1. Bridging Update in KOREA In-Jin Jang, MD Seoul National University College of Medicine and Hospital

2. Bridging Concept and Regulatory Changes in Korea

3. Major regulatory changes Adoption of the Bridging Concept : effective since June 2001 Separation of IND from NDA : Participation in international study enabled since December 2002 since 1999

4. Bridging Concept “Bridging Data” = “Korean Data” “Bridging Study” = “A trial conducted in Korean” “Bridging Data” means data on the results of trials conducted in Koreans living home and abroad, which are excerpted or selected from the clinical data package or obtained from the bridging study. “Bridging Study” means a trial conducted in Koreans in Korea for the purpose of obtaining bridging data in case it is difficult to apply the foreign clinical data as it is because there is a difference in an ethnic factor relating to the safety and efficacy of a drug.

5. New Product Approval New Product Candidate 7 waiver categories At least ONE Bridging Study in KOREAN (Global or Local) At least ONE Bridging Study in KOREAN (Global or Local) Bridging Exemption

6. Bridging Waiver Category Orphan drugs Drugs for life-threatening diseases Diagnostic reagents No systemic effect Proven ethnic insensitivity New drugs being developed inside or outside of Korea that are intended to conduct clinical trials in Korea Other drugs given waiver by KFDA

7. Status of Bridging Waiver (2000- Sep.2003) Waiver CategoryProduct Name (Company) No ethnic difference Antibiotic / Antiviral / Antithrombotic Zyvox (Pharmacia) Tamiflu (Roche) Arixtra (Sanofi-Synthelabo) Invanz (MSD) AIDS, Cancer, or Life-threatening disease Asperogilosis / Cancer / HIV Cancidas (MSD) Vfend (Pfizer) TS1 (Che-il, Taiho) Iresa (AstraGeneca) Crixivan (MSD)

8. Status of Bridging Waiver (2000-Sep.2003) -continued CategoryProduct Name (Company) Orphan DrugsZometa (Novartis) Visudyne (Novartis) Agrylin (Yu-han) Diagnostic Reagents, Radio-phacmaceuticals Optimac (I-yeon) Teseos (Sang-jung) No systemic effect Dermal cream etc. Vaniqa (BMS), Olcenon (Yu-han), Renagel (Che-il), Tazorac (Dae- woong), Herepair (Bo-ryung), Elidel (Novartis), Travatan (Alcon), Seoptanest (Sin-won)

9. Bridging Experience

10. KFDA database Increased Number of Clinical Trials

11. KFDA database Increased Number of Multinational Clinical Trials (Dec. 2002 ~ Sep. 2003) Approved drugs for label change;  29 protocol, 21 drugs  28 Phase III & 1 Phase II studies Unapproved new drugs;  Potential bridging data generation  39 protocols, 20 compounds  22 Phase III, 6 Phase II & 1 Phase I studies

12. Reduced KFDA Review Time 20 40 60 80 100 120 140 199819992000200120022003 days year KFDA database

13. Recent Bridging Studies (Sep. 2002 ~ Jul. 2003) Nine products (10 protocols) got IND’s for bridging studies Phase III; 6 protocols  Antibiotic, Antiepileptic, Antirheumatic (Biological), Osteoporosis Rx., Lipid lowering drug, Anticoagulant Phase I; 4 protocols  Antihistamine, CV biological drug, Lipid lowering drug, Antibiotic Seven protocols from domestic sponsors for product licensing-in from Japan and Italy (1)

14. CompanyProductActive Ingredient Indication GlaxowelcomeAvandiaRosiglitazone maleate Oral hypoglycemic agent (Diabetes ) GlaxowelcomeLotronexAlosetron HCLIrritable bowel syndrome LillyActosPioglitazoneOral hypoglycemic agent (Diabetes ) BayerLevitraVardenafilPDE5 inhibitor NovartisZelmacTegaserodIrritable bowel syndrome Approved products by PK bridging * Ten more drugs are under PK bridging study - Five in review or reporting process - Five in study or protocol development process

15. Bridging Issues in Korea Acceptability of Asian Data  Asian; Same ethnicity ?  Mutual recognition of Asian data ? Statistics  Statistically meaningful sample size ?  Multinational study; subgroup analysis ? Many study design issues  Similarity ? What metric?  Titration drug  Placebo Need more scientific and flexible design & review  Bayesian, Mixed effect modeling, Simulation, Pharmacogenomics, etc.