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nasir ☆ Jordan, 2014-02-14 07:38 (4513 d 13:28 ago) Posting: # 12419 Views: 6,849 |
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Hi Folks, As per EMA guideline, 3 way or 4 way replicate design should be done for HVD in order to be able to widen Cmax limits. My question is if drug was shown as HVD in a pilot RR study. Then can we go for 2 way design, with Cmax limits widened?  Thanks Nasir |
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d_labes ★★★ Berlin, Germany, 2014-02-14 10:27 (4513 d 10:39 ago) @ nasir Posting: # 12425 Views: 6,538 |
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Dear nasir, ❝ My question is if drug was shown as HVD in a pilot RR study. Then can we go for 2 way design, with Cmax limits widened? No chance  . The EMA guidance clearly states: "For the acceptance interval to be widened the bioequivalence study must be of a replicate design where it has been demonstrated that the within-subject variability for Cmax of the reference compound in the study is >30%." (Emphasis by me). Don't forget the sentence just before the above citation: "Those HVDP for which a wider difference in Cmax is considered clinically irrelevant based on a sound clinical justification can be assessed with a widened acceptance range." — Regards, Detlew |
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Helmut ★★★   Vienna, Austria, 2014-02-14 15:35 (4513 d 05:31 ago) @ d_labes Posting: # 12426 Views: 6,225 |
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Hi Nasir, ❝ "For the acceptance interval to be widened the bioequivalence study must be of a replicate design where it has been demonstrated that the within-subject variability for Cmax of the reference compound in the study is >30%." Referring to high variability in another study (pilot, literature) is not acceptable. If CVWR in the study ≤30% you may not widen the acceptance range. Keep that in mind when planning the sample size. — 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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kvgreddy06 ☆ India, 2014-02-14 17:18 (4513 d 03:47 ago) @ nasir Posting: # 12427 Views: 6,181 |
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❝ As per EMA guideline, 3 way or 4 way replicate design should be done for HVD in order to be able to widen Cmax limits. Why EMA suggesting widening of limits for Cmax only why not AUC? 'AUC is also one of the primary PK parameter'. Thanks KVGR |
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PK_Lover ☆ Portugal, 2014-02-14 19:37 (4513 d 01:29 ago) @ kvgreddy06 Posting: # 12429 Views: 6,067 |
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d_labes ★★★ Berlin, Germany, 2014-02-14 21:03 (4513 d 00:03 ago) @ PK_Lover Posting: # 12430 Views: 6,302 |
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Dear PK_Lover, ❝ I would say that it is because a wider difference in AUC is considered clinically relevant. I'm not quite sure if this gets the point. I have the impression that this decision was driven purely by 'political' reasons (Whatever these reasons were ).If it were due to some 'scientific' reasons I would not understand why the FDA does allow widening (or better said scaled ABE) also for AUC. — Regards, Detlew |
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Helmut ★★★ Vienna, Austria, 2014-02-15 16:10 (4512 d 04:56 ago) @ PK_Lover Posting: # 12433 Views: 6,109 |
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Hi PK_Lover, I agree with Detlew about the “political reasons” (for the history see this post). From a scientific point of view limiting ABEL to Cmax doesn’t make sense – think about bisphosphonates… I think that the cap at 50% CVWR was introduced to keep consistency with the many studies which were performed in the past. EMA didn’t want to aim higher. — 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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nasir ☆ Jordan, 2014-02-18 08:24 (4509 d 12:42 ago) (edited on 2014-02-18 10:52) @ Helmut Posting: # 12436 Views: 5,939 |
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Hi Folks, Thank you all for this. I beleive Cmax (a single point in PK profile) but not AUC (all points in PK profile) limits widened since is more sensetive to high CV than AUC. Nasir Edit: Full quote removed. Please delete everything from the text of the original poster which is not necessary in understanding your answer; see also this post! [Ohlbe] |
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Helmut ★★★ Vienna, Austria, 2014-02-18 14:03 (4509 d 07:03 ago) @ nasir Posting: # 12437 Views: 5,872 |
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Hi Nasir, ❝ I beleive Cmax (a single point in PK profile) but not AUC (all points in PK profile) limits widened since is more sensetive to high CV than AUC. Yes, it it correct that Cmax as a single point metric is inherently more variable than AUC. But still: Some products are highly variable in AUC as well – and have to be shown to be safe and efficacious despite their high variability. Therefore, in the EU we have to deal with politics rather than science. — 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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nasir ☆ Jordan, 2014-02-18 20:57 (4509 d 00:09 ago) @ Helmut Posting: # 12441 Views: 5,863 |
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Hi Helmut, I agree with you about politics. I have 2 related questions about this matter:
Nasir Edit: Full quote removed. Please delete everything from the text of the original poster which is not necessary in understanding your answer; see also this post! [Helmut] |
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Helmut ★★★ Vienna, Austria, 2014-02-18 21:38 (4508 d 23:28 ago) @ nasir Posting: # 12442 Views: 6,035 |
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Hi Nasir, ❝ 1. I wonder if we can widen Cmax limits for MR product using replicate design? (i.e. is allowed for IR and MR products). I’m pretty optimistic about Cmax. Partial AUCs and Cmin were also discussed in the MR draft. Let’s see. ❝ 2. If answer to above is yes, then do we need replicate design in the SS study too? Yes. — 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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nasir ☆ Jordan, 2014-02-19 08:09 (4508 d 12:56 ago) @ Helmut Posting: # 12444 Views: 5,806 |
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Helmut ★★★ Vienna, Austria, 2014-02-19 14:10 (4508 d 06:55 ago) @ nasir Posting: # 12445 Views: 5,813 |
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Hi Nasir, ❝ It will really be a nightmare for MR industry. Wouldn’t say that. In some parts it will be easier. Note this part of the current MR NfG: It may be valuable to assess the intra-individual variability. This could be achieved by either repeated measurements of the concentration profile at steady state or by performing a single dose study with replicate design. Seems that applicants ignored that and regulators didn’t insist. At least I have never seen such a study in the past.❝ Any idea when the MR draft go into force? Six months after adoption.  It is difficult to estimate how long it will take EMA’s PK working party to chew through the comments and agree on changes. It took them one year for the IR GL and 26 months for the GL on Bioanalytical Method Validation. My guess:: This autumn?PS: In the future please delete everything from the text of the original poster which is not necessary in understanding your answer; see also this post! — 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