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Malottki K, Barton P, Tsourapas A, et al. Adalimumab, Etanercept, Infliximab, Rituximab and Abatacept for the Treatment of Rheumatoid Arthritis After the Failure of a Tumour Necrosis Factor Inhibitor: A Systematic Review and Economic Evaluation. Southampton (UK): NIHR Journals Library; 2011 Mar. (Health Technology Assessment, No. 15.14.)

2Definition of the decision problem

Decision problems

According to the final scope issued by NICE for this technology appraisal, the decisions to be made are:

  • Decision problem 1: whether there are significant differences in clinical effectiveness and cost-effectiveness between ADA, ETN, IFX, RTX and ABT (referred to as ‘the interventions’ hereafter), when used within their licensed indications in adults with active RA who have had an inadequate response to a first TNF inhibitor prescribed according to current NICE guidance.
  • Decision problem 2: whether the interventions are clinically effective and cost-effective compared with previously untried conventional DMARDs (such as LEF and CyA).
  • Decision problem 3: whether the interventions are clinically effective and cost-effective compared with other biologic agents (including TOC, golimumab and certolizumab pegol).
  • Decision problem 4: whether the interventions are clinically effective and cost-effective compared with supportive care (including conventional DMARDs to which patients have had inadequate response).
  • Decision problem 5: whether the clinical effectiveness and cost-effectiveness of the interventions differ significantly between certain subgroups of patients (see Definition of the interventions).

The assessment report set out to address these decision problems as they apply to potential patient pathways in the UK. The nature of evidence and the timelines for this technology appraisal constrain the focus of the assessment report to key clinically relevant questions.

Definition of the interventions

The interventions being considered are:

Population and relevant subgroups

The population being considered is adults with active RA who have had an inadequate response to a first TNF inhibitor.

Potentially relevant subgroups are numerous and include:

  • patients having had primary or secondary (had initial response, but subsequently lost the response over time) failure of response to the first TNF inhibitor or having withdrawn from the first TNF inhibitor mainly owing to adverse effects
  • subgroups defined by autoantibody status [e.g. presence or absence of RF and/or anti-cyclic citrullinated peptide (anti-CCP) antibodies]
  • subgroups defined by different doses of the intervention (within licence)
  • patients with comorbidities for which some treatments may be contraindicated (e.g. heart failure).

The specific subgroups examined in the effectiveness review of this report were determined in light of available evidence and in consultation with clinical experts. Subgroups were not considered in the economic modelling as compelling evidence of differential effectiveness between subgroups was lacking from the effectiveness review.

Clarification of population of interest

The NICE guidance states that an alternative (second) TNF inhibitor may be considered for patients in whom treatment is withdrawn because of an AE before the initial 6-month assessment of efficacy. This group of patients (withdrawal because of an early AE) is strictly speaking outside the remit of this technology appraisal and should ideally be excluded from the technology assessment. However, in practice, the reason for the withdrawal of a TNF inhibitor may not be clear-cut as a decision to withdraw may be related to both efficacy and adverse effects (and the balance of risk and benefit for the patient).

Relevant comparators

Potential comparators include:

  • supportive care (including corticosteroids and ongoing or reinstated conventional DMARDs, such as MTX, sulfasalazine to which the patients have had inadequate response previously)
  • conventional DMARDs which have not been tried prior to trying a TNF inhibitor for example AZA, CyA and GST, either as monotherapy or combined with other DMARDs or corticosteroids
  • biologic agents including TOC, golimumab and certolizumab pegol
  • the interventions being considered compared with each other.

Clarification of comparators

The assessment report focuses on key clinically relevant questions, including, where data allow, comparing each of the interventions with supportive care and comparing each of the interventions against each other. This was based on the following considerations:

  • The majority of patients considered in this technology appraisal may have already had inadequate response to at least two conventional DMARDs, including MTX tried for an adequate length of time and at adequate doses, as indicated in the current NICE guidance. These DMARDs may still be continued in the comparator (and intervention) arm(s) of trials in patients who have responded inadequately to these options. In such cases continued use of these DMARDs was regarded as supportive care rather than as a credible alternative treatment option. Therefore, a clear distinction was made between conventional DMARDs depending on whether the patients had tried them before and if there was a history of inadequate response to the DMARD tried.
  • Only conventional DMARDs to which the patients have not had inadequate response or have not tried were to be regarded as separate comparators. The evidence for use of conventional DMARDs in patients who have failed to respond to TNF inhibitors was expected to be very limited.
  • Although conventional DMARDs which are continued and to which the patients had an inadequate response were regarded as supportive care, subgroup analysis was considered (where relevant and evidence permits) to assess whether the presence or absence of these (failed) DMARDs in the control and intervention groups influenced the estimated treatment effects of the interventions.
  • Tocilizumab, golimumab and certolizumab pegol were potentially relevant comparators. These drugs are not yet available in the UK, but all are (or are potentially) the subject of STAs by NICE. The inclusion of these three drugs in the final scope as comparators means that there were no formal submissions from their manufacturers for this technology appraisal. This may have had implications with regard to the acquisition of evidence for these comparators. It was proposed that TOC, golimumab and/or certolizumab pegol could have been reviewed in the assessment report as a comparator if marketing authorisation of the technology was obtained before the submission of the protocol for this assessment report. This condition was not met.

Relevant outcomes

Key outcomes considered appropriate to the decision problem were:

  • withdrawals (with reason)
  • treatment response (ACR)
  • disease activity (DAS)
  • physical function (HAQ)
  • joint damage/radiological progression
  • pain
  • fatigue
  • serious AEs (including death)
  • other AEs potentially associated with treatment
  • health-related QoL (HRQoL).

Key issues

Key issues have been mentioned, where relevant, earlier in this section and also in the background section of this report.

Further key issues predominantly concern the limited availability of evidence from controlled trials and the impact this has on the assessment of clinical effectiveness and cost-effectiveness of each of the interventions compared with the potential comparators (and the other interventions), and the ability to identify relevant subgroups in whom the technologies are more or less beneficial.

Place of the intervention in the treatment pathway(s)

Based on the final scope, the interventions are to be used when patients have had an inadequate response to a TNF inhibitor.

Overall aims and objectives of assessment

The overall aims and objectives were to address the decision questions outlined in section Decision problems. These aims were to be achieved by:

  • A systematic review of RCTs of the efficacy, tolerability and safety of ADA, ETN, IFX, RTX and ABT for the treatment of RA in adults who have had an inadequate response to a first TNF inhibitor.
  • As the volume of RCT evidence was expected to be relatively small, relevant non-randomised comparative studies and uncontrolled studies were also reviewed.
  • A systematic review of published studies on the cost and cost-effectiveness of the technologies in the treatment of RA in adults who have had an inadequate response to a first TNF inhibitor.
  • A review of economic evaluations included in any manufacturer's submissions (MSs) for this appraisal.
  • A focused, model-based economic evaluation of the cost-effectiveness of the technologies from the perspective of the UK NHS.
© 2011, Crown Copyright.

Included under terms of UK Non-commercial Government License.

Cover of Adalimumab, Etanercept, Infliximab, Rituximab and Abatacept for the Treatment of Rheumatoid Arthritis After the Failure of a Tumour Necrosis Factor Inhibitor: A Systematic Review and Economic Evaluation
Adalimumab, Etanercept, Infliximab, Rituximab and Abatacept for the Treatment of Rheumatoid Arthritis After the Failure of a Tumour Necrosis Factor Inhibitor: A Systematic Review and Economic Evaluation.
Health Technology Assessment, No. 15.14.
Malottki K, Barton P, Tsourapas A, et al.
Southampton (UK): NIHR Journals Library; 2011 Mar.

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