Bioequivalence and Bioavailability Forum • Confuse a Cat Inc.

Confuse a Cat Inc. [BE/BA News]

posted by Helmut – Vienna, Austria, 2022-04-11 15:59 (602 d 18:45 ago) – Posting: # 22925
Views: 4,377

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 t_max in all subjects) and
likely narrower intervals than usual.

As shown in my example in the other post t_max 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 t_max 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 t_max. So what?
Not by chance. It’s common that the time point of E_max is < t_max.

❝ 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

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes

Complete thread:

EMA: New product-specific guidances Helmut 2022-04-08 15:17 [BE/BA News]
- How would you implement it? ElMaestro 2022-04-09 11:45
  - Confuse a Cat Inc. Helmut 2022-04-09 18:40
    - Confuse a Cat Inc. ElMaestro 2022-04-09 21:47
      - Confuse a Cat Inc. Ohlbe 2022-04-11 11:29
        
        Confuse a Cat Inc.Helmut 2022-04-11 13:59
        
        Range Ohlbe 2022-04-11 15:48
        
        Range Helmut 2022-04-11 16:07
        
        Range Ohlbe 2022-04-11 16:20
        
        Range Helmut 2022-07-28 14:43
      - So many questions, so few answers Helmut 2022-04-11 13:03
      - Preliminary simulations Helmut 2022-04-30 14:59
        
        Preliminary simulations ElMaestro 2022-04-30 19:10
        
        Preliminary simulations Helmut 2022-05-01 15:56
        Revisions of the PSGLs final Helmut 2023-06-23 13:29
        
        Revisions of the PSGLs final dshah 2023-06-28 14:43
        
        EMA: No problems with many sampling time points… Helmut 2023-06-28 15:59
        New simulations & some desultory thoughts Helmut 2023-06-29 11:34
        
        SCNR. A heretic alternative. Helmut 2023-06-30 11:50
      - Simulated distributions Helmut 2022-05-02 13:43