- On 8 Jul 2004 at 15:32:45, jljacob.at.unilab.com.ph sent the message
Dear colleagues,

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I would appreciate your advice on these BE issues - what is the best

option to consider if the confidence interval for Cmax and AUC fall slightly

above the upper limit of the 80-125% e.g. 130% ? How about if it falls

slightly below the lower limit e.g 78% ? For our bioequivalence (BE)

studies, we have standardized our sample size - 18 normal volunteers are being

used in all our BE studies. By the way, we normally use the randomized 2-way

cross-over single dose-design for most, if not all our BE studies.

Thank you.

Joy - On 12 Jul 2004 at 07:40:53, "Bonate, Peter" (pbonate.at.ilexonc.com) sent the message
Joy,

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My view is that BE is not like handgrenades. Close does not cut it.

If you are not entirely within 80 to 125% then you have failed.

Probably not what you wanted to hear.

Pete bonate

Peter L. Bonate, PhD, FCP

Director, Pharmacokinetics

ILEX Oncology

4545 Horizon Hill Blvd

San Antonio, TX 78229

phone: 210-949-8662

fax: 210-949-8219

email: pbonate.-at-.ilexonc.com - On 12 Jul 2004 at 12:23:25, "Joel S. Owen" (joel.-at-.cognigencorp.com) sent the message
If the BE study is being performed for US regulatory purposes, any CI

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limit outside the bioequivalence interval indicates failure to

demonstrate equivalence. Assuming the appropriate statistical analyses

have been performed to establish the confidence intervals in the

existing data, there isn't much one can do with the existing data. If

the test to reference mean ratios are near one, the formulations may in

fact be equivalent, but the study was not powered to demonstrate this.

If the test formulation is believed to be equivalent to the reference

one could run an additional study with more subjects in order to power

the study appropriately for the variability of the specific compound.

Standardizing BE studies to 18 subjects in a two-way crossover design

does not acknowledge the range of intrasubject variability which exists

across compounds and the need to increase sample size to appropriately

power studies for products with greater variability.

Joel

Joel S. Owen, Ph.D.

Director PK/PD

Cognigen Corporation

395 S. Youngs Road

Buffalo, NY 14221

(v) (716) 633-3463 ext. 247

(f) (716) 633-7404

(e) joel.owen.-a-.cognigencorp.com

http://www.cognigencorp.com/ - On 13 Jul 2004 at 13:04:09, =?ISO-8859-1?Q?"Helmut_Schutz"?= (helmut.schuetz.aaa.chello.at) sent the message
Dear Joy,

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probably you just standardized the wrong thing.

The sample size in BE studies depends on following variables:

1) acceptance range for any given parameter (AUC, Cmax,...)

2) intrasubject variability

3) expected deviation of test from reference

4) alpha-risk

5) beta-risk (the chance to fail to show BE if it really exists)

where

1) generally 80% - 125%, but may be set in some jurisdictions narrower

or wider based on clinical grounds (safety, efficacy)

2) is obtained from literature or a reasonably sized pilot study

3) generally is set to \0xB15% (or an estimate from a pilot study; in

Canada \0xB10%!)

4) fixed to 5% (for a patient = 10% for the population)

5) power = 1 - beta; generally set to 80% or 90%

If your confidence interval is *outside* the a-priori set acceptance

range, but the point estimate is *within*, your study is underpowered,

i.e., you have inclosed fewer subjects than need to show equivalence.

Therefore it's a bad idea to *standardize the sample size* for any

arbitrary number of e.g., 18 subjects.

Best regards,

Helmut

Helmut Sch\0xB8tz

BABECon Biokinet GmbH / Dept Biostatistics

Neubaugasse 36/11 Nattergasse 4

A-1070 Vienna/Austria A-1170 Vienna/Austria

tel/fax +43 1 9713935 tel +43 1 4856969 62

no cell phone ;-) fax +43 1 4856969 90

http://www.goldmark.org/netrants/no-word/attach.html - On 13 Jul 2004 at 14:57:49, fabrice_nollevaux.-at-.sgs.com sent the message
Dear Joy,

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I am probably wrong, but...

By saying "...we have standardized our sample size - 18 normal

volunteers are being used in all our BE studies...",

do you mean you are conducting all your BE studies with 18 subjects,

whatever the tested drug ?

If it is well the case, you are very likely to get unconclusive results

(point estimate within the BE range but limits of the 90% CI outside

this range) from a lot of your BE studies.

For example, considering a quite common situation with an intra-subject

CV for a drug equal to 25% and with a true T/R ratio for the parameter

of interest actually equal to 0.97, the power to demonstrate the BE

using a 0.8-1.25 interval is only 64%, meaning that 36% (i.e. more than

one third!) of the studies performed with 18 subjects will not be able

to conclude to the bioequivalence.

On another side, if you include 32 subjects, the chance to demonstrate

the 0.8-1.25 bioequivalence rises up to 90%.

Normally, the sample size should be calculated a priori, based on the

intra-subject variability observed in previous studies or found in the

litterature, on the expected T/R ratio and on the target power

(generally >80%).

This sample size is then to be justified in the protocol.

This is clearly stated in both US (Guidance for Industry - Statistical

Approaches to Establish Bioequivalence: \0xDF V.B and Appendix V) and EU

(Note for Guidance on the Investigation of Bioavailability and

Bioequivalence: \0xDF 3.1 Design) guidelines.

For sample size calculations, there are some references in the

litterature (e.g. Diletti et al. 2001, Int J Clin Pharmacol Ther

Toxicol, 29:1-8) or you can also consider the use of dedicated

softwares (e.g. nQuery Advisor).

Hope this helps,

Fabrice

Fabrice Nollevaux, M.Sc.

Senior Biostatistician

SGS Biopharma - Wavre - Belgium

www.sgsbiopharma.com - On 23 Nov 2004 at 09:28:41, "yagna pravin" (yagnap.-a-.glenmarkpharma.com) sent the message
Hi

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I just want to know that is it necessary to have 90% confidence

intervals for Tmax for an immediate release dosage formulation to

establish bioequivalence. The guidelines says 90% confidence intervals

of the geometric mean ratio of three PK parameters i.e AUC(0-t) ,

AUC(0-infinity) and Cmax between the test and the reference fall

within 80-125%.

Kindly suggest

Regards

Yagna

Research officer

Glenmark Pharmaceuticals Ltd.,

Nashik.

Maharastra

INDIA - On 22 Nov 2004 at 21:44:22, Vishwottam K N (vishwottam.at.yahoo.com) sent the message

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Dear Yagna

Unlike CI on logtransformed data of Cmax, AUCt & AUCinf, statistical

test for Tmax to be done on nontransformed data by wilcoxin ranken mean

test, whose explanation is as follows:

Many biological data correspond more closely to a log normal

distribution. AUC and Cmax tend to be skewed and their variances

increase with the means.

Log transformation makes the variances independent of the mean and the

frequency distribution is made more symmetrical. The third measure of

bioavailability, Tmax, poses a somewhat different problem.

What makes Tmax different is the discreteness of its measurement, as

well as the fact that it is measured with an error that will depend on

the study's sampling times. While Hauck and Anderson contended that

none of the statistical procedures available for use in the analysis of

bioequivalence studies appear to be appropriate for Tmax, Westlake has

suggested that a C.I. on the difference of the Tmax for standard and

test formulations following an ANOVA on the untransformed data seems

appropriate.

However, the regulatory agencies recommend that differences in Tmax be

evaluated by non-parametric tests (Wilcoxon signed rank test, Wilcoxon

rank sum test) on the untransformed values (additive model).

Nonparametric methods for estimating a population median include the

Sign test and the Wilcoxan Signed-ranks test.

Thanking you and Regards

Vishwottam K N

Senior Scientist - Biopharmaceutical Research

SUVEN LIFE SCIENCES Ltd

Serene Chambers, Road # 7,

Banjara Hills, Hyderabad 500 034

Phone : 9140 2355 6039, 3092 1169

Fax : 9140 2354 1152 - On 23 Nov 2004 at 08:49:44, "Art Straughn" (astraughn.at.utmem.edu) sent the message

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Yagan,

Depending the FDA may request CI on Early Exposue (see below from

Guidance

on BA/BE)

For orally administered immediate-release drug products, BE can

generally be

demonstrated by measurements of peak and total exposure. An early

exposure

measure may be informative on the basis of appropriate clinical

efficacy/safety trials and/or pharmacokinetic/pharmacodynamic studies

that

call for better control of drug absorption into the systemic circulation

(e.g., to ensure rapid onset of an analgesic effect or to avoid an

excessive

hypotensive action of an antihypertensive). In this setting, the

guidance

recommends use of partial AUC as an early exposure measure. We recommend

that the partial area be truncated at the population median of Tmax

values

for the reference formulation. We also recommend that at least two

quantifiable samples be collected before the expected peak time to allow

adequate estimation of the partial area.

Art Straughn

Department of Pharmaceutical Sciences

College of Pharmacy

University of Tennessee - On 27 Nov 2004 at 09:44:35, "yagna pravin" (yagnap.-at-.glenmarkpharma.com) sent the message
Hi

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Please interpret the following

"Test and reference product are equivalent with respect to the extent of

absorption but not with respect to the rate of absorption".

This was the case with an immediate release dosage form where 90%

confidence

intervals of AUC(0-t) , AUC(0-infinity) and Cmax between the test and

the

reference were well within 80-125%.But Tmax slightly differed, in

connection

with the same I would like to ask what is the criteria to establish Tmax

(for an immediate release dosage formulation) to be bioequivalent.

Warm Regards

Yagna

Research Officer

Glenmark Pharmaceuticals Ltd.,

Nashik,

Maharastra,

INDIA. - On 27 Nov 2004 at 11:20:50, prasadkum.-at-.drreddys.com sent the message

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"For T max - no criteria exist," but it should be comparable to the

reference product that means T max of Test product should not be

differed

much from Reference.

You can refer the USFDA guideline " Food effect Bioavailability and Feb

Bioequivalence studies - Page no 8" for further clarification.

Thanxs

KUM Prasad

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