Researcher101
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Egypt,
2021-02-23 20:40
(79 d 00:09 ago)

Posting: # 22224
Views: 1,321

## Scaling/Widening of AUC [Regulatives / Guidelines]

I'm asking if there is any guidance allowing scaling of AUC in case of highly variable drugs and what is the range of scaling if applicable

Edit: See this post #3. [Helmut]
Loky do
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Egypt,
2021-02-24 13:13
(78 d 07:35 ago)

@ Researcher101
Posting: # 22227
Views: 915

## Scaling/Widening of AUC

Dears
Also Regarding AUC widening, is it applicable in both partially and fully replicate designs or fully replicate design only as FDA referred to the published book chapter for RSABE for AUC and Cmax in fda draft guidance for progesterone? So could we apply it in general or it’s not applicable?
Helmut
★★★

Vienna, Austria,
2021-02-24 14:46
(78 d 06:02 ago)

@ Loky do
Posting: # 22228
Views: 910

## RSABE…

Hi Loky do,

» Regarding AUC widening, is it applicable in both partially and fully replicate designs …

If the main condition for RSABE is fulfilled (high variabilty), yes. Contrary to jurisdictions applying ABEL, a clinical justification and assessment of ‘outliers’ is not required.
In RSABE you don’t ‘widen’ the limits. That’s a simplification. For the background see this post and the guidance you mentioned.

» … or fully replicate design only as FDA referred to the published book chapter for RSABE

Which book are you referring to?

» So could we apply it in general or it’s not applicable?

For the FDA you can apply RSABE for any PK metric (AUCs, partial AUCs, Cmax, ) if its $$\small{s_{\textrm{wR}}\geq 0.294\;(CV_{\textrm{wR}}\geq\approx0.300469\ldots)}$$
If $$\small{s_{\textrm{wR}}<0.294}$$ you have to evaluate the respective PK metric for ABE.

Dif-tor heh smusma 🖖
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
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Loky do
☆

Egypt,
2021-02-24 15:30
(78 d 05:19 ago)

@ Helmut
Posting: # 22230
Views: 884

## RSABE…

Hi Dear Helmut,

» Which book are you referring to?
»
» For the FDA you can apply RSABE for any PK metric (AUCs, partial AUCs, Cmax, ) if its $$\small{s_{\textrm{wR}}\geq 0.294\;(CV_{\textrm{wR}}\geq\approx0.300469\ldots)}$$
» If $$\small{s_{\textrm{wR}}<0.294}$$ you have to evaluate the respective PK metric for ABE.

I didn't find this statement in FDA guidance for bioequivalence studies just in progesterone guidance so, is it enough to refer to this guide while submitting the study to regulatory (as the intrasubject variability CV% equal 57%, partially replicate design), or is there another guide would support this way? please advice?

Helmut
★★★

Vienna, Austria,
2021-02-24 15:47
(78 d 05:02 ago)

@ Loky do
Posting: # 22231
Views: 876

## RSABE…

Hi Loky do,

» I didn't find this statement in FDA guidance for bioequivalence studies …

RSABE appears in the ANDA draft guidance of December 2013 (footnote 10 on page 4 = page 8 of the PDF).
Don’t waste your money and get the book mentioned there – the chapter is not helpful. Get the paper by Davit et al.* instead. Free and better.

» … just in progesterone guidance so, is it enough to refer to this guide while submitting the st udy to regulatory (as the intrasubject variability CV% equal 57%, partially replicate design), or is there another guide would support this way?

Any one would do, IMHO.

• Davit BM, Chen ML, Conner DP, Haidar SH, Kim S, Lee CH, Lionberger RA, Makhlouf FT, Nwa­kama PE, Patel DT, Schuirmann DJ, Yu LX. Implementation of a Reference-Scaled Average Bioequivalence Approach for Highly Variable Generic Drug Products by the US Food and Drug Administration. AAPS J. 2012; 14(4): 915–24. doi:10.1208/s12248-012-9406-x. PMC Free Full text.

Dif-tor heh smusma 🖖
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
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Helmut
★★★

Vienna, Austria,
2021-02-24 15:29
(78 d 05:20 ago)

@ Researcher101
Posting: # 22229
Views: 885

## Scaling/Widening of AUC

Hi Researcher101,

» I'm asking if there is any guidance allowing scaling of AUC in case of highly variable drugs and what is the range of scaling if applicable
Appetizer. Maybe useful articles about ABEL, RSABE, and a comparison.

Dif-tor heh smusma 🖖
Helmut Schütz

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

Egypt,
2021-02-24 16:13
(78 d 04:35 ago)

@ Helmut
Posting: # 22232
Views: 863

## Scaling/Widening of AUC

Many Thanks, very helpful
dshah
★

India,
2021-03-16 06:39
(58 d 14:09 ago)

@ Helmut
Posting: # 22269
Views: 663

## Scaling/Widening of AUC

Thank you Helmut!

I am having few doubts for harmonization.
Why regulatory bodies does have different requirement for scaling acceptance for PK parameter (Cmax and AUC) and widening limit (based on Swr/ ISCV)?
Does any regulatory have advantage over other body that their approach is superior than other body w.r.t. to efficacy and safety?
For HVD/HVDP we know that variability is bound to happen. So as per FDA- both Cmax and AUC limit can be widen, but for EMA- we cant widen AUC. So is there any safety concern database by which they are justifying that widening of limit is not permissible? or there is not safety and efficacy issue in US but it could be there EMA or other regulatory body?
Or for NTI- limit of 90.00-111.11 is more relevant than RSABE approach and does justify the safety and efficacy?
Regards,
Dshah
Helmut
★★★

Vienna, Austria,
2021-03-16 13:55
(58 d 06:54 ago)

@ dshah
Posting: # 22271
Views: 634

## Scaling/Widening of AUC

Hi dshah,

» I am having few doubts for harmonization.

Welcome to the club!

» Why regulatory bodies does have different requirement for scaling acceptance …

IMHO, not related to science at all but to politics.
I attended all conferences of the ‘Global Bioequivalence Harmonization Initiative’ and was a member of the panel of the session ‘Scaling Procedure and Adaptive Design(s) in BE Assessment of Highly Variable Drugs’ (2nd GBHI, Rockville, September 2016). Justifications? Not really. I guess (‼):
• The FDA essentially walked in the footsteps of IBE (where reference-scaling was part of the method). Being aware that problems may exist with any PK-metric, RSABE not limited to Cmax.
• In Europe many products were approved in the 1990s based on wider limits for Cmax (Δ of 0.30 → 70.00–142.86%). Do these numbers look familiar?
• Health Canada faced no problems with Cmax in the past because the confidence interval was never required.

» Or for NTI- limit of 90.00-111.11 is more relevant than RSABE approach and does justify the safety and efficacy?

Good question, next question.

Dif-tor heh smusma 🖖
Helmut Schütz

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