Interagency Registry for Mechanically Assisted Circulatory Support NHLBI Contract #HHSN268200548198C

1. Interagency Registry for Mechanically Assisted Circulatory Support NHLBI Contract #HHSN268200548198C

2. NOTICE • INTERMACS® is currently using Protocol 2.2; however, the slides that you are about to view are in reference to Protocol 2.3. • Protocol 2.3 will “go live” on March 4, 2009.

3. Learning Objectives • Participants will be familiar with the purpose and structure of INTERMACS® • Participants will know how to enroll and activate their centers in INTERMACS ® • Participants will be familiar with hospital membership criteria and the audit process • Participants will be familiar with INTERMACS ® Adverse Event Definitions • Participants will know how to contact INTERMACS ® Support for help with enrollment and data entry issues

4. “Implantation of an MCSS 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 MCSS patients should be followed, through a registry, for the remainder of their lives...Maintaining a registry of MCSS 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 MCSS patients.” The Artificial Heart: Prototypes Policies and Patients; Institute of Medicine Report, 1991.

5. NHLBI Contract #HHSN268200548198C Award date:June 1, 2005 Duration:5 years To: University of Alabama at Birmingham Subcontracts:United Network for Organ Sharing University of Pittsburgh Brigham and Women’s Hospital Cleveland Clinic PI: James K. Kirklin, MD Co PI’s: Robert L. Kormos, MD Lynne W. Stevenson, MD David C. Naftel, PhD Study Chair: James B. Young, MD

6. “Interagency” means NHLBI, CMS, and FDA National Heart, Lung and Blood Institute ● Centers for Medicare and Medicaid Services ● Food and Drug Administration

7. Operations Committee Marissa Miller, Karen Ulisney, James Young, James Kirklin, Lynne Stevenson, Robert Kormos, Tim Baldwin, Patrice Nickens, David Naftel, Leah Edwards, Eric Chen, Wolf Sapirstein Subcommitees Data Access, Analysis and Publications F Pagani Hospital Training and Standards W. Pae Adverse Events And Adjudication R Kormos W Holman Pediatrics E Blume Steering Committee Industry Relations And Device Development J Watson Focused Research and Mission Activities S Koenig M Jessup Coordinators Council K Chisholm T Martin S Wissman

8. NHLBI FDA CMS Clinical sites (data collection) Web-based Data entry Expertise Industry Physician Expertise Data Analysis Expertise

9. Goals of the Registry • Facilitate the refinement of patient selection to maximize outcomes with current and new device options. • Improve and expedite new device clinical trials by providing historical control data, reliable enough to serve as Objective Performance Criteria (OPC) standards for FDA. • Develop consensus “best practice” guidelines to improve clinical management by reducing short and long term complications of MCSD therapy.

10. Goals of the Registry (continued) • Improve economic outcomes by identifying and optimizing factors affecting cost-effectiveness. • Utilize MCSD Registry information to guide improvements in technology, particularly as next generation devices evolve. • Promote research into the underlying pathophysiologic substrate of advanced heart failure in order to define and promote the conditions necessary for myocardial recovery. • Evaluate parameters of quality of life before and after device implantation.

11. Site Benefits • Fulfills CMS reporting requirements for destination therapy to a national registry. Please see theMedicare National Coverage Determinations Manual, Section 20.9 - Artificial Hearts And Related Devices: • http://new.cms.hhs.gov/manuals/downloads/ncd103c1_Part1.pdf • Fulfills JCAHO’s proposed requirements for VAD Certification at: • http://www.jointcommission.org/Certificationprograms/ • INTERMACS sites will receive quarterly site specific reports, including confidential comparisons to the Registry results.

12. Medical Center Eligibility Any medical center in the United States that has an active ventricular assist device therapy program is eligible to contribute to INTERMACS.

13. INTERMACS SupportAvailable Monday - Friday, 8:00 – 5:00 EST • Jo Smith • INTERMACS Coordinator • (804) 782-4926 • smithjw@unos.org Rochelle Taylor INTERMACS Coordinator (804) 782-4869 taylorrr@unos.org Susan Groff INTERMACS Coordinator (804) 782-4859 groffsus@unos.org Ruth Henson INTERMACS Audit Coordinator (804) 782-4858 hensonrb@unos.org

14. INTERMACS SupportAvailable Tuesday - Friday, 8:00 – 5:00 EST Kathryn Philibin Assistant Director, Clinical Affairs (804) 782-4854 philibka@unos.org

15. Participation Requirements • Completion of INTERMACS online training (this PowerPoint Presentation) • Enrollment • IRB Approval and IRB-approved Informed Consent Templates, and current FWA number • Participation Agreement, signed by legally authorized representative of the hospital • Conflict of Interest Disclosure Form for each Principal Investigator and all Co-Investigators • Documentation of Human Subjects Protection training for every user who has INTERMACS-related contact with patients • Completion of INTERMACS practical training (remote Microsoft Live Meeting session with INTERMACS Trainer)

16. Requirement #1INTERMACS Online Training A minimum of one staff member from your institution should review this online PowerPoint presentation in its entirety before proceeding to steps 2 – 7.

17. Requirement #2Online Enrollment • Enroll your medical center by accessing the following link: www.intermacs.org, then click on the “INTERMACS Membership” link. • INTERMACS Support is available Monday through Friday, 8:00 – 5:00 (EST) to provide technical assistance. Contact INTERMACS Support at support@intermacs.org.

18. Enrollment (cont) • In order to complete the online enrollment process, you will be required to assign staff to the following roles from your facility: Principal Investigator: responsible for oversight of data submission and registry compliance Site Administrator: responsible as “point person” for data related inquiries, receipt of reports and audit coordination

19. Enrollment (cont) • Membership Changes after enrollment process is complete: Once initial enrollment has been completed, you will no longer be able to make changes to your INTERMACS account. INTERMACS Support will add and remove staff members only as requested by your medical center Site Administrator.

20. Requirement #3IRB Approval • Your IRB must approve your center’s participation in INTERMACS • You will not be activated to enter patients until INTERMACS Support has received documentation of IRB approval, IRB-approved Informed Consent templates, and your IRB’s current FWA number • IRB guidelines and examples of patient consent forms are included in the Manual of Operations, Appendices B and C, for your reference at www.intermacs.org, then click on the “All Things INTERMACS” link.

21. Requirement #3 (cont.)Informed Consents • Three patient Informed Consents may be required by your IRB: Patient consent for data entry into INTERMACS HIPAA Authorization Blood and Tissue Collection

22. Requirement #4Conflict of Interest Disclosure • Before data entry in INTERMACS can commence, your Principal Investigator and any Co-Investigator(s) must complete the Conflict of Interest Disclosure Form included in the Manual of Operations, Appendix E, located at the following link: www.intermacs.org, then click on the “All Things INTERMACS” link.

23. Requirement #5Participation Agreement • Before entering patients, a legally authorized representative from your hospital is required to sign the participation agreement. This form is located in the Manual of Operations, Appendix D, and may be downloaded and printed from the following link: www.intermacs.org, then click on the “All Things INTERMACS” link. • Please fax your participation agreement to INTERMACS Support at 1-800-809-7688.

24. Documentation of Human Subjects Training (CITI or other NIH-approved HST course) must be submitted for every INTERMACS user who has or intends to have INTERMACS-related contact with patients. Requirement #6 Documentation of Human Subjects Training

25. Complete a live, interactive training with INTERMACS Support after your center has submitted all required documents (IRB Approval, Informed Consent Templates, Human Subjects Training Documentation, Conflict of Interest Disclosure Form, and Participation Agreement) Requirement #7Practical Training

26. Activation • Upon completion of all seven membership requirements, a medical center is eligible for “activation”. • Once activated, your center will be eligible to enter patient data online at www.intermacs.org • Upon activation by INTERMACS Support, each enrolled user at the medical center will receive notification and usernames and passwords.

27. Data Security

28. Data Security • INTERMACS is fully compliant with the Health Insurance Portability and Accountability Act (HIPAA) • UNOS is Certified by the Health Resources and Services Administration (HRSA) • Access to INTERMACS data by UNOS personnel is limited based on job description

29. Data Security (cont.) • The database and web servers reside in an environment providing multiple levels of physical and systems security. • INTERMACS is fully compliant with the Security Act of 2002 and the Federal Information System Management Act. Routine audits verify compliance. • Microsoft best security practices and group policy recommendations from the National Institute for Standards in Technology are followed for the Windows 2003 framework.

30. Data Security (cont.) • Servers are monitored 24 / 7 for intrusion and vulnerabilities by an integrated third party software package. • The network is protected by an anti-virus retrieval and deployment system. • Firewall software prevents hacking, virus and other outside security risks. • Servers reside on a segmented part of the VLAN that protects it from any adverse internal forces.

31. Users’ Access to INTERMACS • Access to INTERMACS is login and password protected. • Logins and passwords are assigned to enrolled hospital participants by INTERMACS Support and relayed via e-mail. • Know your username and password. • Keep them secure.

32. Compliance

33. INTERMACS Data Compliance • Participating medical centers must submit data on all consented recipients of a durable, FDA-approved MCSD. • Participating medical centers should maintain a screening record of all MCSD recipients that do not meet the inclusion criteria for enrollment into INTERMACS ®.

34. Data Compliance (cont) • All data fields must be completed before a form can be submitted. • Status Fields (“ST =” ) will provide alternative options if requested data is unavailable. Examples of Status field options may include: unknown not done not done, too sick not done, other

35. Data Submission Schedule Patient Demographics 30 days from implant date Pre-Implant 30 days from implant date Operative Details 30 days from implant date 1 Week Follow-up 30 days from implant date Discharge 30 days from discharge date 3 & 6 month Follow-ups 30 days from exam date Q6 month Follow-ups30 days from exam date Rehospitalization 30 days from occurrence Adverse Events 30 days from occurrence *Device Malfunction Explant 30 days from date of explant Death 30 days from date of death * FDA requires initial device malfunctions be reported within 72 hours of occurrence. (See Users Guide for instructions)

36. Site Audits

37. Onsite Audits of INTERMACS Centers • Each participating medical center will participate in one scheduled on-site audit during the 5 year contract period • Site audits began September, 2007 • Audit notification will be provided no less than 60 days prior to audit date • Patient records will be audited to verify correct and complete database entries

38. Web-Based Data Entry Application

39. How will data be collected for submission to INTERMACS? • Medical Record Review • EUROQoL Questionnaire (Quality of Life patient self-assessment) • Trail Making Test (Neurocognitive evaluation) • Blood and Tissue information at: Implant Explant/Transplant

40. Time Points for Data Collection • Pre-Implant • Implant Hospitalization Discharge Form • Follow-Up 1 week, 1 Month, 3 Months, 6 Months and q 6 Months • Adverse Events (AE’s) and Serious Adverse Events (SAE’s) • Rehospitalization • Death • Explant/Transplant

41. Adverse Event Definitions

42. Major Bleeding An episode of suspected internal or external bleeding that results in one or more of the following: a. Death, b. Reoperation, c. Hospitalization, d. Transfusion of red blood cells as follows: During first 7 days post implant • Adults (≥ 50 kg): ≥ 4U packed red blood cells (PRBC) within any 24 hour period during first 7 days post implant. • Pediatric (< 50 kg): ≥ 20 cc/kg packed red blood cells (PRBC) within any 24 hours period during first 7 days post implant. After 7 days post implant • Any transfusion of packed red blood cells (PRBC) after 7 days following implant with the investigator recording the number of units given. (record number of units given per 24 hour period) NOTE: Hemorrhagic stroke is considered a neurological event and not as a separate bleeding event.

43. Cardiac Arrhythmia Any documented arrhythmia that results in clinical compromise (e.g., diminished VAD flow, oliguria, pre-syncope or syncope) that requires hospitalization or occurs during a hospital stay. Cardiac arrhythmias are classified as 1 of 2 types: 1) Sustained ventricular arrhythmia requiring defibrillation or cardioversion. 2) Sustained supraventricular arrhythmia requiring drug treatment or cardioversion.

44. Pericardial Fluid Collection Accumulation of fluid or clot in the pericardial space that requires surgical intervention or percutaneous catheter drainage. This event will be subdivided into those with clinical signs of tamponade (e.g. increased central venous pressure and decreased cardiac/VAD output) and those without signs of tamponade.

45. Device Malfunction Device malfunction denotes a failure of one or more of the Components of the MCSD system which either directly causes or could potentially induce a state of inadequate circulatory support (low cardiac output state) or death. The manufacturer must confirm device failure. A failure that was iatrogenic or recipient-induced will be classified as an Iatrogenic/Recipient-Induced Failure. Device failure should be classified according to which components fails as follows: 1) Pump failure(blood contacting components of pump and any motor or other pump actuating mechanism that is housed with the blood contacting components). In the special situation of pump thrombosis, thrombus is documented to be present within the device or its conduits that result in or could potentially induce circulatory failure. 2) Non-pump failure( e.g.,external pneumatic drive unit, electric power supply unit, batteries, controller, interconnect cable, compliance chamber)

46. Hemolysis A plasma-free hemoglobin value that is greater than 40 mg/dl, in association with clinical signs associated with hemolysis (e.g., anemia, low hematocrit, hyperbilirubinemia) occurring after the first 72 hours post-implant. Hemolysis related to documented non-device-related causes (e.g., transfusion or drug) is excluded from this definition.

47. Hepatic Dysfunction An increase in any two of the following hepatic laboratory values (total bilirubin, aspartate aminotransferase/AST and alanine aminotranferease/ALT) to a level greater than three times the upper limit of normal for the hospital, beyond 14 days post-implant (or if Hepatic dysfunction is the primary cause of death).

48. Hypertension New onset of blood pressure elevation greater than or equal to 140 mm Hg systolic or 90 mm Hg diastolic (pulsatile pump) or 110 mm Hg mean pressure (rotary pump). Pediatric patients: for patients under 18 years of age weighing < 50 kg, hypertension is defined as systolic, diastolic, or mean blood pressure greater than the 95th percentile for age which requires the addition of iv or oral therapy for management.

49. Major Infection A clinical infection accompanied by pain, fever, drainage and/or leukocytosis that is treated by anti-microbial agents (non-prophylactic). A positive culture from the infected site or organ should be present unless strong clinical evidence indicates the need for treatment despite negative cultures. The general categories of infection are listed below: Localized Non-Device Infection Infection localized to any organ system or region (e.g., mediastinitis) without evidence of systemic involvement (see sepsis definition), ascertained by standard clinical methods and either associated with evidence of bacterial, viral, fungal or protozoal infection, and/or requiring empirical treatment. (continued on next slide)

50. Major Infection (cont) Percutaneous Site and/or Pocket Infection A positive culture from the skin and/or tissue surrounding the drive line or from the tissue surrounding the external housing of a pump implanted within the body, coupled with the need to treat with antimicrobial therapy, when there is clinical evidence of infection such as pain, fever, drainage, or leukocytosis. Internal Pump Component, Inflow or Outflow Tract Infection Infection of blood-contacting surfaces of the LVAD documented by positive site culture. (There should be a separate data field for paracorporeal pump that describes infection at the percutaneous cannula site, e.g. Thoratec PVAD). Sepsis Evidence of systemic involvement by infection, manifested by positive blood cultures and/or hypotension.