Reporting of cross-over clinical trials of analgesic treatments for chronic pain: Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks systematic review and recommendations

Abstract

Cross-over trials are typically more efficient than parallel group trials in that the sample size required to yield a desired power is substantially smaller. It is important, however, to consider some issues specific to cross-over trials when designing and reporting them, and when evaluating the published results of such trials. This systematic review evaluated the quality of reporting and its evolution over time in articles of cross-over clinical trials of pharmacologic treatments for chronic pain published between 1993 and 2013. Seventy-six (61%) articles reported a within-subject primary analysis, or if no primary analysis was identified, reported at least 1 within-subject analysis, which is required to achieve the gain in power associated with the cross-over design. For 39 (31%) articles, it was unclear whether analyses conducted were within-subject or between-group. Only 36 (29%) articles reported a method to accommodate missing data (eg, last observation carried forward, n = 29), and of those, just 14 included subjects in the analysis who provided data from only 1 period. Of the articles that identified a within-subject primary analysis, 21 (51%) provided sufficient information for the results to be included in a meta-analysis (ie, estimates of the within-subject treatment effect and variability). These results and others presented in this article demonstrate deficiencies in reporting of cross-over trials for analgesic treatments. Clearer reporting in future trials could improve readers' ability to critically evaluate the results, use these data in meta-analyses, and plan future trials. Recommendations for proper reporting of cross-over trials that apply to any condition are provided.

CONSORT 2010 statement: extension to randomised crossover trials

“…Gewandter and colleagues investigated 124 crossover clinical trials of drug treatments for chronic pain published between 1993 and 2013. They found that 28% (35/124) of trials reported baseline and post washout pain levels, and only 31% (23/75) reported a sample size calculation that specifically indicated that it was based on within participant variability 27. Straube and colleagues considered 98 crossover trials on chronic painful conditions published between 1990 and 2014 and indexed on PubMed.…”

Research design considerations for randomized controlled trials of spinal cord stimulation for pain: Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials/Institute of Neuromodulation/International Neuromodulation Society recommendations

“… 105 A pain-specific supplement to CONSORT is also available from Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION), 52 as well as a discussion of issues that arise in the reporting of crossover trials. 54 A guideline for describing complex interventions in clinical trial reports has been published. 66 Additional recommendations for the reporting of SCS trials for pain are provided in Tables 3 and 4 .…”

John D. Loeser Award Lecture: Size does matter, but it isn't everything: the challenge of modest treatment effects in chronic pain clinical trials

“…Cross-over designs can be used to reduce sample size requirements when studying pain conditions that are expected to remain stable throughout the trial duration and treatments that have relatively fast onset and offset of their pharmacodynamic effects. 26 , 40 , 94 However, cross-over trials also have several potential limitations, including carry-over effects, in which the effect of an active treatment in the first period may carry over to a placebo condition in the next period and reduce the second period treatment-placebo difference. Various methods for addressing these effects have been proposed, but the best approach is to design the trial to minimize potential carry-over effects and any other causes of treatment-by-period interaction.…”