Bioequivalence and Bioavailability Forum

Dear Boonchai!

❝ Who define HVD?

Convention (aka old hat).
Was first stated at the Bio-International ’89 in Toronto, Canada as 25% CV being “problematic” and 30% considered highly variable. ≥30% Was agreed upon at the Bio-International ’92 in Bad Homburg, Germany.^1,2
Nitpicking terminology: We distinguish between HVDs (Highly Variable Drugs: CV of a solution ≥30%) and HVDPs (Highly Variable Drug Products: CV of a formulation ≥30%). EMA adopted this wording in the current guideline.

❝ Does it subject to the regulator in each country? Is it useless?

No and no.
In some countries widening of the BE-limits is acceptable:

• Arbitrary to 75–133% for C_max if based on clinical grounds: old EMEA guideline, Australia, ASEAN states,…
  
• For C_max and AUC in product-specific GLs of the FDA (no clinical justification); RSABE-scaling, GMR restriction 80–125%.
  
• For C_max according to current EMA-GL: ABEL limited with CV≤50%, clinical justification, GMR restriction 80–125%. Note that generally HVDs/HVDPs are defined with CV at least 30%; EMA states CV greater than 30%.
  
• For AUC according to Canada’s TPD drafted-GL: unlimited ABEL, no GMR restriction.

So far about global harmonization.


Note that the bioequivalence limits are displayed in ln-scale in order to show the symmetry around 1:
ln(1) = 0 and ln(0.80, 1.25) = ∓0.2231.

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1. Blume HH, Midha KK. Bio-International ’92, Conference on Bioavailability, Bioequivalence and Pharmacokinetic Studies. Int Pharm J. 1993;7(5):201–5. doi:10.1002/jps.2600821125.
   
2. Blume HH, Midha KK, editors. Bio-International. Bioavailability, Bioequivalence and Pharmacokinetics. Stuttgart: medpharm Scientific Publishers; 1993.