Bioequivalence and Bioavailability Forum

Researcher101 ☆ Egypt, 2021-02-23 21:40 (1329 d 14:03 ago) Posting: # 22224 Views: 4,188	Scaling/Widening of AUC [Regulatives / Guidelines] Post reply
	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 ★ Egypt, 2021-02-24 14:13 (1328 d 21:30 ago) @ Researcher101 Posting: # 22227 Views: 3,449	Scaling/Widening of AUC Post reply
	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designs or fully replicate design only as FDA referred to the published book chapter for RSABE for AUC and Cmax in fda draft guidance for progesterone?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 15:46
(1328 d 19:57 ago)

@ Loky do
Posting: # 22228
Views: 3,499

RSABE…

Post reply

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, C_max, :blahblah:

) 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 🖖🏼 Довге життя Україна!
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 16:30
(1328 d 19:13 ago)

@ Helmut
Posting: # 22230
Views: 3,415

RSABE…

Post reply

Hi Dear Helmut,

Many thanks for your reply :-D

❝ Which book are you referring to?

❝

❝ For the FDA you can apply RSABE for any PK metric (AUCs, partial AUCs, C_max, :blahblah: ) 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?

Thanks in advance

Helmut
★★★

Vienna, Austria,
2021-02-24 16:47
(1328 d 18:57 ago)

@ Loky do
Posting: # 22231
Views: 3,454

RSABE…

Post reply

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 🖖🏼 Довге життя Україна!
Helmut Schütz

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

Helmut
★★★

Vienna, Austria,
2021-02-24 16:29
(1328 d 19:15 ago)

@ Researcher101
Posting: # 22229
Views: 3,445

Scaling/Widening of AUC

Post reply

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

The FDA and China accept reference-scaling for any PK-metric (see this post).
Health Canada accepts ABEL for AUC.
The WHO accepts ABEL for AUC if the study is performed in a full replicate design and variabilities of products are compared. Duno how that should be done.
In jurisdictions applying ABEL (Australia, ASEAN states, Chile, Brazil, the East African Community, Egypt, EMA, the Eurasian Economic Union, New Zealand) it is not acceptable.
However, at least for the EMA, ABEL for partial AUCs is acceptable.
Members of the Gulf Cooperation Council do not accept widening the limits for AUC.

Appetizer. Maybe useful articles about ABEL, RSABE, and a comparison.

—
Dif-tor heh smusma 🖖🏼 Довге життя Україна!
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 17:13 (1328 d 18:30 ago) @ Helmut Posting: # 22232 Views: 3,523	Scaling/Widening of AUC Post reply
	Many Thanks, very helpful

dshah
★★

India,
2021-03-16 07:39
(1309 d 04:04 ago)

@ Helmut
Posting: # 22269
Views: 3,230

Scaling/Widening of AUC

Post reply

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 14:55
(1308 d 20:48 ago)

@ dshah
Posting: # 22271
Views: 3,156

Scaling/Widening of AUC

Post reply

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’ (2^nd 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 C_max.
In Europe many products were approved in the 1990s based on wider limits for C_max (Δ of 0.30 → 70.00–142.86%). Do these numbers look familiar?
Health Canada faced no problems with C_max 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 🖖🏼 Довге життя Україна!
Helmut Schütz

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

Scaling/Widening of AUC [Regulatives / Guidelines]

Scaling/Widening of AUC

RSABE…

RSABE…

RSABE…

Scaling/Widening of AUC

Scaling/Widening of AUC

Scaling/Widening of AUC

Scaling/Widening of AUC