SCALE EFFECT IN BIOEQUIVALENCE EVALUATIONS

Objective: The objective of the study was to evaluate the relationship between the magnitude of the sample means for a bioavailability measu re and the ratio of the sample means in bioequivalence evaluations. Me thods: We assumed that bioavailability data were obtained from crossov er trials on a test and a reference drug products. The true test-refer ence ratio was constructed as a function of dosage strength under cert ain dose-response relationship assumptions, and was used for deriving analytical results of assessing the scale effect due to dosage strengt h. In addition, the test-reference ratio of sample means was construct ed as a function of the true test-reference ratio and the correlated s ampling deviation in the sample means, and was used in a deterministic simulation for quantifying the scale effect due to the correlated sam pling deviation, Results: The major systematic factors that influence the magnitude of the sample means include the dosage strength, dose-re sponse relationship, and the positively correlated sampling deviation in the sample means. Results of this study showed that the true test-r eference ratios can be improved with increasing dosage strength in mos t of the situations studied, but at a diminishing rate. The correlated sampling deviation can alter the test-reference ratio of the sample m eans through changing magnitude of the sample means, especially for dr ug products with low bioavailability. Conclusions: For extended releas e drug products with multiple dosage strengths, the development effort s should focus on the lowest strength if there is little or Ilo formul ation by dose interaction effect. Pilot studies should be conducted fo r both the highest and the lowest strength instead for possible formul ation by dose interaction effect. The magnitude of observed means for bioavailability measures on the reference drug product can indicate th e degree of systematic variation in the ratio of means. The expected m ean values of the reference drug product can be derived from previous trial(s) and/or from other information sources. If the sample mean for the reference drug product in a failed bioequivalence trial is lower than expected, the investigator should consider repeating the trial.