Bioequivalence and Bioavailability Forum

Hi BEQool,

❝ so the most appropriate design for 2 test treatments and replicated reference is a below one?

❝ ❝ T1  R   T2   R

❝ ❝ R   T1  R   T2

❝ ❝ T2  R   T1  R

❝ ❝ R   T2  R   T1

I think so. I performed such studies but only as pilots. The pivotals were full replicates with the most promising candidate.¹

❝ Do you think EMA regulators would have any objections if this is was pivotal study (of course bearing Bonferroni adjustment in mind)?

No idea.

❝ Probably following designs would be worse?:

Yes (see below why).

❝ a) EMA suggested replicate design with additional test treatment

❝ TRR|T2

❝ RTR|T2

❝ RRT|T2

❝ b) 3x6x3 Williams design with additional reference treatment

❝ ABC|C

❝ ACB|C

❝ BAC|C

❝ BCA|C

❝ CAB|C

❝ CBA|C

That’s the same idea as in the so-called ‘extra-reference design’² (a two-sequence partial replicate TRR|RTR). This design – like both of yours – is biased in the presence of true period effects.

---

1. Evaluate two IBDs by excluding either T1 or T2. Select the candidate with a T/R-ratio closer to 1. If similar, select the one with lower CV_w.
   
2. Chow, SC, Shao J, Wang H. Individual bioequivalence testing under 2×3 designs. Stat Med. 2002; 21(5): 629–48. doi:10.1002/sim.1056.