title: Comparing vaccines: a systematic review of the use of the non-inferiority margin in vaccine trials.
abstract: BACKGROUND
  Non-inferiority (NI) randomized controlled trials (RCTs) aim to demonstrate that a new treatment is no worse than a comparator that has already shown its efficacy over placebo within a pre-specified margin. However, clear guidelines on how the NI margin should be determined are lacking for vaccine trials. A difference (seroprevalence/risk) of 10% or a geometric mean titre/concentration (GMT) ratio of 1.5 or 2.0 in antibody levels is implicitly recommended for vaccine trials. We aimed to explore which NI margins were used in vaccine RCTs and how they were determined.
  
  
  METHODS
  A systematic search for NI vaccine RCTs yielded 177 eligible articles. Data were extracted from these articles using a standardized form and included general characteristics and characteristics specific for NI trials. Relations between the study characteristics and the NI margin used were explored.
  
  
  RESULTS
  Among the 143 studies using an NI margin based on difference (n=136 on immunogenicity, n=2 on efficacy and n=5 on safety), 66% used a margin of 10%, 23% used margins lower than 10% (range 1-7.5%) and 11% used margins larger than 10% (range 11.5-25%). Of the 103 studies using a NI margin based on the GMT ratio, 50% used a margin of 0.67/1.5 and 49% used 0.5/2.0. As observed, 85% of the studies did not discuss the method of margin determination; and 19% of the studies lacked a confidence interval or p-value for non-inferiority.
  
  
  CONCLUSIONS
  Most NI vaccine RCTs used an NI margin of 10% for difference or a GMT ratio of 1.5 or 2.0 without a clear rationale. Most articles presented enough information for the reader to make a judgement about the NI margin used and the conclusions. The reporting on the design, margins used and results of NI vaccine trials could be improved; more explicit guidelines may help to achieve this end.
authors: Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands; Department of Pathology, VU University Medical Centre (VUmc), Amsterdam, The Netherlands. Electronic address: robine.donken@rivm.nl.
authors: R
authors: R
authors: Donken
authors: Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
authors: H E
authors: HE
authors: de Melker
authors: Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
authors: N Y
authors: NY
authors: Rots
authors: Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
authors: G
authors: G
authors: Berbers
authors: Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
authors: M J
authors: MJ
authors: Knol
mesh_terms: D006801:Humans; D016032:Randomized Controlled Trials as Topic / Q000706:statistics & numerical data*; D016036:Seroepidemiologic Studies; D014612:Vaccines
chemical_list: D014612:Vaccines
keywords: Non-inferiority margin; Trials; Vaccine