title: Randomized trials are frequently fragmented in multiple secondary publications.
abstract: To assess the frequency and features of secondary publications of randomized controlled trials (RCTs).
  
  
  
  For 191 RCTs published in high-impact journals in 2009, we searched for secondary publications coauthored by at least one same author of the primary trial publication. We evaluated the probability of having secondary publications, characteristics of the primary trial publication that predict having secondary publications, types of secondary analyses conducted, and statistical significance of those analyses.
  
  
  
  Of 191 primary trials, 88 (46%) had a total of 475 secondary publications by 2/2014. Eight trials had >10 (up to 51) secondary publications each. In multivariable modeling, the risk of having subsequent secondary publications increased 1.32-fold (95% CI 1.05-1.68) per 10-fold increase in sample size, and 1.71-fold (95% CI 1.19-2.45) in the presence of a design article. In a sample of 197 secondary publications examined in depth, 193 tested different hypotheses than the primary publication. Of the 193, 43 tested differences between subgroups, 85 assessed predictive factors associated with an outcome of interest, 118 evaluated different outcomes than the original article, 71 had differences in eligibility criteria, and 21 assessed different durations of follow-up; 176 (91%) presented at least one analysis with statistically significant results.
  
  
  
  Approximately half of randomized trials in high-impact journals have secondary publications published with a few trials followed by numerous secondary publications. Almost all of these publications report some statistically significant results.
authors.affiliation: Stanford Prevention Research Center, Department of Medicine, Stanford University, 1265 Welch Road, Stanford, CA 94305, USA; Meta-Research Innovation Center at Stanford (METRICS), School of Medicine, Stanford University, 1265 Welch Road, Stanford, CA 94305, USA; Department of Clinical Epidemiology & Biostatistics, McMaster University, 1200 Main Street West, Hamilton, Ontario L8S 4K1, Canada; Department of Anesthesia, McMaster University, 1200 Main Street West, Hamilton, Ontario L8S 4K1, Canada; Prevention Lab and Systematic Overviews through advancing Research Technology (SORT), SickKids Research Institute, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada.
authors.forename: Shanil
authors.initials: S
authors.lastname: Ebrahim
authors.affiliation: Department of Trauma and Orthopaedics, University Health Network, 399 Bathurst Street, Toronto, Ontario M5T 2S8, Canada.
authors.forename: Luis
authors.initials: L
authors.lastname: Montoya
authors.affiliation: Department of Clinical Epidemiology & Biostatistics, McMaster University, 1200 Main Street West, Hamilton, Ontario L8S 4K1, Canada.
authors.forename: Mostafa
authors.initials: M
authors.lastname: Kamal El Din
authors.affiliation: Department of Clinical Epidemiology & Biostatistics, McMaster University, 1200 Main Street West, Hamilton, Ontario L8S 4K1, Canada; Population Genomics Program, Faculty of Health Sciences, McMaster University, 1200 Main Street West, Hamilton, Ontario L8S 4K1, Canada; Faculty of Medicine, 1 King's College Circle, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Zahra N
authors.initials: ZN
authors.lastname: Sohani
authors.affiliation: Faculty of Medicine, 1 King's College Circle, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Arnav
authors.initials: A
authors.lastname: Agarwal
authors.affiliation: Department of Applied Psychology and Human Development, Ontario Institute for Studies in Education, 252 Bloor Street West, Toronto, Ontario M5S 1V6, Canada.
authors.forename: Sheena
authors.initials: S
authors.lastname: Bance
authors.affiliation: Department of Family and Community Medicine, Qassim University, Buraydah, Saudi Arabia.
authors.forename: Juliann
authors.initials: J
authors.lastname: Saquib
authors.affiliation: College of Medicine, Sulaiman AlRajhi Colleges, Al Bukayriyah, Saudi Arabia.
authors.forename: Nazmus
authors.initials: N
authors.lastname: Saquib
authors.affiliation: Stanford Prevention Research Center, Department of Medicine, Stanford University, 1265 Welch Road, Stanford, CA 94305, USA; Meta-Research Innovation Center at Stanford (METRICS), School of Medicine, Stanford University, 1265 Welch Road, Stanford, CA 94305, USA; Department of Health Research and Policy, Stanford University School of Medicine, 150 Governor's Ln, Stanford, CA 94305, USA; Department of Statistics, Stanford University School of Humanities and Sciences, Building 1, Main Quad, Stanford, CA 94305, USA. Electronic address: jioannid@stanford.edu.
authors.forename: John P A
authors.initials: JP
authors.lastname: Ioannidis
mesh_terms: D006801:Humans; D010506:Periodicals as Topic / Q000706:statistics & numerical data*; D016032:Randomized Controlled Trials as Topic / Q000706:statistics & numerical data*
keywords: Clinical trial; Individual patient data; Multiplicity; Randomized controlled trial; Secondary findings; Secondary publications