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

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

2004-4-18

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

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

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

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, 2004. 11. 22-23

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…

Taiwan

Taiwan

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, 2004. 11. 22-23

( 2003. 7 )

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

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.

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

Japan seriously searching for R&D partners…

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…

Other countries?

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

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

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

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

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.

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

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

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

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

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

US FDA Critical Path Initiative Challenges in Drug Discovery & Development

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

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?

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

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

Korean & US Combined PK by NONMEM Parameter Estimate StdErr %SE --------- ------ ------ ---- THETA #1 KA 2.50 0.883 35.32 THETA #2 CL 3.16 0.145 4.59 THETA #3 V2 29.3 1.29 4.40 THETA #4 orig -0.416 0.0403 9.69 OMEGA #1 CL 0.109 0.0151 13.85 SIGMA #1 - 0.181 0.0140 7.73 $PK PJ=0 IF(PROJ .EQ. 7110115) 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+0.000001 IRES=DV-IPRED IWRES=IRES/W Y = F*EXP(ERR(1))

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

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

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 = -3.0745 53.2 percentile Median = -3.04 Distribution of 300 Mean Changes in FBG (mM) of Korean 30 mg Group

전자임상시험 기술 개발 (예)

전자임상시험 기술 개발 (장기 목표의 예)

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

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