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

The Food and Drug Administration (FDA) has proposed replacing the 1992 aver age bioequivalence (ABE) with population and individual bioequivalence (PBE & IBE), as outlined in the preliminary draft guidance of December 1997, wh ich was subsequently replaced by the draft guidances of August 1999 and res olved in the final guidance of October 2000. This has led to considerable p ublic debate among regulatory, academic, and industry experts at numerous c onferences (e.g,, FDA/AAPS March 1998, FDA/AAPS August-September 1999, FDA Pharmaceutical Sciences Advisory Committee September 1999) and in the liter ature. 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 th e specific drug classes of controlled release formulations and highly varia ble 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 whi ch data suitable to evaluate the operating characteristics of PBE and IBE w ould be generated, analyzed, and discussed among interested parties. A comp rehensive 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 fro m 20 replicate cross-over bioequivalence studies have been analyzed (n = 12 -96) using the statistical methodology in the most recent FDA draft guidanc e. The results are presented below. [GRAPHICS] Review of the database reveals many interesting features, most notably the lack of consistent results within a given data set across all three criteri a. The sensitivity of subject-by formulation interaction to sample size and inherent variability of the compounds is further explored through simulati on studies. It is concluded that additional simulation assessments must be considered when evaluating the value of a data collection Period for PBE an d IBE assessment. It will be shown that definitive conclusions regarding so me of the operating characteristics of PBE and IBE can be achieved through a combination of data-driven hypotheses followed by simulation studies to f urther evaluate the hypotheses. Some recommendations for further data colle ction will be made. (C) 2001 the American College of Clinical Pharmacology.