Japan-USA Synergies: Academic View Mitchell W. Krucoff, MD, FACC Professor, Medicine/Cardiology Duke University Medical Center Director, Cardiovascular Devices Unit Duke Clinical Research Institute

Mitchell W. Krucoff, MD DISCLOSURES Consulting Fees Biosensors International, Terumo Medical Corporation Grants/Contracted Research Boston Scientific Corporation, Medtronic CardioVascular, Inc. Honoraria Abbott Vascular, Cordis, a Johnson & Johnson company

Clinical Evaluation of New Medical Devices Global Clinical Evaluation Clinical Evaluation of New Medical Devices Iceland Norway Finland Russia Estonia Canada U.K. Denmark Latvia Ireland Netherlands Poland Lithuania Germany Belgium China Czech Rep. Switz. Austria Slovenia Ukraine France Hungary Romania Italy Bulgaria Georgia Spain United States Portugal Greece Turkey Japan Israel Egypt Mexico United Arab Emirates Taiwan Dominica India Hong Kong Redundancy Guatemala Panama Thailand El Salvador Venezuela Malaysia Columbia Singapore Indonesia Added Cost Brazil Paraguay Australia Chile Time Delay South Africa Uruguay Argentina New Zealand Less Information October 2002

Perceptions of a Japan-USA Trial Synergies Complementary clinical practice patterns Integrated not interlocked informative trials Growing interest levels: Patients Academics Regulators Industry Media Risks connecting two markets Interlocked timelines Interlocked regulatory steps Added risks and cost Departure from traditional corporate global plan “silos”

“Harmonization By Doing” Japan-USA Program MHLW-PMDA “Harmonization By Doing” Japan-USA Program Professional Societies Medical Industry

http://www.fda.gov/cdrh/international/hbdpilot.html

Proof of Concept: DES The Regulatory Landscape in Japan and USA New DES Guidance in USA Some angiographic follow up Clinical follow up separately, or accounting for impact of protocol angiography New Paradigms in Japan More GCP capable sites Faster trial enrollment First DES RCT

Proof of Concept: DES The Clinical Trial Landscape Japan and USA Fewer sites overall Good and bad quality sites More expensive per pt Follow up is routine cath clinical practice USA Many sites Good and bad quality sites Fairly expensive per pt Follow up cath is protocol “active control” study less efficient enrollment More lost to follow up “Occulostenotic” events

Proof of Concept: DES Integrated (NOT Interlocked) Studies Design Japan Multicenter RCT Per clinical practice: primary angiographic outcome 100% angio follow up Some USA sites Addl safety info from pivotal USA study USA Multicenter RCT Per clinical practice: primary non-angio clinical outcome No protocol angiography Some Japanese sites Angio f/u info from pivotal Japan study concomitant enrollment, or “Japan first” design Japan-USA study leadership, CEC, DSMC opportunities

Proof of Concept: DES What it would take? Prospective SAP for each: Shonin and PMA Model justifying relevance of angio & clinical observations between human subjects in Japan and USA Dialogue across MHLW/PMDA and FDA

Proof of Concept: DES What It Could Deliver Individual, flexible Japan and USA filing timelines 1-3 years acceleration of approval times Better overall safety and effectiveness data Potentially “Japan first” scenario Integrated post-market landscape

Japan-USA Synergies: Academic View Mitchell W. Krucoff, MD, FACC Professor, Medicine/Cardiology Duke University Medical Center Director, Cardiovascular Devices Unit Duke Clinical Research Institute