title: The prevalence and cost of unapproved uses of top-selling orphan drugs.
abstract: BACKGROUND
  The Orphan Drug Act encourages drug development for rare conditions. However, some orphan drugs become top sellers for unclear reasons. We sought to evaluate the extent and cost of approved and unapproved uses of orphan drugs with the highest unit sales.
  
  
  METHODS
  We assessed prescription patterns for four top-selling orphan drugs: lidocaine patch (Lidoderm) approved for post-herpetic neuralgia, modafinil (Provigil) approved for narcolepsy, cinacalcet (Sensipar) approved for hypercalcemia of parathyroid carcinoma, and imatinib (Gleevec) approved for chronic myelogenous leukemia and gastrointestinal stromal tumor. We pooled patient-specific diagnosis and prescription data from two large US state pharmaceutical benefit programs for the elderly. We analyzed the number of new and total patients using each drug and patterns of reimbursement for approved and unapproved uses. For lidocaine patch, we subcategorized approved prescriptions into two subtypes of unapproved uses: neuropathic pain, for which some evidence of efficacy exists, and non-neuropathic pain.
  
  
  RESULTS
  We found that prescriptions for lidocaine patch, modafinil, and cinacalcet associated with non-orphan diagnoses rose at substantially higher rates (average monthly increases in number of patients of 14.6, 1.45, and 1.58) than prescriptions associated with their orphan diagnoses (3.12, 0.24, and 0.03, respectively (p<0.001 for all)). By contrast, for imatinib, approved uses increased significantly over off-label (0.97 vs. 0.47 patients, p<0.001). Spending on off-label uses was highest for lidocaine patch and modafinil (>75%). Increases in lidocaine patch use for non-neuropathic pain far exceeded neuropathic pain (10.2 vs. 3.6 patients, p<0.001).
  
  
  CONCLUSIONS
  In our sample, three of four top-selling orphan drugs were used more commonly for non-orphan indications. These orphan drugs treated common clinical symptoms (pain and fatigue) or laboratory abnormalities. We should continue to monitor orphan drug use after approval to identify products that come to be widely used for non-FDA approved indications, particularly those without adequate evidence of efficacy.
authors.affiliation: Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America. akesselheim@partners.org
authors.forename: Aaron S
authors.initials: AS
authors.lastname: Kesselheim
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Myers
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Solomon
authors.forename: Wolfgang C
authors.initials: WC
authors.lastname: Winkelmayer
authors.forename: Raisa
authors.initials: R
authors.lastname: Levin
authors.forename: Jerry
authors.initials: J
authors.lastname: Avorn
mesh_terms: D001559:Benzhydryl Compounds / Q000191:economics / Q000494:pharmacology; D000069449:Cinacalcet; D003365:Costs and Cost Analysis; D017277:Drug Approval / Q000706:statistics & numerical data; D006801:Humans; D008012:Lidocaine / Q000191:economics / Q000494:pharmacology / Q000627:therapeutic use; D000077408:Modafinil; D009281:Naphthalenes / Q000191:economics / Q000494:pharmacology; D009437:Neuralgia / Q000188:drug therapy; D056687:Off-Label Use / Q000191:economics* / Q000706:statistics & numerical data; D009965:Orphan Drug Production / Q000191:economics* / Q000706:statistics & numerical data; D055553:Prescription Drugs / Q000191:economics; D011634:Public Health; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D001559:Benzhydryl Compounds; D009281:Naphthalenes; D055553:Prescription Drugs; D008012:Lidocaine; D000077408:Modafinil; D000069449:Cinacalcet