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NK ☆ India, 2024-09-13 08:48 (129 d 21:32 ago) Posting: # 24198 Views: 2,217 |
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Dear All, In our BE study, We observed Cmax at 0.25 hours (15 minutes) which is our first post dose time point. Do we need to exclude those subjects with Cmax at 15 min for statistical analysis? USFDA guidance says "In the BE study, collection of blood samples at an early time point, between 5 and 15 minutes after dosing, followed by additional sample collections (e.g., two to five) in the first hour after dosing is usually sufficient to assess peak drug concentrations. Failure to include early (5- to 15-minute) sampling times leading to first time point Cmax values may result in FDA excluding the data from affected subjects from the BE analysis." To avoid exclusion of subject for statistical analysis, do we need to keep first point "at 15 minutes" or "between 5 and 15 minutes eg. 10 minutes"? Kindly clarify. Is it applicable for modified Release product also? Thanks and Regards NK Edit: Category changed; see also this post #1. Guidance linked. [Helmut] |
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Helmut ★★★   Vienna, Austria, 2024-09-17 10:38 (125 d 19:42 ago) @ NK Posting: # 24200 Views: 1,882 |
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Hi NK, ❝ In our BE study, We observed Cmax at 0.25 hours (15 minutes) which is our first post dose time point. ❝ Do we need to exclude those subjects with Cmax at 15 min for statistical analysis? The first point of a concentration-time curve in a BE study, based on blood or plasma measurements, is sometimes the highest point, which raises questions of bias in the estimation of Cmax because of insufficient early sampling times. A carefully conducted pilot study can enable an applicant to avoid this problem. Did you perform a pilot study or were you fishing in the dark? With a pilot study you would have an argument.You may provide the complete data as a sensitivity analysis, though I strongly doubt that the FDA will give much – if any – weight to it, especially without a pilot where no first point Cmax was observed. The ICH M13A is only a little bit more permissive in “Section 2.1.8.1”. The sampling schedule should include frequent sampling around the anticipated tmax to provide a reliable estimate of Cmax. In particular, the occurrence of Cmax at the first post-dose sampling time point should be avoided by careful consideration of the known PK properties of the drug and selection of a suitable early sampling schedule. For example, for drug products with rapid absorption, collection of blood samples at an early time point, between 5 and 15 minutes after dosing, followed by additional sample collections, e.g., two to five samples in the first hour after dosing, is usually sufficient to assess peak drug concentrations. When absorption is rapid, time points earlier than 5 minutes are generally not expected. ❝ To avoid exclusion of subject for statistical analysis, do we need to keep first point "at 15 minutes" or "between 5 and 15 minutes eg. 10 minutes"? ❝ … (15 minutes) which is our first post dose time point. ❝ Is it applicable for modified Release product also? — 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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kimhuang ☆ China, 2024-11-27 09:49 (54 d 19:31 ago) @ Helmut Posting: # 24298 Views: 959 |
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Dear Helmut, ❝ For subjects where Cmax occurs at the first post-dose sampling time, the actual Cmax may have been missed as it could have occurred at an earlier time point. When this occurs, the robustness of the study results in relation to the potential missed Cmax should be discussed. This could include additional analysis where data from the affected subjects are removed from the analysis. ❝ In other words, it is the other way around than for the FDA. Keep the subject(s) in the primary analysis and exclude them in a sensitivity analysis. Q: Since ICH M13A and FDA requirements are inconsistent, which guidelines need to be followed? |
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Helmut ★★★ Vienna, Austria, 2024-11-27 14:50 (54 d 14:30 ago) @ kimhuang Posting: # 24302 Views: 939 |
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Hi Kim, ❝ Q: Since ICH M13A and FDA requirements are inconsistent, which guidelines need to be followed? Good question. The guidance ‘Bioequivalence Studies With Pharmacokinetic Endpoints for Drugs Submitted Under an ANDA’ of August 2021 deals with both IR and MR. Although it is still a draft, it would be wise to follow it. On 30 October 2024 the FDA published its final version of M13A. IMHO, it overrules sections dealing with IR products of the 2021 ANDA draft and an update of the ANDA guidance is expected for next year. From last week’s SBIA webinar: ![[image]](img/uploaded/image910.png) — 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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dshah ★★ India, 2024-11-27 13:50 (54 d 15:30 ago) @ NK Posting: # 24301 Views: 930 |
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Hi NK! I would agree with Helmut but is the median Tmax- 15 min? If so, does the literature also supports the same? If yes, it means the sampling time points were not considered effectively. If no- then is median Tmax of 15 min observed for both treatments (considering 2TCO)? If it is only observed for Test or Reference- identify PKPD issue/toxicity challenges. Divyen Edit: Post moved. [Helmut] |
Ing. Helmut Schütz