title: Highly variable drugs: observations from bioequivalence data submitted to the FDA for new generic drug applications.
abstract: BACKGROUND
  It is widely believed that acceptable bioequivalence studies of drugs with high within-subject pharmacokinetic variability must enroll higher numbers of subjects than studies of drugs with lower variability. We studied the scope of this issue within US generic drug regulatory submissions.
  
  
  METHODS
  We collected data from all in vivo bioequivalence studies reviewed at FDA's Office of Generic Drugs (OGD) from 2003-2005. We used the ANOVA root mean square error (RMSE) from bioequivalence statistical analyses to estimate within-subject variability. A drug was considered highly variable if its RMSE for C (max) and/or AUC was > or =0.3. To identify factors contributing to high variability, we evaluated drug substance pharmacokinetic characteristics and drug product dissolution performance.
  
  
  CONCLUSIONS
  In 2003-2005, the OGD reviewed 1,010 acceptable bioequivalence studies of 180 different drugs, of which 31% (57/180) were highly variable. Of these highly variable drugs, 51%, 10%, and 39% were either consistently, borderline, or inconsistently highly variable, respectively. We observed that most of the consistent and borderline highly variable drugs underwent extensive first pass metabolism. Drug product dissolution variability was high for about half of the inconsistently highly variable drugs. We could not identify factors causing variability for the other half. Studies of highly variable drugs generally used more subjects than studies of lower variability drugs.
  
  
  CONCLUSIONS
  About 60% of the highly variable drugs we surveyed were highly variable due to drug substance pharmacokinetic characteristics. For about 20% of the highly variable drugs, it appeared that formulation performance contributed to the high variability.
authors.affiliation: US Food and Drug Administration, Center for Drug Evaluation and Research, Office of Generic Drugs, 7520 Standish Place, Rockville, Maryland 20855, USA. barbara.davit@fda.hhs.gov
authors.forename: Barbara M
authors.initials: BM
authors.lastname: Davit
authors.forename: Dale P
authors.initials: DP
authors.lastname: Conner
authors.forename: Beth
authors.initials: B
authors.lastname: Fabian-Fritsch
authors.forename: Sam H
authors.initials: SH
authors.lastname: Haidar
authors.forename: Xiaojian
authors.initials: X
authors.lastname: Jiang
authors.forename: Devvrat T
authors.initials: DT
authors.lastname: Patel
authors.forename: Paul R H
authors.initials: PR
authors.lastname: Seo
authors.forename: Keri
authors.initials: K
authors.lastname: Suh
authors.forename: Christina L
authors.initials: CL
authors.lastname: Thompson
authors.forename: Lawrence X
authors.initials: LX
authors.lastname: Yu
mesh_terms: D002986:Clinical Trials as Topic / Q000379:methods / Q000592:standards; D017277:Drug Approval / Q000379:methods*; D016568:Drugs, Generic / Q000493:pharmacokinetics* / Q000592:standards*; D006801:Humans; D013810:Therapeutic Equivalency; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D016568:Drugs, Generic