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 Technology Assessment Group, University of York (see the "Availability of Companion Documents" field).
Critique of the Methods of Review(s)
The manufacturer's submission (MS) described the search strategies used to identify relevant clinical effectiveness studies about the use of aflibercept for the treatment of metastatic colorectal cancer (mCRC) previously treated with an oxaliplatin-containing regimen.
The electronic databases MEDLINE and MEDLINE In-Process (via PubMed), EMBASE and Cochrane Central Register of Controlled Trials (CENTRAL) were searched to identify clinical studies on the use of aflibercept in the second-line treatment of mCRC. In addition to this, abstracts of conference proceedings from the American Society of Clinical Oncology (ASCO) and the European Society of Medical Oncology (ESMO) were reviewed.
Searches were conducted on 19 December 2012. The searches covered the period 1 January 1992 to December 2012, were limited to English language publications, and excluded animal studies. In addition, the EMBASE search strategy excluded all 'conference' publication types and the 'review' publication type. The manufacturer did not explain why the search was limited by date range and to only English language publications.
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. Information about the EMBASE service provider was not provided, but was subsequently provided via the Points of Clarification letter.
There were some issues with the use of MeSH and EMTREE terms. The PubMed search strategy included both MeSH and Major MeSH index terms; Major MeSH terms are redundant when used alongside the equivalent MeSH terms. Further, the MeSH terms used ('Colorectal Neoplasms', 'Colonic Neoplasms' and 'Rectal Neoplasms') were not exploded, and so additional MeSH terms found further down the MeSH hierarchy would not have been searched for. In the EMBASE search strategy MESH terms are used instead of EMTREE terms in search line #1.
Other issues included: a missing Boolean operator (OR) in search line #2; a redundant search line (line #11); and unnecessary repetition of search terms (lines #4 and #36). The drug name aflibercept (and related terms) was not included in the search strategies and so it is possible that potentially useful records were not retrieved. The search strategies used in the manufacturer's submission were limited to RCTs and phase II and phase III 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, EMBASE and the Cochrane Library were derived from validated search filters. The addition of the following EMTREE terms would have improved the filter used in EMBASE: 'Randomized Controlled Trial' and 'Controlled Clinical Trial'.
Despite the issues identified above, 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. It is unlikely that any relevant studies have been missed. No separate search strategy was undertaken to identify relevant studies for the meta-analysis of the adverse effects of aflibercept.
RCTs of all current second-line chemotherapy regimens (including, but not limited to, bevacizumab; irinotecan; folinic acid/5-fluorouracil/irinotecan [FOLFIRI]; folinic acid/5-fluorouracil/oxaliplatin 4 [FOLFOX4]; FOLFOX6; capecitabine/oxaliplatin [capeOX, XELOX]) compared with placebo, best supportive care or the same or a different second-line chemotherapy regimen, for adult patients with mCRC were eligible for inclusion in the review. Trials had to assess outcomes relating to survival, progression, response, adverse effects or quality of life to be included in the review. Only English language articles were eligible for inclusion. The inclusion criteria were appropriate for a systematic review of all second-line chemotherapy regimens for adult patients with mCRC. It appears that at the study selection stage the inclusion criteria were narrowed down so that the only intervention eligible for inclusion in the review was aflibercept.
No inclusion criteria were presented for the meta-analysis of the adverse effects of aflibercept.
ERG Comment on Manufacturer's Review of Cost-effectiveness Evidence
The manufacturer's submission described the search strategies used to identify cost-effectiveness studies relevant to this appraisal of aflibercept for the treatment of mCRC. The review was performed as part of a wider systematic review aimed to identify utility, resource use and cost estimates relevant to the appraisal. Search strategies were only briefly described in the main submission, however full details were provided in the Appendix 10 of the MS.
The electronic databases MEDLINE and MEDLINE In-Process (via PubMed), EMBASE (Dialog), EconLit (EBSCO), the Cochrane Library (Wiley) including the NHS Economic Evaluation Database (NHS EED) and the Health Technology Assessment (HTA) database were searched. In addition to this, abstracts of conference proceedings from ASCO, ESMO, World Conference on Gastrointestinal Cancer, and International Society for Pharmacoeconomics and Outcomes Research (ISPOR) were searched. Regulatory organisation websites were also searched, including NICE, the Scottish Medicines Consortium (SMC), and the All Wales Medicines Strategy Group (AWMSG).
Database searches were performed on 27 June 2012. Internet searches were performed between 27 June and 6 July 2012. The searches covered the period 2010 to 27 June 2012. Searches were not performed for publications before 2010 because the NICE multiple-technology appraisal for cetuximab, bevacizumab, and panitumumab was published that year and provided relevant economic literature to that point. Further, the manufacturer did not expect there to be any aflibercept economic analyses prior to 2010. The searches were limited to English language publications, and excluded animal studies as well as the publication types 'review' and 'case reports', and the MeSH term 'Review Literature as Topic'.
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 abstracts of conference proceedings and regulatory body websites. An update of the searches closer to submission might have been useful.
Methodological search filters were included to identify economic studies and utilities in MEDLINE, EMBASE and the Cochrane Library. The economic study design search filter may have excluded potentially useful records from the NHS EED database in the Cochrane Library search as this database is already limited by study design.
Inclusion/Exclusion Criteria Used for Study Selection
The manufacturer undertook a series of systematic searches to identify published economic evaluations, including cost-effectiveness, and cost-utility analyses, as well as utility, resource use and cost studies. The ERG believes that the inclusion/exclusion criteria were appropriate, and would have identified any relevant studies.