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JOI ☆ Brazil, 2011-11-16 12:57 (4925 d 12:02 ago) Posting: # 7676 Views: 6,579 |
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Dear all We found in one of the study subjects, drug levels above LLOQ at the pre-dose sample of the first study period. This came out on both analytes under study (ethinyl estradiol and gestodene), somehow confirming this was not an artifact. Since levels were below 5% of the Cmax, our first approach was to include this subject in the analysis anyway. It was also noticed that the statistical analysis shows a significant sequence effect (p ~= 0,048) Sequence effect does not show up taking this subject out of the analysis. I think this is just a coincidence since the pk profile for this subject is almost coincident for both ref and test drugs. (Cmax 325.46 vs 315.95 pg/mL and AUC 0-t 2859 vs 3017 [pg x hr]/mL, for ethinyl, for example). I'm wondering what would be the "best" approach to report the final results - including or excluding this volunteer - since our regulators usually "don't like" volunteer exclusions. By the way, BE results are the same (bioequivalent) including or excluding this volunteer from the BE analysis. Thanks in advance for your comments Edit: Category changed. [Helmut] |
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Helmut ★★★   Vienna, Austria, 2011-11-16 14:59 (4925 d 10:00 ago) @ JOI Posting: # 7677 Views: 5,616 |
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Dear Jaime! ❝ We found in one of the study subjects, drug levels above LLOQ at the pre-dose sample of the first study period. ❝ This came out on both analytes under study (ethinyl estradiol and gestodene), somehow confirming this was not an artifact. ❝ ❝ Since levels were below 5% of the Cmax, our first approach was to include this subject in the analysis anyway.
❝ It was also noticed that the statistical analysis shows a significant sequence effect (p ~= 0,048) Is ANVISA still asking for that? To be honest I have given up to fix the many broken links in the Guidance page. Do you have a working URL? ❝ Sequence effect does not show up taking this subject out of the analysis. I think this is just a coincidence since the pk profile for this subject is almost coincident for both ref and test drugs. (Cmax 325.46 vs 315.95 pg/mL and AUC 0-t 2859 vs 3017 [pg x hr]/mL, for ethinyl, for example). ❝ ❝ I'm wondering what would be the "best" approach to report the final results - including or excluding this volunteer - since our regulators usually "don't like" volunteer exclusions. What have you stated in the protocol? ❝ By the way, BE results are the same (bioequivalent) including or excluding this volunteer from the BE analysis. Lucky you! I would submit whatever you have stated in the protocol as primary analysis and show the data after exclusion as a sensitivity analysis (supportive). — 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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JOI ☆ Brazil, 2011-11-16 18:11 (4925 d 06:48 ago) @ Helmut Posting: # 7678 Views: 5,599 |
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Dear Helmut Thank you for your swift reply ❝
Unfortunately, maybe due to any cultural reason, it is difficult to get a positive return from some of the volunteers in these cases. But we are quite sure this was the case, since levels are almost 5% of the Cmax, which is compatible with taking a pill from 3 to 7 days earlier. Anyway, as you said, lucky me to have no influence on the study outcome. ❝ ... To be honest I have given up to fix the many broken links in the Guidance page. Do you have a working URL? I'll have a look, hoping to provide you the correct links nowadays. Many thanks, Jaime |
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Helmut ★★★ Vienna, Austria, 2011-11-16 19:11 (4925 d 05:48 ago) @ JOI Posting: # 7679 Views: 5,646 |
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Dear Jaime! ❝ Unfortunately, maybe due to any cultural reason, it is difficult to get a positive return from some of the volunteers in these cases. I think that this is not due to cultural differences. Subjects rarely ‘confess’ that they have violated study’s restrictions fearing they will never be included again (not without a cause…). ❝ But we are quite sure this was the case, since levels are almost 5% of the Cmax, which is compatible with taking a pill from 3 to 7 days earlier. Even if you don’t get a positive response from the volunteer I would include this reasoning in the report. ❝ ❝ ... To be honest I have given up to fix the many broken links in the Guidance page. Do you have a working URL? ❝ ❝ I'll have a look, hoping to provide you the correct links nowadays. THX, would be nice. I asked colleagues from ANVISA personally and by e-mail numerous times. They all agreed to help, but actually never did…  — 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 |
Ing. Helmut Schütz