w wz 19«1y Kor. J. Clin. Pharm., Vol. 19, No. 1. 2009 ƒ j (highly variable drug w x w x sƒ y B Á x B Á«Ÿ B B û w w w w (2009 5 15 Á2009 6 12 Á2009 6 15 Bioequivalence Approaches for Highly Variable Drugs: Issue and Solution In-hwan Baek a, Soo-hyeon Seong a, and Kwang-il Kwon a, * a College of Pharmacy, Chungnam National University, Daejeon, Korea (Received May 15, 2009ÁRevised June 12, 2009ÁAccepted June 15, 2009 Highly variable drugs (within-subject variability greater than 30% have been difficult to meet current regulatory acceptance criteria using a reasonable number of study subjects. In this study, we reviewed previous studies presenting alternative approaches for bioequivalence evaluation of highly variable drugs, and focused on an approach for widening the bioequivalence acceptance limits using within-subject variability. We discussed the suggested five solutions for highly variable drug including the deletion of C max of the bioequivalence criteria, direct expansion of bioequivalence limit, multiple dose studies in steady state, bioequivalence assessment on the metabolite, add-on study, and widening the bioequivalence acceptance limits based on reference variability. The methods for widening of bioequivalence limits based on reference variability are scaled average bioequivalence containing within-subject variability on reference drug (σ WR, population bioequivalence derived from total variability on reference drug (σ TR and test drug (σ TT, and individual bioequivalence derived from subject by formulation interaction variability (σ D and within subject variability on reference drug (σ WR and test drug (σ TR. To apply these methods, the switching variability (σ 0 will have to be set by the regulatory authorities. The proposals of bioequivalence evaluation approach for the highly variable in Korea are presented for both of new drug and reevaluation drug. Key words - Highly variable drug, bioequivalence, within-subject variability, switching variability ü KFDA (Korea Food and Drug Administration, t t w w ( x w w ü x, yx z ùkü t w w w n ƒ m w w w» w w x w. 1 x 12 e w p ƒ w, x w z, 2 2 x œ k x n 1z n w e wš. w ƒ x š, 1 Correspondence to : «Ÿ Ÿ w 79 û w 305-764 w w 406y w Tel: +82-42-821-7310, Fax: +82-42-823-6781 E-mail: kwon@cnu.ac.kr z n w sƒw x š w (area under the concentration-time curve, AUC t š x (the peak or maximum concentration, C max yw m w, yw s³e 90% log 0.8 log 1.25 ü w. 1 ü x» ƒ» w j ƒ. 2,3 NIHS (the National Institute of Health Sciences x» ü» w wš, 4 FDA (Food and Drug Administration» ü» w AUC t C max m w yw s³e 90% log 0.8 log 1.25 ü w, FDA average bioequivalence (ABE š w. 5 w FDA ABE population bioequivalence (PBE individual bioequivalence (IBE wš, ƒ bioequivalence w x ww PBE IBE w. 6 50
ƒ j (highly variable drug w x w x sƒ 51 EMEA (European Medicines Agency ü» w AUC t C max m w yw s ³e 90% log 0.8 log 1.25 ü ³ wš., C max ƒ z w e 90% log 0.75 log 1.33 ü w y w. 7 eù HFPB sƒ w AUC t x yw s³e 90% log 0.8 log 1.25 ü ³ wù, C max 90% w ³ x yw s³e (the Geometric Mean Ratio, GMR 80% 125% ü ƒ w q wš. 8 ù» w x» w., x v w, ƒ j (highly variable drug, HVD x w wš, x» w m w w š ù ƒ j. p w x p y š w ³ p» x w w. x FDA p w w» sww w x» 15ƒ w ƒ w š š,»k w w 15ƒ ƒ ƒ wš. 9,10 EMEA w x» 7 ù 40 ƒ œ x œwš. 9,11 eù HPFB w x» p w š w 17ƒ ù ƒ œwš. 9,12 p» v w ƒ j (highly variable drug, HVD š HVD w Áü ³ š HVD w p» ( w» wš w. w» ( ƒ š z scaled average bioequivalence (SABE, population bioequivalence (PBE individual bioequivalence (IBE w š, ü y š w w HVD p» w wš w. wš ù, 16 x FDAƒ w wz American Association of Pharmaceutical Scientists (AAPS sww w z t ƒ ù t ƒ» ww ƒ AUC t C max within-subject variabilityƒ 30% HVD w. 7,17-19 FDAƒ 2003 2005 ANDAs (Abbreviated New Drug Applications FDA m t AUC t C max within-subject variabilityƒ 30% w,» w 32% (180 57, t» w 19% (524 t 101 t, x œ x sww x z» w 11% (1010 x 111 ƒ HVD š 2008 tw. 20 t HVDƒ w y w, HVD w ƒ p ƒ dw. dw HVD p wù x vx sww w x y HVD q, p HVD w. x š HVD j v (chlorpromazine, v qr (propafenone, q (verapamil, ù (nadolol kp (simvastatin ù, 18,19,37,42,59 x ww ù v x x w w HVD š, HVD ƒ, HVD w üá x w t x ¾ w. FDA tw t HVDƒ w y w wù» HVD w t» w HVD û, œ x x sww x z» w HVDƒ w û w» ³ x vx, BE limit w HVD w qw y. ƒj IJHIMZWBSJBCMFESVH ƒ j (highly variable drug, HVD w x k w q l AUC t C max ü (withinsubject variability intra-subject variabilityƒ 30% w. 13,14,15 x AUC t C max within-subject variabilityƒ 25% HVD š w x WBSJBUJPO w x (variation j x ƒvw w (inescapable variation x w w j» w (controllable variation ù. x ƒvw w vx w w
52 Kor. J. Clin. Pharm., Vol. 19, No. 1, 2009 Table 1. Source of variation in bioequivalence studies Inescapable variation Controllable variation Subject differences - Between-subject variation - Within-subject variation Genetic polymorphism Formulation differences Subject-by formulation interactions Random error (between-subject variability inter-subject variability ü (within-subject variability intra-subject variability (Table 1. 21,22 ü mp (total variance w, HVD» within-subject variability 2 3 2 4 x (replicated w z mw w (eq.1. σ 8M = ---------------------------------- ( χ ( O + O JML χ ML L = J = n k = k n i = vx (i=1, 2,, n k l= drug (l=test drug reference drug O L Carryover effects - Drug metabolite residue - Induction or inhibition Time factor - Sampling time - Storage factors Physiological factors - Gastric emptying - Food fluid and other drugs - Diurnal variation (eq.1 Within-subject variability x w, w, n ù (BCS class IV, x sww x, y,, x (genetic polymorphism x w. 20,23-26 w x 2 2 x w vx ƒ x ( x 1z n w x (non-replicated eq. 1 mw within-subject variability w.»k (residual variance mw w ANOVA-CV withinsubject variability w (eq.2. 18,21,27 Within subject variability ANOVA CV = ANOVA CV = residual variance 100% (eq. 2 2 2 x residual variance kw ùkù ü wš, ü variation x w»e w w (unexplained random variation sww. 18,28,29 x residual variance mw ANOVA-CV ƒw ü t t w œ w sƒ v K-BE test 2007 (ver 1.1.0 w x w ANOVA- CV y w. ü l w w HVD HVD» w wš y w z ƒ. JHIMZWBSJBCMFESVH» w» wv w ƒ j (HVD» ƒ j x ƒ w m w» w vx ƒ v w. 14,30, within-subject variabilityƒ 35% HVD x ƒ 100% w š ƒ w x ³ AUC t C max 90% ƒ 0.8 1.25 ü» w 54 ƒ v w, ƒ 5% ƒw HVD w vx»w ƒw (Table 2. 31 üá IJHIMZWBSJBCMFESVH» ƒ j (HVD w» w w Áü HVD w ƒ x wš. ü t t œw w» (š 2008-22y, HVD w y ù ƒ j Table 2. The needed number of subjects to conclude average bioequivalence (2 2 non-replication Within subject Relative bioavailability (real difference variability (ANOVA-CV% 1.00 1.05 1.10 1.15 25 30 36 66 152 30 40 52 92 214 35 54 68 124 288 40 68 86 158 368 42 84 106 196 456 50 100 168 236 552
ƒ j (highly variable drug w x w x sƒ 53 n w k (steady-state g x w. 1» y w» w ƒ j w ƒ yw v ƒ, w» HVD w» k w, w š mw w. ü w HVD w x w š š wš, v» vx mw ƒ x (add-on study, n x (multiple dose study, study w š wš. 4 wz FDA t x mw HVD w» w w, HVD w» w ü xk. ƒ mw wš» average bioequivalence wš, ƒ population bioequivalence (PBE individual bioequivalence (IBE wš. PBE IBE» (BE limit w ƒƒ w reference-scaled method ƒ» w w constant-scaled method ù, ƒ j reference-scaled method constant-scaled method w z,» ƒ ( w kw w (mixed-scaled method. 6 m mw 2 2 x 4» x (replicated mw HVD w. 32 scaled average bioequivalence (SABE m wš, SABE ƒ ƒ z š w ƒ m. 33,34 2006 BA/BE for HVDs/HVDPs ƒ mw HVD AUC t C max within-subject variabilityƒ 30% w, 35 z 2008 7 ƒ w C max ƒ z w š, x mw within-subject variabilityƒ 30%, x z C max š w 90% 75~133% y w w š š wš. 7 eù ³ C max w 90% ³ w š,»ws³ (GMR 80~125% ³ w q wš HVD w p» š w š. 8, ƒ w HVD w discussion w w variability, HVD», HVD (chloropromazine HVD p Table 3. Alternative approaches bioequivalence evaluation of highly variable drugs Method Reasonability Efficiency Deletion of C max Low High Direct expansion of BE limit Low High Multiple dose studies for steady state High Low Assessment bioequivalence on the metabolite Medium Medium Add-on study Medium Low The widening of BE limits based on reference variability High High» ( wš. 18 IJHIMZWBSJBCMFESVHp» x HVD ƒw w ƒ mw p» ù w HVD ƒ w p» ( FDA, EMEA, eù HFPB x w t mw š. HVD w p» ( j 6ƒ w (Table 3. w sƒw $ NBY ƒ j (HVD w sƒw C max ƒ AUC t j (variability ƒ. 36,37 C max ƒ HVD w q w» š ƒ w AUC t ƒ š HVD w q w p» (. AUC t» (BE limit ³ ƒ 90% 0.8 1.25 ü w w» w. 38 w sƒw $ NBY» #& MJNJU y p» ( ƒ j (HVD w sƒw C max ƒ AUC t j (variability ƒ wš. 36,37 AUC t w BE limit 90% 0.8 1.25 ü wš, C max w BE limit w x v w v x w» ww. 39,40 p» ( x EMEA wš, EMEA HVD w p» C max w 90%
54 Kor. J. Clin. Pharm., Vol. 19, No. 1, 2009 0.75 1.33 ü ³ wš. 7 n mw k TUFBEZTUBUF x n w k k HVD ü ƒ k HVD w w w ƒ w š. 41,42 x ü ƒ w š. 1 ù p» ( HVD w» š. t el-tahtawy AA n w s HVD C max monte carlo simulation mw dw., z n w n w s C max x, C max z n w n w. 41 n mw k x HVD w p» ( w ƒ š. NFUBCPMJUFd mw x ü xk w parent w y ù ƒ HVD parent d w w q w» š. 43 p terfenadine parent terfenadine AUC t C max within-subject variabilityƒ 48.3%, AUC t C max within-subject variability 14.7% j, d mw HVD t y š. 43,44 ù p» ( w» š., ƒ HVD w, w p z m z ƒ j w e d mw ƒ. 40,43 d mw HVD w» w ƒ š w w. ƒ x BEEPOTUVEZ mw x ü w, eù ƒ j (HVD w ³ w ww mw x w w within-subject variability. p» ( ƒ x mw w. x mw ƒ x ww w vx ƒ ƒw within-subject variability w p» (. 40,45 w vx ƒw HVD w» w vx v w z, Table 2 mw» w. WBSJBCJMJUZ š w» #&MJNJU y FDA EMEA, eù HFPB š HVD p» variability mw BE limit 90% 0.8 1.25. 18,27,39,40 variability š w BE limit y w scaled average bioequivalence (SABE, population bioequivalence (PBE, individual bioequivalence (IBEƒ, 3ƒ œm variability š Table 4. Variance and study for average bioequivalence, scaled average bioequivalence, population bioequivalence, and individual bioequivalence Bioequivalence Variation Study Average bioequivalence No variation 2 2 non-replication Scaled average bioequivalence Population bioequivalence Individual bioequivalence Within-subject variability on reference drug or residual variance Switching variance Within-subject variability on reference drug or residual variance Total variance Switching variance Within-subject variability on reference drug Within-subject variability on test drug Subject by formulation interaction variance Switching variance 2 2 non-replication 2 3, 2 4 replication 2 2 non-replication 2 3, 2 4 replication 2 3, 2 4 replication
ƒ j (highly variable drug w x w x sƒ 55 w switching variance ( ƒ» w w BE limit w (Table 4. 38,40,47» y w m p» ( w š z, ƒ š l w x w. 6,16,46 Scaled average bioequivalence (SABE 2 2 x mw AUC t C max s³ mw» (BE limit 0.8 1.25 ü ³ w average bioequivalence š w, ùký (eq.3. 6,48 0.8 mean T ---------------- 1.25 meanr (eq. 3 yw txw txw (eq. 4. 0.223 ( µ T µ R 0.223 µ T : x y sƒw s³ µ R : y sƒw s³ (eq. 4 SABE ABE within-subject variability (σ WR ƒ w switching variance (σ W0 š w xw, (eq. 5 2 2 x (nonreplication study 2 3 2 4 x (replication study ƒ w., 2 2 x w within-subject variability (σ WR residual variance mw w ANOVA-CV w. 46,49,50 0.223 ------------ σ WR µ T µ R σ W 0 ( σ W 0 0.223 ------------ σ WR σ W0 : ƒ» w (switching variance σ WR : within-subject variability µ T : x y sƒw s³ µ R : y sƒw s³ (eq. 5 Population bioequivalence (PBE PBE s³ š w w m x total variance (σ TR, σ TT m w BE limit w. 6,51,52 Total variance ü (within-subject variability (between-subject variability ww yw w» w 2 3 2 4 x (replication study w, 2 2 x (nonreplication study within-subject variability residual variance mw total variance w. PBE ³ w BE limit (θ P w eq. 6. 6,53 θ 1 (*O + ε 1 = ----------------------------------, ε 1 = ( σ 55 σ 53 σ 5 θ P :» (BE limit σ TT : x total variance σ TR : total variance σ T0 : ƒ» w (switching variance (eq. 6 w BE limit w» w 90% eq. 7 w w. σ TR w ùkü reference-scaled method š σ T0 w ùkü constant-scaled method, ƒ j (HVD σ TR σ T0 j w 90% w (mixed-scaled method. µ 5 µ ( 3 + ( σ 55 σ 53 σ 53 ------------------------------------------------------------- θ 1 PS µ 5 µ ( 3 + ( σ 55 σ 53 ------------------------------------------------------------- θ 1 σ 5 θ P =» (BE limit µ T : x y sƒw s³ µ R : y sƒw s³ σ TT = x total variance σ TR = total variance σ T0 : ƒ» w (switching variance (eq. 7 x total variance w BE limit ³ w PBE x (2 2 x x (2 3 2 4 x ƒ w x w x w f š, x w x w ƒ. Individual bioequivalence (IBE IBE x y s³ (µ T - µ R w vx formulation n w ùkú x vx y (σ D x within-subject variability (σ R σ T š w BE limit w. 2 2 x (non-replication study mw š, 2 3 2 4 x
56 Kor. J. Clin. Pharm., Vol. 19, No. 1, 2009 x (replication study w. 6,54-56 IBE ³ w BE limit (θ I w eq. 8. θ * (*O + ε * = ---------------------------------, ε * = σ % + ( σ 85 σ 83 σ 8 θ I :» (BE limit σ D : x vx y variance σ WT : x within-subject variability σ WR : within-subject variability σ W0 : ƒ» w (switching variance (eq. 8 w BE limit w» w 90% eq. 9 w w. PBE ƒ σ TR w ùkü reference-scaled method š σ T0 w ùkü constant-scaled method, ƒ j (HVD σ TR σ T0 j w 90% w (mixed-scaling method. µ 5 µ ( 3 + σ % + ( σ 85 σ 83 σ 83 ------------------------------------------------------------------------------- θ * PS µ 5 µ ( 3 + σ % + ( σ 85 σ 83 σ 8 ------------------------------------------------------------------------------- θ * θ I =» (BE limit µ T : x y sƒw s³ µ R : y sƒw s³ σ D : x vx y variance σ WT : x within-subject variability σ WR : within-subject variability σ W0 : ƒ» w (switching variance ƒ w TXJUDIJOHWBSJBODF σ (eq. 7 Switching variance ƒ j (HVD Table 5. Types of switching variance (σ 0 Switching variance» (BE limit w w σ D t»w, m SABE IBE σ W0, PBE σ T0 t»w. 6,50 σ D BE limit ³ w» y, switching variance 0.2, 0.223, 0.25, 0.294 4ƒ ƒ (Table 5. p individual bioequivalence criterion (IBC mw w 0.2 Health Canada Therapeutic Products Directotate (TPD w 0.25ƒ š. 8,16,38,47 switching variance ƒ j w xƒ» ƒ ³ w j ƒ. #&MJNJUy x w SABE, PBE, IBE within-subject variability š w BE limit y w HVD p» ( w š w, BE limit w w 1x (type I error 2x (type II error x. 15, 1x (type I error x t w x w q w, 2x (type II error t w x w q w w. 1x (type I error 2x (type II error, 1x (type I errorƒ w y ƒ w š, 2x (type II error ƒ w z ƒ w, w x w w w wù. 57,58 SABE, PBE IBE w BE limit y w 1x (type I errorƒ w ƒ f. w w y 90% wì x yw s³e (the Geometric Mean Ratio, GMR 80% 125% ³ w Calculated base The constant was calculated by individual bioequivalence criteria. 0.2 It can be most widen bioequivalence limit. The constant was calculated by 0.223 ------------ = 1 0.223 σ 0 It is useful for application to scaled average bioequivalence (SABE. 0.25 The constant was suggested by Health Canada. 0.294 The constant was calculated by 0.3= FYQ ( σ The most strict constant for establishment BE limit.
ƒ j (highly variable drug w x w x sƒ 57. w monte carlo simulation mw y w. Within-subject variabilityƒ 35% HVD v x 24 mw w ƒ w wš» w w y 42.6% w,» (BE limit 70% 143% ü y w p» w w y 94.1% ƒw. w 35%ƒ ƒ û wš y p» w w y 14.9% ƒ.» x yw s³e (the Geometric Mean Ratio, GMR 80% 125% ³ w, ƒ w 94% w, ƒ 35% ƒ ú w y 6.8% û. x yw s³e (GMR 80% 125% ³ w 90% y w HVD w w 1x (type I error (Table 6. 15 ü w IJHIMZWBSJBCMFESVH p» mw ƒ j w ƒ š w, p» ( scaled average bioequivalence (SABE, population bioequivalence (PBE, individual bioequivalence mw w» (BE limit k w y w, x yw s³e (GMR 80% 125% ³ w. w ƒ w switching variance (σ 0 0.2 0.25 w. ü w w» ù w w z sƒ ƒ, ü p w y š w HVD w p» ( ü ü q» z z sƒw ù w. Table 6. Comparisons of bioequivalence pass rate (% by geometric mean ratio (GMR and 90% confidence interval (C.I.. Bioequivalence rate (% (within subject variability=35%, n=24 True ratio GMR 80~125% 90% C.I. 80~125% No constraint GMR. 90% C.I. 70~143% GMR 80~125% 90% C.I. 70~143% 1.0 42.6 94.1 94 1.05 38.2 91.4 91.3 1.15 17.2 69.4 67.1 1.25 4.9 37 29.5 1.35 0.9 14.9 6.8 1.45 0.1 3.8 0.8 xƒ w7%p» HVD HVD withinsubject variability y q w v ƒ, ³ ƒ w v ƒ. 2 3 2 4 x (replicated ww withinsubject variability wš, w» (BE limit scaled average bioequivalence (SABE population bioequivalence (PBE individual bioequivalence (IBE wù kw HVD w k w. ƒ ³ w switching variance 0.2 0.25 w ³ w 0.25 kw w, ³ w ƒ j (HVD within-subject variabilityƒ 25% ³ Table 7. Bioequivalence study suggested for HVD of new drug and re-evaluation drug system in Korea New drug Re-evaluation drug Biostatistics SABE PBE IBE SABE PBE IBE Study Variability 2 3 reference replicated or 2 4 replicated Within subject variability of reference drug 2 3 reference replicated or 2 4 replicated Total variance (within subject variability + between subject variability 2 4 replicated 2 2 non-replicated Within subject variability of reference drug and test Residual variance drug 2 2 non-replicated Total variance (residual variability + between subject variability 2 4 replicated Within subject variability of reference drug and test drug Switching variance 0.25 0.25 0.25 0.2 0.2 0.2
58 Kor. J. Clin. Pharm., Vol. 19, No. 1, 2009 w w (Table 7. z sƒ w7%p» z sƒ HVD ƒ y w, x ƒ ³ y ³ w. 2 3 2 4 x (replicated mw within-subject variability 2 2 x (nonreplicated mw residual variance y w w. w» (BE limit residual variance w scaled average bioequivalence (SABE population bioequivalence (PBE w. w ƒ ³ w switching variance 0.2 0.25 y ³ w 0.2 kw w, p» ( w ƒ j within-subject variability ANOVA-CV (residual variance mw w within-subject variability 20% ³ w. w z ƒ w 2 3 2 4 x mw SABE PBE IBE w (Table 7. ƒ j (HVD p» v š HVD p» ( wš w ƒ j w w w. 6ƒ HVD p» ( ƒ w š ü (within-subject variability mw 90% y w, w scaled average bioequivalence (SABE, population bioequivalence (PBE individual bioequivalence (IBE 3ƒ ƒ.» w» w 2 3 2 4 x (replicated mw w ü (within-subject variability w š, 2 2 x (non-replicated mw»k (residual variance w ANOVA-CV (withinsubject variability w y w. w w» w ƒ w (switching variance ³ w w, ƒ 0.2 0.25ƒ. ü z sƒ p w y, ƒ j w p» ( w ³ w xƒw w w w. ƒ j x v w x, p x w x, z x w x š w x p» v w wì w w, mw ü t w w» mw ƒ y w. 2008 t t (08092 185 w w. š x 1. t t. w x» (š 2008-22y. : t t, 2008 2. Hauschke D, Steinijans VW, Diletti E. A distribution-free procedure for the statistical analysis of bioequivalence studies. Int J Clin Pharmacol Ther Toxicol 1990; 28: 72-78. 3. Schulz HU, Steinijans VW. Striving for standards in bioequivalence assessment: a review. Int J Clin Pharmacol Ther Toxicol 1992; 30: S1-S6. 4. The National Institute of Health Sciences (NIHS. Guideline for Bioequivalence Studies of Generic Product. Tokyo: The National Institute of Health Sciences (NIHS, 1997 5. The U.S. Food and Drug Administration (FDA. Guidance for industry: bioavailability and bioequivalence studies for orally administered drug products- general considerations. Rockville: The U.S. Food and Drug Administration (FDA, 2003 6. The U.S. Food and Drug Administration (FDA. Guidance for industry: statistical Approaches Establishing Bioequivalence. Rockville: The U.S. Food and Drug Administration (FDA, 2001 7. The Committee for Medicinal Products for Human Use (CHMP. Guidance on the Investigation of Bioequivalence. Rondon: The European Medicines Agency (EMEA, 2008 8. Health Canada. Guidance for Industry, Conduct and Analysis of Bioavailability and Bioequivalence Studies- Part A. Minister of Public Works and Government Services Canada, 1992 9. http://bebac.at/guidelines.htm
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