jag009
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NJ,
2012-03-29 19:34

Posting: # 8349
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 0 hr Pre-dose concentration but less than 5% of Cmax [Regulatives / Guidelines]

Hi everyone,

Regarding the FDA guidance on pre-dose concentration:

"If the predose concentration is less than or equal to 5 percent of Cmax value in that subject, the subjects data without any adjustments can be included in all pharmacokinetic measurements and calculations. If the predose value is greater than 5 percent of Cmax, the subject should be dropped from all BE study evaluations."

What if a subject has a pre-dose concentration in period 1? Should the subject still be kept or needs to be removed since he shouldn't have any pre-dose concentration in period 1.

Clinic shows no deviations and data was reviewed.

Thanks

John
Helmut
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2012-03-29 19:50

@ jag009
Posting: # 8350
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 0 hr Pre-dose concentration but less than 5% of Cmax

Dear John!

» What if a subject has a pre-dose concentration in period 1? Should the subject still be kept or needs to be removed since he shouldn't have any pre-dose concentration in period 1.
»
» Clinic shows no deviations and data was reviewed.

Shit happens. But:
  • The guidance does not distinguish between period 1 and the others. Though you are right that pre-dose values in period 1 are less likely (carry-over due to too short wash-out are possible in higher ones).
  • If you have an SOP for pharmacokinetic repeats in place perform a reanalysis. Maybe the value will not be confirmed.
  • Remember the requirements for testing interferences in method validation: none out of six independent sources of matrix. If 0/6 is OK does that imply that 1/7 is OK as well? In other words even if your method was validated – in a large study you may see interferences. Keep the subject.

Cheers,
Helmut Schütz
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jag009
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NJ,
2012-03-29 20:10

@ Helmut
Posting: # 8351
Views: 6,355
 

 0 hr Pre-dose concentration but less than 5% of Cmax

Thanks Helmut

» Shit happens. But:
  • The guidance does not distinguish between period 1 and the others. Though you are right that pre-dose values in period 1 are less likely (carry-over due to too short wash-out are possible in higher ones).
    »
  • If you have an SOP for pharmacokinetic repeats in place perform a reanalysis. Maybe the value will not be confirmed.
    »
  • Remember the requirements for testing interferences in method validation: none out of six independent sources of matrix. If 0/6 is OK does that imply that 1/7 is OK as well? In other words even if your method was validated – in a large study you may see interferences. Keep the subject.

That's what I thought as well (Keeping the subject) since the guidance just stated the 5% rule but nothing about period 1 or period n.

John
Helmut
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2012-03-29 23:17

@ jag009
Posting: # 8352
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 Reanalysis if possible

Dear John!

» That's what I thought as well (Keeping the subject) since the guidance just stated the 5% rule but nothing about period 1 or period n.

OK, but if ever possible perform a reanalysis in duplicate. If the value was not too far away from the LLOQ it may have been pure chance as well.

Cheers,
Helmut Schütz
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jag009
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NJ,
2012-03-30 15:06

@ Helmut
Posting: # 8354
Views: 6,273
 

 Reanalysis if possible

Hi Helmut,

» OK, but if ever possible perform a reanalysis in duplicate. If the value was not too far away from the LLOQ it may have been pure chance as well.

Thanks. Yes the lab did reanalysis and came to the same conclusion (as per their SOP). It's just kind of strange to see value at 0 on period 1 that's all.

Have you seen CROs which go the full length and pre-screen subjects for exposure to the study drug prior to the first dosing day?

Thanks

John
Helmut
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2012-03-30 15:16

@ jag009
Posting: # 8355
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 >6 sources of matrix

Dear John!

» Yes the lab did reanalysis and came to the same conclusion (as per their SOP). It's just kind of strange to see value at 0 on period 1 that's all.

OK, at least you know now that it wasn’t pure chance but at true interference.

» Have you seen CROs which go the full length and pre-screen subjects for exposure to the study drug prior to the first dosing day?

Only once (in 30+ years) – drug was Δ9-THC. :smoke:
Another time I came across a very difficult ligand-binding assay where matrix effects were common. During method development the CRO screened ~60 subjects and in validation another 30.

Cheers,
Helmut Schütz
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jag009
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NJ,
2012-03-30 20:40

@ Helmut
Posting: # 8360
Views: 6,248
 

 >6 sources of matrix

Hi Helmut

» Only once (in 30+ years) – drug was Δ9-THC. :smoke:
» Another time I came across a very difficult ligand-binding assay where matrix effects were common. During method development the CRO screened ~60 subjects and in validation another 30.

Haha, figures! Don't tell me you ran the study in Amsterdam :clap:

John
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2012-03-31 00:23

@ jag009
Posting: # 8362
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 >6 sources of matrix

Hi John!

» » […] drug was Δ9-THC. :smoke:
» Haha, figures! Don't tell me you ran the study in Amsterdam :clap:

Austrian volunteers are also a funny bunch. :-D

Cheers,
Helmut Schütz
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jag009
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NJ,
2012-04-04 16:32

@ Helmut
Posting: # 8382
Views: 6,118
 

 >6 sources of matrix

Hi Helmut,

» » Yes the lab did reanalysis and came to the same conclusion (as per their SOP). It's just kind of strange to see value at 0 on period 1 that's all.
»
» OK, at least you know now that it wasn’t pure chance but at true interference.

This just popped into my head (flashback... Nightmare, whatever you called it)...

Should the lab adjust the concentration profile to remove the residual levels caused by the pre-dose concentration???? ie. using the t1/2 and determine the amount of pre-dose concentration remaining throughout the timepoints and subtract it from the respective concentrations.

I remember one lab doing this and they said it's part of their SOP...

Thanks

John
Helmut
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Vienna, Austria,
2012-04-05 16:10

@ jag009
Posting: # 8386
Views: 6,255
 

 Flashback

Hi John!

» This just popped into my head (flashback... Nightmare, whatever you called it)...

For me – flashback. We performed a pilot study of a drug with a nice average [sic] half-life of ~50 hours, sampling up to 216 hours (since truncated AUC wasn’t common at that time), washout 2 weeks. No predose concentrations… The pivotal was a 6×3 in 36 subjects, but:
  • only ½ of the dose of the pilot was administered and
  • the LLOQ of analytical method was improved by a factor of 9 [sic].
Result: We measured pre-dose values (maximum 7.8% of Cmax) in 54% of samples of periods 2 & 3 (none in period 1). Since we had a blinded plausibility review in place we were able to come up with a statistical amendment while analytics were still running:
  • Primary analysis based on period 1’s data as a parallel design. The sponsor had too much money – so the cross-over was extremely overpowered. The total CV was quite low and we expected still ~75% power. Since no pretesting (sequence or unequal carry-over) was done (Grizzle’s flawed method), the patient’s risk was not compromised.
  • Exploratory 1: Ignoring the carry-over and performing the comparison as originally planned. Nowadays we would go a similar track: 86% of the subjects with pre-dose values <5% would stay in the analysis.
  • Exploratory 2: Estimating λz not only from data of the respective treatment, but including the pre-dose value of the next period. Subtracting estimated concentrations of the next period from measured ones.
Results:
  • Confirmatory: AUC passed, upper limit of Cmax failed.
  • Exploratory 1 & 2: AUC and Cmax passed easily.
Lessons learned: Never base the washout on mean-values (large studies not even on x±SD) and think twice if you improve the analytical method too much. ;-)

P.S.: The product was approved based on this study in the EU in 2002 and by the FDA in 2003.

» Should the lab adjust the concentration profile to remove the residual levels caused by the pre-dose concentration???? ie. using the t1/2 and determine the amount of pre-dose concentration remaining throughout the timepoints and subtract it from the respective concentrations.

See above. I cannot imaging that any regulatory agency would accept this (any more).

» I remember one lab doing this and they said it's part of their SOP...

Referring to an SOP is alway the worst (pseudo-)justification I can think of.

“Hey, let’s jump from the cliff!” Lemming’s SOP


Cheers,
Helmut Schütz
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jag009
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NJ,
2012-04-05 17:51

@ Helmut
Posting: # 8388
Views: 6,038
 

 Flashback

Hi Helmut,

» » Should the lab adjust the concentration profile to remove the residual levels caused by the pre-dose concentration???? ie. using the t1/2 and determine the amount of pre-dose concentration remaining throughout the timepoints and subtract it from the respective concentrations.
»
» See above. I cannot imaging that any regulatory agency would accept this (any more).

Question, can the pre-dose (0 hr) concentration be set to 0 if it is less than 5% of Cmax? FDA that is...

Thanks

John
Helmut
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2012-04-05 18:08

@ jag009
Posting: # 8390
Views: 6,135
 

 No correction if ≤5% Cmax

Hi John!

» […] can the pre-dose (0 hr) concentration be set to 0 if it is less than 5% of Cmax? FDA that is...

Can? Technically, yes. But I wouldn’t recommend it (see the [image] 2003 guidance):
  • If the predose concentration is ≤ 5 percent of Cmax value in that subject, the subject’s data without any adjustments can be included in all pharmacokinetic measurements and calculations.
(my emphasis; interpreting “can” as “should”…)

Cheers,
Helmut Schütz
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navoday
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India,
2012-08-15 20:37

@ Helmut
Posting: # 9070
Views: 5,521
 

 No correction if ≤5% Cmax

» » […] can the pre-dose (0 hr) concentration be set to 0 if it is less than 5% of Cmax? FDA that is...

Dear Helmut...

wishing you and all members of forum a very happy independence day (india)

should we submit statistical data with inclusion and exclusion of that subject having predose concentration more than 5% of Cmax or simply delete that subject from all analysis? what if study is partial replicate (3WSABE)and that subject has completed TR sequence? as it may help for estimating t1/2 and tmax if average bioequivalence is there.
Helmut
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2012-08-16 16:36

@ navoday
Posting: # 9073
Views: 5,567
 

 excluded period(s)

Hi Navoday!

» should we submit statistical data with inclusion and exclusion of that subject having predose concentration more than 5% of Cmax or simply delete that subject from all analysis?

Even complying with the guidance I always state the planned procedure in the protocol. I report the PK data (in order to give the assessor a mean to check them) but exclude the subject in a 2×2 cross-over from comparative assessments. If the pre-dose concentration is observed not in all periods and the study is either a replicate or a higher-order cross-over, I proceed as following:
  • Replicate: Keep the data if at least one period after test and reference is available and the study is analyzed by mixed effects model.
  • Higher-order (e.g., one tests and two references): If the pre-dose concentration is observed after one of the references, keep the other data.

» what if study is partial replicate (3WSABE)and that subject has completed TR sequence? as it may help for estimating t1/2 and tmax if average bioequivalence is there.

Since according to the FDA a partial replicate has to be analyzed by SAS Proc GLM (or similar) IMHO all data of the subject will be dropped from the analysis (even if you observe a pre-dose concentration in just one period).

» as it may help for estimating t1/2 and tmax if average bioequivalence is there.

Don’t understand what you mean here. :confused:

Cheers,
Helmut Schütz
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rajasekharkakarla
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India,
2019-09-20 07:57

@ Helmut
Posting: # 20630
Views: 1,177
 

 excluded period(s)

Hi Helmut sir!

» Since according to the FDA a partial replicate has to be analyzed by SAS Proc GLM (or similar) IMHO all data of the subject will be dropped from the analysis (even if you observe a pre-dose concentration in just one period).

if we get the Swr less than 0.294 then we need to go for ABE approach in that can can we include those subjects in ABE calculation if subject completed 1 test and 1 reference treatment period.

what about in case of fully replicated designs, if we got the 5 % cmax in 4th period with 2 reference periods completed or one Test and Reference treatment period completed.

please help me..
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