title: Modified Regulatory Pathways to Approve Generic Drugs in the US and a Systematic Review of Their Outcomes.
abstract: BACKGROUND
  Generic drugs are approved on the basis of pharmaceutical equivalence and bioequivalence. Some drug products have unique structural or functional attributes, necessitating modified approaches to bioequivalence determinations.
  
  
  OBJECTIVE
  The aim of this systematic review was to identify studies that evaluated laboratory or clinical outcomes of six drugs approved via modified bioequivalence approaches.
  
  
  METHODS
  We conducted a systematic review of articles published through February 2014 in MEDLINE, EMBASE, and International Pharmaceutical Abstracts related to six recent drugs subject to modified regulatory approaches: venlafaxine extended release tablet (Effexor XR), acarbose (Precose), enoxaparin (Lovenox), vancomycin capsules (Vancocin), sodium ferric gluconate (Ferrlecit), and calcitonin salmon nasal spray (Miacalcin NS). We included all empirical evaluations (whether in vivo or in vitro) and excluded case studies, qualitative analyses, and pharmacoeconomic evaluations. Studies were summarized and evaluated on their methodological quality and assessed for bias using the Cochrane Risk of Bias Assessment Tool. Articles were divided into studies of US FDA-approved generics and non-FDA-approved generics available in non-US locations.
  
  
  METHODS
  We extracted drug(s) studied, study design, setting, sample size, population characteristics, study endpoints and results, and source of funding.
  
  
  RESULTS
  After retrieving 1408 articles and searching through the full text of 106 articles, we found 26 articles that met our inclusion criteria-8 examining FDA-approved versions and 18 examining non-FDA-approved versions. Among FDA-approved generics, five studies of enoxaparin showed minor variations in biologic activities of unclear clinical importance, and no publications involved acarbose, venlafaxine ER, or vancomycin capsules. Among non-FDA-approved generics, nine studies of enoxaparin supported generic bioequivalence, despite three showing minor variations in drug activity. Four of six studies of venlafaxine ER supported generic bioequivalence, while two found a lack of bioequivalence with a Canadian generic version of the drug. Most studies were either highly susceptible to bias (12/26) or were not able to be assessed for bias (13/26), in part because eight studies were abstracts/posters without full reports.
  
  
  CONCLUSIONS
  Pharmaceutical manufacturers sometimes raise scientific concerns related to potential generic versions of their drugs; however, in the six cases we reviewed, these companies did not follow up the pre-approval concerns they raised with any methodologically rigorous post-approval testing using clinical endpoints. Despite their pre-approval controversy, experience with these generic drugs provides reassurance of their clinical interchangeability. Systematized post-approval study of certain generic drug bioequivalence determinations is needed.
authors.affiliation: Program On Regulation, Therapeutics, And Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 1620 Tremont Street, Suite 3030, Boston, MA, 02120, USA, akesselheim@partners.org.
authors.forename: Aaron S
authors.initials: AS
authors.lastname: Kesselheim
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Polinski
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Fulchino
authors.forename: Danielle L
authors.initials: DL
authors.lastname: Isaman
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Gagne
mesh_terms: D017277:Drug Approval / Q000331:legislation & jurisprudence* / Q000379:methods*; D016568:Drugs, Generic; D006801:Humans; D013810:Therapeutic Equivalency; D016896:Treatment Outcome; D014481:United States; D014486:United States Food and Drug Administration / Q000331:legislation & jurisprudence
chemical_list: D016568:Drugs, Generic
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