Bioequivalence and Bioavailability Forum • highly variable drugs-Cmax

nuka2020
☆

United Arab Emirates,
2020-11-19 12:09
(1693 d 13:50 ago)

Posting: # 22067
Views: 4,102

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:

Helmut
★★★

Vienna, Austria,
2020-11-19 13:05
(1693 d 12:54 ago)

@ nuka2020
Posting: # 22068
Views: 3,444

GCC: HV Cmax (fixed limits)

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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 🖖🏼 Довге життя Україна!
Helmut Schütz

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wienui
★

Germany/Oman,
2020-11-19 19:04
(1693 d 06:55 ago)

(edited on 2020-11-20 07:13)
@ nuka2020
Posting: # 22069
Views: 3,499

highly variable drugs-Cmax

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Hi nuka & Helmut,

❝ 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:

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 21:58
(1693 d 04:01 ago)

@ wienui
Posting: # 22070
Views: 3,531

highly variable drugs-Cmax

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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 CV_wR >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 CV_wR 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!

Wrong! See this thread.

—
Dif-tor heh smusma 🖖🏼 Довге життя Україна!
Helmut Schütz

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