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

2. The focus of my talk is to demonstrate the importance and value of the OpenClinica Enterprise in Japan. 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.

3. The focus of my talk is to demonstrate the importance and value of the OpenClinica Enterprise in Japan. 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.

4. 1.High cost per patient 2.Poor performance 3.Pharma and Biotech exclude Japan from global development program until POC trial promising results. 4. Poor experience in FIH, POC or international collaborative clinical trials in Japan 5.Many trials designed to confirm overseas trials 2 ～ 6 times more expensive than either USA or EU Nine out of 10 compounds in clinical trials fail to get approved. Too many sites, too few patients per site per trial - requiring J-GCP to enforce each trial site have independent IRB (1997). Lack of enthusiasm of physicians Difficult to develop clinical trial leaders and infrastructure Japanese Clinical Trial System

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

6. Japan Lags behind Many Countries in International Collaborative Trials ＜ Data from 2008 European Federation of Pharmaceutical Companies, PhRMA ＞ Japan ranked 60 th among 87 countries Total protocols: 413 Ran k CountryProtocol% 1USA26463.9 2Canada17542.4 3Germany17141.4 4Spain13332.2 5France13232.0 6England12430.0 7Poland11026.6 8Italy10826.2 9Belgium10625.7 10Australia10525.4 11Mexico8620.8 12Czech Republic8320.1 13 Netherlands, Russia 7919.1 Ran k Country Protoco l % 15Hungary, Sweden7518.2 17Argentina7317.7 18South Africa7117.2 19Brazil, Denmark6315.3 21India5914.3 22Korea, Taiwan5112.3 41Hong Kong276.5 47Singapore235.6 50China184.4 54Pakistan102.4 57Indonesia71.7 60Japan61.5 68Vietnam20.5

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

8. Ranking of Basic and Clinical Research Basic Research Clinical Research Nature Med, Cell, J. Exp. Med. NEJM, Lancet, JAMA 1993~971998~20022003~07 1993~97 1998~20022003~07 USA3,097 (1)2769 (1)2674 (1)3314 (1)3695 (1)2677 (1) Germany321 (3)404 (2)442 (2)253 (6)511 (3)343 (4) Japan236 (6)371 (3)369 (3)122 (12)183 (12)74 (18) UK365 (2)352 (4)314 (4)920 (2)1484 (2)873 (2) France239 (5)256 (5)269 (5)274 (5)432 (5)300 (5) Canada227 (7)209 (6)204 (6)377 (3)502 (4)462(3) Switzerland 244 (4)209 (6)166 (7)166 (8)261 (9)252 (9) Italy132 (8) 155 (8)236 (7)374 (7)279 (7) Holland109 (9)114 (9)127 (9)277 (4)410 (6)294 (6) Australia97 (10) 106(10)120(10)155 (9)282 (8)260 (8) China1 (36)8 (25)53 (13)20 (30)59 (21)102 (15) S. Korea － 15 (22)39 (18) －－－

9. World Competitiveness Rankings by IMD* IMD*: International Institute for Management Development Announcement started in 1989 World Competitiveness Rankings USA (1) Germany (8) UK (15) Japan (17) France (19) China (31) 2011 Rankings 1 Hong Kong 1 USA 3 Singapore 4 Sweden 5 Switzerland 6 Taiwan 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 Where is innovative Japanese Industry? Toyota, Honda, Nissan, Isuzu, Mitsubishi, Mazda, Subaru, Panasonic, SONY, Toshiba, Hitachi, SANYO, Fujitsu, Shiseido, Kikkoman, Kirin, Nintendo, Tamagocchi, Seiji Ozawa, Tonegawa, iPS by Yamanaka, Ichiro, Gozzila, etc?

10. The focus of my talk is to demonstrate the importance and value of the OpenClinica Enterprise in Japan. 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.

11. High cost Poor performance Excluded and isolated Lack of global experience Lack of leaders Immature infrastructure Drug lag & Device lag Pre-PMDA consultation Networking & Grouping Central IRB ICH-GCP CDISC FDA 21 CFR Part 11 Education for clinical research GCP training & seminars PMDA/YCU joint graduate course Public Private Partnership International workshop High performance High quality Low cost Paperless Remote Eliminate drug lag and device lag Revive Japan in Life Innovation KSLION 2008 2012 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 Seminar December 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. DateSpeakerTitle 1 2009/9/28Peter J. TonellatoMethodology and Infrastructure for Translational Science 2 2009/10/5Takako Takai Activities in education and research on translational research at Tokyo Medical and Dental University, Japan. 3 2009/10/19Vince FusaroUsing Existing Data to Improve Translational Research 4 2009/10/26Mark Boguski Clinical and Educational Genomics -Personal experiences with direct-to-consumer genotyping- 5 2009/11/2Dennis Wall Disentangling autism through cross-disease computational analysis 6 2009/11/16Sa'ndor SzalmaTranSMART - data warehouse for translational research 7 2009/11/23 Akihiko Konagaya Virtual Patient Population Convergence: A New Framework for Translational Biomedical Informatics 8 Hiroshi Tanaka Structure of protein interaction network and their implication on drug design 9 2009/11/30Yutaka Natsumeda Status of translational and clinical research in Japan and YCU's vision 10 2009/12/7Vikas P. SukhatmePromoting Translational Medicine 11 2009/12/14 Vince Fusaro Closing Remarks on the Fall '09 Palaver Peter J. Tonellato 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 Saffitz March 3, 2010

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

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

23. February ～ April, 2011 Name SponsorShionogi CROLINICAL SitesFukui General Hospital, other 10 sites in Fukui prefecture SMO IT Services Sehma iSiD Achieved in the trial 1.Feasibility search for the sites for the trial 2.Paperless IRB review and approval 3.Prompt and secure delivery of safety information 4.Remote source document verification (R-SDV) 5.Secure storage of the document 6.Delivery of the information only to the authorized members A Test Trial to Implement IntraLinks (Highly Secure Cloud Storage System) into Clinical Trial Sites and Central IRB

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

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-PMDA functions 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. 26 Regenerative Medicine Cancer/ Lifestyle diseases Preventive Medicine Collaborations among 4 Major Sites TonomachiSuehiroFukuura YCU Minatomirai Medicine/Technology KSLION YCU Conferences, Exhibitions RIKEN

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

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

29. OpenClinica Training Seminar Dates: January 30 - February 1. 2013 Wednesday 9:30-13:00 - Business Administration 14:00-17:00 - Data Management Thursday 9:30-12:30 - Data Management (con’t…) 13:30-14:30 - Monitoring 15:30-17:00 - Clinical Research Coordination / Data Entry Friday 9:30-12:00 - Investigators / Data Specialists 12:00-17:00 - CRF Design/ Additional questions/tutoring 29

30. Influence of Nuclear Power Plant Disaster to the Residents in Fukushima A cohort study should be done and 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 60,000 people moved out from Fukushima. A total of 94 Red Cross hospitals in Japan

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 （資料） CREI, アジア防災センター ( 内 閣府） Disasters Asia ３６ ６ （３ ７％） Deaths Asia 1.34 M （ 59 ％） Victims Asia 977 M （ 89 ％） Damage Asia $605 B （ 45 ％） 被災者数（百万 人） 被害額（億ド ル） Nuclear Power Plants in East Asia Natural disasters in the world (1978 – 2008) 31 Natural disasters in Asia (1978 – 2008)

32. 32 A Project to Build Large Hospital Ships Be ready 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 Responders only 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. Traditional clinical trials Pharmacogenomics- based trials 10-12 years5-7 years

35. History of Metformin 1922 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. The focus of my talk is to demonstrate the importance and value of the OpenClinica Enterprise in Japan. 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!