title: Randomized controlled trials for influenza drugs and vaccines: a review of controlled human infection studies.
abstract: OBJECTIVE
  Controlled human infection, the intentional infection of healthy volunteers, allows disease pathogenesis to be studied and vaccines and therapeutic interventions to be evaluated in a controlled setting. A systematic review of randomized controlled trials of countermeasures for influenza that used the experimental human infection platform was performed. The primary objective was to document the scope of trials performed to date and the main efficacy outcome in the trials. The secondary objective was to assess safety and identify serious adverse events.
  
  
  METHODS
  The PubMed database was searched for randomized controlled influenza human challenge studies with predetermined search terms. Review papers, papers without outcomes, community-acquired infections, duplicated data, pathogenesis studies, and observational studies were excluded.
  
  
  RESULTS
  Twenty-six randomized controlled trials published between 1947 and 2014 fit the study inclusion criteria. Two-thirds of these trials investigated antivirals and one-third investigated influenza vaccines. Among 2462 subjects inoculated with influenza virus, the incidence of serious adverse events was low (0.04%). These challenge studies helped to down-select three antivirals and one vaccine that were subsequently approved by the US Food and Drug Administration (FDA).
  
  
  CONCLUSIONS
  Controlled human infection studies are an important research tool in assessing promising influenza vaccines and antivirals. These studies are performed quickly and are cost-effective and safe, with a low incidence of serious adverse events.
authors.affiliation: Lee Kong Chian School of Medicine, Nanyang Technology University, Singapore 308232, Singapore. Electronic address: sbalasingam@ntu.edu.sg.
authors.forename: Shobana
authors.initials: S
authors.lastname: Balasingam
authors.affiliation: Lee Kong Chian School of Medicine, Nanyang Technology University, Singapore 308232, Singapore.
authors.forename: Annelies
authors.initials: A
authors.lastname: Wilder-Smith
mesh_terms: D000998:Antiviral Agents / Q000008:administration & dosage*; D006801:Humans; D007252:Influenza Vaccines / Q000008:administration & dosage* / Q000276:immunology; D007251:Influenza, Human / Q000188:drug therapy / Q000276:immunology / Q000517:prevention & control*; D016032:Randomized Controlled Trials as Topic; D012107:Research Design
chemical_list: D000998:Antiviral Agents; D007252:Influenza Vaccines
keywords: Challenge studies; Controlled human infection; Influenza; Influenza therapeutics; Influenza vaccine; Randomized controlled trials