title: Evaluating the Feasibility of Use of a Foreign Reference Product for Generic Drug Applications: A Retrospective Pilot Study.
abstract: OBJECTIVE
  The adoption of a domestic reference product in bioequivalence (BE) studies for generic drug applications is required by some countries. The objective of this study is to assess the feasibility of this by investigating whether innovative products from different countries are bioequivalent.
  
  
  METHODS
  Data were collected from all generic drug applications received by the Taiwan regulatory authority 2012-2016. If a submission package contained BE studies, that generic product was compared separately with different reference products, and the resulting data included in this analysis. A method of adjusted indirect comparison was used to evaluate the BE of reference products from different sources. The relationship between in vitro dissolution and in vivo BE was also explored.
  
  
  RESULTS
  The present study included 10 drugs and a total of 11 comparisons. Seven comparisons for maximum concentration (Cmax) (63.6%) and all comparisons (100.0%) for area under the curve up to last measurable time point (AUC) complied with the BE criterion. Similar in vitro dissolution profiles were observed in all comparisons. Among the comparisons that failed to demonstrate BE, only one was considered to be possibly related to product difference, with point estimates of indirect comparison for Cmaxsignificantly greater than unity (22%). Discordance between in vitro and in vivo observations was probably due to either drugs with highly variable properties or a lack of discriminatory dissolution testing method.
  
  
  CONCLUSIONS
  Although this retrospective analysis only included a few drugs and product formulation types, i.e., immediate release, delayed release, and orally disintegrating tablet, these preliminary results suggest that using a foreign reference product in BE studies for generic drug applications could be a feasible approach, but with some restrictions: comparable dissolution profiles, same innovator company, same size, weight, and type of coating as the domestic reference product, etc. Further investigations for other complex formulations are required.
authors.affiliation: Division of Pharmaceutical Science, Center for Drug Evaluation (CDE), 3F, No.465, Sec.6, Zhongxiao E. Rd., Taipei, 11557, Taiwan.
authors.forename: Yi-Lin
authors.initials: YL
authors.lastname: Wang
authors.affiliation: Division of Pharmaceutical Science, Center for Drug Evaluation (CDE), 3F, No.465, Sec.6, Zhongxiao E. Rd., Taipei, 11557, Taiwan. Lfhsu@cde.org.tw.
authors.forename: Li-Feng
authors.initials: LF
authors.lastname: Hsu
mesh_terms: D065546:Drug Liberation; D016568:Drugs, Generic / Q000493:pharmacokinetics* / Q000592:standards*; D006801:Humans; D010865:Pilot Projects; D012015:Reference Standards; D012189:Retrospective Studies; D013810:Therapeutic Equivalency
chemical_list: D016568:Drugs, Generic