Appendix B: IRB Guidelines - Page 1 of 4

Manual of Operations Version 5.0

Institutional Review Board/Ethics Board

Guidelines for IRB/EB Submissions

Title of the project:

Interagency Registry of Mechanically Assisted Circulatory Support

Registry PI:

James K. Kirklin, MD

James and John Kirklin Institute for Research in Surgical Outcomes (KIRSO)

University of Alabama at Birmingham

Note: Sites will need to choose their local site PI.

Sponsor:

Note: For the local sites, participation is voluntary, and there is no financial “sponsorship” i.e., reimbursement, although participation will aid in CMS and Joint Commissioncompliance. The sponsor of the IntermacsData and ClinicalCoordinating Center is:

National Heart Lung and Blood Institute (NHLBI)

Contract #HHSN268201100025C

Number and Type of Participants and Controls

This is a multi-site observational registry of patients receiving a mechanical circulatory support device (MCSD) to treat end-stage heart failure as either destination therapy, as bridge to transplant, or as bridge to recovery. It is anticipated that up to 1,500 patients per year will be enrolled at over 150 hospitals in North America. There are no age restrictions and no control patients. There are no restrictions on gender or racial/ethnic composition of the patients included in the registry. Participating sites are asked to include all patients with a mechanical circulatory support device in the registry. Incarcerated persons (prisoners) are excluded.

Note: If asked about Special Populations: This is an observational quality assurance registry of patients with end-stage heart failure receiving a mechanical circulatory support device. Sites are asked to submit data on all patients receiving an MCSD. There are no restrictions that would prevent the inclusion of special populations such as pregnant women, neonates/nonviable neonates, minors, students, mentally retarded, impaired mental capacity, or employees. Incarcerated persons (prisoners) are excluded.

Duration of Study

Duration of entire study: March 1, 2006 to July 31, 2017

Total amount of time each subject will be involved: Specific patient involvement begins at time of implant and ends at time of death, transplant, or removal of the MCSD. The current contract ends July; 31, 2017, but there is a possibility that the registry would be funded for an additional funding period.

Location of Study

The Data and Clinical Coordinating Center of the registry is housed at the University of Alabama at Birmingham, James and John Kirklin Institute for Research in Surgical Outcomes (KIRSO), with James K. Kirklin, MD, as the Principal Investigator. Hospitals throughout North Americaimplanting MCSDs mayenroll patients.

Purpose of Project

The goal of the program is to contribute to the national registry of patients receiving a mechanical circulatory support device (MCSD) to treat end-stage heart failure. The registry collects and analyzes clinical and laboratory data from patients who receive MCSDs for end-stage heart failure at over 150 participating hospitals. It is anticipated that the registry will collect data from approximately 1,500 new patients per year.

Background

Over the last two decades, MCSDs have been developed to augment or supplant failing myocardial performance. This therapy has been used successfully as a bridge to heart transplantation, a bridge to recovery, and as permanent implantation or “destination therapy” for intractable heart failure. Although cardiac transplantation offers life saving therapy for selected patients, its use is limited by a supply of donor organs which currently meets less than one-tenth the need. As a consequence, the number of MCSD implantations has increased in recent years and this trend is expected to continue especially in view of the October 1, 2003 decision of the Centers for Medicare and Medicaid Services (CMS) to provide reimbursement for MCSD implantation surgery.

Despite favorable survival and quality of life outcomes, MCSDs do have severe and sometimes life-threatening complications associated with infection, thrombosis, and device failure. The development of new procedures and devices to reduce these complications will be expedited by the work of this proposed registry involving systematic, independent analysis of MCSD implantation procedures and outcomes. NHLBI will collaborate with CMS and the FDA in monitoring the work of the proposed registry to permit the development of standard reporting of patient characteristics, indications, implantation procedures, and adverse events. These results are expected to facilitate clinical evaluation and patient management while aiding better device development. The work should also enhance future research and facilitate appropriate regulation and reimbursement of MCSD implantations.

Methodology

This is an observational quality assurance registry of clinical events. Clinical data from patient medical charts, quality of life questionnaires, the Trail Making neurocognitive test and Kansas City Cardiomyopathy Questionnaire (KCCQ) will be collected.

Patient concerns

Time: Medical chart abstraction for clinical data will require no additional patient time. The quality of life questionnaires and the Trail Making neurocognitive test (for centers using these as standard of care) will be administered pre-implant and at 3 months post-implant and every 6 months post-implant until the patient is transplanted, dies, or has the MCSD removed due to recovery. The quality of life questionnaires and the Trail Making neurocognitive test require approximately 20 minutes of patient time each.

Payment:Patients will not be paid for their participation in this registry.

Risk-benefit ratio: The only risk to the patient for being in the registry is the very minimal risk of broken confidentiality. Every precaution will be taken to protect the participants’ information. There is no direct benefit to the patient for participating in the registry. It is possible that the knowledge of potentially helping others with mechanical circulatory support devices in the future could bring some positive feeling.

Recruitment: All subjects will be in the end stages of advanced heart failure and will likely be suffering from associated symptoms. There will be no template advertising or recruitment materials sent from the DCC to the sites.

Procedures to Maintain Confidentiality

Describe the nature of the information and to whom the information will be given: De-identified, aggregate data will be given to the sponsor, NHLBI (including the Observational StudyMonitoring Board) and to Food and Drug Administration and Centers for Medicare and Medicaid Services on a monthly, quarterly, and yearly basis. Aggregate, de-identified data will also be given to the participating sites on a bi-annual basis.

Describe the manner and method in which research data will be stored and how confidentiality will be maintained. Intermacs® complies with all US patient privacy regulations. All registry data is maintained on secure servers with appropriate safeguards in place. All Intermacs®employees have passed US Health and Human Services (HHS) background checks forgovernment clearance. Access to the production databases containing Protected Health Information (PHI) is on aneed-to-know basis only. Intermacs® personnel will periodically review all activitiesinvolving PHI to ensure that such safeguards, including standard procedures, are beingfollowed. Any breach of confidentiality and immediate mitigation steps will be reportedto the appropriate oversight bodies (e.g., the NHLBI and the local security informationofficial or IRB/EB, if applicable, according to their institutional policies) and theseimmediate mitigation steps will be implemented.

The database and web servers reside in an environment that provides multiple layers ofphysical and systems security. Intermacs® is compliant with the US Security Act of 2002 and the US Federal Information System Management Act (FISMA). Regular auditstake place to verify compliance.

Systems security is deployed with third party software and hardware, strict adherence topolicy, and regular verification and auditing. The servers that host the web applicationsare built within the Windows 2012R2 framework. They follow Microsoft’s best securitypractices and group policy recommendations from the US National Institute for Standards and Technology (NIST).

Each server is monitored 24x7 for both intrusion and vulnerabilities by an integratedthird-party software package. Microsoft System Center Configuration Manager 2012R2is used for deploying any system patches in accordance with security policies. Thenetwork is also protected by an automated anti-virus retrieval and deployment system.Physical and virtual firewalls, including Intrusion Detection Software (IDS), assists inpreventing virus and other security risks internally and externally. Internally, the serversreside on a segmented part of the Virtual Local Area Networks (VLAN) that is isolatedfrom the rest of the network protecting it from any adverse internal forces. All serveraccess requires use of second level authentication for administrative access. Regularinternal and external penetration and vulnerability tests are conducted by third-partycontractors to determine any weaknesses in the network.

Data and Safety Monitoring Board (DSMB)

Rather than a DSMB which monitors clinical trials, the registry is monitored by an Observational Study Monitoring Board (OSMB) appointed by NHLBI. The principal role of the OSMB is to monitor regularly the data from the registry, review and assess the performance of its operations, and make recommendations, as appropriate, to NHLBI with respect to:

the performance of individual centers (including possible recommendation on actions to be taken regarding any centers that performs unsatisfactorily;
issues related to participant safety and informed consent (if required), including notification of and referral for abnormal findings
adequacy of study progress in terms of recruitment, quality control, data analysis, and publications;
issues pertaining to participant burden;
impact of proposed ancillary studies and sub studies on participant burden and overall achievement on the main study goals;
possible modifications in the study protocol; and
overall scientific direction of the registry

The OSMB is composed of a Chair and members with expertise in biostatistics, clinical trials, bioethics, heart failure, cardiac surgery, bioengineering and device complications. Consultants may be added to the OSMB when it may be helpful to have greater representation of expertise in the relevant scientific field. All standing members of an OSMB may vote. Consultants have the same voting rights as an official OSMB member when reviewing the protocol.

The OSMB will discuss the registry monitoring plans for data quality and subject safety. The Data and Clinical Coordinating Center (DCC), in consultation with the Executive Committee, will be responsible for determining the selection and organization of the materials. Meeting materials will be distributed by the DCC.

Data Oversight - The registry CoordinatingCenter will prepare and distribute data reports. The basic format for the presentation of ongoing data and the need to provide these data within a certain time frame will be established at the initial OSMB meeting.

Version Date: 05/09/2016