Loky do
★

Egypt,
2021-06-16 00:49
(124 d 03:20 ago)

Posting: # 22414
Views: 1,288

## Outlier in fully replicate BE study [Outliers]

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?
drgunasakaran1
★★

2021-06-16 08:59
(123 d 19:10 ago)

@ Loky do
Posting: # 22416
Views: 1,149

## Outlier in fully replicate BE study

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,
2021-06-16 15:38
(123 d 12:31 ago)

(edited by mittyri on 2021-06-16 15:57)
@ drgunasakaran1
Posting: # 22418
Views: 1,106

## Widening for clopidogrel BE study

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?

mittyri
★★

Russia,
2021-06-16 16:04
(123 d 12:05 ago)

@ Loky do
Posting: # 22419
Views: 1,111

## Widening for clopidogrel BE study

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,
2021-06-16 17:08
(123 d 11:02 ago)

@ mittyri
Posting: # 22420
Views: 1,102

## Widening for clopidogrel BE study

» 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,
2021-06-16 17:27
(123 d 10:42 ago)

@ Loky do
Posting: # 22421
Views: 1,106

## Widening for clopidogrel BE study - cherry-picking?

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 product-specific guidance is quite old and was issued before RSABE first appeared as an option.
BTW that smells like cherry-picking, sorry
Most probably it will be rejected taking into account audit trail of the Protocol changes/dates of analysis.

Kind regards,
Mittyri
drgunasakaran1
★★

2021-06-17 12:01
(122 d 16:08 ago)

@ Loky do
Posting: # 22422
Views: 1,035

## Widening for clopidogrel BE study

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,
2021-06-19 12:32
(120 d 15:37 ago)

@ Loky do
Posting: # 22423
Views: 983

## Hypotheses

Hi Loky do,

in addition to what Mittyri and Dr Gunasakaran wrote, a general remark about confirmatory studies:
1. You state a null hypothesis H0 and an alternative hypothesis H1.
In bioequivalence H0 is inequivalence – which you desire to reject.
2. You state an appropriate statistical method, most commonly the confidence inclusion approach.
3. You perform the study and assess #1 by #2.
The outcome is dichotomous, i.e., either the study passed (H0 rejected) or it failed (H0 not rejected).
What you must not do: The study failed according to the planned conditions and then you change #1 and/or #2 in order to make it pass. That’s the cherry-picking Mittyri was talking about.
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.

Dif-tor heh smusma 🖖
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
Loky do
★

Egypt,
2021-07-06 11:51
(103 d 16:18 ago)

@ Helmut
Posting: # 22458
Views: 736

## Hypotheses

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?

Helmut
★★★

Vienna, Austria,
2021-07-06 16:17
(103 d 11:52 ago)

@ Loky do
Posting: # 22460
Views: 724

## ABEL ≠ RSABE

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/R-ratio, CV, dropout-rate), one out of five will fail be pure chance. That’s life.
If the T/R-ratio is worse, and/or the CV higher, and/or the dropout-rate 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 CVwR = 50% for the EMA (max. expansion 69.84–143.19%) and CVwR ~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.

library(PowerTOST) CV     <- sort(c(seq(40, 90, 10), 85)) theta0 <- 0.95 design <- "2x2x4" target <- 0.80 res    <- data.frame(CV = CV, n = NA_integer_,                      power.ABEL = NA_real_, power.RSABE = NA_real_,                      power.ABEL.n1 = NA_real_, power.RSABE.n1 = NA_real_) for (j in 1:nrow(res)) {   tmp                <- sampleN.scABEL(CV = CV[j]/100, theta0 = theta0,                                        design = design, targetpower = target,                                        details = FALSE, print = FALSE)   res$n[j] <- tmp[["Sample size"]] res$power.ABEL[j]  <- tmp[["Achieved power"]]   res$power.RSABE[j] <- power.RSABE(CV = CV[j]/100, theta0 = theta0, design = design, n = res$n[j])   if (j == 1) {     res$power.ABEL.n1[j] <- res$power.ABEL[j]     res$power.RSABE.n1[j] <- res$power.RSABE[j]   } else {     res$power.ABEL.n1[j] <- power.scABEL(CV = CV[j]/100, theta0 = theta0, design = design, n = res$n[1])     res$power.RSABE.n1[j] <- power.RSABE(CV = CV[j]/100, theta0 = theta0, design = design, n = res$n[1])   } } names(res)[5:6] <- c(paste0("power.ABEL (n=", res$n[1], ")"), paste0("power.RSABE (n=", res$n[1], ")")) res$CV <- sprintf("%.0f%%", res$CV) print(res, row.names = FALSE)

Gives:

  CV  n power.ABEL power.RSABE power.ABEL (n=20) power.RSABE (n=20)  40% 20    0.82131     0.86422           0.82131            0.86422  50% 22    0.84475     0.90013           0.79996            0.86790  60% 24    0.80957     0.90602           0.71029            0.85313  70% 30    0.81094     0.91987           0.57715            0.82659  80% 38    0.82330     0.92529           0.43569            0.79581  85% 40    0.80422     0.91998           0.36923            0.78044  90% 44    0.80858     0.92106           0.30796            0.76509

That’s why your study failed with ABEL and may have passed with RSABE.

» … 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 data-driven. OK, you can but it will not be accepted.

Dif-tor heh smusma 🖖
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes