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Back to the forum  Query: 2017-07-25 10:52 CEST (UTC+2h)
 
M.tareq
Junior

2017-02-26 09:34

Posting: # 17110
Views: 1,402
 

 Fed VS Fast state in BE studies [Design Issues]

Dear all ,.
question about fed state design and fast one in a modified release drug

due to expected high variability in fed state study we will use partial replicate design,
however there's no expected high variability in fast state (PPI drug)
my question is the design for the fed state should be the same for fast one ? i.e partial replicate ? and the basis for that if yes, mean we are comparing the test in fed state vs ref in fed state and vice versa

N.B according to EMA guidelines

Thanks in advance

best regards
Dr_Dan
Senior

2017-02-27 11:01

@ M.tareq
Posting: # 17112
Views: 1,208
 

 Fed VS Fast state in BE studies

Dear M.tareq
the design for the fed state study does not need to be the same as for the fasted study. In fact it would be unethical to treat more subjects in the fasted study in a more elaborated design than you would need to demonstrate bioequivalence.

Kind regards and have a nice day
Dr_Dan
Helmut
Hero
Homepage
Vienna, Austria,
2017-02-27 11:32

@ Dr_Dan
Posting: # 17113
Views: 1,200
 

 PPIs sometimes highly variable even in fasted state

Dear Dan and M.tareq,

» the design for the fed state study does not need to be the same as for the fasted study.

Agree.

» In fact it would be unethical to treat more subjects in the fasted study in a more elaborated design than you would need to demonstrate bioequivalence.

When it comes to PPIs I only partly agree. There are no safety concerns (in some contries some PPIs are even available OTC). Sometimes PPIs show a CVwR >30% even in fasted state. IMHO, I could make sense to design both studies in a replicate design – though the sample size could be different.

» » i.e partial replicate ?

The partial replicate is lousy design (search the forum…). See this post why a 4-period full replicate is preferable over 3-period replicates.

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Helmut Schütz 
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DavidManteigas
Regular

Portugal,
2017-02-27 16:08

@ Helmut
Posting: # 17114
Views: 1,090
 

 PPIs sometimes highly variable even in fasted state

Dear all,

Sometimes FDA ask for both fed and fast studies for products for which the SmPC states that no interaction with food occur. In those cases, would it be acceptable to use different designs for each study? Even when the variability in the fed study was preivously found to be higher in pilot studies, for example?

Never happened to me. I'm asking just for curiosity, since from my experience fed studies generally have higher variability than fast studies even when no food effect is expected.

Regards
Helmut
Hero
Homepage
Vienna, Austria,
2017-02-27 16:25

@ DavidManteigas
Posting: # 17115
Views: 1,117
 

 Refuse-to-Receive Standards

Hi David,

» […] would it be acceptable to use different designs for each study? Even when the variability in the fed study was preivously found to be higher in pilot studies, for example?

A replicate design is advantageous if aiming at reference-scaling. However, the FDA is special. If RSABE is not stated in the respective product-specific guidance1 (as an alternative to ABE) I would not risk it2 without controlled correspondence first – otherwise one may fall into this trap.

» […] from my experience fed studies generally have higher variability than fast studies even when no food effect is expected.

Indeed.


  1. Most in draft state and published before April 2010 (when RSABE was for the first time mentioned by the FDA).
    Omeprazole, Pantoprazole: No. Lansoprazole: Yes (only fasting :confused:).
  2. Of course, in statistical terms any replicate design – even if aimed only at ABE – is better than a simple crossover.

[image]All the best,
Helmut Schütz 
[image]

The quality of responses received is directly proportional to the quality of the question asked. ☼
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M.tareq
Junior

2017-03-17 13:11

@ Helmut
Posting: # 17161
Views: 810
 

 Refuse-to-Receive Standards

sorry for the late reply

Thanks Dan and Helmut

question about unexpected high variability in fast state, and sample size estimation based on published assessment reports other BE studies
read in your lectures about pooling of CV, however the validity of sample size estimation based on these studies, what if we ended up with higher CV than expected, would be allowable to go with a 2nd stage, after power evaluation ?


thanks in advance
nobody
Senior

2017-03-17 16:27

@ Helmut
Posting: # 17162
Views: 787
 

 Refuse-to-Receive Standards

» ...
» Lansoprazole: Yes (only fasting :confused:).

Must be a typo/missing sentence, see Guide for orally disintegrating lansoprazole tablets dated OCT-2016 ;-)

Kindest regards, nobody
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