title: Safety-related regulatory actions for orphan drugs in the US and EU: a cohort study.
abstract: BACKGROUND
  Drugs for rare diseases, so-called orphan drugs, are often intended for serious or chronically debilitating diseases. Safety information is more limited at the time of approval for orphan drugs as a result of various factors, such as the limited number of patients in clinical trials, quality of the clinical trials and special approval procedures. Several studies have been conducted on safety-related regulatory actions for drugs, but none of these have specifically focused on orphan drugs.
  
  
  OBJECTIVE
  To determine the frequency and nature of safety-related regulatory actions for orphan drugs in the US and EU.
  
  
  METHODS
  This cohort study examined publicly available data from the websites of US and EU regulatory authorities on orphan drugs approved in the US and/or the EU between January 2000 and December 2007. The main outcome measures were the nature, frequency and timing of safety-related regulatory actions, defined as (i) safety withdrawals; (ii) 'black-box' warnings; and (iii) written communications to healthcare professionals issued by the US FDA or the European Medicines Agency between January 2000 and June 2008.
  
  
  RESULTS
  Ninety-five orphan drugs were approved during the study period (75 in the US, 44 in the EU, and 24 in both regions). Ten products (10.5%) received a safety-related regulatory action. No safety withdrawals, four black-box warnings and 12 written communications were identified. The probability of a first safety-related regulatory action for orphan drugs was 20.3% after 8 years of follow-up. Orphan drugs approved by accelerated approval (relative risk [RR] 3.32; 95% CI 1.06, 10.42), oncological products (RR 7.83; 95% CI 0.96, 63.82) and products for gastrointestinal and metabolism indications (RR 10.44; 95% CI 1.25, 87.27) may have a higher risk for a safety-related regulatory action.
  
  
  CONCLUSIONS
  The probability of a first safety-related regulatory action for an orphan drug was slightly lower than that reported in the literature for biologicals in one study and new molecular entities in another study. However, detection of safety issues may be complicated by the limited experience with orphan drugs in practical use due to the low prevalences of the diseases they are used for. Doctors and pharmacists should therefore be vigilant with regard to the occurrence of a safety-related issue for orphan drugs.
authors.affiliation: Division of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3508 TB Utrecht, the Netherlands.
authors.forename: Harald E
authors.initials: HE
authors.lastname: Heemstra
authors.forename: Thijs J
authors.initials: TJ
authors.lastname: Giezen
authors.forename: Aukje K
authors.initials: AK
authors.lastname: Mantel-Teeuwisse
authors.forename: Remco L A
authors.initials: RL
authors.lastname: de Vrueh
authors.forename: Hubert G M
authors.initials: HG
authors.lastname: Leufkens
mesh_terms: D016907:Adverse Drug Reaction Reporting Systems; D015331:Cohort Studies; D017277:Drug Approval; D004348:Drug Labeling; D005062:European Union; D006801:Humans; D007880:Legislation, Drug; D009965:Orphan Drug Production; D014481:United States