- On 11 Feb 2005 at 19:34:32, Shruti Agrawal (shrutiagrawal02.aaa.yahoo.co.in) sent the message

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Dear all

We have developed two formulations and want to test the bioequivalence

of both the products in coparison to marketed product. the study design

would be three sequence three period (two tests and one reference) BE

study.

What would be the appropriate statistical test to determine BE of both

the formulations from this study design?

Thanks in advance

Shruti

Dr. Shruti Agrawal

Department of Pharmaceutics

Ernest Mario School of Pharmacy

Rutgers, The State University of New Jersey

160 Frelinghyusen road

Piscataway NJ 08854 - On 11 Feb 2005 at 15:40:34, "Labadie, Robert" (robert.labadie.at.pfizer.com) sent the message

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The following message was posted to: PharmPK

Shruti,

You need to do a six sequence Williams square (special Latin square)

design

for your study which is balanced for carryover effects. Run all your

data

through the same statistical model as your classic 2x2 crossover but

use the

appropriate contrast statements to obtain your unbiased treatment

estimates

and CIs.

Regards.

Rob - On 14 Feb 2005 at 17:07:32, =?ISO-8859-1?Q?Helmut_Sch=FCtz?= (helmut.schuetz.aaa.bebac.at) sent the message

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The following message was posted to: PharmPK

Dear Shruti,

as Robert already pointed out, you need a six-sequence Williams' design

(a three sequence simply will not work, because it's not balanced both

for

treatment and carry-over).

Bellow you will find the six sequences (T1 and T2 are the test

formulations, R is the reference)

S#|P1|P2|P3

------------

#1|T1|T2|R

#2|T2|R |T1

#3|R |T1|T2

#4|T1|R |T2

#5|T2|T1|R

#6|R |T2|T1

Since Williams' design is balanced, you are also able to extract

pairwise

comparisons - which you may need for nonparametric testing of Tmax ;-)

One Caveat:

According to my experience, such a design is only acceptable for

regulatory applications if you _drop_ one of the formulations in the

later drug development process, i.e., only one of the formulations

will actually be marketed - the study helped you in deciding, which one.

If you want to use both formulations (e.g., two different galenic

forms should _both_ show BE to the reference) you will run into

multiplicity issues: two simultaneous tests at alpha=0.05 lead to an

increased patient's risk of 1-(1-0.05)^2=0.0975!

The calculation of a Bonferroni-corrected 95% confidence interval -

instead of the 90% CI - is needed to keep the overall alpha-risk at 5%:

alpha-adj=1-(1-0.05/2)^2=0.0494, which is <0.05.

You will have to adjust the sample size in study planning accordingly.

Regards

Helmut

--

Helmut Schutz

BEBAC

Consultancy Services for Bioequivalence and Bioavailability Studies

Neubaugasse 36/11

A-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

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