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Back to the forum  2018-07-20 11:06 CEST (UTC+2h)
mmw
Junior

India,
2017-07-14 14:50

Posting: # 17548
Views: 3,369
 

 EMA Product Specific GL [Regulatives / Guidelines]

Dear all,

EMA adopted a new batch of product specific guidances. Published on 10/07/2017:

Crizotinib
Elvitegravir / cobicistat / emtricitabine / te­no­fovir disoproxil
Elvitegravir
Emtricitabine, rilpivirine, tenofovir, disopro­xil
Vortioxetine

Thanks

MMW
Helmut
Hero
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Vienna, Austria,
2017-07-28 12:40

@ mmw
Posting: # 17620
Views: 2,806
 

 EMA Product Specific GL


Cheers,
Helmut Schütz
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Helmut
Hero
avatar
Homepage
Vienna, Austria,
2017-08-03 17:47

@ Helmut
Posting: # 17660
Views: 2,747
 

 tlag‽

Dear all,

In the product-specific guidance for Dimethyl fumarate gastro-resistant capsules 120 mg and 240 mg we find:

Main pharmacokinetic variables:
Single dose: AUC0-t, AUCinf, Cmax (tlag and tmax)
90% confidence interval: 80.00–125.00% for AUC0-t, AUCinf, Cmax. Comparable median and range for tlag and tmax.


I beg your pardon, tlag
For delayed release products any change in tlag directly translates into a shifted tmax (see this presentation, slides 53–58). Whilst the latter PK metric is generally already covered by rich sampling (in order to “catch” Cmax) this is not the case for tlag. I don’t get it.

Cheers,
Helmut Schütz
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BRB
Junior

Canada,
2017-12-20 16:25

@ Helmut
Posting: # 18067
Views: 1,927
 

 tlag‽

Hello Helmut and others,

I don't get it either regarding the evaluation of tlag.

How would one show that there is, "Comparable median and range for tlag" between the test and reference?
Non-parametric test?

Any feedback would be appreciated.

Thanks!
BRB
Helmut
Hero
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Homepage
Vienna, Austria,
2017-12-21 13:28

@ BRB
Posting: # 18072
Views: 1,904
 

 tlag‽

Hi BRB,

» How would one show that there is, "Comparable median and range for tlag" between the test and reference?

By a combination of :blahblah: and box plots?

» Non-parametric test?

Unlikely… Let’s actuate our time machine and have a look what was / is suggested for tmax and tlag.
  1. Note for Guidance (1992) III/54/89-EN
    Statistical evaluation of tmax only makes sense if there is a clinically relevant claim for rapid release or action or signs for a relation to adverse effects. The non-parametric 90% confidence interval for this measure of relative bioavailability should lie within a clinically determined range.
  2. Note for Guidance (2001) CPMP/EWP/QWP/1401/98
    Statistical evaluation of tmax only makes sense if there is a clinically relevant claim for rapid release or action […]. The non-parametric 90% confidence interval for this mea­sure of relative bioavail­ability should lie within a clinically determined range.
  3. IR BE-GL (2010) CPMP/EWP/QWP/1401/98 Rev. 1/ Corr **
    A statistical evaluation of tmax is not required. However, if rapid release is claimed to be clinically relevant and of importance for onset of action or is related to adverse events, there should be no apparent difference in median tmax and its variability between test and reference product.
  4. MR BE-GL (2014) EMA/CPMP/EWP/280/96 Corr1
    For delayed and multiphasic release formulations differences in tmax is also recommended to be assessed, especially for products where a fast onset of action is important. A formal statistical evaluation of tmax is not required. However, there should be no apparent difference in median tmax and its range between test and reference product.
  5. Dimethyl fumarate gastro-resistant capsules 120 mg and 240 mg product-specific BE guidance (draft 2017) EMA/CHMP/421315/2017
    Comparable median and range for tlag and tmax.
The EMA is allergic to non-parametrics. In #3 (though in the section about log-transformation and ANOVA) we find: A non-parametric analysis is not acceptable. tlag is not mentioned in #1–#4.
For my current practice see this post and why assessing the range is crazy, this one. When it comes to tlag I hope that this PK metric will be dropped in the final version of the dimethyl fumarate guidance.

Try this R-code to see how strangely the difference in ranges (of T and R) might behave:

t <- c(0.5,   0.6667, 0.8333, 1,    1.3333, 1.6667, 2)
p <- c(0.025, 0.1,    0.15,   0.45, 0.15,   0.1,    0.025)
n <- 24
nsims <- 1e4 # Number of bootstrap samples
set.seed(1234567)
res <- data.frame(sim=1:nsims, med.T=NA, med.R=NA, delta.med=NA,
                  rng.T=NA, rng.R=NA, delta.rng=NA,
                  iqr.T=NA, iqr.R=NA, delta.iqr=NA)
for (j in 1:nsims) {
  T <- sample(t, size=n, replace=TRUE, prob=p)
  R <- sample(t, size=n, replace=TRUE, prob=p)
  res$med.T[j] <- median(T)
  res$med.R[j] <- median(R)
  res$rng.T[j] <- diff(range(T)) # span
  res$rng.R[j] <- diff(range(R)) # span
  res$iqr.T[j] <- IQR(T)
  res$iqr.R[j] <- IQR(R)
}
res$delta.med <- res$med.T - res$med.R
res$delta.rng <- res$rng.T - res$rng.R
res$delta.iqr <- res$iqr.T - res$iqr.R
windows(record=TRUE)
op <- par(ask=TRUE)
# common axes for all histograms
xlim <- c(-1,1)*max(abs(range(res$delta.med, res$delta.rng, res$delta.iqr)))
ylim <- c(0, max(hist(res$delta.med, plot=FALSE)$density))
hist(res$delta.med, col="bisque", freq=FALSE, xlim=xlim, ylim=ylim,
     xlab="\u2206 of medians", main="", las=1)
box()
hist(res$delta.iqr, col="bisque", freq=FALSE, xlim=xlim, ylim=ylim,
     xlab="\u2206 of IQRs", main="", las=1)
box()
hist(res$delta.rng, col="bisque", freq=FALSE, xlim=xlim, ylim=ylim,
     xlab="\u2206 of ranges", main="", las=1)
box()
par(op)


Cheers,
Helmut Schütz
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nobody
Senior

2017-12-21 14:17

@ Helmut
Posting: # 18073
Views: 1,862
 

 tlag‽

...backdoor? These are REALY ugly times we life in...

Kindest regards, nobody
Helmut
Hero
avatar
Homepage
Vienna, Austria,
2017-12-21 14:43

@ nobody
Posting: # 18074
Views: 1,904
 

 tlag‽

Hi nobody,

» ...backdoor? These are REALY ugly times we life in...

IMHO, just crazy: This is the comment I’ve send to the EMA on 31 October:

For gastric-resistant formulations any [sic] difference in tlag is reflected in tmax as well. In other words: Any shift in tlag will lead to exactly the same shift in tmax.
Whereas rich sampling close to the expected tmax likely is already applied in the study (in order to get reliable estimates of Cmax) this is generally not the case around the expected tlag. In order to get reliable estimates of tlag, additional samples would have to be drawn in the absorption phase. Concerns:

  1. Unnecessary burden to the subjects renders this requirement ethically doubtful.
  2. Contrary to Cmax, early concentrations might be close to the analytical limit of quantification – which leads to high variability and hence, likely ill-defined estimates of tlag.
  3. (As in other guidelines) it is an unresolved question what a “comparable” median is.
  4. The range has a breakdown point of one (i.e., a single extreme value distorts the estimate towards this value). Example: Values after both the test and reference product are identical and 1. If we add another subject with T=1 and R=24, the medians will be still 1 for both products. For T the range will be 0 but for R it will be 23. This lacks any relevance.

Proposed change (if any):
Remove tlag from the required PK variables.


Cheers,
Helmut Schütz
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nobody
Senior

2017-12-21 15:18

@ Helmut
Posting: # 18076
Views: 1,826
 

 tlag‽

...somebody had a look at the ADRs (mostly upper GI-tract-related, therefore the gastroresistant formulation) and said, hey, we have to "quantitate" the quality of the gastroresistant part of the formulations. Let's do tlag!

afaik the SmPC recommends application in fed state, due to better tolerability. The EMA guideline gives no recommendation re. fasted/fed?!

On the other hand: Modified release with one single-dose study only?

Kindest regards, nobody
Helmut
Hero
avatar
Homepage
Vienna, Austria,
2017-12-21 15:41

@ nobody
Posting: # 18077
Views: 1,821
 

 tlag‽

Hi nobody,

» ...somebody had a look at the ADRs (mostly upper GI-tract-related, therefore the gastroresistant formulation) and said, hey, we have to "quantitate" the quality of the gastroresistant part of the formulations. Let's do tlag!

Splendid idea! Why not an early partial AUC?

» afaik the SmPC recommends application in fed state, due to better tolerability.

Yep.

» The EMA guideline gives no recommendation re. fasted/fed?!

Strange. The MR-GL suggests for delayed release multiple unit formulations (if SmPC recommends intake under fed conditions): SD fasting and fed.

» On the other hand: Modified release with one single-dose study only?

Do you mean why no MD study? That’s consistent with the MR-GL.

Cheers,
Helmut Schütz
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The quality of responses received is directly proportional to the quality of the question asked. ☼
Science Quotes
nobody
Senior

2017-12-21 15:57

@ Helmut
Posting: # 18078
Views: 1,822
 

 tlag‽

...no, more related to fasted/fed... :-)

Kindest regards, nobody
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