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

Early Introduction for Top 20 US Market New Drugs Table

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Unpublished Data compiled by Joseph Lee, CDE, 2010 Aug.

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

• “Partnership in Harmonization” of

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

pregulatory convergence can minimize trade cost, bureaucratic inefficiencies and non-tariff barriers

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

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APEC Network under ISTWGsince 1999 and APEC BRP since 2011

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

(2004)

(2002, 2006)

2007, 2008, 2009, 2011)2007, 2008, 2009, 2011)

Partnership inPartnership inHarmonizationHarmonization

with ICHwith ICHBest Regulatory Practice

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“APEC Network of Pharmaceutical Regulatory Science-Theme and Topics

Clinical Trial

Bridging Study

Level of E Global Drug Development

5

02000 2002 2004 2006 2007 2008 2009

mphasis

Development

Harmonization InitiativeICH GCGAPEC LSIFASEANEAPRS

Year

RA update

2010 2011

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Classification of intrinsic and extrinsic ethnic factors

ClimateSunlightPollution

CultureSocioeconomic status

Educational status

Age(Children-elderly)

Li

Gender

EnvironmentalPhysiological and pathological conditionsGenetic

ExtrinsicIntrinsic

HeigheBodyweight

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Educational statusLanguage

Medical practiceDisease definition/diagnostic

Therapeutic approachDrug compliance

Regulatory practice/GCPMethodology/Endpoints

LiverKidney

Cardiovascular functions

Diseases

Race

Genetic polymorphism

Genetic diseases

ADMEReceptor sensitivity

SmokingAlcohol

Food habitsStress

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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

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p g j g p

• 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

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Genetic Distance of Southern vs Northern Asian

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

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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

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cou se, p og os s, espo se to ot e medications with similar mechanism

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

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

D I = C

D : Drug CharacteristicsI : Epidemiology of “Indication”

l l b d k

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C : Clinical impact based on risk –benefit approach

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Country/ Major 1502 SJS/TENRegion Population a.f. AssociationTaiwan Han-Chinese 5.9 StrongHong Kong Han-Chinese 10.2 Strong

S

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

Thailand 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

• 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

Challenge in Oncology Trials

pp y g& 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,….

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

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

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Examples of Ethnic Sensitivities

D x I C Reason

1. Rosuvastation Hyperlipidemia ± PK

2. Gefitinib NSCLC ++ EGFR mutation

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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

Bridging Study Evaluation for Ethnicity

• In general, accept all Asian data as good reference

• 60% NME considered ethnic insensitive

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Build up Regulatory Infrastructure – New IND from 1994~2010

95106

131 138

115

116130

162

189

173

100

150

200

Phase I~III

Local RegistrationTrial

Bridging StudyEvaluation

IND New System

GCP-Taiwan

SARS

Pro

toco

187

17

1614

90

9587

63 66

115

74

6781

3562 67 66

125 4 4 3 6

16 14

0

50

100 Phase IV

CDEestablished

QualifiedSite

ol N

o.

Year

21

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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)-Ph.I: 0 cases, Ph.II: 0 cases, Ph.III 80 cases)

give incentive in stead of administrative

requirement

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• 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

2010.8.18 Clinical Trials Notification

• 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%)

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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

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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 17.3

Sponsor’s Time 6.27 days for Non-CTN IND

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,

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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

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

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

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Regulatory Convergence for Ethnicity Consideration : Regression Towards the Mean

2011

2000

Regulatory Convergence

Regulatory Science/SGDDP

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Ethnic Sensitivity/Market Size

ASEANRest of World

Low High

TaiwanKoreaChina

JapanEMAUS

Thank you for your attention

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