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.
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References
U.S. Food and Drug Administration. Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally Administered Drug Products—General Considerations, March 2003.
L. B. Sheiner. Bioequivalence Revisited. Stat. Med. 11:1777–1788 (1992).
R. Schall, and H. G. Luus. On Population and Individual Bioequivalence. Stat. Med. 12:1109–1124 (1993).
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).
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).
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).
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).
L. Tothfalusi, and L. Endrenyi. Limits for the scaled average bioequivalence of highly variable drugs and drug products. Pharm. Res. 20:382–389 (2003).
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).
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).
V. Karalis, M. Symillides, and P. Macheras. Novel scaled average bioequivalence limits based on GMR and variability considerations. Pharm. Res. 21:1933–1942 (2004).
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.
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.
Japan National Institute of Health, Division of Drugs. Guideline for Bioequivalence Studies of Generic Drug Products. 1997.
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).
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).
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).
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).
T. Hyslop, F. Hsuan, and D. J. Holder. A small sample confidence interval approach to assess individual bioequivalence. Stat. Med. 19:2885–2897 (2000).
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).
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).
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.
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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
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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
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DOI: https://doi.org/10.1208/s12248-008-9053-4