Bioequivalence and Bioavailability Forum

Dear All,

We have a BE study for a fixed dose combination (FDC) product (T) which does not have an original reference. So our reference product (R) becomes administration of R1 and R2 in combination (R=R1+R2). However in other periods these original products are administered as monotherapy as per local regulations.

The protocol mentions the BE conclusion will be based on T vs. R.

Now my question is, what's the best approach for the statistical analysis?

1. Treat the study as 2 period with T vs. R and code accordingly:
   (Treatments= T, R; Periods= 1, 2; Sequence= TR, RT).
   
   
2. Treat the study as 3 period with T vs. R and R1 since R2 will not have one of the active ingredients, and code accordingly:
   (Treatments=T, R, R1; Periods: 1, 2, 3; Sequence:TRR1, TR1R, R1RT)
   
   
3. Treat the study as 4 period with T vs. R, R1, and R2, and code accordingly:
   (Treatments=T, R, R1, R2; Periods: 1, 2, 3, 4; Sequence:TRR1R2, RR1TR2, ....)

From my point of view the best approach will be the first option but I'd like to hear some expert comments. Is there any other options, suggestions?

Thank you in advance for your kind support.