Note from the National Guideline Clearinghouse (NGC): The National Institute for Health and Clinical Excellence (NICE) commissioned an independent academic centre to perform a systematic literature review on the technology considered in this appraisal and prepare an Evidence Review Group (ERG) report. The ERG report for this technology appraisal was prepared by the Liverpool Reviews and Implementation Group (see the "Availability of Companion Documents" field).
Clinical Effectiveness
Search Strategy
Direct Comparison
Three electronic databases were searched (Medline, EMBASE and the Cochrane Library) covering the period 1993 to 17th October 2006. In addition, two sets of conference abstracts, European League Against Rheumatism (EULAR) (annual meetings 2002-2005) and American College of Rheumatology (ACR) (annual meetings 2002-2006), were searched via the following websites: http://www.eular.org/ and http://www.rheumatology.org respectively.
Search terms for electronic databases appropriately included a combination of free-text and index terms (rheumatoid arthritis) combined with drug name (rituximab) used as free-text terms. However, the search strategy details do not include any information on the subject index headings (for example, medical subject headings [MeSH]) and the relationship between the search terms (for example, Boolean), details of any additional searches (e.g. searches of company databases).The Evidence Review Group (ERG) was therefore unable to reproduce these searches. However, the ERG is confident that all relevant published trials were identified by the company.
Indirect Comparisons
Searches were conducted focusing on (1) treatment failure and (2) randomised controlled trials (RCTs) of anti-rheumatic drugs that satisfied the following criteria: ACR response criteria as an outcome measure; adult rheumatoid arthritis (RA) patients and trial duration of at least six months. The first search was carried out in Medline (1996 to March Week 4 2005) while the second was carried out in Medline (1966 to March Week 4 2005) and EMBASE (1988 to 2005 Week 21) with additional searches of the Cochrane Library and National Institute for Health and Clinical Excellence Health Technology Assessment (NICE HTA) reports.
For both searches, search strategy details include information on the subject index headings (for example, MeSH) and the relationship between the search terms (for example, Boolean). However, the search was conducted in April 2005 and has not been updated to inform the current submission (November 2006).
Regarding the first search, the company recognises and discusses the difficulties in targeting a search to the concept of treatment failure due to limited MeSH terms and reliance on text string searching.
Regarding the second search which is limited to RCTs, recognised filters which have been tested, validated and proven to be effective in systematically retrieving RCTs were not utilised.
Inclusion and Exclusion Criteria
Direct Comparison
Details of inclusion and exclusion criteria are provided in Table 3-2 of the ERG Report (see the "Availability of Companion Documents" field) and are considered appropriate and complete.
Indirect Comparisons
Information about the inclusion and exclusion criteria used for the indirect comparisons were not included in the original company submission. However, on request, the company did provide broad reasons as to why papers were excluded from the treatment failure search. For the ACR response criteria search, the company provided the inclusion criteria and broad reasons why studies were included and excluded. The criteria described in Table 3-3 of the ERG Report (see the "Availability of Companion Documents" field) appear to be appropriate.
Application of Inclusion Criteria
Direct Comparison
A flow diagram in the company submission indicates that for direct comparisons, 69 citations were identified by the electronic database search (of which 23 were excluded on the basis of title) and 56 conference abstracts were also identified. One citation and six abstracts describing the phase III, double-blind REFLEX trial (WA17042) and open-label extension to the REFLEX trial (WA17531) met the inclusion criteria set out in the company report.
For the long-term efficacy analyses and safety analyses, the company included data from two phase II RCTs (WA17043 and WA16291); no explanation was given for including additional data sources in their analyses. Both of these trials were appropriately excluded from the systematic review because they included patients who had no prior exposure to a tumour necrosis factor alpha inhibitor(s) (TNFi) and who had received unlicensed doses of rituximab.
Indirect Comparisons
Information provided by the company, upon request, shows the number of results found by each search term and the number of citations excluded by the relevant exclusion criteria; 99/99 citations were excluded for treatment failure leaving no relevant articles; 264 citations were found for ACR response criteria of which 44 were included in the review. However, only six of these studies were used for calculating specific treatment adjusted ACR response rates. The criteria used to select these six studies were not stated. In addition, the company did not provide a flow diagram or present details of the excluded studies or the reasons for their exclusion.
Cost-Effectiveness
Health Economics Literature Search for Rituximab Related Articles
The submission identifies two abstracts describing the cost effectiveness of rituximab in the treatment of rheumatoid arthritis (RA). No details of the search strategy used are provided. The abstracts are neither summarised nor discussed in the submission; the company state that they reflect the economic evaluation in the company submission. Other conference abstracts presented by the company discussing the cost effectiveness of rituximab in RA have also been published but are not identified in the submission.
Health Economics Literature Search for TNFi Related Articles
The company conducted a review which was intended to update and supplement the health economics review that was published in the recent Health Technology Assessment report entitled "A systematic review of the effectiveness of adalimumab, etanercept and infliximab for the treatment of RA in adults and an economic evaluation of their cost-effectiveness". The company did not provide a summary of the methods or the results of this previously published review of the health economics literature.
As part of their review, the company developed a search strategy to "identify economic models, information on costs and cost-effectiveness of TNFi for the treatment of RA"
Identification and Description of Studies
The submission included full details of the electronic search strategy used in the review update. The ERG was therefore able to replicate the electronic searches undertaken by the company. The databases searched were described with dates. The total number of papers initially found and the number of papers excluded from the review were reported. Reasons for excluding papers were also provided.
Stated inclusion criteria were:
Study design: Cost-consequence analysis, cost-benefit analysis, cost-effectiveness analysis, cost-utility analysis, cost studies (UK only), quality of life studies
Population: People with RA; other forms of arthritis are excluded
Intervention: Etanercept, infliximab, or adalimumab
Comparator: Disease modifying anti-rheumatic drugs
Outcome: Quality of life estimates, cost estimates, cost-effectiveness
Time horizon: February 2005 to October 2006
Using these inclusion criteria, the company identified three studies for inclusion in the review; none of the studies included rituximab as a comparator to TNFi.