Bioequivalence and Bioavailability Forum

Dear Dan,

❝ Do you agree with these considerations?

No, sorry I don't...

If the reason for ISR failure is metabolite back-conversion, I have two concerns:

• metabolites can have a lower intra-CV than the parent (I have seen a few examples; clopidogrel, well-known for metabolite back-conversion, is one of them). If what you measure is a mix of parent and metabolite, you will get a lower intra-CV and increase your chances to demonstrate BE;
  
• according to the BE guideline, metabolites are less sensitive to detect differences in formulation than the parent. I have seen a nice example too, where we had differences in dissolution profiles between the test and the reference; bioequivalence was demonstrated for the metabolite but not for the parent. Again if what you measure is a mix of parent and metabolite, you could get a point estimate closer to 1.

Even if ISR fails for another reason than metabolite back-conversion, I always had problems with justifications like "my method is just as bad for the reference as for the test, so there should be no impact in the end". Sorry !

I also have problems to say that an increase in the analytical variability can only decrease chances to demonstrate bioequivalence. You can't exclude that it will result in a point estimate closer to 1, or in a slightly decreased intra-CV (difficult to predict the influence of a random effect, isn't it ?). It would be great to run some sims:

• take a BE trial with 24 subjects, borderline failing for Cmax (let's say 90 % CI 79-98 %). Consider these Cmax values as "true values".
  
• add some analytical variability to the Cmax values (CV 10 %, 15 %, 20 %, 25 %, 30 %)
  
• see how often the study passes in the end (just the 5 % alpha, or more ?). How often does the point estimate get closer to 1 and by how much, and how often is the intra-CV reduced.

To be honest I don't expect much changes for AUC, but Cmax could be more problematic.
I'm afraid I just don't know how to fire such sims. If any of our sims-specialists gets bored during the Christmas break

Regards
Ohlbe