swapnil.kuche
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2011-03-09 08:19
(4769 d 06:13 ago)

Posting: # 6730
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 Handling of outlier (EU) [Outliers]

Dear All,

Due to one outlier subject one of our pivotal study is failing. In such case can we perform redosing for approximately 20% (of original sample size) subjects to confirm the results and to support our application (MA). Nowadays this approach is used for USFDA but can you please update me regarding EU view on the same.

Thanks in advance
Swapnil
Helmut
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Vienna, Austria,
2011-03-09 13:40
(4769 d 00:52 ago)

@ swapnil.kuche
Posting: # 6732
Views: 7,794
 

 EU: no re-dosing

Dear Swapnil!

❝ Due to one outlier subject one of our pivotal study is failing.


How did you judge that the subject was an outlier?

❝ In such case can we perform redosing for approximately 20% (of original sample size) subjects to confirm the results and to support our application (MA).


Sometimes. You are aware that FDA hates such an approach and it should not be considered standard?

❝ Nowadays this approach is used for USFDA but can you please update me regarding EU view on the same.


Re-dosing is not acceptable in the EU. Sorry.

Reasons for exclusion must be pre-specified in the protocol. Besides clinical events (vomiting, diarrhoea,…), PK reasons are:
  • […] subjects in a crossover trial who do not provide evaluable data for both of the test and reference products […] should not be included.
  • A subject with lack of any measurable concentrations or only very low plasma concentrations for reference medicinal product [may be excluded]. 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.
(my emphases)

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swapnil.kuche
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2011-03-10 07:39
(4768 d 06:53 ago)

@ Helmut
Posting: # 6735
Views: 7,510
 

 EU: no re-dosing

Dear HS,

Thanks a lot for for your prompt reply.

❝ How did you judge that the subject was an outlier?


On review of p'cokinetic data it was observed that one of subject is showing highest T/R ratio for Cmax and AUC. So we just recalculate 90% CI by excluding that subject and those results were within acceptance limit. No specific outlier test is applied here.

Infact this is about fed biequivalence study for gastro-resistant formulation and importanly we have positive results for fasting study for the same formulation.

What should be our future strategy in the same regard.

Regards,
Swapnil


Edit: Original quote restored. [Helmut]
ElMaestro
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Denmark,
2011-03-10 13:20
(4768 d 01:12 ago)

@ swapnil.kuche
Posting: # 6736
Views: 7,438
 

 difficult to eliminate a subject

Hi SK,

❝ On review of p'cokinetic data it was observed that one of subject is showing highest T/R ratio for Cmax and AUC. So we just recalculate 90% CI by excluding that subject and those results were within acceptance limit. No specific outlier test is applied here.


If you have just pulled out the subject with the highest T/R without any further qualification then that won't be acceptable. If you have confirmed technical issues with the samples then you may be able to take out the subject, same thing if the subject vomited etc.

Pass or fail!
ElMaestro
Helmut
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2011-03-10 13:39
(4768 d 00:53 ago)

@ ElMaestro
Posting: # 6739
Views: 7,481
 

 difficult to eliminate a subject

Dear ElMaestro!

❝ If you have just pulled out the subject with the highest T/R without any further qualification then that won't be acceptable. If you have confirmed technical issues with the samples then you may be able to take out the subject, same thing if the subject vomited etc.


Not necessarily (see the second point of my previous post). Of course the last sentence is not encouraging.

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Helmut
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2011-03-10 13:29
(4768 d 01:03 ago)

@ swapnil.kuche
Posting: # 6737
Views: 7,514
 

 EU: ways out?

Dear Swapnil!

❝ On review of p'cokinetic data it was observed that one of subject is showing highest T/R ratio for Cmax and AUC. So we just recalculate 90% CI by excluding that subject and those results were within acceptance limit. No specific outlier test is applied here.


Caution: This might give assessors the impression of cherry-picking. :cherry picking: Never fiddle around with evaluations – ‘just to see what happens’.
Have you ever heard the phrase “Don’t worry, it’s too late!”…?
You might consider sticking to the full data set and present the reduced data set as a sensitivity analysis - supported by the points below.

❝ Infact this is about fed biequivalence study for gastro-resistant formulation and importanly we have positive results for fasting study for the same formulation.


You are not alone. Quite often gastric-resistant formulations ‘behave’ nicely in fasted state and awful in fed state, not only caused by the formulation itself, but also due to GI-physiology. See the Q&A-document, 4. Bioequivalence of gastro-resistant preparations (e.g. omeprazole).

❝ What should be our future strategy in the same regard.


Follow the GL (the second point in my previous post) and the Q&A-document.

[…] only under the conditions that sampling times are designed to identify very delayed absorption and that the incidence of this outlier behaviour is observed with a comparable frequency in both, test and reference products, these incomplete profiles can be excluded from statistical analysis provided that it has been considered in the study protocol.


Only few studies are designed in such a way that they are able to ‘catch’ very delayed and/or low profiles to the same quality as earlier/high ones. For an example see this presentation (slide 41). Another point is ‘the incidence of this outlier behaviour is observed with a comparable frequency in both, test and reference products’. That’s a rather vague statement - what’s a ‘comparable frequency’? See the same presentation, slide 40. In a study in 24 subjects up to 4 outliers in one formulation (and none in the other) would be of comparable frequency (Fisher’s exact test, p>0.05).
You should consider a full replicate design in the future - you are in a much better position in an argument if you see the outlier behaviour only in one of the repeated administrations. A subject-by-formulation interaction could be ruled out in such a case.

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swapnil.kuche
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2011-03-11 06:26
(4767 d 08:07 ago)

@ Helmut
Posting: # 6747
Views: 7,334
 

 EU: ways out?

Dear HS,

Thanks for such a elaborative analysis of this topic. I think this disscussion will really help to handle gastro resistant products BE studies in future.


Regards,
Swapnil
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