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ratnakar1811 ★ India, 2008-04-02 13:20 (5861 d 09:11 ago) Posting: # 1748 Views: 38,608 |
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Dear All, Can any body throw some more light on this, as per FDA guidline, " Data deletion due to vomiting: • We recommend that data from subjects who experience emesis during the course of a BE Study for immediate-release products be deleted from statistical analysis if vomiting occurs at or before 2 times median Tmax. In the case of modified-release products, the data from Subjects who experience emesis any time during the labeled dosing interval can be deleted." From where to take the median Tmax? Is it from the same study (i.e. after considering the subject who had emesis during the clinical phase PK and stat to be conducted and then based on the result his inclusion to be decided) or from the published literature? If it is from the same study we will have to continue the subject in the clinical phase which may be unethical if we are sure that this subject is definitely will fall in the said window (i.e. 2 times median Tmax) and if from the published literature then chances of getting different median Tmax value is also more. Thanking you in advance. Best regards, Ratnakar |
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Helmut ★★★   Vienna, Austria, 2008-04-02 17:44 (5861 d 04:47 ago) @ ratnakar1811 Posting: # 1753 Views: 37,956 |
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Dear Ratnakar! ❝ From where to take the median Tmax? You hit the critical point! ❝ Is it from the same study (i.e. after considering the subject who had emesis during the clinical phase PK and stat to be conducted and then based on the result his inclusion to be decided) or from the published literature? If it is from the same study we will have to continue the subject in the clinical phase which may be unethical if we are sure that this subject is definitely will fall in the said window (i.e. 2 times median Tmax) and if from the published literature then chances of getting different median Tmax value is also more. The label of the RLD rarely states the median (quite often it's still the arithmetic mean). Furthermore the value depends on the sampling schedule. I always interpreted 'median Tmax of the reference' as a study-specific value, as mentioned in the '[…] In this setting, the guidance recommends use of partial AUC as an early exposure measure. We recommend that the partial area be truncated at the population median of Tmax values for the reference formulation. We also recommend that at least two quantifiable samples be collected before the expected peak time to allow adequate estimation of the partial area.' See also this comment of August 2002 from the GPhA on the draft version of the guideline and Canada's Notice to Industry for rapid onset drugs (June 2005).Edit: FDA-link corrected to latest archived copy. [Helmut] — Dif-tor heh smusma 🖖🏼 Довге життя Україна! ![[image]](https://static.bebac.at/pics/Blue_and_yellow_ribbon_UA.png) Helmut Schütz ![[image]](https://static.bebac.at/img/CC by.png) The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes |
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ratnakar1811 ★ India, 2008-04-04 07:35 (5859 d 14:56 ago) (edited by Ohlbe on 2008-04-04 09:48) @ Helmut Posting: # 1760 Views: 37,631 |
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Dear HS, Thanks for your prompt reply, but the question remained unanswered that when we should exclude the subject from the study, is after bioanalysis or at the time of clinical phase only and if at the clininal phase what should be used as a basis for the same? And as you have suggested considering the partial area, how it should be done practically? Best Regards, Ratnakar -- Edit: Full quote removed. Please see this post! [Ohlbe] |
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Helmut ★★★ Vienna, Austria, 2008-04-04 13:49 (5859 d 08:42 ago) @ ratnakar1811 Posting: # 1762 Views: 37,516 |
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Dear Radnakar! ❝ […] but the question remained unanswered that when we should exclude the subject from the study, is after bioanalysis or at the time of clinical phase only and if at the clininal phase what should be used as a basis for the same? Did you read the reference I quoted? Also the guideline itself: 'We recommend that data from subjects who experience emesis during the course of a BE Study for immediate-release products be deleted from statistical analysis if vomiting occurs at or before 2 times median Tmax.'
❝ And as you have suggested considering the partial area, how it should be done practically? No, I didn’t suggest that. I just gave this quote from the guideline to show that median Tmax is seen as a study-specific parameter by the FDA. The FDA is interested in ‘total exposure’ (i.e., AUC) and ‘peak exposure’ (i.e., Cmax). Based on clinical grounds – rapid onset of effect, AEs – ‘early exposure’ (partial AUC truncated at median Tmax of the reference) should be assessed instead of the formerly used metric Tmax. Also Health Canada / TGD: […] Reftmax […] is defined as […] the time of the maximum concentration of the reference product, calculated for each study subject. — 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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ratnakar1811 ★ India, 2008-04-07 09:09 (5856 d 13:22 ago) @ Helmut Posting: # 1765 Views: 39,883 |
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Dear HS, From this can we interpret that the subject should be continued in the clinical phase irrespective at what time and which period (in case replicated design if emesis occurs in period 1) he had vomiting and the samples of that subject needs to be analyzed also? Now the question is regarding the median Tmax, when we say the median Tmax is a study specific value, and we have to exclude the subject from the statistical analysis based on the median Tmax then which value should be considered as median Tmax, as we can have two median Tmax values:
Thanking you in advance. Ratnakar |
Ing. Helmut Schütz