1.法規制度、品質、效率、人才與未來發展2.從華人族群基因、特有疾病到執行國際級 臨床認驗

胡 幼 圃 特 聘 教 授胡 幼 圃 特 聘 教 授考試院考試委員考試院考試委員

國防醫學院國防醫學院 // 台大醫學院台大醫學院 100.3.25

兩岸臨床試驗利基與競爭力 ( 一 )

內容

1. 海峽兩岸醫藥衛生合作協議 2. 我們臨床試驗之現況3. 華人族群基因4. 華人特有疾病5. 我們的利基合作進行國際級臨床試驗

1. 海峽兩岸醫藥衛生合作協議

海峽兩岸醫藥衛生合作協議 第三章 醫藥品安全管理及研發

十、 合作範圍 本協議所稱醫藥品，指藥品、醫療器材、健康食品（保健食品）及化粧品，不包括中藥材。 雙方同意就兩岸醫藥品的非臨床檢測、臨床試驗、上市前審查、生產管理、上市後管理等制度規範，及技術標準、檢驗技術與其他相關事項，進行交流與合作。

十四、 臨床試驗合作

雙方同意就彼此臨床試驗的相關制度規範、執行機構及執行團隊的管理、受試者權益保障和臨床試驗計畫及試驗結果審核機制等，進行交流與合作。 在符合臨床試驗管理規範（ GCP ）標準下，以減少重複試驗為目標，優先以試點及專案方式，積極推動兩岸臨床試驗及醫藥品研發合作，並在此基礎上，探討逐步接受雙方執行的結果。

2. 我們臨床試驗之現況

Domestic trial vs multi-national trial

Volume of Clinical Trials in Asia PacVolume of Clinical Trials in Asia Pacific Regionific Region- - Taiwan is a major site allocated by big pharmaTaiwan is a major site allocated by big pharma

Data accessed from www.clinicaltrials.gov 2009

193

625

125

511

216

596

99

394

21 38

113

831

0

100

200

300

400

500

600

700

800

900

No

. of

Clin

ica

l Tri

als

Ranking of countries for Phase II-III industry sponsored trial sites

Ranking ↑

　 2005-2007

2006-2008

Japan 8 6India 18 12China 27 23Korea 30 28Taiwa

n32 30

16 14

95 87

63

106

131 138

115 116130

162

199183

81

5362 67

90

644

74 67

66344512

100

66

0

50

100

150

200

250

94' 95' 96' 97' 98' 99' 00' 01' 02' 03' 04' 05' 06' 07' 08' 09'

Year

Pro

toc

ol

No

.

NEW IND in Taiwan (1994-2009)

Local Registration Trial

GCP-Taiwan

CDE established

Bridging studyEvaluation

628 Announcement

SARS

↑Qualified Site

IND New System

   Distribution of CT Phases

P: protocol S: site

2004 2005 2006 2007 2008 2009.9

P S P S P S P S P S P S

Phase I

8 12 14 26 12 20 10 18 11 14 15 16

Phase II

22 57 33 78 32 98 46 158

46 120

37 114

Phase III

85 237 69 242

86 300

106

391

132 527

71 284

Phase IV/ 其它

4 10 4 5 3 4 6 14 16 21 11 13

Total 119 316 120

351

133 422

168

581

205 682

134 427

(2009.1.1~9.30 IND 完成審查案件 , 共 134 件 )

1982 1987 1993~ 1996 1998

我國二十五年藥政風華我國二十五年藥政風華Milestone of Regulation in Milestone of Regulation in

TaiwanTaiwan

RegistrationTrial7.7 公告

JIRBSRBC.T. Training

CDE

C.T. GuidanceDSRBGLPADR Center

GMPBA/BE

2000 2001 2002

Race Disease PDT and Drug Act藥品 CGMPBridging studyC.T. WaiverGCRC醫材 GMP醫材重新分類(class)Drug Relief

Non-FSCNon-FSCTDRFTDRFConsultationConsultation windowwindow

APEC APEC (II)(II)

cGTPcGTP

Gene Gene TherapyTherapy

籌備籌備Taiwan Taiwan FDAFDA(( 第一次第一次送行政院送行政院 ))

APEC(III)APEC(III)

DIA 38th DIA 38th Annual Annual MeetingMeeting

APEC APEC Network Network projectproject

我國二十五年藥政風華我國二十五年藥政風華Milestone of Regulation in Milestone of Regulation in

TaiwanTaiwan

Results of GCP Inspection

Year 2002 2003 2004 2005 2006 2007 2008 2009

Case No. 37 47 36 34 38 23 29 34

Case Rejected

4 4 5 2 2 1 5 3

Case Rejected %

11% 9% 14% 6% 5.2% 4.3% 22% 12 ％

3. 華人族群基因

Working Definition of Special Populations

• Age• Body weight• Gender• Genotype• Organ dysfunction

• Diet• Drug interactions• Food interactions• Herbal products• Smoking habit

Intrinsic Factors Extrinsic Factors

Adapted from ICH Guideline E5: Ethnic Factors inthe Acceptability of Foreign Clinical Data, 1998

PK/PD/PG for Drug Response

NEJM 348;6, 2003

Pharmacogenetic Assessment

• Ultimate goal of drug development – providing safe therapies with meaningful clinical benefit

• Most promising impact of genomics – applying biomarkers to inform therapeutic decisions

Drug – Gene Interactions Optimal Dosing

We Can and Should Do Better Finding the Optimal Dose

FDA Critical Path Document: Challenges the traditional drug development process ~ 1 in 4 approved drugs undergoes

relabeling because of inadequate dosing

FDA White Paper, Challenge and Opportunity on the Critical Path to New Medical Products, 2004

Result #1: Unpredictable Variability in Efficacy

Drug Class EfficacyRate

Disease Efficacy Rate

SSRI 25-90% Diabetes 57%

Beta-blockers 75-85% Osteoporosis 48%

Statins 30-70% Alzheimer's 30%

Beta-2-agonists

30-60% Cancer 25%

Spear et al. Trends in Molecular Medicine, 7:201 (2001).

1. Assement of Phase I and II Enzyme SNPs Affect Pharmacokinetic Parameters

Summary of SNPs

• Total Single Nucleotide Polymorphisms (SNP): 96 SNPs of 8 metabolic enzymes– CYP2A6: 13 SNPs– CYP2C9: 11 SNPs– CYP2C19: 14 SNPs– CYP2D6: 25 SNPs– CYP2E1: 5 SNPs– CYP3A4: 13 SNPs– CYP3A5: 11 SNPs– UGT2B7: 4 SNPs

2. Assess the effects of phase I and II

metabolic enzyme SNPs in drug

metabolism (PK parameters)

Acknowledgement

• NDMC– 胡幼圃 , Ph.D.– 熊正輝 , Ph.D.

• 中研院– 陳垣崇 , 所長 ,Ph.D.– 王慧虹 , Ph.D.

• Clinical trial volunteers• PK analysis teams• CRO - 佳生、明生、世宬、昌達、美時

4. 華人特有疾病

華人特有疾病 -肝病 PK in Special Population

美國 FDA 推薦之肝功能測定新法

Galactose Single Point(GSP) method

Guidance for IndustryPharmacokinetics in Patients withImpaired Hepatic Function: Study

Design, Data Analysis, andImpact on Dosing and Labeling

U.S. Department of Health and Human ServicesFood and Drug Administration

Center for Drug Evaluation and Research (CDER)Center for Biologics Evaluation and Research (CBER)

May 2003Clinical Pharmacology

Quantitative Marker of Liver Residual Function - GSP

• Galactose Single Point (GSP) status– US FDA Guidance– ROC DOH Guidance– Text Book

• GSP method

• GSP application

肝功能不全病患的藥動學試驗基準－臨床試驗設計、數據分析以及對劑量調整與標示的影響

GUIDANCE FOR PHARMACOKINETICS IN PATIENTS WITH IMPAIRED HEPATIC FUNCTION: STUDY

DESIGN, DATA ANALYSIS, AND IMPACT ON DOSING AND LABELING

行 政 院 衛 生 署中華民國九十年七月

IV infused 0.5g/kg of galactose, and measuring whole blood (collected by dry filter papers) galactose concentration enzymatically at 60 minutes later

Galactose Single Point (GSP) Method

GSP Sampling

GSP Method Recent Application in Medical Centers of R.O.C.

• Diagnostic Drug: Galactose injection( 干能糖 , 衛署藥製字第 046996 號 )

• Medical Centers: NTUH( 台大 ) 、 TSGH( 三總 ) 、 TVGH( 榮總 ) 、 CGMH( 長庚 ) 、 CTH( 耕莘 ) …: 23 hospitals and clinics

• Subjects: 766 (Chronic hepatitis: 58; Cirrhosis: 24; Hepatocellular Carcinoma: 66; Liver normal: 618)

• The GSP values were significantly different between patients with various liver function

Hu OYP, Tang HS and Sheeng TY, J Pharm Sci 1995;84:111-4

兩岸華人臨床試驗之利基1.共同族群基因 - 例如 CYP Enzymes2.共同特有疾病 - 例如肝病3.優質卓越的臨床試驗設施，人才制度 經驗及廣大市場4.建構兩岸臨床研究合作機制

Thank you for your attention!