Bioequivalence and Bioavailability Forum

Hi SP,

❝ Can anyone help me with your experience or suggestions. Which sequence should i prefer for crossover study design to Reference Replicate and Two Different Test product (T1 and T2).

I have seen this one: T1RT2R | RT1RT2
Evaluation was done after excluding the respective other T-treatment, which gave two partial replicates with incomplete blocks (the pooled analysis will lead to limbo for unequal variances):
T1R• R | RT1R• and
• RT2R | R• RT2
As usual with partial replicates, the FDA’s covariance specification (in SAS-lingo FA0(2)) did not converge for PK metrics with s_WR <0.294 (no RSABE). Furthermore, one has to assume lacking period effects, since neither R nor the two test are administered in all periods. The evaluation was not easy. Since nobody knows whether or not there were true period effects, the outcome was doubtful at least. I would not go there.

Maybe it is better to opt for a modified Williams’ design T1T2RR | T2RT1R | RT1RT2 | RRT2T1 which gives
T1• RR | • RT1R | RT1R•  | RR• T1 and
• T2RR | T2R• R | R• RT2 | RRT2• 
At least balanced for T₁ and T₂ (once in every period).
However, we have R twice in periods 1&2 and only once in periods 3&4.

If you really want to have everything balanced, you might end up with even more sequences. The FDA argues against more than two sequences (confounded effects) anyway. Duno. Never have been there.

I would perform two separate three period full replicate studies:
T1RT1 | RT1R and T2RT2 | RT2R
No statistical pitfalls. As a bonus you get also the intra-subject variabilities of T₁ and T₂. If T₁/R and T₂/R are similar, select the one with lower variability for the pivotal study (full replicate, please – the partial replicate is crap).