title: Comparative rates of harms in randomized trials from more developed versus less developed countries may be different.
abstract: We set up to evaluate the relative risk of harms in trials performed in less developed vs. more developed countries.
  
  
  
  Meta-epidemiologic evaluation using the Cochrane Database of Systematic Reviews. We considered meta-analyses with at least one randomized clinical trial (RCT) in a less developed country and one RCT in a more developed country. We targeted severe adverse events (AEs), discontinuations due to AEs, any AE, organ system-specific AEs, individual AEs, and all discontinuations due to any reason. We estimated the relative odds ratio (ROR) of harms between more and less developed countries for each topic and the summary ROR (sROR) across topics under each category of harms.
  
  
  
  We identified 42 systematic reviews (128 meta-analyses, 521 independent RCTs). Summary sRORs did not differ significantly from 1.00 for any harm category. Nominally significant RORs were found in only 6/128 meta-analyses. However, in 27% (35/128) of meta-analyses the ROR point estimates indicated relative differences between country settings >2-fold. Considering also ROR 95% confidence intervals, in 92% (118/128) of meta-analyses one could not exclude a 2-fold difference in both directions.
  
  
  
  We identified limited comparative evidence on harms in trials from these two country settings. Substantial differences in the risk point estimates were common; the potential for modest differences could rarely be excluded with confidence.
authors.affiliation: Department of Pediatrics, Division of Infectious Diseases, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA, 94305-5107, USA; Palo Alto Medical Foundation Research Institute, 795 El Camino Real, Ames Building, Room 2A027B, Palo Alto, CA, 94301, USA; Meta-Research Innovation Center at Stanford (METRICS), 1070 Arastradero Road, Palo Alto, CA, 94304, USA. Electronic address: dcontop@stanford.edu.
authors.forename: Despina
authors.initials: D
authors.lastname: Contopoulos-Ioannidis
authors.affiliation: Leeds Teaching Hospital, NHS Trust, Great George Street, Leeds LS1 3EX, UK.
authors.forename: Xanthippi
authors.initials: X
authors.lastname: Tseretopoulou
authors.affiliation: Medecins San Frontieres, 8 Rue Saint-Sabin, Paris 75011, France.
authors.forename: Megan
authors.initials: M
authors.lastname: Ancker
authors.affiliation: Mendocino Coast District Hospital, 700 River Dr, Fort Bragg, CA 95437, USA.
authors.forename: Juan N
authors.initials: JN
authors.lastname: Walterspiel
authors.affiliation: Division of Cancer Epidemiology & Genetics, National Cancer Institute, National Institute of Health, 9609 Medical Center Dr., Room 7E136, Bethesda, MD 20892, USA.
authors.forename: Orestis A
authors.initials: OA
authors.lastname: Panagiotou
authors.affiliation: Department of Pediatrics, Division of Infectious Diseases, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA, 94305-5107, USA; Department of Health Research and Policy, Stanford University School of Medicine, Redwood Building T152, 150 Governor's Lane, Stanford, CA 94305-5405, USA; Faculty Development and Diversity, Stanford University School of Medicine, 291 Campus Drive, Stanford, CA 94305, USA.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Maldonado
authors.affiliation: Meta-Research Innovation Center at Stanford (METRICS), 1070 Arastradero Road, Palo Alto, CA, 94304, USA; Department of Health Research and Policy, Stanford University School of Medicine, Redwood Building T152, 150 Governor's Lane, Stanford, CA 94305-5405, USA; Stanford Prevention Research Center, Department of Medicine, Stanford University School of Medicine, Medical School Office Building, 1265 Welch Road, Stanford, CA 94305, USA; Department of Statistics, Stanford University School of Humanities and Sciences, Sequoia Hall, 390 Serra Mall, Stanford, CA 94305-4065, USA.
authors.forename: John P A
authors.initials: JP
authors.lastname: Ioannidis
mesh_terms: D019049:Developed Countries / Q000706:statistics & numerical data*; D003906:Developing Countries / Q000706:statistics & numerical data*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology*; D016021:Epidemiologic Studies; D006801:Humans; D015201:Meta-Analysis as Topic; D016017:Odds Ratio; D016032:Randomized Controlled Trials as Topic / Q000706:statistics & numerical data*; D012196:Review Literature as Topic; D012306:Risk
keywords: Comparative harms; Comparative safety; Less developed countries; Meta-analyses; More developed countries; Randomized trials