cr.maroj
☆    

UK,
2013-09-19 13:00
(4252 d 10:26 ago)

Posting: # 11522
Views: 33,921
 

 Bioequivalence Recommendations for Specific Pro­ducts [Regulatives / Guidelines]

Post reply
Hi there,

Could someone please help me with this. Do we get Bioequivalence Recommendations for Specific Products on EMA site, the way they are available on FDA site. (http://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/guidances/ucm075207.htm)

My requirement is, per FDA recommendations for Spironolactone, analytes to be measured for showing BE is just the parent compound. But as we are planning for MHRA submission, I am not sure if MHRA insists on metabolites as well.

Literature shows that, Spironolactone is extensively metabolized; it has three known active metabolites: canrenone, 7-thiomethylspironolactone, and 6-hydroxy-7-thiomethylspironolactone.

Your advise on this will be highly appreciated.

Kind regards
CR
 
Ohlbe
★★★

France,
2013-09-19 13:45
(4252 d 09:42 ago)

@ cr.maroj
Posting: # 11523
Views: 30,378
 

 Bioequivalence Recommendations for Specific Pro­ducts

Post reply
Dear CR,

❝ Do we get Bioequivalence Recommendations for Specific Products on EMA site


Not yet. But there are plans.

❝ My requirement is, per FDA recommendations for Spironolactone, analytes to be measured for showing BE is just the parent compound. But as we are planning for MHRA submission, I am not sure if MHRA insists on metabolites as well.


MHRA follows the EMA guideline. Parent is sufficient, if it can be measured reliably.
—
Regards
Ohlbe
 
Helmut
★★★
avatar
Homepage
Vienna, Austria,
2013-11-15 16:45
(4195 d 05:42 ago)

@ Ohlbe
Posting: # 11892
Views: 29,855
 

 EMA: Draft product-specific guidances ♬

Post reply
Dear all,

❝ ❝ Do we get Bioequivalence Recommendations for Specific Products on EMA site

❝ Not yet. But there are plans.


Today EMA published the first set of draft product-specific guidances for a three-months consultation period (until 15 Feb 2014):
  1. Capecitabine
    500 mg single dose cross-over in patients (fed state), parent in plasma (achiral),
    Acceptance Range (AR) 80.00–125.00% for AUCt and Cmax (no scaling, “critical dose” drug).
  2. Carglumic acid
    200 mg single dose cross-over in healthy subjects (fasting state), parent in plasma (achiral),
    AR 80.00–125.00% for AUC72 and Cmax (HVD status not reviewed).
  3. Dasatinib
    140 mg single dose cross-over in healthy subjects (fasting state), parent in plasma (achiral),
    AR 80.00–125.00% for AUCt and Cmax (HVD status not reviewed).
  4. Emtricitabine/tenofovir disoproxil
    Emtricitabine 200 mg / tenofovir disoproxil 245 mg single dose cross-over in healthy subjects (fed state), parent (emtricitabine) and metabolite (tenofovir) in plasma (achiral),
    AR 80.00–125.00% for AUCt and Cmax (HVD status not reviewed).
  5. Erlotinib
    150 mg single dose cross-over in healthy subjects (fasting state), parent in plasma (achiral),
    AR 80.00–125.00% for AUC72 and Cmax (HVD status not reviewed).
  6. Imatinib
    400 mg single dose cross-over in healthy subjects (fasting or fed state; fasting preferred, but fed acceptable according to GL/SmPC of reference), parent in plasma (achiral),
    AR 80.00–125.00% for AUC72 and Cmax (HVD status not reviewed).
  7. Memantine
    Any strength single dose cross-over in healthy subjects (fasting state), parent in plasma (achiral),
    AR 80.00–125.00% for AUC72 and Cmax (HVD status not reviewed).
  8. Miglustat
    100 mg single dose cross-over in healthy subjects (fasting state), parent in plasma (achiral),
    AR 80.00–125.00% for AUCt and Cmax (HVD status not reviewed).
  9. Oseltamivir
    75 mg single dose cross-over in healthy subjects (fasting state), parent in plasma (achiral),
    AR 80.00–125.00% for AUCt and Cmax (HVD status not reviewed)
  10. Posaconazole
    400 mg single dose cross-over in healthy subjects (fed state), parent in plasma (achiral),
    AR 80.00–125.00% for AUCt and Cmax (scaling for Cmax if CVWR >30% demonstrated in a replicate design).
  11. Repaglinide
    2 mg single dose cross-over in healthy subjects (fasting state), parent in plasma (achiral),
    AR 80.00–125.00% for AUCt and Cmax (HVD status not reviewed).
  12. Sirolimus
    No strict dose-proportionality between 0.5 and 5 mg tablets.
    0.5 and 5 mg tablets, 1 mg/ml solution (if similarity requirements not fulfilled). Single dose cross-overs in healthy subjects (fasting and fed state), parent in blood (achiral),
    AR 90.00–111.11% for AUCt (NTID) and 80.00–125.00% for for Cmax.
  13. Sorafenib
    200 mg single dose cross-over in healthy subjects (fasting state), parent in plasma (achiral),
    AR 80.00–125.00% for AUC72 and Cmax (HVD status not reviewed).
  14. Tadalafil
    20 mg single dose cross-overs in healthy subjects (fasting and fed state), parent in plasma (achiral),
    AR 80.00–125.00% for AUC72 and Cmax (HVD status not reviewed).
  15. Telithromycin
    400 mg single dose cross-over in healthy subjects (fasting state), parent in plasma (achiral),
    AR 80.00–125.00% for AUCt and Cmax (HVD status not reviewed).
  16. Voriconazole
    200 mg single dose cross-over in healthy subjects (fasting state), parent in plasma (achiral),
    AR 80.00–125.00% for AUCt and Cmax (HVD status not reviewed).
Interesting points:
  • Guidances, not guidelines.
  • Capecitabine: 500 mg in metastatic breast or colorectal cancer patients? Unethical, IMHO.
    The standard treatment scheme is 2,500 mg/m2/day in two divided doses for two weeks followed by a one week treatment-free interval. For a patient with a 2 m2 body surface area a single dose is 5×500 mg – not just 500 mg.
  • No enantioselective analytical methods in all [sic] cases!
  • What does “HVD status not reviewed” mean? I always thought that one can scale the acceptance range for Cmax if there are no clinical issues and CVWR >30% is demonstrated in a reference-replicated study. Do we have to wait until the mighty oracle allows scaling in a GL?
Edit 2013-12-06: List continues here.
The complete list with the respective end of consultation here.
—
Dif-tor heh smusma 🖖🏼 Довге життя Україна! [image]
Helmut Schütz
[image]

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

India,
2013-11-19 07:35
(4191 d 14:52 ago)

(edited on 2013-11-19 12:59)
@ Helmut
Posting: # 11907
Views: 28,873
 

 EMA: Draft product-specific guidances ♬

Post reply
For Imatinib Single dose study on healthy volunteers ;-)

FDA need to learn some lession from EMEA
—
~A happy Soul~
 
mittyri
★★  

Russia,
2013-12-10 16:33
(4170 d 05:53 ago)

@ Helmut
Posting: # 12030
Views: 29,039
 

 EMA: Capecitabine product-specific guidance ♬

Post reply
Dear Helmut & all,

Could you explain, why does Capecitabine draft have no scaling at least for Cmax?

❝ Acceptance Range (AR) 80.00–125.00% for AUCt and Cmax (no scaling, “critical dose” drug).


According to the Cassidy J, Twelves C, Cameron D, et al. (Bioequivalence to two tablet formulations of capecitabine) capecitabine Cmax has high variability and low clinical significance:
  1. The maximum tolerated dose (MTD) of 3000 mg/m2 per day for an intermittent dosing schedule produced a mean Cmax of 13.4 lg/ml for 5-DFUR, which is greater than the value of 6.1 lg/ml obtained at the MTD of 1657 mg/m2 per day following a continuous dosing schedule. Thus, safety in humans does not correlate with Cmax values.
  2. Preclinical experiments in mice have shown that the antitumor activity is similar when the same daily dose of capecitabine is administered once or twice daily (H. Ishitsuka). Therefore, this suggests that AUC and not Cmax correlates with antitumor activity in mice.
  3. In vitro studies investigating the cell killing eff€ect of 5-FU have shown that 5-FU is an 'AUC-dependent drug', that is, short exposure requires high concentrations to obtain the cell killing e€ect whereas the same eff€ect can be obtained with longer exposure to lower concentrations.
  4. In the clinical use of cytotoxic agents, efficacy generally correlates better with AUC rather than with Cmax.
—
Kind regards,
Mittyri
 
Helmut
★★★
avatar
Homepage
Vienna, Austria,
2013-12-10 17:11
(4170 d 05:15 ago)

@ mittyri
Posting: # 12031
Views: 28,552
 

 EMA: Capecitabine product-specific guidance ♬

Post reply
Hi Mittyri,

❝ Could you explain, why does Capecitabine draft have no scaling at least for Cmax?


Very, very unlikely that EMA currently accepts scaling for anything else than Cmax. The only case I know is the first partial AUC for ER methylphenidate. Early pAUC and Cmin are under discussion (draft MR GL).
  • Scaling for Cmax would only be acceptable if CVWR >30% is demonstrated in a replicate design and “a wider difference in Cmax is considered clinically irrelevant”. Since the PKWP classified capecitabine as a “critical dose” drug, end of story. Be happy that they didn’t classify it as an NTID. ;-)
  • From your reference one cannot conclude CVWR >30%. Cmax in a 2×2 cross-over showed a CVintra of ~38%. That’s only a hint.
  • For many drugs the effect primarily correlates with AUC, not Cmax. Sometimes Cmax correlates with AEs. However, EMA is interested in the biopharmaceutical performance of the formulations (in vivo release in ”human test-tubes”).
  • BTW, in Russia an AR of 75–133% for Cmax is acceptable for all drugs without a clinical justification, right?
—
Dif-tor heh smusma 🖖🏼 Довге життя Україна! [image]
Helmut Schütz
[image]

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

Russia,
2013-12-14 12:57
(4166 d 09:30 ago)

@ Helmut
Posting: # 12058
Views: 28,579
 

 Russian GL 2013: harmonisation to EMA

Post reply
Hi, Helmut!

❝ • BTW, in Russia an AR of 75–133% for Cmax is acceptable for all drugs without a clinical justification, right?[/list]


Changes are coming...
Scientific Center for Expertise of Medical Products (regmed.ru) has published a new Guideline for drugs Expertise this year. Meanwhile you cannot find this GL on the site. Why?:confused:
They published a book! I think that's a perfect decision! :-D

The chapter about the statistics in BEQ studies is a good translation of EMA GL 2010. So at this moment we are closer to the European requirements than ever. ;-)
There's only one difference: biowaiver procedure is not mentioned and not approved.

Are you thinking that harmonisation is finished?
That's too easy! :-D
GL 2013 is not approved by MoH! No one can say what kind of GL should we use in preparing our studies - 2004 (approved by MoH), 2008 or 2013. All of them are acceptable till MoH will finally approve new GL...

PS If anyone have additional information - please correct me.
I'm waiting for a good analytical post with a comparison of the past and new requirements from my colleague Beholder
—
Kind regards,
Mittyri
 
pash413
★    

India,
2013-12-18 13:35
(4162 d 08:51 ago)

@ Helmut
Posting: # 12073
Views: 28,073
 

 EMA: Draft product-specific guidances ♬

Post reply
Dear All
Wondering about the Imatinib product specific guideline where BE criteria suggested is AUC72 and Cmax.
However as per SPC halflife is 18 hours and literature shows halflife around 16 hours in healthy subjects. In few subjects at 72.0 hour concentration is zero.

What is the criteria set by EMEA for long half life drugs. :confused:
 
Helmut
★★★
avatar
Homepage
Vienna, Austria,
2013-12-18 15:35
(4162 d 06:52 ago)

@ pash413
Posting: # 12075
Views: 28,227
 

 EMA: Use of AUC72 not dependent on t½

Post reply
Hi Pash,

❝ What is the criteria set by EMEA for long half life drugs.


There is none. For IR products the use of truncated AUC72 is not limited to drugs with a long half life. See the GL Section “Sampling times”:

AUC truncated at 72 h (AUC(0-72h)) may be used as an alternative to AUC(0-t) for com­parison of extent of exposure as the absorption phase has been covered by 72 h for immediate release formulations. A sampling period longer than 72 h is therefore not considered necessary for any immediate release formulation irrespective of the half life of the drug.


❝ […] In few subjects at 72.0 hour concentration is zero.


I hope you mean BLQ?
—
Dif-tor heh smusma 🖖🏼 Довге життя Україна! [image]
Helmut Schütz
[image]

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
 
Helmut
★★★
avatar
Homepage
Vienna, Austria,
2014-02-10 19:33
(4108 d 02:53 ago)

@ Helmut
Posting: # 12387
Views: 27,303
 

 End of consultation approaching‼

Post reply
Dear all,

just a little reminder: The consultation period of the first fifteen guidances ends this Saturday. Better to speak out now, than to complain in the end.
—
Dif-tor heh smusma 🖖🏼 Довге життя Україна! [image]
Helmut Schütz
[image]

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

Germany,
2016-01-28 10:27
(3391 d 11:59 ago)

@ Helmut
Posting: # 15872
Views: 20,322
 

 End of consultation approaching‼

Post reply
Hi Helmut and all other
Do you think that we ever get a final version? ;-)
As you know I am not a fan of these product specific bioequivalence guidelines. Interestingly one of the guidances was commented by the originator who requested that additional studies need to be performed and provided information on variability which IMHO are not correct. So we need to carefully evaluate the comments (especially of originators and their straw men) and to make EMA aware not to follow lobbyists.
Kind regards
Dr_Dan
—
Kind regards and have a nice day
Dr_Dan
 
Helmut
★★★
avatar
Homepage
Vienna, Austria,
2016-01-28 14:32
(3391 d 07:55 ago)

@ Dr_Dan
Posting: # 15878
Views: 20,404
 

 Guesstimates

Post reply
Hi Dan,

❝ Do you think that we ever get a final version? ;-)


Sure. The first 17 were adopted 9–15 months after the end of consultation. Given that I expect to see the final versions of #18–26 in December 2016 to April 2017.

❝ Interestingly one of the guidances was commented by the originator who requested that additional studies need to be performed and provided information on variability which IMHO are not correct.


I’m too lazy to search. Which one and where did you find the comment?
—
Dif-tor heh smusma 🖖🏼 Довге життя Україна! [image]
Helmut Schütz
[image]

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
 
Helmut
★★★
avatar
Homepage
Vienna, Austria,
2013-09-19 13:48
(4252 d 09:39 ago)

@ cr.maroj
Posting: # 11524
Views: 30,050
 

 EMA: generally no product-specific GLs

Post reply
Hi CR,

❝ Do we get Bioequivalence Recommendations for Specific Products on EMA site…


Nope. Apart from biosimilars and a few drugs/formulations in the Q&A-document EMA hasn’t published product specific guidelines so far – though considering for the future.

❝ My requirement is, per FDA recommendations for Spironolactone, analytes to be measured for showing BE is just the parent compound. But as we are planning for MHRA submission, I am not sure if MHRA insists on metabolites as well.


Spironolactone it tough, but possible. Therefore, that’s the way to go. Personally I’m not sure whether spironolactone cannot be classified as a pro-drug. Did you search MHRA’s PARs?

❝ […] Spironolactone is extensively metabolized; it has three known active metabolites: canrenone, 7-thiomethylspironolactone, and 6-hydroxy-7-thiomethylspironolactone.


Yep. As usual metabolites show nicer variability; my studies (CV%):
                       AUC              Cmax        n
                  x    min   max    x   min   max
Spironolactone  28.9  19.8  43.0  28.0 23.6  34.1   4
Canrenone        9.49  6.98 12.2  13.1  9.09 17.8  10
7-α-TMS         14.4  11.8  21.2  18.3 15.3  16.0   3

If you succeed in convincing MHRA that spironolactone is a pro-drug, you would have to show BE only for one metabolite (active or not). I would opt for canrenone.
—
Dif-tor heh smusma 🖖🏼 Довге життя Україна! [image]
Helmut Schütz
[image]

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

UK,
2013-09-19 15:03
(4252 d 08:24 ago)

@ Helmut
Posting: # 11525
Views: 29,793
 

 Thank you

Post reply
Thank you Ohlbe and Helmut.

Best regards,
CR
 
The Outlaw Torn
★    

Europe,
2013-09-20 09:52
(4251 d 13:34 ago)

@ Helmut
Posting: # 11527
Views: 29,868
 

 EMA: generally no product-specific GLs

Post reply

❝ If you succeed in convincing MHRA that spironolactone is a pro-drug, you would have to show BE only for one metabolite (active or not). I would opt for canrenone.


Good morning Helmut,

I'm not sure if I picked up some decaf by mistake this morning or I'm still hungover from a Thrusday night binge, but this bit above doesn't look quite right to me. According to the guideline:

Also for inactive prodrugs, demonstration of bioequivalence for parent compound is recommended. The active metabolite does not need to be measured.

So, if spironolactone can indeed be measured, I'm not sure it matters whether it's a prodrug or not. Did I miss something?:ponder:

Torn
 
Helmut
★★★
avatar
Homepage
Vienna, Austria,
2013-09-20 11:02
(4251 d 12:25 ago)

@ The Outlaw Torn
Posting: # 11528
Views: 29,661
 

 EMA: parent whenever possible

Post reply
Hi Torn,

❝ Also for inactive prodrugs, demonstration of bioequivalence for parent compound is recommended. The active metabolite does not need to be measured.

❝

❝ So, if spironolactone can indeed be measured, I'm not sure it matters whether it's a prodrug or not.


Correct. That’s what Ohlbe said. Spironolactone was problematic in the past, nowadays doable. Prodrug or not. Sorry for the confusion.
—
Dif-tor heh smusma 🖖🏼 Довге життя Україна! [image]
Helmut Schütz
[image]

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

UK,
2013-09-20 12:14
(4251 d 11:13 ago)

@ Helmut
Posting: # 11529
Views: 29,448
 

 EMA: parent whenever possible

Post reply
Dear Helmut,

❝ Spironolactone was problematic in the past, nowadays doable. Prodrug or not. Sorry for the confusion.


So, do you recommend analysing both Spironolactone and the metabolites? If so, BE criteria (for MHRA) will be based on parent or both?

Thank you,
Kind regards,
CR
 
Helmut
★★★
avatar
Homepage
Vienna, Austria,
2013-09-20 14:53
(4251 d 08:34 ago)

@ cr.maroj
Posting: # 11531
Views: 29,486
 

 EMA: parent whenever possible

Post reply
Hi CR,

❝ So, do you recommend analysing both Spironolactone and the metabolites? If so, BE criteria (for MHRA) will be based on parent or both?


If you reliably can measure spironolactone, there is no need to measure any of its metabolites.
—
Dif-tor heh smusma 🖖🏼 Довге життя Україна! [image]
Helmut Schütz
[image]

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

France,
2013-09-20 15:52
(4251 d 07:34 ago)

@ Helmut
Posting: # 11532
Views: 29,395
 

 EMA: parent whenever possible

Post reply
Dear CR,

❝ If you reliably can measure spironolactone, there is no need to measure any of its metabolites.


And if you can't, you'll have to explain why and how hard you tried :-D. Particularly if others have succeeded.
—
Regards
Ohlbe
 
mittyri
★★  

Russia,
2013-09-20 16:55
(4251 d 06:32 ago)

@ Ohlbe
Posting: # 11534
Views: 29,362
 

 EMA: parent whenever possible

Post reply
Dear Ohlbe, Helmut & ALL,

❝ Also for inactive prodrugs, demonstration of bioequivalence for parent compound is recommended. The active metabolite does not need to be measured.


Could you explain why the bioequivalence guideline states that?
If we have an inactive parent compound and active metabolite, wouldn't it be logical to measure active metabolite only?

There is some different recommendation at russian GL:
If the drug substance couldn’t be detected in blood as a result of presystemic elimination and/or doesn’t possess biological activity (pro-drug), than the concentration of biologically active metabolite must be detected.

So could you explain this disrepancy?
—
Kind regards,
Mittyri
 
Helmut
★★★
avatar
Homepage
Vienna, Austria,
2013-09-20 21:21
(4251 d 02:06 ago)

@ mittyri
Posting: # 11535
Views: 29,596
 

 EMA vs. Russia

Post reply
Hi mittyri,

❝ could you explain this disrepancy?


Yes. Russia’s GL is somewhat “closer” to the clinical situation (which was also the case in the EU in the past), whereas EMA concentrates on in vivo release (aka human test tubes). Keeping that in mind that an – even inactive pro-drug – is more sensitive to detect potential differences between formulations than any metabolite (especially of the rate of absorption).
BTW, I like Russia’s approach more, but I’m a dinosaur.
—
Dif-tor heh smusma 🖖🏼 Довге життя Україна! [image]
Helmut Schütz
[image]

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

India,
2013-12-20 08:36
(4160 d 13:51 ago)

@ Helmut
Posting: # 12084
Views: 28,907
 

 FDA: Prasugrel

Post reply
Dear Helmut,

How about this bioequivalence requirement [based on USFDA individual product bioequivalence recommendations] for Prasugrel Hydrochloride

Active ingredient: Prasugrel Hydrochloride

Analytes to measure (in appropriate biological fluid): Inactive metabolite R-95913 and active metabolite R-138727 in plasma.

Bioequivalence based on (90% CI): Inactive metabolite R-95913.

Please submit the data of active metabolite (R-138727) including individual and mean concentrations, individual and mean pharmacokinetic parameters, and geometric means and ratios of means for AUC and Cmax, as supportive evidence of comparable therapeutic outcome.

Can I justify my ANDA if test formulation is bioequivalent for the active metabolite (R-138727) and not bioequivalent for the Inactive metabolite R-95913? :confused:

Edit: Subject line changed. [Helmut]
—
Thanks & Regards,
IP.
 
Helmut
★★★
avatar
Homepage
Vienna, Austria,
2013-12-20 14:46
(4160 d 07:41 ago)

@ intuitivepharma
Posting: # 12085
Views: 28,274
 

 FDA: Prasugrel

Post reply
Hi intuitivepharma,

❝ […] bioequivalence requirement [based on USFDA individual product bioequivalence recommendations] for Prasugrel Hydrochloride

❝

❝ Can I justify my ANDA if test formulation is bioequivalent for the active metabolite (R-138727) and not bioequivalent for the Inactive metabolite R-95913?


Following the – nonbinding – recommendations of the guidance:
  • You should not perform BE assessment (PE, 90% CI) of R-138727 – only report the PK metrics.
  • If R-95913 is not BE, bad luck.
—
Dif-tor heh smusma 🖖🏼 Довге життя Україна! [image]
Helmut Schütz
[image]

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

India,
2013-12-24 07:38
(4156 d 14:48 ago)

@ Helmut
Posting: # 12100
Views: 27,999
 

 FDA: Prasugrel

Post reply
Dear Helmut,

Thanks for the reply. In such a precarious situation my only hope to defend the ANDA would be based on the following assumptions.

The guidance recommendations are nonbinding
The demonstration of bioequivalence to an active metabolite is more “closer” to the actual clinical situation than demonstration of bioequivalence to an inactive metabolite.

Can any one let know why for Prasugrel, bioequivalence is based on inactive metabolite and active metabolite PK is submitted as supportive data. The condition that data on active metabolite is required implies that it can be quantified. Enlighten me if I am missing some thing over here.
—
Thanks & Regards,
IP.
 
Helmut
★★★
avatar
Homepage
Vienna, Austria,
2013-12-24 15:15
(4156 d 07:12 ago)

@ intuitivepharma
Posting: # 12103
Views: 28,177
 

 FDA: Alternative approaches…

Post reply
Hi intuitivepharma,

❝ […] In such a precarious situation my only hope to defend the ANDA would be based on the following assumptions.

❝ The guidance recommendations are nonbinding


Yes, but:

“You can use an alternative approach if the approach satisfies the re­quire­­ments of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the Office of Generic Drugs.”


The guidance was already published in March 2011. What does your protocol state?
  • If you targeted the active R-138727 (contrary to the guidance), why didn’t you contact the OGD beforehand?
  • If you stated the inactive R-95913, you cannot switch to R-138727 only because you don’t like the outcome.

❝ The demonstration of bioequivalence to an active metabolite is more “closer” to the actual clinical situation than demonstration of bio­equivalence to an inactive metabolite.

❝ Can any one let know why for Prasugrel, bioequivalence is based on inactive metabolite and active metabolite PK is submitted as suppor­tive data.

[image]
© Anypodetos @ Wikimedia Commons

We had this discussion ∞ times. Current thinking at most regulatory author­ities is to demonstrate similarity of the in vivo performance of formulations. Since prasugrel is a pro-drug the inactive R-95913 is closer related to the drug release than the active – but secondary! – R-138727. Regulators are not inter­ested any more in the “clinical situation” – which would call for the most active metabolite with the longest half-life in steady state in many cases.
That’s history.

❝ The condition that data on active metabolite is required implies that it can be quantified.


Yes, but only as supportive data.
Face it: According to the guidance your study failed.
—
Dif-tor heh smusma 🖖🏼 Довге життя Україна! [image]
Helmut Schütz
[image]

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

India,
2013-12-26 06:11
(4154 d 16:16 ago)

@ Helmut
Posting: # 12108
Views: 27,980
 

 FDA: Alternative approaches…

Post reply
Thanks Helmut. Accept with you.
—
Thanks & Regards,
IP.
 
Helmut
★★★
avatar
Homepage
Vienna, Austria,
2013-12-26 15:35
(4154 d 06:52 ago)

@ intuitivepharma
Posting: # 12113
Views: 27,984
 

 FDA: RTR

Post reply
Hi intuitivepharma,

see also this recent thread. Bad luck.
—
Dif-tor heh smusma 🖖🏼 Довге життя Україна! [image]
Helmut Schütz
[image]

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

India,
2013-12-31 06:34
(4149 d 15:53 ago)

@ Helmut
Posting: # 12115
Views: 27,740
 

 FDA: RTR

Post reply
Thanks Helmut.
—
Thanks & Regards,
IP.
 
meghalvakil20
☆    

2015-07-23 18:32
(3580 d 04:55 ago)

@ Helmut
Posting: # 15131
Views: 23,779
 

 FDA: RTR

Post reply
hi Helmut

can you help me with a copy of Prasugrel Bioequivalence FDA requirements before it was revised in June 2015. if anyone else can help me it would be great.
 
Helmut
★★★
avatar
Homepage
Vienna, Austria,
2015-07-23 18:58
(3580 d 04:28 ago)

@ meghalvakil20
Posting: # 15133
Views: 23,739
 

 WayBack Machine

Post reply
Hi meghalvakil20,

❝ […] Prasugrel Bioequivalence FDA requirements before it was revised in June 2015.


http://web.archive.org/web/20120303002932/http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM249251.pdf
See this post to do it yourself next time.

No double-posts please (I deleted another one).
—
Dif-tor heh smusma 🖖🏼 Довге життя Україна! [image]
Helmut Schütz
[image]

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
 
meghalvakil20
☆    

2015-07-23 19:03
(3580 d 04:23 ago)

@ Helmut
Posting: # 15134
Views: 23,646
 

 WayBack Machine

Post reply
thank you so much
sorry about that i am new and this was my first post. you are the best..!! based on your experience are you aware if FDA stores these draft bio guidances on their site or remove them completely once revised.

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! [Helmut]
 
Helmut
★★★
avatar
Homepage
Vienna, Austria,
2015-07-23 19:28
(3580 d 03:58 ago)

@ meghalvakil20
Posting: # 15136
Views: 23,774
 

 Old stuff

Post reply
Hi meghalvakil20,

❝ sorry about that i am new and this was my first post.


No problem. Please read the Forum’s Policy. You can edit your posts for 24 hours. No need for a new one (I deleted yet another one).

❝ you are the best..!!


In which respect? :-D I’m internet-literate.

❝ based on your experience are you aware if FDA stores these draft bio guidances on their site or remove them completely once revised.


Unfortunately the latter. Agencies want from us revision-control, audit-trails, etc. but themselves, well, cough…
See this post, Section “Problems”. If you don’t succeed you can only ask here whether somebody by chance has a local copy.
—
Dif-tor heh smusma 🖖🏼 Довге життя Україна! [image]
Helmut Schütz
[image]

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

Denmark,
2013-09-20 21:35
(4251 d 01:51 ago)

@ mittyri
Posting: # 11536
Views: 29,790
 

 EMA: parent whenever possible

Post reply
Hi mittyri,

❝ Could you explain why the bioequivalence guideline states that?

❝ If we have an inactive parent compound and active metabolite, wouldn't it be logical to measure active metabolite only?


Absolutely. It has been debated a million times, and there are many people who agree with you. One reason for testing the parent is that if there is equivalence in terms of the parent, then it is very unlikely there'd be inequivalence in the active. (You may speculate some scenarios where it could happen but are there many actual examples? And you may counter-counter that the ISR was an example of a what-f that translated into new requirements with no or few real-life examples proving its necessity).
Another argument is that BE is about rate and extent of absorption (of the parent, naturally; usually no such thing as absorption of the active). We can directly address that by looking at the parent itself.

Counterarguments are of course that it is more directly linked to efficacy to look at the active, and that the current terminology (rate and extent / active) does not provide much of relevance to that issue.

There are numerous such schismas. If we want to prove effecacy and safety of a drug in its intended population, how can we accept hevo's in BE studies? If we know the residual is not Gaussian why do we have to use a parametric method? If Europe can accept Indian hevo's in BE studies why can't Russia? And so on.


❝ There is some different recommendation at russian GL:

❝ (...) So could you explain this disrepancy?


Yes. They think differently. Nothing more and nothing less. Thinking, and thinking differently, is often what drives science forward :-D
—
Pass or fail!
ElMaestro
 
luvblooms
★★  

India,
2013-11-19 14:00
(4191 d 08:26 ago)

@ ElMaestro
Posting: # 11912
Views: 28,964
 

 EMA: Sirolimus product-specific GL

Post reply
Dear HS and All

❝ Sirolimus

❝ No strict dose-proportionality between 0.5 and 5 mg tablets.

❝ 0.5 and 5 mg tablets, 1 mg/ml solution (if similarity requirements not fulfilled). Single dose cross-overs in healthy subjects (fasting and fed state), parent in blood (achiral),

❝ AR 90.00–111.11% for AUCt (NTID) and 80.00–125.00% for for Cmax.


Have a small doubt that is there some typographic error or something in Sirolimus guidance?

If I am right, in EU Rapamune is available in following strengths (as per the SmPC approved/updated in Sep-13)

Rapamune® 0.5 mg coated tablets
Rapamune® 1 mg coated tablets
Rapamune® 2 mg coated tablets
Rapamune® 1 mg/ml oral solution

Now from where 5 mg strength came in picture?

Rapamune® 5 mg Tablets are only approved in Canada (not in US- was there earlier but not discontinued or EU)?

What if one wants to develop only two strengths 1mg and 2 mg?

Am I missing something over here or getting too paranoid? :confused:
—
~A happy Soul~
 
UA Flag
Activity
 Admin contact
23,424 posts in 4,927 threads, 1,670 registered users;
131 visitors (0 registered, 131 guests [including 6 identified bots]).
Forum time: 23:27 CEST (Europe/Vienna)

Lack of clarity is always a sign of dishonesty.    Celia Green

The Bioequivalence and Bioavailability Forum is hosted by
BEBAC Ing. Helmut Schütz
HTML5