1. 1 Bridging Study Evaluation - The Three-year Experience in Taiwan Center for Drug Evaluation Center for Drug Evaluation Yi-jin Chiou, Ph.D. Yi-jin Chiou, Ph.D. October 28, 2003 October 28, 2003

2. 2 Regulatory Reform in Clinical Trials July 7 Announcement (1993): An approved study report of a local clinical trial is required for the new drug application in Taiwan Double 12 Announcement (2000): Bridging Studies *2001: BSE optional; BS optional if not waived *2003: BSE mandatory; BS optional if not waived *2004: BSE mandatory; BS only if not waived

3. 3 Current Checklist for Assessing Ethnic Sensitivity PK/PD Properties 1. Linear or non-linear PK in therapeutic dose range 2. Steep or flat concentration-effect curve for efficacy and safety 3. Narrow or wide therapeutic dose range 4. Whether it is highly metabolized, especially via a single pathway 5. Whether it is metabolized by genetically polymorphic enzymes 6. Whether it is administered as a prodrug via variable enzymatic conversion 7. High or low inter-subject variation in bioavailability 8. High or low bioavailability Clinical Properties 1. Likelihood of use in a setting of multiple co-medications 2. Likelihood of inappropriate use 3. Different indications and/or epidemiology 4. Other factors of ethnic sensitivity (e.g. medical practice, culture, climate)

4. 4 Results for BS Evaluation (I) (01/2001-8/2003)  Application － 74 cases  Case evaluated (62) 33 (53%) Asian data 29 (47%) No Asian data  BS waived (49)(79%) 26 (79%) 23 (79%) Asian data No Asian data

5. 5  13 cases-bridging study not waived (21 %) Case #Asian dataPKPDEfficacySafetyExtrinsic factors 1Yes ★ 2 ★★ 3 ★★★★ 4 ★★ 5No ★ ★★ ★★ ★★ ★ 6Yes ★★ 7No ★★ 8 ★ ★★ ★ 9Yes ★★ ★★ ★ 10Yes ★★★ 11 Yes ★★★★ ★★ ★ 12No ★ 13No ★ 14Yes ★★★ 15Yes ★★ ★ Concerns of drug-drug interactions; ★ Concerns of dose adjustment

6. 6  13 cases-bridging study not waived (21 %) Case #Asian dataReasons for not waiving BS 1YesPK studies not meeting regulatory requirement 2YesProposed dose and AE incidence higher in Asians 3NoNon-linear PK? ethnic difference in efficacy/safety? 4NoNon-linear PK; lack of Asian data; safety concern 5YesNon-linear PK; drug-drug interaction; dose concern; medical practice (antibiotics) 6YesEthnic difference in efficacy/safety? 7NoInsufficient dose-response data 8NoPotential drug-drug interaction (high CL); lack of Asian data 9YesInsufficient PK and efficacy/safety data; dose concern 10YesPK difference; lack of PD data; dose concern 11 YesDose concern; different medical practice/disease prevalence 12NoInsufficient PK data 13NoLack of Asian data; difference between Caucasian and Black 14YesDifferent PK between Caucasian/Japanese; insufficient Asian data; liver AE at high dose 15YesMetabolism unclear; PK higher than in Chinese; lack of dose- response; dose concern

7. 7 Recommended Checklist for Assessing Ethinic Sensitivity PK/PD Properties 1. Linear or non-linear PK in therapeutic dose range 2. Steep or flat concentration-effect curve for efficacy and safety 3. Narrow or wide therapeutic dose range 4. Whether it is highly metabolized, especially via a single pathway 5. Whether it is metabolized by genetically polymorphic enzymes 6. Whether it is administered as a prodrug via variable enzymatic conversion 7. High or low inter-subject variation in bioavailability 8. High or low bioavailability Clinical Properties 1. Likelihood of use in a setting of multiple co-medications 2. Likelihood of inappropriate use 3. Whether notable hepatobiliary side effects exist 4. Whether clinically alarming drug resistance exists in the new region 5. Likelihood of higher incidence of an AE due to a different standard of care 6. Likelihood of poor tolerability because of major side effects 7. Administration by titration or fixed dose Lin et al. DIA 37: 143-145, 155-158, 2003