aanrin
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United Arab Emirates,
2015-07-27 13:45
(3167 d 01:41 ago)

Posting: # 15149
Views: 10,581
 

 Esmeprazole Gastro resistant tablet BE study [Study As­sess­ment]

Dear Sir/Madam,

The following BE study results for Esmeprazole Gastro resistant tablet

Fed Study - The Test to Reference ratio of geometric LSmeans for the Cmax was outside the acceptance range of 80 to 125% and the corresponding 90% confidence interval was also outside the widened range of 75 to 133%. The Test to Reference ratio of geometric LSmeans for the AUCT and AUC∞ were within the acceptance range of 80 to 125%, however, their corresponding 90% confidence intervals were outside this range.

Fasting Study - meets all criterias and found to be bioequivalent.

Please advice me whether the product will be accepted as generic by the regulatory authority if the fed study fails but fasting study is succesful.

Wityh Regards

Aan


Edit: Category changed. [Helmut]
Helmut
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Vienna, Austria,
2015-07-27 14:14
(3167 d 01:13 ago)

@ aanrin
Posting: # 15150
Views: 9,183
 

 PE outside the acceptance range

Dear Aan,

❝ Fed Study - The Test to Reference ratio of geometric LSmeans for the Cmax was outside the acceptance range of 80 to 125%


OK, that’s the end of the story – even for the least restrictive (i.e., Canadian) requirement.

❝ 90% confidence interval was also outside the widened range of 75 to 133%.

❝ Please advice me whether the product will be accepted as generic by the regulatory authority if the fed study fails but fasting study is succesful.


In the future please tell us which regulatory agency you are aiming at. Requirements differ around the globe. A (prespecified!) widened acceptance range of 75–133% is rarely applicable nowadays.

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aanrin
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United Arab Emirates,
2015-07-27 14:18
(3167 d 01:08 ago)

@ Helmut
Posting: # 15151
Views: 9,112
 

 PE outside the acceptance range

Thanks for the reply.

But the fasting study meets all the criteria. only fed study fails.

So please let me know for Modified release products both fasting and fed study should be successful?
Helmut
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Vienna, Austria,
2015-07-27 14:22
(3167 d 01:04 ago)

@ aanrin
Posting: # 15152
Views: 9,214
 

 PE outside the acceptance range

Hi Aan,

as mentioned above, please tell us the regulatory agency you want to submit the studies.

❝ But the fasting study meets all the criteria. only fed study fails.


❝ So please let me know for Modified release products both fasting and fed study should be successful?


Counterquestion: Why did you perform studies in both fasting and fed conditions?

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aanrin
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United Arab Emirates,
2015-07-27 14:27
(3167 d 00:59 ago)

@ Helmut
Posting: # 15153
Views: 9,087
 

 PE outside the acceptance range

Hi

As per the regulatory requirements and guidelines for modified release tablet both fasting and fed study is recommended (MHRA, USFDA etc).

Regulatory agency - MHRA UK, canada, MOH UAE. will they accept the study if fasting meets the criteria and the fed study fails.
Helmut
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Vienna, Austria,
2015-07-27 14:36
(3167 d 00:51 ago)

@ aanrin
Posting: # 15154
Views: 9,182
 

 PE outside the acceptance range

Hi Aan,

❝ As per the regulatory requirements and guidelines for modified release tablet both fasting and fed study is recommended (MHRA, USFDA etc).


Exactly. BTW, MHRA follows EMA’s GLs.

❝ Regulatory agency - MHRA UK, canada, MOH UAE. will they accept the study if fasting meets the criteria and the fed study fails.


Why should they (i.e., ignoring their own rules)?
Esomeprazole exhibits a pronounced food effect (reduced BA). Although dosing in the fasted state is recommended in the innovator product’s label/SmPC in a generic application you have to show BE for both fasting/fed conditions. I don’t know on which side your product failed (upper = less food effect or lower = higher food effect). Even in the former case, the test product is not similar to the reference, but “better”. In some legislations you could opt for a “hybrid application” which would require an additional clinical study.

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aanrin
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United Arab Emirates,
2015-08-24 11:08
(3139 d 04:19 ago)

@ Helmut
Posting: # 15326
Views: 8,481
 

 PE outside the acceptance range

Hi Helmut,

Thanks for your kind reply.please find my comments below for your advice.

From the results obtained from the BE studies the reference product achieves mean AUCt values as high as 3377.07 ng·h/ml in fasting conditions and as low as 1382.98 ng·h/ml in fed condition.

Based on the Reference product’s claim in the SmPC, stating that decreased and delayed absorption of esomeprazole due to food effect has no significant influence on its clinical efficacy, then the clinical efficacy should be guaranteed within the range 3377.07 – 1382.98 ng·h/ml.

In another word, the mean AUCt values of the Test product are well within the reference product range 3377.07 – 1382.98 ng·h/ml. Therefore, the clinical efficacy of the test product should be guaranteed when it was taken under fed condition.

So in this case a additional clinical study is required ? or the same BE study is enough for the submission to the regulatory as Generic.?
Ohlbe
★★★

France,
2015-08-24 15:34
(3138 d 23:53 ago)

@ aanrin
Posting: # 15327
Views: 8,312
 

 PE outside the acceptance range: end of the story

Aanrin,

You're not answering Helmut's comments (lower or higher food effect compared to the reference ?). Regulators want bioequivalence to be demonstrated both fasted and fed. It is not. Based on the information you provided up to now, that's the end of the story.

Regards
Ohlbe
Shuanghe
★★  

Spain,
2015-08-24 17:43
(3138 d 21:43 ago)

@ aanrin
Posting: # 15328
Views: 8,354
 

 PE outside the acceptance range

Hi Aan,

For a long answer, I think there are 2 aspects here: scientific and regulatory point of views, which, unfortunately, are not always the same.

From what you said I would summarise/infer the following based on my experience:

--- in fasting, reference has mean AUC of 3377.07 ng.h/ml and in fed, reference has mean AUC 1382.98 ng.h/ml, which is expected; after all, food effect of PPI is well known.
--- In fasting, test is BE to reference but in fed, test has much higher AUC values but those values are lower than the AUC values of reference in fasting; in another word, AUC of test in fed is much less than 3377.07 ng.h/ml.

If so, from a pure scientific point of view, I’d say that you have a “better” formulation since your formulation has less food effect, as pointed out by Helmut, which is not a surprise really since most of PPI products are old formulations and the technology improved so much recently the new formulation would have less food effect (at least this is my experience of 4 PPIs). In addition, there shouldn't be any safety concern if the above assumption is true.

Of course, to actually claim that you have a "better" formulation you would need clinical study to prove it but that’s beyond the point we are talking about.

From regulatory point of view, for a product to be fulfil the definition of generic, at least according to EMA’s guideline, your formulation should be “as good as” or “as bad as” the reference product, so to speak. Your product seems as good as the reference in fasting but not as bad as the reference in fed. This was the “end of story” Helmut and Ohlbe referred to. And I agree of course.

However, I do have a different opinion with regard to “additional clinical study” for “hybrid application” as mentioned by Helmut.

I had similar product with the same situation and we registered the product in several EU countries based on "hybrid" application without any additional study. We also managed to register it as generic product in one EU country based on scientific argument (don't ask me where and how ;-)). So I guess it may also depend on who’s actually evaluating your dossier.

So to answer your question,

❝ So in this case a additional clinical study is required ? or the same BE study is enough for the submission to the regulatory as Generic.?


I would say that it would be really difficult to submit the dossier nowadays as generic but the probability of register it via hybrid application without any additional study is high.

I hope this helps.

All the best,
Shuanghe
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