Achievwin
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US,
2022-05-20 06:44
(701 d 14:47 ago)

Posting: # 23005
Views: 2,357
 

 Switchability with replicate design studies [Design Issues]

Question for study design experts.

If we want to introduce assessment or claim using BE study which design is more appropriate? 3-way cross over partial study or 4-way cross full replicate design. Please share your experience.

Sincerely,

Achiewin


Edit: Category changed; see also this post #1[Helmut]
Helmut
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2022-05-20 11:17
(701 d 10:14 ago)

@ Achievwin
Posting: # 23006
Views: 2,014
 

 Switchability = IBE

Hi Achievwin,

population BE (prescribability) and individual BE (switchability) are of historic interest only. Both are not assessed in any of the currently recommended approaches (average BE, reference-scaled BE, average BE with expanding limits).

❝ If we want to introduce assessment or claim using BE study which design is more appropriate?


Define ‘appropriate’. An appetizer.

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Achievwin
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US,
2022-05-20 16:19
(701 d 05:12 ago)

@ Helmut
Posting: # 23007
Views: 1,932
 

 Switchability = IBE

❝ population BE (prescribability) and individual BE (switchability) are of historic interest only. Both are not assessed in any of the currently recommended approaches (average BE, reference-scaled BE, average BE with expanding limits).


Thanks for the clarification

I vaguely recall when you don't have subject by formulation interaction in a replicate study design (4-period full replicate design???) you can request switchability (Metadate ANDA I guess)

My question is can we assess this subject by formulation interaction in a 3-period partial replicate design?) what additional statistical test one needs for documenting this?
Helmut
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2022-05-20 17:33
(701 d 03:58 ago)

@ Achievwin
Posting: # 23008
Views: 2,073
 

 S × F interaction

Hi Achievwin,

❝ I vaguely recall when you don't have subject by formulation interaction in a replicate study design (4-period full replicate design???) you can request switchability (Metadate ANDA I guess)


No idea (too lazy to search).

❝ […] can we assess this subject by formulation interaction in a 3-period partial replicate design?) what additional statistical test one needs for documenting this?


Not sure whether it will work. The partial replicate is a nasty beast (for potential problems see there).

IIRC, in the late 1990s concerns about the Subject-by-Formulation interaction emerg­ed. Temporarily studies had to be performed in a replicated design. After assessing the results, the FDA con­cluded that the S × F interaction is practically not relevant and the temporary requirement was lifted.
Furthermore, none of the simulations performed by various authors or by the FDA which lead to RSABE contained an S × F-interaction term in the model.

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Achievwin
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US,
2022-05-21 01:32
(700 d 19:59 ago)

@ Helmut
Posting: # 23010
Views: 1,989
 

 S × F interaction

Thanks Helmut
Brus
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Spain,
2023-06-06 13:02
(319 d 08:29 ago)

@ Helmut
Posting: # 23577
Views: 1,188
 

 S × F interaction

Dear Helmut,

I don't understand the subject-by-formulation effect, can it only be studied in full replicated designs? If the subject-by-formulation effect is the change between test and reference difference means from one subject to another, in a 2x2 design it should be possible to study it. Right?

And in that case it could also be measured in partial replicate. Right?

Maybe I'm confused or don't understand something.

Thank you so much

Best regards,
Helmut
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2023-06-07 12:34
(318 d 08:57 ago)

@ Brus
Posting: # 23580
Views: 1,167
 

 S × F interaction

Hi Brus,

❝ I don't understand the subject-by-formulation effect, …

You are not alone.

❝ … can it only be studied in full replicated designs?

Yes.

❝ If the subject-by-formulation effect is the change between test and reference difference means from one subject to another, in a 2x2 design it should be possible to study it. Right?

No. In a 2×2×2 crossover we have already aliased effects (are victims of confounding). See this article.
Adding S × F will not work. Didn’t try it yet. Either you get zero degrees of freedom in a fixed effects model or a mixed-effects model will collapse.

❝ And in that case it could also be measured in partial replicate. Right?

Nope.

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Achievwin
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US,
2023-06-08 12:21
(317 d 09:10 ago)

@ Helmut
Posting: # 23581
Views: 1,140
 

 S × F interaction

I agree switchability can only be studied by full replicate design, follow up question is now that partial replicate or reference replicate are GONE (??? really) in the new statistics guidance can we study switchability by 3-period replicate design (as it is balanced)....

and

Can we measure the additional parameter needed for NTIDs by 3-period replicate (balanced design)

"Applicants should use the average bioequivalence approach with BE limits of
80-125%. The within-subject variability of test and reference products should be
compared and the upper limit of the 90% confidence interval for the test-to-reference
ratio of the within-subject variability should be ≤ 2.5. For details about the Method for
Statistical Analysis comparing within-subject variability of test and reference products,
refer to Guidance on Warfarin Sodium."


Edit: Full quote removed. Please delete everything from the text of the original poster which is not necessary in understanding your answer; see also this post #5[Helmut]
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