title: Methods of defining the non-inferiority margin in randomized, double-blind controlled trials: a systematic review.
abstract: There is no consensus on the preferred method for defining the non-inferiority margin in non-inferiority trials, and previous studies showed that the rationale for its choice is often not reported. This study investigated how the non-inferiority margin is defined in the published literature, and whether its reporting has changed over time.
  
  
  
  A systematic PubMed search was conducted for all published randomized, double-blind, non-inferiority trials from January 1, 1966, to February 6, 2015. The primary outcome was the number of margins that were defined by methods other than the historical evidence of the active comparator. This was evaluated for a time trend. We also assessed the under-reporting of the methods of defining the margin as a secondary outcome, and whether this changed over time. Both outcomes were analyzed using a Poisson log-linear model. Predictors for better reporting of the methods, and the use of the fixed-margin method (one of the historical evidence methods) were also analyzed using logistic regression.
  
  
  
  Two hundred seventy-three articles were included, which account for 273 non-inferiority margins. There was no statistically significant difference in the number of margins that were defined by other methods compared to those defined based on the historical evidence (ratio 2.17, 95% CI 0.86 to 5.82, p = 0.11), and this did not change over time. The number of margins for which methods were unreported was similar to those with reported methods (ratio 1.35, 95% CI 0.76 to 2.43, p = 0.31), with no change over time. The method of defining the margin was less often reported in journals with low-impact factors compared to journals with high-impact factors (OR 0.20; 95% CI 0.10 to 0.37, p < 0.0001). The publication of the FDA draft guidance in 2010 was associated with increased reporting of the fixed-margin method (after versus before 2010) (OR 3.54; 95% CI 1.12 to 13.35, p = 0.04).
  
  
  
  Non-inferiority margins are not commonly defined based on the historical evidence of the active comparator, and they are poorly reported. Authors, reviewers, and editors need to take notice of reporting this critical information to allow for better judgment of non-inferiority trials.
authors.affiliation: Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Utrecht University, PO Box 80082, 3408 TB, Utrecht, The Netherlands.
authors.forename: Turki A
authors.initials: TA
authors.lastname: Althunian
authors.affiliation: Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Utrecht University, PO Box 80082, 3408 TB, Utrecht, The Netherlands.
authors.forename: Anthonius
authors.initials: A
authors.lastname: de Boer
authors.affiliation: Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Utrecht University, PO Box 80082, 3408 TB, Utrecht, The Netherlands.|Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Huispost Str. 6.131, 3508 GA, Utrecht, The Netherlands.
authors.forename: Olaf H
authors.initials: OH
authors.lastname: Klungel
authors.affiliation: Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Utrecht University, PO Box 80082, 3408 TB, Utrecht, The Netherlands.
authors.forename: Widya N
authors.initials: WN
authors.lastname: Insani
authors.affiliation: Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Utrecht University, PO Box 80082, 3408 TB, Utrecht, The Netherlands. R.H.H.Groenwold@umcutrecht.nl.|Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Huispost Str. 6.131, 3508 GA, Utrecht, The Netherlands. R.H.H.Groenwold@umcutrecht.nl.
authors.forename: Rolf H H
authors.initials: RH
authors.lastname: Groenwold
mesh_terms: D003627:Data Interpretation, Statistical; D004311:Double-Blind Method; D000074099:Equivalence Trials as Topic; D006801:Humans; D015233:Models, Statistical; D016032:Randomized Controlled Trials as Topic / Q000379:methods* / Q000706:statistics & numerical data; D012107:Research Design / Q000706:statistics & numerical data
keywords: Drug regulation; Methodology; Non-inferiority margin; Non-inferiority trials