A systematic review of the effectiveness of adalimumab

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iv Abstract £50,000 per QALY in late RA. Sensitivity analyses showed that the results were sensitive to the estimates of Health Assessment Questionnaire (HAQ) progression while on TNF inhibitors and the effectiveness of DMARDs, but not to changes in mortality ratios per unit HAQ. TNF inhibitors are most cost-effective when used last. The ICER for etanercept used last is £24,000 per QALY, substantially lower than for adalimumab (£30,000 per QALY) or infliximab (£38,000 per QALY). First line use as monotherapy generates ICERs around £50,000 per QALY for adalimumab and etanercept. Using the combination of methotrexate and a TNF inhibitor as first line treatment generates much higher ICERs, as it precludes subsequent use of methotrexate, which is cheap. The ICERs for sequential use are of the same order as using the TNF inhibitor alone. Conclusions: Adalimumab, etanercept and infliximab are effective treatments compared with placebo for RA patients who are not well controlled by conventional DMARDs, improving control of symptoms, improving physical function, and slowing radiographic changes in joints. The combination of a TNF inhibitor with methotrexate was more effective than methotrexate alone in early RA, although the clinical relevance of this additional benefit is yet to be established, particularly in view of the well-established effectiveness of MTX alone. An increased risk of serious infection cannot be ruled out for the combination of methotrexate with adalimumab or infliximab. The results of the economic evaluation based on BRAM are consistent with the observations from the review of clinical effectiveness, including the ranking of treatments. TNF inhibitors are most cost-effective when used as last active therapy. In this analysis, other things being equal, etanercept may be the TNF inhibitor of choice, although this may also depend on patient preference as to route of administration. The next most cost-effective use of TNF inhibitors is third line, as recommended in the 2002 NICE guidance. Direct comparative RCTs of TNF inhibitors against each other and against other DMARDs, and sequential use in patients who have failed a previous TNF inhibitor, are needed. Longer term studies of the quality of life in patients with RA and the impact of DMARDs on this are needed, as are longer studies that directly assess effects on joint replacement, other morbidity and mortality.
Glossary and list of abbreviations ............. vii Executive summary .................................... xi 1 Aims of the review ..................................... 1 2 Background ................................................ 3 Summary .................................................... 3 Description of underlying health problem ...................................................... 3 Current service provision ........................... 8 Description of the technology .................... 8 Current NICE guidance for use of TNF inhibitors .................................................... 10 Degree of diffusion and anticipated costs ............................................................ 11 3 Effectiveness ............................................... 13 Summary .................................................... 13 Methods for reviewing effectiveness .......... 13 Results for effectiveness review .................. 16 Summary of effectiveness review and additional evidence .................................... 69 4 Health economics ...................................... 73 Summary of review of existing economic evaluations .................................................. 73 Systematic review of economic evaluations .................................................. 73 Review of industry cost-effectiveness submissions ................................................. 80 Economic analysis used in this report ....... 86 Results ........................................................ 100 5 Implications for other parties .................... 113 6 Factors relevant to the NHS ..................... 115 7 Discussion ................................................... 117 Summary .................................................... 117 Principal findings ....................................... 117 Assumptions, limitations and uncertainties ............................................... 120 Implications for research ........................... 122 Contents Health Technology Assessment 2006; Vol. 10: No. 42 8 Conclusions ................................................ 123 Acknowledgements .................................... 125 References .................................................. 127 Appendix 1 Details of key outcomes used in RA trials ................................................. 139 Appendix 2 Searches: clinical effectiveness ................................................ 141 Appendix 3 List of excluded studies for clinical effectiveness review ........................ 143 Appendix 4 Additional tables for clinical effectiveness review .................................... 147 Appendix 5 Searches: economic evaluations .................................................. 155 Appendix 6 Searches: decision-analytic models ........................................................ 157 Appendix 7 Searches: systematic reviews of DMARDs .................................................... 159 Appendix 8 Existing economic evaluations: appraisal and data extraction .................... 161 Appendix 9 Details of strategy sets used in BRAM ......................................................... 175 Appendix 10 Sensitivity analysis ................ 179 Appendix 11 Ongoing research ................ 229 Health Technology Assessment reports published to date ....................................... 231 Health Technology Assessment Programme ................................................ 245 v
Page 1 and 2: A systematic review of the effectiv
Page 3 and 4: A systematic review of the effectiv
Page 5: Objectives: This report reviews the
Page 10 and 11: viii Glossary and list of abbreviat
Page 13 and 14: Background Rheumatoid arthritis (RA
Page 15: increased risk of serious infection
Page 19 and 20: Summary RA is a common, chronic, in
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40 Effectiveness TABLE 9 Summary of
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42 Effectiveness Review: Etanercept
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54 Effectiveness TABLE 11 Summary o
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56 TABLE 12 Description of included
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58 TABLE 13 Quality of included RCT
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60 Effectiveness per week and escal
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62 Effectiveness significant advant
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64 Effectiveness Review: Infliximab
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66 Effectiveness Review: Infliximab
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68 Effectiveness FIGURE 44 Malignan
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70 TABLE 17 Effectiveness Summary o
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Summary of review of existing econo
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TABLE 20 Summary of published ICERs
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TABLE 21 Published etanercept econo
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TABLE 23 Published economic analyse
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TABLE 25 Treatment sequences: adali
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management of RA, i.e. 1st and 2nd
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To estimate the long-term consequen
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TABLE 32 TNF inhibitors as last act
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TABLE 34 Basic structure of the mod
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een quit on grounds of toxicity, ad
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TABLE 39 Strategy set: adalimumab a
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TABLE 43 Beta distributions for HAQ
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TABLE 44 Early cessation of DMARDs:
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TABLE 46 Unit costs for tests and v
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following properties, according to
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TABLE 52 Base case: TNF inhibitors
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TABLE 54 Base case: TNF inhibitors
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TABLE 59 Third TNF inhibitor follow
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TABLE 65 Sensitivity analyses: TNF
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TABLE 67 Sensitivity analyses: TNF
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The substantial economic impact of
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Summary Effectiveness: principal fi
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inhibitors, although the incrementa
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introduce bias which generally exag
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Adalimumab, etanercept and inflixim
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1. Jobanputra P, Barton P, Bryan S,
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46. Young A, Dixey J, Cox N, Davies
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tumor necrosis factor therapy in th
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arthritis: a 12-week, double-blind,
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171. Geborek P, Crnkic M, Petersson
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216. Schotte H, Willeke P, Mickholz
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The Health Assessment Questionnaire
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Cochrane Library (CENTRAL) 2005 Iss
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Appendix 3 © Queen’s Printer and
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TABLE 69 Studies excluded from clin
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148 Appendix 4 TABLE 71 Meta-analys
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150 Appendix 4 TABLE 73 Meta-analys
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152 Appendix 4 Infliximab versus pl
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154 Appendix 4 Infliximab plus MTX
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Ovid MEDLINE(R) 1966 to February we
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TABLE 79 Wong et al., 2002 161 © Q
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TABLE 80 Kobelt et al., 2003 162 (c
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Extensive sensitivity analysis was
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TABLE 96 Variation 1: TNF inhibitor
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A systematic review of the effectiveness of adalimumab

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