Bioequivalence and Bioavailability Forum

❝ So, if we consider Fully replicated crossover design-conventional ABE with two-stage sequential approach for BE study then, is it acceptable to canadian submission?

• Nothing is stated in HC’s guidance, but: “Alternate approaches to the principles and prac­tices described in this document may be acceptable provided they are supported by ade­quate justification. Alternate approaches should be discussed in advance with the rele­vant program area to avoid the possible finding that applicable statutory or regulatory require­ments have not been met.”
  (my emphases)
  
• Since nothing is published, you have to set up Monte Carlo simulations for a matrix of poss­ible combinations of stage 1 sample sizes (n₁) and CVs in order to find and validate a suit­able adjusted α (i.e., which maintains the overall type I error at 5%). Due to the slow con­ver­gence you have to simulate 10⁶ BE-studies at a T/R-ratio of 1.25 (for α) and 10⁵ at the ex­pected T/R-ratio (for power) for every combination of n₁ and CV. Keep in mind that in a fully replicated design CV_WR not necessarily equals CV_WT.