Helmut ★★★ Vienna, Austria, 2021-01-26 11:47 (1408 d 14:40 ago) Posting: # 22190 Views: 3,848 |
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Dear all, I recently came across a deficiency letter of the Polish agency.
Pharmacokinetics The applicant is asked to comment on the following questions regarding documentation on bioequivalence. Primary pharmacokinetic parameters determined Cmax and AUC(0-t) of ██████ of the test product against the reference product does not meet the assumption on the bioequivalence criteria contained in the guideline CPMP/EWP/QWP/1401/98 Rev. 1/Corr ** and in the Study protocol. — 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 |
ElMaestro ★★★ Denmark, 2021-01-26 13:26 (1408 d 13:01 ago) @ Helmut Posting: # 22191 Views: 3,248 |
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Hi Hötzi, I understand your frustration. Here's a good basis for answering, just remember: 1. They do not know all the stuff that you know. 2. You cannot educate them. The rest is easy. — Pass or fail! ElMaestro |
Helmut ★★★ Vienna, Austria, 2021-01-26 19:52 (1408 d 06:35 ago) @ ElMaestro Posting: # 22192 Views: 3,236 |
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Hi ElMaestro, ❝ I understand your frustration. I’m not frustrated. Just extremely surprised. ❝ Here's a good basis for answering, just remember: ❝ ❝ 1. They do not know all the stuff that you know. Given. ❝ 2. You cannot educate them. Sooo sad! ❝ The rest is easy. Define ‘the rest’. Crude -script at the end. The example’s output:
To quote the WHO:
— 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 |
ElMaestro ★★★ Denmark, 2021-01-26 23:34 (1408 d 02:53 ago) @ Helmut Posting: # 22193 Views: 3,225 |
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Hi Hötzi, ❝ Define ‘the rest’. Just explain what you think, without in any way suggesting that your way of thinking is the only way of thinking, the right way of thinking or a better way of thinking than theirs. Just present it as you see it. Briefly. Express your point without too much technical detail; for the Polish agency I would not emphasize my point with simulations, I don't think this will change much. I am sure you will get approval. As I read it this is a minor thing to the assessor anyway. — Pass or fail! ElMaestro |
zizou ★ Plzeň, Czech Republic, 2021-01-31 02:07 (1404 d 00:20 ago) @ Helmut Posting: # 22195 Views: 3,414 |
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Dear Helmut. ❝ 3. ANOVA analysis of variance showed statistically significant (at a 5% significance level) differences in AUC(0-t) between investigational products, which further exacerbated the uncertainty about fulfillment of the bioequivalence criteria. The statistically significant formulation effect for AUC(0-t) is quite common. The sample size is usually estimated with intra-subject CV of Cmax (as it is usually higher than of AUC(0-t)). To continue with your example: Assumed intra-subject CV of Cmax = 25% -> with assumed PE of 95% for target power 90%: n = 38 Assumed intra-subject CV of AUC(0-t) e.g. 10% When assumed parameters used for sample size estimation will be theoretically observed in the study, i.e. the observed GMR will be 95% and observed intra-subect CV will be 10%, we will get 90% CI equal to 91.40-98.74% and statistically significant formulation effect (at a 10% significance level). If the 90% CI does not contain 100%, the p value will always be <0.1 but how it could further exacerbated the uncertainty about fulfillment of the bioequivalence criteria? (Question for regulators.) ❝
I just want to point that it's observed more often for AUC(0-t) than for Cmax and it would be interesting to know the percentage of that also for AUC(0-t) with lower variability. ;) ❝ 2. Lack of a posteriori data on the power... The only good thing on this point is that the regulators believe that test and reference IMPs are bioequivalent. (As they deal with power.) Posteriori power is never ending story. The question on the power should be raised to the protocol, if it is addressed to the report, it is just a suggestion for future projects. Additionaly You can remind them what the low power means: With lower power, the type II error (sponsor's risk) is higher - it means that the bioequivalent preparations could be assessed wrongly as not bioequivalent with higher probability. The regulators should sleep well with higher type II error (unless the study was designed for e.g. 50% power from the start - but such protocols should be rejected). I wish the regulators would be interested also in the type I error - it would mean that regulators do not believe that test and reference IMPs are bioequivalent. The probability of approving non-bioequivalent test product should be up to 5%. I noticed several studies which suprised me more than this deficiency letter. E.g. by using:
Btw. I am also sure you will get approval. As even studies where 90% CI was (partly) outside 80-125% were approved at the end. Best regards, zizou PT Frustration - not related to vaccine |
Helmut ★★★ Vienna, Austria, 2021-01-31 16:46 (1403 d 09:41 ago) @ zizou Posting: # 22196 Views: 3,133 |
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Hi zizou, ❝ The statistically significant formulation effect for AUC(0-t) is quite common. The sample size is usually estimated with intra-subject CV of Cmax (as it is usually higher than of AUC(0-t)). Correct. ❝ To continue with your example: ❝ Assumed intra-subject CV of Cmax = 25% -> with assumed PE of 95% for target power 90%: n = 38 ❝ Assumed intra-subject CV of AUC(0-t) e.g. 10% ❝ When assumed parameters used for sample size estimation will be theoretically observed in the study, i.e. the observed GMR will be 95% and observed intra-subect CV will be 10%, we will get 90% CI equal to 91.40-98.74% and statistically significant formulation effect (at a 10% significance level). Correct as well. A study should be powered for the worst case combination (assumed CV, PE) of PK metrics. Naturally, PK metrics with ‘better combinations’ will have higher power. ❝ If the 90% CI does not contain 100%, the p value will always be <0.1 but how it could further exacerbated the uncertainty about fulfillment of the bioequivalence criteria? (Question for regulators.) Sorry, I can’t answer. ❝ ❝
❝ I just want to point that it's observed more often for AUC(0-t) than for Cmax and it would be interesting to know the percentage of that also for AUC(0-t) with lower variability. ;) Your wish is my command I (-script upon request).
❝ ❝ 2. Lack of a posteriori data on the power... ❝ The only good thing on this point is that the regulators believe that test and reference IMPs are bioequivalent. (As they deal with power.) ❝ Posteriori power is never ending story. The question on the power should be raised to the protocol, if it is addressed to the report, it is just a suggestion for future projects. ❝ Additionaly You can remind them what the low power means: With lower power, the type II error (sponsor's risk) is higher - it means that the bioequivalent preparations could be assessed wrongly as not bioequivalent with higher probability. The regulators should sleep well with higher type II error (unless the study was designed for e.g. 50% power from the start - but such protocols should be rejected). Agree, though in the statistical sense we assume (i.e., believe) that products are not bioequivalent (that’s the Null) and hope that it will rejected. ❝ ❝ I wish the regulators would be interested also in the type I error - … So do I. Inflated Type I Error in reference-scaling – another issue generally ignored. ❝ … it would mean that regulators do not believe that test and reference IMPs are bioequivalent. The probability of approving non-bioequivalent test product should be up to 5%. Correct. ❝ I noticed several studies which suprised me more than this deficiency letter… Funny stories! Assessors of the MHRA are a strange bunch. The most bizarre I have seen was this one:
The MHRA wanted to see a pooled (pooled ‼) analysis of all four studies. What the heck? The applicant replied that the first formulation went into the waste bin and hence, only market authorization of the second one was sought. The purpose of #2.a. was just to design #2.b. – which stands on its own. Refused to pool any of the studies. Pointed also out that the studies were evaluated with α 0.05 and by pooling the consumer risk cannot be controlled by any means. Then the MHRA insisted to get a pooled analysis of #2 (with a 95% CI II). Passed AUC, failed Cmax (by a small margin). Accepted and market authorization granted… ❝ PT Frustration - not related to vaccine Yep.
— 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 |