title: Fixed-Dose Combination Drug Approvals, Patents and Market Exclusivities Compared to Single Active Ingredient Pharmaceuticals.
abstract: BACKGROUND
  Fixed-dose combinations (FDC) contain two or more active ingredients. The effective patent and exclusivity life of FDC compared to single active ingredient has not been assessed.
  
  
  OBJECTIVE
  Trends in FDA approved FDC in the period 1980-2012 and time lag between approval of FDC and single active ingredients in the combination were assessed, and the effective patent and exclusivity life of FDC was compared with their single active ingredients.
  
  
  METHODS
  New molecular entities (NMEs), new therapeutic biologics license applications (BLAs) and FDC data were collected from the FDA Orange Book and Drugs@FDA. Analysis included FDC containing one or more NMEs or BLAs at first FDA approval (NMEs-FDC) and only already marketed drugs (Non-NMEs-FDC). Descriptive, Kruskal-Wallis and Wilcoxon Rank Sum analyses were performed.
  
  
  RESULTS
  During the study period, the FDA approved 28 NMEs-FDC (3.5% of NMEs) and 117 non-NMEs-FDC. FDC approvals increased from 12 in the 1980s to 59 in the 2000s. Non-NMEs-FDC entered the market at a median of 5.43 years (interquartile range 1.74, 10.31) after first FDA approval of single active ingredients in the combination. The Non-NMEs-FDC entered the market at a median of 2.33 years (-7.55, 2.39) before approval of generic single active ingredient. Non-NME-FDC added a median of 9.70 (2.75, 16.24) years to the patent and exclusivity life of the single active ingredients in the combination.
  
  
  CONCLUSIONS
  FDC approvals significantly increased over the last twenty years. Pharmaceutical companies market FDC drugs shortly before the generic versions of the single ingredients enter the market extending the patent and exclusivity life of drugs included in the combination.
authors.affiliation: School of Public Health and Health Sciences, University of Massachusetts, Amherst, Massachusetts, United States of America, 01003.
authors.forename: Jing
authors.initials: J
authors.lastname: Hao
authors.affiliation: School of Public Health and Health Sciences, University of Massachusetts, Amherst, Massachusetts, United States of America, 01003.
authors.forename: Rosa
authors.initials: R
authors.lastname: Rodriguez-Monguio
authors.affiliation: Massachusetts College of Pharmacy and Health Sciences, Boston, Massachusetts, United States of America, 02115; Brigham and Women's Hospital, Division of General Medicine and Primary Care, Boston, Massachusetts, United States of America.
authors.forename: Enrique
authors.initials: E
authors.lastname: Seoane-Vazquez
mesh_terms: D017277:Drug Approval / Q000191:economics / Q000706:statistics & numerical data*; D004338:Drug Combinations; D004339:Drug Compounding / Q000191:economics / Q000379:methods / Q000706:statistics & numerical data; D016568:Drugs, Generic / Q000191:economics / Q000600:supply & distribution; D005252:Fees, Pharmaceutical / Q000706:statistics & numerical data; D006801:Humans; D040541:Marketing / Q000379:methods / Q000706:statistics & numerical data*; D010330:Patents as Topic / Q000706:statistics & numerical data*; D013997:Time Factors; D014481:United States; D014486:United States Food and Drug Administration / Q000706:statistics & numerical data / Q000639:trends
chemical_list: D004338:Drug Combinations; D016568:Drugs, Generic