Bioequivalence and Bioavailability Forum

Dear members,

After having performed numerous dissolution tests, a pilot PK study (failed, with different test formulations than currently developed) and a study in a gastrointestinal model, we have arrived at two candidate test formulations for a certain MR matrix tablet (generic of a reference tablet, not a one-to-one copy). As we are still rather uncertain which test formulation to take to a pivotal BE study (but wanting to avoid a new pilot PK study as we are ready for process validation and a pivotal study, and do not want to "waste" time/money), we would like to perform a two-stage pivotal BE study with three treatments (T1 vs T2 vs R; Williams' design).

The idea is to use the first stage as an internal pilot in order to select the best matching test formulation and estimate a total sample size (partly) based on the results (CV) of the first stage. The "bad" test formulation would be dropped from the study after the interim thereby making the second stage a two treatment study. This approach would not only save us time/money, but also allows us to make an educated decision on the test formulation. Moreover, dropping a "bad" test formulation and estimating a sample size based on results of the "best" test formulation, thereby exposing a limited amount of healthy volunteers to an inferior product and including only the amount of subjects required to demonstrate BE, may be regarded as ethical...

However, in my opinion, such a design sounds pretty dodgy, more from a statistical than from an ethical perspective... Is such a design acceptable from a regulatory (EU) point of view? What are the statistical implications (e.g. papers of Potvin et al.: spending of alpha, sample size estimation)? Is a two-stage study with three treatments allowed (not to mention dropping one treatment after the interim)?

Or are we back at square one having to choose between:

• performing a pilot study with current test formulations to select the best test formulation (and subsequently performing a standard 2x2x2 single-stage pivotal study on the best test with a sample size based on the results of the pilot [conservative planning, CV not carved in stone ]), and
  
• performing a two-stage two-treatment pivotal study at risk with the test product we "think" performs best in comparison to the reference product?

Many thanks in advance for your ideas, brainwaves, comments...