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Comparative effect sizes in randomised trials from less developed and more developed countries: meta-epidemiological assessment

BMJ 2013; 346 doi: (Published 12 February 2013) Cite this as: BMJ 2013;346:f707
  1. Orestis A Panagiotou, research associate1,
  2. Despina G Contopoulos-Ioannidis, clinical associate professor23,
  3. John P A Ioannidis, director4, C F Rehnborg professor in disease prevention, professor of medicine, and professor of health research and policy5
  1. 1Clinical Trials and Evidence-Based Medicine Unit, Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, University Campus, Ioannina, Greece
  2. 2Division of Infectious Diseases, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA
  3. 3Health Policy Research, Palo Alto Medical Foundation Research Institute, Palo Alto, CA, USA
  4. 4Stanford Prevention Research Center, Department of Medicine
  5. 5Department of Health Research and Policy, Stanford University School of Medicine, Stanford, CA 94305, USA
  1. Correspondence to: J P A Ioannidis jioannid{at}
  • Accepted 30 January 2013


Objective To compare treatment effects from randomised trials conducted in more developed versus less developed countries.

Design Meta-epidemiological study.

Data sources Cochrane Database of Systematic Reviews (August 2012).

Data extraction Meta-analyses with mortality outcomes including data from at least one randomised trial conducted in a less developed country and one in a more developed country. Relative risk estimates of more versus less developed countries were compared by calculating the relative relative risks for each topic and the summary relative relative risks across all topics. Similar analyses were performed for the primary binary outcome of each topic.

Results 139 meta-analyses with mortality outcomes were eligible. No nominally significant differences between more developed and less developed countries were found for 128 (92%) meta-analyses. However, differences were beyond chance in 11 (8%) cases, always showing more favourable treatment effects in trials from less developed countries. The summary relative relative risk was 1.12 (95% confidence interval 1.06 to 1.18; P<0.001; I2=0%), suggesting significantly more favourable mortality effects in trials from less developed countries. Results were similar for meta-analyses with nominally significant treatment effects for mortality (1.15), meta-analyses with recent trials (1.14), and when excluding trials from less developed countries that subsequently became more developed (1.12). For the primary binary outcomes (127 meta-analyses), 20 topics had differences in treatment effects beyond chance (more favourable in less developed countries in 15/20 cases).

Conclusions Trials from less developed countries in a few cases show significantly more favourable treatment effects than trials in more developed countries and, on average, treatment effects are more favourable in less developed countries. These discrepancies may reflect biases in reporting or study design as well as genuine differences in baseline risk or treatment implementation and should be considers when generalising evidence across different settings.


  • Contributors: JPAI conceived the original idea. OAP, DGC-I, and JPAI designed the study. OAP and DGC-I identified the eligible reviews and performed the data extraction. OAP and JPAI performed the statistical analyses. OAP, DGC-I, and JPAI interpreted the data and wrote the manuscript. All authors have critically commented on and approved the final version of the manuscript. JPAI is the guarantor. All authors, external and internal, had full access to all of the data (including statistical reports and tables) in the study and can take responsibility for the integrity of the data and the accuracy of the data analysis.

  • Funding: This study received no funding.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years, no other relationships or activities that could appear to have influenced the submitted work.

  • Ethical approval: Not required.

  • Data sharing: The statistical code and datasets are available from the corresponding author at

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