Bioequivalence and Bioavailability Forum

» You can’t verify anything in science.
» In statistics you can only try reject a properly stated null hypothesis – which is in your case what? Any test at level \(\small{\alpha}\) has an unavoidable false positive rate. Do you want to exclude \(\small{(100\times\alpha)\%}\) of subjects although they are in (pseu­do) steady state?

I will not exclude any subjects from analysis, I just need to check achievement of steady state in compliance with EMA guideline. The guideline didn't specify the verification method.
I have reviewed the comments raised for this guidance, the proposed changes in page 53 and page 54 include visual inspection of the last three pre-dose concentrations to verify steady state achievement and the feasibility to use the last 2 pre-dose concentrations and the Ctau instead of the last 3 pre-dose concentrations.
EMA has evaluated the comments.
They mentioned in page 4 that clarifications on steady state evaluation was included in the final guidance following stakeholder comments. I searched for this final guidance but I didn't find it, the published effective version is still the one came into effect in 2015.
Is it feasible to verify steady state visually?

» » I need your help to perform this verification using Helmert transformation method …
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» Do you have a reference demonstrating its application in PK? Never came across this approach in 40+ years. See there why statistical tests are nonsense – essentially because we don’t have a proper null.

No, I don't have references. It was suggested as the best method for steady state verification by a reviewer during protocol preparation two years ago and accordingly documented in the protocol.

Thanks for your cooperation.