thailand babe guideline

8/15/2019 Thailand BABE Guideline

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THAILAND GUIDELINES

FOR

THE CONDUCT OF

BIOAVAILABILITY AND

BIOEQUIVALENCE STUDIES

DRUG CONTROL DIVISON

FOOD AND DRUG ADMINISTRATION

MINISTRY OF PUBLIC HEALTH THAILAND

Adopted from the ASEAN Gude!"e# for the Co"du$t of Bo%&%!%'!t( %"d

Boe)u&%!e"$e Stude# *h$h # %d%pted from the CPMP Note for Gud%"$e o" The

I"&e#t+%to" of Bo%&%!%'!t( %"d Boe)u&%!e"$e, -../


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TABLE OF CONTENTS

page

1. INTRODUCTION 0

2. DEFINITIONS 1

-2/ Ph%rm%$eut$%! e)u&%!e"$e 1

-2- Ph%rm%$eut$%! %!ter"%t&e# 1

-23 Bo%&%!%'!t( 1-20 Boe)u&%!e"$e 4-21 E##e"t%!!( #m!%r produ$t# 4-24 Ther%peut$ e)u&%!e"$e 5

3. DESIGN AND CONDUCT OF STUDIES 5

32/ De#+" 632- Su'7e$t# 8

32-2/ Se!e$to" of #u'7e$t# 832-2- St%"d%rd#%to" of the #tud( 8

32-23 I"$!u#o" of p%te"t# /.

32-20 Ge"et$ phe"ot(p"+ /.

323 Ch%r%$ter#t$# to 'e "&e#t+%ted /.

320 Chem$%! %"%!(## //

321 Refere"$e %"d te#t produ$t /-

324 D%t% %"%!(## /3

3242/ St%t#t$%! %"%!(## /3

3242- A$$ept%"$e r%"+e for ph%rm%$o9"et$ p%r%meter# /3

32423 H%"d!"+ de&%to"# from the #tud( p!%" /0

32420 A rem%r9 o" "d&du%! %"d popu!%to" 'oe)u&%!e"$e /0325 I" &tro d##o!uto" $omp!eme"t%r( to % 'oe)u&%!e"$e #tud( /0

326 Report"+ of re#u!t# /1

4. APPLICATIONS FOR PRODUCTS CONTAINING NEW ACTIVE

SUBSTANCES /4

02/ Bo%&%!%'!t( /4

02- Boe)u&%!e"$e /4

. APPLICATIONS FOR PRODUCTS CONTAINING APPROVED ACTIVE

SUBSTANCES /4

12/ Boe)u&%!e"$e #tude# /412/2/2 Or%! mmed%te re!e%#e form# *th #(#tem$ %$to" /4

12/2-2 Or%! #o!uto"# /6

12/232 No":or%! mmed%te re!e%#e form# *th #(#tem$ %$to" /6

12/202 Modfed re!e%#e %"d tr%"#derm%! do#%+e form# /6

12/212 F;ed $om'"%to"# produ$t# /6

12/242 P%re"ter%! #o!uto"# /6

12/252 G%#e# /6

12/262 Lo$%!!( %pp!ed produ$t# /8

12- I" &tro d##o!uto" /8

123 V%r%to"# /8

Dru+ Co"tro! D&#o" p%+e -


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1. INTRODUCTION

To e;ert %" optm%! ther%peut$ %$to" %" %$t&e moet( #hou!d 'e de!&ered to t# #te of

%$to" " %" effe$t&e $o"$e"tr%to" for the de#red perod2 To %!!o* re!%'!e pred$to" of the ther%peut$ effe$t the perform%"$e of the do#%+e form $o"t%""+ the %$t&e #u'#t%"$e

#hou!d 'e *e!! $h%r%$ter#ed2

I" the p%#t, #e&er%! ther%peut$ m#%d&e"ture# re!%ted to dffere"$e# " 'o%&%!%'!t( >e2+2

d+o;", phe"(to", prmdo"e? te#tf( to the "e$e##t( of te#t"+ the perform%"$e of

do#%+e form# " de!&er"+ the %$t&e #u'#t%"$e to the #(#tem$ $r$u!%to" %"d there'( to

the #te of %$to"2 Thu# the 'o%&%!%'!t( of %" %$t&e #u'#t%"$e from % ph%rm%$eut$%!

produ$t #hou!d 'e 9"o*" %"d reprodu$'!e2 Th# # e#pe$%!!( the $%#e f o"e produ$t

$o"t%""+ o"e $ert%" %$t&e #u'#t%"$e # to 'e u#ed "#te%d of t# ""o&%tor produ$t2 I"

th%t $%#e the produ$t #hou!d #ho* the #%me ther%peut$ effe$t " the $!"$%! #tu%to"2 It #

+e"er%!!( $um'er#ome to %##e## th# '( $!"$%! #tude#2

Comp%r#o" of ther%peut$ perform%"$e# of t*o med$"%! produ$t# $o"t%""+ the #%me

%$t&e #u'#t%"$e # % $rt$%! me%"# of %##e##"+ the po##'!t( of %!ter"%t&e u#e 'et*ee"

the ""o&%tor %"d %"( e##e"t%!!( #m!%r med$"%! produ$t2 A##um"+ th%t " the #%me

#u'7e$t %" e##e"t%!!( #m!%r p!%#m% $o"$e"tr%to" tme $our#e *!! re#u!t " e##e"t%!!(

#m!%r $o"$e"tr%to"# %t the #te of %$to" %"d thu# " %" e##e"t%!!( #m!%r effe$t,

ph%rm%$o9"et$ d%t% "#te%d of ther%peut$ re#u!t# m%( 'e u#ed to e#t%'!#h e)u&%!e"$e=

'oe)u&%!e"$e2

It # the o'7e$t&e of th# +ud%"$e to def"e, for produ$t# *th % #(#tem$ effe$t, *he"

'o%&%!%'!t( or 'oe)u&%!e"$e #tude# %re "e$e##%r( %"d to formu!%te re)ureme"t# for

ther de#+", $o"du$t, %"d e&%!u%to"2 The po##'!t( of u#"+ " &tro "#te%d of " &&o

#tude# *th ph%rm%$o9"et$ e"d po"t# # %!#o e"&#%+ed2

Th# +ude!"e #hou!d 'e re%d " $o"7u"$to" *th other pert"e"t e!eme"t# out!"ed "

$urre"t %"d future ASEAN, EU %"d ICH +ude!"e# %"d re+u!%to"# e#pe$%!!( tho#e o"=

@ Ph%rm%$o9"et$ Stude# " M%"

@ Modfed Re!e%#e Or%! %"d Tr%"#derm%! Do#%+e Form#= Se$to" I

>Ph%rm%$o9"et$ %"d C!"$%! E&%!u%to"?

@ Modfed Re!e%#e Or%! %"d Tr%"#derm%! Do#%+e Form#= Se$to" II >u%!t(?

@ I"&e#t+%to" of Chr%! A$t&e Su'#t%"$e#@ F;ed Com'"%to" Med$"%! Produ$t#

@ C!"$%! Re)ureme"t# for Lo$%!!( App!ed, Lo$%!!( A$t"+ Produ$t# Co"t%""+

"o*" Co"#ttue"t#

@ The I"&e#t+%to" of Dru+ I"ter%$to"#

@ De&e!opme"t Ph%rm%$eut$#

@ ASEAN Pro$e## V%!d%to"

@ M%"uf%$ture of the F"#hed Do#%+e Form

@ ASEAN A"%!(t$%! V%!d%to"

@ Stru$ture %"d Co"te"t of C!"$%! Stud( Report# >ICH top$ E3?

@ Good C!"$%! Pr%$t$e= Co"#o!d%ted Gude!"e >ICH top$ E4?

@ Ge"er%! Co"#der%to"# for C!"$%! Tr%!# >ICH top$ E6?

Dru+ Co"tro! D&#o" p%+e 0


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@ St%t#t$%! Pr"$p!e# for C!"$%! Tr%!# >ICH top$ E8?

@ Cho$e of Co"tro! Group " C!"$%! Tr%!# >ICH top$ E!.?

@ ASEAN Commo" Te$h"$%! Do$ume"t

@ Mu!t#our$e >Ge"er$? Ph%rm%$eut$%! Produ$t#= Gude!"e# o" Re+#tr%to"

Re)ureme"t# to E#t%'!#h I"ter$h%"+e%'!t( >HO?

For med$"%! produ$t# "ot "te"ded to 'e de!&ered "to the +e"er%! $r$u!%to" the

$ommo" #(#tem$ 'o%&%!%'!t( %ppro%$h $%""ot 'e %pp!ed2 U"der the#e $o"dto"# the

>!o$%!? %&%!%'!t( m%( 'e %##e##ed, *here "e$e##%r(, '( me%#ureme"t# )u%"tt%t&e!(

ref!e$t"+ the pre#e"$e of the %$t&e #u'#t%"$e %t the #te of %$to" u#"+ method#

#pe$%!!( $ho#e" for th%t $om'"%to" of %$t&e #u'#t%"$e %"d !o$%!#%to" >#ee #e$to"

12/26?2 I" th# $%#e, %# *e!! %# " other#, %!ter"%t&e method# m%( 'e re)ured #u$h %#

#tude# u#"+ ph%rm%$od("%m$ e"d po"t#2 Furthermore, *here #pe$f$ re)ureme"t#

for dffere"t t(pe# of produ$t# %re "eeded, the %ppropr%te e;$epto"# %re me"to"ed

there"2

Th# +ude!"e# doe# "ot e;p!$t!( %pp!( to 'o!o+$%! produ$t#2

2. DEFINITIONS

Before def""+ 'o%&%!%'!t( %"d re!%ted term"o!o+( #ome def"to"# pert%""+ todo#%+e %"d $hem$%! form# %re +&e"=

2.1 P)a*+a"e,%-"a e/,-0ae$"e

Med$"%! produ$t# %re ph%rm%$eut$%!!( e)u&%!e"t f the( $o"t%" the #%me %mou"t of

the #%me %$t&e #u'#t%"$e>#? " the #%me do#%+e form# th%t meet the #%me or $omp%r%'!e#t%"d%rd#2

Ph%rm%$eut$%! e)u&%!e"$e doe# "ot "e$e##%r!( mp!( 'oe)u&%!e"$e %# dffere"$e# "the e;$pe"t# %"d


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- Bo%&%!%'!t( # u"der#tood to 'e the e;te"t %"d the r%te %t *h$h % #u'#t%"$e

or t# %$t&e moet( # de!&ered from % ph%rm%$eut$%! form %"d 'e$ome# %&%!%'!e "

the +e"er%! $r$u!%to"2

It m%( 'e u#efu! to d#t"+u#h 'et*ee" the %'#o!ute 'o%&%!%'!t( of % +&e" do#%+eform %# $omp%red *th th%t >/..? fo!!o*"+ "tr%&e"ou# %dm"#tr%to" >e2+2 or%!

#o!uto" &2?, %"d the re!%t&e 'o%&%!%'!t( %# $omp%red *th %"other form

%dm"#tered '( the #%me or %"other "o" "tr%&e"ou# route >e2+2 t%'!et# or%! #o!uto"?2

2.4 B-#e/,-0ae$"e

T*o med$"%! produ$t# %re 'oe)u&%!e"t f the( %re ph%rm%$eut$%!!( e)u&%!e"t or

ph%rm%$eut$%! %!ter"%t&e# %"d f ther 'o%&%!%'!te# %fter %dm"#tr%to" " the #%me

mo!%r do#e %re #m!%r to #u$h de+ree th%t ther effe$t#, *th re#pe$t to 'oth eff$%$( %"d

#%fet(, *!! 'e e##e"t%!!( the #%me2

A!ter"%t&e!( to $!%##$%! 'o%&%!%'!t( #tude# u#"+ ph%rm%$o9"et$ e"d po"t# to

%##e## 'oe)u&%!e"$e, other t(pe# of #tude# $%" 'e $o"du$ted, e2+2 hum%" #tude# *th

$!"$%! or ph%rm%$od("%m$ e"d po"t#, #tude# u#"+ %"m%! mode!# or " &tro #tude#

%# !o"+ %# the( %re %ppropr%te!( 7u#tfed %"dt%'!et# %"d $%p#u!e#? *th the#%me %$t&e #u'#t%"$e2

The "eed for % $omp%r%t&e 'o%&%!%'!t( #tud( to demo"#tr%te 'oe)u&%!e"$e #

de"tfed u"der 12/2 Co"$er"# %'out dffere"$e# " e##e"t%!!( #m!%r med$"%! produ$t#

!e o" the u#e of dffere"t e;$pe"t# %"d method# of m%"uf%$ture th%t u!tm%te!( m+ht

h%&e %" "f!ue"$e o" #%fet( %"d eff$%$(2 A 'oe)u&%!e"$e #tud( # the *de!( %$$epted

me%"# of demo"#tr%t"+ th%t the#e dffere"$e# h%&e "o mp%$t o" the perform%"$e of the

formu!%to" *th re#pe$t to r%te %"d e;te"t of %'#orpto", " the $%#e of mmed%te

re!e%#e do#%+e form#2 It # de#r%'!e th%t e;$pe"t# mu#t 'e de&od of %"( effe$t or ther

#%fe u#e # e"#ured '( %ppropr%te *%r""+ " the p%$9%+e !%'e! %"d "ot "terfere *th

ether the re!e%#e or the %'#orpto" pro$e##2

A" e##e"t%!!( #m!%r produ$t $%" 'e u#ed "#te%d of t# ""o&%tor produ$t2 A"

""o&%tor produ$t # % med$"%! produ$t %uthor#ed %"d m%r9eted o" the '%## of % fu!!

do##er 2e2 "$!ud"+ $hem$%!, 'o!o+$%!, ph%rm%$eut$%!, ph%rm%$o!o+$%!:

to;$o!o+$%! %"d $!"$%! d%t%2 A Refere"$e Produ$t mu#t 'e %" ""o&%tor produ$t2 >#ee

321?2



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If the ""o&%tor produ$t # "ot %&%!%'!e " the $ou"tr(, %" %!ter"%t&e $omp%r%tor produ$t

%ppro&ed '( dru+ re+u!%tor( %uthort( of the $ou"tr( $%" 'e u#ed2

2.5 T)e*ape,%-" e/,-0ae$"e

A med$"%! produ$t # ther%peut$%!!( e)u&%!e"t *th %"other produ$t f t $o"t%"# the

#%me %$t&e #u'#t%"$e or ther%peut$ moet( %"d, $!"$%!!(, #ho*# the #%me eff$%$( %"d

#%fet( %# th%t produ$t, *ho#e eff$%$( %"d #%fet( h%# 'ee" e#t%'!#hed2

I" pr%$t$e, demo"#tr%to" of 'oe)u&%!e"$e # +e"er%!!( the mo#t %ppropr%te method of

#u'#t%"t%t"+ ther%peut$ e)u&%!e"$e 'et*ee" med$"%! produ$t#, *h$h %re

ph%rm%$eut$%!!( e)u&%!e"t or ph%rm%$eut$%! %!ter"%t&e#, pro&ded the( $o"t%"

e;$pe"t# +e"er%!!( re$o+"#ed %# "ot h%&"+ %" "f!ue"$e o" #%fet( %"d eff$%$( %"d

$omp!( *th !%'e!!"+ re)ureme"t# *th re#pe$t to e;$pe"t# >#ee -21?2

Ho*e&er, " #ome $%#e# *here #m!%r e;te"t of %'#orpto" 'ut dffere"t r%te# of %'#orpto" %re o'#er&ed the produ$t# $%" #t!! 'e 7ud+ed ther%peut$%!!( e)u&%!e"t f

tho#e dffere"$e# %re "ot of ther%peut$ re!e&%"$e2 A $!"$%! #tud( to pro&e th%t

dffere"$e# " %'#orpto" r%te %re "ot ther%peut$%!!( re!e&%"t *!! pro'%'!( 'e "e$e##%r(2

3. DESIGN AND CONDUCT OF STUDIES

I" the fo!!o*"+ #e$to"#, re)ureme"t# for the de#+" %"d $o"du$t of 'o%&%!%'!t( or

'oe)u&%!e"$e #tude# %re formu!%ted2 It # %##umed th%t the %pp!$%"t # f%m!%r *th

ph%rm%$o9"et$ theore# u"der!("+ 'o%&%!%'!t( #tude#2 The de#+" #hou!d 'e '%#ed

o" % re%#o"%'!e 9"o*!ed+e of the ph%rm%$od("%m$# %"d


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3.1 De-g$

The #tud( #hou!d 'e de#+"ed " #u$h % *%( th%t the formu!%to" effe$t $%" 'e

d#t"+u#hed from other effe$t#2 If the "um'er of formu!%to"# to 'e $omp%red # t*o, %

t*o:perod, t*o #e)ue"$e $ro##o&er de#+" # ofte" $o"#dered to 'e the de#+" of $ho$e2

Ho*e&er, u"der $ert%" $r$um#t%"$e# %"d pro&ded the #tud( de#+" %"d the #t%t#t$%!%"%!(#e# %re #$e"tf$%!!( #ou"d %!ter"%t&e *e!!:e#t%'!#hed de#+"# $ou!d 'e $o"#dered#u$h %# p%r%!!e! de#+" for &er( !o"+ h%!f:!fe #u'#t%"$e# %"d rep!$%te de#+"# for #u'#t%"$e# *th h+h!( &%r%'!e d#po#to"2

I" +e"er%!, #"+!e do#e #tude# *!! #uff$e, 'ut there %re #tu%to"# " *h$h #te%d(:#t%te#tude#

@ m%( 'e re)ured, e2+2 " the $%#e of

: do#e: or tme:depe"de"t ph%rm%$o9"et$#,

: #ome modfed re!e%#e produ$t# >" %ddto" to #"+!e do#e "&e#t+%to"#?,@ or $%" 'e $o"#dered, e2+2

: f pro'!em# of #e"#t&t( pre$!ude #uff$e"t!( pre$#e p!%#m% $o"$e"tr%to"

me%#ureme"t# %fter #"+!e do#e %dm"#tr%to"2

: f the "tr%:"d&du%! &%r%'!t( " the p!%#m% $o"$e"tr%to" or d#po#to"

pre$!ude# the po##'!t( of demo"#tr%t"+ 'oe)u&%!e"$e " % re%#o"%'!(

#ed #"+!e do#e #tud( %"d th# &%r%'!t( # redu$ed %t #te%d( #t%te2

I" #u$h #te%d(:#t%te #tude# the %dm"#tr%to" #$heme #hou!d fo!!o* the u#u%! do#%+ere$omme"d%to"#2

The "um'er of #u'7e$t# re)ured # determ"ed '(%? the error &%r%"$e %##o$%ted *th the prm%r( $h%r%$ter#t$ to 'e #tuded %#

e#tm%ted from % p!ot e;perme"t, from pre&ou# #tude# or from pu'!#hed d%t%,

'? the #+"f$%"$e !e&e! de#red,$? the e;pe$ted de&%to" from the refere"$e produ$t $omp%t'!e *th 'oe)u&%!e"$e

>de!t% 2e2 per$e"t%+e dffere"$e from /.. ?%"d

d? the re)ured po*er2

The $!"$%! %"d %"%!(t$%! #t%"d%rd# mpo#ed m%( %!#o "f!ue"$e the #t%t#t$%!!(

determ"ed "um'er of #u'7e$t#2 Ho*e&er, +e"er%!!( the m"mum "um'er of #u'7e$t#

#hou!d 'e "ot #m%!!er th%" /- u"!e## 7u#tfed2

Washout period

Su'#e)ue"t tre%tme"t# #hou!d 'e #ep%r%ted '( perod# !o"+ e"ou+h to e!m"%te the

pre&ou# do#e 'efore the "e;t o"e >%de)u%te *%#h out perod#?2 I" #te%d(:#t%te #tude#

*%#h out of the pre&ou# tre%tme"t !%#t do#e $%" o&er!%p *th the 'u!d:up of the #e$o"d

tre%tme"t, pro&ded the 'u!d:up perod # #uff$e"t!( !o"+ >%t !e%#t three tme# the

term"%! h%!f:!fe?2

Sampling

The #%mp!"+ #$hedu!e #hou!d 'e p!%""ed to pro&de %" %de)u%te e#tm%to" of C m%; %"d to

$o&er the p!%#m% $o"$e"tr%to" tme $ur&e !o"+ e"ou+h to pro&de % re!%'!e e#tm%te of

the e;te"t of %'#orpto"2 Th# # +e"er%!!( %$he&ed f the AUC der&ed from me%#ureme"t#



9/27

# %t !e%#t 6. of the AUC e;tr%po!%ted to "f"t(2 If % re!%'!e e#tm%te of term"%! h%!f:

!fe # "e$e##%r(, t #hou!d 'e o't%"ed '( $o!!e$t"+ %t !e%#t three to four #%mp!e# dur"+

the term"%! !o+ !"e%r ph%#e2

I" order to #tud( 'o%&%!%'!t( u"der #te%d(:#t%te $o"dto"# *he" dffere"$e# 'et*ee"mor""+ %"d e&e""+ or "+ht!( do#"+ %re 9"o*", >e2+2 f t # 9"o*" th%t the $r$%d%"

rh(thm # 9"o*" to h%&e %" "f!ue"$e o" 'o%&%!%'!t(?, #%mp!"+ #hou!d 'e $%rred out

o&er % fu!! -0 hour# $($!e2

For dru+# *th % !o"+ h%!f:!fe, re!%t&e 'o%&%!%'!t( $%" 'e %de)u%te!( e#tm%ted u#"+

tru"$%ted AUC %# !o"+ %# the tot%! $o!!e$to" perod # 7u#tfed2 I" th# $%#e the #%mp!e

$o!!e$to" tme #hou!d 'e %de)u%te to e"#ure $omp%r#o" of the %'#orpto" pro$e##2

3.2 S,6e"%

3.2.1 See"%-#$ #7 ,6e"%

The #u'7e$t popu!%to" for 'oe)u&%!e"$e #tude# #hou!d 'e #e!e$ted *th the %m to

m"m#e &%r%'!t( %"d permt dete$to" of dffere"$e# 'et*ee" ph%rm%$eut$%! produ$t#2

Therefore, the #tude# #hou!d "orm%!!( 'e performed *th he%!th( &o!u"teer#2 The

"$!u#o"%t !e%#t /1.

mL? #hou!d 'e $o"#t%"t2 A!! me%!# %"d f!ud# t%9e" %fter the tre%tme"t #hou!d %!#o 'e



10/27

#t%"d%rd#ed " re+%rd to $ompo#to" %"d tme of %dm"#tr%to" dur"+ the #%mp!"+

perod2

Pror to %"d dur"+ e%$h #tud( ph%#e, >/? #u'7e$t# #hou!d 'e %!!o*ed *%ter %# de#red

e;$ept for o"e hour 'efore %"d %fter dru+ %dm"#tr%to", >-? hot dr"9 or 7u$e m%( 'e pro&ded %fter 3 hour# of dru+ %dm"#tr%to", >3? #t%"d%rd me%!# for e%$h #tud( perod#

$%" 'e pro&ded "o !e## th%" 0 hour# %fter dru+ %dm"#tr%to"2

O"e u"t of the h+he#t m%r9eted #tre"+th or % $!"$%! u#u%! do#e #hou!d +e"er%!!( 'e

+&e"2 A h+her do#e *h$h doe# "ot e;$eed the m%;m%! do#e of the do#%+e re+me or

!%'e!!ed do#e r%"+e m%( 'e emp!o(ed *he" %"%!(t$%! dff$u!te# e;#t2

Ho*e&er, f the %d&er#e e&e"t# %re too +re%t or too r#9(, the" the #m%!!er do#e u"t #

%!!o*ed2

The #u'7e$t# #hou!d "ot t%9e other med$"e# dur"+ % #ut%'!e perod 'efore %"d dur"+the #tud( %"d #hou!d %'#t%" from food %"d dr"9#, *h$h m%( "ter%$t *th $r$u!%tor(,

+%#tro"te#t"%!, !&er or re"%! fu"$to" >e2+2 %!$oho!$ or ;%"th"e:$o"t%""+ 'e&er%+e# or

$ert%" frut 7u$e#?2 A# the 'o%&%!%'!t( of %" %$t&e moet( from % do#%+e form $ou!d 'e

depe"de"t upo" +%#tro"te#t"%! tr%"#t tme# %"d re+o"%! '!ood f!o*#, po#ture %"d

ph(#$%! %$t&t( m%( "eed to 'e #t%"d%rd#ed2

3.2.3 I$",-#$ #7 pa%-e$%

If the "&e#t+%ted %$t&e #u'#t%"$e # 9"o*" to h%&e %d&er#e effe$t# %"d the

ph%rm%$o!o+$%! effe$t# or r#9# %re $o"#dered u"%$$ept%'!e for he%!th( &o!u"teer# t m%(

'e "e$e##%r( to u#e p%te"t# "#te%d, u"der #ut%'!e pre$%uto"# %"d #uper&#o"2 I" th#

$%#e the %pp!$%"t #hou!d 7u#tf( the %!ter"%t&e2

3.2.4. Ge$e%-" p)e$#%p-$g

Phe"ot(p"+ %"d


11/27

Boe)u&%!e"$e determ"%to"# '%#ed o" met%'o!te# #hou!d 'e 7u#tfed " e%$h $%#e

'e%r"+ " m"d th%t the %m of % 'oe)u&%!e"$e #tud( # "te"ded to $omp%re the in vivo

perform%"$e of te#t %"d refere"$e produ$t#2 I" p%rt$u!%r f met%'o!te# #+"f$%"t!(

$o"tr'ute to the "et %$t&t( of %" %$t&e #u'#t%"$e %"d the ph%rm%$o9"et$ #(#tem # "o":!"e%r, t # "e$e##%r( to me%#ure 'oth p%re"t dru+ %"d %$t&e met%'o!te p!%#m%

$o"$e"tr%to"# %"d e&%!u%te them #ep%r%te!(2

I" 'o%&%!%'!t( #tude#, the #h%pe of %"d the %re% u"der the p!%#m% $o"$e"tr%to" &er#u#

tme $ur&e# %re mo#t!( u#ed to %##e## e;te"t %"d r%te of %'#orpto"2 The u#e of ur"e

e;$reto" d%t% m%( 'e %d&%"t%+eou# " determ""+ the e;te"t of dru+ "put " $%#e of

produ$t# predom"%te!( e;$reted re"%!!(, 'ut h%# to 'e 7u#tfed *he" u#ed to e#tm%te the

r%te of %'#orpto"2 S%mp!"+ po"t# or perod# #hou!d 'e $ho#e", #u$h th%t the tme:

$o"$e"tr%to" prof!e # %de)u%te!( def"ed #o %# to %!!o* the e#tm%to" of re!e&%"t

p%r%meter#2

From the prm%r( re#u!t#, the 'o%&%!%'!t( $h%r%$ter#t$# de#red %re e#tm%ted, "%me!(

AUCt, AUC∞, Cm%;8 tm%;, Aet, Ae∞ %# %ppropr%te, or %"( other 7u#tf%'!e $h%r%$ter#t$# >$f

Appe"d; I?2 The method of e#tm%t"+ AUC:&%!ue# #hou!d 'e #pe$fed2 For %ddto"%!

"form%to" t /


12/27

re#u!t# %re= >/? #t%'!t( of the #to$9 #o!uto"# %"d of the %"%!(te>#? " the 'o!o+$%! m%tr;

u"der pro$e##"+ $o"dto"# %"d dur"+ the e"tre perod of #tor%+e >-? #pe$f$t( >3?

%$$ur%$( >0? pre$#o" >1? !mt of )u%"tf$%to" %"d >4? re#po"#e fu"$to"2

The &%!d%to" of % 'o%"%!(t$%! method #hou!d $ompr#e t*o d#t"$t ph%#e#= >/? the pre:#tud( ph%#e " *h$h the $omp!%"$e of the %##%( *th the #; $h%r%$ter#t$# !#ted %'o&e

# &erfed %"d >-? the #tud( ph%#e t#e!f " *h$h the &%!d%ted 'o%"%!(t$%! method #

%pp!ed to the %$tu%! %"%!(## of #%mp!e# from the 'o#tud( m%"!( " order to $o"frm the

#t%'!t(, %$$ur%$( %"d pre$#o"2

A $%!'r%to" $ur&e #hou!d 'e +e"er%ted for e%$h %"%!(e " e%$h %"%!(t$%! ru" %"d t

#hou!d 'e u#ed to $%!$u!%te the $o"$e"tr%to" of the %"%!(te " the u"9"o*" #%mp!e# " the

ru"2 A "um'er of #ep%r%te!( prep%red u%!t( Co"tro! #%mp!e# #hou!d 'e %"%!(#ed *th

pro$e##ed te#t #%mp!e# %t "ter&%!# '%#ed o" the tot%! "um'er of #%mp!e#2 I" %ddto", t #

"e$e##%r( to &%!d%te the method of pro$e##"+ %"d h%"d!"+ the 'o!o+$%! #%mp!e#2

A!! pro$edure# #hou!d 'e performed %$$ord"+ to pre:e#t%'!#hed St%"d%rd Oper%t"+

Pro$edure# >SOP#?2 A!! re!e&%"t pro$edure# %"d formu!%e u#ed to &%!d%te the 'o%"%!(t$%!

method #hou!d 'e #u'mtted %"d d#$u##ed2 A"( modf$%to" of the 'o%"%!(t$%! method

'efore %"d dur"+ %"%!(## of #tud( #pe$me"# m%( re)ure %de)u%te re&%!d%to" %!!

modf$%to"# #hou!d 'e reported %"d the #$ope of re&%!d%to" 7u#tfed2

A$$ord"+ to the re)ureme"t# of the "ote for +ud%"$e o" the I"&e#t+%to" of Chr%!

A$t&e Su'#t%"$e#, 'oe)u&%!e"$e #tude# #upport"+ %pp!$%to"# for e##e"t%!!( #m!%r

med$"%! produ$t# $o"t%""+ $hr%! %$t&e #u'#t%"$e# #hou!d 'e '%#ed upo" e"%"tomer$

'o:%"%!(t$%! method# u"!e## >/? 'oth produ$t# $o"t%" the #%me #t%'!e #"+!e e"%"tomer

>-? 'oth produ$t# $o"t%" the r%$em%te %"d 'oth e"%"tomer# #ho* !"e%r

ph%rm%$o9"et$#2

3. Re7e*e$"e a$ %e% p*#,"%

Te#t produ$t# " %" %pp!$%to" for % +e"er$ produ$t %re "orm%!!( $omp%red *th the

$orre#po"d"+ do#%+e form of %" ""o&%tor >#ee -21? med$"%! produ$t >refere"$e

produ$t?2 The $ho$e of refere"$e produ$t #hou!d 'e 7u#tfed '( the %pp!$%"t %"d %+reed

upo" '( the re+u!%tor( %uthort(2

If the ""o&%tor produ$t # "ot %&%!%'!e, %" %!ter"%t&e $omp%r%tor produ$t %ppro&ed '(dru+ re+u!%tor( %uthort( of the $ou"tr( $%" 'e u#ed2

The te#t produ$t# u#ed " the 'o#tud( mu#t 'e prep%red " %$$ord%"$e *th GMP:

re+u!%to"#2 B%t$h $o"tro! re#u!t# of the te#t produ$t #hou!d 'e reported2

I" the $%#e of or%! #o!d form# for #(#tem$ %$to" the te#t produ$t #hou!d u#u%!!( or+"%te

from % '%t$h of %t !e%#t /


13/27

S%mp!e# of the produ$t from fu!! produ$to" '%t$he# #hou!d 'e $omp%red *th tho#e of thete#t '%t$h, %"d #hou!d #ho* #m!%r " &tro d##o!uto" prof!e# *he" emp!o("+ #ut%'!ed##o!uto" te#t $o"dto"# >#ee Appe"d; II?2

The #tud( #po"#or *!! h%&e to ret%" % #uff$e"t "um'er of %!! "&e#t+%to"%! produ$t#%mp!e# " the #tud( for o"e (e%r " e;$e## of the %$$epted #he!f !fe or t*o (e%r# %fter $omp!eto" of the tr%! or u"t! %ppro&%! *h$he&er # !o"+er to %!!o* re:te#t"+, f t #re)ue#ted '( the %uthorte#2

Refere"$e %"d te#t produ$t mu#t 'e p%$9ed " %" "d&du%! *%( for e%$h #u'7e$t "$!uded "

the 'oe)u&%!e"$e tr%!2 E&er( effort #hou!d 'e m%de to %!!o* % pre$#e tr%$9"+ of

%dm"#tr%to" of the refere"$e %"d te#t produ$t# to the #u'7e$t#, for "#t%"$e '( the u#e of

!%'e!# *th % te%r:off porto"2

3.5 Da%a a$a-

The prm%r( $o"$er" of 'oe)u&%!e"$e %##e##me"t # to )u%"tf( the dffere"$e " 'o%&%!%'!t( 'et*ee" the refere"$e %"d te#t produ$t# %"d to demo"#tr%te th%t %"( $!"$%!!(mport%"t dffere"$e # u"!9e!(2

3.5.1 S%a%-%-"a a$a-

The #t%t#t$%! method for te#t"+ re!%t&e 'o%&%!%'!t( >e2+2 'oe)u&%!e"$e? # '%#ed upo"the 8. $o"fde"$e "ter&%! for the r%to of the popu!%to" me%"# >Te#te2+2

ANOVA? #hou!d t%9e "to %$$ou"t #our$e# of &%r%to" th%t $%" 'e re%#o"%'!( %##umed to

h%&e %" effe$t o" the re#po"#e &%r%'!e2 A #t%t#t$%!!( #+"f$%"t #e)ue"$e effe$t #hou!d 'e

h%"d!ed %ppropr%te!(2

Ph%rm%$o9"et$ p%r%meter# der&ed from me%#ure# of $o"$e"tr%to", e2+2 AUC, Cm%; #hou!d 'e %"%!(#ed u#"+ ANOVA2 The d%t% #hou!d 'e tr%"#formed pror to %"%!(## u#"+ %!o+%rthm$ tr%"#form%to"2

If %ppropr%te to the e&%!u%to" the %"%!(## te$h")ue of tm%; #hou!d 'e "o":p%r%metr$ %"d#hou!d 'e %pp!ed to u"tr%"#formed d%t%2 For %!! ph%rm%$o9"et$ p%r%meter# of "tere#t "%ddto" to the %ppropr%te 8. $o"fde"$e "ter&%!# for the $omp%r#o" of the t*oformu!%to"#, #umm%r( #t%t#t$# #u$h %# med%", m"mum %"d m%;mum #hou!d 'e +&e"2

3.5.2 A""ep%a$"e *a$ge 7#* p)a*+a"#9-$e%-" pa*a+e%e*

The ph%rm%$o9"et$ p%r%meter# to 'e te#ted, the pro$edure for te#t"+ %"d the%$$ept%"$e r%"+e# #hou!d 'e #t%ted 'eforeh%"d " the proto$o!2

I" #tude# to determ"e %&er%+e 'oe)u&%!e"$e the %$$ept%"$e "ter&%!# for the m%"$h%r%$ter#t$# %re det%!ed %# fo!!o*#=

Dru+ Co"tro! D&#o" p%+e /3


14/27

AUC-ratio

The 8. $o"fde"$e "ter&%! for th# me%#ure of re!%t&e 'o%&%!%'!t( #hou!d !e *th"

%" %$$ept%"$e "ter&%! of .26.:/2-12 I" #pe$f$ $%#e# of % "%rro* ther%peut$ r%"+e the

%$$ept%"$e "ter&%! m%( "eed to 'e t+hte"ed2

I" r%re $%#e# % *der %$$ept%"$e r%"+e m%( 'e %$$ept%'!e f t # '%#ed o" #ou"d $!"$%!

7u#tf$%to"2

C max-ratio

The 8. $o"fde"$e "ter&%! for th# me%#ure of re!%t&e 'o%&%!%'!t( #hou!d !e *th"

%" %$$ept%"$e "ter&%! of .26.:/2-12 I" #pe$f$ $%#e# of % "%rro* ther%peut$ r%"+e the

%$$ept%"$e "ter&%! m%( "eed to 'e t+hte"ed2

I" $ert%" $%#e# % *der "ter&%! m%( 'e %$$ept%'!e2 The "ter&%! mu#t 'e pro#pe$t&e!(

def"ed e2+2 .251:/233 %"d 7u#tfed %ddre##"+ " p%rt$u!%r %"( #%fet( or eff$%$(

$o"$er"# for p%te"t# #*t$hed 'et*ee" formu!%to"#2

Others

St%t#t$%! e&%!u%to" of tm%; o"!( m%9e# #e"#e f there # % $!"$%!!( re!e&%"t $!%m for

r%pd re!e%#e or %$to" or #+"# re!%ted to %d&er#e effe$t#2 The "o":p%r%metr$ 8.

$o"fde"$e "ter&%! for th# me%#ure of re!%t&e 'o%&%!%'!t( #hou!d !e *th" %

$!"$%!!( determ"ed r%"+e2

For other >#ee 323? ph%rm%$o9"et$ p%r%meter# " $omp%r#o" re!%t&e 'o%&%!%'!t(

>e2+2 Cm", F!u$tu%to", t/


15/27

The re#u!t# of " &tro d##o!uto" te#t#, o't%"ed *th the '%t$he# of te#t %"d refere"$e

produ$t# th%t *ere u#ed " the 'oe)u&%!e"$e #tud( #hou!d 'e reported2 The re#u!t#

#hou!d 'e reported %# prof!e# of per$e"t of !%'e!!ed %mou"t d##o!&ed &er#u# tme2

The #pe$f$%to"# for the in vitro d##o!uto" of the produ$t #hou!d 'e der&ed from thed##o!uto" prof!e of the '%t$h th%t *%# fou"d to 'e 'oe)u&%!e"t to the refere"$e

produ$t %"d *ou!d 'e e;pe$ted to 'e #m!%r to tho#e of the refere"$e produ$t >#ee

Appe"d; II?2

For mmed%te re!e%#e produ$t#, f the d##o!uto" prof!e of the te#t produ$t # d##m!%r

$omp%red to th%t of the refere"$e produ$t %"d the " &&o d%t% rem%" %$$ept%'!e the

d##o!uto" te#t method #hou!d 'e re:e&%!u%ted %"d optm#ed2 I" $%#e th%t "o

d#$rm"%tor( te#t method $%" 'e de&e!oped *h$h ref!e$t# " &&o 'oe)u&%!e"$e %

dffere"t d##o!uto" #pe$f$%to" for the te#t produ$t $ou!d 'e #et2

3.; Rep#*%-$g #7 *e,%

The report of % 'o%&%!%'!t( or % 'oe)u&%!e"$e #tud( #hou!d +&e the $omp!ete

do$ume"t%to" of t# proto$o!, $o"du$t %"d e&%!u%to" $omp!("+ *th GCP:ru!e# %"d

re!%ted EU %"d ICH E3 +ude!"e#2 Th# mp!e# th%t the %uthe"t$t( of the *ho!e of the

report # %tte#ted '( the #+"%ture of the pr"$p%! "&e#t+%tor2 The re#po"#'!e

"&e#t+%tor>#?, f %"(, #hou!d #+" for ther re#pe$t&e #e$to"# of the report2

N%me# %"d %ff!%to"# of the re#po"#'!e "&e#t+%tor>#?, #te of the #tud( %"d perod of t#

e;e$uto" #hou!d 'e #t%ted2 The "%me# %"d '%t$h "um'er# of the produ$t# u#ed " the #tud(

%# *e!! %# the $ompo#to">#?, f"#hed produ$t #pe$f$%to"# %"d $omp%r%t&e d##o!uto"

prof!e# #hou!d 'e pro&ded2 I" %ddto", the %pp!$%"t #hou!d #u'mt % #+"ed #t%teme"t

$o"frm"+ th%t the te#t produ$t # the #%me %# the o"e th%t # #u'mtted for m%r9et"+

%uthor#%to"2

A!! re#u!t# #hou!d 'e $!e%r!( pre#e"ted %"d #hou!d "$!ude d%t% from #u'7e$t# *ho

e&e"tu%!!( dropped:out2 Drop:out %"d *thdr%*%! of #u'7e$t# #hou!d 'e fu!!( do$ume"ted

%"d %$$ou"ted for2 The method u#ed to der&e the ph%rm%$o9"et$ p%r%meter# from the

r%* d%t% #hou!d 'e #pe$fed2 The d%t% u#ed to e#tm%te AUC #hou!d 'e reported2 If

ph%rm%$o9"et$ mode!# %re u#ed to e&%!u%te the p%r%meter# the mode! %"d $omput"+

pro$edure u#ed #hou!d 'e 7u#tfed2 De!eto" of d%t% #hou!d 'e 7u#tfed2

A!! "d&du%! #u'7e$t d%t% #hou!d 'e +&e" %"d "d&du%! p!%#m% $o"$e"tr%to"

the re#u!t# for %!! #t%"d%rd %"d )u%!t( $o"tro! #%mp!e# %# *e!!2 A repre#e"t%t&e "um'er of

$hrom%to+r%m# or other r%* d%t% #hou!d 'e "$!uded $o&er"+ the *ho!e $o"$e"tr%to"

r%"+e for %!!, #t%"d%rd %"d )u%!t( $o"tro! #%mp!e# %# *e!! %# the #pe$me"# %"%!(#ed2 The

%"%!(t$%! &%!d%to" report #hou!d 'e #u'mtted %# *e!!2

The #t%t#t$%! report #hou!d 'e #uff$e"t!( det%!ed to e"%'!e the #t%t#t$%! %"%!(## to 'e

repe%ted, e2+2 r%"dom#%to" #$heme, demo+r%ph$ d%t%, &%!ue# of ph%rm%$o9"et$

p%r%meter# for e%$h #u'7e$t, de#$rpt&e #t%t#t$# for e%$h formu!%to" %"d perod2 A



16/27

det%!ed ANOVA %"de2+2 "ot te$h"$%!!( fe%#'!e or for #%fet(

re%#o"#? the 'o%&%!%'!t( re!%t&e to % #ut%'!e or%! #o!uto" or #u#pe"#o" #hou!d 'e

determ"ed2 I" the $%#e of % prodru+ the "tr%&e"ou# refere"$e #o!uto" #hou!d prefer%'!(

'e m%de of the %$t&e moet(2

4.2 B-#e/,-0ae$"e

Dur"+ de&e!opme"t 'oe)u&%!e"$e #tude# %re "e$e##%r( %# 'rd+"+ #tude# 'et*ee" >?

p&ot%! %"d e%r!( $!"$%! tr%! formu!%to"# >? p&ot%! $!"$%! tr%! formu!%to"#,

e#pe$%!!( tho#e u#ed " the do#e f"d"+ #tude#, %"d the to:'e:m%r9eted med$"%!

produ$t >? other $omp%r#o"# depe"d"+ o" the #tu%to"2 Su$h #tude# m%( 'e

e;empted f the %'#e"$e of dffere"$e# " the " &&o perform%"$e $%" 'e 7u#tfed '(

#%t#f%$tor( " &tro d%t% >#ee 12/2/ %"d 12-?2

. APPLICATIONS FOR PRODUCTS CONTAINING APPROVED ACTIVE

SUBSTANCES

.1 B-#e/,-0ae$"e %,-e

I" &&o 'oe)u&%!e"$e #tude# %re "eeded *he" there # % r#9 th%t po##'!e dffere"$e# "

'o%&%!%'!t( m%( re#u!t " ther%peut$ "e)u&%!e"$e2

The 9"d of #tude# to 'e performed m%( &%r( *th the t(pe of produ$t, %# fo!!o*#2

.1.1. O*a -++e-a%e *eeae 7#*+


17/27

%? Ch%r%$ter#t$# re!%ted to the %$t&e #u'#t%"$e=

i - risk of therapeutic failure or adverse drug reactions:

th# r#9 depe"d# o" the re)ureme"t# of #pe$%! pre$%uto"# *th re#pe$tto pre$#o" %"d %$$ur%$( of do#"+ of the %$t&e #u'#t%"$e, e2+2 the "eed

for $rt$%! p!%#m% $o"$e"tr%to"#

ii - risk of bioinequivalence:

e&de"$e of 'o%&%!%'!t( pro'!em# or 'o"e)u&%!e"$e e;#t# for #ome#pe$f$ %$t&e #u'#t%"$e#

i ii - solubilit:

he" the %$t&e #u'#t%"$e # h+h!( *%ter #o!u'!e, the produ$t $ou!d 'e "+e"er%! e;empted from 'oe)u&%!e"$e #tude# u"!e##, $o"#der"+ theother $h%r%$ter#t$#, the e;empto" $ou!d e"t%! % pote"t%! r#92Po!(morph#m %"d p%rt$!e #e %re m%7or determ"%"t# of d##o!uto" r%te%"d #pe$%! %tte"to" #hou!d 'e p%d to the#e $h%r%$ter#t$#2 A" %$t&e#u'#t%"$e # $o"#dered h+h!( *%ter #o!u'!e f the %mou"t $o"t%"ed "the h+he#t do#e #tre"+th of %" mmed%te re!e%#e produ$t # d##o!&ed "-1. m! of e%$h of three 'uffer# *th" the r%"+e of pH /:6 %t 35JC>prefer%'!( %t or %'out pH /2., 024, 426?

iv - pharmacokinetic properties:

!"e%r %"d $omp!ete %'#orpto" "d$%t"+ h+h perme%'!t( redu$e# the po##'!t( of %" mmed%te re!e%#e do#%+e form "f!ue"$"+ the

'o%&%!%'!t(2

'? Ch%r%$ter#t$# re!%ted to the med$"%! produ$t=

i - rapid dissolution

" $%#e of e;empto" from 'oe)u&%!e"$e #tude#, " &tro d%t% #hou!d

demo"#tr%te the #m!%rt( of d##o!uto" prof!e 'et*ee" the te#t produ$t

%"d the refere"$e produ$t " e%$h of three 'uffer# *th" the r%"+e of pH

/:6 %t 35JC >prefer%'!( %t or %'out pH /2., 024, 426?2 Ho*e&er, " $%#e#

*here more th%" 61 of the %$t&e #u'#t%"$e# %re d##o!&ed *th" /1

m"ute#, the #m!%rt( of d##o!uto" prof!e# m%( 'e %$$epted %#

demo"#tr%ted >#ee %ppe"d; II?

ii- excipients

the e;$pe"t# "$!uded " the $ompo#to" of the med$"%! produ$t %re

*e!! e#t%'!#hed %"d "o "ter%$to" *th the ph%rm%$o9"et$# of the %$t&e

#u'#t%"$e # e;pe$ted2 I" $%#e of %t(p$%!!( !%r+e %mou"t# of 9"o*"

e;$pe"t# or "e* e;$pe"t# 'e"+ u#ed, %ddto"%! do$ume"t%to" h%# to

'e #u'mtted



18/27

iii - manufacture

the method of m%"uf%$ture of the f"#hed produ$t " re!%to" *th $rt$%!

ph(#$o$hem$%! properte# of the %$t&e #u'#t%"$e >e2+2 p%rt$!e #e,

po!(morph#m? #hou!d 'e %de)u%te!( %ddre##ed %"d do$ume"ted " the

de&e!opme"t ph%rm%$eut$# #e$to" of the do##er2

.1.2 O*a #,%-#$

If the produ$t # %" %)ueou# or%! #o!uto" %t tme of %dm"#tr%to" %"d $o"t%"# %" %$t&e

#u'#t%"$e " the #%me $o"$e"tr%to" %# %" or%! #o!uto" $urre"t!( %ppro&ed %# % med$"%!

produ$t, "o 'oe)u&%!e"$e #tud( # re)ured, pro&ded the e;$pe"t# $o"t%"ed " t do

"ot %ffe$t +%#tro"te#t"%! tr%"#t, %'#orpto" or " &&o #t%'!t( of the %$t&e #u'#t%"$e2

I" tho#e $%#e# *here %" or%! #o!uto" h%# to 'e te#ted %+%"#t %" or%! mmed%te re!e%#eformu!%to" % $omp%r%t&e 'o%&%!%'!t( #tud( *!! 'e re)ured u"!e## %" e;empto" $%"

'e 7u#tfed >#ee 12/2/?2

.1.3 N#$=#*a -++e-a%e *eeae 7#*+ e "#+-$a%-#$ p*#,"%

Com'"%to" produ$t# #hou!d " +e"er%! 'e %##e##ed *th re#pe$t to 'o%&%!%'!t( %"d

'oe)u&%!e"$e of "d&du%! %$t&e #u'#t%"$e# ether #ep%r%te!( >" the $%#e of % "e*

$om'"%to"? or %# %" e;#t"+ $om'"%to"2 Crter% u"der 12/2/ *!! %pp!( to "d&du%!

$ompo"e"t#2 The #tud( " $%#e of % "e* $om'"%to" #hou!d 'e de#+"ed " #u$h % *%(

th%t the po##'!t( of % ph%rm%$o9"et$ dru+:dru+ "ter%$to" $ou!d 'e dete$ted2

.1.5 Pa*e$%e*a #,%-#$

The %pp!$%"t # "ot re)ured to #u'mt % 'oe)u&%!e"$e #tud( f the produ$t # to 'e

%dm"#tr%to" %# %" %)ueou# "tr%&e"ou# #o!uto" $o"t%""+ the #%me %$t&e #u'#t%"$e" the #%me $o"$e"tr%to" %# the $urre"t!( %uthor#ed produ$t2

I" the $%#e of other p%re"ter%! route#, e2+2 "tr%mu#$u!%r or #u'$ut%"eou#, f the produ$t

# of the #%me t(pe of #o!uto" >%)ueou# or o!(?, $o"t%"# the #%me $o"$e"tr%to" of the

#%me %$t&e #u'#t%"$e %"d the #%me or $omp%r%'!e e;$pe"t# %# the med$"%! produ$t

$urre"t!( %ppro&ed, the" 'oe)u&%!e"$e te#t"+ # "ot re)ured2

.1.: Gae

If the produ$t # % +%# for "h%!%to" % 'oe)u&%!e"$e #tud( # "ot re)ured2



19/27

.1.; L#"a app-e p*#,"%

%? Lo$%!!( %$t"+

For produ$t# for !o$%! u#e >%fter or%!, "%#%!, "h%!%to", o$u!%r, derm%!, re$t%!, &%+"%! et$2%dm"#tr%to"? "te"ded to %$t *thout #(#tem$ %'#orpto" the %ppro%$h to determ"e

'oe)u&%!e"$e '%#ed o" #(#tem$ me%#ureme"t# # "ot %pp!$%'!e %"d ph%rm%$od("%m$

or $omp%r%t&e $!"$%! #tude# %re " pr"$p!e re)ured2 The !%$9 of them #hou!d 'e

7u#tfed >#ee #pe$f$ Note for Gud%"$e?2

he"e&er #(#tem$ e;po#ure re#u!t"+ from !o$%!!( %pp!ed, !o$%!!( %$t"+ med$"%!

produ$t# e"t%!# % r#9 of #(#tem$ %d&er#e re%$to"#, #(#tem$ e;po#ure #hou!d 'e

me%#ured2

'? S(#tem$%!!( %$t"+

For !o$%!!( %pp!ed produ$t# *th #(#tem$ %$to" % 'oe)u&%!e"$e #tud( # %!*%(#

re)ured2

.2 I$ 0-%*# -#,%-#$

D##o!uto" #tude# %re %!*%(# "e$e##%r( %"d $o"#e)ue"t!( re)ured2 2 I" &tro d##o!uto"te#t"+ form# % p%rt of the %##e##me"t of % 'oe)u&%!e"$e *%&er re)ue#t '%#ed o" $rter%%# de#$r'ed " #e$to" 12/2 D##o!uto" #tude# mu#t fo!!o* the +ud%"$e %# !%d out "Appe"d; II2

.3 Va*-a%-#$

If % produ$t h%# 'ee" reformu!%ted from the formu!%to" "t%!!( %ppro&ed or the

m%"uf%$tur"+ method h%# 'ee" modfed '( the m%"uf%$turer " *%(# th%t $ou!d 'e

$o"#dered to mp%$t o" the 'o%&%!%'!t(, % 'oe)u&%!e"$e #tud( # re)ured, u"!e##

other*#e 7u#tfed2 A"( 7u#tf$%to" pre#e"ted #hou!d 'e '%#ed upo" +e"er%!

$o"#der%to"#, e2+2 %# per 12/2/, or o" *hether %" %$$ept%'!e " &&o


20/27

he" &%r%to"# to %" e##e"t%!!( #m!%r produ$t %re m%de the refere"$e produ$t for the 'oe)u&%!e"$e #tud( #hou!d 'e the ""o&%tor produ$t2

.4 D#e p*#p#*%-#$a-% -$ -++e-a%e *eeae #*a #age 7#*+

If % "e* %pp!$%to" $o"$er"# #e&er%! #tre"+th# of the %$t&e #u'#t%"$e % 'oe)u&%!e"$e

#tud( "&e#t+%t"+ o"!( o"e #tre"+th m%( 'e %$$ept%'!e2 Ho*e&er the $ho$e of the

#tre"+th u#ed #hou!d 'e 7u#tfed o" %"%!(t$%!, ph%rm%$o9"et$ %"d #%fet( +rou"d#2

Furthermore %!! of the fo!!o*"+ $o"dto"# #hou!d 'e fu!f!!ed=

the ph%rm%$eut$%! produ$t# %re m%"uf%$tured '( the #%me m%"uf%$turer %"d pro$e##

the dru+ "put h%# 'ee" #ho*" to 'e !"e%r o&er the ther%peut$ do#e r%"+e >f th# # "ot

the $%#e the #tre"+th# *here the #e"#t&t( # !%r+e#t to de"tf( dffere"$e# " the t*o

produ$t# #hou!d 'e u#ed?

the )u%!t%t&e $ompo#to" of the dffere"t #tre"+th# # the #%me e;$ept " the $%#e

of f!%&our#!e## th%"

1?, the r%to 'et*ee" the %mou"t# of e;$pe"t# # #m!%r

the d##o!uto" prof!e #hou!d 'e #m!%r u"der de"t$%! $o"dto"# for the %ddto"%!

#tre"+th# %"d the #tre"+th of the '%t$h u#ed " the 'oe)u&%!e"$e #tud(2

If % "e* #tre"+th >*th" the %ppro&ed do#e r%"+e? # %pp!ed for o" the '%## of %" %!re%d(%ppro&ed med$"%! produ$t %"d %!! of the #t%ted $o"dto"# ho!d the" % 'oe)u&%!e"$e#tud( # "ot "e$e##%r(2

. S,p*a-#a0a-a--%

If #upr%'o%&%!%'!t( # fou"d, 2e2 f the "e* produ$t d#p!%(# %" e;te"t of %'#orpto"

%ppre$%'!( !%r+er th%" the %ppro&ed produ$t, reformu!%to" to % !o*er do#%+e #tre"+th

#hou!d 'e $o"#dered2 I" th# $%#e, the 'oph%rm%$eut$%! de&e!opme"t #hou!d 'e reported

%"d % f"%! $omp%r%t&e 'o%&%!%'!t( #tud( of the reformu!%ted "e* produ$t *th the o!d

%ppro&ed produ$t #hou!d 'e #u'mtted2

I" $%#e reformu!%to" # "ot $%rred out the do#%+e re$omme"d%to"# for the

#upr%'o%&%!%'!e produ$t *!! h%&e to 'e #upported '( $!"$%! #tude#2 Su$h %

ph%rm%$eut$%! produ$t #hou!d "ot 'e %$$epted %# ther%peut$%!!( e)u&%!e"t to the e;#t"+

refere"$e produ$t2 If m%r9et"+ %uthor#%to" # o't%"ed, the "e* produ$t m%( 'e

$o"#dered %# % "e* med$"%! produ$t2

To %&od $o"fu#o" for 'oth pre#$r'er# %"d p%te"t#, t # re$omme"ded th%t the "%me of

#upr%'o%&%!%'!e produ$t pre$!ude# $o"fu#o" *th the o!der %ppro&ed produ$t

Supr%'o%&%!%'!e produ$t# $%""ot $!%m e##e"t%! #m!%rt( >#ee #e$to" -21? *th the

""o&%tor


21/27

APPENDI' I

E>pa$a%-#$ #7 %)e +# -$ pa*ag*ap) 3.3

Cm%;= m%;m%! p!%#m% $o"$e"tr%to"

Cm"= m"m%! p!%#m% $o"$e"tr%to"

C%&= %&er%+e p!%#m% $o"$e"tr%to"

tm%;= tme p%##ed #"$e %dm"#tr%to" %t *h$h the p!%#m% $o"$e"tr%to"

m%;mum o$$ur#

AUCt= %re% u"der the p!%#m% $o"$e"tr%to" $ur&e from %dm"#tr%to" to !%#t

o'#er&ed $o"$e"tr%to" %t tme t

AUC∞= %re% u"der the p!%#m% $o"$e"tr%to" $ur&e e;tr%po!%ted to "f"te tme

AUCτ= AUC dur"+ % do#%+e "ter&%! " #te%d( #t%te

MRT= me%" re#de"$e tme

Aet= $umu!%t&e ur"%r( e;$reto" from %dm"#tr%to" u"t! tme t

Ae∞= $umu!%t&e ur"%r( e;$reto" e;tr%po!%ted to "f"te tme

t/Cm%; K Cm"?


22/27

APPENDI' II

D-#,%-#$ %e%-$g

A med$"%! produ$t # $ompo#ed of dru+ #u'#t%"$e %"d e;$pe"t# %"d the proporto" 'et*ee" them, the t(pe of e;$pe"t# %"d the m%"uf%$tur"+ method of the f"%! produ$t

%re $ho#e" '%#ed o" the $o"te"t, the ph(#$o$hem$%! %"d the 'u!9 properte# of the dru+

%"d o" t# %'#orpto" properte#2 T%9e" %# % *ho!e th# +&e# e%$h produ$t $ert%"

d##o!uto" $h%r%$ter#t$#2

Dur"+ the de&e!opme"t of % med$"%! produ$t % d##o!uto" te#t # u#ed %# % too! to

de"tf( formu!%to" f%$tor# th%t %re "f!ue"$"+ %"d m%( h%&e % $ru$%! effe$t o" the

'o%&%!%'!t( of the dru+2 A# #oo" %# the $ompo#to" %"d the m%"uf%$tur"+ pro$e## %re

def"ed % d##o!uto" te#t # u#ed " the )u%!t( $o"tro! of #$%!e:up %"d of produ$to"

'%t$he# to e"#ure 'oth '%t$h to:'%t$h $o"##te"$( %"d th%t the d##o!uto" prof!e# rem%"

#m!%r to tho#e of p&ot%! $!"$%! tr%! '%t$he#2 Furthermore, % d##o!uto" te#t $%" 'e u#edto #upport the 'o%&%!%'!t( of % "e* dru+ produ$t, the 'oe)u&%!e"$e of %" e##e"t%!!(

#m!%r produ$t or &%r%to"#2

Therefore, d##o!uto" #tude# $%" #er&e #e&er%! purpo#e#=

i- !ualit assurance

To +et "form%to" o" the te#t '%t$he# u#ed " 'o%&%!%'!t(&%r%to"# %"d "e*, e##e"t%!!( #m!%r produ$t# "$!uded? %"d the refere"$e med$"%!

produ$t

To $o!!e$t "form%to" o" '%t$h to '%t$h $o"##te"$( of the produ$t# >te#t %"d

refere"$e? to 'e u#ed %# '%## for the #e!e$to" of %ppropr%te '%t$he# for the " &&o

#tud(

The te#t methodo!o+( #hou!d 'e " %$$ord%"$e *th ph%rm%$opoe%! re)ureme"t# u"!e##

tho#e re)ureme"t# %re #ho*" to 'e u"#%t#f%$tor(2 A!ter"%t&e method# $%" 'e $o"#dered

*he" 7u#tfed th%t the#e %re d#$rm"%tor( %"d %'!e to dffere"t%te 'et*ee" '%t$he# *th

%$$ept%'!e %"d "o":%$$ept%'!e perform%"$e of the produ$t " &&o2

Dru+ Co"tro! D&#o" p%+e --


23/27

If %" %$t&e #u'#t%"$e # $o"#dered h+h!( #o!u'!e, t # re%#o"%'!e to e;pe$t th%t t *!! "ot

$%u#e %"( 'o%&%!%'!t( pro'!em# f, " %ddto", the do#%+e #(#tem # r%pd!( d##o!&ed "

the ph(#o!o+$%! pH:"ter&%! e;pe$ted %fter produ$t %dm"#tr%to"2 A 'oe)u&%!e"$e

#tud( m%( " tho#e #tu%to"# 'e *%&ed '%#ed o" $%#e h#tor( %"d #m!%rt( of d##o!uto"

prof!e# *h$h %re '%#ed o" d#$rm"%tor( te#t"+, pro&ded th%t the other e;empto"$rter% " 12/2/ %re met2 The #m!%rt( #hou!d 'e 7u#tfed '( d##o!uto" prof!e#, $o&er"+

%t !e%#t three tme po"t#, %tt%"ed %t three dffere"t 'uffer# >"orm%!!( pH r%"+e /:426 "

$%#e# *here t # $o"#dered "e$e##%r( pH r%"+e /:6?2

I" the $%#e of % dru+ or e;$pe"t# th%t %re "#e"#t&e to pH, prof!e# from o"!( t*o 'uffer #(#tem# %re re)ured2

If %" %$t&e #u'#t%"$e # $o"#dered to h%&e % !o* #o!u'!t( %"d % h+h perme%'!t(, the

r%te !mt"+ #tep for %'#orpto" m%( 'e do#%+e form d##o!uto"2 Th# # %!#o the $%#e

*he" o"e or more of the e;$pe"t# %re $o"tro!!"+ the re!e%#e %"d #u'#e)ue"t d##o!uto"

#tep of the %$t&e #u'#t%"$e2

I" tho#e $%#e# % &%ret( of te#t $o"dto"# # re$omme"ded %"d %de)u%te #%mp!"+ #hou!d

'e performed u"t! ether 8. of the dru+ # d##o!&ed or %" %#(mptote # re%$hed2

"o*!ed+e of d##o!uto" properte# u"der dffere"t $o"dto"# e2+2 pH, %+t%to", o"$

#tre"+th, #urf%$t%"t#, &#$o#t(, o#mot$ pre##ure # mport%"t #"$e the 'eh%&our of the

#o!d #(#tem " &&o m%( 'e $rt$%! for the dru+ d##o!uto" "depe"de"t of the ph(#$o:

$hem$%! properte# of the %$t&e #u'#t%"$e2 A" %ppropr%te e;perme"t%! #t%t#t$%! de#+"

m%( 'e u#ed to "&e#t+%te the $rt$%! p%r%meter# %"d for the optm#%to" of #u$h

$o"dto"#2

A"( method# to pro&e #m!%rt( of d##o!uto" prof!e# %re %$$epted %# !o"+ %# the( %re 7u#tfed2

The #m!%rt( m%( 'e $omp%red '( mode!:"depe"de"t or mode!:depe"de"t method# e2+2

'( !"e%r re+re##o" of the per$e"t%+e d##o!&ed %t #pe$fed tme po"t#, '( #t%t#t$%!

$omp%r#o" of the p%r%meter# of the e'u!! fu"$to" or '( $%!$u!%t"+ % #m!%rt( f%$tor

e2+2 the o"e def"ed 'e!o*=

ƒ- 1. • !o+

I" th# e)u%to" f # # the #m!%rt( f%$tor, " # the "um'er of tme po"t#, R>t? # the me%"

per$e"t dru+ d##o!&ed of e2+2 % refere"$e produ$t, %"d T>t? # the me%" per$e"t dru+

d##o!&ed of e2+2 % te#t produ$t2

The e&%!u%to" of #m!%rt( # '%#ed o" the $o"dto"# of

A m"mum of three tme po"t# >ero e;$!uded?

Dru+ Co"tro! D&#o" p%+e -3N/

/..


24/27

/- "d&du%! &%!ue# for e&er( tme po"t for e%$h formu!%to"

"ot more th%" o"e me%" &%!ue of 61 d##o!&ed for e%$h formu!%to"

th%t the #t%"d%rd de&%to" of the me%" of %"( produ$t #hou!d 'e !e## th%" /. from#e$o"d to !%#t tme po"t2

A" f - &%!ue 'et*ee" 1. %"d /.. #u++e#t# th%t the t*o d##o!uto" prof!e# %re #m!%r2 I"

$%#e# *here more th%" 61 of the dru+ %re d##o!&ed *th" /1 m"ute#, d##o!uto"

prof!e# m%( 'e %$$epted %# #m!%r *thout further m%them%t$%! e&%!u%to"2

Dru+ Co"tro! D&#o" p%+e -0


25/27

SUPPLE(ENT I

S,gge%e C-$-"a La#*a%#* Te% 7#* B-#e/,-0ae$"e S%,

Re"%! Fu"$to" Te#t

L&er Fu"$to" Te#t

B!ood G!u$o#e

Comp!ete B!ood Cou"t

Sero!o+( > HIV, Hep B ? = Opto"%!

Pre+"%"$( Te#t = If "e$e##%r(

/-: Le%d E!e$tro$%rdo+r%m

Dru+ Co"tro! D&#o" p%+e -1


26/27

SUPPLE(ENT I

B-#e/,-0ae$"e S%, Rep#*%-$g F#*+a%

Stud( ttt!e

N%me of #po"#or

N%me %"d %ddre## of $!"$%! !%'or%tor(

N%me %"d %ddre## of %"%!(t$%! !%'or%tor(

D%te# of $!"$%! #tud( >#t%rt, $omp!eto"?

S+"%ture P%+e N%me of Pr"$p%! %"d C!"$%! I"&e#t+%tor>#?S+"%ture %"d d%te

L#t of other #tud( per#o""e!

Stud( Proto$o!I"trodu$to"

Stud( O'7e$t&eStud( tre%tme"t#

Stud( method#Refere"$e %"d Te#t Produ$t I"form%to"

N%me, B%t$h Num'er, B%t$h #e >te#t produ$t?, formu!%to", %$t&e "+rede"t, %mou"t of%$t&e "+rede"t %"d e;pr( d%te, f"#hed produ$t #pe$f$%to"#, $omp%r%t&e d##o!uto" prof!e#

C!"$%! %"d S%fet( Re$ord#

A##%( Methodo!o+( %"d V%!d%to"A##%( method de#$rpto"V%!d%to" pro$edure %"d re#u!t#

Ph%rm%$o9"et$ P%r%meter# %"d Te#t#

Def"to" %"d $%!$u!%to"#F+ure# %"d T%'!e#

St%t#t$%! A"%!(#e#

Re#u!t# %"d d#$u##o"

Co"$!u#o"#

Appe"d$e#Stud( Proto$o!Letter of Appro&%! of I"#ttuto"%! Re&e* Bo%rd


27/27

thailand babe guideline

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