Bioequivalence and Bioavailability Forum

Hi Helmut,

Agree with the first 2 points.

❝ 3. By fully replicate you talk about the four-period RTRT|TRTR. No doubt about three missing periods. It’s tricky if both administrations of the test are missing. Although IMHO it is a little bit strange why a subject missing a period should come back for others. But EMA’s Q&A-document contains such a wacky example data set and I have seen a case in the wild. Would you keep the subject in the analysis only to get a better estimate of CV_WR? I would not; this time agreeing with EMA’s GL above.

Well, for FDA you might need to do it differently.

I asked FDA (along with other questions) if subject who missed 2 periods of test but has data of 2 periods of reference should be included to have a better estimate of S_WR and after 1 year and 3 months I finally got answers from them:

For 4-period replicate BE study subject who has 2 periods of reference should be included for S_WR (even if they has no data of test product) but for estimate the difference between T and R only subjects who have no missing period should be included (so if subject has only 3 periods, exclude him).

The response is shockingly slow but at least it leaves no doubt on this topic.

I think the principle for estimation of S_WR should be the same for EMA study as well for which I usually clearly stated in the protocols that subject with 2 periods of reference (even if no test data) will be included to estimate the S_WR but for evaluation of BE subject will have crossed at least once (minimum 1T and 1R) as indicated in the guideline and in the sample dataset in Q&A document.