- On 14 Jun 2003 at 20:40:04, david (david.aaa.db5.hsc.net.ou.edu) sent the message

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From: pablo.-at-.unidavi.edu.br

Date: Thu, 5 Jun 2003 13:04:09 -0300

Subject: sample size in BE

The following message was posted to: PharmPK

Dears, I have an basic doubt. How Do I determine the sample size for

bioequivalence studies? Thanks, Pablo A. Pereira - On 25 Jun 2003 at 00:13:33, =?ISO-8859-1?Q?Helmut_Sch=FCtz?= (helmut.schuetz.-a-.chello.at) sent the message

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Hi Pablo,

all following references are given for AVERAGE bioequivalence.

Tables give EXACT sample sizes for given variability, alpha- and

beta-error, estimated deviation of the point estimate from unity (or

zero) at an desired level of statistical power. Don't interpolate

within table values, since power curves are VERY nonlinear, use the

approximations instead.

Approximations are easy to implement in any spreadsheet application (or

if you are a little patient, give results with only the aid of a table

of the t-distribution and a pocket calculator within a couple of

minutes). Estimated same sizes return table values or are sligthly

higher (i.e., conservative, so you are on the safe side anyway). They

are very useful if you want to estimate "exotic" input (e.g., point

estimate -7%, acceptance range 0.75-1.33, 85% power).

ADDITIVE MODEL (RAW DATA), 2x2 CROSSOVER

==

TABLES

K.F. PHILLIPS;

Pharmacometrics. Power of the Two One-Sides Tests

J. Pharmacokin. Biopharm 18/2, 137-144 (1990)

APPROXIMATION

LIU, J.-P. and S.-C. CHOW;

Sample Size Determination for the Two One-Sided Tests Procedure in

Bioequivalence

J. Pharmacokin. Biopharm 20/1, 101-104 (1992)

MULTIPLICATIVE MODEL (LOG-TRANSFORMED DATA), 2x2 CROSSOVER

==

TABLES

DILETTI, E., HAUSCHKE, D. and V.W. STEINIJANS;

Sample size determination for bioequivalence assessment by means of

confidence intervals

Int. J. Clin. Pharm. Ther. Toxicol. 29/1, 1-8 (1991)

DILETTI, E., HAUSCHLE, D. and V.W. STEINIJANS;

Sample size determination: Extended tables for the multiplicative model

and bioequivalence ranges of 0.9 to 1.11 and 0.7 to 1.43

Int. J. Clin. Pharm. Ther. Toxicol. 30/Suppl.1, S59-62 (1992)

APPROXIMATION

HAUSCHKE, D., STEINIJANS, V.W., DILETTI, E. and M. BURKE;

Sample Size Determination for Bioequivalence Assessment Using a

Multiplicative Model

J. Pharmacokin. Biopharm. 20/5, 557-561 (1992)

Tables and Appoximation-formulas for all the cases above plus the

parallel design are given at

S.-C. CHOW and H. WANG;

On Sample Size Calculation in Bioequivalence Trials

J. Pharmacokin. Pharmacodyn. 28/2, 155-169 (2001)

unfortunately the original reference contains a lot of typographical

errors, so please also consult with

D. HAUSCHKE;

A Note on Sample Size Calculation in Bioequivalence Trials

J. Pharmacokin. Pharmacodyn. 29/1, 89-94 (2002)

P. BLOOD;

Sample Size Calculation in Bioequivalence Trials

J. Pharmacokin. Pharmacodyn. 29/1, 95-97 (2002)

and author's response and errata

J. Pharmacokin. Pharmacodyn. 29/1, 99-102 (2002)

Tables for 4 different replicate designs (Balaam's, 2-sequence dual,

4-period 2-sequence, 4-period 4 sequence), both in raw scale and

log-transformed are given at

CHEN, K.-W., CHOW, S.-C., and G. LI;

A Note on Sample Size Determination for Bioequivalence Studies with

Higher-Order Crossover Designs

J. Pharmacokin. Biopharm. 25/6, 753-765 (1997)

many useful references are also given in

S.C. CHOW and J.-P. LIU;

Design and Analysis of Bioavailability and Bioequivalence Studies

Second Edition, Revised and Expanded

Marcel Dekker, New York, Basel 2000

Since you are located in Brazil, don't forget ANVISA ;-)

http://www.anvisa.gov.br/hotside/genericos/legis/resolucoes/

478_02_re_e.htm

Resolution No 478 of March 19, 2002 states under 1.f)

"The minimum number of subjects is generally 24..."

Regards

Helmut Schütz

Head Biostatistics

Biokinet GmbH Tel +43(0)1 4856969-62

Nattergasse 4 Fax +43(0)1 4856969-90

A-1170 Vienna/Austria mailto:helmut.schuetz.at.chello.at

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