In April, 2010, "the Pharmaceutical Science and Clinical Pharmacology Advisory Committee (104715) (PSCPAC)" discussed the issues related to the bioequivalence standard.
"The statistical analysis and acceptance criteria seem to be the most confusing aspects of regulatory bioequivalence evaluation. The current statistical analysis, the two one-sided tests procedure, is a specialized statistical method that is capable of testing for “sameness” or equivalence between the two comparator products. The pharmacokinetic parameters, calculated from the bioequivalence study data, area under the plasma concentration-time curve, (AUC) and maximum plasma concentration (Cmax) represent the extent and rate of drug availability, respectively. All data is log-transformed and the analysis of variance (ANOVA) is used to calculate the 90% confidence intervals of the data for both AUC and Cmax. To be confirmed as bioequivalent, the 90% confidence intervals for the test (generic product) to reference (marketed innovator product) ratio must fall between 80 to 125%. This seemingly unsymmetrical criteria is due to the logtransformation of the data."
However, this one-size-fits-all approach may not be adequate for all pharmaceutical products. One category of the pharmaceutical products is called "critical dose (CD) drugs". CD drugs are also called "narrow therapeutic index (NTI) drugs" and are medicines for which comparatively small differences in dose or concentration may lead to serious therapeutic failures and/or serious adverse drug reactions. It is reasonable to assume that a more stringent bioequivalence criteria should be employed to ensure the safety of the product.
According to the voting results from advisory committee, advisory committee agreed that CD drugs are a distinct group of products; the FDA should develop a list of CD drugs; and the current BE standards are not sufficient for CD drugs.
The FDA proposes that in addition to 80-125% criteria based on 90% confidence interval, a limit of 90-111% on the geometric mean (point estimate) of all BE parameters (i.e., Cmax, AUC0-t, AUC0-∞) is added to the more stringent bioequivalence criteria. However, this proposal was not agreed by the advisory committee. Panelists commented that the scientific basis for the proposed limit of 90-111% was not justified. Some members specified that they did not favor use of Cmax in the proposal, but likely would have been swayed if it focused solely on AUC.
To claim the bioequivalence, should both AUC and Cmax meet the bioequivalence criteria? While regulatory guidance mentioned that AUC and Cmax are typically parameters for evaluating bioequivalence, there is no guidance formerly requiring that both AUC and Cmax have to be demonstrated. In some situation, Cmax may not be applicable in showing the bioequivalence. For example, when comparing the drug giving in different administration routes (intravenous vs subcutaneous), equivalence in AUC could be established while equivalence in Cmax could not be established.