- On 24 Jan 2006 at 04:06:14, H Kumar (hkumar1574.-at-.yahoo.com) sent the message

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Dear Group,

We have a product which we intend to submit to the US FDA. We have

done Fed and fasted BE study as per the US regulatory requirements.

In fed state, we have excellent results for the Cmax and AUC. The

point estimate is around 100 and the CIs (Confidence Intervals) are

not farther than +/- 5% from the mean for both the PK parameters.

However, in fasted study, surprisingly we have the CIs for Cmax

failing on the higher side just by a whisker with 125.5% as the upper

limit value. The point estimate is also on the higher side with a

value of about 117%.

Upon observing the data, we found that we have two volunteers, whose

T/R ratios are almost 200%. We have calculated the data without these

volunteers, even when one of these volunteer is eliminated from the

study, the study is passing successfully.

Since we have already passed the fed study comfortably, we don't

intend to do any changes in the formulation.

My query is:

1. Can we consider these two (or one of these two) as an outlier's?

And to do a mini-study involving these two volunteers plus some new

volunteer, to confirm the same.

1. Considering FDA's view point is it possible to repeat the

analysis of these two volunteers. Or to repeat the analysis of the

entire set of volunteers. Then to report the PK parameters based on

the repeat analysis results.

1. If none of these options are acceptable and we want to repeat the

study under fasted state with higher number of volunteers, i s it

justifiable to do the same with same formulation?

Thanks you all in advance.

Regards,

Kumar - On 24 Jan 2006 at 21:07:36, =?ISO-8859-1?Q?Helmut_Sch=FCtz?= (helmut.schuetz.at.bebac.at) sent the message

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The following message was posted to: PharmPK

Hi Kumar,

please first have a look a my previous answer to Isra's question

about retesting (especially the problem with no a-priori strategy

for dealing with outliers).

<>Just some interesting points:

Your confidence intervals are rather narrow (10% in the fed study and

17% in the fasted study).

Two subjects with a T/R ratio of 200% can only pull up the mean from

100% to 117% if your sample size is 12 and the other subjects 'stay'

at 100%. In order to get such a confidence interval I am guessing

your CV to be rather small (<10%) - therefore your drug is not a

*prazole ;-)

>Since we have already passed the fed study comfortably, we don't

>intend to do any changes in the formulation.

>

Ok, maybe it's a product failure of the reference - but what if it's

a subject-by-formulation interaction?

>1. Can we consider these two (or one of these two) as an outlier's?

>And to do a mini-study involving these two volunteers plus some new

>volunteer, to confirm the same.

>

<>Yes, but what is your decision rule? Just exclude them, because you

don't like the results?

If you retest these two volunteers, you should also retest some of

the 'normal performing' subjects - not new ones.

One Caveat: Statistics will be very tricky - nothing for M$-Excel ;-)

>2. Considering FDA's view point is it possible to repeat the

>analysis of these two volunteers. Or to repeat the analysis of the

>entire set of volunteers. Then to report the PK parameters based on

>the repeat analysis results.

>

IMHO no way (both questions).

>3. If none of these options are acceptable and we want to repeat the

>study under fasted state with higher number of volunteers, i s it

>justifiable to do the same with same formulation?

>

<>Even if you repeat the study with a higher sample size, you are

'forcing'

BE. And maybe you will face the same problems again. One option would

be planning for a bail out procedure based on your previous study.

Presumably your data are not (log-)normally distributed (which is a

prerequisite for ANOVA), so you may opt for a nonparametric method.

Or you define exclusion rules which have to be applied prior to the

statistical analysis.

But: in my experience FDA don't like it, and it will be a risky business

without prior consultation with FDA's review staff.

Good luck,

Helmut

--

Helmut Schuetz

BEBAC

Consultancy Services for Bioequivalence and Bioavailability Studies

Neubaugasse 36/11

1070 Vienna/Austria

tel/fax +43 1 2311746

http://BEBAC.at

Bioequivalence/Bioavailability Forum at http://forum.bebac.at

http://www.goldmark.org/netrants/no-word/attach.html - On 25 Jan 2006 at 14:13:27, manish Issar (m.issar.-a-.gmail.com) sent the message

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Hi Kumar

It would be good idea to identify one subject that is really making a

difference when removed form the BE stats. The better way to go would

be to redose that particular subject along with approximately 20% of

the total number of subjects used in that particular study. Subjects

that comprise the 20% would behave as controls for the add-on study.

All you have to show is that the Cmax ratio of the outlier subject is

in allignment to the geomean Cmax ratios of the main study. once the

add-on study indicates that particular subject was indeed an outlier

then that subject could be removed from the final BE stats report of

your main study.

Repeat analysis should be performed with a clear objective. Too many

repeats are not considered good by the federal agency. I agree too,

that too many repeats are indicative of a lack of control on the

assay at that first glance. If repeats are to be done it should be

performed on a particular timepoint that is suspicious and should

also be justified for.

Yes, you could repeat that study with the same formulation but have

to base reasons to show that the product is BioInequivalent and not

really product failure.

Hope this helps

Manish Issar, Ph.D

Sandoz Inc.

4700 Sandoz Drive

Wilson, NC-27893

USA

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