mahmoud-teaima ★ 2017-05-22 15:55 (2862 d 01:33 ago) Posting: # 17387 Views: 6,070 |
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Dear all, Please, advise on sample size estimation and setting of BE limits in the following situations where ISV for Cmax and AUC are far apart. ![]() Greetings. — Mahmoud Teaima, PhD. |
Helmut ★★★ ![]() ![]() Vienna, Austria, 2017-05-22 17:16 (2862 d 00:12 ago) @ mahmoud-teaima Posting: # 17388 Views: 5,236 |
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Salam Mahmoud, ❝ Please, advise on sample size estimation and setting of BE limits in the following situations where ISV for Cmax and AUC are far apart. You have to demonstrate BE for both. Since in your example Cmax seems to be highly variable I assumed a T/R-ratio of 0.9 (and not the observed despite that it is close to 1) and the same for AUC. Target power 80%. Two options for the EMA:
You can see that the variability of Cmax (even for reference-scaling) drives the sample size. However, you get an incentive. Power for AUC will be (much) higher than the target. Hence, its T/R-ratio can deviate more from 1 than expected (as shown above in the column GMRlo ) or its CV can be higher whilst still maintaining the target level.— 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 |
mahmoud-teaima ★ 2017-05-23 14:31 (2861 d 02:57 ago) @ Helmut Posting: # 17392 Views: 5,171 |
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Salam Helmut, Thank you for the detailed, evidence-proofed explanation. The problem here is that literature data archiving the PKs and output of previous BE studies on simvastatin show border ISV with CV around 30% (29% - 33%). On the contrary, till the moment, the FDA guidance for BE study on Simvastatin doesn't involve reference scaling https://www.fda.gov/downloads/Drugs/.../Guidances/ucm086171.pdf https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm089636.pdf So, the straightforward question is: Does the BE study of Simvastatin involve reference scaling due the border ISV of simvastatin derived from literature though the regulator doesn't imply that? Greetings. — Mahmoud Teaima, PhD. |
Helmut ★★★ ![]() ![]() Vienna, Austria, 2017-05-23 15:15 (2861 d 02:13 ago) @ mahmoud-teaima Posting: # 17394 Views: 5,226 |
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Salam Mahmoud, ❝ The problem here is that literature data archiving the PKs and output of previous BE studies on simvastatin show border ISV with CV around 30% (29% - 33%). ❝ ❝ On the contrary, till the moment, the FDA guidance for BE study on Simvastatin doesn't involve reference scaling https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm089636.pdf Note that this guidance was recommended in August 2008 – way before the FDA considered reference scaling acceptable (Progesterone, April 2010). ❝ Does the BE study of Simvastatin involve reference scaling due the border ISV of simvastatin derived from literature though the regulator doesn't imply that? Until the FDA updates the product-specific guidance, it is still worthwhile to give it a try. See the draft guidance “Bioequivalence Studies with Pharmacokinetic Endpoints for Drugs Submitted Under an ANDA” lines 119–121 and footnote 10. For the FDA you have to submit the protocol for review anyway. See also Section VI.B. of “ANDA Submissions – Refuse-to-Receive Standards”. — 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 |
mahmoud-teaima ★ 2017-05-23 18:20 (2860 d 23:08 ago) @ Helmut Posting: # 17400 Views: 5,021 |
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Salam Helmut, ❝ submit the protocol for review anyway. Totally, agree with that. Many thanks for advise. Greetings. Edit: Standard quotes restored; see also this post #8. [Helmut] — Mahmoud Teaima, PhD. |