Bioequivalence and Bioavailability Forum • Outliers US FDA submission

Chiku
☆

India,
2013-03-04 12:30
(3861 d 14:50 ago)

Posting: # 10147
Views: 7,079

Outliers US FDA submission [Outliers]

Dear all,

We received Following results for an ER product for US market:

All Subjects
Cmax: 115.45 (106.16 - 125.16)
AUC0-t: 118.53 ( 108.52 - 129.46)
AUC0-inf: 117.81 (108.17 - 128.32)

After reviewing, the results we observed that one particular subject is qualifying as an statistical outlier for all the three PK parameters i.e Cmax, AUC0-t and AUC0-inf (Reference product was not released at all). The data is within BE acceptance limits after deleting the subject , here is the data for your reference.

After removing statistical outlier:

Cmax: 112.70 (104.47 - 121.59)
AUC0-t: 115.37 ( 106.67 - 124.78)
AUC0-inf: 114.88 (106.40 - 124.02)

Still the data is on Boarder case, kindly suggest a way forward:

1. Submit as such data (wait for deficiency, upon deficiency redosing study) will it be acceptable or “refuse to file”?
2. Redosing study and then file the ANDA (this will take 5 months as we do not have BE NOC as of now)

Regards,

ElMaestro
★★★

Denmark,
2013-03-04 12:47
(3861 d 14:32 ago)

@ Chiku
Posting: # 10148
Views: 6,006

Outliers US FDA submission

Post reply

Dear Chiku,

These cases are unfortunately seen now and then. But that's not the end of the world.

❝ After reviewing, the results we observed that one particular subject is qualifying as an statistical outlier for all the three PK parameters i.e Cmax, AUC0-t and AUC0-inf (Reference product was not released at all). The data is within BE acceptance limits after deleting the subject 83, here is the data for your reference.

Could you just briefly explain what you mean when you say it is a statistical outlier? Did you do a formal statistical test?
You mention ref. not released - sure? Or ref. possibly not ingested or not absorbed or not analysed correctly to BLQ? Did you audit the study, clin. + bioanalytics?

—
Pass or fail!
ElMaestro

Chiku ☆ India, 2013-03-04 12:56 (3861 d 14:24 ago) @ ElMaestro Posting: # 10149 Views: 5,937	Outliers US FDA submission Post reply
	Dear Elmaestro, Thanks for the promt reply. Yes we have done Box plot analysis, Lund's test for statistical out lier. Reference conc was detected so may be not absorbed (reference is OROS tablet). T/R for that particular subject was 1300. There was no unusual observation @ clinic or bioanalytical. Regards,

ElMaestro
★★★

Denmark,
2013-03-04 14:12
(3861 d 13:07 ago)

@ Chiku
Posting: # 10150
Views: 5,915

Outliers US FDA submission

Post reply

Dear Chiku,

❝ Reference conc was detected so may be not absorbed (reference is OROS tablet). T/R for that particular subject was 1300.

❝

❝ There was no unusual observation @ clinic or bioanalytical.

On basis of common sense I imagine I would submit.
FDA's guidance suggests that outliers are caused by product failure or SxF interaction. Whatever the case here it can be argued that your product is not associated with the 'issue' the ref. suffers from.

But I'd recommend to make sure you can argue with very thorough argumentation that you have eliminated all other sources of trouble.

audit analytics, esp. chromatography in the run associated with the outlier, plus a few normal ones for comparison.
audit clinics, esp. CRF's relevant to the issue. If subject in question who got the ref. had a systemic AE after dosing and the PI noted it was drug related then the story would turn quite interesting.

—
Pass or fail!
ElMaestro