Bioequivalence and Bioavailability Forum

Hi Helmut,

❝ If I trust in Google-translate:

Lately it's getting better. I recently read quite a long piece of BE guideline in Russian to look for something specific. I can't imagine I'd be able to do that without it.

❝ AUC_0–72 only for drugs with a long half-life. What does the last sentence mean?

Basically it's a translation from the FDA's guidance in the corresponding section:
"For drugs demonstrating high intrasubject variability in distribution and clearance, AUC truncation should not be used."

❝ Seemingly no reference-scaling.

It was mentioned in the section about general study design (page 4 of the word file) but there's no details. There's only one sentence about HVDP and I gave the rough translation as follows:

"With regard to high variable drug product, depending on the intra-subject variability of the reference product, the bioequivalence criteria can be adjusted appropriately; however, such adjustment should be based on adequate evidence."

There are more details about HVDP in the appendix of Chinese Pharmacopedeia 2015. It was mentioned that for Cmax the maximum criteria can be widened to 69.84% to 143.19% (ratio within 80–125%) but they didn't copy the rest information such as [U, L] = exp [±k·sWR], from EMA's guide (So if one doesn't know EMA's method, how can he/she obtain criteria for any particular CV%? )

From a presentation in BE training course given by CFDA staff in 2017, it seems they are using EMA's approach for HVDP.

❝ Multiple strengths of drugs with nonlinear PK (grater than proportional increase in AUC)?

❝ EMA: highest strength.

❝ FDA: highest therapeutic dose.

❝ CFDA?

I think that FDA also recommend highest strength, same as EMA. See line 316–319 in the draft guidance. Where did it mention highest therapeutic dose?

For CFDA, highest strength.

To summarise, I think CFDA mixed EMA's and FDA's latest BE guides as their BE guide and took a stricter one when there's difference betweem EMA and FDA. e.g., fasting + fed for almost all drug as FDA does but there's cap of Cmax criteria for HVDP as EMA does.