Belarus = member of the EEU [Regulatives / Guidelines]
❝ Due to logistic issues (a small clinical center and a highly variable drug) we have to conduct a bioequivalence study in multiple groups (two).
Are you aiming at reference-scaling for Cmax, i.e., perform the study in a replicate design? Even if not, opt for the “staggered approach” – not the “stacked” one (see above).
❝ Our competent authority requires a justification not to include the group effect in the proposed statistical model.
IMHO, stupid – but according to the GL.

❝ The groups will be separated by a week at maximum.
Very good.
❝ It seems that we meet criteria set out by FDA to use a statistical model without including the group effect. Our competent authority can accept the FDA position on this issue, but we should properly reference it.
See this presentation summarizing my current thinking. Note that (since I don’t speak Russian) my remarks given on slide 16 are only partly correct. A justification in the protocol (as you rightly mentioned) should be acceptable. In the discussion following my presentation it became clear that:
- Pooling (i.e., model III without a justification in the protocol) lead to rejection of the study. A justification in the report only was never consider sufficient by – Russian – experts.
- Nobody tried model II without a pre-test (this would be a much better option than the FDA’s step-wise models). Why? Duno. No inflation of the Type I Error and the loss in power would be limited (see my small meta-analysis above) and would be compliant with the FDA’s 2001 guidance Section VII.A.:
- […] the statistical model should be modified to reflect the multigroup nature of the study. In particular, the model should reflect the fact that the periods for the first group are different from the periods for the second group.
❝ Thus, where can I find this information under FOI (link) …
FDA’s step-wise models (which I would never ever use) are given here and there (maybe there are some more; too lazy to google). However, in the second document you find Comment 9:
If ALL of the following criteria are met, it may not be necessary to include Group-by-Treatment in the statistical model:
- the clinical study takes place at one site;
- all study subjects have been recruited from the same enrollment pool;
- all of the subjects have similar demographics;
- all enrolled subjects are randomly assigned to treatment groups at study outset.
- In this latter case, the appropriate statistical model would include only the factors Sequence, Period, Treatment and Subject (nested within Sequence).
❝ … might it be possible that someone can share a copy of letter signed by Barbara Davit where it is outlined requirements to ignore the group effect in a statistical model?
I can’t share mine (chained to my table by a CDA). Maybe Detlew can share his. Note that the wording of Barbara’s letter is identical to the second reference above.
Dif-tor heh smusma 🖖🏼 Довге життя Україна!
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Helmut Schütz
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The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
Complete thread:
- Russian «Экспертами» and their hobby Helmut 2017-04-29 00:46 [Regulatives / Guidelines]
- Low power of Group-by-Treatment interaction mittyri 2017-04-29 22:57
- Let’s forget the Group-by-Treatment interaction, please! Helmut 2017-04-30 13:54
- Let’s forget the Group-by-Treatment interaction, please! ElMaestro 2017-05-01 16:19
- Some answers Helmut 2017-05-02 01:10
- Some answers ElMaestro 2017-05-02 09:04
- Example Helmut 2017-05-02 12:35
- Sensitivity of term? mittyri 2017-05-02 18:29
- Simulations Helmut 2017-05-05 14:38
- loosing specificity due to low sensitivity mittyri 2017-05-08 23:28
- loosing specificity due to low sensitivity Helmut 2017-05-09 00:55
- loosing specificity due to low sensitivity mittyri 2017-05-08 23:28
- Loss in power Helmut 2017-05-06 17:31
- Interval between groups Helmut 2017-05-08 19:02
- IMP handling mittyri 2017-05-08 23:40
- IMP handling Helmut 2017-05-09 01:08
- IMP handling mittyri 2017-05-08 23:40
- Loss in power Helmut 2017-05-14 17:22
- Simulations Helmut 2017-05-05 14:38
- Some answers ElMaestro 2017-05-02 09:04
- No convergence in JMP and Phoenix WinNonlin Helmut 2017-05-25 15:26
- Ouch?!??? ElMaestro 2017-05-25 16:24
- Some answers Helmut 2017-05-02 01:10
- Let’s forget the Group-by-Treatment interaction, please! ElMaestro 2017-05-01 16:19
- Let’s forget the Group-by-Treatment interaction, please! Helmut 2017-04-30 13:54
- Russian «Экспертами» and their hobby Artem Gusev 2017-05-02 16:13
- be careful with mixed models mittyri 2017-05-02 17:53
- be careful with mixed models Artem Gusev 2017-05-03 11:02
- p-value(s) in model 2 Helmut 2017-05-05 14:48
- be careful with mixed models mittyri 2017-05-02 17:53
- Russian «Экспертами» following the EEU GLs Helmut 2017-05-24 20:17
- Russian «Экспертами» following the EEU GLs Beholder 2017-05-24 22:37
- Penalty for carelessness mittyri 2017-05-25 08:52
- Russian «Экспертами» following the EEU GLs Beholder 2017-05-25 10:43
- Russian «Экспертами» following the EEU GLs Mikalai 2018-01-04 10:43
- Belarus = member of the EEUHelmut 2018-01-04 13:08
- Belarus = member of the EEU Mikalai 2018-01-04 19:49
- Trying your model for EEU mittyri 2018-01-04 22:04
- Trying your model for EEU Helmut 2018-01-05 00:06
- help us to stop it, please... Astea 2018-01-10 12:09
- help us to stop it, please... Beholder 2018-01-10 12:49
- regulators convinced by science? d_labes 2018-01-10 15:15
- regulators convinced by science? Beholder 2018-01-10 17:14
- Чёрт побери! d_labes 2018-01-10 18:53
- regulators convinced by science? Astea 2018-01-10 19:10
- regulators convinced by science? Beholder 2018-01-10 17:14
- help us to stop it, please... Astea 2018-01-10 12:09
- Trying your model for EEU Helmut 2018-01-05 00:06
- Belarus = member of the EEUHelmut 2018-01-04 13:08
- Russian «Экспертами» following the EEU GLs Beholder 2017-05-24 22:37
- Low power of Group-by-Treatment interaction mittyri 2017-04-29 22:57