Bioequivalence and Bioavailability Forum

Hi AchievWin,

❝ Whether we like it or not this question keep popping, can you both or anyone answer my questions above (I have views but I want to hear what other alternatives are there - my views align mostly with Helmut view but.... regulators are regulators)

Again, tell regulators to follow their own guidances. Be polite, if you can.

❝ I am struggling with the basic question how to quantify carry-over?

After a dose we know only one thing for sure:
The concentration is not zero.¹

A good part of Stephen Senn’s textbook² can be understood as an essay against carryover in the model.

If you are really interested in the behavior of the drug/formulation, you could only try PK modeling. Good luck. Even if you succeed, then what? Subtract the estimated concentration-time course of previous period(s) from the observed ones to get the ‘true’ concentrations? No regulator would accept that.

See there (Case 1, slides 4–7). I subtracted the fitted concentrations and presented it as a supportive analysis (after some subjects with pre-dose concentrations in higher periods we amended the SAP). Luckily the total (between- + within-subject) variability was low. The German agency accepted the study based on the data of the first period evaluated as a parallel design (new primary analysis; we crossed fingers). The study passed but it was a close shave.
BTW, with the current ≤5% C_max rule evaluation as a crossover would have been not be a problem…

❝ and for some products that <5% of Cmax rule is not applied (this is a news for me)

Are you talking about endogenous compounds? Nasty beasts.

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1. Harold Boxenbaum at: Analytical Methods Validation: Bioavailability, Bioequivalence and Pharma­co­ki­netic Studies. (Crystal City I Con­fe­rence). Arlington, VA. December 3–5, 1990.
   
2. Senn S. Cross-over Trials in Clinical Research. Chichester: Wiley; 2^nd ed. 2002. ISBN: 978-0-471-49653-3.