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The Outlaw Torn ★ Europe, 2012-05-14 17:34 (5140 d 12:40 ago) Posting: # 8566 Views: 3,802 |
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Hello everyone, We conducted an isotretinoin BE study way back yonder when the current guideline was merely a twinkle in a reform-minded regulator's eye (meaning, it was more than a couple years ago). We recently submitted this study as part of an MAA. The study was conducted with a "light breakfast" when the current climate requires a delicious high-fat, high-calorie meal (hey, I'm a big fan of bacon and eggs). We've been called on this in a deficiency letter. I understand that it is super easy for the regulator to dismiss any justification we might come up with, however the deficiency is worded in a way that suggests they are willing to be convinced to "look the other way" (It should therefore be justified that the bioequivalence study results can be extrapolated to other types of meals). We are willing to test their apparent good will. I'm putting something together about standardisation of studies, etc, as we speak. So, my questions to you all is the following: what justification would you put together to convince the regulator to look the other way on the inadequate breakfast (about 450 kcal and 42% fat)? Thank you, Torn |
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Dr_Dan ★★ Germany, 2012-05-14 17:38 (5140 d 12:36 ago) @ The Outlaw Torn Posting: # 8568 Views: 2,961 |
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Dear Torn Due to gastro-intestinal complications you have to take isotretinoin with a meal. At time of clinical conduct of your study Guideline CPMP/QWP/EWP/1401/98 with the respective Q&A document EMEA/CHMP/EWP/40326/2006 was effective. In general, a bioequivalence study should be conducted under fasting conditions as this is considered to be the most sensitive condition to detect a potential difference between formulations (CPMP/QWP/EWP/1401/98 Rev. 1). This would also be the case for isotretinoin if this drug could be administered in the fasted state which is due to gastro-intestinal complications not possible. The SmPC does not contain any information about the composition of a meal to be taken with isotretinoin. The Q&A document points out that: “The composition of the meal should be described and taken into account, since a light meal might sometimes be preferable to mimic clinical conditions, especially when the fed state is expected to be less sensitive to differences in pharmacokinetics.” I hope this helps Kind regards Dan — Kind regards and have a nice day Dr_Dan |
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The Outlaw Torn ★ Europe, 2012-05-15 09:37 (5139 d 20:36 ago) @ Dr_Dan Posting: # 8569 Views: 2,900 |
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❝ At time of clinical conduct of your study Guideline CPMP/QWP/EWP/1401/98 with the respective Q&A document EMEA/CHMP/EWP/40326/2006 was effective. I was going to say something about that, but we've been told on more than a few occasions in other procedures that no matter when the study was conducted it has to abide by the new guideline (ie. there is no grandfather clause). If I can't come up with anything new, I'll definitely throw in this justification re: old note for guidance. I was also considering that fat is needed for the absorption of isotretinoin, so providing a justification that a high-fat meal may actually lessen the variability and that anything south of high-fat is actually more meaningful in distinguishing formulation effects is another avenue to pursue, I think. Thank you, Dr Dan, and if you think of anything else, let me know. Cheers, Torn |
Ing. Helmut Schütz