Transcript Drug-related ethnic specificity & bridging studies

Bridging Study Evaluation
- The Three-year Experience in Taiwan
Center for Drug Evaluation
Yi-jin Chiou, Ph.D.
October 28, 2003
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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
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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)
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Results for BS Evaluation (I)
(01/2001-8/2003)
 Application－74 cases
Asian data
 Case evaluated
(62)
33 (53%)
No Asian data
29 (47%)
Asian data
 BS waived
(49)(79%)
26 (79%)
No Asian data
23 (79%)
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 13 cases-bridging study not waived (21 %)
Case #
Asian data
PK
1
Yes
★
2
Yes
3
Yes
★
4
Yes
★
5
No
★★
6
Yes
7
No
★
8
No
★★
9
Yes
★
10
Yes
★
11
Yes
★
12
No
★
13
No
★
14
Yes
★
15
Yes
★
PD
Efficacy
★
Safety
Extrinsic factors
★
★
★
★
★
★★
★
★
★
★★
★
★
★
★
★
★
★ Concerns of drug-drug interactions; ★ Concerns of dose adjustment
★★
★
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 13 cases-bridging study not waived (21 %)
Case #
Asian data
Reasons for not waiving BS
1
Yes
PK studies not meeting regulatory requirement
2
Yes
Proposed dose and AE incidence higher in Asians
3
No
Non-linear PK? ethnic difference in efficacy/safety?
4
No
Non-linear PK; lack of Asian data; safety concern
5
Yes
Non-linear PK; drug-drug interaction; dose concern; medical practice
(antibiotics)
6
Yes
Ethnic difference in efficacy/safety?
7
No
Insufficient dose-response data
8
No
Potential drug-drug interaction (high CL); lack of Asian data
9
Yes
Insufficient PK and efficacy/safety data; dose concern
10
Yes
PK difference; lack of PD data; dose concern
11
Yes
Dose concern; different medical practice/disease prevalence
12
No
Insufficient PK data
13
No
Lack of Asian data; difference between Caucasian and Black
14
Yes
Different PK between Caucasian/Japanese; insufficient Asian data;
liver AE at high dose
15
Yes
Metabolism unclear; PK higher than in Chinese; lack of dose-
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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
<Ref> Lin et al. DIA 37: 143-145, 155-158, 2003
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