raghup
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India,
2021-05-28 12:44
(59 d 13:20 ago)

Posting: # 22376
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 AUCrefTmax [Regulatives / Guidelines]

For an NSAID immediate release Soft gelatin capsules with two way crossover study although if AUCt and Cmax are with in acceptance limits and there is no difference in median Tmax of both Test and Reference, but for AUCrefTmax 90% CI is not within 80-125% (will Health Canada accept the BE study). No outliers detected in the study.


Edit: Please follow the Forum’s Policy[Helmut]
Helmut
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Vienna, Austria,
2021-05-28 12:58
(59 d 13:06 ago)

@ raghup
Posting: # 22377
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 AUCrefTmax (Health Canada)

Hi raghup,

» For an NSAID immediate release Soft gelatin capsules with two way crossover study although if AUCt and Cmax are with in acceptance limits and there is no difference in median Tmax of both Test and Reference, but for AUCrefTmax 90% CI is not within 80-125% (will Health Canada accept the BE study).
  • Rapid onset of effect is important. According to the guidance AUCrefTmax should be reported.
    IMHO, a statistical comparison is not required.
  • For Cmax only the point estimate has to lie within 80.0–125.0%.
    If the CI passes 80.0–125.0%, nice to know but not required.
  • What does you protocol say?

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raghup
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India,
2021-05-28 13:16
(59 d 12:48 ago)

@ Helmut
Posting: # 22378
Views: 427
 

 AUCrefTmax (Health Canada)

»
  • Rapid onset of effect is important. According to the guidance AUCrefTmax should be reported. IMHO, a statistical comparison is not required.
    »
  • What does you protocol say?

Hi Helmut,

Thank you for the note.
https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/applications-submissions/guidance-documents/bioavailability-bioequivalence/comparative-bioavailability-standards-formulations-used-systemic-effects.html
section 2.1.1.5, reads about AUCrefTmax and its relative mean area of Test and Ref to be in 80-125%. Correct me if I am wrong. Here I understood 90% CI is not required. Only point estimate has to be with in 80 to 125%

Protocol is slient on AUCrefTmax.


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[Helmut]
Helmut
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Vienna, Austria,
2021-05-28 13:23
(59 d 12:42 ago)

@ raghup
Posting: # 22379
Views: 451
 

 AUCrefTmax (Health Canada)

Hi raghup,

» https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/applications-submissions/guidance-documents/bioavailability-bioequivalence/comparative-bioavailability-standards-formulations-used-systemic-effects.html
» section 2.1.1.5, reads about AUCrefTmax and its relative mean area of Test and Ref to be in 80-125%. Correct me if I am wrong. Here I understood 90% CI is not required. Only point estimate has to be with in 80 to 125%

THX, I missed that. You are right.

» Protocol is slient on AUCrefTmax.

;-)

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dshah
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India,
2021-05-31 10:15
(56 d 15:49 ago)

@ raghup
Posting: # 22381
Views: 348
 

 AUCrefTmax (Health Canada)

Dear Raghup!

As per section 2.1.1.5 Drugs with an important time of onset of effect or rate of absorption:

For drugs for which an early time of onset or rapid rate of absorption is important for therapeutic effects, for example, an analgesic for rapid relief of pain, the following standard should be met, in addition to the requirements listed in Section 2.1 above:
a) The relative mean area under the curve to the time of the maximum concentration of the reference product (AUCReftmax) of the test to reference product should be within 80.0% ‐ 125.0% inclusive.
The AUCReftmax ratio for each subject should be calculated using values for test and reference products obtained with that subject, and not using a central value (mean or median) for the reference product.
This applies to comparative bioavailability (bioequivalence) studies only. Submissions that make a claim of a more rapid onset of effect, compared to that of the reference product, may require additional pharmacokinetic, pharmacodynamic or clinical data.

where AUCReftmax is: The area under the curve, for a test product, to the time of the maximum concentration of the reference product, calculated for each study subject.

If your study is comparative study, and the values are calculated as per guideline, the ratio needs to be within 80-125%. On the otherhand- if test product claims to have more rapid onset of action compared to refence may require PD or clinical data.
Regards,
Dshah
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