Bioequivalence and Bioavailability Forum

Dear Ioanam
i have some points to add to the discussion below. i am making certain assumptions regarding the study design ioanam mentioned.
HS talks here about problem re steady state phase. of course, it depends on the drug, but you will rarely come across a drug that will not show concentrations above the LOQ on multiple dosing!!!!! and yes, the washout period will be longer than in the single dose, naturally. no regulatory body recommends a washout less than at least 7-10 half-lives in steady state studies. the fact that the study has been coducted as a crossover, shows that there was a possibility of an effective washout period. of course, if the drug has accumulated and not completely removed from body in the washout period, it will show up as significant pre-dose concentration in the next period,and there you are caught!!! then the second period will never be considered for PK and statistical analysis at all.
HS has raised a point regarding blood loss. with new,more accurate and precise analytical methods coming up, you don't need to take 10ml or even 5ml blood to carry out analysis for such a long study. the only problem you would have to face here is subject compliance!!!!! and possibly ethical issues about taking so many ambulatory samples.
As to taking relevant data from respective periods, it is generally accepted that such issues can be predefined in the protocol to avoid regulatory problems.
As to the last point re regulatory acceptance. i am sure the regulatory says "In addition to the single-dose studies described ........, a comparison should be made between .......................... at steady state." its how you interpret it. when you say "in addition to", does it mean in a separate trial, or a different phase?
"musable" issues, if you ask me.
i found a recent declaration by the DKMA quite amusing. it said that "the 90% confidence interval for the ratio test versus reference should include 100% irrespective of whether acceptance limits of 80-125% or narrower are employed.". looks like someone was playing hookey with the guidelines!!!!
SN

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Edit: Full quote removed. [HS]