May 18, 2011 Herng-Der Chern, M.D., Ph.D. Distinguished Research Fellow Center for Drug Evaluation (CDE), Chinese Taipei

Regulatory Convergence for Ethnicity Consideration in Simultaneous Global Drug Development -Taiwan’s Regulatory Approach and Experience

May 18, 2011Herng-Der Chern, M.D., Ph.D.Distinguished Research FellowCenter for Drug Evaluation (CDE), Chinese Taipei

2

Unpublished Data compiled by Joseph Lee, CDE, 2010 Aug.

Early Introduction for Top 20 US Market New Drugs Table

Drug Information Association www.diahome.org

• New drug development and registration is regulatory intensive business across the region

• “Partnership in Harmonization” of regulatory convergence can minimize trade cost, bureaucratic inefficiencies and non-tariff barriers

• Promote public health with cheaper, faster, easier drug development and registration

Expand Regulatory Cooperation and Advance Regulatory Convergence – Proposed by 2011 APEC Hosting Country USA

3Drug Information Association www.diahome.org

APEC Network under ISTWGsince 1999 and APEC BRP since 2011

Chinese Taipei (2000, 2001, 2003, 2005, 2007, 2008, 2009, 2011)

(2004)

(2002, 2006)

Partnership in Harmonization

with ICHBest Regulatory Practice


5

“APEC Network of Pharmaceutical Regulatory Science-Theme and Topics

Clinical Trial

Bridging Study

02000 2002 2004 2006 2007 2008 2009

Level of Emphasis

Global Drug Development

Harmonization InitiativeICH GCGAPEC LSIFASEANEAPRS

Year

RA update2010 2011


6

Classification of intrinsic and extrinsic ethnic factors

ClimateSunlightPollution

CultureSocioeconomic status

Educational statusLanguage

Medical practiceDisease definition/diagnostic

Therapeutic approachDrug compliance

Regulatory practice/GCPMethodology/Endpoints

Age(Children-elderly)

LiverKidney

Cardiovascular functions

Diseases

Gender

Race

Genetic polymorphism

Genetic diseases

EnvironmentalPhysiological and pathological conditionsGenetic

ExtrinsicIntrinsic

HeigheBodyweight

ADMEReceptor sensitivity

SmokingAlcohol

Food habitsStress


7

Pharmacogenetic Consideration of “Race”

• Appearance of race determined by a few genes• Extrinsic factors are more important than intrinsic

factors• Genetic distance has major branches

corresponding to major racial groups• Intra-ethnic differences is greater than inter-

ethnic mean difference• Genetically, Asian can be barely categorized as

“Southern Asian” and “Northern Asian” using Yang-Tze Riveras nature border


8

Genetic Distance of Southern vs Northern Asian

Lin,et al. Tissue Antigens 2001, 27:192-199


9

Ethnic Group

• Not defined by “race”, or “citizenship”• Defined by “Drug characteristics” and “Target

patient population”• Epidemiology: incidence, etiology, nature

course, prognosis, response to other medications with similar mechanism

• China composed of Southern, Northern Asian and some minority races


10

Working Definition of Ethnic Sensitivity for ICH-E5 (Bridging Study Evaluation)

D I = C

D : Drug CharacteristicsI : Epidemiology of “Indication”C : Clinical impact based on risk – benefit approach


Country/ Major 1502 SJS/TENRegion Population a.f. AssociationTaiwan Han-Chinese 5.9 StrongHong Kong Han-Chinese 10.2 StrongThailand Thai 8.5 StrongChina Southern Han-Chinese 7.1 StrongChina Northern Han-Chinese 1.9 NAJapan Japanese 0.1 NoKorea Korean 0.2 NoGermany European 0 NoFrance European 0 No

Association of HLA-B*1502 with CBZ-induced SJS/TEN in different populations.

• Cancer-mutation spectrum and frequency may have ethnic sensitivity, e.g. NSCLC & Irresa

• Medical practice in diagnosis, standard therapy, best supportive care may be different e.g. HCC & Nexavar

• Philosophy to death may be different – die in ICU, general ward, hospice, home, resuscitate or not may affect “overall survival”

• Different epidemiology for common cancers: HCC, Gastric Ca., Cervical Ca., NPC,….

Challenge in Oncology Trials

12

13

Sorafenib data from Asian vs Caucasian: different severity of liver cancer patients

Sorafenib data from China vs Korea and Chinese Taipei-Medical Practice vs Genetics

14

Drug Information Association www.diahome.org 15

Examples of Ethnic Sensitivities

D x I C Reason

1. Rosuvastation Hyperlipidemia ± PK

2. Gefitinib NSCLC ++ EGFR mutation

3. Sorafenib HCC + Medical practice

4. Carbamazepine SJS ++ Southern Asian genotype

5. Omeprazole Peptic Ulcer ± CYP2C19

• Checking list and flow chart for BSE• Consider all factors in totality• Clinical impact is the key• In general, accept all Asian data as good

reference• 60% NME considered ethnic insensitive


Bridging Study Evaluation for Ethnicity

17

Build up Regulatory Infrastructure – New IND from 1994~2010

1614

90

9587

63

106

66

131 138

115

116130

162

189

173

74

67

100

81

3562 67 66

125 4 4 3 6

16 14

0

50

100

150

200

94'96'

98'00'

02'04'

06'08'

Phase I~III

Phase IV

09'

Local Registration Trial

Bridging StudyEvaluation

IND New System

GCP-Taiwan

CDEestablished

SARS

QualifiedSite

Protocol No.

Year

10'

187

21


Drug Price Incentive for C.T. Conduct

2010 BNHI announced 10% drug price mark

up for clinical trial conduct in Taiwan (draft

Ph.I: 10 cases, Ph.II: 20 cases, Ph.III 80 cases)-

give incentive in stead of administrative

requirement


• Plateau on C.T., need more early trials• Reviewers overloading• CTN route, no science review in general• If join MRCT with IND reviewed by one of

10 reference countries (26/138,19%), efficiency (predictable, save 21 days), early trials (25% to 50%)

2010.8.18 Clinical Trials Notification


20

CTN 案現況 (2010. 8. 18~2011.3.31)

Month Non CTN CTN Non CTN Review Time (calendar day)

CTN Review Time (Calendar day)

8/18~8/31 6 0 39.3 -

9 月 21 5 43.0 15.2

10 月 10 3 38.6 20.7

11 月 14 3 26.8 20.7

12 月 17 4 29.9 15.5

2011.1 月 17 2 29.4 18

2011.2 月 10 2 32.4 20.5

2011.3 月 17 7 16.7 10.2

Total/ 平均 112 26 32.01 17.3Sponsor’s Time 6.27 days for Non-CTN IND

21

CTN Cases Characteristics

• Ph. I 1, Ph. II 12, Ph. III 13 cases, from 10 Big Pharma and 1 domestic companies

• Indication: Cancer 11, DM 5, Hepatitis 3, Psoriasis 2, CV1,Asthma 1, Depression 1, Eye 1, Orphan Drug 1 cases.

• Asian Countries Involved: Japan 9, Korea12,China 4, Hong Kong 9

• No question asked, no disapproval, no case considered as high risk

• Project supported by Canada, China, Indonesia, Korea, Malaysia, Mexico, Peru, Philippine, Thailand, USA

• Good Review Practice Workshop for Drug and Device, Taipei, Oct. 11-15, 2011

• APEC PER Scheme for exchange of Pharmaceutical Evaluation Report with consent from the license holder

• Ethnic sensitivity will be emphasized for regulatory convergence


2011-12 APEC “Best Regulatory Practice” Led by Taiwan


Regulatory Convergence for Ethnicity Consideration : Regression Towards the Mean

2011

2000

Regulatory Convergence

Regulatory Science/SGDDP

Ethnic Sensitivity/Market Size

ASEANRest of World

Low High

TaiwanKoreaChina

JapanEMAUS


Thank you for your attention

24

Documents

May 18, 2011 Herng-Der Chern, M.D., Ph.D. Distinguished Research Fellow Center for Drug Evaluation (CDE), Chinese Taipei