title: Limits of 80%-125% for AUC and 70%-143% for Cmax. What is the impact on bioequivalence studies?
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%.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Biostatistics Section, Division of Clinical Pharmacology, Thomas Jefferson University, Philadelphia, PA 19107, USA. whauck@lac.jci.tju.edu
authors.forename: W W
authors.initials: WW
authors.lastname: Hauck
authors.forename: A
authors.initials: A
authors.lastname: Parekh
authors.forename: L J
authors.initials: LJ
authors.lastname: Lesko
authors.forename: M L
authors.initials: ML
authors.lastname: Chen
authors.forename: R L
authors.initials: RL
authors.lastname: Williams
mesh_terms: D019540:Area Under Curve; D005215:Fasting; D006801:Humans; D010599:Pharmacokinetics; D012016:Reference Values; D012107:Research Design; D018401:Sample Size; D013810:Therapeutic Equivalency; D014481:United States; D014486:United States Food and Drug Administration