Bioavailability / Bioequivalence: Sample Size Planning (Literature References, Pilot Studies)

Selection of CROs
Selection of a Reference Product
Metrics (AUC, C
max
/t
max
, Shape of Profile)
Acceptance Ranges (!" # $!%& and 'e(ond)
Sample Si)e Planning (*iterature References, Pilot

Studies)
Steps in 'ioanal(tical +alidation (+alidation Plan,

Pre,Stud( +alidation, -n,Stud( +alidation)
Stud( .esigns
Protocol -ssues
/0aluation of Studies
Ad0anced 1opics
A0oiding Pitfalls
2ioa0aila'ilit( / 2ioe3ui0alence
1
next Lecture
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Sample Si)e Planning (*iterature References,

Pilot Studies)
Suggested References
S.-C. Chow and J.-p. Liu;

Design and Analysis of Bioaaila!ility and Bioe"uialence
Studies.
#arcel De$$er% &ew 'or$ ()
nd
ed. )***+
S.-C. Chow% Shao% J. and ,. -ang;

Sa.ple Si/e Calculations 0n Clinical Research.
#arcel De$$er% &ew 'or$ ()**1+
)
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Pilot Studies)
2he nu.!er of su!3ects re"uired is deter.ined !y
the error ariance associated with the pri.ary characteris-

tic to !e studied as esti.ated fro.
a pilot e4peri.ent%
preious studies% or
pu!lished data%
the significance leel desired%
the e4pected deiation (+ fro. the reference product co.-

pati!le with B5 and%
the re"uired power.

1
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Pilot Studies)
6ro!le.s7Solutions
8 the error ariance associated with the primary charac-

teristic to !e studied 8
Since B5 .ust !e shown !oth for A9C and C

.a4
% and
if you plan your sa.ple si/e only for the :pri.ary charac-
teristic; (e.g.% A9C+% in .any cases you will fail for the secon-
dary para.eter (e.g.% C
.a4
+% which .ost li$ely shows higher
aria!ility < your study will !e underpowered.
Based on the assu.ption% that C= is identical for test and

reference (what if only the reference for.ulation has high
aria!ility% e.g.% pra/oles>+.
?
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Pilot Studies)

a pilot e4peri.ent%
preious studies% or
pu!lished data%

the re"uired power.

@
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Pilot Studies)
6ro!le.s7Solutions
8 as esti.ated fro.
a pilot experiment%
previous studies% or
published data%
2he correct order should readA

preious studies pilot study pu!lished data.
Bnly in the first case you :$now; all constraints resulting in

aria!ility.
6ilot studies are often too s.all to get reliable esti.ates of

aria!ility.
Adisa!le only if you hae data fro. a couple of studies.

C
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Pilot Studies)

a pilot e4peri.ent%
preious studies% or
pu!lished data%

the re"uired power.

D
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Pilot Studies)
6ro!le.s7Solutions
8 the significance level desired8
2hroughout the &fE the significance leel (% error type 0A

patient;s ris$ to !e treated with an !ioine"uialent drug+ is
fi4ed to @ F (corresponding to a G* F confidence interal+.
Bnly in so.e ery restrictie legislations (e.g.% Bra/il;s

A&=0SA+% .ust !e tightened to ).@ F for &20Ds (G@ F
confidence interal+.
'ou .ay desire a lower significance leel% !ut you will not
get an approal anywhereH
I
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Pilot Studies)

a pilot e4peri.ent%
preious studies% or
pu!lished data%

the re"uired power.

G
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Pilot Studies)
6ro!le.s7Solutions
8 the expected deviation ( ) from the reference8
Relia!le esti.ate only fro. a preious full-si/ed study.
0f you are using data fro. a pilot study% allow for a safety
.argin.
0f no data are aaila!le% co..only a test7reference-ratio of

*.G@ ( J @ F+ is used.
0f .ore than J 1* F is e4pected% "uestions fro. the 5thics

Co..ittee are li$ely.
1*
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Pilot Studies)

a pilot e4peri.ent%
preious studies% or
pu!lished data%

the re"uired power.

11
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Pilot Studies)
6ro!le.s7Solutions
8 the required power.
Eenerally the power is set to at least I* F (% error type 00A

producers;s ris$ to get no approal for a !ioe"uialent drug;
power J 1 < +.
Re.e.!erA 1 out of @ studies will failH
0f you plan for power of less than D* F% pro!le.s with the

5thics Co..ittee are li$ely.
0f you plan for power of .ore than G* F (especially with low

aria!ility drugs+% pro!le.s with the Regulator are li$ely
(:forced !ioe"uialence;+.
Add su!3ects according to the e4pected drop-out rate.

1)
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Sample Si)e Planning (*iterature References)
Literature References
Should !e applied with caution (sa.e dosage leel and

regi.en% single dose 7 .ultiple dose% analytical .ethod%
log-transfor.ed data% year of pu!lication%8+.
6refera!le pooled data for. a couple of studies.

Blu.e% ,. and 5. #utschler (eds.% in Eer.an only+;
BioK"uialen/. LualitKts!ewertung wir$stoffgleicher Mertigar/nei.ittel.
Anleitung < #ethoden < #aterialien.
EB=0% Mran$furt75sch!orn% loose-leaf-collection (1GIG-1GGC+
Steini3ans% =.-. et al.;
Reference ta!les for the intrasu!3ect coefficient of ariation in !ioe"uialence
studies.
0nt. J. Clin. 6har.. 2herap. 11(I+% ?)D-?1* (1GG@+
11
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Sample Si)e Planning (*iterature References)

1?
1*
1@
)*
)@
1*
)** .g
1** .g
total
*
)
?
C
I
1*
1)
f
r
e
"
u
e
n
c
y
FC=
1D B5-studies fro. Blu.e7#utschler (do4icycline+
next Lecture
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Sample Si)e Planning (Pilot Studies)
6ilot Studies
Bnly reasona!ly large study (e.g.% nJ1C+ helpful for the

selection of the :!est; of seeral si.ilar for.ulations.
5sti.ates of 6N para.eters fro. s.all studies hae large

confidence interals.
5sti.ate of the intrasu!3ect ariance een .ore uncertain.

1@
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1C
5sti.ates of intrasu!3ect ariance (1G studies+
1**F
1)@F
1@*F
1D@F
)**F
1) 1I )? 1* 1C
sa.ple si/e
u
p
p
e
r

G
@

F

C
L

7

C
=
.
e
a
n
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1D
O*.I* < 1.)@P C=J)*F nJ)?
@*F
C*F
D*F
I*F
G*F
1**F
*.I@ *.G* *.G@ 1.** 1.*@ 1.1* 1.1@
e4pected B5 ratio
p
o
w
e
r
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Pilot Studies)
5sti.ation of Sa.ple Si/e
2a!les
Diletti% 5.% ,ausch$e% D. and =.-. Stein3ans;

Sa.ple si/e deter.ination for !ioe"uialence assess.ent
!y .eans of confidence interals.
0nt. J. Clin. 6har.. 2her. 2o4icol. )G(1+% 1-I (1GG1+
Diletti% 5.% ,ausch$e% D. and =.-. Stein3ans;

Sa.ple si/e deter.inationA 54tended ta!les for the .ultipli-
catie .odel and !ioe"uialence ranges of *.G to 1.11 and
*.D to 1.?1.
0nt. J. Clin. 6har.. 2her. 2o4icol. 1*7Suppl.1% S@G-C) (1GG)+
1I
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Pilot Studies)
Appro4i.ations (.ay !e i.ple.ented in a Spreadsheet+
,ausch$e% D. et al.;
Sa.ple Si/e Deter.ination for Bioe"uialence Assess.ent
9sing a #ultiplicatie #odel.
J. 6har.aco$in. Biophar.. )*(@+% @@D-@C1 (1GG)+
Chow% S.-C. and ,. -ang;

Bn Sa.ple Si/e Calculation in Bioe"uialence 2rials.
J. 6har.aco$in. 6har.acodyn. )I()+% 1@@-1CG ()**1+
5rrataA J. 6har.aco$in. 6har.acodyn.)G()+% 1*1-1*) ()**)+
1G
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Pilot Studies)
6rogra.s
nLuery Adisor
C.*1% Statistical Solutions ()**@+
6ASS
)**@% &CSS ()**@+
S2A20S20CA 6ower Analysis

D% StatSoft ()**@+
StudySi/e
1.*G% CreoStat ()**?+
Mor.ulas .ay !e progra..ed in any language7pac$age

which supports the noncentral t-distri!ution (SAS% SQ% R%8+
)*
next Lecture
previous Lecture
next Lecture
Selection of CROs
Selection of a Reference Product
Metrics (AUC, C
max
/t
max
, Shape of Profile)
Acceptance Ranges (!" # $!%& and 'e(ond)
Sample Si)e Planning (*iterature References, Pilot

Studies)
Steps in 'ioanal(tical +alidation (+alidation Plan,

Pre,Stud( +alidation, -n,Stud( +alidation)
Stud( .esigns
Protocol -ssues
/0aluation of Studies
Ad0anced 1opics
A0oiding Pitfalls
)1
next Lecture
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next Lecture
Steps in 'ioanal(tical +alidation (+alidation

Plan, Pre,Stud( +alidation, -n,Stud( +alidation)
5ssential Docu.ents
2he 5uropean Agency for the 5aluation of #edicinal 6roducts% ,u.an
#edicines 5aluation 9nit;
C6#670C,71I17G@A 0C, L)A &ote for Euidance on =alidation of Analytical
#ethodsA Definitions and 2er.inology. Step @ (&oe.!er 1GG?+
2he 5uropean Agency for the 5aluation of #edicinal 6roducts% ,u.an
#edicines 5aluation 9nit;
C6#670C,7)I17G@A 0C, L)B &ote for Euidance on =alidation of Analytical
#ethodsA #ethodology. Step ? (&oe.!er 1GGC+
Mood and Drug Ad.inistrationA Center for Drug 5aluation and Research
(CD5R+% Center for =eterinary #edicine (C=#+;
Euidance for 0ndustry. Bioanalytical #ethod =alidation. (#ay )**1+
))
next Lecture
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9seful Docu.ents
Cartwright% A.C. et al.;
0nternational har.oni/ation and consensus D0A .eeting on !ioaaila!ility
and !ioe"uialence testing re"uire.ents and standards.
Drug 0nfor.ation Journal )@% ?D1 (1GG1+
Shah% =.6. et al.;
Analytical .ethods alidationA Bioaaila!ility% !ioe"uialence and
phar.aco$inetic studies.
0nt. J. 6har.. I)% 1-D (1GG)+
Shah% =.6.% et al.;
Bioanalytical #ethod =alidation < A Reisit with a Decade of 6rogress.
6har.. Res. 1D% 1@@1-1@@D ()***+
)1
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9seful Docu.ents
Brganisation for 5cono.ic Co-operation and Deelop.ent% 5niron.ent
Directorate 7 Che.icals Eroup and #anage.ent Co..ittee;
B5CD 6rinciples on Eood La!oratory 6ractice (as reised in 1GGD+
Docu.ent 5&=7#C7C,5#(GI+1D
0nA B5CD Series on 6rinciples of Eood La!oratory 6ractice and Co.pliance
#onitoring% 6aris% )1-Jan-1GGI
Bra/ilian Sanitary Sureillance Agency (A&=0SA+;
#anual for Eood Bioaaila!ility and Bioe"uialence Studies.
=olu.e 1% #odule )A Analytical Step.
httpsA77www.anisa.go.!r7eng7!io7.anual7olu.e1./ip
BrasRlia ()***+
)?
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Steps in 'ioanal(tical +alidation4 +alidation Plan
#ethod used for "uantitatie .easure.ent of

analytes in a gien !iological .atri4 .ust !e reli-
a!le and reproduci!le for the intended use.
Accurracy
6recision
Selectiity
Sensitiity
Reproduci!ility
Sta!ility
)@
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Mull =alidation
Deeloping and i.ple.enting a new !ioanalytical .ethod%

or adding .eta!olites to an e4isting assay.
Selecti0it(
Lac$ of interferences a!oe the Lower Li.it of Luantitation
(LLBL+ in C different sources of .atri4.
Accurac(
Replicate (@+ analysis of $nown concentrations .easured
at 1 leels (low% inter.ediate% high+.
#ean alues within S1@ F of e4pected (e4cept at LLBL%
where S)* F is accepta!le+.
)C
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Mull =alidation

Precision
Replicate (@+ analysis of $nown concentrations .easured
at 1 leels (low% inter.ediate% high+.
Coefficient of =ariation (C=+ 1@ F at each concentration
(e4cept at LLBL% where )* F is accepta!le+.
intra,'atch
within analytical run.
inter,'atch
!etween analytical runs (a$a repeata!ility+.
)D
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Mull =alidation

Reco0er(
2he detector response o!tained fro. an a.ount of the anal-
yte added to and e4tracted fro. the !iological .atri4% co.-
pared to the detector response o!tained for the true concen-
tration of the pure authentic standard. Recoery of the anal-
yte need not !e 1** F% !ut the e4tent of recoery of an anal-
yte and of the internal standard should !e consistent% pre-
cise% and reproduci!le..
#easured at low7inter.ediate7high leel.
)I
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Mull =alidation

Cali'ration/Standard Cur0e
Sa.e .atri4 as the sa.ples in the intended study spi$ed
with $nown concentrations. &u.!er of standardsA function of
the anticipated range of analytical alues% nature of the
analyte7response relationship. Concentrations of standards
chosen on !asis of the concentration range e4pected.
Blan$ sa.ple (.atri4 sa.ple processed without internal

standard+%
Tero sa.ple (.atri4 sa.ple processed with internal standard+%
C < I non-/ero sa.ples coering the e4pected range% including

LLBL.
)G
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Mull =alidation

Si.plest .odel that ade"uately descri!es the concentration-

response relationship should !e used.
Selection of weighting and use of a co.ple4 regression

e"uation should !e 3ustified.
Response at LLBL @ ti.es response of !lan$.
Response at LLBLA precision )* F% accuracy S)* F fro.

no.inal concentration.
Response at other leelsA accuracy S1@ F fro. no.inal

concentration.
1*
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Mull =alidation

At least four out of si4 non-/ero standards should .eet the

a!oe criteria% including the LLBL and the cali!ration standard
at the highest concentration.
54cluding the standards should not change the .odel used.

11
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Mull =alidation

Sta'ilit(
Sta!ility of the analytes during sa.ple collection and
handling.
1hree free)e,tha5 c(cles

1 ali"uots at low and high leels stored for )? hours and
thawed at roo. te.perature. -hen co.pletely thawed% refro/en
for 1) < )? hours. 2his cycle two .ore ti.es repeated% then
analy/ed after the third cycle. 0f insta!leA sa.ples should !e
fro/en at -D* UC during another M2-cylce.
1)
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Mull =alidation

Sta'ilit(
handling.
Short,1erm Storage (!ench top% roo. te.perature+A

2hree ali"uots of each of the low and high concentrations
should !e thawed at roo. te.perature and $ept at this te.pe-
rature fro. ? < )? hours (!ased on the e4pected duration that
sa.ples will !e .aintained at roo. te.perature in the intended
study+ and analy/ed.
11
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Mull =alidation

Sta'ilit(
handling.
*ong,1erm Storage (fro/en at the intended storage

te.perature+ should e4ceed the ti.e !etween the date of first
sa.ple collection and the date of last sa.ple analysis.
Deter.ined !y storing 1 ali"uots of low7high leels under the
sa.e conditions as the study sa.ples. =olu.e should !e suffi-
cient for analysis on 1 separate occasions. Concentrations of all
the sta!ility sa.ples should !e co.pared to the .ean of !ac$-
calculated alues for the standards at the appropriate concent-
rations fro. the first day of long-ter. sta!ility testing.
1?
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Mull =alidation

Sta'ilit(
handling.
Stoc6 Solution Sta'ilit( of drug and the internal standard

should !e ealuated at roo. te.perature for C hours. 0f the
stoc$ solutions are refrigerated or fro/en for the releant period%
the sta!ility should !e docu.ented. After co.pletion of the de-
sired storage ti.e% the sta!ility should !e tested !y co.paring
the instru.ent response with that of freshly prepared solutions.
1@
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Mull =alidation

Sta'ilit(
handling.
Post,Preparati0e Sta'ilit(
Sta!ility of processed sa.ples% including the resident ti.e in the
autosa.pler% should !e deter.ined. 2he sta!ility of the drug
and the internal standard should !e assessed oer the anticipat-
ed run ti.e for the !atch si/e in alidation sa.ples !y deter.in-
ing concentrations on the !asis of original cali!ration standards.
1C
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6artial =alidation
#ethod transfers !etween la!oratories (or analysts+.
Change in analytical .ethodology (e.g.% change in

detection syste.s+.
Change in anticoagulant in haresting !iological fluid.
Change in .atri4 within species (e.g.% hu.an plas.a to

hu.an urine+.
Change in sa.ple processing procedures.
Change in species within .atri4 (e.g.% rat plas.a to .ouse

plas.a+.
1D
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6artial =alidation
Change in releant concentration range.
Changes in instru.ents and7or software platfor.s.
Li.ited sa.ple olu.e (e.g.% pediatric study+.
Rare .atrices.
Selectiity de.onstration of an analyte in the presence of

conco.itant .edications and7or specific .eta!olites.
1I
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Cross-=alidation
Co.parison of alidation para.eters when two or .ore

!ioanalytical .ethods are used to generate data within the
sa.e study or across different studies. An e4a.ple of
cross-alidation would !e a situation where an original ali-
dated !ioanalytical .ethod seres as the reference and the
reised !ioanalytical .ethod is the comparator.
Cross-alidation should also !e considered when data

generated using different analytical techni"ues (e.g.%
LC-#S7#S vs. 5L0SA+ in different studies are included in a
regulatory su!.ission.
1G
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Cross-=alidation% 54a.pleA Clinda.ycin

?*
clindam(cin 7 mg p.o.
1*
1**
1***
1****
1*****
* ? I 1) 1C )* )?
ti.e OhP
c
o
n
c
e
n
t
r
a
t
i
o
n

O
n
g
7
.
l
P
,6LC79= (nJ)?+
tVA @.C1 h; rJ*.GI1
EC7#S (nJ)*+
tVA ).)) h; rJ*.GGG
LBLA )* ng7.l
next Lecture
previous Lecture
next Lecture
Cross-=alidation% 54a.pleA Clinda.ycin

?1
yJ)@.G?DQ*.G@DW4Qeps
*C,MS/MS 8ng/ml9
:
*
P
C
/
U
+

8
n
g
/
m
l
9
*
1***
)***
1***
?***
* 1*** )*** 1*** ?***
yJ11.GC?Q*.G*IW4Qeps
*C,MS/MS 8ng/ml9
:
*
P
C
/
U
+

8
n
g
/
m
l
9
*
@*
1**
1@*
* @* 1** 1@*
next Lecture
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-ritten Docu.ent descri!ing which steps will !e

perfor.ed in the =alidation.
6urpose of =alidation (e.g.% :=alidation of !ioanalytical

.ethod X for the deter.ination of ' in hu.an plas.a;+.
Reference to already esta!lished .ethod (SB6+.

?)
next Lecture
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next Lecture
Steps in 'ioanal(tical +alidation4

Pre,Stud( +alidation
6erfor.ance of =alidation according to the

=alidation 6lan.
Results .ust co.ply with li.its set in the =alidation 6lan.
Report of Results
:#ethod =alidation Report;.
-ill !e referred in the Analytical 6rotocol of BA7B5-studies.

?1
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-n,Stud( +alidation
Study Sa.ples should !e analy/ed according to

the Analytical 6rotocol.
Luality Control Sa.ples (LCs+ should !e analy/ed

together with Cali!rators and study sa.ples.
*o5 / intermediate / high concentration le0els

At least Duplicates at each leel.
LowA within 1ti.es the LLBL.
0nter.ediateA near the center of the cali!ration range.
,ighA near the upper !oundary.
??
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-n,Stud( +alidation
Study Sa.ples should !e analy/ed according to

the Analytical 6rotocol.
Acceptance Criteria for an anal(tical run
;Cs
I@ F < 11@ F accuracy for single deter.inations of LCs;
not .ore than two different of si4 per run should !e out of
range.
Standard Cur0e
I@ F < 11@ F accuracy for D@ F of standard points% e4cept
for LLBL (I* F < 1)* F+. =alues outside can !e discarded%
proided they do not change the esta!lished .odel.
?@
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Bioavailability / Bioequivalence: Sample Size Planning (Literature References, Pilot Studies)

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Bioavailability / Bioequivalence: Sample Size Planning (Literature References, Pilot Studies)

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Selection of CROs

Selection of a Reference Product

Acceptance Ranges (!" # $!%& and 'e(ond)

Sample Si)e Planning (*iterature References, Pilot

Steps in 'ioanal(tical +alidation (+alidation Plan,

Sample Si)e Planning (*iterature References,

S.-C. Chow and J.-p. Liu;

S.-C. Chow% Shao% J. and ,. -ang;

Sample Si)e Planning (*iterature References,

2he nu.!er of su!3ects re"uired is deter.ined !y

the error ariance associated with the pri.ary characteris-

the significance leel desired%

the e4pected deiation (+ fro. the reference product co.-

the re"uired power.

Sample Si)e Planning (*iterature References,

8 the error ariance associated with the primary charac-

Since B5 .ust !e shown !oth for A9C and C

Based on the assu.ption% that C= is identical for test and

Sample Si)e Planning (*iterature References,

2he nu.!er of su!3ects re"uired is deter.ined !y

the error ariance associated with the pri.ary characteris-

the significance leel desired%

the e4pected deiation (+ fro. the reference product co.-

the re"uired power.

Sample Si)e Planning (*iterature References,

2he correct order should readA

Bnly in the first case you :$now; all constraints resulting in

6ilot studies are often too s.all to get reliable esti.ates of

Adisa!le only if you hae data fro. a couple of studies.

Sample Si)e Planning (*iterature References,

2he nu.!er of su!3ects re"uired is deter.ined !y

the error ariance associated with the pri.ary characteris-

the significance leel desired%

the e4pected deiation (+ fro. the reference product co.-

the re"uired power.

Sample Si)e Planning (*iterature References,

8 the significance level desired8

2hroughout the &fE the significance leel (% error type 0A

Bnly in so.e ery restrictie legislations (e.g.% Bra/il;s

Sample Si)e Planning (*iterature References,

2he nu.!er of su!3ects re"uired is deter.ined !y

the error ariance associated with the pri.ary characteris-

the significance leel desired%

the e4pected deiation (+ fro. the reference product co.-

the re"uired power.

Sample Si)e Planning (*iterature References,

8 the expected deviation ( ) from the reference8

Relia!le esti.ate only fro. a preious full-si/ed study.

0f no data are aaila!le% co..only a test7reference-ratio of

0f .ore than J 1* F is e4pected% "uestions fro. the 5thics

Sample Si)e Planning (*iterature References,

2he nu.!er of su!3ects re"uired is deter.ined !y

the error ariance associated with the pri.ary characteris-

the significance leel desired%

the e4pected deiation (+ fro. the reference product co.-

the re"uired power.

Sample Si)e Planning (*iterature References,

8 the required power.

Eenerally the power is set to at least I* F (% error type 00A

0f you plan for power of less than D* F% pro!le.s with the

0f you plan for power of .ore than G* F (especially with low

Add su!3ects according to the e4pected drop-out rate.