Skip to main content
Log in

Evaluation of a Scaling Approach for the Bioequivalence of Highly Variable Drugs

  • Research Article/Theme: Bioequivalence, BCS and Beyond/Guest Editors: J.E. Polli, B.S. Abrahamsson; L.X.Yu
  • Published:
The AAPS Journal Aims and scope Submit manuscript

An Erratum to this article was published on 18 September 2008

Abstract

Various approaches for evaluating the bioequivalence (BE) of highly variable drugs (CV ≥ 30%) have been debated for many years. More recently, the FDA conducted research to evaluate one such approach: scaled average BE. A main objective of this study was to determine the impact of scaled average BE on study power, and compare it to the method commonly applied currently (average BE). Three-sequence, three period, two treatment partially replicated cross-over BE studies were simulated in S-Plus. Average BE criteria, using 80–125% limits on the 90% confidence intervals for C max and AUC geometric mean ratios, as well as scaled average BE were applied to the results. The percent of studies passing BE was determined under different conditions. Variables tested included within subject variability, point estimate constraint, and different values for σ w0, which is a constant set by the regulatory agency. The simulation results demonstrated higher study power with scaled average BE, compared to average BE, as within subject variability increased. At 60% CV, study power was more than 90% for scaled average BE, compared with about 22% for average BE. A σ w0 value of 0.25 appears to work best. The results of this research project suggest that scaled average BE, using a partial replicate design, is a good approach for the evaluation of BE of highly variable drugs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. U.S. Food and Drug Administration. Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally Administered Drug Products—General Considerations, March 2003.

  2. L. B. Sheiner. Bioequivalence Revisited. Stat. Med. 11:1777–1788 (1992).

    Article  PubMed  CAS  Google Scholar 

  3. R. Schall, and H. G. Luus. On Population and Individual Bioequivalence. Stat. Med. 12:1109–1124 (1993).

    PubMed  CAS  Google Scholar 

  4. S. H. Haidar, B. Davit, M-L. Chen, D. Conner, L. M. Lee, Q. H. Li, R. Lionberger, F. Makhlouf, D. Patel, D. J. Schuirmann, and L. X. Yu. Bioequivalence approaches for highly variable drugs and drug products. Pharm. Res. 25:237–241 (2008).

    Article  PubMed  CAS  Google Scholar 

  5. S. D. Patterson, N. M.-D. Zariffa, T. H. Montague, and K. Howland. Non-traditional study designs to demonstrate average bioequivalence for highly variable drug products. Eur. J. Pharm. Sci. 57:663–670 (2001).

    Article  CAS  Google Scholar 

  6. K. K. Midha, M. J. Rawson, and J. W. Hubbard. The bioequivalence of highly variable drugs and drug products. Int. J. Clin. Pharmacol. Therap. 43:485–498 (2005).

    CAS  Google Scholar 

  7. A. W. Boddy, F. C. Snikeris, R. O. Kringle, G. C. G. Wei, J. A. Opperman, and K. K. Midha. An approach for widening the bioequivalence acceptance limits in the case of highly variable drugs. Pharm. Res. 12:1865–1868 (1995).

    Article  PubMed  CAS  Google Scholar 

  8. L. Tothfalusi, and L. Endrenyi. Limits for the scaled average bioequivalence of highly variable drugs and drug products. Pharm. Res. 20:382–389 (2003).

    Article  PubMed  CAS  Google Scholar 

  9. L. Tothfalusi, L. Endrenyi, and K. K. Midha. Scaling or wider bioequivalence limits for highly variable drugs and for the special case of Cmax. Int. J. Clin. Pharmacol. Ther. 41:217–225 (2003).

    PubMed  CAS  Google Scholar 

  10. L. Tothfalusi, L. Endrenyi, K. K. Midha, M. J. Rawson, and J. W. Hubbard. Evaluation of the bioequivalence of highly variable drugs and drug products. Pharm. Res. 18:728–733 (2001).

    Article  PubMed  CAS  Google Scholar 

  11. V. Karalis, M. Symillides, and P. Macheras. Novel scaled average bioequivalence limits based on GMR and variability considerations. Pharm. Res. 21:1933–1942 (2004).

    Article  PubMed  CAS  Google Scholar 

  12. Health Canada, Ministry of Health, Guidance for Industry: Conduct and Analysis of Bioavailability and Bioequivalence Studies—Part A: Oral Dosage Formulations Used for Systemic Effects. 1992.

  13. Committee for Proprietary Medicinal Products (CPMP), the European Agency for the Evaluation of Medicinal Products (EMEA). Note for Guidance on the Investigation of Bioavailability and Bioequivalence. 2001.

  14. Japan National Institute of Health, Division of Drugs. Guideline for Bioequivalence Studies of Generic Drug Products. 1997.

  15. S. H. Haidar. Bioequivalence of Highly Variable Drugs: Regulatory Perspectives. Food and Drug Administration Advisory Committee for Pharmaceutical Science Meeting, April 14, 2004. http://www.fda.gov/ohrms/dockets/ac/04/slides/4034S2_07_Haidar_files/frame.htm (Accessed 03/20/08).

  16. S. H. Haidar. Evaluation of a Scaling Approach for Highly Variable Drugs. Food and Drug Administration Advisory Committee for Pharmaceutical Science Meeting, October 6, 2006. http://www.fda.gov/ohfdrms/dockets/ac/06/slides/2006-4241s2_4_files/frame.htm (Accessed 03/20/08).

  17. B. M. Davit. Highly variable drugs—bioequivalence issues: FDA proposal under consideration. Meeting of FDA Committee for Pharmaceutical Science, October 6, 2006. http://www.fda.gov/ohrms/dockets/ac/06/slides/2006-4241s2_5.htm (accessed 3/12/2007).

  18. S. H. Haidar. BE for Highly Variable Drugs—FDA Perspective. AAPS Workshop on BE, BCS and Beyond. May 22, 2007. http://www.aapspharmaceutica.com/meetings/files/90/22Haidar.pdf (Accessed 03/20/08).

  19. T. Hyslop, F. Hsuan, and D. J. Holder. A small sample confidence interval approach to assess individual bioequivalence. Stat. Med. 19:2885–2897 (2000).

    Article  PubMed  CAS  Google Scholar 

  20. D. J. Schuirmann. A comparison of the two one-sided tests procedure and the power approach for assessing the equivalence of average bioavailability. J. Pharmacokinet. Biopharm. 15:657–680 (1987).

    Article  PubMed  CAS  Google Scholar 

  21. W. W. Hauck, A. Parekh, L. J. Lesko, M.-L. Chen, and R. L. Williams. Limits of 80%–125% for AUC and 70%–143% for Cmax, What is the impact on bioequivalence studies. Int. J. Clin. Pharmacol. Ther. 39:350–355 (2001).

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors would like to acknowledge the following individuals for their contributions to FDA’s Highly Variable Drugs working group: Mei-Ling Chen, Devvrat Patel, Lai Ming Lee, and Robert Lionberger.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Sam H. Haidar.

Additional information

The views expressed in this paper are those of the authors’ and do not necessarily represent the policy of the U.S. Food and Drug Administration.

An erratum to this article can be found at http://dx.doi.org/10.1208/s12248-008-9059-y

Rights and permissions

Reprints and permissions

About this article

Cite this article

Haidar, S.H., Makhlouf, F., Schuirmann, D.J. et al. Evaluation of a Scaling Approach for the Bioequivalence of Highly Variable Drugs. AAPS J 10, 450–454 (2008). https://doi.org/10.1208/s12248-008-9053-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12248-008-9053-4

Key words

Navigation