Averroes
☆    

Spain,
2017-10-04 14:01
(2367 d 10:15 ago)

Posting: # 17850
Views: 5,644
 

 EMA Q&A vs EMA Product Specific guideline [Regulatives / Guidelines]

Dear all,

I would like to know the opinion of the members of the forum about the following point regarding additional modes of administration stated on EMA Q&A on bioequivalence.

According to EMA Q&A on bioequivalence (point 3.6) here if the SmPC of the reference product allows for the possibility to administer the tablet crushed/disintegrated (and dispersed in food), bioequivalence should also be demonstrated, in principle, for a test product with this additional mode of administration.

This point of the Q&A may be confusing and may clash to what is indicated in the product specific quidelines of some products. An example:

-Ticagrelor: SmPC of Ticagrelor indicates that the tablets can be crushed to a fine powder mixed with 1/2 glass of water and administered. It also allows to administer via nasogastric tube. However the Product specific guideline here ask only for fasting study.

Taking into account that Ticagrelor is not BCS class I or III the question is:
Is it supossed a generic should also test these additional modes of administrations (crushed and nasogastric :confused::surprised:)? or, as indicated in the specific guideline a fasting study would be enough?

I have had not checked all Product Specific guidelines but it's possible there could be some other products with a similar situation.

In my opinion this point of EMA Q&A could be the starting point and opens a Pandora's box on new requirements for generics when additional method of administration is stated in the SmPC of the reference. It seems this may lead that for BCS class II or IV the most sensitive method to detect difference in formularion (i.e. fasting/fed, crushed/whole, ...) is not clear for EMA (may always be formulation-dependent) and they are asking to check everything (like they already did for Tadalafil).

What do you think?

Thanks,
Averroes
☆    

Spain,
2018-01-09 13:00
(2270 d 10:17 ago)

@ Averroes
Posting: # 18152
Views: 4,124
 

 Crushed Rivaroxaban?

❝ This point of the Q&A may be confusing and may clash to what is indicated in the product specific quidelines of some products. An example:


❝ -Ticagrelor: SmPC of Ticagrelor indicates that the tablets can be crushed to a fine powder mixed with 1/2 glass of water and administered. It also allows to administer via nasogastric tube. However the Product specific guideline here ask only for fasting study.


I just realized the same may apply to Rivaroxaban: According to point 3.6 of EMA's Q&A regulators could ask for a BE study on crushed tablets while the Product Specific Guideline ask "only" for fast (10 mg) and fed (20 mg) studies.

Could we expect a new version of this Product Specific Guideline?

Thanks,
lukamar
☆    

Poland,
2018-08-20 14:24
(2047 d 09:53 ago)

@ Averroes
Posting: # 19187
Views: 3,481
 

 Crushed Rivaroxaban?

❝ I just realized the same may apply to Rivaroxaban: According to point 3.6 of EMA's Q&A regulators could ask for a BE study on crushed tablets while the Product Specific Guideline ask "only" for fast (10 mg) and fed (20 mg) studies.


❝ Could we expect a new version of this Product Specific Guideline?


That's very valid point. As far as I know regulators do ask for such study for mentioned products, referring to Q&A which should be read in conjuction with product specific guidelines. Draft of Apixaban product specific guideline already requires such study, unless justified. It's unknown if EMA will update Riva and Tica guidelines. Anyway, for me this whole concept of product specific guielines makes not much sense, if you still need to verify if finalized gudieline is consistent with current EMA thinking published in other documents. Especially that date of coming of these gudeiline into effect was same as publishing Q&A (NOV 2016). So they were already outdated when coming into effect (!).
wienui
★    

Germany/Oman,
2019-12-03 19:20
(1577 d 03:57 ago)

@ lukamar
Posting: # 20910
Views: 2,273
 

 specific BE study with administration of crushed/disintegrated tablet

Dear All,

❝ As far as I know regulators do ask for such study for mentioned products, referring to Q&A which should be read in conjuction with product specific guidelines. Draft of Apixaban product specific guideline already requires such study, unless justified. It's unknown if EMA will update Riva and Tica guidelines. Anyway, for me this whole concept of product specific guielines makes not much sense, if you still need to verify if finalized gudieline is consistent with current EMA thinking published in other documents. Especially that date of coming of these gudeiline into effect was same as publishing Q&A (NOV 2016). So they were already outdated when coming into effect (!).


The EMA has revised its position on this topic on March 2019, Now, It is no need to conduct any further studies with this additional mode of administration.


https://www.ema.europa.eu/en/human-regulatory/research-development/scientific-guidelines/clinical-pharmacology-pharmacokinetics/clinical-pharmacology-pharmacokinetics-questions-answers


the PKWP has revised its position on this topic and presently considers that it is highly unlikely that the change in bioavailability will be different between test and reference, once bioequivalence has been shown between test and reference with the intact or non-dispersed tablet.

Consequently, if the SmPC of the reference product allows for the possibility to administer the tablet crushed/disintegrated (and dispersed in food), bioequivalence does not need to be also demonstrated with this additional mode of administration.

Best regards,
Osama

Cheers,
Osama
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