Bioequivalence and Bioavailability Forum

Dear Maulik!

❝ I am a new member of this family.

Welcome to the club.

❝ I have a question that if "A" drug having the intra subject variability >30% hence BE range will be broader than 80-125% now if i do a study with "A" drug considering as a standard and comparing my test drug "B" and i found intra subject variability <30% (by any reason) for "A" drug. Then my BE range will be more than 80-125% or it will be stringent to 80-125%?

❝

❝ I hope you understand.

Only if I substitute ‘drug’ by ‘formulation’. If you have a highly variable drug (CV_intra of a solution >30%) I don’t expect to see a CV <30% for the formulation. The acceptance range for highly variable drugs / drug products (HVDs/HVDPs) depends on the regulation. Scaling or widening may be applicable, e.g.,

• FDA: AUC and/or C_max if CV ≥30% in a replicate design
  
• EMA: Only for C_max if no safety concerns (high variability alone is not enough) and CV >30% in a replicate design
  
• Canada: Scaling for AUC under consideration, no confidence interval required for C_max (only T/R within 80–125%)
  
• New Zealand: C_max 75–133% if no safety concerns, no replicate design necessary
  
• Russia: C_max 75–133% (all drugs, no replicate design necessary)
  
• …

If the CV_intra (of the reference!) in the study <30% you are not allowed to scale / widen the acceptance range. See FDA’s progesterone guidance (Step 1a) and EMA’s BE guideline (Section 4.1.10).