Abstract

Objective: The US Food and Drug Administration (FDA) currently uses bioequivalence (BE) limits for fasting BE studies that are based on the 90% confidence interval for the ratio of difference of the test and reference products Cmax and AUC falling within 80% to 125%. The FDA has also proposed that BE limits be used similarly for AUC and Cmax measurements from fed BE studies. In some cases, regulatory agencies have considered a wider BE limit for Cmax, because of the typically higher variability of Cmax compared to AUC. We investigated the consequences of changing from an 80%/ 125% limit for both pharmacokinetic measures to one that uses a limit of 80%/125% for AUC and 70%/143% for Cmax. Methods: We computed the sample sizes required for BE studies using 80%/ 125% for AUC and 70%/143% for Cmax as BE limits. We also determined the range of the ratios of Cmax and AUC values in a study that could meet the 70%/143% and 80%/125% BE limits. Results: The sample size for the study, in order to have adequate power with 80%/125% for AUC and 70%/143% for Cmax, will be determined primarily by the intrasubject variability of AUC, though with a substantial proportion of studies (about one third) still determined by the variability of Cmax. The ratio of mean Cmax values that can pass a wider 70%/143% BE limit could easily be as high as 128%. Conclusion: Without further scientific or clinical rationale, we find it difficult to justify widening the bioequivalence limit for Cmax to 70%/143% for either fasting or fed BE studies.

Author Details

Authors

• W.W. Hauck¹
• A. Parekh²
• L.J. Lesko²
• M.-L. Chen³
• R.L. Williams³,⁴

Departments

• ¹ Biostatistics Section, Division of Clinical Pharmacology, Thomas Jefferson University, Philadelphia,
• ² Office of Clinical Pharmacology and Biopharmaceutics, Office of Pharmaceutical Science,
• ³ Office of Pharmaceutical Science, Center for Drug Evaluation and Research, Food and Drug Administration, and
• ⁴ US Pharmacopeia, Rockville, MD, USA

Address

Dr. W.W. Hauck; Biostatistics Section, Division of Clinical Pharmacology, Thomas Jefferson University, 125 South 9th Street, #402, Philadelphia, PA 19107, USA
Email: [email protected]

Citation