Intended for healthcare professionals

Research Methods & Reporting

Use of multiple period, cluster randomised, crossover trial designs for comparative effectiveness research

BMJ 2020; 371 doi: (Published 04 November 2020) Cite this as: BMJ 2020;371:m3800
  1. Karla Hemming, statistician1,
  2. Monica Taljaard, senior scientist2 3,
  3. Charles Weijer, professor4,
  4. Andrew B Forbes, professor5
  1. 1Institute of Applied Health Research, University of Birmingham, Birmingham B15 2TT, UK
  2. 2Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
  3. 3School of Epidemiology and Public Health, University of Ottawa, Ottawa, ON, Canada
  4. 4Departments of Medicine, Epidemiology, and Biostatistics, and Philosophy, Western University, London, ON, Canada
  5. 5School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia
  1. Correspondence to: K Hemming k.hemming{at}
  • Accepted 18 September 2020

Many treatments are adopted into clinical practice without a solid evidence base and might be used heterogeneously across settings. Rigorous randomised controlled trials are therefore needed to inform decisions about the comparative effectiveness of treatments in common use. The mainstay of comparative effectiveness research is pragmatic trial design, which emphasises broad eligibility criteria, simple logistics, routinely collected outcome data, and cost efficient designs. Although treatment differences at the individual level might be small, they can become important when aggregated across large populations. To detect these small differences, very large trials are often required. In multiple period, cluster randomised, crossover trials, the study design randomises clusters (eg, hospitals) to exposure to different interventions in a randomly determined order, and is an attractive design for comparative effectiveness research. The trial design can be highly statistically efficient, compared with other competing designs, and can have many logistical advantages. Several prominent examples of this trial design have been published recently, yet practical guidance is lacking on how best to design these trials to ensure that they provide robust evidence. Some considerations include how to determine the frequency and number of crossovers, the importance of a time balanced design, how to determine the required sample size, and how to analyse appropriately. The justification for using this design (over a design randomising on the level of individual patients) also raises ethical concerns when used to evaluate individual level interventions without the prospective informed consent of individual participants. In this article, we outline the key methodological and ethical requirements needed for the robust design of multiple period, cluster randomised, crossover trials.

Many treatments are adopted into clinical practice without a solid evidence base and might be used heterogeneously across settings.12 Furthermore, differences between competing treatments are often small but can nevertheless be important at a …

View Full Text