Harmonization By Doing HBD 2003 2018 History Significance

Harmonization By Doing (HBD) 2003 -2018 History, Significance & Future Prospects Mitchell W. Krucoff MD, FACC, FSCAI, FAHA Professor of Medicine / Cardiology Duke University Medical Center Director, Cardiovascular Devices Unit Director, MDEpi. Net Coordinating Center Duke Clinical Research Institute mitchell. krucoff@duke. edu

Disclosure Statement of Financial Conflict of Interest Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below. Affiliation/Financial Relationship n Grant/Research Support Company n n n n n Consulting Fees/Honoraria n n n Orbus. Neich Medtronic Boston Scientific Abbott Vascular Biosensors CSI Cook Medical Cordis J&J Orbus. Neich Medtronic CSI Boston Scientific Abbott Vascular Biosensors

HB Doing Program History

December 2003 http: //www. fda. gov/cdrh/international. html

2003 -2004: Japan MHLW launches PMDA

April 2004: PMDA Adopts Early Consultation • • Early discussion of clinical trial science & strategy Potential to coordinate with pre-IDE discussions in USA

HBD Global regulatory convergence

Regulatory Convergence: Ethics, Methods and Science of Human Studies Regulatory Focus, April 2010 Regulatory Focus, January 2013

HBD Research infrastructure efficiencies

HBD Site Visits March 2004: Shonan Kamakura

Advancing Research Infrastructure: Study processes – time lines ü Protocol development ü Study design ü Site selection ü Steering Committee ü DSMC ü Safety Desk ü CEC ü Site start-up ü Training üInvestigator and Coordinator Meeting ü Site Queries ü Monitoring Database lock ü Operations Team ü Study Documents ü Contracting ü First Patient in ü Randomization ü CEC üSafety Reporting ü Last Patient in

HBD Stakeholder education & engagement

Japan Circulatory Society March 2004 Tokyo, Japan TCT, CRT, ACC, CVIT, CCT, JCS, 2004 -2018: CIT, Sing Live, From “Japan-USA Barriers ” RAPS, JFMDA, Advamed, CSRC, to “Japan-USA Synergies” Euro. PCR

HB Doing Pilot “POC” Projects: Registry-based evidence “Harmonization By Data”

Linking Post-Market Surveillance: LVADS JMACS

Peripheral Academic Research Consortium (PARC) Face to Face Workshops FDA Headquarters, White Oak, Maryland February 2012 & 2013

PARC Stakeholders: 2012 -2013 Regulatory Academia Societies Industry n FDA n Columbia Universtiy n ACC n Abbott n PMDA n Duke University n SCAI n Cook Medical n Harvard Medical School n ESC n Cordis/J&J n ISCTR n Covidien n C. R. Bard Inc n Lutonix n Medtronic n Pleuistem n Terumo AROs n Cardialysis n CRF n DCRI n HCRI n Juntendo University n Kokura Memorial n Mass General Hosp n n Mt. Sinai Medical Center Mayo Clinic Ochsner Clinic n UC Irvine n UCSF n Patel MR et al, JACC 2015: 65: 931 -41

Real World Evidence Structure, Quality & Capture Coordinated Registry Networks (CRNs) August 24, 2015 www. mdepinet. org Krucoff MW, Normand SL et al, JAMA 2015

NEST: The Vision Real World Evidence of Device Benefit/Risk, Safety Ø More real world Ø Less unique effort & cost Ø More value across ecosystem: Regulatory decisions Ø Best practice guidelines Ø Payer decisions Ø Patient information Ø Ø Learning model: Ø Ø Ø Use/re-use structure solutions Linked registry architecture International application JAMA Published online July 11, 2016

Registry Assessment of Peripheral Interventional Devices (RAPID): Core Minimum Data Set for Device Evaluation Jack L. Cronenwett, M. D. Dartmouth-Hitchcock Medical Center Pablo Morales, M. D. U. S. FDA Robert Thatcher CEO 4 C Medical Mitchell W. Krucoff, M. D. Duke University Medical Center/Duke Clinical Research Institute

RAPID Partners • 3 Major U. S. Societies / Registries • American College of Cardiology (ACC) • National Cardiovascular Disease Registry (NCDR) • Society of Interventional Radiology (SIR) • National Interventional Radiology Quality Registry (NIRQR) • Society for Vascular Surgery (SVS) • Vascular Quality Initiative (VQI) • 5 International Partners • Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) • Global Medical Device Nomenclature Agency (GMDNA) • Australian Vascular Audit • German Vascular Society • Northern German Association for Vascular Medicine 21

RAPID Partners • 12 Device Manufacturers • • • Abbott Aortic Medical Inc. Avinger Boston Scientific Cardiovascular Systems Inc Cook Medical CR Bard Medtronic Spectranetics Corp Terumo Volcano Corp/Phillips Health Technology WL Gore 22

https: //nestcc. org/demo-announcement/

HB Doing Pilot “POC” Projects: Prospective Clinical Trials Uchida T et al, Circulation Journal 2013

2005: Endeavor Japan (Medtronic) • • • Identical inclusion/exclusion Identical endpoints Identical core laboratories Enhanced poolability Enhanced interpretability

2007: SPIRIT III Japan (Abbott Vascular): Enhanced poolability & interpretability • • Concomitant enrollment Identical inclusion/exclusion Identical endpoints Identical core laboratories

2009: Zilver PTX (Cook Medical) Single protocol global RCT

COAST Study (CSI) Diamondback 360® Coronary OAS Micro Crown § To evaluate the performance of the Coronary OAS Micro Crown in treating de novo, severely calcified coronary lesions § Prospective, single-arm, multi-center Investigational Device Exemption (IDE) study conducted in Japan and the USA § Harmonization by Doing (regulatory collaboration between Japan and the USA) 100 patients enrolled 74 patients USA 12 sites Japan 26 patients 5 sites 1 -year follow-up completed* (93/100) *6 subjects died and 1 subject lost to follow-up 14

Harmonized Assessment by Randomized Multicenter Study of Orbus. NEich’s COMBO St. Ent Japan-USA HARMONEE: Primary Report Of A Randomized Trial of a Bioabsorbable Polymer-Based DES With A Luminal CD 34+ Antibody Coating vs A Durable Polymer-Based DES in Patients With Coronary Artery Disease The COMBO Plus Dual Therapy Stent

HB Doing New & Future Directions

HB Doing Early Feasibility Studies (EFS)

Early Feasibility Studies: Can We Do Together? https: //www. fda. gov/downloads/Medical. Devices/Device. Regulationand. Guidance/Guidance. Documents/ucm 279103. pdf

2017 TCT Denver EFS in Japan: PMDA View Sara Takahashi Reviewer Office of Medical Devices III Pharmaceuticals and Medical Devices Agency (PMDA), Japan

Percutaneous Mitral Valve EFS POC

HB Doing HBD for Children

POC candidates industry Covered CP Stent Medtronic Melody Transcatheter Pulmonary Valve AMPLATZER muscular VSD occluder Nu. MED Medtronic ST. JUDE MEDICAL

HBD: 15 Years & Beyond Identifying & Transforming Barriers to Device Innovation n n Pre-competitive collaboration, trust & good will n International regulatory convergence n Research infrastructure efficiencies Global market fragmentation n Information fragmentation & redundancy n Competitive approaches to pre-competitive barriers n Structured data elements & definitions n n Stakeholder education engagement Isolated stakeholders, not&ecosystem n Pilot “POC” projects Krucoff MW et al, J Am Coll Cardiol Intv 2012; 5: 790– 6) Uchida T et al, Circulation Journal 2013