title: Effectiveness, safety and costs of orphan drugs: an evidence-based review.
abstract: BACKGROUND
  Several orphan drugs have been approved by the European Medicines Agency (EMA) over the past two decades. However, the drugs are expensive, and in some instances, the evidence for effectiveness is not convincing at the time of regulatory approval. Our objective was to evaluate the clinical effectiveness of orphan drugs that have been granted marketing licenses in Europe, determine the annual costs of each drug, compare the costs of branded orphan drugs against their generic equivalents, and explore any relationships between orphan drug disease prevalence and annual costs.
  
  
  METHODS
  We searched the EMA database to identify orphan drugs granted marketing authorisation up to April 2014. Electronic searches were also conducted in PubMed, EMBASE and Google Scholar, to assess data on effectiveness, safety and annual costs. 2 reviewers independently evaluated the levels and quality of evidence, and extracted data.
  
  
  RESULTS
  We identified 74 orphan drugs, with 54 (73%) demonstrating moderate quality of evidence. 85% showed significant clinical effects, but serious adverse events were reported in 86.5%. Their annual costs were between £726 and £378,000. There was a significant inverse relationship between disease prevalence and annual costs (p = 0.01); this was largely due to the influence of the ultra-orphan diseases. We could not determine whether the balance between effectiveness and safety influenced annual costs. For 10 drugs where generic alternatives were available, the branded drugs were 1.4 to 82,000 times more expensive.
  
  
  CONCLUSIONS
  The available evidence suggests that there is inconsistency in the quality of evidence of approved orphan drugs, and there is no clear mechanism for determining their prices. In some cases, far cheaper generic agents appear to be available. A more robust, transparent and standard mechanism for determining annual costs is imperative.
authors.affiliation: Nuffield Department of Primary Care Health Sciences, University of Oxford, Centre for Evidence-Based Medicine, Oxford, UK.
authors.forename: Igho J
authors.initials: IJ
authors.lastname: Onakpoya
authors.affiliation: Nuffield Department of Primary Care Health Sciences, University of Oxford, Centre for Evidence-Based Medicine, Oxford, UK.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Spencer
authors.affiliation: Department of Family Medicine, University of Washington, Seattle, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Thompson
authors.affiliation: Nuffield Department of Primary Care Health Sciences, University of Oxford, Centre for Evidence-Based Medicine, Oxford, UK.
authors.forename: Carl J
authors.initials: CJ
authors.lastname: Heneghan
mesh_terms: D000368:Aged; D017277:Drug Approval / Q000191:economics / Q000379:methods / Q000706:statistics & numerical data; D005060:Europe; D019317:Evidence-Based Medicine; D005260:Female; D006801:Humans; D008297:Male; D009965:Orphan Drug Production / Q000191:economics* / Q000706:statistics & numerical data*; D016896:Treatment Outcome
keywords: GENERAL MEDICINE (see Internal Medicine); ORPHAN DRUGS; PRIMARY CARE