## Confuse a Cat Inc. [BE/BA News]

Hi Ohlbe,

❝ My gut feeling is that all they expect to get are descriptive statistics: report median Tmax for Test, median Tmax for Reference, …

So far so good. Standard for ages.

❝ … calculate a % difference (however inappropriate this may be), …

It is indeed.

❝ … pass if it is not more than 20%, otherwise fail.

That’s my understanding as well.

❝ Consequence: if you have more than 20% difference between sampling times around the expected Tmax, you're screwed if median Tmax values are different even by just one sampling time, …

Correct. IMHO, you need
• equally spaced intervals until absorption is essentially complete (in a one compartment model at least two times the expected tmax in all subjects) and
• likely narrower intervals than usual.
As shown in my example in the other post tmax will drive the sample size. How much larger will it have to be? Not the slightest idea. Likely much larger.

❝ … even if this has strictly no clinical relevance (this could be brought up in the comments to the draft guideline: come on guys, are you sure a Tmax of 10' for one formulation and 15' for the other is really something totally unacceptable ?

Exactly. Recall what the almighty oracle stated in the BE-GL:

[…] if rapid release is claimed to be clinically relevant and of importance for onset of action or is related to adverse events, there should be no apparent difference in median tmax and its variability between test and reference product.

It boils down to: Is it clinically relevant? If not, a comparison is not required. Furthermore: PK PD.

❝ I mean, even for tadalafil you should be able to keep yourself busy until it works).

Tadalafil shows an effect before tmax. So what?
Not by chance. It’s common that the time point of Emax is < tmax.

❝ Range: no expectation described. No idea.

The range is completely useless. Like the mean it has a breakdown point of zero. Imagine with $$\small{n\rightarrow \infty}$$: $$\small{\left\{R_1=1,\ldots, R_n=1\phantom{.25}\right\} \rightarrow \textrm{Range}(R)=0\phantom{.25}}\\\small{\left\{T_1=1,\ldots, T_n=1.25\right\} \rightarrow \textrm{Range}(T)=0.25}$$ Good luck in calculating a ratio.

❝ Of course I may be totally wrong.

So am I.

Dif-tor heh smusma 🖖🏼 Довге життя Україна!
Helmut Schütz

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