Aymanmy
☆    

Jordan,
2019-12-18 08:51

Posting: # 20990
Views: 1,022
 

 BEQ inquiry from health authority [Study As­sess­ment]

Hi colleagues
Recently we submitted a BE study to EU, and we recieved an inquiry about in some subjects (5 out of 60) the LLOQ is more than 5% of the Cmax, plz need to know how can we reply about this case since the method was applicable for more than 90% of the subjects in the study and the LLOQ is actually less than 5% of the average Cmax, and no detected concentrations in the predose samples for these subjects.
Kind regards


Edit: Category changed; see also this post #1[Helmut]
Dr_Dan
★★  

2019-12-18 14:46

@ Aymanmy
Posting: # 20991
Views: 693
 

 BEQ inquiry from health authority

Hi Aymanmy
perform a sensitivity analysis and demonstrate how these subjects influenced the bioequivalence decision
KR
Dr_Dan

Kind regards and have a nice day
Dr_Dan
Helmut
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Vienna, Austria,
2019-12-18 15:16

@ Aymanmy
Posting: # 20993
Views: 672
 

 Method not sensitive enough

Hi Aymanmy,

the requirement of LLOQ ≤ 5% of Cmax is used to assess carry-over. For the future: Never develop an analytical method based on an average Cmax. Since to have to comply for all subjects in all periods plan for the worst case (i.e., subjects with the lowest concentrations). This is particularly important for drugs with high between-subject variability.

» […] no detected concentrations in the predose samples for these subjects.

Yep but the method was not sensitive enough for these subjects. Hence, I support Dan’s suggestion (exclude the subjects and check whether you still pass BE).

Cheers,
Helmut Schütz
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The quality of responses received is directly proportional to the quality of the question asked. 🚮
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mittyri
★★  

Russia,
2019-12-18 16:52

@ Helmut
Posting: # 20997
Views: 652
 

 Revalidation?

Hi Helmut and Dan,

» » […] no detected concentrations in the predose samples for these subjects.
» Yep but the method was not sensitive enough for these subjects. Hence, I support Dan’s suggestion (exclude the subjects and check whether you still pass BE).

I heard about approach when the method is revalidated taking into account Cmax values of that subjects (LLOQ should be less than 5% min Cmax of those) and then the affected volunteers are reanalyzed (of course till the moment of database lock). What do you think?

Kind regards,
Mittyri
Helmut
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Vienna, Austria,
2019-12-18 17:40

@ mittyri
Posting: # 21000
Views: 663
 

 Revalidation?

Hi Mittyri,

» […] approach when the method is revalidated taking into account Cmax values of that subjects (LLOQ should be less than 5% min Cmax of those) and then the affected volunteers are reanalyzed (of course till the moment of database lock). What do you think?

Yes, why not? As long as the data are not unblinded, it should not hurt. However,

» Recently we submitted a BE study to EU…

(my emphasis)

Hence, it can be just another kind of sensitivity analysis.


Posting # 21,000. :-D

Cheers,
Helmut Schütz
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The quality of responses received is directly proportional to the quality of the question asked. 🚮
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Aymanmy
☆    

Jordan,
2019-12-18 17:58

@ Helmut
Posting: # 21001
Views: 653
 

 Method not sensitive enough

Hi Helmut and colleagues
thanks for your replies and interactions,
my concern is the study is already submitted by the sponsor to the H.A, and the study results are known, also the samples are out of studied long term stability, can we just exclude the results of the affected subjects from the statistics?
and plz to confirm that every individual subject should fulfil the less than 5% of Cmax criteria for the future?

thanks again very much for your inteaction, its highly appreciated.
Helmut
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Vienna, Austria,
2019-12-18 18:54

@ Aymanmy
Posting: # 21002
Views: 644
 

 Method not sensitive enough

Hi Aymanmy,

» my concern is the study is already submitted by the sponsor to the H.A, and the study results are known, also the samples are out of studied long term stability, can we just exclude the results of the affected subjects from the statistics?

Yes, that’s Dan’s sensitivity analysis. If it fails to show BE, expect uncomfortable discussions with the sponsor. If the study passes BE, it is up to the agency to accept the outcome – or not. There’s no guarantee.

» and plz to confirm that every individual subject should fulfil the less than 5% of Cmax criteria for the future?

It is not necessary that all subjects pass. The rule is simple:
  • If the pre-dose concentration is ≤ 5% of the subject’s Cmax, keep the subject in the analysis.
  • If the pre-dose concentration is > 5% of the subject’s Cmax, exclude the subject from the analysis.
But in order to make this assessment your method must be sensitive enough for all subjects (LLOQ = 5% of lowest observed Cmax).

However, we don’t have a crystal ball. Sometimes our assumption is wrong. For such a case state in the protocol that you will exclude the subject anyhow. With any exclusion you will loose power. You don’t want to end up with a lot of excluded subjects. My personal rule of thumb: Up to 10–15% are OK, then it will start to hurt.
If possible improve the method / revalidate it instead (like Mittyri suggested). If you succeeed, the best approach.

Cheers,
Helmut Schütz
[image]

The quality of responses received is directly proportional to the quality of the question asked. 🚮
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Aymanmy
☆    

Jordan,
2019-12-19 08:21

@ Helmut
Posting: # 21003
Views: 591
 

 Method not sensitive enough

Thank you Helmut and colleagues
your thoughts are highly valuable and appreciated
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