Journal of Pharmacokinetics and Biopharmaceutics

, Volume 24, Issue 1, pp 133–149 | Cite as

Towards a practical strategy for assessing individual bioequivalence

  • Robert Schall
  • Roger L. Williams
  • Food and Drug Administration Individual Bioequivalence Working Group


Bioequivalence of two drug formulations is currently defined by drug regulatory authorities in terms of the mean responses following administration of the test and reference formulations (average bioequivalence). However, the various potential shortcomings of average bioequivalence are now understood, and switchability, and thus individual bioequivalence, has become a reasonable expectation when changing from one pharmaceutically equivalent drug product to another. Progress has been made in developing criteria for individual bioequivalence, and an overview and classification of most of the different approaches to the assessment of individual bioequivalence have been achieved. As a consequence of this classification, the different character of scaled and unscaled bioequivalence measures has been recognized and, in turn, this leads to the proposal, made in this paper, of using both scaled and unscaled criteria for bioequivalence assessment of different classes of drugs, depending on their within-subject variability and therapeutic range. This strategy addresses the shortcomings of average bioequivalence, and, when applied to data sets from bioequivalence studies with four-period replicate crossover designs, turns out to have some satisfactory properties. Open questions and areas for further research are discussed.

Key Words

bootstrap individual bioequivalence moment-based criteria population bioequivalence probability-based criteria scaled criteria unscaled criteria 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Statistical Procedures for Bioequivalence Studies Using a Standard Two-Treatment Crossover Design, Guidance, Division of Bioequivalence, Office of Generic Drugs, Food and Drug Administration (revision date: 1 July 1992).Google Scholar
  2. 2.
    Investigation of bioavailability and bioequivalence. InThe Rules Governing Medicinal Products in the European Community, Vol. 2, Addendum No. 2, Office for Official Publications of the European Communities, Luxemburg, May 1992, pp. 149–168.Google Scholar
  3. 3.
    S. Hwang, P. B. Huber, M. Hesney and K. C. Kwan. Bioequivalence and interchangeability (letter).J. Pharma. Sci. 67:IV (1978).CrossRefGoogle Scholar
  4. 4.
    S. Anderson and W. W. Hauck. Consideration of individual bioequivalence.J. Pharmacokin. Biopharma. 18:259–273 (1990).CrossRefGoogle Scholar
  5. 5.
    G. Ekbohm and H. Melander.On Variation, Bioequivalence and Interchangeability, Report 14, Department of Statistics, Swedish University of Agricultural Science, 1990.Google Scholar
  6. 6.
    L. B. Sheiner. Bioequivalence revisited.Statist. Med. 11:1777–1788 (1992).CrossRefGoogle Scholar
  7. 7.
    R. Schall and H. G. Luus. On population and individual bioequivalence.Statis. Med. 12:1109–1124 (1993).CrossRefGoogle Scholar
  8. 8.
    L. Endrenyi. A procedure for the assessment of individual bioequivalence. In K. K. Midha and H. H. Blume (eds.),Bio-International. Bioavailability, Bioequivalence and Pharmacokinetics, Medpharm, Stuttgart, 1993, pp. 141–146.Google Scholar
  9. 9.
    D. J. Holder and F. Hsuan. Moment-based criteria for determining bioequivalence.Biometrika 80:835–846 (1993).CrossRefGoogle Scholar
  10. 10.
    J. D. Esinhart and V. M. Chinchilli. Extension to the use of tolerance intervals for the assessment of individual bioequivalence.J. Biopharm. Statist. 4:39–52 (1994).CrossRefGoogle Scholar
  11. 11.
    R. Schall. Assessment of individual and population bioequivalence using the probability that bioavailabilities are similar.Biometrics 51:615–626 (1995).PubMedCrossRefGoogle Scholar
  12. 12.
    W. W. Hauck and S. Anderson. Measuring switchability and prescribability: when is average bioequivalence sufficient?J. Pharmacokin. Biopharma. 22:551–564 (1994).CrossRefGoogle Scholar
  13. 13.
    R. Schall. A unified view of individual, population, and average bioequivalence. In H. H. Blume and K. K. Midha (eds.),Bio-International 2. Bioavailability, Bioequivalence and Pharmacokinetic Studies, Medpharm, Stuttgart, 1995, pp. 91–106.Google Scholar
  14. 14.
    W. J. Westlake. Bioavailability and bioequivalence of pharmaceutical formulations. In K. E. Peace (ed.),Pharmaceutical Statistics for Drug Development, Marcel Dekker, New York, 1988, pp. 329–352.Google Scholar
  15. 15.
    G. Ekbohm and H. Melander. The subject-by-formulation interaction as a criterion of interchangeability of drugs.Biometrics 45:1249–1254 (1989).CrossRefGoogle Scholar
  16. 16.
    L. Z. Benet. Bioavailability and bioequivalence: Definitions and difficulties in acceptance criteria. In K. K. Midha and H. H. Blume (eds.),Bio-International. Bioavailability, Bioequivalence and Pharmacokinetics, Medpharm, Stuttgart, 1993, pp. 27–35.Google Scholar

Copyright information

© Plenum Publishing Corporation 1996

Authors and Affiliations

  • Robert Schall
    • 1
  • Roger L. Williams
    • 2
  • Food and Drug Administration Individual Bioequivalence Working Group
  1. 1.Division of Biometry, Department of PharmacologyUniversity of the Orange Free StateBloemfonteinSouth Africa
  2. 2.Food and Drug AdministrationCDERRockville

Personalised recommendations