The Use and Reporting of the Cross-Over Study Design in Clinical Trials and Systematic Reviews: A Systematic Assessment

Abstract

Background: Systematic reviews of treatment interventions in stable or chronic conditions often require the synthesis of clinical trials with a cross-over design. Previous work has indicated that methodology for analysing cross-over data is inadequate in trial reports and in systematic reviews assessing trials with this design.

Objective: We assessed systematic review methodology for synthesising cross-over trials among Cochrane Cystic Fibrosis and Genetic Disorders Group reviews published to July 2015, and assessed the quality of reporting among the cross-over trials included in these reviews.

Methodology: We performed data extraction of methodology and reporting in reviews, trials identified and trials included within reviews.

Principal findings: We reviewed a total of 142 Cochrane systematic reviews including 53 reviews which synthesised evidence from 218 cross-over trials. Thirty-three (63%) Cochrane reviews described a clear and appropriate method for the inclusion of cross-over data, and of these 19 (56%) used the same method to analyse results. 145 cross-over trials were described narratively or treated as parallel trials in reviews but in 30 (21%) of these trials data existed in the trial reports to account for the cross-over design. At the trial level, the analysis and presentation of results were often inappropriate or unclear, with only 69 (32%) trials presenting results that could be included in meta-analysis.

Conclusions: Despite development of accessible, technical guidance and training for Cochrane systematic reviewers, statistical analysis and reporting of cross-over data is inadequate at both the systematic review and the trial level. Plain language and practical guidance for the inclusion of cross-over data in meta-analysis would benefit systematic reviewers, who come from a wide range of health specialties. Minimum reporting standards for cross-over trials are needed.

Fig 1. Study Flow Diagram.

Flow diagram of selection of Cochrane Cystic Fibrosis and Genetic Disorders (CFGD) reviews and included cross-over trials^a-d. ^a All numbers in Fig 1 refer to number of trials, some of which were published across multiple reports. Where this was the case, we extracted only from the primary reference as stated in the Cochrane review or according to our judgement of which reference was the most relevant. ^b In one review, review level and included trial level data was extracted following initial identification of reviews and trials up to January 2015. An update of this review was published in May 2015 in which five cross-over trials previously included were excluded (for reasons not due to cross-over design). These excluded cross-over trials were retained in the data extraction and results. ^c Note: in forty reviews which did not consider cross-over trials to be an eligible design; 13 cross-over trials were listed as “Excluded Studies” in these reviews due to design (one of which was included in another review). ^d Note: in the 102 reviews where cross-over designs were eligible, 10 unique trials listed as ‘Ongoing’ had a cross-over design and 35 unique trials listed as ‘Awaiting Assessment’ had a cross-over design (three of which were included in other reviews).

Fig 2. Review Methodology and Reporting.

Methods planned compared to methods used for and the inclusion of results from cross-over (CO) trials in meta-analysis for 53 reviews.

Fig 3. Trial methodology and reporting.

Analysis and reporting of results in 218 cross-over trials, and the incorporation of results in 53 systematic reviews.

Fig 4. Inclusion of cross-over data in systematic reviews.

How many cross-over trials could be been included in meta-analysis?