Bioequivalence Guidance Summary

PHC331H1

Bioequivalence Guidance Summary

Enter Drug Name Here Regulatory Body Study Design Drug Characteristics

FDA Single Dose 3odi*ied .elease Cri&ical 'ose 'ru( )on( Hal*#li*e 'ru( Hi(+ly ,aria-le 'ru( .a/id 0nse& 'ru( 1on#)inear 2ine&ics

Click here to check the FDA Guidance for Industry: Individual Product Bioequivalence Recommendations

Standards for Bioequivalence

Unless otherwise indicated by a specific guidance, this guidance recommends that the traditional BE limit of 80 to 125 percent for non-narrow therapeutic range drugs remain unchanged for the bioa ailability measures !"U# and #ma$% of narrow therapeutic range drugs& !1% '(0)#* of ln-#ma$, ln-"U#t, ln-"U#inf within 80&00-125&00)& "dditional +, +arameters- "U#0-t, "U#0-., #ma$, /ma$, 01 , and t1223 !1%

Sampling Scheme Criteria

4e recommend that blood samples be drawn at appropriate times to describe the absorption, distribution, and elimination phases of the drug& 5or most drugs, we recommend that 12 to 18 samples, including a predose sample, be collected per sub6ect per dose& /his sampling can continue for at least three or more terminal half li es of the drug& /he e$act timing for sample collection depends on the nature of the drug and the input from the administered dosage form& /he sample collection can be spaced in such a way that the ma$imum concentration of the drug in the blood !#ma$% and terminal elimination rate constant !01% can be estimated accurately& "t least three to four samples can be obtained during the terminal log-linear phase to obtain an accurate estimate of 01 from linear regression& !1% "n ade7uate washout period !e&g&, more than 5 half li es of the moieties to be measured% would separate each treatment& !1%

Fasting and or Fed Required!

we recommend a BE study under fed conditions for all orally administered immediate-release drug products, with the following e$ceptions8 4hen both test product and 9:; are rapidly dissol ing, ha e similar dissolution profiles, and contain a drug substance with high solubility and high permeability !B#< #lass *% !see footnote =%, or 8 4hen the ;><"?E "@; ";A*@*</9"/*>@ section of the 9:; label states that the product should be taBen only on an empty stomach, or 8 4hen the 9:; label does not maBe any statements about the effect of food on absorption or administration& !2% *n "@;"s, BE of the test to the 9:; is demonstrated in a single dose crosso er study& Both treatments should be sprinBled on one of the soft foods mentioned in the labeling, usually applesauce& /he BE data should be analy1ed using a erage BE and the (0 percent #* criteria should be used to declare BE& *f there are 7uestions about other foods, the design, or the analysis of such BE studies, the sponsors and2or applicants should contact the >ffice of ?eneric ;rugs&!2%

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Bioequivalence Guidance Summary

PHC331H1

"arent and or #eta$olite Required!

5or BE studies, measurement of only the parent drug released from the dosage form, rather than the metabolite, is generally recommended& /he rationale for this recommendation is that concentration-time profile of the parent drug is more sensiti e to changes in formulation performance than a metabolite, which is more reflecti e of metabolite formation, distribution, and elimination& /he following are e$ceptions to this general approach& 8 Aeasurement of a metabolite may be preferred when parent drug le els are too low to allow reliable analytical measurement in blood, plasma, or serum for an ade7uate length of time& 4e recommend that the metabolite data obtained from these studies be sub6ect to a confidence inter al approach for BE demonstration& *f there is a clinical concern related to efficacy or safety for the parent drug, we also recommend that sponsors and2or applicants contact the appropriate re iew di ision to determine whether the parent drug should be measured and analy1ed statistically& 8 " metabolite may be formed as a result of gut wall or other presystemic metabolism& *f the metabolite contributes meaningfully to safety and2or efficacy, we also recommend that the metabolite and the parent drug be measured& 4hen the relati e acti ity of the metabolite is low and does not contribute meaningfully to safety and2or efficacy, it does not ha e to be measured& 4e recommend that the parent drug measured in these BE studies be analy1ed using a confidence inter al approach& /he metabolite data can be used to pro ide supporti e e idence of comparable therapeutic outcome& !1%

Blinding and Data %nalysis

<ub6ects with predose plasma concentrations8 *f the predose concentration is C 5 percent of #ma$ alue in that sub6ect, the sub6ectDs data without any ad6ustments can be included in all pharmacoBinetic measurements and calculations& 4e recommend that if the predose alue is E than 5 percent of #ma$, the sub6ect be dropped from all BE study e aluations& ;ata deletion due to omiting8 4e recommend that data from sub6ects who e$perience emesis during the course of a BE study for immediate-release products be deleted from statistical analysis if omiting occurs at or before 2 times median /ma$& *n the case of modified-release products, the data from sub6ects who e$perience emesis any time during the labeled dosing inter al can be deleted& !1%

Reference "roduct
5or "@;"s, we also recommend that the BE study be conducted between the test product and reference listed drug using the strength!s% specified in "ppro ed ;rug +roducts with /herapeutic E7ui alence E aluations !>range BooB%& !1%

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Bioequivalence Guidance Summary

PHC331H1

Com$ining Studies

REFERENCES
!1% ?uidance for *ndustry- Bioa ailability and Bioe7ui alence <tudies for >rally "dministered ;rug +roducts F ?eneral #onsiderations& U&<& ;epartment of Gealth and Guman <er ices, 5ood and ;rug "dministration, #enter for ;rug E aluation and 9esearch !#;E9%H Aarch 200=& B+ 9e ision 1& !2% ?uidance for *ndustry- 5ood-Effect Bioa ailability and 5ed Bioe7ui alence <tudies& U&<& ;epartment of Gealth and Guman <er ices& 5ood and ;rug "dministration& #enter for ;rug E aluation and 9esearch !#;E9%H ;ecember 2002& B+&

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Bioequivalence Guidance Summary

PHC331H1

218338579.xls

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Bioequivalence Guidance Summary

PHC331H1

218338579.xls

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Bioequivalence Guidance Summary

PHC331H1

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B4!B5 Guidelines Summary

Re"ulatory Body

FDA

TPD

! A

6nless o&+er7ise indica&ed -y a s/eci*ic (uidance8 &+is (uidance recommends &+a& &+e &radi&ional B5 limi& o* 8 &o 125 /ercen& *or non#narro7 &+era/eu&ic ran(e dru(s remain unc+an(ed *or &+e -ioavaila-ili&y measures 946C and Cmax: o* narro7 &+era/eu&ic ran(e dru(s. 91: ;9 <C= o* ln$Cma%& ln$A'Ct& ln$A'Cinf 7i&+in ()*))$+,-*)).* 4ddi&ional P2 Parame&ers$ 46C #&8 46C #>8 Cmax8 ?max8 @A 8 and &1!2B 91:

#tandards for B : #in"le Dose #tudies

Cor dru(s 7i&+ uncom/lica&ed c+arac&eris&ics8 &+e *ollo7in( s&andards#o-&ained in sin(le dose cross#over com/ara&ive -ioavaila-ili&y s&udies#de&ermine -ioequivalence$ a: ?+e 9 < con*idence in&erval o* &+e rela&ive mean 46C? o* &+e &es& &o re*erence /roduc& s+ould -e 7i&+in 8 /ercen& &o 125 /ercen&. -: ?+e rela&ive mean measured Cmax o* &+e &es& &o re*erence /roduc& s+ould -e -e&7een 8 /ercen& and 125 /ercen&. ?+ese s&andards mus& -e me& on lo( &rans*ormed /arame&ers calcula&ed *rom D &+e measured da&a8 and D da&a correc&ed *or measured dru( con&en& 9/ercen& /o&ency o* la-el claim: 4ddi&ional P2 Parame&ers &o re/or&$ 46C?8 46C=8 46C?8 46C?!46C=8 Cmax8 ?max8 lam-da. 91:

46C#ra&io$ ?+e 9 < C= *or &+is measure o* rela&ive B4 s+ould lie 7i&+in an acce/&ance in&erval o* .8 #1.25. =n s/eci*ic cases o* a narro7 &+era/eu&ic ran(e &+e acce/&ance in&erval may -e &i(+&ened. =n rare cases a 7ider acce/&ance ran(e may -e acce/&a-le i* i& is -ased on sound clinical Eus&i*ica&ion. Cmax#ra&io$ ?+e 9 < C= *or &+is measure o* rela&ive B4 s+ould lie 7i&+in an acce/&ance in&erval o* .8 #1.25. ?+e da&a s+ould -e &rans*ormed /rior &o analysis usin( a lo(ari&+mic &rans*orma&ion. 91: P2 Parame&ers$ 46C&8 46Cin*8 Cmax8 &max8 45&8 45in*. Cor addi&ional in*orma&ion &1!2 and 3.? can -e es&ima&ed. 91: =* a//ro/ria&e &o &+e evalua&ion &+e analysis &ec+nique *or &max s+ould -e non# /arame&ric and s+ould -e a//lied &o un&rans*ormed da&a. 91: Cor es&a-lis+in( -ioequivalence8 &+e 9 < con*idence in&erval s+ould lie 7i&+in &+e acce/&ance in&erval 9in mos& cases8 .8 F 1.25:8 &+e -orders -ein( included. ?+e conclusion &+a& /roduc&s are -ioequivalen& is -ased on &+e overall scien&i*ic assessmen& o* &+e P2 s&udies8 no& only on mee&in( &+e acce/&ance ran(e. 93:

Cor s&eady#s&a&e s&udies8 7e recommend &+a& &+e measuremen& o* &o&al ex/osure -e &+e area under &+e /lasma8 serum8 or -lood concen&ra&ion#&ime curve *rom &ime Aero &o &ime &au over a dosin( in&erval a& s&eady s&a&e 946C # &au:8 7+ere &au is &+e len(&+ o* &+e dosin( in&erval. 91: P2 Parame&ers$ Cmin 9concen&ra&ion a& &+e end o* a dosin( in&erval:8 Cav 9avera(e concen&ra&ion durin( a dosin( in&erval:8 de(ree o* *luc&ua&ion ;9Cmax# Cmin:!CavB8 and s7in( ;9Cmax#Cmin:!CminB 91:

?+e 9 < con*idence in&erval o* &+e rela&ive mean 46C&au o* &+e &es& &o re*erence *ormula&ion s+ould -e 7i&+in 8 < &o 125<. ?+e rela&ive mean measured Cmax a& s&eady s&a&e o* &+e &es& &o re*erence *ormula&ion s+ould -e 7i&+in 8 < &o 125<. ?+e rela&ive mean measured Cmin a& s&eady s&a&e o* &+e &es& &o re*erence *ormula&ion s+ould no& -e less &+an 8 <. ;me& on -o&+ /o&ency uncorrec&ed and correc&ed da&aB P2 Parame&ers$ 46C&au8 Cmax8 ?max8 C/d8 Cmin8 *luc&ua&ion.

H+enever mul&i/le dose s&udies are /er*ormed i& s+ould -e demons&ra&ed &+a& s&eady s&a&e +as -een reac+ed. 92: P2 Parame&ers$ 46C&au8 Cmax8 Cmin8 *luc&ua&ion.

#tandards for B : #teady #tate #tudies

Cor s&eady#s&a&e s&udies o* dru(s 7i&+ uncom/lica&ed c+arac&eris&ics8 a& leas& &+ree consecu&ive /re#dose concen&ra&ion levels 9C/d: are required &o /rovide evidence o* s&eady s&a&e. Generally8 o-serva&ions o* C/d *or &+e &es& and re*erence /roduc&s s+ould -e recorded a& &+e same &ime o* &+e day. 0ne o* &+ese measuremen&s could -e &aGen -ased on &+e *irs& sam/le o* &+e s&udy day in 7+ic+ a /ro*ile over &+e dosin( in&erval is -ein( es&a-lis+ed. S&eady s&a&e is usually ac+ieved 7+en re/ea&ed doses o* a *ormula&ion are adminis&ered over a /eriod &+a& exceeds *ive dis/osi&ion +al*#lives o* &+e modi*ied#release *orm. 9%: Analysis of Tma%& lam/da& and fluctuation should /e carried out on the ra0 scale& 0hile calculations for A'C1& A'CT& A'Ctau& A'CI& Cmin& C2d& and Cma% should use the lo"arithmic 3ln4 scale* 354

Ra2id 6nset Dru"s

.4P=' 01S5?$ 4n early ex/osure measure may -e in*orma&ive on &+e -asis o* a//ro/ria&e clinical e**icacy!sa*e&y &rials and!or /+armacoGine&ic!/+armacodynamic s&udies &+a& call *or -e&&er con&rol o* dru( a-sor/&ion in&o &+e sys&emic circula&ion 9e.(.8 &o ensure ra/id onse& o* an anal(esic e**ec& or &o avoid an excessive +y/o&ensive ac&ion o* an an&i+y/er&ensive:. =n &+is se&&in(8 &+e (uidance recommends use o* /ar&ial 46C as an early ex/osure measure. He recommend &+a& &+e /ar&ial area -e &runca&ed a& &+e /o/ula&ion median o* ?max values *or &+e re*erence *ormula&ion. He also recommend &+a& a& leas& &7o quan&i*ia-le sam/les -e collec&ed -e*ore &+e ex/ec&ed /eaG &ime &o allo7 adequa&e es&ima&ion o* &+e /ar&ial area. 91:

.4P=' 01S5?$ ?o da&e &+is s&andard +as only -een a//lied &o &7o dru(s8 (el *ormula&ions o* i-u/ro*en and &a-le& *ormula&ions o* suma&ri/&an. ?+is no&ice serves &o clari*y &+a& -ioequivalence s&andards *or dru(s *or 7+ic+ an early &ime o* onse& or ra/id ra&e o* a-sor/&ion is im/or&an& -ecause o* &+era/eu&ic or &oxic e**ec&s 9*or exam/le8 an anal(esic *or ra/id relie* o* /ain: are as descri-ed in curren& ?P' (uidelines and /olicy s&a&emen&s. =n addi&ion8 &+e rela&ive mean 46C.e*&max o* &+e &es& &o re*erence *ormula&ion s+ould -e 7i&+in 8 &o 125<8 7+ere 46C.e*&max *or a &es& /roduc& is de*ined as &+e area under &+e curve &o &+e &ime o* &+e maximum concen&ra&ion o* &+e re*erence /roduc&8 calcula&ed *or eac+ s&udy su-Eec&. He rei&era&e &+a& &+is no&ice a//lies &o com/ara&ive -ioavaila-ili&y 9-ioequivalence: s&udies only. Su-missions in su//or& o* com/ara&ive 9su/eriori&y: claims8 suc+ &+a& &ime &o onse& o* e**ec& is im/or&an&8 may need addi&ional /+armacoGine&ic#/+armacodynamic or clinical da&a. 9":

.4P=' 01S5?$ S&a&is&ical evalua&ion o* &max only maGes sense i* &+ere is a clinically relevan& claim *or ra/id release or ac&ion or si(ns rela&ed &o adverse e**ec&s. ?+e non# /arame&ric 9 < con*idence in&erval *or &+is measure o* rela&ive -ioavaila-ili&y s+ould lie 7i&+in a clinically de&ermined ran(e.

#2ecifics for !odified Release Dru"s

30'=C=5' .5)54S5$ Cor modi*ied#release /roduc&s su-mi&&ed as 41'4s8 &+e *ollo7in( s&udies are recommended$ 91: a sin(le#dose8 nonre/lica&e8 *as&in( s&udy com/arin( &+e +i(+es& s&ren(&+ o* &+e &es& and re*erence lis&ed dru( /roduc& and 92: a *ood# e**ec&8 nonre/lica&e s&udy com/arin( &+e +i(+es& s&ren(&+ o* &+e &es& and re*erence /roduc& 9see sec&ion ,=.4:. Because sin(le#dose s&udies are considered more sensi&ive in addressin( &+e /rimary ques&ion o* B5 9i.e.8 release o* &+e dru( su-s&ance *rom &+e dru( /roduc& in&o &+e sys&emic circula&ion:8 mul&i/le#dose s&udies are (enerally no& recommended8 even in ins&ances 7+ere nonlinear Gine&ics are /resen&. 91: 5x&ra P2 /arame&ers$ D )a(#&ime 9&la(: *or modi*ied#release /roduc&s8 i* /resen& 92:

30'=C=5' .5)54S5 94PP)=5S ?0 S=1G)5 '0S5:$ P2 Parame&ers$ 46CI8 46C?8 46C=8 46CI!46C=8 46C?!46C=8 Cmax8 ?max8 lam-da. Cor *ormula&ions &+a& are liGely &o accumula&e 9i.e.8 46CI!46C= J .8:8 sa*e&y requires &+a& s&eady#s&a&e s&udies -e /er*ormed in addi&ion &o &+e sin(le#dose s&udies. H+ere &+e 46CI!46C= ra&io canno& -e relia-ly de&ermined8 accumula&ion mus& -e assumed &o occur. 97:

#tandards for B : 7i"h varia/ility dru"s

8on$9inear :inetics 3Re2ort C4

H=GH)K ,4.=4B)5 '.6G$ 4 dru( /roduc& is called +i(+ly varia-le i* i&s in&ra#individual 9i.e. 7i&+in#su-Eec&: varia-ili&y is (rea&er &+an 3 <. 4 +i(+ C, as es&ima&ed *rom &+e 410,4 model is &+us an indica&or *or +i(+ 7i&+in#su-Eec& varia-ili&y. Ho7ever8 a re/lica&e desi(n is needed &o assess 7i&+in#su-Eec& varia-ili&y. 93: 9 < C= o* 46C ra&io$ =n rare cases a 7ider acce/&ance ran(e may -e acce/&a-le i* i& is -ased on sound clinical Eus&i*ica&ion. 9 < C= o* Cmax ra&io$ =n s/eci*ic cases o* a narro7 &+era/eu&ic ran(e &+e acce/&ance in&erval may -e &i(+&ened. =n cer&ain cases a 7ider in&erval may -e acce/&a-le. ?+e in&erval mus& -e /ros/ec&ively de*ined e.(. .75#1.33 and Eus&i*ied addressin( in /ar&icular any sa*e&y or e**icacy concerns *or /a&ien&s s7i&c+ed -e&7een *ormula&ions. 91: ?+e 1*G s&a&es under 3.%.2 &+a& LHi&+ res/ec& &o &+e ra&io o* Cmax &+e 9 < con*idence in&erval *or &+is measure o* rela&ive -ioavaila-ili&y s+ould lie 7i&+in an acce/&ance ran(e o* .8 F 1.25. =n s/eci*ic cases8 suc+ as a narro7 &+era/eu&ic ran(e8 &+e acce/&ance in&erval may need &o -e &i(+&ened.M ?+e 1*G also s&a&es &+a& L=n cer&ain cases a 7ider in&erval may -e acce/&a-le. ?+e in&erval mus& -e /ros/ec&ively de*ined8 e.(. .75 F 1.338 and Eus&i*ied addressin( in /ar&icular any sa*e&y or e**icacy concerns *or /a&ien&s s7i&c+ed -e&7een *ormula&ionsM. ?+e /ossi-ili&y o**ered +ere -y &+e (uideline &o 7iden &+e acce/&ance ran(e o* .8 F 1.25 *or &+e ra&io o* Cmax 9no& *or 46C: s+ould -e considered exce/&ional and limi&ed &o a small 7idenin( 9 .75 N 1.33:. Cur&+ermore8 &+is /ossi-ili&y is res&ric&ed &o &+ose /roduc&s *or 7+ic+ a& leas& one o* &+e *ollo7in( cri&eria a//lies$ 1. 'a&a re(ardin( P2!P' rela&ions+i/s *or sa*e&y and e**icacy are adequa&e &o demons&ra&e &+a& &+e /ro/osed 7ider acce/&ance ran(e *or Cmax does no& 101#)=154. 2=15?=CS$ ?+ese requiremen&s mus& -e me& in -o&+ &+e *as&in( and *ed s&a&es exce/& 7+ere a**ec& /+armacodynamics in a clinically si(ni*ican& 7ay. 2. =* P2!P' da&a are ei&+er inconclusive or no& availa-le8 clinical sa*e&y and i& +as -een demons&ra&ed &+a& *ood does no& modi*y -ioavaila-ili&y a& doses e**icacy da&a may s&ill -e used *or &+e same /ur/ose8 -u& &+ese da&a s+ould 7i&+in &+e ran(e o* s&ren(&+s &o -e marGe&ed. 98: -e s/eci*ic *or &+e com/ound &o -e s&udied and /ersuasive. ?+e *ollo7in( /+armacoGine&ic /arame&ers s+ould -e calcula&ed *rom sin(le 3. ?+e re*erence /roduc& +as a +i(+ly varia-le 7i&+in#su-Eec& -ioavaila-ili&y. dose s&udies$ 46CI8 46C=8 Cmax and8 7+ere /ossi-le8 lam-da. ?+e *ollo7in( Please re*er &o &+e Oues&ion on +i(+ly varia-le dru( or dru( /roduc&s *or /arame&ers s+ould -e calcula&ed *rom s&eady s&a&e s&udies$ 46C&au8 Cmax8 (uidance on +o7 &o address &+is issue a& &+e /lannin( s&a(e o* &+e C/d8 and Cmin. -ioequivalence &rial. S?41'4.'S C0. 101#)=154. 2=15?=CS '.6GS$ 4 /os& +oc Eus&i*ica&ion o* an acce/&ance ran(e 7ider &+an de*ined in &+e /ro&ocol Sin(le 'ose$ S&andards *or -ioavaila-ili&y and -ioequivalence are &+ose canno& -e acce/&ed. =n*orma&ion &+a& 7ould -e required &o Eus&i*y resul&s descri-ed in .e/or& 4$ PBioavaila-ili&y o* 0ral 'osa(e Cormula&ions o* 'ru(s lyin( ou&side &+e conven&ional acce/&ance ran(e a& &+e /os& +oc s&a(e s+ould -e 6sed *or Sys&emic 5**ec&sP. u&ilised a& &+e /lannin( s&a(e8 ei&+er *or a scien&i*ic Eus&i*ica&ion o* a C+ronic 'ose$ Cor dru(s requirin( c+ronic dose s&udies &+e *ollo7in( 7ider acce/&ance ran(e *or Cmax 8 or *or selec&in( an ex/erimen&al a//roac+ -ioavaila-ili&y and -ioequivalence s&andards are required$ &+a& allo7s &+e assessmen& o* di**eren& sources o* varia-ili&y. 93: 1. ?+e 9 < con*idence in&erval o* &+e rela&ive mean 46C&auQ o* &+e &es& &o re*erence *ormula&ion s+ould -e 7i&+in 8 &o 125<. 2. ?+e rela&ive mean measured Cmax o* &+e &es& &o re*erence *ormula&ion s+ould -e 7i&+in 8 &o 125<. 3. ?+e rela&ive mean measured Cmin o* &+e &es& &o re*erence *ormula&ion s+ould -e 7i&+in 8 &o 125<. 46C&auQ is de*ined as &+e area under &+e /lasma concen&ra&ion# &ime curve a*&er several doses indica&in( P/seudoP s&eady s&a&e. Because o* &+e non#lineari&y8 s&eady s&a&e may -e di**icul& &o discern. ?+ese s&andards mus& -e me& on /arame&ers calcula&ed *rom -o&+ &+e measured da&a and da&a correc&ed *or measured dru( con&en&. 98:

9on" 7alf$9ife

)01G H4)C#)=C5 '.6GS$ =n a B4 or /+armacoGine&ic s&udy involvin( an oral /roduc& 7i&+ a lon( +al*#li*e dru(8 adequa&e c+arac&eriAa&ion o* &+e +al*#li*e calls *or -lood sam/lin( over a lon( /eriod o* &ime. Cor a B5 de&ermina&ion o* an oral /roduc& 7i&+ a lon( +al*#li*e dru(8 a nonre/lica&e8 sin(le#dose8 crossover s&udy can -e conduc&ed8 /rovided an adequa&e 7as+ou& /eriod is used. =* &+e crossover s&udy is /ro-lema&ic8 a B5 s&udy 7i&+ a /arallel desi(n can -e used. Cor ei&+er a crossover or /arallel s&udy8 7e recommend &+a& sam/le collec&ion &ime -e adequa&e &o ensure com/le&ion o* (as&roin&es&inal &ransi& 9a//roxima&ely 2 &o 3 days: o* &+e dru( /roduc& and a-sor/&ion o* &+e dru( su-s&ance. Cmax and a sui&a-ly &runca&ed 46C can -e used &o c+arac&eriAe /eaG and &o&al dru( ex/osure8 res/ec&ively. Cor dru(s &+a& demons&ra&e lo7 in&rasu-Eec& varia-ili&y in dis&ri-u&ion and clearance8 an 46C &runca&ed a& 72 +ours 946C #72 +r: can -e used in /lace o* 46C #& or 46C #>. Cor dru(s demons&ra&in( +i(+ in&rasu-Eec& varia-ili&y in dis&ri-u&ion and clearance8 46C &runca&ion 7arran&s cau&ion. =n suc+ cases8 7e also recommend &+a& s/onsors and!or a//lican&s consul& &+e a//ro/ria&e revie7 s&a**. 91:

)01G H4)C#)=C5 '.6GS$ ?+is no&ice serves &o clari*y &+a& *or dru(s 7+ic+ ex+i-i& a &erminal elimina&ion +al*#li*e (rea&er &+an 2" +ours8 -ioequivalence s&andards in com/ara&ive -ioavaila-ili&y s&udies 7ill -e a//lied &o 46C #72+. Cor &+e /ur/ose o* -ioequivalence assessmen&8 i& 7ill no& -e necessary &o sam/le *or more &+an 72 +ours /os&#dose8 re(ardless o* &+e +al*#li*e. 4l&erna&e desi(ns suc+ as /arallel s&udies could -e considered. 93:

)01G H4)C#)=C5 '.6GS$ Cor dru(s 7i&+ a lon( +al*#li*e8 rela&ive -ioavaila-ili&y can -e adequa&ely es&ima&ed usin( &runca&ed 46C as lon( as &+e &o&al collec&ion /eriod is Eus&i*ied. =n &+is case &+e sam/le collec&ion &ime s+ould -e adequa&e &o ensure com/arison o* &+e a-sor/&ion /rocess. 91:

C.=?=C4) '0S5 '.6GS$ 6nless o&+er7ise indica&ed -y a s/eci*ic (uidance8 &+is (uidance recommends &+a& &+e &radi&ional B5 limi& o* 8 &o 125 /ercen& *or non#narro7 &+era/eu&ic ran(e dru(s remain unc+an(ed *or &+e -ioavaila-ili&y measures 946C and Cmax: o* narro7 &+era/eu&ic ran(e dru(s. 91:

#tandards for B : Critical Dose Dru"s

C.=?=C4) '0S5 '.6GS$ 1. ?+e 9 < con*idence in&erval o* &+e rela&ive mean 46C o* &+e &es& &o re*erence *ormula&ion s+ould -e 7i&+in 9 . &o 112. <R &+e relevan& 46C or 46Cs as descri-ed in Guidelines 4 and B are &o -e de&ermined. 2. ?+e 9 < con*idence in&erval o* &+e rela&ive mean measured Cmax o* &+e &es& &o re*erence *ormula&ion s+ould -e -e&7een 8 . and 125. <. 3. ?+ese requiremen&s are &o -e me& in -o&+ &+e *as&ed and *ed s&a&es. ". ?+ese s&andards s+ould -e me& on lo( &rans*ormed /arame&ers calcula&ed *rom &+e measured da&a and *rom da&a correc&ed *or measured dru( con&en& 9/ercen& /o&ency o* la-el claim:. 5. S&eady#s&a&e s&udies are no& required *or Lcri&ical dose dru(sM unless 7arran&ed -y exce/&ional circums&ances. =* a s&eady#s&a&e s&udy is required8 &+e 9 < con*idence in&erval o* &+e rela&ive mean measured Cmin o* &+e &es& &o re*erence *ormula&ion s+ould also -e -e&7een 8 . and 125. <. 9%:

C.=?=C4) '0S5 '.6GS$ ;9 < C= o*B 46C#ra&io$ =n s/eci*ic cases o* a narro7 &+era/eu&ic ran(e &+e acce/&ance in&erval may -e &i(+&ened. ;9 < C= o*B Cmax#ra&io$ =n s/eci*ic cases o* a narro7 &+era/eu&ic ran(e &+e acce/&ance in&erval may need &o -e &i(+&ened. 91:

Su-Eec&s 7i&+ /redose /lasma concen&ra&ions$ D =* &+e /redose concen&ra&ion is S 5 /ercen& o* Cmax value in &+a& su-Eec&8 &+e su-Eec&Ts da&a 7i&+ou& any adEus&men&s can -e included in all /+armacoGine&ic measuremen&s and calcula&ions. He recommend &+a& i* &+e /redose value is U &+an 5 /ercen& o* Cmax8 &+e su-Eec& -e dro//ed *rom all B5 s&udy evalua&ions. 'a&a dele&ion due &o vomi&in($ D He recommend &+a& da&a *rom su-Eec&s 7+o ex/erience emesis durin( &+e course o* a B5 s&udy *or immedia&e#release /roduc&s -e dele&ed *rom s&a&is&ical analysis i* vomi&in( occurs a& or -e*ore 2 &imes median ?max. =n &+e case o* modi*ied#release /roduc&s8 &+e da&a *rom su-Eec&s 7+o ex/erience emesis any &ime durin( &+e la-eled dosin( in&erval can -e dele&ed. 91: Data to Analy;e

?+e analyses s+ould include all da&a *or all su-Eec&s 9see Sec&ion 3."8 P'ro/#ou&s and Hi&+dra7al o* Su-Eec&s *rom a S&udyP: on measured da&a. Su//lemen&ary analyses may also -e carried ou& 7i&+ selec&ed /oin&s or su-Eec&s ini&ially excluded *rom &+e analyses. Suc+ exclusions mus& -e Eus&i*ied. =& is rarely acce/&a-le &o exclude more &+an 5 /ercen& o* &+e su-Eec&s or more &+an 1 /ercen& o* &+e da&a *or a sin(le su-Eec&#*ormula&ion com-ina&ion. 91:

?+e me&+od o* analysis s+ould -e /lanned in &+e /ro&ocol. ?+e /ro&ocol s+ould also s/eci*y me&+ods *or +andlin( dro/#ou&s and *or iden&i*yin( -iolo(ically im/lausi-le ou&liers. Pos& +oc exclusion o* ou&liers is (enerally no& acce/&ed. =* modellin( assum/&ions made in &+e /ro&ocol 9e.(. *or ex&ra/ola&in( 46C &o in*ini&y: &urn ou& &o -e invalid8 a revised analysis in addi&ion &o &+e /lanned analysis 9i* &+is is *easi-le: s+ould -e /resen&ed and discussed. 91: 6nder 3.%.3 &+e 1*G s&a&es &+a& LPos&#+oc exclusion o* ou&liers is (enerally no& acce/&edM -u& a& &+e same &ime acGno7led(es &+a& L&+e /ro&ocol s+ould also s/eci*y me&+ods *or iden&i*yin( -iolo(ically im/lausi-le ou&liersM. 6n-iased assessmen& o* resul&s *rom randomised s&udies requires &+a& all su-Eec&s are o-served and &rea&ed accordin( &o &+e same rules &+a& s+ould -e inde/enden& *rom &rea&men& or ou&come. =n consequence8 /+armacoGine&ic da&a can only -e excluded -ased on non#s&a&is&ical reasons &+a& +ave -een ei&+er de*ined /reviously in &+e /ro&ocol or8 a& &+e very leas&8 es&a-lis+ed -e*ore revie7in( &+e da&a. 4cce/&a-le ex/lana&ions &o exclude /+armacoGine&ic da&a or &o exclude a su-Eec& 7ould -e /ro&ocol viola&ions liGe vomi&in(8 diarr+oea8 analy&ical *ailure8 e&c. ?+e searc+ *or suc+ ex/lana&ions mus& a//ly &o all su-Eec&s in all (rou/s inde/enden&ly o* &+e siAe o* &+e o-served /+armacoGine&ic /arame&ers or i&s ou&lyin( /osi&ion. 5xclusion o* da&a can never -e acce/&ed on &+e -asis o* s&a&is&ical analysis or *or /+armacoGine&ic reasons alone8 -ecause i& is im/ossi-le &o dis&in(uis+ -e&7een *ormula&ion e**ec&s and /+armacoGine&ic e**ec&s. 5xce/&ional reasons may Eus&i*y /os&#+oc da&a exclusion -u& &+is s+ould -e considered 7i&+ u&mos& care. =n suc+ a case8 &+e a//lican& mus& demons&ra&e &+a& &+e condi&ion s&a&ed &o cause &+e devia&ion is /resen& in &+e ou&lier9s: only and a-sence o* &+is condi&ion +as -een inves&i(a&ed usin( &+e same cri&eria *or all o&+er su-Eec&s. .esul&s o* s&a&is&ical analyses 7i&+ and 7i&+ou& &+e (rou/ o* excluded su-Eec&s s+ould -e /rovided. 93:

He recommend &+a& -lood sam/les -e dra7n a& a//ro/ria&e &imes &o descri-e &+e a-sor/&ion8 dis&ri-u&ion8 and elimina&ion /+ases o* &+e dru(. Cor mos& dru(s8 7e recommend &+a& 12 &o 18 sam/les8 includin( a /redose sam/le8 -e collec&ed /er su-Eec& /er dose. ?+is sam/lin( can con&inue *or a& leas& &+ree or more &erminal +al* lives o* &+e dru(. ?+e exac& &imin( *or sam/le collec&ion de/ends on &+e na&ure o* &+e dru( and &+e in/u& *rom &+e adminis&ered dosa(e *orm. ?+e #am2lin" sam/le collec&ion can -e s/aced in suc+ a 7ay &+a& &+e maximum concen&ra&ion #cheme Criteria o* &+e dru( in &+e -lood 9Cmax: and &erminal elimina&ion ra&e cons&an& 9@A: can -e es&ima&ed accura&ely. 4& leas& &+ree &o *our sam/les can -e o-&ained durin( &+e &erminal lo(#linear /+ase &o o-&ain an accura&e es&ima&e o* @A *rom linear re(ression. 91:

?+e dura&ion o* -lood or urine sam/lin( in a s&udy s+ould -e su**icien& &o accoun& *or a& leas& 8 /ercen& o* &+e Gno7n 46C &o in*ini&y 946C=:. ?+is /eriod is usually a& leas& &+ree &imes &+e &erminal +al*#li*e o* &+e dru(. ?o /ermi& Calcula&ion o* &+e relevan& /+armacoGine&ic /arame&ers8 *rom 12 &o 18 sam/les s+ould -e collec&ed /er su-Eec& /er dose. ?+ere may -e considera-le inaccuracies in &+e es&ima&es o* &+e &erminal dis/osi&ion ra&e cons&an& i* &+e cons&an& is es&ima&ed *rom linear re(ression usin( only a *e7 /oin&s. ?o reduce &+ese inaccuracies i& is /re*era-le &+a& *our or more /oin&s -e de&ermined durin( &+e &erminal lo(#linear /+ase o* &+e curve. 91:

?+e sam/lin( sc+edule s+ould -e /lanned &o /rovide an adequa&e es&ima&ion o* Cmax and &o cover &+e /lasma concen&ra&ion &ime curve lon( enou(+ &o /rovide a relia-le es&ima&e o* &+e ex&en& o* a-sor/&ion. ?+is is (enerally ac+ieved i* &+e 46C derived *rom measuremen&s is a& leas& 8 < o* &+e 46C ex&ra/ola&ed &o in*ini&y. =* a relia-le es&ima&e o* &erminal +al*#li*e is necessary8 i& s+ould -e o-&ained -y collec&in( a& leas& &+ree &o *our sam/les durin( &+e &erminal lo( linear /+ase. 91:

4n adequa&e 7as+ou& /eriod 9e.(.8 more &+an 5 +al* lives o* &+e moie&ies &o -e measured: 7ould se/ara&e eac+ &rea&men&. 91: <ashout

?+e in&erval s+ould -e &+e same *or all su-Eec&s and8 &o accoun& *or varia-ili&y in Su-sequen& &rea&men&s s+ould -e se/ara&ed -y adequa&e 7as+ ou& /eriods. elimina&ion ra&e -e&7een su-Eec&s8 normally s+ould -e no& less &+an 1 &imes &+e mean &erminal +al*#li*e o* &+e dru(. 9(enerally8 &+e in&erval -e&7een s&udy days s+ould no& exceed *our 7eeGs:. 9187: Cor uncom/lica&ed dru(s in immedia&e#release dosa(e *orms8 i* &+ere is a documen&ed serious sa*e&y risG &o su-Eec&s *rom sin(le#dose adminis&ra&ion o* &+e dru( or dru( /roduc& in &+e a-sence o* *ood8 &+en an a//ro/ria&ely desi(ned s&udy conduc&ed in &+e /resence o* only a su**icien& quan&i&y o* *ood &o /reven& &+e &oxici&y may -e acce/&a-le *or /ur/oses o* B5 assessmen&. 95: Su-Eec&s s+ould /re*era-ly -e *as&in( a& leas& durin( &+e ni(+& /rior &o adminis&ra&ion o* &+e /roduc&s. =* &+e Summary o* Produc& C+arac&eris&ics o* &+e re*erence /roduc& con&ains s/eci*ic recommenda&ions in rela&ion 7i&+ *ood in&aGe rela&ed &o *ood in&erac&ion e**ec&s &+e s&udy s+ould -e desi(ned accordin(ly. 91:

7e recommend a B5 s&udy under *ed condi&ions *or all orally adminis&ered immedia&e#release dru( /roduc&s8 7i&+ &+e *ollo7in( exce/&ions$ D H+en -o&+ &es& /roduc& and .)' are ra/idly dissolvin(8 +ave similar dissolu&ion /ro*iles8 and con&ain a dru( su-s&ance 7i&+ +i(+ solu-ili&y and +i(+ /ermea-ili&y 9BCS Class =: 9see *oo&no&e 3:8 or D H+en &+e '0S4G5 41' 4'3=1=S?.4?=01 sec&ion o* &+e .)' la-el s&a&es &+a& &+e /roduc& s+ould -e &aGen only on an em/&y s&omac+8 or D H+en &+e .)' la-el does no& maGe any s&a&emen&s a-ou& &+e e**ec& o* *ood on a-sor/&ion or adminis&ra&ion. 92: =n 41'4s8 B5 o* &+e &es& &o &+e .)' is demons&ra&ed in a sin(le dose crossover Fastin" vs* Fed: s&udy. Bo&+ &rea&men&s s+ould -e s/rinGled on one o* &+e so*& *oods men&ioned in #in"le Dose &+e la-elin(8 usually a//lesauce. ?+e B5 da&a s+ould -e analyAed usin( avera(e B5 and &+e 9 /ercen& C= cri&eria s+ould -e used &o declare B5. =* &+ere are ques&ions a-ou& o&+er *oods8 &+e desi(n8 or &+e analysis o* suc+ B5 s&udies8 &+e s/onsors and!or a//lican&s s+ould con&ac& &+e 0**ice o* Generic 'ru(s.92:

He recommend &+a& *ood#e**ec& B4 and *ed B5 s&udies -e /er*ormed *or all modi*ied release dosa(e *orms. Fastin" vs* Fed: !odified Release

?+e recommenda&ions concernin( *ood in&aGe in &+e SPC are no& su**icien& *or re(ula&ory decisions on &+e adequacy o* -ioequivalence s&udies. Pre*era-ly8 &+e *ollo7in( condi&ions s+ould -e considered se/ara&ely 7+en &+e SPC recommends adminis&ra&ion o* &+e su-s&ance &o(e&+er 7i&+ *ood in&aGe$ 1. =* &+e recommenda&ion o* *ood in&aGe in &+e SPC is -ased on /+armacoGine&ic /ro/er&ies suc+ as +i(+er -ioavaila-ili&y8 &+en a -ioequivalence s&udy under *ed condi&ions is (enerally required. 2. =* &+e recommenda&ion o* *ood in&aGe is in&ended &o decrease adverse even&s or &o im/rove &olera-ili&y8 a -ioequivalence s&udy under *as&in( condi&ions is considered acce/&a-le al&+ou(+ i& 7ould -e advisa-le &o /er*orm &+e s&udy under *ed condi&ions. 3. =* &+e SPC leaves a c+oice -e&7een *as&in( and *ed condi&ions8 &+en -ioequivalence s+ould /re*era-ly -e &es&ed under *as&in( condi&ions as &+is si&ua&ion 7ill -e more sensi&ive &o di**erences in /+armacoGine&ics. ?+e com/osi&ion o* &+e meal s+ould -e descri-ed and &aGen in&o accoun&8 since a li(+& meal mi(+& some&imes -e /re*era-le &o mimic clinical condi&ions8 es/ecially 7+en &+e *ed s&a&e is ex/ec&ed &o -e less sensi&ive &o di**erences in /+armacoGine&ics. Ho7ever8 *or modi*ied release /roduc&s8 a +i(+ *a& meal is required. Cor /roduc&s 7i&+ release c+arac&eris&ics di**erin( *rom conven&ional immedia&e release 9e.(. im/roved release8 dissolu&ion or a-sor/&ion:8 even i* &+ey canno& -e classi*ied as modi*ied release /roduc&s /rolon(ed 4 second or su-sequen& marGe& en&ry 3. *ormula&ion s+ould -e com/ared 7i&+ 'i**eren& modi*ied release *ormula&ions o* &+e same dru( 7i&+ su-s&ance mayor di**er delayed release8 -ioequivalence s&udies&+e may -e necessary in -o&+ &+e Grou/ = or == 3. /roduc& 7i&+ 7+ic+ -ioequivalence is claimed. Bo&+ 7i&+ res/ec& &o *ood in&erac&ion. Hence8 in*luence o* *ood on &+e&+e *as&ed and *ed s&a&es. *ormula&ions s+ould -e adminis&ered as sin(le doses. ?+e o-Eec&ive o* &+ese -ioavaila-ili&y o*93: oral modi*ied release *ormula&ions mus& -e inves&i(a&ed *or s&udies is &o evalua&e &+e -ioequivalence o* &+e &es& and re*erence dru( /roduc&s sa*e&y and e**icacy /ur/oses. 92: under -o&+ *as&in( and *ed condi&ions. Ho7ever8 sa*e&y o* &+e su-Eec&s may require &+a& an inves&i(a&ion -e conduc&ed a*&er &+e adminis&ra&ion o* an a//ro/ria&e meal a& a s/eci*ied &ime -e*ore &aGin( &+e dru(. =n &+is case8 manu*ac&urers s+ould consul& 7i&+ Heal&+ Canada -e*ore under&aGin( &+e s&udy. 97: C.=?=C4) '0S5$ =n (eneral B5 s+ould -e demons&ra&ed under -o&+ *as&ed and *ed condi&ions. Cor com/lica&ed dru(s in immedia&e#release dosa(e *orm ;V5.2B and dru(s in modi*ied#release dosa(e *orms ;V5.3B8 i* &+ere is a documen&ed serious sa*e&y risG &o su-Eec&s *rom sin(le#dose adminis&ra&ion o* &+e dru( or dru( /roduc& in ei&+er &+e a-sence or /resence o* *ood8 &+en an a//ro/ria&ely desi(ned s&udy conduc&ed in &+e indica&ed condi&ion o* use 9*ed or *as&ed s&a&e: may -e acce/&a-le *or /ur/oses o* B5 assessmen&. 95: =* /ossi-le8 &+e s&udy s+ould -e conduc&ed in suc+ a 7ay &+a& &+e su-Eec& is no& a7are o* 7+ic+ /roduc& is adminis&ered. Cur&+ermore8 &+e /erson c+ecGin( *or adverse reac&ions and &+e /erson conduc&in( &+e analysis o* sam/les mus& no& Gno7 7+ic+ /roduc& 7as adminis&ered. 0&+er individuals involved in &+e adminis&ra&ion o* &+e dru(s8 &+e surveillance o* &+e /a&ien&s8 or &+e analysis o* /lasma 9or -lood8 or serum: da&a s+ould no& Gno7 7+ic+ /roduc& 7as adminis&ered. 91:

Fastin" vs* Fed: Critical Dose

Blindin"

Reference Product

Cor 41'4s8 7e also recommend &+a& &+e B5 s&udy -e conduc&ed -e&7een &+e &es& /roduc& and re*erence lis&ed dru( usin( &+e s&ren(&+9s: s/eci*ied in 4//roved 'ru( Produc&s 7i&+ ?+era/eu&ic 5quivalence 5valua&ions 90ran(e BooG:. 91: Cor B5 s&udies8 measuremen& o* only &+e /aren& dru( released *rom &+e dosa(e *orm8 ra&+er &+an &+e me&a-oli&e8 is (enerally recommended. ?+e ra&ionale *or &+is recommenda&ion is &+a& concen&ra&ion#&ime /ro*ile o* &+e /aren& dru( is more sensi&ive &o c+an(es in *ormula&ion /er*ormance &+an a me&a-oli&e8 7+ic+ is more re*lec&ive o* me&a-oli&e *orma&ion8 dis&ri-u&ion8 and elimina&ion. ?+e *ollo7in( are exce/&ions &o &+is (eneral a//roac+. D 3easuremen& o* a me&a-oli&e may -e /re*erred 7+en /aren& dru( levels are &oo lo7 &o allo7 relia-le analy&ical measuremen& in -lood8 /lasma8 or serum *or an adequa&e len(&+ o* &ime. He recommend &+a& &+e me&a-oli&e da&a o-&ained *rom &+ese s&udies -e su-Eec& &o a con*idence in&erval a//roac+ *or B5 demons&ra&ion. =* &+ere is a clinical concern rela&ed &o e**icacy or sa*e&y *or &+e /aren& dru(8 7e also recommend &+a& s/onsors and!or a//lican&s con&ac& &+e a//ro/ria&e revie7 division &o de&ermine 7+e&+er &+e /aren& dru( s+ould -e measured and analyAed s&a&is&ically. D 4 me&a-oli&e may -e *ormed as a resul& o* (u& 7all or o&+er /resys&emic me&a-olism. =* &+e me&a-oli&e con&ri-u&es meanin(*ully &o sa*e&y and!or e**icacy8 7e also recommend &+a& &+e me&a-oli&e and &+e /aren& dru( -e measured. H+en &+e rela&ive ac&ivi&y o* &+e me&a-oli&e is lo7 and does no& con&ri-u&e meanin(*ully &o sa*e&y and!or e**icacy8 i& does no& +ave &o -e measured. He recommend &+a& &+e /aren& dru( measured in &+ese B5 s&udies -e analyAed usin( a con*idence in&erval a//roac+. ?+e me&a-oli&e da&a can -e used &o /rovide su//or&ive evidence o* com/ara-le &+era/eu&ic ou&come. 91:

D a dru( /roduc& &+a& +as -een issued a no&ice o* com/liance /ursuan& &o sec&ion 4 W.e*erence Produc&W mus& -e an Winnova&orW /roduc&. 91: C. 8. " o* &+e Cood and 'ru( .e(ula&ions8 and is curren&ly marGe&ed in Canada -y &+e innova&or8 or D a dru( /roduc& acce/&a-le &o &+e 'irec&or. 91: 'e&ermina&ion o* -ioequivalence s+ould -e -ased on da&a *or &+e /aren& dru(. =n mos& cases evalua&ion o* -ioavaila-ili&y and -ioequivalence 7ill -e -ased u/on &+e measured concen&ra&ions o* &+e /aren& com/ound. =n some si&ua&ions8 Haiver o* &+e measuremen& o* &+e /aren& dru( 7ill no& -e considered8 unless +o7ever8 measuremen&s o* an ac&ive or inac&ive me&a-oli&e may -e necessary concen&ra&ions o* &+e /aren& dru( canno& -e relia-ly measured8 e.(.8 i* &+e /aren& ins&ead o* &+e /aren& com/ound. Suc+ si&ua&ions include cases 7+ere &+e use o* dru( is no& de&ec&a-le due &o ra/id -io&rans*orma&ion or limi&a&ions in availa-le a me&a-oli&e may -e advan&a(eous &o de&ermine &+e ex&en& o* dru( in/u&8 e.(. i* assay me&+odolo(y. =n suc+ ins&ances8 &+e use o* me&a-oli&e da&a may -e &+e concen&ra&ion o* &+e ac&ive su-s&ance is &oo lo7 &o -e accura&ely measured acce/&a-le. ?+e measured me&a-oli&e s+ould -e a /rimary 9*irs& s&e/: and maEor in &+e -iolo(ical ma&rix 9e.(. maEor di**icul&y in analy&ical me&+od8 /roduc& ins&a-le one8 and a//ro/ria&e scien&i*ic Eus&i*ica&ion *or a 7aiver o* &+e measuremen& o* in &+e -iolo(ical ma&rix or +al*#li*e o* &+e /aren& com/ound &oo s+or&: &+us (ivin( &+e /aren& dru( and &+e use o* me&a-oli&e da&a s+ould -e /rovided. ?+e c+oice rise &o si(ni*ican& varia-ili&y. o* usin( &+e me&a-oli&e ins&ead o* &+e /aren& dru( is &o -e clearly s&a&ed8 a /riori8 in &+e o-Eec&ive o* &+e s&udy in &+e s&udy /ro&ocol. Bioequivalence de&ermina&ions -ased on me&a-oli&es s+ould -e Eus&i*ied in eac+ case -earin( in mind &+a& &+e aim o* a -ioequivalence s&udy is in&ended &o Cor &+e /ur/ose o* &+is (uidance8 a /ro#dru( is &o -e &rea&ed as a X/aren& dru(T. com/are &+e in vivo /er*ormance o* &es& and re*erence /roduc&s. =n /ar&icular i* ?+a& is8 i* &+e su-s&ance released *rom &+e dosa(e *orm is a-sor-ed in&ac& and is me&a-oli&es si(ni*ican&ly con&ri-u&e &o &+e ne& ac&ivi&y o* an ac&ive su-s&ance and relia-ly measura-le in &+e sys&emic circula&ion8 i& s+ould -e used in &+e &+e /+armacoGine&ic sys&em is non#linear8 i& is necessary &o measure -o&+ /aren& assessmen& o* -ioequivalence. =& is no& (enerally considered necessary &o dru( and ac&ive me&a-oli&e /lasma concen&ra&ions and evalua&e &+em se/ara&ely. measure -o&+ 91: /aren& dru( and me&a-oli&e levels *or &+e /ur/ose o* -ioequivalence assessmen&. Ho7ever8 quan&i&a&ion o* me&a-oli&e levels may some&imes -e 4ccordin( &o &+e (uideline8 &+e only si&ua&ions 7+ere me&a-oli&e da&a can -e +el/*ul8 e.(.8 &o ex/lain ex&reme values caused -y me&a-olic c+an(es 7i&+in a used &o es&a-lis+ -ioequivalence are$ su-Eec&. =n &+ose rare si&ua&ions 7+ere use o* dru( concen&ra&ions in urine is 1. L=* &+e concen&ra&ion o* &+e ac&ive su-s&ance is &oo lo7 &o -e accura&ely Eus&i*ia-le *or &+e assessmen& o* rela&ive -ioavaila-ili&y8 only /aren& dru( measured in &+e -iolo(ical ma&rix8 &+us (ivin( rise &o si(ni*ican& varia-ili&yM. concen&ra&ions may -e used. ?+a& is8 use o* me&a-oli&e concen&ra&ions in urine is Commen&s. 3e&a-oli&e da&a can only -e used i* &+e 4//lican& /resen&s no& considered acce/&a-le in &+e assessmen& o* -ioequivalence. 93 # '.4C?: convincin(8 s&a&e#o*#&+ear& ar(umen&s &+a& measuremen&s o* &+e /aren& com/ound H+en a /ro#dru( is adminis&ered8 &+e ac&ive com/onen& s+ould -e measured. 97 are unrelia-le. 5ven so8 i& is im/or&an& &o /oin& ou& &+a& Cmax o* &+e me&a-oli&e is # .e/or& B: s&udies +ave -een com/le&ed8 &+ey may -e /ooled i* cer&ain less sensi&ive &o di**erences in &+e ra&e o* a-sor/&ion &+an Cmax o* &+e =* &7o or more /aren& dru(. ?+ere*ore8 7+en &+e ra&e o* a-sor/&ion is considered o* clinical requiremen&s are me&. im/or&ance8 -ioequivalence s+ould8 i* /ossi-le8 -e de&ermined *or Cmax o* &+e a: ?+e same /ro&ocol mus& -e used *or all s&udies. S/eci*ically8 &+is means &+a& &+e same analy&ical me&+od is &o -e used8 &+e -lood /aren& com/ound8 i* necessary a& a +i(+er dose. Cur&+ermore8 7+en usin( me&a-oli&e da&a as a su-s&i&u&e *or /aren& dru( concen&ra&ions8 &+e a//lican& sam/les dra7n a& &+e same &ime8 and &+e same lo&s o* &+e same *ormula&ions s+ould /resen& da&a su//or&in( &+e vie7 &+a& &+e /aren& dru( ex/osure 7ill -e used. -: ?7o consis&ency &es&s mus& -e done on &+e s&udies &o ensure &+a& /oolin( is re*lec&ed -y me&a-oli&e ex/osure. 2. L=* me&a-oli&es si(ni*ican&ly con&ri-u&e &o &+e ne& ac&ivi&y o* an ac&ive su-s&ance meanin(*ul. ?+e *irs& &es& is &+e &es& o* equali&y o* &+e residual mean squares. ?aGe &+e ra&io and &+e /+armacoGine&ic sys&em is non#linearM. Commen&s. ?o evalua&e &+e si(ni*icance o* &+e con&ri-u&ion o* me&a-oli&es8 o* &+e residual *rom &+e *irs& s&udy &o &+e residual *or eac+ o* &+e o&+er s&udies. rela&ive 46Cs and non#clinical or clinical /+armacodynamic ac&ivi&ies s+ould -e 9Cor eac+ ra&io8 &+e smaller o* &+e &7o residuals mus& -e used as &+e com/ared 7i&+ &+ose o* &+e /aren& dru(. P2!P' modelin( may -e use*ul. =* denomina&or.: ?+is ra&io is com/ared &o an C s&a&is&ic8 usin( &+e de(rees o* *reedom associa&ed 7i&+ &+e residuals. =* &+e ra&io is (rea&er &+an &+e 5< C value8 cri&eria *or si(ni*ican& con&ri-u&ion &o ac&ivi&y and /+armacoGine&ic non#lineari&y are me&8 &+en Li& is necessary &o measure -o&+ /aren& dru( and ac&ive me&a-oli&e &+e s&udies may no& -e com-ined. ?+e second &es& is &+e *ormula&ion -y s&udy /lasma concen&ra&ions and evalua&e &+em se/ara&elyM. 4ny discre/ancy in&erac&ion and is carried ou& as s+o7n in ?a-le 7#4. 91: -e&7een &+e resul&s o-&ained 7i&+ &+e /aren& com/ound and &+e me&a-oli&es s+ould -e discussed -ased on rela&ive ac&ivi&ies and 46Cs. =* &+e discre/ancy lies in Cmax 8 &+e resul&s o* &+e /aren& com/ound s+ould usually /revail. Poolin( o* &+e /lasma concen&ra&ions or /+armacoGine&ic /arame&ers o* &+e /aren& dru( and i&s me&a-oli&e *or calcula&ion o* -ioequivalence is no& acce/&a-le. 93: 91: Guidance *or =ndus&ry$ Conduc& and 4nalysis o* Bioavaila-ili&y and 91: Commi&&ee *or Pro/rie&ary 3edicinal Produc&s 9CP3P: # 1o&e *or Guidance Bioequivalence S&udies # Par& 4$ 0ral 'osa(e Cormula&ions 6sed *or Sys&emic on &+e =nves&i(a&ion o* Bioavaila-ili&y and Bioequivalence. 5**ec&s. Heal&+ Produc&s and Cood Branc+ Guidance 'ocumen& 91992:. CP3P!5HP!OHP!1" 1!98. )ondon8 2% Zuly 2 1.

!eta/olites

Com/inin" #tudies

#ources: 91: Guidance *or =ndus&ry$ Bioavaila-ili&y and Bioequivalence S&udies *or 0rally 4dminis&ered 'ru( Produc&s Y General Considera&ions. 6.S. 'e/ar&men& o* Heal&+ and Human Services8 Cood and 'ru( 4dminis&ra&ion8 Cen&er *or 'ru( 5valua&ion and .esearc+ 9C'5.:R 3arc+ 2 3. BP .evision 1. 92: Guidance *or =ndus&ry$ Cood#5**ec& Bioavaila-ili&y and Ced Bioequivalence S&udies. 6.S. 'e/ar&men& o* Heal&+ and Human Services. Cood and 'ru( 4dminis&ra&ion. Cen&er *or 'ru( 5valua&ion and .esearc+ 9C'5.:R 'ecem-er 2 2. BP.

92: '.4C? G6='41C5 C0. =1'6S?.K$ 6se o* 3e&a-oli&e 'a&a in Com/ara&ive Bioavaila-ili&y S&udies. Heal&+ Produc&s and Cood Branc+8 2 "! 5! 5. 93: 10?=C5 ?0 =1'6S?.K$ Bioequivalence .equiremen&s *or )on( Hal*#li*e 'ru(s. *ile 5#113899#75 . Zune 228 2 5.

92: Commi&&ee *or Pro/rie&ary 3edicinal Produc&s 9CP3P: # 1o&e *or Guidance on 3odi*ied .elease 0ral and ?ransdermal 'osa(e Corms$ Sec&ion == 9P+armacoGine&ic and Clinical 5valua&ion:. CP3P!5HP!28 !9% 28 Zuly 1999. 93: CH3P 5CC=C4CK H0.2=1G P4.?K: ?H5.4P56?=C S6BG.06P 01 PH4.34C02=15?=CS 95HP#P2:$ Oues&ions [ 4ns7ers on &+e Bioavaila-ili&y and Bioequivalence GuidelineR 5354!CH3P!5HP!" 32%!2 %R )ondon8 27 Zuly 2 %

9": 10?=C5 ?0 =1'6S?.K$ Bioequivalence .equiremen&s *or 'ru(s *or H+ic+ an 5arly ?ime o* 0nse& or .a/id .a&e o* 4-sor/&ion =s =m/or&an& 9ra/id onse& dru(s:. 5#113913#859. Zune 228 2 5. 95: G6='41C5 C0. =1'6S?.K$ Bioequivalence .equiremen&s$ Com/ara&ive Bioavaila-ili&y S&udies Conduc&ed in &+e Ced S&a&e. Heal&+ Produc&s and Cood Branc+. 5#11"8%5#1%". Zuly 218 2 5. 9%: G6='41C5 C0. =1'6S?.K$ Bioequivalence .equiremen&s$ Cri&ical 'ose 'ru(s. Heal&+ Produc&s and Cood Branc+. %#112871#93 . Zune 78 2 %.

97: G6='41C5 C0. =1'6S?.K$ Conduc& and 4nalysis o* Bioavaila-ili&y and Bioequivalence S&udies # Par& B$ 0ral 3odi*ied .elease Cormula&ions. Heal&+ Produc&s and Cood Branc+ Guidance 'ocumen&. 199%. 98: .e/or& on Bioavaila-ili&y o* 0ral 'osa(e Cormula&ions o* 'ru(s 6sed *or Sys&emic 5**ec&s. .e/or& C$ .e/or& on Bioavaila-ili&y o* 0ral 'osa(e Cormula&ions8 1o& in 3odi*ied .elease Corm8 o* 'ru(s 6sed *or Sys&emic 5**ec&s8 Havin( Com/lica&ed or ,aria-le P+armacoGine&ics. 5x/er& 4dvisory Commi&&ee on Bioavaila-ili&y. Heal&+ Pro&ec&ion Branc+8 'ecem-er 1992.

Canadian B% BE Drug Classification System

Critical Dose Drugs #yclosporine ;igo$in 5lecainide :ithium +henytoin <irolimus /acrolimus /heophylline 4arfarin # - #ritical ;ose ;rug # - #ritical ;ose ;rug # - #ritical ;ose ;rug # - #ritical ;ose ;rug # - #ritical ;ose ;rug # - #ritical ;ose ;rug # - #ritical ;ose ;rug # - #ritical ;ose ;rug # - #ritical ;ose ;rug

Drugs &ith Non'(inear )inetics "cetylsalicylic acid # - @on-:inear ,inetics !5or /+;, chronic dose studies may be re7uired% "cyclo ir # - @on-:inear ,inetics !5or /+;, chronic dose studies may be re7uired% #arbama1epine # - @on-:inear ,inetics !5or /+;, chronic dose studies may be re7uired% #ephalosporins # - @on-:inear ,inetics !5or /+;, chronic dose studies may be re7uired% ;isopyramide # - @on-:inear ,inetics !5or /+;, chronic dose studies may be re7uired% 5luorouracil # - @on-:inear ,inetics !5or /+;, chronic dose studies may be re7uired% ?lucocorticosteroids # - @on-:inear ,inetics !5or /+;, chronic dose studies may be re7uired% ?riseoful in # - @on-:inear ,inetics !5or /+;, chronic dose studies may be re7uired% :e odopa # - @on-:inear ,inetics !5or /+;, chronic dose studies may be re7uired% +henytoin # - @on-:inear ,inetics !5or /+;, chronic dose studies may be re7uired% +ropranolol # - @on-:inear ,inetics !5or /+;, chronic dose studies may be re7uired% 9ifampin # - @on-:inear ,inetics !5or /+;, chronic dose studies may be re7uired% Ialproic acid # - @on-:inear ,inetics !5or /+;, chronic dose studies may be re7uired% Ierpamil # - @on-:inear ,inetics !5or /+;, chronic dose studies may be re7uired%

FD% Special Guidances E*ceptions+ Bioequivalence

FD% Special Guidances+ #lo1apine +otassium #hloride FD% E*ceptions+ /he following drugs are defined by the 2008 5;" >range BooB as, L;9U? +9>;U#/< 4G*#G AU</ ;EA>@</9"/E *@ I*I> B*>"I"*:"B*:*/M >@:M *5 +9>;U#/ 5"*:< /> "#G*EIE ";ENU"/E ;*<<>:U/*>@L Source$ +&&/$!!777.*da.(ov!cder!oran(e!o-annual./d*

<teady-state study in patients re7uired at 100 mg& <ee http-22www&fda&go 2#;E92?U*;"@#E <teady-state study re7uired& <ee http-22www&fda&go 2#;E92?U*;"@#E2old1(5fn&pdf

www&fda&go 2#;E92?U*;"@#E2J0KKfnl&pdf ?U*;"@#E2old1(5fn&pdf