Assessment of the impact of partial area under the curve in a bioavailability/bioequivalence study on generic prolonged-release formulations.

ABSTRACT

The requirement for multiple-dose bioequivalence studies for the approval of generic prolonged-release (PR) formulations is not agreed upon by the EMA and FDA. While the EMA requests these studies, the FDA has no specific requirement, nor does ANVISA. Additional metrics are suggested for the assessment of prolonged-release products, and the partial Area Under the Curve (pAUC) metric has received increasing regulatory recognition. The objective of this work was to investigate whether the evaluation of the partial AUC in studies assessed by ANVISA can detect differences between 2 prolonged-release formulations that have demonstrated bioequivalence by the usual metrics. Twenty-four studies in a total of 117, which were already approved by ANVISA considering the usual metrics in the last 14 years, failed to demonstrate bioequivalence for partial AUC, which is related to 33.9% of evaluated PR products. For 76.92% of the studies, there was no significant increase in the intrasubject variability observed in the partial AUC analysis compared to the usual metrics, with a CV < 30% for both cases, calculated individually for each study, indicating that there is no need to increase the sample size to perform such analysis. The results of this paper demonstrate that the current criteria for assessing the bioequivalence of some prolonged-release formulations are insufficient and that the evaluation of partial AUC could be useful to assure the therapeutic parity of two products.