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RegisterCritical review of EU BE guideline (Rev.1) [Regulatives / Guidelines]
posted by Helmut 
– Vienna, Austria, 2008-08-23 04:02 (6520 d 18:37 ago) – Posting: # 2236
Views: 28,822
Dear D. Labes!
Exactly! See Section 4.1 (page 5, lines 142-144):
'The clinical overview [...] should list all studies carried out with the product applied for. All bioequivalence studies [...] must be submitted.'
An anecdote from my side to lift your mood:
Recently we had a discussion with one of the members of the 'pharmacokinetolophystic subgroup' (©2008 by ElMaestro) about a hypothetical example.
Study 1 in 24 subjects; 1 subject showing a low response of the reference, not BE due to variability higher than the one used in sample size planing. BE in nonparametric analysis and additional parametric analysis after removal of the outlier (even if planned in the protocol):
Study 2 is Study 1 repeated in the same 24 subjects; the outlying subject from Study 1 shows a 'normal' response, BE demonstrated:
Why? We have a tendency to believe in repeated values (just think about laboratory screenings). Maybe results seen in Study 2 were just by chance and Study 1 'correct' (subpopulation?).
Anyhow, pooling of Studies 1 & 2:
Again, why?
Study 3 in 48 subjects; 1 subject showing a low response of the reference, but BE demonstrated due to lower (by sqrt(2)) variability as compared to Study 1:
Do you get the idea?
4.1.2 Reference and test product (page 6, lines 193-194)
'When variations to a generic product are made, the comparative medicinal product for the bioequivalence study should be the reference medicinal product.'
IMHO, this a very good idea - nothing was stated about it in the 'old' NfG, and I think generally once a generic was approved, variations were studied in comparison to the company's own product - not the innovator.
Lines 202-207 are also a good idea - although a difference in content of more than 5% is rarely seen - it protects against surprises in the biostudy if ±5% are used in sample size planing.
4.1.2 Reference and test product (page 7, lines 218-220)
'The study sponsor will have to retain a sufficient number of all investigational product samples in the study for one year in excess of the accepted shelf life or two years after completion of the trial or until approval whichever is longer to allow re-testing, if it is requested by the authorities.'
Fine. And if a request comes, what about the results of re-testing years after the shelf life? Back-extrapolate with the parameters found in stability testing for the IMPs - endless discussions approaching.
❝ I can not get the point. What has the failed study to do with the study now showing BE? The formulation for which now BE is claimed is the reformulated, a new product.
❝ Generalizing this would mean that all unsuccessfull efforts and attempts during pharmacists or other work within the development must be reported.
Exactly! See Section 4.1 (page 5, lines 142-144):
'The clinical overview [...] should list all studies carried out with the product applied for. All bioequivalence studies [...] must be submitted.'
❝ Evaluation of data from several bioequivalence studies, page 13/14 (lines 537-542)
❝ '2. [...] It is not acceptable to pool together two ambigous studies to reach a positive conclusion.'
❝ This may be ok from the regulators point of view (He would like to see at least one study showing BE), but it is against all principles of a meta analysis. Pooling together studies and obtaining a clearer picture is why meta analysis was invented.
An anecdote from my side to lift your mood:
Recently we had a discussion with one of the members of the 'pharmacokinetolophystic subgroup' (©2008 by ElMaestro) about a hypothetical example.
Study 1 in 24 subjects; 1 subject showing a low response of the reference, not BE due to variability higher than the one used in sample size planing. BE in nonparametric analysis and additional parametric analysis after removal of the outlier (even if planned in the protocol):
--> not acceptableStudy 2 is Study 1 repeated in the same 24 subjects; the outlying subject from Study 1 shows a 'normal' response, BE demonstrated:
--> acceptable, even if the regulator knows of Study 1.Why? We have a tendency to believe in repeated values (just think about laboratory screenings). Maybe results seen in Study 2 were just by chance and Study 1 'correct' (subpopulation?).
Anyhow, pooling of Studies 1 & 2:
--> not acceptableAgain, why?
Study 3 in 48 subjects; 1 subject showing a low response of the reference, but BE demonstrated due to lower (by sqrt(2)) variability as compared to Study 1:
--> acceptableDo you get the idea?
4.1.2 Reference and test product (page 6, lines 193-194)
'When variations to a generic product are made, the comparative medicinal product for the bioequivalence study should be the reference medicinal product.'
IMHO, this a very good idea - nothing was stated about it in the 'old' NfG, and I think generally once a generic was approved, variations were studied in comparison to the company's own product - not the innovator.
Lines 202-207 are also a good idea - although a difference in content of more than 5% is rarely seen - it protects against surprises in the biostudy if ±5% are used in sample size planing.
4.1.2 Reference and test product (page 7, lines 218-220)
'The study sponsor will have to retain a sufficient number of all investigational product samples in the study for one year in excess of the accepted shelf life or two years after completion of the trial or until approval whichever is longer to allow re-testing, if it is requested by the authorities.'
Fine. And if a request comes, what about the results of re-testing years after the shelf life? Back-extrapolate with the parameters found in stability testing for the IMPs - endless discussions approaching.
—
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Helmut Schütz
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The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
Dif-tor heh smusma 🖖🏼 Довге життя Україна!
Helmut Schütz
The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
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Ing. Helmut Schütz