A systematic review of the effectiveness of adalimumab

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122 Discussion for example from BeSt, described in this report, suggest that alternative approaches may be more effective. Implications for research ● Direct comparative RCTs of TNF inhibitors against each other and against other DMARDs are needed. ● Trials of different anti-TNFs in patients who have failed a previous TNF inhibitor are also needed. ● Longer term studies of the QoL in patients with RA and the impact of DMARDs and other interventions on QoL are needed. ● Longer term studies or follow-up, directly assessing the impact of DMARDs, including TNF inhibitors, on joint replacement, other disease and drug-related morbidity, and mortality, are required. ● Continued vigilance about the potential harms of TNF inhibitors is necessary and work is needed to improve the assessment of cause and effect relationships in patients who experience adverse effects, especially as RA itself can cause multisystem disease. 35
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. When used alone, adalimumab is marginally less effective and etanercept is marginally more effective than methotrexate, in methotrexate-naïve patients. The combination of a TNF inhibitor with methotrexate was more effective than methotrexate alone in this population, although the clinical relevance of this additional benefit is yet to be established, particularly in view of the well-established effectiveness of methotrexate alone. In addition, an increased risk of serious infection cannot be ruled out for the combination of methotrexate with adalimumab and infliximab. Results of published economic evaluations vary: some analyses suggest that the use of TNF inhibitors may fall within the usual acceptable cost-effectiveness ranges, whereas others report very high ICERs. Although most are of high quality, none of them used all of the appropriate parameters, effectiveness data, perspective and comparators required to make their results generalisable to the NHS context. The societal perspective generates more favourable ICERs. All economic evaluations submitted by the manufacturers report ICERs that fall within the currently accepted thresholds of cost-effectiveness. However, these models make assumptions and use data that favour the TNF inhibitor being evaluated, the appropriateness of which can be questioned. The results of the economic evaluation based on BRAM are consistent with the observations from Chapter 8 Conclusions © Queen’s Printer and Controller of HMSO 2006. All rights reserved. Health Technology Assessment 2006; Vol. 10: No. 42 the review of clinical effectiveness, including the ranking of treatments. TNF inhibitors are most cost-effective when used as last active therapy, with the ICER for etanercept (£24,000 per QALY) being significantly lower than the ICERs for adalimumab (£30,000 per QALY) or infliximab (£38,000 per QALY). Other things being equal, etanercept would be, therefore, the TNF inhibitor of choice. However, the most appropriate choice of TNF inhibitor 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, which gives ICERs around £30,000 per QALY using early RA effectiveness data. Using data for late RA, however, gives an ICER of around £50,000 per QALY for etanercept, with higher figures for adalimumab and infliximab. First-line use gives ICERs around £50,000 per QALY for adalimumab and etanercept as monotherapies, with much higher figures for combinations with methotrexate. This study only modelled sequential use of TNF inhibitors with the TNF inhibitors starting as third-line therapy and using the late RA values for the TNF inhibitors. The results are similar to those using the given TNF inhibitor as the sole TNF inhibitor in third place, except that the two other TNF inhibitors are somewhat less costeffective if used after etanercept. Direct head-to-head trials of DMARDs and the TNF inhibitors are needed to establish with more certainty the relative values of the different agents. Longer term follow-up and postmarketing surveillance are needed to ascertain the true risk of adverse events. 123
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A systematic review of the effectiv
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A systematic review of the effectiv
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Objectives: This report reviews the
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Glossary and list of abbreviations
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viii Glossary and list of abbreviat
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Background Rheumatoid arthritis (RA
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increased risk of serious infection
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Summary RA is a common, chronic, in
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(IL-2) and interleukin-6 (IL-6), pr
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Assessment of response to DMARDs Re
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combination with methotrexate or al
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disease between clinic appointments
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14 Effectiveness in juvenile arthri
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16 Effectiveness adalimumab plus me
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18 Effectiveness Monoclonal Antibod
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20 TABLE 1 Description of included
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22 TABLE 2 Quality of included RCTs
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24 Effectiveness change in modified
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26 Effectiveness TABLE 4 Meta-analy
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28 Effectiveness Review: Adalimumab
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30 Effectiveness Review: Adalimumab
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32 TABLE 6 Effectiveness Descriptio
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34 TABLE 6 Effectiveness Descriptio
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36 TABLE 7 Effectiveness Quality of
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38 Effectiveness etanercept trials.
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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
Page 89 and 90: Summary of review of existing econo
Page 91 and 92: TABLE 20 Summary of published ICERs
Page 93 and 94: TABLE 21 Published etanercept econo
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Page 97 and 98: TABLE 25 Treatment sequences: adali
Page 99 and 100: management of RA, i.e. 1st and 2nd
Page 101 and 102: To estimate the long-term consequen
Page 103 and 104: TABLE 32 TNF inhibitors as last act
Page 105 and 106: TABLE 34 Basic structure of the mod
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Page 109 and 110: TABLE 39 Strategy set: adalimumab a
Page 111 and 112: TABLE 43 Beta distributions for HAQ
Page 113 and 114: TABLE 44 Early cessation of DMARDs:
Page 115 and 116: TABLE 46 Unit costs for tests and v
Page 117 and 118: following properties, according to
Page 119 and 120: TABLE 52 Base case: TNF inhibitors
Page 121 and 122: TABLE 54 Base case: TNF inhibitors
Page 123 and 124: TABLE 59 Third TNF inhibitor follow
Page 125 and 126: TABLE 65 Sensitivity analyses: TNF
Page 127 and 128: TABLE 67 Sensitivity analyses: TNF
Page 129: The substantial economic impact of
Page 133 and 134: Summary Effectiveness: principal fi
Page 135 and 136: inhibitors, although the incrementa
Page 137: introduce bias which generally exag
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Page 145 and 146: 46. Young A, Dixey J, Cox N, Davies
Page 147 and 148: tumor necrosis factor therapy in th
Page 149 and 150: arthritis: a 12-week, double-blind,
Page 151 and 152: 171. Geborek P, Crnkic M, Petersson
Page 153 and 154: 216. Schotte H, Willeke P, Mickholz
Page 155 and 156: The Health Assessment Questionnaire
Page 157 and 158: Cochrane Library (CENTRAL) 2005 Iss
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Page 170 and 171: 154 Appendix 4 Infliximab plus MTX
Page 173: Ovid MEDLINE(R) 1966 to February we
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TABLE 86 Kobelt et al., 2005 167 (c
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176 Appendix 9 TABLE 89 Strategy se
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Extensive sensitivity analysis was
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TABLE 96 Variation 1: TNF inhibitor
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TABLE 99 Variation 2: TNF inhibitor
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TABLE 102 Variation 3: TNF inhibito
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TABLE 132 Variation 10: TNF inhibit
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A systematic review of the effectiveness of adalimumab

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