title: A cohort study exploring determinants of safety-related regulatory actions for biopharmaceuticals.
abstract: BACKGROUND
  The characteristics of biopharmaceuticals may require a tailored approach to their safety management. However, information on what tools and methods are employed to assess the safety of biopharmaceuticals post-authorization is lacking.
  
  
  OBJECTIVE
  This study investigates determinants that contribute to the post-authorization management of biopharmaceuticals.
  
  
  METHODS
  A cohort study was performed including all centrally approved biopharmaceuticals for which a Direct Healthcare Professional Communication (DHPC) was issued during 1997-2009. Safety-related regulatory actions were defined as updates of the summary of product characteristics through type II variations. Determinants of these actions were identified based on publicly available data. Urgent variations, defined as variations accompanied by a DHPC, were compared with other, 'non-urgent', safety-related variations.
  
  
  RESULTS
  We identified 133 variations relating to 15 products, 24 urgent and 109 other variations. For 55% of urgent variations, spontaneous reports were the sole source of regulatory action, post-approval studies accounted for 33%, and 12% were based on other sources or combinations of sources. For the non-urgent variations, spontaneous reports were the sole source for 36%, post-approval studies for 28%, and 36% were based on other sources or combinations. Overall, most variations included safety issues categorized as 'infections and infestations' (33.1%), 'general disorders and administration site conditions' (25.6%), and 'neoplasms' (14.3%).
  
  
  CONCLUSIONS
  Determinants of urgent and non-urgent safety-related regulatory actions of biopharmaceuticals are largely similar. Spontaneous reports are an important pillar for both urgent and non-urgent actions and remain an important tool in the post-authorization safety management of biopharmaceuticals.
authors.affiliation: Utrecht Institute for Pharmaceutical Sciences-UIPS, Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, the Netherlands.
authors.forename: Hans C
authors.initials: HC
authors.lastname: Ebbers
authors.forename: Aukje K
authors.initials: AK
authors.lastname: Mantel-Teeuwisse
authors.forename: Ellen H M
authors.initials: EH
authors.lastname: Moors
authors.forename: Fakhredin A
authors.initials: FA
authors.lastname: Sayed Tabatabaei
authors.forename: Huub
authors.initials: H
authors.lastname: Schellekens
authors.forename: Hubert G M
authors.initials: HG
authors.lastname: Leufkens
mesh_terms: D016907:Adverse Drug Reaction Reporting Systems / Q000331:legislation & jurisprudence / Q000592:standards*; D001688:Biological Products / Q000009:adverse effects*; D015331:Cohort Studies; D005062:European Union; D006801:Humans; D016032:Randomized Controlled Trials as Topic; D012189:Retrospective Studies; D012306:Risk
chemical_list: D001688:Biological Products