In recent years, as more generic drug products became available, the quality, safety, and efficacy of generic drugs became a great concern. As a result, the assessment of bioequivalence between the generic drug products and the innovator product has become an important topic in drug development. This paper provides an overview of current regulatory requirements and unresolved scientific issues in the assessment of bioequivalence. These issues include three key statistical issues raised in the 1992 Food and Drug Administration (FDA) guidance, alternative decision rules and pharmacokinetic parameters, the use of female subjects, intrasubject variability and drug interchangeability, population and individual bioequivalence, in vitro dissolution as a surrogate for in vivo bioequivalence, pharmacodynamic measures, postapproval bioequivalence assessment, and international harmonization for bioequivalence requirements.
ChowSCLiuJP. Design and Analysis of Bioavailability and Bioequivalence Studies. New York: Marcel Dekker Inc.; 1992.
2.
FDA.Guidance on Statistical Procedures for Bioequivalence Studies Using a Standard Two-Treatment Crossover Design. Division of Bioequivalence, Office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, Maryland; 1992.
3.
ChowSCLiuJP. Recent statistical developments in bioequivalence trials—a review of the FDA guidance. Drug Inf J.1994;28:851–864.
4.
ChowSCLiuJP. On assessment of bioequivalence under a higher-order crossover design. J Biopharm Stat.1992;2:239–256.
5.
JonesBKenwardMG. Design and Analysis of Cross-over Trials. New York and London; Chapman and Hall: 1989.
6.
LundRE. Tables for an approximate test outliers in linear models. Technometrics.1975;17:473–476.
7.
ChowSCTseSK. Outlier detection in bioavailability/bioequivalence studies. Stat Med.1990;9: 549–558.
8.
LiuJPWengCS. Detection of outlying data in bioavailability/bioequivalence studies. Stat Med.1991;10:1357–1389.
9.
KiFLiuJPWangWChowSC. The impact of outlying subjects on decision in bioequivalence. J Biopharm Stat.1995;5:171–193.
10.
PurichE.Bioavailability/bioequivalency Regulation: An FDA Perspective in Drug Absorption and Disposition: Statistical Considerations. AlbertKS, ed. American Pharmaceutical Association, Academy of Pharmaceutical Sciences, Washington, DC: 115–137.
11.
BTF. Report by the Bioequivalence Task Force on Recommendation from the Bioequivalence Hearing Conducted by the FDA, January 1990.
12.
EndrenyiLFritschSYanW.Cmax/AUC is a clearer measure than Cmax for absorption rates in investigations of bioequivalence. Int J Clin Pharmacol Ther Toxicol.1991;29:394–399.
ChenML. An alternative approach for assessment of rate of absorption in bioequivalence studies. Pharm Res.1992;9:1380–1385.
15.
HwangE.Testing for individual and population bioequivalence of two treatments based on the proportion of similar responses. Presented at a meeting on Bioequivalence Issues in Pharmaceutical Research at Rhône-Poulenc Rorer Central Research, October 12, Collegeville, PA.
16.
FDA.Guideline for General Considerations for the Clinical Evaluation of Drugs. Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, Maryland; 1977.
17.
FDA.Guideline for the Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs. Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, Maryland; 1993.
18.
NIH.NIH Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical Research. Federal Register. (59 FR 14508-14513), March 28, 1994.
19.
MetzlerCMHuangDC. Statistical methods for bioavailability and bioequivalence. Clin Res Pract Drug Reg Affairs.1983;1:109–132.
20.
LiuJP. Bioequivalence and instrasubject variability variability. J Biopharm Stat.1991;2:205–219.
21.
HauckWWAndersonS.Types of bioequivalence and related statistical considerations. Int J Clin Pharmacol Ther Toxicol.1992;3:181–187.
22.
LiuJPChowSC. On the assessment of variability in bioavailability/bioequivalence studies. Comm Stat-Theory Methods.1992;21:2591–2608.
23.
LiuJP. Use of the repeated crossover designs in assessing bioequivalence. Stat. Med.1995; 14.
24.
AndersonSHauckWW. Considerations of individual bioequivalence. J Pharmacokin Biopharm.1990;8:259–273.
25.
EsinhartJDChinchilliVM. Extension to the use of tolerance intervals for assessment of individual bioequivalence. J Biopharm Stat.1994;4:39–52.
26.
SheinerLB. Bioequivalence revisited. Stat Med.1992;11:1777–1788.
27.
SchallRLuusRE. On population and individual bioequivalence. Stat Med.1993;12:1109–1124.
28.
HolderDJHsuanF.Moment-based criteria for determining bioequivalence. Biometrika.1993;80:835–846.
29.
SchallR.Unified approach to the assessment of individual and population bioequivalence. Proceedings of the Biopharmaceutical Section of the American Statistical Association, 1995.
30.
ChowSCLiuJP. Statistical Design and Analysis in Pharmaceutical Science. New York: Marcel Dekker, Inc.; 1995.
31.
CartwrightAC. International harmonization and consensus DIA meeting on bioavailability and bioequivalence testing requirements and standards. Drug Inf J.1991;25:471–482.
32.
SteinijansVWHauschkeD.International harmonization of regulatory bioequivalence requirements. Clin Research Reg Affairs.1993;10:203–220.
33.
BlumeHHSchugBS. Current and future status of international harmonization of requirements for BA/BE. Presented at the DIA Bioavailability and Bioequivalence Symposium, September 19-20, 1994 Rockville, Maryland.
