1. Interagency Registry for Mechanically Assisted Circulatory Support Marissa A. Miller, DVM, MPH National Heart, Lung, & Blood Institute

2. “Implantation of an MCSD is not a simple, time-limited treatment episode. Because of the patient’s total dependence on the device and because problems can occur at any time, clinical trial subjects should be followed closely during the trials: they and other MCSD patients should be followed, through a registry, for the remainder of their lives... Maintaining a registry of MCSD recipients should be considered a routine aspect of this care…The committee recommends that NHLBI…support long term follow up studies of an adequate sample of MCSD patients.” The Artificial Heart: Prototypes Policies and Patients; Institute of Medicine Report, 1991.

3. What does INTERAGENCY mean? National Heart Lung and Blood Institute Patrice Nickens, Tim Baldwin, Marissa Miller, Karen Ulisney Centers for Medicare and Medicaid Services Marcel Salive, Joanna Baldwin Food and Drug Administration Wolf Sapirstein, Eric Chen, Tom Gross, Bram Zuckerman

4. Objective To advance the understanding and application of mechanical circulatory support in order to improve the duration and quality of life of patients with advanced heart failure.

5. Purpose To collect and analyze clinical and laboratory data and tissue and blood samples from patients who are receiving MCSDs for whom discharge from the hospital is feasible (including destination therapy for end stage heart failure, bridge to transplantation and bridge to recovery patients).

6. To disseminate information that will refine: Patient selection Establish best practices to improve clinical management Expedite new clinical trials Improve economic outcomes Evaluate function and quality of life of patients Guide next generation device development Promote research into heart failure and recovery Goals of the Registry

7. NHLBI Contract #N01-HV-58198 Data Coordinating Center Site:Univ. of Alabama at Birmingham PI James Kirklin, MD Date:May 31, 2005 Duration:5 years Subcontracts:United Network of Organ Sharing Robert L. Kormos, MD Lynne W. Stevenson, MD Study Chair:James B. Young, MD

8. NHLBI,FDA CMS Funding, regulation, reimbursement Clinical sites Data collection Steering Committee Medical expertise Industry Device expertise DCC UAB Data Analysis UNOS Web-based Data entry

10. Protocol Development INTERMACS Timeline Contract Awarded to UAB 06/01/05 Training 101 Coord 35 PIs 84 Sites 02/28/06 Data Element Development Refine WBDE Hospital Enrollment Patient Enrollment Launch 06/23/06 CMS Destination Therapy 03/27/07

11. Measure of Study Quality (Study Design, Data Analysis) Good Clinical Trial Typical Registry The Major Task for the INTERMACS Registry

12. Measure of Study Quality (Study Design, Data Analysis) Good Clinical Trial Typical Registry Planned (thoughtful) Analyses Complete Data Adverse Event Definitions All Cases Audits Complete Follow-up Adjudication of Outcome Events Local PI Certification Data Freeze OSMB Inclusion/Exclusion Criteria

13. Site enrollment and compliance Number of enrolled, and trained sites Number of enrolled patients Timely and complete submission of data Descriptive Statistics Demographics and characteristics of patients Type and number of devices-*ability to capture high proportion of devices implanted in US Outcomes and Risk Factors Death, survival, adverse events, transplantation Data Collection and Analysis

14. Inclusive Process Engaged experts in specific areas: AEs, QOL, HF, Bioengineering Included academic, industry and government Series of Steering Committee Meetings 6 face-to-face meetings over 6 months to develop and refine the data elements Meetings with FDA and CMS to harmonize Coordinators Training and Site Testing Coordinators’ training January 27& 28, 2006 Over 100 sites sent representatives to participate Dialogue and feedback process Data Element & Adverse Event Definition Development

15. Standardized definitions & data elements Adverse event definitions developed in conjunction with FDA and Industry Potential to use in pre-market and clinical trials Direct reporting of adverse events/MDRs to FDA Majority of data collected on MEDWATCH Form 3500A available in INTERMACS. Event adjudication process through INTERMACS experts meeting quarterly Web-based data entry Ongoing, rapid and user-friendly Future integration of ISHLT-MCSD data Innovations

16. 1.Fulfills CMS reporting requirements to a national registry for destination therapy. 2.Semi-annual site specific reports, including confidential comparisons to aggregate results. 3.Sites already contributing to ISHLT MCSD database will be “grandfathered in” if they desire. Clinical Site Benefits

17. 1.Provides CMS detailed data on sites placing MCSDs for destination therapy. 2.Has obviated the need for sites to report mechanical device failures to FDA. 3.Adverse event definitions are being utilized in pre and post-market device studies. 4.Industry is utilizing registry data for regulatory trials and studies. Stakeholder Benefits

18. Device Strategy at Implant n % of 420 Bridge to Recovery21 5% Bridge to Transplant* 336 80% Listed 179 43% Likely to be listed 83 20% Moderate likely to be listed 44 10% Unlikely to be listed 30 7% Destination Therapy63 15% Total 420 100% *In all subsequent slides “Bridge to Transplant” will include the four subcategories. June 2006 – December 2007 (n=420)

19. June 2006 – December 2007 Device Strategy: Bridge to Transplant, n=336 Months after Device Implant Proportion of Patients Alive (still waiting) 33% Death (before transplant) 22% Transplant 42% Explanted (recovery) 3% 20% 24% 53% 3%

20. June 2006 – December 2007 Device Strategy: Destination Therapy, n=63 Months after Device Implant Proportion of Patients Alive (still waiting) 68% Death (before transplant) 25% Transplant 5% Explanted (recovery) 2% 53% 37% 8% 2%

21. June 2006 – December 2007 (n=420) Device Strategy at Implant Months after Device Implant % Survival Destination Therapy n=63, deaths=19 Event: Death Bridge to Recovery or Rescue Therapy n=21, deaths=11 Bridge to Transplant (includes BTT subcategories) n=336, deaths=74 p=.006

22. Summary 92 Sites/969 Patients INTERMACS reflects extensive cooperation and collaboration across government, academia and industry It is a national registry that fulfills CMS requirements for reporting of destination device placements FDA has optimized upon INTERMACS definitions for adverse events and considers the enterprise beneficial to their mission Utilization of INTERMACS platform can benefit Industry and advance the development of new devices, especially critical for ‘orphan’ products such as pediatric devices Challenge include extending into pediatric populations, premarket and international areas and sustainability.

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