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Back to the forum  Query: 2017-11-24 06:40 CET (UTC+1h)
 
Anand
Junior

India,
2017-10-30 06:38

Posting: # 17945
Views: 681
 

 ULOQ [Study As­sess­ment]

Dear All,

Request to clarify,

In our Pivotal BE Study ULOQ was observed, whether we should exclude from PK?
After Dilution also it found ULOQ.
Method should be redeveloped or revalidated?
If included,What justification we should provide to Regulatory Agency?

Thanks in advance.

Regards,
A.A


Edit: Category changed; see also this post #1. [Helmut]
Helmut
Hero
Homepage
Vienna, Austria,
2017-10-30 10:30

@ Anand
Posting: # 17947
Views: 626
 

 ULOQ

Hi Anand,

» In our Pivotal BE Study ULOQ was observed, whether we should exclude from PK?
» After Dilution also it found ULOQ.
» Method should be redeveloped or revalidated?

Perform a partial validation with a higher dilution. If passing the usual criteria for A&P, re-analyse the sample(s) with high concentrations.

» If included,What justification we should provide to Regulatory Agency?

IMHO, that’s not possible.

[image]Regards,
Helmut Schütz 
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Ohlbe
Hero

France,
2017-10-30 10:35

@ Anand
Posting: # 17948
Views: 598
 

 ULOQ

Dear Anand,

» After Dilution also it found ULOQ.
»
» Method should be redeveloped or revalidated?

You should dilute further, till you get a result below your ULOQ. If this requires a dilution factor greater than what you tested during validation, then you need to do a partial validation with a greater dilution factor. If you have many results above the ULOQ you may wish to consider to expand your calibration range with a partial validation.

You can't exclude subjects or data points because they are ULOQ: the ULOQ result would be the Cmax for that subject. If you exclude the data, you will bias the outcome of the study.

Regards
Ohlbe
Helmut
Hero
Homepage
Vienna, Austria,
2017-10-30 10:59

@ Ohlbe
Posting: # 17950
Views: 598
 

 ULOQ

Hi Ohlbe,

» You can't exclude subjects or data points because they are ULOQ: the ULOQ result would be the Cmax for that subject. If you exclude the data, you will bias the outcome of the study.

Really? Let’s assume that the subject with concentrations >ULOQ is observed in the last batch and we are already close to the validated long-term stability. Even if we revalidate with a higher dilution, we may exhaust the storage interval – resulting in unacceptable results as well. In such a case we have to exclude the subject.

[image]Regards,
Helmut Schütz 
[image]

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Ohlbe
Hero

France,
2017-10-30 15:10

@ Helmut
Posting: # 17953
Views: 564
 

 ULOQ

Hi Helmut,

» Let’s assume that the subject with concentrations >ULOQ is observed in the last batch and we are already close to the validated long-term stability. Even if we revalidate with a higher dilution, we may exhaust the storage interval – resulting in unacceptable results as well. In such a case we have to exclude the subject.

If the storage interval is limited by the duration studied during validation (e.g. stability demonstrated for 30 days, still fine at the end): I would extend the validated period (always keep some extra stability samples in the freezer, just in case !). If the stab failed at the last time point: indeed in trouble. But I think that regulators would not see with a very positive eye the exclusion of the one subject with the highest Cmax in the whole study. Particularly if his Cmax was within range in the other period.

Regards
Ohlbe
Helmut
Hero
Homepage
Vienna, Austria,
2017-10-30 17:34

@ Ohlbe
Posting: # 17954
Views: 548
 

 Not excluding invalid data?

Hi Ohlbe,

» […] I think that regulators would not see with a very positive eye the exclusion of the one subject with the highest Cmax in the whole study. Particularly if his Cmax was within range in the other period.

Let me play the devil’s advocate. I think there are two worst case scenarios. (1) Further dilution fails A&P or (2) the storage cannot be extended (fails as well). Now what? All reanalysed concentrations (>ULOQ is mentioned as a reason in the BMV-GL) are not valid. Given the high variability generally observed for Cmax, the value in the other period is not relevant. Even with true F=1, Cmax might be ≤ULOQ in one period and >ULOQ in the other.

What do you think a regulator would prefer?
  1. Excluding the subject and assess BE based on valid data only.
  2. Keep the subject though the reanalysed Cmax in one period is not valid.
I’m not a regulator (:-D) but (a) would not bias the treatment comparison. Only the producer’s risk increases. IMHO, (b) contradicts all rules about using valid data only and the treatment comparison might be biased.

[image]Regards,
Helmut Schütz 
[image]

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Ohlbe
Hero

France,
2017-10-30 18:03

@ Helmut
Posting: # 17956
Views: 538
 

 Excluding invalid data

Hi Helmut,

» What do you think a regulator would prefer?
  1. Excluding the subject and assess BE based on valid data only.
    »
  2. Keep the subject though the reanalysed Cmax in one period is not valid.

Please don't misunderstand what I mean. I'm certainly not pleading to use data which were not demonstrated to be valid during method validation. I would not extrapolate above the ULOQ and I would not analyse a sample beyond its stability period. But let me play the devil's advocate too. Let's imagine your subject had a Cmax at midrange of the calibration curve in Period 1 and is at least 5 x ULOQ in Period 2 (still ULOQ after a 1/5 dilution). Regulators would not be happy with the exclusion of the subject. Which doesn't mean that they would like possibly unreliable data to be used instead: rather that they may reject the study as a whole :-(. Regulators don't wear Armani suits.

OK, we're discussing rather extreme situations. Let's remain optimistic and hope that Anand still has enough plasma for re-analysis, that the analyte is stable, and that the validation of the higher dilution factor will pass :-)

Regards
Ohlbe
ElMaestro
Hero

Denmark,
2017-10-30 13:18

@ Anand
Posting: # 17952
Views: 579
 

 ULOQ

Hi Anand,

dilute the sample you already diluted; use the already validated dilution factor and inject. Continue doing that until you get a measurable concentration.

It does require that you have started the dilution series with sufficient volume.

I could be wrong, but…


Best regards,
ElMaestro

No, I still don't believe much in the usefulness of IVIVCs for OIPs when it comes to picking candidate formulations for the next trial. This is not the same as saying I don't believe in IVIVCs.
Helmut
Hero
Homepage
Vienna, Austria,
2017-10-30 17:53

@ ElMaestro
Posting: # 17955
Views: 553
 

 Serial dilutions? Don’t!

Hi öberster größter Meister,

» dilute the sample you already diluted; use the already validated dilution factor and inject. Continue doing that until you get a measurable concentration.

Really? Quoting the BMV-GL:

4.1.7. Dilution integrity
Dilution of samples should not affect the accuracy and precision. If applicable, dilution integrity should be demonstrated by spiking the matrix with an analyte concentration above the ULOQ and diluting this sample with blank matrix (at least five determinations per dilution factor). Accuracy and precision should be within the set criteria, i.e. within ±15%. Dilution integrity should cover the dilution applied to the study samples.

(my emphasis)

If you want to dilute ×2, ×4, ×8 those are the dilution factors – not serial ones like 1×2, 2x2, 2x2x2. Imagine a propagation of error which results in an accuracy of 90% in each of the steps. If done properly (only one dilution), you pass the requirements (within ±15%). With serial dilutions you would fail already in the second step (81% outside ±15%) and even more in the third (73%). But: Since you didn’t validate it, you falsely assume that the accuracy is still 90%. You don’t want to go there.
Of course, you could validate serial dilutions as well but I don’t see any rationale for doing so.

[image]Regards,
Helmut Schütz 
[image]

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