Note from the National Guideline Clearinghouse (NGC): The National Institute for Health and Care Excellence (NICE) commissioned an independent academic centre to perform an assessment of the manufacturer's submission 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 Centre for Reviews and Dissemination/Centre for Health Economics (CRD/CHE), University of York (see the "Availability of Companion Documents" field).
The manufacturer's submission described the search strategies used to identify relevant clinical effectiveness studies about the use of teriflunomide for the treatment of relapsing–remitting multiple sclerosis (RRMS) in adults.
The electronic databases MEDLINE and MEDLINE In-Process (via PubMed), EMBASE (via Embase.com) and Cochrane Central Register of Controlled Trials (CENTRAL) were searched to identify clinical studies on the use of teriflunomide and other comparators. In addition to this, grey literature was searched in several medical society and regulatory body Web sites and a hand search was carried out.
Searches were conducted in May 2012 and subsequently updated on 12 November 2012. The searches covered the period 1st January 1980–November 12 2012, were limited to English language publications, and excluded letters, editorials, comments and animal studies.
Overall the searches were appropriate and well documented, and included the use of both subject indexing terms (MeSH and EMTREE) and free text searching. Field searching, Boolean operators and truncation were used where required. All the databases required by NICE were searched, though only CENTRAL was searched in the Cochrane Library when it might have been useful to have searched the Cochrane Database of Systematic Reviews (CDSR), the Database of Abstracts of Reviews of Effects (DARE) and the Health Technology Assessment (HTA) database. For this reason the manufacturer missed a protocol of a Cochrane Systematic Review on teriflunomide for the treatment of multiple sclerosis that is finished and published now.
The trade name of teriflunomide and the trade name of its comparators were not included in the search strategies. It is possible (though not likely) that potentially useful records were not retrieved. The search strategies used in the manufacturer's submission were limited to experimental trials. However a search for other study designs such as cohort or case control studies may have provided useful supplementary information about safety. It is not clear if the methodological search filters used in PubMed and EMBASE were derived from validated search filters.
The manufacturer outlined appropriate inclusion criteria for population, interventions and comparators, outcomes and study designs. It is noted that eligibility criteria for the review included patients with secondary progressive multiple sclerosis (SPMS). All included direct trials of teriflunomide had a small percentage of patients with SPMS (at least 87% were patients with RRMS). The Committee considered this to be overall acceptable but it is noted, in contrast, that the trials in the mixed treatment comparison (MTC) largely had 100% RRMS.
The manufacturer included open-label extension studies in addition to randomised controlled trials (RCTs) in order to assess long-term safety of teriflunomide. This approach is acceptable. However the efficacy data from these trials should be treated with some caution as there is no concurrent placebo group and therefore no information on natural course of disease.
The restriction to English language trials only could have led to trials being missed but in this instance the ERG is unaware of any missing trials. The manufacturer's flow diagram does not include data (no. of studies, etc.) included and excluded from the direct evidence.
The manufacturer's submission described the search strategies used to identify cost-effectiveness studies relevant to this appraisal of teriflunomide for the treatment of relapsing-remitting multiple sclerosis in adults.
The electronic databases MEDLINE, MEDLINE In-Process (via EMBASE) and EMBASE (via EMBASE), EconLit (Ovid), the Cochrane Library (Wiley) including the NHS Economic Evaluation Database (NHS EED) were searched. In addition to this, a grey literature search was performed.
Database searches were performed on 10th and 11th October 2012. Search strategies for each database were documented. The searches covered the period 1966–October 2012 for MEDLINE and EMBASE, 1961–October 2012 for Econlit and 1968–October 2012 for NHS EED. No language or date limits were applied to the search. The search excluded animal studies as well as the publication types 'letter' and 'editorial', and 'note'.
The searches were appropriate and comprehensive, and included the use of both subject indexing terms and free text searching. Field searching, Boolean operators and truncation were used where required. All NICE required databases were searched, as well as medical society and regulatory body websites.
A methodological search filter adapted from the Scottish Intercollegiate Guidelines Network Grading (SIGN) was included to identify economic studies and utilities in MEDLINE and EMBASE. The adapted economic study design search filter may have excluded potentially useful records from MEDLINE and EMBASE.
The addition of the following EMTREE terms would have improved the filter used in EMBASE and MEDLINE: 'Economic evaluation' and 'Cost utility'.
An important issue is that the manufacturer didn't adapt the search for MEDLINE, instead they searched EMBASE and MEDLINE together from the EMBASE interface. They used the same search and the same methodological filter developed for EMBASE. The Cochrane Manual advises to adapt the searches to every database.
The systematic review of the literature resulted in no cost-effectiveness analyses of teriflunomide. Two cost-effectiveness analyses of other treatments were identified to help inform the development of the de novo model.