Bridging Update in KOREA InJin Jang MD Seoul

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

Bridging Concept and Regulatory Changes in Korea

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

Bridging Concept n n “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.

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

Bridging Waiver Category n n n n 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

Status of Bridging Waiver Category No ethnic difference Antibiotic / Antiviral / Antithrombotic (2000 - Sep. 2003) Product Name (Company) Zyvox (Pharmacia) Tamiflu (Roche) Arixtra (Sanofi-Synthelabo) Invanz (MSD) AIDS, Cancer, or Life-threatening Cancidas (MSD) disease Vfend (Pfizer) Asperogilosis / Cancer / HIV TS 1 (Che-il, Taiho) Iresa (Astra. Geneca) Crixivan (MSD)

Status of Bridging Waiver(2000 -Sep. 2003) -continued Category Product Name (Company) Orphan Drugs Zometa (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 (Daewoong), Herepair (Bo-ryung), Elidel (Novartis), Travatan (Alcon), Seoptanest (Sin-won)

Bridging Experience

Increased Number of Clinical Trials KFDA database

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

Reduced KFDA Review Time KFDA database 140 120 100 days 80 60 40 20 1998 1999 2000 2001 2002 2003 year

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

Approved products by PK bridging Company Product Active Ingredient Indication Glaxowelcome Avandia Rosiglitazone maleate Oral hypoglycemic agent (Diabetes ) Glaxowelcome Lotronex Alosetron HCL Irritable bowel syndrome Lilly Actos Pioglitazone Oral hypoglycemic agent (Diabetes ) Bayer Levitra Vardenafil PDE 5 inhibitor Novartis Zelmac Tegaserod Irritable bowel syndrome * Ten more drugs are under PK bridging study - Five in review or reporting process - Five in study or protocol development process

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