title: The detection of adverse events in randomized clinical trials: can we really say new medicines are safe?
abstract: BACKGROUND
  While it is well known that randomized controlled trials (RCTs) are usually designed with sufficient sample size and power to detect the efficacy but not safety of a medicine, the extent to which RCTs quantify safety has not been well ascertained.
  
  
  OBJECTIVE
  The aim of this study was to assess the safety data available for five commonly prescribed medicines at the time of marketing.
  
  
  METHODS
  Published RCTs for five medicines risperidone, sertraline, donepezil, strontium ranelate and tramadol extended release were identified. All adverse events (AEs) in the trials were independently extracted by two clinical researchers. Using the sample size in the trials, the power to detect the observed difference in AEs rates between the treatment and placebo groups was calculated. A power of 80% or more was deemed adequate to detect AEs; studies with power of < 80% were deemed insufficiently powered to detect AEs.
  
  
  RESULTS
  12 RCTs were identified. Six trials were insufficiently powered to detect any of the potential AEs reported. Of the 150 evaluated AEs, the trials were insufficiently powered to detect 81% (122/150) of the AEs reported. For the adverse events that were detected with adequate powered clinical trials, only 53% (10/19) of potentially very common AEs (≥10%) and 17% (18/106) of potentially common AEs (1%-<10%) were identified.
  
  
  CONCLUSIONS
  Trials are insufficiently powered to detect the majority of adverse events that are reported in clinical trials, even for common adverse events. Observations other than primary efficacy endpoints such as AEs that are not prespecified with adequate power should be treated as hypothesis generating only and not justification of evidence. Claims of safety based on trial evidence not designed for the safety endpoint are often premature.
authors.affiliation: School of Pharmacy and Medical Sciences, Quality Use of Medicines and Pharmacy Research Centre, Sansom Institute, University of South Australia, GPO Box 2471, Adelaide 5001, South Australia, Australia. ayyiy001@mymail.unisa.edu.au
authors.forename: Izyan A
authors.initials: IA
authors.lastname: Wahab
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Pratt
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Kalisch
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Roughead
mesh_terms: D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology*; D023381:Endpoint Determination; D006801:Humans; D016032:Randomized Controlled Trials as Topic / Q000379:methods*; D012107:Research Design; D018401:Sample Size