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 assessment report. The assessment report for this technology appraisal was prepared by West Midlands Technology Assessment Collaboration (see the "Availability of Companion Documents" field).
Clinical Effectiveness
A scoping search was undertaken to identify existing reviews and other background material and to estimate the volume and nature of primary studies. Among this literature a recent well-conducted Cochrane Review was identified, which assessed the effectiveness of epoetin alfa and beta up to 2001.
It was agreed that the review commissioned by NICE for the effectiveness part of this technology assessment would build onto the work of the Cochrane review.
Search Strategy
The Cochrane systematic review formed the basis of the Assessment Group's review regarding epoetin alfa and epoetin beta so their search strategy ran from 2000 onwards for these two drugs. In the case of darbepoetin alfa the search ran from 1996, the year before phase I trials were initiated on it. Searches ended in September 2004, studies identified after this date were acknowledged but not included in the analysis. There were no language restrictions. (Refer to Appendix 2 of the Assessment Report [see the "Availability of Companion Documents" field] for search strategies).
The main purpose of the search was to comprehensively identify completed randomised controlled trials (RCTs) of erythropoietin. To this end the following sources were searched:
- Bibliographic databases including Cochrane Library (CENTRAL), MEDLINE, EMBASE and the Science Citation Index
- Research Registers of ongoing trials including the National Research Register, Current Controlled Trials metaRegister, and ISRCTN database and ClinicalTrials.gov
- Citation lists of relevant studies
- Contact with experts in the field
- Invited industry submissions
- Conference proceedings
Ongoing Trials
A search for ongoing trials was also undertaken, terms for the intervention (erythropoietin, epoetin, darbepoetin) and condition of interest (anaemia/anemia) were used to search the following trials registers: National Research Register 2004 Issue 2, Current Controlled Trials metaRegister, ClinicalTrials.gov, National Cancer Institute PDQ database and International Cancer Research Portfolio for ongoing trials. Trials that did not relate to cancer-induced or chemotherapy-related anaemia were removed by handsorting. Finally duplicates, identified via their study identification numbers where possible, were removed, leaving a final list of 29 potentially relevant trials. (Searches carried out 5/7/2004).
Inclusion and Exclusion Criteria
Study Design
Only RCTs were included. Non-randomised trials, in particular quasi-randomised such as where allocation is based on date of birth or day of month were excluded. Also excluded were RCTs with fewer than 10 patients in any study arm.
Population
Patients had to be diagnosed with malignant disease, using clinical and histological/cytological criteria (any type of malignant disease was included, irrespective of stage or previous therapy); trials in patients with anaemia resulting from chemotherapy and/or radiotherapy or underlying malignant disease were included. Other causes of anaemia such as haemolysis, iron deficiency and occult bleeding should have been excluded in the participants of the included trials. There were no age restrictions; however, it is recognised that the licences for all three drugs do not cover erythropoietin use in children. Studies where erythropoietin was given in the context of myelo-ablative chemotherapy ahead of bone marrow or peripheral blood stem cell transplantation, or for short-term preoperative treatment to correct anaemia or to support collection of autologous blood prior to cancer surgery, were excluded.
Intervention
Epoetin alfa (Exprex, Ortho biotec), epoetin beta (NeoRecormon, Roche) or darbepoetin alfa (Nesp, Amgen). Concomitant anaemia therapy such as iron or granulocyte-colony-stimulating factor (G-CSF) supplementation was permitted, as were red blood cell transfusions (RBCT).
Comparator
Within the Cochrane review any comparator was acceptable provided that the only difference between the treatment and control arms was the use of erythropoietin. However, at the NICE Consultee Meeting on 2nd September 2004, after discussion, it was felt that there may be trials in which concomitant supportive anaemia treatments such as G-CSF or iron supplementation had been given to patients receiving erythropoietin but not to patients in the control arm, which if excluded would cause valuable information to be lost. It was therefore agreed to include these trials, but also to acknowledge that these trials do have different comparators to trials where concomitant supportive anaemia treatments are given to patients equally in each arm of the trials.
It was anticipated that comparators would be either placebo or best supportive care. In both, it was anticipated that RBCT would be given when a patient's haemoglobin (Hb) fell to an unacceptably low level. Ideally a protocol for when RBCT should be instigated should have been described (i.e., "transfusion trigger"). The same rules on rescue regarding RBCT should also have been applied in the erythropoietin arm.
Outcomes
Outcomes sought from the studies fell into 4 categories: anaemia related outcomes, malignancy related outcomes, adverse events data, and patient specific outcomes such as quality of life outcomes and patients preferences.
Refer to Section 3.1.3 of the Assessment Report (see the "Availability of Companion Documents" field) for more information on outcomes.
Cost-Effectiveness
Search
The following sources were searched up to 30/7/04 to identify economic evaluations as part of wider search to identify all aspects of information on costs, cost-effectiveness and quality of life outcomes:
- MEDLINE (Ovid) 1966 – July week 4 2004
- EMBASE (Ovid) 1980 – 2004 week 30
- Database of Reviews of Effects (DARE) 2004 Issue 3
- National Health Service Economic Evaluations Database (NHS EED) 2004 Issue 3
- Office of Health Economics Health Economic Evaluation Database (OHE HEED) July 2004 issue
The search strategy, detailed in full in Appendix 2 of the Assessment Report (see the "Availability of Companion Documents" field) combined groups of terms capturing the intervention of interest (erythropoietin), with terms capturing the target condition (cancer), with terms capturing the study design of interest (cost-effectiveness, cost and quality of life). There were no language restrictions. The submissions from the three industry sponsors were searched for additional references.
Inclusion Criteria
Originally the Assessment Group had intended to restrict the review to cost-utility studies undertaken since 2000. However, because several widely cited studies were published in the period 1995 to 2000, the search period and range of included study designs were extended. The review reported here was thus of all economic evaluations (cost-benefit, cost-utility, cost-effectiveness, and cost-consequence analyses) of erythropoietin for anaemia associated with cancer treatment from 1995 to July 2004. Inclusion decisions were made by one reviewer.