Loky do ★ Egypt, 20210616 02:49 (1156 d 03:06 ago) Posting: # 22414 Views: 5,773 

Dear colleagues, During bioanalysis of a fully replicate BE study for drug known to has a potential for back conversion (clopidogrel), one volunteer shows drug concentrations below LLOQ in 3 phases and only one phase (Reference product) shows very low drug concentration, no probability of not swallowing the tablets (mouth check was assured) what could be the reason of this results ? Knowing that the ISR results for the study is accepted? Thanks in advance 
drgunasakaran1 ★★ 20210616 10:59 (1155 d 18:56 ago) @ Loky do Posting: # 22416 Views: 5,202 

Dear Mr Loky do, ❝ During bioanalysis of a fully replicate BE study for drug known to has a potential for back conversion (clopidogrel) ,one volunteer shows drug concentrations below LLOQ in 3 phases and only one phase (Reference product) shows very low drug concentration, no probability of not swallowing the tablets (mouth check was assured) what could be the reason of this results ? Knowing that the ISR results for the study is accepted? As per regulatory guidance, you can exclude this subject if the following criteria is fulfilled; A subject with lack of any measurable concentrations or only very low plasma concentrations for reference medicinal product. A subject is considered to have very low plasma concentrations if its AUC is less than 5% of reference medicinal product geometric mean AUC (which should be calculated without inclusion of data from the outlying subject). The exclusion of data due to this reason will only be accepted in exceptional cases and may question the validity of the trial. Reference: EMA's Guideline on the Investigation of Bioequivalence Also, be informed that Genetic Polymorphisms of Cytochrome P450 enzymes (CYP2C19, CYP3A, CYP2B6 and CYP1A2) and Esterases will affect the Pharmacokinetic profile of clopidogrel in some subjects. — Dr S Gunasakaran MBBS MD Disclaimer: The replies/posts are my personal opinions and it does not represent my company views on the same. 
Loky do ★ Egypt, 20210616 17:38 (1155 d 12:17 ago) @ drgunasakaran1 Posting: # 22418 Views: 5,086 

many Thanks, drgunasakaran1 for your reply Dears I also have a question regarding Clopidogrel BE study design, as per ema questions and answers, is widening of Cmax accepted in clopidogrel BE studies with fully replicate design or not? thanks in advance Edit: link restored. [mittyri] 
mittyri ★★ Russia, 20210616 18:04 (1155 d 11:51 ago) @ Loky do Posting: # 22419 Views: 5,099 

Dear Loky do ❝ is widening of Cmax accepted in clopidogrel BE studies with fully replicate design or not? You linked the EMA Q&A where it is stated unequivocally: Under these circumstances, the widening of 90% confidence intervals for Cmax is not recommended. — Kind regards, Mittyri 
Loky do ★ Egypt, 20210616 19:08 (1155 d 10:47 ago) @ mittyri Posting: # 22420 Views: 5,161 

❝ You linked the EMA Q&A where it is stated unequivocally: ❝ Under these circumstances, the widening of 90% confidence intervals for Cmax is not recommended. Ok, in my case, the study fails as per EMA guidance, but if we used the FDA method for calculations it passes, regarding a drug as clopidogrel with many therapeutic issues, could it be accepted by different authorities, considering FDA guidelines (sponsor requests to submit an appeal to authorities to use calculations as per FDA guidelines as the protocol uses EMA guidance for statistical calculations)? thanks 
mittyri ★★ Russia, 20210616 19:27 (1155 d 10:27 ago) @ Loky do Posting: # 22421 Views: 5,064 

Dear Loky do, ❝ Ok, in my case, the study fails as per EMA guidance, but if we used the FDA method for calculations it passes, regarding a drug as clopidogrel with many therapeutic issues, could it be accepted by different authorities, considering FDA guidelines (sponsor requests to submit an appeal to authorities to use calculations as per FDA guidelines as the protocol uses EMA guidance for statistical calculations)? The productspecific guidance is quite old and was issued before RSABE first appeared as an option. BTW that smells like cherrypicking, sorry Most probably it will be rejected taking into account audit trail of the Protocol changes/dates of analysis. — Kind regards, Mittyri 
drgunasakaran1 ★★ 20210617 14:01 (1154 d 15:54 ago) @ Loky do Posting: # 22422 Views: 4,994 

Dear Mr Loky Do, ❝ Ok, in my case, the study fails as per EMA guidance, but if we used the FDA method for calculations it passes, regarding a drug as clopidogrel with many therapeutic issues, could it be accepted by different authorities, considering FDA guidelines (sponsor requests to submit an appeal to authorities to use calculations as per FDA guidelines as the protocol uses EMA guidance for statistical calculations)? Most of the times, the regulatory agency may not accept the change in the statistical plan after the Statistical Evaluation for the reason since it fails as per EMA guidance. — Dr S Gunasakaran MBBS MD Disclaimer: The replies/posts are my personal opinions and it does not represent my company views on the same. 
Helmut ★★★ Vienna, Austria, 20210619 14:32 (1152 d 15:22 ago) @ Loky do Posting: # 22423 Views: 4,976 

Hi Loky do, in addition to what Mittyri and Dr Gunasakaran wrote, a general remark about confirmatory studies:
In simple terms: The entire \({\small{\alpha=0.05}}\) was already ‘spent’ in the original analysis. Hence, any ‘alternative’ evaluation will increase the patient’s risk, which is not acceptable. — Diftor heh smusma 🖖🏼 Довге життя Україна! _{} Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes 
Loky do ★ Egypt, 20210706 13:51 (1135 d 16:04 ago) @ Helmut Posting: # 22458 Views: 4,687 

Thanks, Helmut for your reply but I am quite confused, some products show high intrasubject variability more than anticipated or published in the literature and I think this variability affect the reliability of results, for example, I have a BE study for (lansoprazole), partially replicate design, the published intrasubject variability ~ 40% but the practical intrasubject variability we had was near 85% study protocol also stated using ema guidelines for scaling but the study failed, when I used FDA method it passes does this high variability have a role in this confusing results? also in the future protocol can I specify that if the intrasubject variability is more than 50% can I switch to the FDA method for calculation, as many authorities we submit our studies to follow ema guidelines? Thanks in advance 
Helmut ★★★ Vienna, Austria, 20210706 18:17 (1135 d 11:38 ago) @ Loky do Posting: # 22460 Views: 4,718 

Hi Loky do, ❝ but I am quite confused, some products show high intrasubject variability more than anticipated or published in the literature … If you design studies for 80% power and all of your assumptions are exactly realized (T/Rratio, CV, dropoutrate), one out of five will fail be pure chance. That’s life. If the T/Rratio is worse, and/or the CV higher, and/or the dropoutrate higher, you loose power though you might still pass (see there). Happens all the time. ❝ … and I think this variability affect the reliability of results, … Not necessarily. ❝ … for example, I have a BE study for (lansoprazole), partially replicate design, the published intrasubject variability ~ 40% … That’s on the lower end for lansoprazole. I’ve seen studies with substantially higher CVs. ❝ … but the practical intrasubject variability we had was near 85% Bad luck if you designed the study for 40%. Was risky. ❝ … study protocol also stated using ema guidelines for scaling but the study failed, when I used FDA method it passes We are going in circles. Since you stated in the protocol that the study will be assessed for the EMA’s approach, you failed. Full stop. The fact that you would pass with RSABE is irrelevant. ❝ … does this high variability have a role in this confusing results? Of course, it does. In ABEL you impose an upper limit to expanding the limits, which is at CV_{wR} = 50% for the EMA (max. expansion 69.84–143.19%) and CV_{wR} ~57.4% for Health Canada (66.7–150.0%). For the FDA’s RSABE there is no such restriction. Hence, for any CV, the sample size for RSABE will be lower than the ones for the variants of ABEL. Or the other way ’round: For a given CV and sample size, RSABE has more power than ABEL. See there.
❝ … also in the future protocol can I specify that if the intrasubject variability is more than 50% can I switch to the FDA method for calculation, as many authorities we submit our studies to follow ema guidelines? No, you can’t. That’s datadriven. OK, you can but it will not be accepted. — Diftor heh smusma 🖖🏼 Довге життя Україна! _{} Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes 
BEQool ★ 20231009 16:47 (310 d 13:08 ago) @ Helmut Posting: # 23747 Views: 2,964 

Hello! I have seen this or similar explanation several times: ❝ If you design studies for 80% power and all of your assumptions are exactly realized (T/Rratio, CV, dropoutrate), one out of five will fail be pure chance. That’s life. ... but I still can't get my head around this. Lets say I plan study with theta0=0.95, CV=0.20, design="2x2", targetpower=0.8 (all except CV are default settings in PowerTOST), so with sampleN.TOST I get N=20 and power=0.834680 > sampleN.TOST(theta0=0.95, CV=0.20, design="2x2", targetpower=0.8, print=FALSE) If all of my assumptions in a study are exactly realized, doesnt it mean that I would 100% always get bioequivalent formulations (and the study would never fail)? If all of my assumptions in a study are exactly realized (pe=0.95, CV=0.20, design="2x2", n=20) then I would get the following confidence interval: > CI.BE(pe=0.95,CV=0.20,n=20) So because a confidence interval is completely within limits 80125%, my formulations would always be bioequivalent because I would always get this confidence interval with same numbers (CV,n,pe)? What am I not understanding here? Thank you and best regards BEQool 
mittyri ★★ Russia, 20231011 14:42 (308 d 15:12 ago) @ BEQool Posting: # 23749 Views: 2,842 

Dear BEQool! ❝ Lets say I plan study with theta0=0.95, CV=0.20, design="2x2", targetpower=0.8 (all except CV are default settings in PowerTOST), so with sampleN.TOST I get N=20 and power=0.834680 ❝
❝ Design alpha CV theta0 theta1 theta2 Sample size Achieved power Target power ❝ ❝ If all of my assumptions in a study are exactly realized, doesnt it mean that I would 100% always get bioequivalent formulations (and the study would never fail)? ❝ If all of my assumptions in a study are exactly realized (pe=0.95, CV=0.20, design="2x2", n=20) then I would get the following confidence interval: ❝
❝ lower upper
I think exactly realized means a bit different thing. Take a look at power.TOST.sim() function in PowerTOST packageThe description says: Power is calculated by simulations of studies (PE via its normal distribution, MSE via its associated χ2 distribution) and application of the two onesided ttests. Power is obtained via ratio of studies found BE to the number of simulated studies. So exactly realized means that the variance and centers of distributions used in power estimation were close to the true values, nothing more. > power.TOST.sim(n = 20, CV = 0.2, theta0 = 0.95, nsims = 1000) — Kind regards, Mittyri 
BEQool ★ 20231015 13:29 (304 d 16:25 ago) @ mittyri Posting: # 23758 Views: 2,831 

Hello Mittyri, thanks for the answer and explanation! So power takes into account probability distributions of PEs (normal distribution) and CVs (Chisquared distribution) and then shows probability that we will be bioequivalent based on the variabilities of PEs and CVs? Regards BEQool 
mittyri ★★ Russia, 20231020 23:47 (299 d 06:07 ago) @ BEQool Posting: # 23765 Views: 2,790 

Hi BEQool, yes, seems correct to me — Kind regards, Mittyri 
Helmut ★★★ Vienna, Austria, 20231023 12:48 (296 d 17:06 ago) @ mittyri Posting: # 23766 Views: 2,747 

Hi Mittyri & BEQool, ❝ yes, seems correct to me I think that the documentation of power.TOST.sim() is confusing and needs some improvement in the next release of the package.With its (default) argument logscale = TRUE the simulations are performed with log(theta0) – following a normal distribution, which gives lognormal distributed point estimates.— Diftor heh smusma 🖖🏼 Довге життя Україна! _{} Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes 
BEQool ★ 20231023 21:55 (296 d 08:00 ago) @ Helmut Posting: # 23767 Views: 2,737 

Mittyri and Helmut, thank you both for your answers. Maybe a basic questions but it came to mind when I was thinking about this. Distributions (both normal and lognormal) are determined by their mean and variance. As discussed above, in order to get power we need distribution of PE; the mean is of course PE but what about the variance? Is the variance of PE distribution MSE? Or something else? BEQool 
mittyri ★★ Russia, 20231031 16:40 (288 d 12:15 ago) @ BEQool Posting: # 23770 Views: 2,664 

Dear BEQool! ❝ Distributions (both normal and lognormal) are determined by their mean and variance. As discussed above, in order to get power we need distribution of PE; the mean is of course PE but what about the variance? Is the variance of PE distribution MSE? Or something else? I think it is better to look into the code
# simulate point est. via normal distribution So the variance is calculated based on MSE, design constant and the number of subjects: — Kind regards, Mittyri 
BEQool ★ 20231102 12:22 (286 d 16:33 ago) @ mittyri Posting: # 23772 Views: 2,571 

Dear Mittyri, thank you very much, everything is clear now! BEQool 