nuka2020
☆

United Arab Emirates,
2020-11-19 11:09
(8 d 01:04 ago)

Posting: # 22067
Views: 327

## 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??
Helmut
★★★

Vienna, Austria,
2020-11-19 12:05
(8 d 00:08 ago)

@ nuka2020
Posting: # 22068
Views: 293

## 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.

Dif-tor heh smusma 🖖
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
wienui
★

Germany, Oman,
2020-11-19 18:04
(7 d 18:09 ago)

(edited by wienui on 2020-11-20 07:13)
@ nuka2020
Posting: # 22069
Views: 266

## 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??

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
★★★

Vienna, Austria,
2020-11-19 20:58
(7 d 15:15 ago)

@ wienui
Posting: # 22070
Views: 250

## 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%

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:

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!

Dif-tor heh smusma 🖖
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes