ramgopi
☆

India,
2018-03-14 10:29
(882 d 15:30 ago)

Posting: # 18533
Views: 4,426

## Outlier in BE [Study As­sess­ment]

Dear All,

Greetings!

We have discussed enough regarding discordant outliers in BE study in the past, but we have struct with typical situation and i would like to know experts opinion on this regard.

we have a done a BE study for GCC submission with two way crossover, here one subject shows less concentration in reference product and the T/R ratio for Cmax 2.43 and AUCt 2.35, because of this subject the study failed in border, if we excluded this as a outlier the 90% CI is within the acceptance limit.

90% CI before excluding particular subject

Dependent   Ratio_  %RefCI_90_Lower  CI_90_Upper    CV% Ln(Cmax)    115.46      106.23         125.49      19.47% Ln(AUClast) 110.25      102.66         118.40      16.64%

90% CI After excluding particular subject

Dependent   Ratio_  %RefCI_90_Lower  CI_90_Upper    CV% Ln(Cmax)    112.14      104.48         120.36      16.12% Ln(AUClast) 107.34      101.29         113.75      13.27

It is evident that something happen for this subject during clinical phase but the CRO failed to notify the incident.

GCC just following EMA guidance so as per EMA this is failed study, but out of my curiosity Is there any way to scientifically justify and exclude this subject from statistical calculation.

thanks & Regards

Gopinath

Helmut
★★★

Vienna, Austria,
2018-03-14 15:38
(882 d 10:21 ago)

@ ramgopi
Posting: # 18546
Views: 3,828

## Low AUC after reference product

Hi Gopinath,

» we have a done a BE study for GCC submission with two way crossover, here one subject shows less concentration in reference product and the T/R ratio for Cmax 2.43 and AUCt 2.35, …

The GCC-Guidelines are practically identical to the EMA’s when it comes to exclusion of subjects.

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).

» … because of this subject the study failed in border, if we excluded this as a outlier the 90% CI is within the acceptance limit.
» It is evident that something happen for this subject during clinical phase but the CRO failed to notify the incident.

Why is it evident? The staff of the CRO couldn’t look into the GIT of the subject. You cannot exclude a product failure.

» GCC just following EMA guidance so as per EMA this is failed study, …

Correct – if you didn’t state such a possible reason for exclusion it in the protocol. Post hoc exclusion (the study failed, let’s try something else) is rarely accepted.

» … but out of my curiosity Is there any way to scientifically justify and exclude this subject from statistical calculation.

No. You can only try to refer in the report to the GL and cross fingers.

Dif-tor heh smusma 🖖
Helmut Schütz

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

Russia,
2018-03-15 09:56
(881 d 16:03 ago)

@ Helmut
Posting: # 18550
Views: 3,719

## Low AUC after reference product

Hi Helmut,

» Correct – if you didn’t state such a possible reason for exclusion it in the protocol.

If 5% GMR for ref is not mentioned in the Protocol isn't possible just to refer to EMA or other appropriate GL (depending on the jurisdiction)?

Have you ever seen lucky guys in EMA jurisdiction who stated in the protocol some additional reasons for exclusion (not mentioned in GL) after ending the bioanalytical part and successfully applied them in borderline case like that?

Kind regards,
Mittyri
ramgopi
☆

India,
2018-03-18 06:44
(878 d 19:15 ago)

@ ramgopi
Posting: # 18567
Views: 3,599

## Outlier in BE

Thank you HS, we will see the possibility of repeating the study.

Thanks & Reagrds
Gopinath
ElMaestro
★★★

Belgium?,
2018-03-18 13:43
(878 d 12:16 ago)

@ ramgopi
Posting: # 18570
Views: 3,646

## Outlier in BE

Hi Gopinath,

how about auditing the study before you take any further decisions?

I am hearing you more or less say that you think the products in spite of the data are BE. That's why you want to exclude the subject in question, and that's why you think there is a grounds to believe the subject in question does not reflect the product's average performance, variance taken into consideration .

Therefore, a for-cause audit might have merit. If your audit illustrates a general issue at the CRO then that's some pretty valuable knowledge to have prior to deciding on a repeat study (and especially where it is to take place).

I could be wrong, but...

Best regards,
ElMaestro

"Pass or fail" (D. Potvin et al., 2008)
ramgopi
☆

India,
2018-03-19 09:55
(877 d 16:04 ago)

@ ElMaestro
Posting: # 18573
Views: 3,439

## Outlier in BE

Hi ElMaestro

We didn’t took any decision and still data under scrutinization

Your point is well taken, auditing the facility would suffice the purpose definitely we will think over it.

Regards
Gopinath