In a bioequivalence study, for the main pharmacokinetic parameters, the 90% confidence interval for the ratio of the investigational and reference medicinal products must be within the acceptance range of 80,00% to 125,00%.
For highly variable medicinal products (intra-subject variability of the parameter is more than 30%), an extended acceptance range for Cmax may be considered. In this case, the bioequivalence study must be conducted with a replicate design, where it must be demonstrated that the intra-subject variability for Cmax of the reference medicinal product is > 30%.The applicant must justify that the calculated intra-subject variability is reliably estimated and is not the result of outliers.The requirementfor extending the interval must be pre-specified in the protocol with appropriate justification.
The possibility of extending the acceptance criteria based on high intra-subject variability does not apply to AUC; for AUC the acceptance range must remain 80.00-125.00% regardless of variability.
