care 32,410 ACR, American College of Rheumatology; BRAM, Birmingham Rheumatoid Arthritis Model; DMARD-IR, disease-modifying antirheumatic drug inadequate responder; EQ-5D, European Quality of Life-5 Dimensions; HAQ, Health Assessment Questionnaire; ICER, incremental costeffectiveness ratio; MTC, mixed-treatment comparison; MTX, methotrexate; RCT, randomised controlled trial; TCZ, tocilizumab; TNF, tumour necrosis factor. symptoms (another TNF-α inhibitor may be tried if the first has failed due to side effects); the DMARD-IR model explored this possibility 2. could replace rituximab as a biologic DMARD to try after a TNF-α inhibitor has failed to control symptoms; the TNF-IR model explored this possibility (Note: it is not mandatory that rituximab should be tried if TNF-α inhibitors have failed.) 3. could be added to the pathway after failure of a TNF-α inhibitor and rituximab; the submission does not explore this possibility. According to the reported MTC, tocilizumab has a higher relative effectiveness than combined TNF-inhibitors (etanercept, adalimumab and infliximab). The MTC was reanalysed and when the three drugs were examined separately they did not have similar estimated relative effectiveness. Etanercept had a lower relative effectiveness than tocilizumab (1.65 vs 3.19) if all RCTs were included, but if one RCT 3 was removed then etanercept had a higher relative effectiveness (5.32 vs 3.19). So, a key question is whether this RCT should have been included or excluded from the MTC. As it was the only RCT to mention that it specifically included patients who were likely to benefit from MTX treatment, rather than having failed MTX treatment, it was different to the other RCTs. The submission decision problem statement was quite clear in that the manufacturers were only going to investigate adults with moderate or severe active rheumatoid arthritis (RA) who have either responded inadequately to or, or who were intolerant to, previous therapy with one or more disease modifying anti-rheumatic drugs (DMARDs). Therefore, the Klareskog et al. RCT 3 should not have been included in the MTC. As tocilizumab was costed in the submission to be the same price as etanercept at a dose of 8 mg/kg then the decision as to which one to use could be based on differential effectiveness and factors such as ease of use, administration costs and adverse effects rather than drug cost. Etanercept is delivered by subcutaneous injection by patients or carers at home, whereas Queen s Printer and Controller of HMSO This work was produced by Meads et al. under the terms of a commissioning contract issued by the Secretary of State for Health.

10 8 Tocilizumab for the treatment of rheumatoid arthritis tocilizumab, at present, is given by intravenous infusions in a health-care facility. It is unclear whether etanercept or tocilizumab has more or worse side effects. TA126 guidance is that Rituximab in combination with methotrexate is recommended as an option for the treatment of adults with severe active RA who have had an inadequate response to or intolerance of other disease modifying antirheumatic drugs (DMARDs), including treatment with at least one tumour necrosis factor α (TNF-α) inhibitor therapy. According to the MTC, tocilizumab has a higher relative effectiveness than rituximab. Rituximab was costed in the submission to be less expensive than tocilizumab ( 4980 vs 9295). It is unclear whether or not the estimated additional effectiveness of tocilizumab is worth the additional cost. Summary of NICE guidance issued as a result of the STA At the time of writing, the guidance document issued by NICE (August 2010) states that: For people whose RA has responded inadequately to one or more previous DMARDs, tocilizumab plus MTX is not recommended for the treatment of moderate to severe active RA before, or as an alternative to, treatment with TNF-α inhibitors. For people whose RA has responded inadequately to one or more previous TNF-α inhibitors, tocilizumab plus MTX is not recommended for the treatment of moderate to severe active RA before, or as an alternative to, treatment with rituximab. The Committee concluded that tocilizumab as monotherapy could also not be recommended as a costeffective use of NHS resources. However, the Committee recommended tocilizumab plus MTX as an option for people whose RA has responded inadequately to treatment with one or more previous TNF-α inhibitors and rituximab. The Committee also recommended tocilizumab plus MTX as an option for people with moderate to severe active RA whose RA has responded inadequately to one or more previous TNF-α inhibitors and in whom rituximab is contraindicated or who had rituximab withdrawn because of an adverse event. Key references 1. National Institute for Health and Clinical Excellence (NICE). Guide to the single technology (STA) process. September URL: (accessed September 2009). 2. Meads C, Jit M, Tsourapas A, Ashfaq K, Connock M, Fry-Smith A, et al. Tocilizumab for the treatment of rheumatoid arthritis. Birmingham: WMHTAC, University of Birmingham; Klareskog L, van der Heijde D, de Jager JP, Gough A, Kalden J, Malaise M, et al. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial. Lancet 2004;363: Hyrich KL, Lunt M, Watson KD, Symmons DP, Silman AJ. Outcomes after switching from one anti-tumor necrosis factor agent to a second anti-tumor necrosis factor agent in patients with rheumatoid arthritis: results from a large UK national cohort study. Arthritis Rheum 2007;56:13 20.