Population and individual bioequivalence: lessons from real data and simulation studies

The Food and Drug Administration (FDA) has proposed replacing the 1992 average bioequivalence (ABE) with population and individual bioequivalence (PBE & IBE), as outlined in the preliminary draft guidance of December 1997, which was subsequently replaced by the draft guidances of August 1999 and resolved in the final guidance of October 2000. This has led to considerable public debate among regulatory, academic, and industry experts at numerous conferences (e.g., FDA/AAPS March 1998, FDA/AAPS August-September 1999, FDA Pharmaceutical Sciences Advisory Committee September 1999) and in the literature. The final guidance calls for ABE to remain as the primary criterion by which new formulations may be judged ready for access to the marketplace. In addition, the FDA recommends the use of replicate study designs for the specific drug classes of controlled-release formulations and highly variable drugs. The final guidance also alludes to the possibility of a sponsor requesting alternative criteria such as PBE and IBE following consultation with the FDA. This procedure amounts to a data collection period during which data suitable to evaluate the operating characteristics of PBE and IBE would be generated, analyzed, and discussed among interested parties. A comprehensive review of currently available databases is useful in determining the ultimate value of this data collection period. This report provides an update to the previous publication by the authors. In all, 28 data sets from 20 replicate cross-over bioequivalence studies have been analyzed (n = 12-96) using the statistical methodology in the most recent FDA draft guidance. The results are presented below. ABE Pass: ABE Fail: Total: AUC/Cmax AUC/Cmax AUC/Cmax AUC/Cmax Pass PBE & IBE 20/14 1/3 21/17 Pass IBE only 1/0 0/0 1/0 Fail PBE and IBE 0/2 0/1 0/3 Fail IBE only 2/3 4/5 6/8 Total 23/19 5/9 28/28 Review of the database reveals many interesting features, most notably the lack of consistent results within a given data set across all three criteria. The sensitivity of subject-by-formulation interaction to sample size and inherent variability of the compounds is further explored through simulation studies. It is concluded that additional simulation assessments must be considered when evaluating the value of a data collection period for PBE and IBE assessment. It will be shown that definitive conclusions regarding some of the operating characteristics of PBE and IBE can be achieved through a combination of data-driven hypotheses followed by simulation studies to further evaluate the hypotheses. Some recommendations for further data collection will be made.