MEETING REPORT:
"Challenges In the Design and Evaluation of Bioequivalence Studies"

Audience at the March 8-10 workshop held in Frankfurt, Germany. The three day workshop featured presentations and discussion of the current issues in the design and evaluation of bioequivalence studies.

As a follow-up to the highly successful Workshop, 'The Role of the Biopharmaceutics Classification System and In Vitro-In Vivo Correlations in the Approval of Oral Drug Products' held in Frankfurt in the Spring of 1998, a further workshop, this time focusing exclusively on bioequivalence issues, was held March 8-10 in Frankfurt, again under the co-sponsorship of AAPS, AAPV (the International Organization for Pharmaceutical Technology), CRS, EUFEPS and the FDA.

The three-day workshop featured presentations and discussion of the current issues in the design and evaluation of bioequivalence studies.
Dr. Roger Williams of the FDA kicked off the workshop with an overview of the role of bioequivalence studies in assuring product quality from the standpoint of the FDA. The remainder of the first day was then devoted to the proper design of bioequivalence studies. Dr. Dale Conner (FDA) set forth the ground rules for study design and the remaining presentations addressed specific issues such as highly variable drugs, when metabolite levels should be measured, whether pharmacodynamic data can be used as a surrogate and the use of population and individual bioequivalence as alternatives to standard average bioequivalence study designs. Dr. Barbara Schug (SocraTec) presented examples of highly variable drugs and indicated that variability could be substantially reduced by going to steady-state measurements and that a replicate study design was also useful in these cases. Dr. Mei-Ling Chan and Dr. Vinod Shah (FDA) indicated that metabolites should only be measured for bioequivalence purposes when there are problems with detection of the parent compound. Several interesting examples of the application of pharmacodynamic data were shown by Professor Luc Balant (University of Geneva). The need for a dose-response study design was stressed. In some cases, where the pharmacological effect is elicited on an all-or-none basis, therapeutic bioequivalence can be achieved even when plasma levels are not similar. This idea led to a lively discussion of whether assessment of pharmacokinetic or therapeutic equivalence is the goal of the study design. Dr. Mei-Ling Chen introduced the most recent FDA thinking on the use of repetition in studies to assess individual bioequivalence. She emphasized the importance of 'switchability' and hence subject - formulation interactions when considering whether two products are bioequivalent. About 40% of studies considered by the FDA to date show a subject - formulation interaction. A consideration of the variance of the test and reference formulation is therefore important to the assessment of bioequivalence. in the current criterion under consideration, the decision is based on an aggregate parameter consisting of the difference between the means and the difference between the variances, divided by the variance of the reference product. With this parameter, a low variance in the test product can enable a wider difference between the means to be accepted. To avoid this, it has been suggested either to add an additional criterion of a maximum allowable difference in the means or to scale the difference in variances. The last two presentations on the first day covered food effects on bioequivalence. Dr. Constantin Efthymiopoulos argued that the mechanistic basis for food-drug interactions should be established. Dr. Aziz Karim (GD Searle) continued with this theme, focusing on the importance of food effect studies in early drug development.

The second day of the Workshop started with evaluation of bioequivalence studies. Dr. Willy Roth (BI Pharma KG) presented his firm's experience with Telmisartan, a combination product. Alternate methods to the standard Cmax, Tmax and AUC for characterization of the plasma profile were then presented by Prof. Panos Macheras (Uni-Athens). The concept of early exposure (i.e. partial AUC) as an alternative to assessment of absorption rate by Cmax and Tmax was generally considered to be a positive development, and some thought was also given to the intercept parameter (y intercept of a semilogarithmic plot of c vs. t normalized to AUC) as a measure of absorption rate. Dr. Tony Hunt (UCSF) gave a thorough description of how the F2 factor can be applied to bioequivalence studies and also how trends in the bootstrapping analysis can be used to identify differences in the mechanism of release between two products. Lastly, Dr. Volker Steinijans compared the FDA's current recommendations for number of subjects and decision criteria to be used in average, population and individual bioequivalence studies, and drew the conclusion that the goalposts allowed are so much wider in the case of some recommendations for individual bloequivalence studies that the natural hierarchy, average/population/individual, is lost. His recommendation was to go to a 2-step decision criterion, i.e. compare the means and variances separately.

In the afternoon, several case studies highlighting some of the issues were presented. These included choice of substance to be measured in the case of seligeline (Dr. Pabst, AAI), absorption profiles of carbamazepine and nifedipine (Prof. Süverkrüp, Uni-Bonn), influence of gender on variability (Dr. Schug, SocraTec), linear characterization of plasma-concentration time profiles (Prof. Mau, Uni-Düsseldorf) and mathematical uncertainty in BA/BE studies (Prof. Mircioiu, Uni-Bucharest).

On the third day, the emphasis moved to regulatory aspects and how bioequivalence is regulated in various parts of the world with an emphasis on possibilities for harmonization. After an introductory overview of trends in international harmonization from Prof. Blume (SocraTec), Dr. Shah described the contents of the forthcoming draft Guidance on Bioequivalence from the FDA. Key points include practical guidelines for conducting studies, biopharmaceutical aspects, choice of decision criteria and use of early and total exposure concepts. Prof. Morals (Uni-Lisbon) followed with a detailed description of the European Guidance, highlighting the differences from the previous (1992) version. The drive to mutual recognition in Europe has led to certain specific problems such as the definition of the reference product and will require harmonization of criteria and exemptions for biowaivers among the different countries. At present, the EMEA feels that there is not enough experience with early exposure concepts to include them in the Guidance. Dr. Limberg (BfARM) stressed the importance of in vitro dissolution test design to assessing bioequivalence, with studies in several relevant media being highly desirable. In the last presentation of the workshop, Ms. Maria Santiago from the Bureau of Food and Drugs in the Philippines described their ambitious government project to establish bioequivalence testing
centers. Until these are fully up and running, it was suggested that appropriate dissolution studies could form the basis of a bioequivalence submission in many cases as a stop-gap solution.