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 the Peninsula Technology Assessment Group (PenTAG), Peninsula Medical School and by the Southampton Health Technology Assessment Centre (SHTAC), Wessex Institute for Health Research and Development (WIHRD), University of Southampton (see the "Availability of Companion Documents" field).
Clinical Effectiveness
Identification of Studies
A search strategy for electronic bibliographic databases was devised and tested by an experienced information scientist (refer to Appendix 3 of the Assessment Report [see the "Availability of Companion Documents" field]). Once finalised it was applied to a number of databases including: The Cochrane Database of Systematic Reviews (CDSR); The Cochrane Central Register of Controlled Trials; Database of Abstracts of Reviews of Effectiveness (DARE); the National Health Service Economic Evaluation Database (NHS EED); Medline (Ovid); Embase (Ovid); National Research Register; Current Controlled Trials; ISI Proceedings (Web of Knowledge); Science Citation Index (Web of Knowledge); and BIOSIS.
Searches were run up to February/March 2006, and were restricted to studies published in English. An update search was conducted in October 2006 to identify any relevant studies published since the original search.
The drug manufacturers' submissions to NICE, which were received in August 2006, were also searched for potentially relevant trials.
All identified studies were downloaded into a Reference Manager database for storage and retrieval as necessary. A keywording system was devised to enable each reference to be categorised according to pre-specified inclusion and exclusion criteria.
Inclusion and Exclusion Criteria
The inclusion and exclusion criteria were specified a priori based on the scope issued by NICE, as agreed in the published protocol.
Intervention
Trials reporting evaluations of the following inhaled corticosteroids (ICSs) were included:
- Beclometasone dipropionate (BDP)
- Budesonide (BUD)
- Fluticasone propionate (FP)
Trials reporting evaluations of the following ICSs combined with long-acting beta 2 agonists (LABAs) in the same inhaler (i.e. combination inhalers) were included:
- BUD/formoterol fumarate (FF) (in children over six years)
- FP/salmeterol (SAL) (as xinafoate) (in children over four years)
Trials reporting ICS delivered by pressured metered dose inhalers (pMDIs) and dry powder inhalers (DPIs) were included; those using nebulisers were excluded.
To be included the intervention had to last for more than four weeks.
Comparators
The ICSs were compared with each other.
The combination inhalers were compared with: each other; and with ICS only. They were also compared with ICSs and LABAs administered in separate inhalers.
Types of Studies
Fully published randomised controlled trials (RCTs) or systematic reviews of RCTs. Double blinding was not a pre-requisite for inclusion, although blinding was assessed as part of critical appraisal.
Trials reported in abstracts or conference presentations from 2004 onwards were retrieved, however their details were not extracted, critically appraised or analysed (however, details were extracted where an abstract was available which provided data supplementary to a fully published trial report of a particular study; this occurred in a handful of cases).
Where unpublished full trial reports were available (e.g., as supplied by the drug manufacturers in their submissions to NICE) these were included.
Population
Children aged under 12 years diagnosed with chronic asthma (the mean age of the study population had to be 12 years or under). Studies in which the patient group was asthmatics with a specific related co-morbidity (e.g., cystic fibrosis) were not included.
Studies reporting the treatment of acute exacerbations of asthma were not included.
Trials reporting the effectiveness of ICSs with LABAs were only included if the patients had been previously treated with an ICS.
Outcomes
At the screening stage studies reporting one or more of the following outcomes were included:
- Objective measures of lung function
- Symptoms
- Incidence of mild and severe acute exacerbations
- Use of systemic corticosteroids
- Adverse effects of treatment
- Health-related quality of life
- Mortality
A list of specific measures for each of these outcomes was devised for the data analysis (refer to Section 5.1.5.1 of the Assessment Report [see the "Availability of Companion Documents" field]).
Titles and abstracts of studies identified by the searches were screened by one reviewer based on the above inclusion/exclusion criteria. A second reviewer checked a random 10% of these. Any discrepancies were resolved through discussion and involvement of a third reviewer where necessary.
Full papers of studies included on title or abstract were requested for further assessment. All full papers were screened independently by one reviewer and checked by a second. Any discrepancies were resolved by discussion with involvement of a third reviewer where necessary.
All included papers were keyworded in the Reference Manager database as to their intervention and comparator, and were coded for the synthesis framework (see Section 5.1.5 in the Assessment Report [see "Availability of Companion Documents" field]) to enable efficient retrieval of sub-sets of studies for analysis.
Economic Analysis
Search Strategy and Critical Appraisal Methods
MEDLINE, EMBASE, and the Cochrane Library (Issue 1, 2006) were searched for cost-effectiveness studies that assessed the cost-effectiveness of BDP, BUD, and FP dipropionate used alone or in combination with a LABA, SAL or FF within their licensed indications and the appropriate step of the British Thoracic Society/Scottish Intercollegiate Guidelines Network (BTS/SIGN) guidelines. The full search strategy is displayed in Appendix 3 of the Assessment Report (see the "Availability of Companion Documents" field).
Inclusion and Exclusion Criteria
Cost-effectiveness analyses, cost-utility analyses, cost-benefit analyses and cost-consequence analyses were eligible for inclusion in the cost-effectiveness review. In addition, separate submissions were received from GlaxoSmithKline, AstraZeneca, Meda Pharmaceuticals Ltd, and Trinity-Chiesi Pharmaceuticals Ltd as part of the NICE technology appraisals process.