2. In-Jin Jang M.D., Ph.D. Clinical Pharmacology Unit, Clinical Trial Center Seoul National University Hospital (SNUH) & Seoul National University College of Medicine Seoul National University Hospital (SNUH) & Seoul National University College of Medicine Experience in Korea on Bridging Studies

3. SNUH-CTC Recent Changes in Korean Regulations for Clinical Trials n n 1999 l l Elimination of compulsory conduction of local clinical trial in Korea as a condition of registration (For the products with < 3yr market experience or, For the products only marketed in the original developing country) n n Introduction of Bridging Study System; Dec. 1999 n n Bridging study waiver until June 2001 l l Allowance for conducting the multi-national, multi-center trials n n 2002 l l Separation of IND system and NDA system. l l Began to collect user-fee but not providing consultation about the clinical trial designs yet.

4. SNUH-CTC n Track for “marketing approval without domestic/Korean bridging data”;  8 drugs l 1 for life-threatening condition, l 4 orphan drugs, l 1 diagnostic, l 1 topical drug, l 1 antibiotic without domestic/Korean clinical data  on the basis of ethnic insensitivity and in vitro microbiological sensitivity test of domestic clinical isolates l 2 failed to register without domestic bridging data  Insulin analogue and one more endocrine drug Bridging Data Generation : Experiences in Korea (1)

5. SNUH-CTC n Track for single pharmacokinetic study for bridging data generation;  11 drugs l Three products were approved with single Korean pharmacokinetic clinical trial data.  Actos, Avandia, Gastrointestinal (GI) drug  GI drug study was done in Koreans living in an other country l Three sponsors finished PK studies  ED, IBS, antimuscarinic l More than 5 sponsors are planning to do PK based bridging data generation  BPH/alopecia, diuretic, vascular, antihyperlipidemic, hormonal agent Bridging Data Generation : Experiences in Korea (2)

6. SNUH-CTC n Track for phase 3 clinical study for bridging data ;  11 drugs, (12 indications) l None approved yet l Open trial: 3, Blinded trial: 9 l Placebo control: 2, Active control: 7 l Sample size: 30 (open) ~ 284 (142 x 2) l Therapeutic class  Analgesics (1), Antibiotic (1), Erectile dysfunction (1), Endocrine (3), Glaucoma (1), Antipsychotic (1), Respiratory (1), Rheumatic (2) Bridging Data Generation : Experiences in Korea (3)

7. SNUH-CTC n Multi-national phase 2/3 clinical study for bridging data ;  19 drugs, (23 trials) l None approved yet l Open trial: 7, Blinded: 12 l Placebo control: 8, Active control: 12 l Sample size: 16, 30/630, 98, 20/700, etc. l Therapeutic class  Antibiotic (3), Anticancer (7), Antifungal (1), Antihypertensive (2), Antiviral (2), ED (1), Dementia (1), Gastrointestinal (2), Osteoporosis (2), Thrombolytic (1), CNS (1) Bridging Data Generation : Experiences in Korea (4)

8. Clinical Trial Center / Clinical Pharmacology Unit Seoul National University Hospital (SNUH) Pharmacokinetics of XX prolonged release capsules in Japanese, Caucasian and Korean healthy volunteers, with a tolerability assessment in the Japanese subjects. A multiple-dose, placebo-controlled sequential dose-escalation study

9. SNUH-CTC Study Summary n Objectives: show similarity in steady state AUC for the active moiety (sum of the unbound parent drug and metabolite1) between Japanese versus Caucasians and Japanese versus Korean subjects n Study design: l Parallel group l Age/weight matching of the Caucasian and Korean groups to Japanese l Single-dose and 5-day multiple dose administration n Dosage and subjects Treatment definition JapaneseCaucasianKorean ActivePlaceboActiveActive x mg 1231212 2x mg 1231212 3x mg 1231212

10. SNUH-CTC SubstancePeriodRatio 90 C.I. Lower bound 90 C.I. Upper bound Active (M1+P)Day 1 incl. outliers0.910.801.03 Metabolite1Day 10.930.821.05 Parent drugDay 1 incl. outliers0.770.501.18 SubstancePeriodRatio 90 C.I. Lower bound 90 C.I. Upper bound Active (M1+P)Day 7 incl. outliers0.900.781.03 Metabolite1Day 7 incl. outliers0.840.710.98 Parent drugDay 7 incl. outliers0.800.511.26 Point estimate and 90 % C.I. for AUC 0-  ratios in Japanese/Caucasian

11. SNUH-CTC SubstancePeriodRatio 90 C.I. Lower bound 90 C.I. Upper bound Active (M1+P)Day 1 incl. outliers0.770.670.89 Metabolite1Day 1 incl. outliers0.810.720.92 Parent drugDay 1 incl. outliers0.500.390.65 SubstancePeriodRatio 90 C.I. Lower bound 90 C.I. Upper bound Active (M1+P)Day 7 incl. outliers0.720.620.83 MetaboliteDay 7 incl. outliers0.700.590.82 Parent drugDay 7 incl. outliers0.520.390.70 Point estimate and 90 % C.I. for AUC 0-24 ratios in Japanese/Korean

12. In-Jin Jang M.D., Ph.D. Clinical Pharmacology Unit /Clinical Trial Center Seoul National University Hospital (SNUH) Phase I Study of YY, Placebo-controlled, Double- blind, Group-comparison, Dose-escalation study to Investigate Safety, Tolerability, and Pharmacokinetics after Single Oral Dosing of 5mg, 10mg and 20mg in Healthy Subjects

13. SNUH-CTC Study Summary n Study design l Placebo-controlled, single ascending dose, parallel group l Double-blind, randomized study n Dosage and subjects StepsDosage Number of Subject Drugs 1 5 mg 8 Active, 5mg tablet 2 Placebo, 5mg tablet 2 10 mg 8 Active, 10mg tablet 2 Placebo, 10mg tablet 3 20 mg 8 Active, 20mg tablet 2 Placebo, 20mg tablet

14. SNUH-CTC Pharmacokinetics Plasma concentration profiles of Study Drug after single oral dosing of 5, 10 and 20 mg under fasting condition

15. SNUH-CTC Korean vs. Caucasian Study Number 000 Race KoreanCaucasian (n=8) (n=24) Dose (mg)510201020 T max (h) b 0.5 (0.5~0.75) 0.5 (0.5~0.75) 0.5 (0.5~1.0) 0.884 (0.50~1.5) 0.992 (0.48~1.5) C max ( ㎍ /L) 9.70/1.40 17.14 /1.76 41.55 /2.19 7.03 /1.73 18.5 /1.52 AUC ( ㎍ *h/L) 17.92/1.4135.26/1.6593.49/1.8828.8/1.6270.0/1.53 T 1/2 (h)3.49/1.443.31/1.323.51/1.334.76/1.514.80/1.36 Vz/F (L/kg)21.54/1.6119.78/1.5716.63/1.5629.6/1.7724.6/1.50 CL/F (L/h)278.9/1.41283.6/1.65213.9/1.88347/1.62286/1.53

16. SNUH-CTC Korean vs. Caucasian

17. Evaluation of Safety and Pharmacokinetics of Single Dose of Rosiglitazone in Healthy Korean Volunteers In-Jin Jang, MD, PhD Clinical Trial Center / Clinical Pharmacology Unit Seoul National University Hospital (SNUH)

18. SNUH-CTC

21. ACTOS ® PK/PD Modeling and Simulation for Bridging In-Jin Jang MD PhD Clinical Trial Center/Clinical Pharmacology Unit Seoul National University Hospital KFDA CPAC 2002.2.22

22. SNUH-CTC DosePioglitazonePlacebo 15 mg 30 mg 45 mg 6 Male + 3 Female 2 Male + 1 Female A Single Dose, Dose-Escalation Study to Assess the Pharmacokinetic Characteristics and Safety/Tolerability of Pioglitazone in Healthy Korean Subjects

23. SNUH-CTC Direct AUC Comparison Koreans vs. Western

24. SNUH-CTC Predicted Glucose Response - AUC Relationships in Korean Populations Glucose -AUC relationships from global data supports 15 and 30 mg as efficacious doses in Koreans

25. SNUH-CTC Parameter Estimate StdErr %SE --------- ------ ------ ---- THETA #1 KA 2.50 0.883 35.32 THETA #2 CL 3.16 0.145 4.59 THETA #3 V2 29.3 1.29 4.40 THETA #4 orig -0.416 0.0403 9.69 OMEGA #1 CL 0.109 0.0151 13.85 SIGMA #1 - 0.181 0.0140 7.73 $PK PJ=0 IF(PROJ.EQ. 7110115) PJ=1 KA=THETA(1) TVCL=THETA(2)*(1 + PJ*THETA(4)) CL =TVCL*EXP(ETA(1)) TVV =THETA(3) V =TVV S2 =V $ERROR IPRED = F W=IPRED+0.000001 IRES=DV-IPRED IWRES=IRES/W Y = F*EXP(ERR(1)) Korean & US Combined PK by NONMEM

26. SNUH-CTC Simulation Plan Korean Study DoseAUC US Study DoseAUCResponse Emax Model Response Actual US Results Comparison

27. SNUH-CTC Trial Simulation Platform 5 dose group (0, 7.5, 15, 30, 45 mg, N=500), 300 replications

28. SNUH-CTC -5.0-4.6-4.2-3.8-3.4-3.0-2.6-2.2-1.8-1.4-0.6-0.2 Distribution of 300 Mean Changes in FBG (mM) of Korean 15mg Group 0 5 10 15 20 25 US 30mg Group Mean Effect = -1.749 20.5 percentile Median = -1.975

29. SNUH-CTC -5.0-4.6-4.2-3.8-3.4-3.0-2.6-2.2-1.8-1.4 Distribution of 300 Mean Changes in FBG (mM) of Korean 30 mg Group 0 5 10 15 20 25 US actual trial 45mg Group Mean Effect = -3.0745 53.2 percentile Median = -3.04

30. SNUH-CTC 0304560 0.07.515.030.045.0 -10 -5 0 5 Predicted CFBG Dose For Korean patients (mg/day) Dose For US patients (mg/day) US Korean Predicted Mean Change From Baseline Overlapping of Effect Range

31. SNUH-CTCConclusion n n Bridging concept is actively applied but regulatory experience is still limited in Korea. n n No official bridging study has been requested by Korean regulatory body until now. n n Differences in pharmacokinetics among ethnic groups (even between Japanese and Korean) were frequently observed. n n Mechanisms and clinical implications of such PK differences should be explored and reflected in local label on scientific bases. n n Need sponsors’ cooperation and changes in attitude (strategy ?) toward more scientific and informative clinical development in Korea.