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nobody
Senior

2017-07-19 10:56

Posting: # 17560
Views: 4,829
 

 Latest FDA product-specific guidelines – Some questions… [Regulatives / Guidelines]

Hy everybody!

Had a quick glance at the latest FDA guidances/revisions and found some stuff I don't understand immediately:

- Aspirin+Omeprazole delayed release tablet: BE for ASS based on both, ASS and SS
- Aspirin ER capsule or Aspirin capsule (from 2015): BE based on ASS alone

Any obvious reason for this?

- Tiopronin tablet (Shkreli compound): Only 1 study in fasted state

Are there more compounds not requiring fed state study?

- Metoprolol tartrate: BCS-biowaiver requires data other than "peer-reviewed articles"

Plausible to me, own experimental data on solubility might be required. Has anybody identified a PAR with successful BCS-biowiaver? :-D

- Propafenon: Highly variable.

Is CYP2D6 substrate, poor/ultrarapid metabolizers might be the reason for high variability? Why not pheno/genotype the volunteers for BE-trial, to minimize variability?

...just asking ;-)

Kindest regards, nobody
jag009
Hero

NJ,
2017-07-20 05:12

@ nobody
Posting: # 17564
Views: 4,478
 

 Latest FDA product-specific guidelines – Some questions…

» Is CYP2D6 substrate, poor/ultrarapid metabolizers might be the reason for high variability? Why not pheno/genotype the volunteers for BE-trial, to minimize variability?

Pheno/Genotype subjects for BE studies? Isn't that not advisable?

John
Achievwin
Junior

US,
2017-07-24 23:23
(edited by Ohlbe on 2017-07-25 09:52)

@ nobody
Posting: # 17606
Views: 4,439
 

 Latest FDA product-specific guidelines – Some questions…

» - Aspirin+Omeprazole delayed release tablet: BE for ASS based on both, ASS and SS
» - Aspirin ER capsule or Aspirin capsule (from 2015): BE based on ASS alone
»
» Any obvious reason for this?

Yosprola is •81 mg delayed-release aspirin and 40 mg immediate-release omeprazole, printed with 81/40, Asprin delayed release is provides increased Asprin levels and minimal salicylic acid levels presence of Omeprazole will facilitate some aspirn break down that must be the reason in this combination product both Acetyl salicylic acid and salicylic acid and also omeprazole are required to for BE.

» - Tiopronin tablet (Shkreli compound): Only 1 study in fasted state
»
» Are there more compounds not requiring fed state study?

there are several drugs that doesn't require Fed BE study.

» - Metoprolol tartrate: BCS-biowaiver requires data other than "peer-reviewed articles"
»
» Plausible to me, own experimental data on solubility might be required. Has anybody identified a PAR with successful BCS-biowiaver? :-D

For Biowaiver: you need to document Highly soluble over the specified pH range and rapidly dissolving as deined under BCS class III (85% by 15 mins) and the biggest challenge you run into is in documenting reliable report on permeability If you can find a ADME paper documenting it is more than 80% bioavailable then that might work.

» - Propafenon: Highly variable.
»
» Is CYP2D6 substrate, poor/ultrarapid metabolizers might be the reason for high variability? Why not pheno/genotype the volunteers for BE-trial, to minimize variability?
»
» ...just asking ;-)

Phenotype is not advisable in generic arena (IMHO) as we want to document that this drug is BE in general populating (meaning any breathing soul)....


Edit: quotes corrected [Ohlbe]
nobody
Senior

2017-07-25 09:30

@ Achievwin
Posting: # 17607
Views: 4,199
 

 Latest FDA product-specific guidelines – Some questions…

there are several drugs that doesn't require Fed BE study.

...any example?

» For Biowaiver: you need to document Highly soluble over the specified pH range and rapidly dissolving as deined under BCS class III (85% by 15 mins) and the biggest challenge you run into is in documenting reliable report on permeability If you can find a ADME paper documenting it is more than 80% bioavailable then that might work.

...totally clear, just wanted to see an example that worked in the end. Could not find one yet.

» Phenotype is not advisable in generic arena (IMHO) as we want to document that this drug is BE in general populating (meaning any breathing soul)....

EMA allows. See Jun 2017 by Laszlos and H- Blume on "real life" vs. "highly discriminative" in BE study requirements in various regions. Spoiler: Very inconsistent, in general... ;-)


Edit: Reference added. [Helmut]
Endrényi L, Blume HH, Tóthfalusi L. The Two Main Goals of Bioequivalence Studies. AAPS J. 2017;19(4):885-90. doi:10.1208/s12248-017-0048-x

Kindest regards, nobody
Achievwin
Junior

US,
2017-07-25 17:33

@ nobody
Posting: # 17610
Views: 4,186
 

 Latest FDA product-specific guidelines – Some questions…

» » Phenotype is not advisable in generic arena (IMHO) as we want to document that this drug is BE in general populating (meaning any breathing soul)....
»
» EMA allows. See Jun 2017 by Laszlos and H- Blume on "real life" vs. "highly discriminative" in BE study requirements in various regions. Spoiler: Very inconsistent, in general... ;-)

BE guidance tries to avoid bias (cherry picking) therefore excluded Phenotyping and avoiding fast and slow metabolizers.... if we allow phenotyping then next someone will come and ask for BMI exceptions and then smoker exclusion where is the end?


Edit: Full quote removed. Please delete everything from the text of the original poster which is not necessary in understanding your answer; see also this post #5 and follow the Forum’s Policy. [Helmut]
Ohlbe
Hero

France,
2017-07-25 18:41

@ Achievwin
Posting: # 17613
Views: 4,176
 

 Standardisation of the population

Dear Achievwin,

» BE guidance tries to avoid bias (cherry picking) therefore excluded Phenotyping and avoiding fast and slow metabolizers.... if we allow phenotyping then next someone will come and ask for BMI exceptions and then smoker exclusion where is the end?

We are already there in Europe - and surviving.

EMA and FDA have a different philosophy there. The FDA wants to have a population that is as representative and varied as possible (males and females, different race/ethnicities...). EMA recommends to standardise the population much more. After arguing a lot, industry and CROs managed to relax the limits for BMI compared to the previous version of the guideline (used to be 18 to 25, now 18.5 to 30). But then:
- Subjects could belong to either sex; however, the risk to women of childbearing potential should be considered (i.e. studies with only males are perfectly acceptable on this side of the Atlantic and are actually quite frequent)
- Subjects should preferably be non-smokers
- Phenotyping and/or genotyping of subjects may be considered for safety or pharmacokinetic reasons

On another note: please pay attention when replying to messages. If you leave the » sign before what you type, we can't distinguish between what you quote and what you write. Please use the Preview button before submitting your message. Helmut and I had to edit a number of your posts. Please also follow the Forum’s Policy.

Regards
Ohlbe
Helmut
Hero
avatar
Homepage
Vienna, Austria,
2017-07-25 19:35

@ Ohlbe
Posting: # 17615
Views: 4,156
 

 Standardisation of the population

Dear Ohlbe,

» The FDA wants to have a population that is as representative and varied as possible (males and females, different race/ethnicities...). EMA recommends to standardise the population much more. After arguing a lot, industry and CROs managed to relax the limits for BMI compared to the previous version of the guideline (used to be 18 to 25, now 18.5 to 30).

I never understood the FDA’s obsession with “the general population” when it comes to the BMI. Honestly, I never had data of an ANDA-study on my desk where subjects were even close to what the US CDC reports:

[image]

† overweight: ≥ 25.0 BMI <30.0

[image]

† obesity: BMI ≥ 30.0


Cheers,
Helmut Schütz
[image]

The quality of responses received is directly proportional to the quality of the question asked. ☼
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Achievwin
Junior

US,
2017-07-25 18:21

@ nobody
Posting: # 17612
Views: 4,171
 

 Latest FDA product-specific guidelines – Some questions…

» » there are several drugs that doesn't require Fed BE study.
»
» ...any example?

e.g Afatinib

» ...totally clear, just wanted to see an example that worked in the end. Could not find one yet.

Floxacins, Solifenacin and there are few drugs with 100% bioavailability. essentially you demonstrate <10% fecal elimination of parent drug and more than 80% absoreption (drug and metabolite combined) or >90% renal elimination of parent drug, with data or permability study data it should work out


Edit: quotes corrected [Ohlbe]
nobody
Senior

2017-07-26 16:27

@ Achievwin
Posting: # 17617
Views: 4,125
 

 Latest FDA product-specific guidelines – Some questions…

» » » there are several drugs that doesn't require Fed BE study.
» »
» » ...any example?
»
» e.g Afatinib

OK, are there any systematics in "fast+fed" or "fasted only" decisions by the FDA guidances? Or is "fasted only" a new trend at the FDA?

» » ...totally clear, just wanted to see an example that worked in the end. Could not find one yet.
»
» Floxacins, Solifenacin and there are few drugs with 100% bioavailability. essentially you demonstrate <10% fecal elimination of parent drug and more than 80% absoreption (drug and metabolite combined) or >90% renal elimination of parent drug, with data or permability study data it should work out

I know exactly what works out/would work out ;-), all I'm looking for is are PARs with examples that actually made it to a biowaiver. Or the other way around: Has this ever worked with the FDA for generics? :-)

Kindest regards, nobody
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