Bioequivalence and Bioavailability Forum

Dear Helmut & Group

You said

❝ "Whereas the first split is a conventional 2x2x2 cross-over, the second one only looks like one.

❝ I wouldn't recommend it."

Why does the second split only "look like" a 2x2x2 cross-over? I guess I am missing something when you write this. It seems like a conventional 2x2x2 cross-over for me.

Also,
I have a query in continuation of the ongoing discussion about a 4 period, 4 treatment design.
While planning a pilot BE study for choosing an optimal formulation, we are comparing 3 different formulations (T1, T2 & T3) given nasally to a rectal formulation (R). To ensure all subjects complete the 4 period study, we plan to administer the rectal formulation which is the reference to all subjects in the first period and randomize the three test formulations across periods 2, 3 and 4. We are doing this to avoid a situation with subjects who receive nasal drug in the first few periods not to return to the rectal administration in the later period due to compliance issues or acceptability.

GP | P1 P2 P3 P4
---+-------------
G1 | R  T1 T2 T3
G2 | R  T2 T3 T1
G3 | R  T3 T1 T2

P1-P4 = Period 1-4
G1-G3 = Group 1-3
Each group will have 4 subjects.

I would like to mention that this will be a pilot study intended to obtain initial estimates of relative BA of the test formulations with respect to the reference and plans to do some exploratory BE analysis which would provide us with sufficient data and initial estimates to design an adequately powered BE study with the best chosen formulation.

Any comments on the design issue would be highly appreciated, both in terms of complexity of determining BE, or with regards to drawbacks of such a design. I understand that lack of balance is one of them. How valid will be the inclusion of Period as a fixed effect?. I guess I have many questions which I could reserve for later based on responses.

I did a literature search for such designs, but could not really come with the correct key words to find a good reference. Any literature references with respect to such study designs would be helpful.

Lastly, I really appreciate the time you take out to respond to questions in detail with appropriate references. I learned a lot from this forum.

Thanks

Vijay

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Edit: Reformatted using BBCodes. [Helmut]