1. 지역임상시험센터 - 현황과 전망 - Kyung-Sang Yu, MD, PhD, MBA
Seoul National University
College of Medicine and Hospital
June 24, 2005

2. Contents 임상시험 = 고부가가치 Growth in Asia Korea 전략적 접근
Asia-Pacific excl. Japan
Japan
Korea
지역임상시험센터
전략적 접근

4. Global Pharmaceutical R&D Expenditure (1992 - 2002p)5 10 15 20 25 30 35 40 45 50
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002p
Year
Global R&D expenditure (US$ billion)
p = projection
Source CMR International

5. Source CMR International
Breakdown of R&D Expenditure by Activity
:2000 (US $42bn)
*2003년 620억$; 임상시험 시장규모 390억$
Discovery
25.1%
Non clinical
17.2%
Regulatory
5.8%
Other
10.0%
Phase I
6.4%
Phase II & III
30.3%
Post-
marketing
5.2%
Total Clinical
41.9%
Source CMR International

6. Increasing R&D expenditure outside the US
$US billion 1 2 3 4 5 6 7 8 9 10
Source : PhRMA

7. Global Drug Development - Asia
>50% of world’s population.
A mix of highly developed and developing countries.
A mix of usual “western diseases” as well as diseases with low prevalence in Western Europe or North America.
Strong support and encouragement from many governments in the region.
High quality investigators and developing infrastructure.
If all the stakeholders can work together to further develop the region:
Asia will become a major force in global drug development
Presentation at APEC Seoul Symposium,

8. What favors this trend? Globalization with ICH harmonization
US FDA / EMEA Acceptance of Foreign Data
Drug Naïve Patient Population from 3rd region
Need of Ethnic Data
Market Growth and local need of their own data
Region Specific Disease…

10. Taiwan

11. Taiwan

12. Presentation at APEC Seoul Symposium, 2004. 11. 22-23
R&D City in Singapore : Biopolis
With effect from 6 September 2004, the CDA and CMDR have relocated to the Biopolis
A dedicated biomedical research park in Singapore
2 million square foot complex operational from mid-2003
Houses the full spectrum of biomedical sciences R&D activities encompassing basic drug discovery research and clinical development and medical devices research
Focal point for synergy and collaboration of new research discoveries between the public and private sector with leading scientists and R&D organisations from all parts of the world
Presentation at APEC Seoul Symposium,

13. ( )

14. Number of clinical trials and study sites in Australia
Source : Therapeutic Goods Administration

15. Obstacles to Clinical Research in Japan
Doctors’ low incentives to clinical research: More oriented to in vitro and non-human studies
Difficulty in accounting: Complexity of accounting system in national universities of Japan
Subject compensation: Investigator-initiated clinical researches have only incomplete compensation for volunteers
Low rate of information transfer and education to doctors: Investigator-initiated trials have been permitted, but most of doctors do not know the precise information.

16. Costs of Clinical Trials in Japan
Relative cost per patient
Presentation by Dr. Uden at 3rd Kitasato-Harvard Symposium, 2002
일본의 상황과 우리의 교훈
일본 제약기업의 국제적 경쟁력 상실
임상시험; 고비용, 연구기간 비효율, 연구의 질 낮음
이유  임상시험 인프라 부족, 연구자 관심 부족, 허가/관리기관의 비효율

17. Japan seriously searching for R&D partners…

20. Multinational subsidiaries are facing two different optional paths…
A Bridging Study or Bridging Exemption for marketing approval ….. already developed or excluding representative Korean data during development.
Early involvement in global clinical development for future bridging data generation strategy in Korea…… relatively large market size of Korea / fair clinical infrastructure / some academicians favor the early involvement…

22. Other countries?

23. Clinical Trial Centers in Korea
Inje Baik Hospital
Busan University Hospital
Kyeongbuk University Hospital
Wonkwang University Hospitaql
Kyeongsang University Hospital
Chungbuk University Hospital
Cheonbuk University Hospital
Cheonnam University Hospital
Seoul National University Hospital
Yonsei University Hospital
Catholic University Hospital
Seoul Asan Hospital
Samsung Seoul Hospital
Samsung Cheil Hospital

25. 2005년도 현재 47개사에서 진행하고 있는 임상시험 Clinical Study Phase 2005년 2010년 합계 평균
2005년도 현재 47개사에서  진행하고 있는 임상시험
Clinical Study
Phase
2005년
2010년 합계 평균
Local Study
   Phase I
36 건
1 건
   Phase II
33 건
   Phase III
109 건
3 건
   Phase IV
91 건
2 건
   Total
284 건
6 건
14 건
International Study
7 건
0 건
16 건
62 건
21 건
127 건
11 건

26. 연간 임상시험 건수 / 수요예측 1상 - 3상 4상 및 PMS IIT* 계 현재(2005년) >50 >40
연간 임상시험 건수 / 수요예측
1상 - 3상
4상 및 PMS
IIT* 계 
현재(2005년)
>50
>40
>250
~200 (진행중 포함시 ~400)
5년후 (2010년)
>100
>80
>500
~400 (진행중 포함시 ~800)
10년후 (2015년)
>150
>120
>750
~600 (진행중 포함시 ~1200)
*IIT 증가의 근거로는 현재 지속적으로 개설 중인 임상연구센터
(연간 >10여 개 센터 * 4개 기관/센터 = 연간 40개 이상의 임상연구)를 함께 고려

27. Government (MHW) Grants for Investigator Initiated Trials
Solid tumor of adulthood
Ischemic heart disease
Chronic obstructive lung disease
Liver cirrhosis
Type 2 DM
Antibiotic use
Depression
Stroke
Chronic renal failure
Rheumatoid arthritis

28. Changes of Governmental Understanding in Korea ;
Start to recognize the Critical Role of Clinical Path for industrialization for New Drug/Biotechnical Products
Priority Planning for Supporting Clinical Infra- Structure
- Regional Clinical Trial Centers – 4 million USD/ 5 yr/center supporting program
Educational Program : IRB member, Investigator, Pharmacist, CRN, CRA, CRC etc.
Slide 24 :
As the last and recent good sign, Korean government start to recognize the importance of clinical infrastructure for the whole national R&D especially for biotechnology industry development. They are priority planning for support Clinical Infra. Especially for supporting Clinical trial center establishment in major hospital just like US NIH GCRC program.

29. Public Support for Clinical Trial Center
보건복지부 지역임상시험센터
2004년 2개
2005년 4개
2006년 9개
보건복지부 임상시험전문인력 교육 프로그램

31. Strategic Approach (1) 서울대학교병원 임상시험센터의 국제적 수준으로의 도약 전략
서울대학교병원 임상시험센터의 국제적 수준으로의 도약 전략
국내 최다 제 1상 임상시험 경험을 토대로 단기간에 1/2상 시험분야의 국제적 수준 도달
첨단 임상시험기술인 영상 biomarker 기술을 이용한 제 1, 2상 임상시험 경쟁력 확보 (차별화)
생성된 자료로 국제적 승인에 활용
다국적 기업 임상시험 수행 경험 활용으로 global development 조기 참여
임상 및 기초의학, 역학, 약학, 통계학 등의 수준 높은 가용 인력 자원 이용
제 2, 3상 임상시험 수준 극대화 전략
인력개발 프로그램 활성화

32. Strategic Approach (2) 제 2, 3상 임상시험 수준 극대화 전략 (국내 핵심센터 역할)
국내 최다 제 1상 임상시험 경험을 토대로 단기간에 1상 시험분야의 국제적 수준 도달
제 2, 3상 임상시험 수준 극대화 전략 (국내 핵심센터 역할)
전자임상시험 개발 및 실용화
분당서울대학교병원과 연계하여 다기관 임상시험 활성화
의학연구협력센터(MRCC) 등 기존의 관련 기구의 시설 및 자료처리, 통계, 전산 전문가 등 전문 인력을 활용
국내 지역임상시험센터/multicenter study 참여기관의 coordination/DB support
인력개발 프로그램 활성화

33. Strategic Approach (3) 국내 임상시험센터 및 의료기관과 네트워킹
국내외 임상시험 네트워크 구축(SMO 기능)을 통한 국제적 경쟁력 확보
국내 (수도권); 아산병원, 국립암센터, 삼성의료원, 연세의료원, 가톨릭대병원
국내 (지방); 인제대병원, 전남대병원
미국; Georgetown 대학, Indiana 대학
스웨덴; Karolinska Institute, Uppsala 대학,
일본; 하마마츠 대학, 쇼와 대학
국내 임상시험센터 및 의료기관과 네트워킹
서울대학교병원
임상시험센터
병원 5
병원 3
병원 2
A 센터
병원 4
C 센터
병원 1
병원 7
병원 6
D 센터
B 센터
수도권 지방

34. Critical Path research
US FDA Critical Path Initiative
Concern: ½ of all drugs moving to PIII fail, drop in number of NDAs
Goals: more quick and safe clinical development, increase the predictability of drug success
Critical Path research

35. US FDA Critical Path Initiative
Challenges in Drug Discovery & Development

36. US FDA Critical Path Initiative; Goal & Examples
The goal: to develop new, publicly available scientific and technical tools that make the development process itself more efficient and effective.
Assessing safety
Minimizing failures in the clinical development due to drug interaction
Demonstrating medical utility (benefit or effectiveness)
Empirical clinical trials vs. mechanism based development
Adoption of a new biomarker or surrogate endpoint for rapid clinical development
Improve the efficiency and effectiveness of the clinical trial process, including trial design, endpoints, and analyses
Model based drug development
Imaging technologies
Pharmacogenomics
Industrialization
Quality control

37. Optimization of lead compound, Personalized Medicine
Application of Genomics in Drug Discovery & Development
Discovery
Develop- ment
Clinical trials
Product launch
Target
Identification
Optimization of lead compound,
Toxicogenomics, etc.
Personalized Medicine
What impact is PG having on clinical development?

38. Functional Imaging (PET) in Phase I Trial of Antipsychotic Drug
BP (Bmax/Kd) + 1
Before
2 hour
6 hour
BP (Bmax/Kd)
Before
2 hour
6 hour
PET와 [11C]Raclopride를 이용한 항정신병약물의 도파민(D2) 수용체 점유율 연구

39. Functional Imaging (PET) in Phase I Trial of Antipsychotic Drug

40. Korean & US Combined PK by NONMEM
Parameter Estimate StdErr %SE
THETA #1 KA
THETA #2 CL
THETA #3 V
THETA #4 orig
OMEGA #1 CL
SIGMA #
$PK
PJ=0
IF(PROJ .EQ ) PJ=1
KA=THETA(1)
TVCL=THETA(2)*(1 + PJ*THETA(4))
CL =TVCL*EXP(ETA(1))
TVV =THETA(3)
V =TVV
S2 =V
$ERROR
IPRED = F
W=IPRED
IRES=DV-IPRED
IWRES=IRES/W
Y = F*EXP(ERR(1))

41. Predicted Glucose Response - AUC Relationships in Korean Populations
Glucose -AUC relationships from global data supports 15 and 30 mg as efficacious doses in Koreans

42. Trial Simulation Platform
5 dose group (0, 7.5, 15, 30, 45 mg, N=500), 300 replications

43. US actual trial 45mg Group Mean Effect = -3.0745
-5.0
-4.6
-4.2
-3.8
-3.4
-3.0
-2.6
-2.2
-1.8
-1.4
-1.0 5 10 15 20 25
US actual trial 45mg Group
Mean Effect =
53.2 percentile
Median = -3.04
Distribution of 300 Mean Changes in FBG (mM) of Korean 30 mg Group

44. 전자임상시험 기술 개발 (예)

45. 전자임상시험 기술 개발 (장기 목표의 예)

46. Differentiation 조기 임상시험 후기 임상시험 Critical path Global development 참여
국내 생성 자료의 국제적 인정
국내 개발 신약의 국제적 승인
후기 임상시험
다국적 임상시험 참여
Critical path
PGx, biomarkers, imaging, M & S, e-trials

47. Knowing is not enough;. We must apply. Willing is not enough;
Knowing is not enough; We must apply. Willing is not enough; We must do Goethe