2013 OpenClinica Global Conference: June 21, 2013

1. 2013 OpenClinica Global Conference: June 21, 2013 OpenClinica Enterprise for Clinical Trial in Japan *YNatsumeda, * T Osako and H Maniwa KSLION * Key Support for Life Innovation (KSLION) Mount Fuji Information Services International Dentsu (iSiD) YokohamaMitsui Building Kanagawa Yokohama Kawasaki Tokyo Tamagawa River Haneda/Tokyo Airport Keihin Life Innovation Global Strategic Zone applied to the Government by Yokohama, Kawasaki, Kanagawa (Sep 2011)

2. Need: Japan has not fully addressed the promise of biotech, health and life innovation, especially in clinical trials. Value: Refinement of the clinical trial process in Japan will promote tremendous innovation and, therefore, value in the Japanese HealthCare System. I will describe recent efforts. Vision: OpenClinica and related modification will streamline the critical path, eliminate drug lag and device lag and revive Japan in life innovation. The focus of my talk is to demonstrate the importance and value of the OpenClinica Enterprise in Japan.

3. Need: Japan has not fully addressed the promise of biotech, health and life innovation, especially in clinical trials. Value: Refinement of the clinical trial process in Japan will promote tremendous innovation and, therefore, value in the Japanese HealthCare System. I will describe recent efforts. Vision: OpenClinica and related modification will streamline the critical path, eliminate drug lag and device lag and revive Japan in life innovation. The focus of my talk is to demonstrate the importance and value of the OpenClinica Enterprise in Japan.

4. Japanese Clinical Trial System • High cost per patient • Poor performance • Pharma and Biotech exclude Japan from global development program until POC trial promising results. • Poor experience in FIH, POC or international collaborative clinical trials in Japan • Many trials designed to confirm overseas trials • 2 ～ 6 times more expensive than either USA or EU • Too many sites, too few patients per site per trial - requiring • J-GCP to enforce each trial site have independent IRB (1997). • Nine out of 10 compounds in clinical trials fail to get approved. • Difficult to develop clinical trial leaders and infrastructure • Lack of enthusiasm of physicians

5. Reality of New Drug Development Safety POC Kola and Landis, Nature Review Drug Discovery, 2004 (3):711-715

6. Japan Lags behind Many Countries in International Collaborative Trials Japan ranked 60th among 87 countries Total protocols: 413 ＜Data from 2008 European Federation of Pharmaceutical Companies, PhRMA＞

7. Japanese clinical trials are designed to replicate and validate previous studies, therefore, results cannot be published in top medical journals. Phase I lag Phase I is initiated only after overseas POC shows promising. Phase I Submission High cost/Poor performance Japan Approval 1.9 years Review 1.8 years Clinical trials 6.1 years Phase I Submission Approval USA Drug lag 3.8 years Clinical trials 4.5 years Review 1.1 years Asahi Newspaper June 9, 2010

8. Ranking of Basic and Clinical Research

9. 2011Rankings 1 Hong Kong 1 USA 3 Singapore 4Sweden 5 Switzerland 6Taiwan 7 Canada 8 Qatar 9 Australia 10 Germany 11 Luxemburg 12 Denmark 13 Norway 14 Holland 15 Finland 16 Malaysia 17 Israel 18 Austria 19 China 20 UK 21 New Zealand 22 South Korea 23 Belgium 24 Ireland 25 Chile 26 Japan 27 Thailand 28 UAE 29 France 30 Czech Republic World Competitiveness Rankings by IMD* World Competitiveness Rankings Where is innovative Japanese Industry? Toyota, Honda, Nissan, Isuzu, Mitsubishi, Mazda, Subaru, Panasonic, SONY, Toshiba, Hitachi, SANYO, Fujitsu, Shiseido, Kikkoman, Kirin, Nintendo, Tamagocchi, SeijiOzawa, Tonegawa, iPS by Yamanaka, Ichiro, Gozzila, etc? USA (1) Germany (8) UK (15) Japan (17) France (19) China (31) IMD*: International Institute for Management Development Announcement started in 1989

10. Need: Japan has not fully addressed the promise of biotech, health and life innovation, especially in clinical trials. Value: Refinement of the clinical trial process in Japan will promote tremendous innovation and, therefore, value in the Japanese HealthCare System. I will describe recent efforts. Vision: OpenClinica and related modification will streamline the critical path, eliminate drug lag and device lag and revive Japan in life innovation. The focus of my talk is to demonstrate the importance and value of the OpenClinica Enterprise in Japan.

11. KSLION High cost Poor performanceExcluded and isolatedLack of global experienceLack of leaders Immature infrastructure Drug lag & Device lag Education for clinical research GCP training & seminars PMDA/YCU joint graduate course Public Private Partnership International workshop 2008 Revive Japan in Life Innovation 2012 Eliminate drug lag and device lag Pre-PMDA consultation Networking & Grouping Central IRB ICH-GCP CDISC FDA 21 CFR Part 11 High performanceHigh quality Low cost Paperless Remote 2013

13. Current Activities & Future Vision of DCRI: Global Collaborations Such as HBD Mitchell W. Krucoff MD, FACC Professor of Medicine / Cardiology Duke University Medical Center Director, Cardiovascular Devices Unit Duke Clinical Research Institute Yokohama City University: Clinical Research SeminarDecember 20, 2008

14. Duke Clinical Research Institute • > 1,000 faculty & staff (205 faculty) • > $100 M annual activity (2/3 from industry) • world’s largest ARO • not for profit • faculty interest-driven mission: • academic & scientific integrity • clinical care for unmet medical needs • public health • different culture from big CROs

15. CBMI Palaver Seminars:Members • Center for Biomedical Informatics, Harvard Medical School • Laboratory for Personalized Medicine, Harvard Medical School • Harvard Molecular Technology Group & Lipper Center for Computational Genetics, Harvard Medical School • Regenerative Biology, Wisconsin University • Great Lakes WATER Institute, Wisconsin University • National Center for Biomedical Computing, USA • The School of Biomedical Science, Tokyo Medical and Dental University • Recombinant Data Corp. , USA • Johnson & Johnson Corp. , USA • The Partners HealthCare Center for Personalized Genetic Medicine, Harvard Medical School Dr. P. Tonellato

16. CBMI Palaver Seminars on Translational Medicine, 2009

17. Joint International Conferences on Translational Research and Personalized Medicine in Yokohama Feb 1, 2010 by YCU and HMS/CBMI To Translate Extensive Basic Research Data into Clinical Research and Practice Feb 2, 2010 by TMDU, YCU and HMS/CBMI The Opening of the Next Generation in Omics-based Medicine Feb 3, 2010 by FDA, DCRI, HMS/CBMI, YCU Strategy and Scientific Tools to Facilitate Processing Basic Discovery Seeds to Meet Medical Needs Minatomirai, Yokohama

20. Harvard Medical School, Mallinckrodt Professor of Pathology, Dr. Jeffrey SaffitzMarch 3, 2010

21. Duke Clinical Research Institute, Chief Operating Officer, Ms. Miriam DonohueMarch 5, 2010

22. PMDA・YCU Joint Graduate Course Started on April 1, 2010 http://www.pmda.go.jp/ Pharmaceuticals and Medical Devices Agency

23. A Test Trial to Implement IntraLinks (Highly Secure Cloud Storage System) into Clinical Trial Sites and Central IRB February ～ April, 2011 Achieved in the trial • Feasibility search for the sites for the trial • Paperless IRB review and approval • Prompt and secure delivery of safety information • Remote source document verification (R-SDV) • Secure storage of the document • Delivery of the information only to the authorized members

24. KSLION Keihin Life Innovation Global Strategic Zone Adopted by the Japanese Government (Dec. 2011) Mount Fuji YokohamaMitsui Building Kanagawa Yokohama Kawasaki Tokyo Tamagawa River Haneda/Tokyo Airport

25. Keihin Life Innovation Global Strategic Zone adopted by the Japanese Government (Dec, 2011) The goals are to develop innovative medicines and devices to achieve personalized medicine. Strategic aims (selected): • International collaborative clinical trials to eliminate drug/device lag • Pre-PMDAfunctions • Efficacious clinical trial network • Partnering and Matching between discovery seeds and medical needs • Construct a biobank integrated with the clinical information database Founded in June, 2012

26. Collaborations among 4 Major Sites Tonomachi Suehiro Fukuura YCU RIKEN Regenerative Medicine YCU Cancer/ Lifestyle diseases YCU Preventive Medicine YCU Medicine/Technology Minatomirai KSLION Conferences, Exhibitions 26

27. Personalized preventive medicine/Innovative drugs and medical devices/Creating new industries FDA/EMA PMDA Basic Research Pre-PMDA Joint graduate course Devices KeihinNW YCU 2 YCU hospitals Adv Med Res Center Clin Pharm Center GCPtrainings Seminars & workshops Academic KSLION Japan NW Clin trial NW Central IRB CRC support Asian NW International collaborative trials Pharmas Bioventures FIH/Phase I US NW Low cost High performance Global standards POC EU NW Keihin Life Innovation Global Strategic Zone

28. CDISC : Clinical Data Interchange Standards Consortium • Paper work to electronic system • Better, Faster, Cheaper • Global standards Global standard EDC (Electronic Data Capture) ・ Commercial source ・ ・ ・ Open source 28

29. OpenClinica Training Seminar Dates: January 30 - February 1. 2013 Wednesday9:30-13:00 - Business Administration14:00-17:00 - Data Management Thursday 9:30-12:30 - Data Management (con’t…)13:30-14:30 - Monitoring15:30-17:00 - Clinical Research Coordination / Data Entry Friday 9:30-12:00 - Investigators / Data Specialists12:00-17:00 - CRF Design/ Additional questions/tutoring 29

30. Influence of Nuclear Power Plant Disaster to the Residents in Fukushima • A cohort study should be doneand exact data should be collected on how the residents are affected with the exposure. • Japan is responsible for reporting the data to the world. • OpenClinica could be used for the cohort study. • Opportunity for the EDC to be implemented in the clinical trial networks all over Japan A total of 94 Red Cross hospitals in Japan 60,000 people moved out from Fukushima.

31. Even if Japan closes all nuclear power plants; • There are many nuclear power plants in East Asia. • Fukushima data will tell how to reduce the risk. 年代別 Nuclear Power Plants in East Asia Natural disasters in the world (1978 – 2008) Natural disasters in Asia (1978 – 2008) Disasters Asia ３６６ （３７％） Deaths Asia 1.34 M （59％） Victims Asia977 M （89％） Damage Asia $605 B （45％） 被災者数（百万人） 被害額（億ドル） （資料）CREI,アジア防災センター(内閣府）

32. A Project to Build Large Hospital Ships Beready for Natural Disaster • Activities at Non-Emergency Situation • Medical Patrol around Medical Depopulated Area • Extend the Medical Patrol to South Asian Countries • Domestic/International Contributions • Downsize/Reduce Weight of Therapeutic and Diagnostic Devices • Promote Industry for Medical and Nursing Devices • Training Young Talents • Creating jobs Yokohama Mercy (USA) 70,000 tons, 273 m x 32 m 1,000 beds, 12 operation rooms

33. Building Realistic, Predictive Models of Disease: Drug Repositioning and Personalized Medicine

34. Pharmacodiagnostics can Streamline Clinical Development and Increase Value. Broad patient population Traditional clinical trials Pharmacogenomics- based trials Responders only 10-12 years 5-7 years Cost of Development Success Rate Patients Per NDA Value >$1,000Million 5-10% >2,000 Good <＄500Million 25-50% >600 Better Source: Pharma 2010: The Threshold of Innovation.

35. History of Metformin • Synthesized • 1927 Shown blood sugar reducing effect in rabbit • 1957 Shown anti-diabetic effect in diabetic patients • 1958 Approved • 2001 Mechanism to reduce blood sugar is shown to activate AMPK

36. Effect of Metformin on Colorectal Aberrant Crypt Foci K Hosono et al. Cancer Prev Res 3:1077-1083, 2010

38. Plans to implement OpenClinica • YCU oncology group working in 6 major hospitals in Keihin area agreed to use it for their studies. • Several other local clinical trial networks such as red-cross, Shikoku, Kyushu, Tokyo metropolitan are under consideration. • Fukushima cohort study is under discussion. • Yokohama city now supports financially KSLION. • US-Japan collaborative clinical trials could be run with OpenClinica. • Japan needs close collaborations with OpenClinica for training and Enterprise supports.

39. Need: Japan has not fully addressed the promise of biotech, health and life innovation, especially in clinical trials. Value: Refinement of the clinical trial process in Japan will promote tremendous innovation and, therefore, value in the Japanese HealthCare System. I will describe recent efforts. Vision:OpenClinica and related modification will streamline the critical path, eliminate drug lag and device lag and revive Japan in life innovation. Thank you! The focus of my talk is to demonstrate the importance and value of the OpenClinica Enterprise in Japan.