nuka2020
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United Arab Emirates,
2020-11-19 11:09
(151 d 08:19 ago)

Posting: # 22067
Views: 880
 

 highly variable drugs-Cmax [Regulatives / Guidelines]

According to the GCC guidelines a wider range of Cmax(i.e 75-133%) can be acceptable for HVDP, where it has been demonstrated that the within- subject variability for Cmax of the reference compound in the study is >30%.
But, i have a study which was performed as per Eu guidelines and accordingly, the acceptance criteria for Cmax can be widened to a maximum of 69.84 – 143.19%. Accordingly, the results of Cmax is: 70.46%-141.90%
Need suggestion whether this studies can be acceptable as per GCC guidelines?? :confused::confused:
Helmut
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Vienna, Austria,
2020-11-19 12:05
(151 d 07:23 ago)

@ nuka2020
Posting: # 22068
Views: 757
 

 GCC: HV Cmax (fixed limits)

Hi nuka2020,

» According to the GCC guidelines a wider range of Cmax(i.e 75-133%) can be acceptable for HVDP, where it has been demonstrated that the within- subject variability for Cmax of the reference compound in the study is >30%.
» … the results of Cmax is: 70.46%-141.90%
» Need suggestion whether this studies can be acceptable as per GCC guidelines??

What do you think?
Though you have practically a perfect PE (99.99%) you failed to show BE by far. For the GCC your study was just underpowered.

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wienui
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Germany, Oman,
2020-11-19 18:04
(151 d 01:24 ago)

(edited by wienui on 2020-11-20 07:13)
@ nuka2020
Posting: # 22069
Views: 739
 

 highly variable drugs-Cmax

Hi nuka & Helmut,

» According to the GCC guidelines a wider range of Cmax(i.e 75-133%) can be acceptable for HVDP, where it has been demonstrated that the within- subject variability for Cmax of the reference compound in the study is >30%.
» But, i have a study which was performed as per Eu guidelines and accordingly, the acceptance criteria for Cmax can be widened to a maximum of 69.84 – 143.19%. Accordingly, the results of Cmax is: 70.46%-141.90%
» Need suggestion whether this studies can be acceptable as per GCC guidelines?? :confused::confused:

Unfortunately, we come back again to this point. Although the GCC GL is adopted from the EMA GL,
but the upper cap of scaling is about only 39% and not 50%!!!!
At the moment, I think you could have a good chance under the conditions that your BE study is demonstrated in a replicate design and that the high within-subject variability for Cmax not caused by outliers.

Cheers,
Osama
Helmut
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Vienna, Austria,
2020-11-19 20:58
(150 d 22:30 ago)

@ wienui
Posting: # 22070
Views: 724
 

 highly variable drugs-Cmax

Hi Osama,

» Although the GCC GL is adopted from the EMA GL, but the upper cap of scaling is about only 39% and not 50%!!!!

library(PowerTOST)
noquote(sprintf("%.2f%%", 100*U2CVwR(U = 1/0.75)))
[1] 39.25%

:-D

I wouldn’t call that scaling. The GL calls for fixed limits of 75.00–133.33% (based on a “clinically not relevant Δ” of 25%) for any CVwR >30% (there is no upper cap and the widened limits are fixed).
That’s the approach mentioned in the EMA’s Q&A-document of July 2006:

[image]

BTW, with fixed limits there are no issues with inflation of the type I error* like in all reference-scaling methods (EMA, Health Canada, FDA). When discussing the EMA’s draft, sponsors complained that ABEL is more restrictive at CVwR 30–39.25% than the “old” approach…

» At the moment, I think you could have a good chance under the conditions that your BE study is demonstrated in a replicate design and that the high within-subject variability for Cmax not caused by outliers.

That’s interesting!



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Helmut Schütz
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