Sereng
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USA,
2022-01-28 19:37
(198 d 12:30 ago)

Posting: # 22757
Views: 738
 

 Sample Size Effi­ci­ency of 4-Period, 2-Seq, 2-Formu­la­tion Design [RSABE / ABEL]

Folks, I really appreciate the guidance from this Forum. We need to conduct a 4-Period, 2-Sequence, 2-Formulation BE study per FDA "product specific guidance" (PSG). The PSG also asks us to use the RSABE approach for properly adjusting the BE acceptance criteria based on "reference variability and comparing test and referenced product within-subject variability". Can we safely assume that conducting such a replicate study would (at least) reduce our sample size by 50% over a 2-Period, 2-Sequence, 2-Formulation BE study? If correct, and assuming no more dropouts (from the longer study), would there be any additional sample size efficiency arising from the use of the RSABE? Any help would be much appreciated! Many thanks!
Helmut
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Vienna, Austria,
2022-01-28 21:06
(198 d 11:02 ago)

@ Sereng
Posting: # 22758
Views: 650
 

 Sample Size Efficiency of 4-Period, 2-Seq, 2-Formulation Design

Hi Sereng,

» […] The PSG also asks us to use the RSABE approach for properly adjusting the BE acceptance criteria based on "reference variability…

So far so good.

» … and comparing test and referenced product within-subject variability".

That’s rather unusual. Can you post a link to the guidance?

» Can we safely assume that conducting such a replicate study would (at least) reduce our sample size by 50% over a 2-Period, 2-Sequence, 2-Formulation BE study?

No, that’s wrong. See there.

» […] would there be any additional sample size efficiency arising from the use of the RSABE?

The idea behind RSABE is to maintain power independent from the CV.

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Sereng
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USA,
2022-01-28 21:40
(198 d 10:28 ago)

@ Helmut
Posting: # 22759
Views: 709
 

 Sample Size Efficiency of 4-Period, 2-Seq, 2-Formulation Design

» Can you post a link to the guidance?

Hi Helmut, many thanks for your response. Below are the PSG links, one PSG asks you to refer to the second, although the first one may have the information (Sorry, I don't know how to attach the document here). I look forward to your guidance. Regards

https://www.accessdata.fda.gov/drugsatfda_docs/psg/Levothyroxine_Sodium%20capsules_NDA%20021924_RC%20Oct%202018.pdf

https://www.accessdata.fda.gov/drugsatfda_docs/psg/Warfarin_Sodium_tab_09218_RC12-12.pdf


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]
Helmut
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Vienna, Austria,
2022-01-29 12:19
(197 d 19:49 ago)

@ Sereng
Posting: # 22760
Views: 595
 

 NTIDs

Hi Najib,

» […] one PSG asks you to refer to the second, …

The Draft Guidance on Warfarin Sodium of 2012 was the first describing the FDA’s method of reference-scaling for NTIDs. All later ones refer to the first and state

For details about the Method for Statistical Analysis Using the Reference-Scaled Average Bioequivalence Approach for narrow therapeutic index drugs, refer to the Guidance on Warfarin Sodium Tablets.


For the sample size estimation see there (including examples and references).

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