title: Factors affecting the causality assessment of adverse events following immunisation in paediatric clinical trials: An online survey.
abstract: BACKGROUND
  Serious adverse events (SAEs) in clinical trials require reporting within 24h, including a judgment of whether the SAE was related to the investigational product(s). Such assessments are an important component of pharmacovigilance, however classification systems for assigning relatedness vary across study protocols. This on-line survey evaluated the consistency of SAE causality assessment among professionals with vaccine clinical trial experience.
  
  
  METHODS
  Members of the clinical advisory forum of experts (CAFÉ), a Brighton Collaboration online-forum, were emailed a survey containing SAEs from hypothetical vaccine trials which they were asked to classify. Participants were randomised to either two classification options (related/not related to study immunisation) or three options (possibly/probably/unrelated). The clinical scenarios, were (i) leukaemia diagnosed 5 months post-immunisation with a live RSV vaccine, (ii) juvenile idiopathic arthritis (JIA) 3 months post-immunisation with a group A streptococcal vaccine, (iii) developmental delay diagnosed at age 10 months after infant capsular group B meningococcal vaccine, (iv) developmental delay diagnosed at age 10 months after maternal immunisation with a group B streptococcal vaccine.
  
  
  RESULTS
  There were 140 respondents (72 two options, 68 three options). Across all respondents, SAEs were considered related to study immunisation by 28% (leukaemia), 74% (JIA), 29% (developmental delay after infant immunisation) and 42% (developmental delay after maternal immunisation). Having only two options made respondents significantly less likely to classify the SAE as immunisation-related for two scenarios (JIA p=0.0075; and maternal immunisation p=0.045). Amongst study investigators (n=43) this phenomenon was observed for three of the four scenarios: (JIA p=0.0236; developmental delay following infant immunisation p=0.0266; and developmental delay after maternal immunisation p=0.0495).
  
  
  CONCLUSIONS
  SAE causality assessment is inconsistent amongst study investigators and can be influenced by the classification systems available to them. There is a pressing need for SAE classification systems to be standardised across study protocols.
authors.affiliation: Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK; Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK. Electronic address: merryn.voysey@phc.ox.ac.uk.
authors.forename: Merryn
authors.initials: M
authors.lastname: Voysey
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK. Electronic address: rahele.tavana@gmail.com.
authors.forename: Rahele
authors.initials: R
authors.lastname: Tavana
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK. Electronic address: Yama.farooq@paediatrics.ox.ac.uk.
authors.forename: Yama
authors.initials: Y
authors.lastname: Farooq
authors.affiliation: Vaccine Institute, St George's, University of London, London, UK. Electronic address: pheath@sgul.ac.uk.
authors.forename: Paul T
authors.initials: PT
authors.lastname: Heath
authors.affiliation: Brighton Collaboration, Basel, Switzerland. Electronic address: j.bonhoeffer@brightoncollaboration.org.
authors.forename: Jan
authors.initials: J
authors.lastname: Bonhoeffer
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Trust, Oxford, UK. Electronic address: matthew.snape@paediatrics.ox.ac.uk.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Snape
mesh_terms: D016907:Adverse Drug Reaction Reporting Systems / Q000592:standards*; D015984:Causality; D002986:Clinical Trials as Topic; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology* / Q000209:etiology*; D004812:Epidemiologic Methods; D006801:Humans; D007114:Immunization / Q000009:adverse effects*; D011795:Surveys and Questionnaires
keywords: Causality; Clinical trial; Serious adverse event; Vaccine