Literature Search

To identify relevant citations, we searched the Cochrane Central Register of Controlled Trials (4th Quarter 2005 Update 1: 3rd Quarter 2007), the Cochrane Database of Systematic Reviews (3rd Quarter 2007), and MEDLINE (1966 to October Week 3 2005; Update 1: September Week 1 2007) using terms for included drugs, indications, and study designs (see Appendix A for complete search strategies). Our literature search was limited to English-language publications. To identify additional studies, we also searched reference lists of included studies and reviews and FDA information.⁹ In addition, dossiers were requested from manufacturers of the included drugs. Dossiers were submitted by the following pharmaceutical companies: AstraZeneca (budesonide aqueous), GlaxoSmithKline (fluticasone furoate), Sanofi-Aventis (triamcinolone acetonide), and Schering-Plough (mometasone furoate).

All citations were imported into an electronic database (EndNote 9.0).

Study Selection

Two reviewers independently assessed abstracts of citations identified from literature searches for inclusion, using the criteria described above. Disagreements were resolved using a consensus process. Full-text articles of potentially relevant abstracts were retrieved and a second review for inclusion was conducted by reapplying the inclusion criteria.

Data Abstraction

The following data were abstracted from included trials: study design, setting, population characteristics (including sex, age, ethnicity, diagnosis), eligibility and exclusion criteria, interventions (dose and duration), comparisons, numbers screened, eligible, enrolled, and lost to follow-up, method of outcome ascertainment, and results for each outcome. We recorded intention-to-treat results when reported. In cases where only per-protocol results were reported, we calculated intention-to-treat results if the data for these calculations were available. In trials with crossover, outcomes for the first intervention were recorded if available. This was because of the potential for differential withdrawal prior to crossover biasing subsequent results and the possibility of either a “carryover effect” (from the first treatment) in studies without a washout period, or “rebound” effect from withdrawal of the first intervention.

Data abstracted from observational studies included design, eligibility criteria duration, interventions, concomitant medication, assessment techniques, age, gender, ethnicity, number of patients screened, eligible, enrolled, withdrawn, or lost to follow-up, number analyzed, and results.

Quality Assessment

We assessed the internal validity (quality) of trials based on the predefined criteria listed in Appendix B. These criteria are based on the U.S. Preventive Services Task Force and the National Health Service Centre for Reviews and Dissemination (U.K.) criteria.^{10, 11} We considered the following factors when rating internal validity: methods used for randomization, allocation concealment, and blinding; the similarity of compared groups at baseline; maintenance of comparable groups; adequate reporting of dropouts, attrition, crossover, adherence, and contamination; loss to follow-up; and the use of intention-to-treat analysis. Trials that had a fatal flaw were rated “poor-quality”; trials that met all criteria were rated “good-quality”; the remainder were rated “fair-quality.” As the fair-quality category is broad, studies with this rating vary in their strengths and weaknesses: the results of some fair-quality studies are likely to be valid, while others are only probably valid. A poor-quality trial is not valid—the results are at least as likely to reflect flaws in the study design as the true difference between the compared drugs. A fatal flaw is reflected by failing to meet combinations of items of the quality assessment checklist. External validity of trials was assessed based on whether the publication adequately described the study population, how similar patients were to the target population in whom the intervention will be applied, and whether the treatment received by the control group was reasonably representative of standard practice. We also recorded the role of the funding source.

Appendix B also shows the criteria we used to rate observational studies. These criteria reflect aspects of the study design that are particularly important for assessing adverse event rates. We rated observational studies as good-quality for adverse event assessment if they adequately met 6 or more of the 7 predefined criteria, fair-quality if they met 3 to 5 criteria and poor-quality if they met 2 or fewer criteria.

Included systematic reviews were also rated for quality based on pre-defined criteria (see Appendix B), based on a clear statement of the questions(s), inclusion criteria, adequacy of search strategy, validity assessment and adequacy of detail provided for included studies, and appropriateness of the methods of synthesis. Overall quality ratings for the individual study were based on internal and external validity ratings for that trial. A particular randomized trial might receive 2 different ratings: one for effectiveness and another for adverse events. The overall strength of evidence for a particular key question reflects the quality, consistency, and power of the set of studies relevant to the question.

Evidence Synthesis