Aber meine Herren das ist keine physik [Regulatives / Guidelines]

posted by Astea – Russia, 2020-06-08 00:08  – Posting: # 21506
Views: 3,536

Dear Helmut and Mittyri!

» Scientifically there is no point on measuring that long (IR only, of course) and the regulatory “≥80%-rule” is made out of thin air.

Do you know a legend about Ehrenfest's parrot? I wish I have that parrot to say: "Aber meine Herren das ist keine Wissenschaft!" every time I get the request to use 80% rule :-D

» If you have a lot of time and nothing better to do, perform simulations.

"Spare time" are the two very funny words, I wish I knew their meaning. Nevertherless thank you for the point, may be I will investigate it one day. Let all dogs be alive!
By the way is not it similar to one used in 1997 by Endrenyi L. et al1?

» In guidelines commonly “should be” is used. What’s your interpretation of the Russian original? Does it smell of a recommendation or rather a requirement?

As far as I know the war almost starts when russian experts try to translate this word properly. For me "должно быть" sounds like an order. We use "следует" to slightly soften the meaning and "рекомендуется" for the recommendation.
("Marain was a synthetic language, designed to be phonetically and philosophically as expressive as the pan-human speech apparatus and the pan-human brain would allow")

» Let’s heighten the absurdity. We want to submit to two agencies, A and B, where B accepts a study with a foreign reference product. Both agencies have GLs asking for AUC0–t. We write the SAPs accordingly. Before the study starts, agency A allows AUC0–72. We write an amendment for agency A. Study performed. We have one (!) data set and will have no problems with agency A but likely receive a deficiency letter from agency B.

This situation is not that absurd. I often deal with protocols where the definition of AUC is ambiguously: in the one part of the protocol they are talking about AUC0–72 and in the other - about AUC0–t (AUClast). Noone understands how it can differ if t=72 hours. About AUC0–t (AUCall) see also Oishi M. et al.2

» Which version of Phoenix are you using? The last triangle is not added in the second data set (containing the 72 h time point and BQL). You would only get AUCall 2376 if you set the last concentration to zero. IMHO, not a good idea.

Yes, you guessed, that was a stupid case of zero as LLOQ. I use 8.2. As Mittyri pointed out upper, the calculation doesn't depend from the version. Anyway one may note that AUC0-72 and AUC0-t when t=72 are not always equal (especially considering the cases with deviations in sampling time).


  1. Endrenyi L, Csizmadia F, Tothfalusi L, Balch AH, Chen ML. The duration of measuring partial AUCs for the assessment of bioequivalence. Pharm Res. 1998;15(3):399‐404. doi:10.1023/A:1011916113082.
  2. Oishi M, Chiba K, Fukushima T, Tomono Y, Suwa T. Different truncation methods of AUC between Japan and the EU for bioequivalence assessment: influence on the regulatory judgment. Drug Metab Pharmacokinet. 2012;27(6):658‐662. doi:10.2133/dmpk.DMPK-12-RG-033.

"Being in minority, even a minority of one, did not make you mad"

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