Randomized trials are frequently fragmented in multiple secondary publications

J Clin Epidemiol. 2016 Nov;79:130-139. doi: 10.1016/j.jclinepi.2016.05.016. Epub 2016 Jul 5.


Objective: To assess the frequency and features of secondary publications of randomized controlled trials (RCTs).

Study design and setting: 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.

Results: 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.

Conclusions: 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.

Keywords: Clinical trial; Individual patient data; Multiplicity; Randomized controlled trial; Secondary findings; Secondary publications.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Humans
  • Periodicals as Topic / statistics & numerical data*
  • Randomized Controlled Trials as Topic / statistics & numerical data*