title: Developing tools for the safety specification in risk management plans: lessons learned from a pilot project.
abstract: OBJECTIVE
  Following the adoption of the ICH E2E guideline, risk management plans (RMP) defining the cumulative safety experience and identifying limitations in safety information are now required for marketing authorisation applications (MAA). A collaborative research project was conducted to gain experience with tools for presenting and evaluating data in the safety specification. This paper presents those tools found to be useful and the lessons learned from their use.
  
  
  METHODS
  Archive data from a successful MAA were utilised. Methods were assessed for demonstrating the extent of clinical safety experience, evaluating the sensitivity of the clinical trial data to detect treatment differences and identifying safety signals from adverse event and laboratory data to define the extent of safety knowledge with the drug.
  
  
  RESULTS
  The extent of clinical safety experience was demonstrated by plots of patient exposure over time. Adverse event data were presented using dot plots, which display the percentages of patients with the events of interest, the odds ratio, and 95% confidence interval. Power and confidence interval plots were utilised for evaluating the sensitivity of the clinical database to detect treatment differences. Box and whisker plots were used to display laboratory data.
  
  
  CONCLUSIONS
  This project enabled us to identify new evidence-based methods for presenting and evaluating clinical safety data. These methods represent an advance in the way safety data from clinical trials can be analysed and presented. This project emphasises the importance of early and comprehensive planning of the safety package, including evaluation of the use of epidemiology data.
authors.affiliation: GlaxoSmithKline (GSK) Ltd, Greenford, Middlesex, UK. andrew.j.cooper@gsk.com
authors.forename: Andrew J P
authors.initials: AJ
authors.lastname: Cooper
authors.forename: Sally
authors.initials: S
authors.lastname: Lettis
authors.forename: Charlotte L
authors.initials: CL
authors.lastname: Chapman
authors.forename: Stephen J W
authors.initials: SJ
authors.lastname: Evans
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Waller
authors.forename: Saad
authors.initials: S
authors.lastname: Shakir
authors.forename: Nassrin
authors.initials: N
authors.lastname: Payvandi
authors.forename: Alison B
authors.initials: AB
authors.lastname: Murray
mesh_terms: D016907:Adverse Drug Reaction Reporting Systems / Q000458:organization & administration*; D016001:Confidence Intervals; D018849:Controlled Clinical Trials as Topic / Q000379:methods*; D003299:Cooperative Behavior; D003627:Data Interpretation, Statistical; D005062:European Union; D019317:Evidence-Based Medicine; D017408:Guidelines as Topic; D006801:Humans; D040541:Marketing / Q000331:legislation & jurisprudence / Q000379:methods*; D016017:Odds Ratio; D010865:Pilot Projects; D012308:Risk Management / Q000379:methods*; D013997:Time Factors