Bioequivalence and Bioavailability Forum

Merhaba BRN!

In the future please don’t reply to your own posts; edit the original one instead. THX!

I don’t know what the current thinking of the Turkish MoH is – or are you aiming at another country? A historical overview of approaches used in the EU:

• Until 2006: Widen the acceptance range (AR) based on high variability observed in previous studies or reported in the literature – if no clinical problems are expected (safety/efficacy). Prospectively stating acceptance ranges for C_max of 70–143% and 75–133% for AUC (in rare cases even to 70–143%) was common. Conventional 2×2 cross-overs were sufficient.
  
• 2006: Prospectively widen the AR (for C_max only) if high variability of the reference was demonstrated in a reference-replicated design. Widening limited to 75–133%.
  
• 2010: Reference-scaling for C_max based on the CV observed in a reference-replicated study. Widening limited to a CV_wR of 50% (i.e., 69.84–143.19%). T/R-ratio within 80–125%.
  
• 2011: Statistical Methods published.

For the FDA 80–125% was mandatory until 2010. Now reference-scaling is possible both for C_max and AUC. No upper limit of the CV, ratio within 80–125%, minimum sample size 24, different statistical method than EMA’s. Other countries are somewhere in between (search the guideline-collection).

❝ Does this replicate design has to be with minimum two reference administration?

Yes.

❝ If we want to design a 3 period crossover, what should we take into consideration, would you suggest a lecture, thread or any other source?

I would suggest my lectures. There are hundreds (!) of  posts covering this topic and many references (literature, guidelines) within.