Prescribability and switchability of highly variable drugs and drug products.

At the AAPS/FDS Workshop (Crystal City, Arlington, VA, March 6-8, 1995), it was agreed that some form of scaling should be permitted for highly variable drugs, although there was no agreement on a method. Currently, much emphasis is focused on developing a practical methodology for individual bioequivalence (IBE) and population bioequivalence (PBE) to replace or complement average bioequivalence (ABE). The latter requires only the mean bioavailabilities of two formulations to be sufficiently similar, whereas PBE also considers their distributions. IBE, on the other hand, is a comparison of the individual responses to the two formulations within subjects and is therefore concerned with switchability (interchangeability) between two multisource formulations. Multisource formulations refer (i) to generic copies of an innovator's formulation or (ii) to different formulations used in stages leading up to the final marked formulation. Evaluation of both PBE and IBE require replicate design studies. The FDA Working Group on IBE has been experimenting with methods in which a one-sided 95% confidence interval is computed based on the Bootstrap technique which ensures that the consumer risk is maintained at 5%. The IBE metric can then be scaled according to the within subject variance of the reference formulation. Thus if the variability of the test formulation (T) is higher than that of the reference (R), the formulation may fail IBE but not ABE. Conversely, if R is more variable than T, then the formulations may be considered to be IBE, even with a difference in means of more than 20%. Experimentation with existing data on our files shows that scaling has a considerable effect on the IBE decision for highly variable drugs. Evidence will also be presented to show that scaling makes the conditions more conservative for potent drugs with steep dose response curves reducing the risk of two generic formulations being BE with the same reference product but not BE with each other. On the other hand, broadening the BE limits for safe, highly variable drugs increases statistical power and reduces the number of subjects required. Even with the introduction of scaling, however, it is clearly difficult to obtain a single IBE criterion suitable to be applied to all drug products/studies.