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Mahesh M ★ India, 2016-08-18 14:50 (3139 d 15:16 ago) Posting: # 16560 Views: 7,544 |
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Dear All, For EMA submission of prolonged release dosage form is it possible to Waiver for multiple dosage study on the basis of evidence of “lack of accumulation (by SPC, PAR or literature) and the provide partial AUC for both fasting and fed two way study as supportive? Regards |
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VStus ★ Poland, 2016-08-24 23:37 (3133 d 06:30 ago) @ Mahesh M Posting: # 16572 Views: 6,236 |
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Hi Mahesh, ❝ “lack of accumulation" (by SPC, PAR or literature) and the provide partial AUC for both fasting and fed two way study as supportive data. On my opinion, it's clearly stated that SPC, PAR or literature is not sufficient as both Test and Reference product's data are required: 6.1.1.2. Multiple dose studies A multiple dose study is needed unless a single dose study has been performed with the highest strength which has demonstrated that the mean AUC(0-tau) after the first dose covers more than 90% of mean AUC(0-∞) for both test and reference, and consequently a low extent of accumulation is expected. Best regards, VStus |
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Mahesh M ★ India, 2016-08-25 11:36 (3132 d 18:30 ago) @ VStus Posting: # 16573 Views: 6,428 |
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Hi VStus, Thank you so much for your response. Can we use partial AUC (labeled dose interval) from both fasting and fed two way study instead of AUC(0-tau)? Please find below link for recently published PAR of metformin. http://www.mhra.gov.uk/home/groups/par/documents/websiteresources/con713246.pdf In this PAR Applicant performed three BE study on 500 mg strength: Fasting 500 mg two way Fed 500 mg two way Multiple 500 mg fed Applicant failed to demonstrate BE on multiple dose fed BE study but got approval on the basis of evidence of “lack of accumulation and the provide partial AUC for both fasting and fed two way study as supportive. Regards |
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VStus ★ Poland, 2016-08-25 20:34 (3132 d 09:33 ago) @ Mahesh M Posting: # 16576 Views: 6,407 |
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Hi, Manesh! ❝ Can we use partial AUC (labeled dose interval) from both fasting and fed two way study instead of AUC(0-tau)? I can only cite same section of the Guideline once more again... Why not if there is no accumulation and partialAUCs will demonstrate BE. What if these parameters will be highly variable? ❝ http://www.mhra.gov.uk/home/groups/par/documents/websiteresources/con713246.pdf Thank you for the reference! Regards, VStus |
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BE-proff ● 2016-08-26 12:45 (3131 d 17:21 ago) @ VStus Posting: # 16580 Views: 6,477 |
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Hi VStus, Unless I am mistaken, to comply with the statement you have cited we need to conduct steady state study anyway. Otherwise, how to get AUC0-tau?  |
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Helmut ★★★   Vienna, Austria, 2016-08-26 13:08 (3131 d 16:59 ago) @ BE-proff Posting: # 16581 Views: 6,268 |
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Hi BE-proff, ❝ Unless I am mistaken, You are. ❝ … to comply with the statement you have cited we need to conduct steady state study anyway. Otherwise, how to get AUC0-tau? The MR GL again, this time with the important part in red: A multiple dose study is needed unless a single dose study has been performed with the highest strength which has demonstrated that the mean AUC(0-τ) after the first dose covers more than 90% of mean AUC(0-∞) for both test and reference, and consequently a low extent of accumulation is expected. Here τ is the intended dosage interval for the labeled posology. Say you want to dose b.i.d. (τ=12). In the SD study you will sample long enough to get a reliable estimate of λz (for the calculation of AUC0-∞). Now you have to show that AUC0–12 covers more than 90% of AUC0-∞ in order to waive the MD study. — 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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Mahesh M ★ India, 2016-08-26 16:17 (3131 d 13:50 ago) @ Helmut Posting: # 16586 Views: 6,149 |
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Hi Helmut, Thank you so much for your response its really help us a lot. Regards |
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mittyri ★★ Russia, 2016-08-26 19:43 (3131 d 10:24 ago) @ Helmut Posting: # 16593 Views: 6,214 |
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Hi Helmut, I've found a presentation released by European Generic and Biosimilar Medicines Association. I suppose you are familiar with it. They are asking very interesting questions, regarding waiving MD too. Could you please comment their questions? At least this one: Accumulation, i.e. AUC0-τ steady state / AUC0-τ after first administration is
For linearity assessment, a ±25% difference in AUC is acceptable. — Kind regards, Mittyri |
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Helmut ★★★ Vienna, Austria, 2016-08-26 21:42 (3131 d 08:25 ago) @ mittyri Posting: # 16594 Views: 6,355 |
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Hi mittyri, ❝ I've found a presentation released by European Generic and Biosimilar Medicines Association. ❝ I suppose you are familiar with it. Yes, I’ve been there. The answer of the panelists (members of the PKWP) essentially was „We want it that way”. When reminded that MD studies are generally not required by the FDA at all (‼), 20% extrapolated AUC is the limit in Canada for many years, and we have no evidence of any problems on the other side of the pond one panelist replied „We could have required 5% as well”… — 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