title: Implementation of a reference-scaled average bioequivalence approach for highly variable generic drug products by the US Food and Drug Administration.
abstract: Highly variable (HV) drugs are defined as those for which within-subject variability (%CV) in bioequivalence (BE) measures is 30% or greater. Because of this high variability, studies designed to show whether generic HV drugs are bioequivalent to their corresponding HV reference drugs may need to enroll large numbers of subjects even when the products have no significant mean differences. To avoid unnecessary human testing, the US Food and Drug Administration's Office of Generic Drugs developed a reference-scaled average bioequivalence (RSABE) approach, whereby the BE acceptance limits are scaled to the variability of the reference product. For an acceptable RSABE study, an HV generic drug product must meet the scaled BE limit and a point estimate constraint. The approach has been implemented successfully. To date, the RSABE approach has supported four full approvals and one tentative approval of HV generic drug products.
authors.affiliation: Office of Generic Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, 7520 Standish Place, Metro Park North One, Rockville, Maryland 20855, USA. barbara.davit@fda.hhs.gov
authors.forename: Barbara M
authors.initials: BM
authors.lastname: Davit
authors.forename: Mei-Ling
authors.initials: ML
authors.lastname: Chen
authors.forename: Dale P
authors.initials: DP
authors.lastname: Conner
authors.forename: Sam H
authors.initials: SH
authors.lastname: Haidar
authors.forename: Stephanie
authors.initials: S
authors.lastname: Kim
authors.forename: Christina H
authors.initials: CH
authors.lastname: Lee
authors.forename: Robert A
authors.initials: RA
authors.lastname: Lionberger
authors.forename: Fairouz T
authors.initials: FT
authors.lastname: Makhlouf
authors.forename: Patrick E
authors.initials: PE
authors.lastname: Nwakama
authors.forename: Devvrat T
authors.initials: DT
authors.lastname: Patel
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Schuirmann
authors.forename: Lawrence X
authors.initials: LX
authors.lastname: Yu
mesh_terms: D017277:Drug Approval / Q000379:methods*; D016568:Drugs, Generic / Q000493:pharmacokinetics* / Q000592:standards; D006801:Humans; D004364:Pharmaceutical Preparations / Q000378:metabolism* / Q000592:standards; D013810:Therapeutic Equivalency; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D016568:Drugs, Generic; D004364:Pharmaceutical Preparations