David A. Gerber, MD Professor and Chief Division of Abdominal Transplantation Department of Surgery University of North Carolina at Chapel Hill

Organ Quality Limits Transplant Outcomes  Insufficient ideal donors; increase in DCD, marginal and expanded criteria donors  Donor quality defined by post-transplant outcomes according to risk of graft loss (patient death or need for retransplantation)  Inferior organ quality engenders recipient morbidity and mortality

The Need for Innovation and Research in Donor Intervention and Treatment  To increase the number of organs available for transplantation  Mitigate waiting list candidate morbidity and mortality  To improve the quality of organs used for transplantation  Mitigate recipient morbidity and mortality

Obstacles to Research and Innovation in Deceased (Brain Dead) Donors Constituents:  Scientific  Ethical  Logistical  Regulatory Investigator Donors / donor families Donor hospitals Organ Procurement Organizations OPTN Waiting list candidates Transplant recipients / centers

Problem  Current infrastructure is inadequate to support effective donor intervention and treatment studies. The magnitude and complexity of the challenges require guidelines/processes to facilitate the optimal design and safe execution of clinical trials in deceased donors.

Donor Intervention Research ACOT Work Group: Key Focus Areas  Protocol and Oversight: – Key elements – Sharing  Donor-Focused Issues: – Donor authorization for research – Ethical considerations  Transplant Center/Recipient Issues: – Risk – Consent

Donor Intervention Research Overview

Specific Actions to be Considered  Identify existing mechanisms, pathways, etc. and alternative pathways that could facilitate unique donor-related research activities

Donor Intervention Research ACOT Work Group  Point of emphasis needs to be on big science with respect to guidance.  This strategy would allow the development of processes that capture all potential donor- related research activities.  Complementary efforts ongoing with IOM  IOM support from transplant organizations and stakeholders

Donor Intervention Research ACOT Work Group—Potential Protocol Process Develop Proposal Input: Personal observation; animal studies; literature review Responsibility: Researcher Key Question: Research question examined Develop Study Plan Input: Colleagues; Research Consortium; literature review Responsibility: Researcher Oversight: Researcher organization Key Question: Process and partners? Scientific Merit Review Input: Current or developed requirements Responsibility: Researcher submitted; Committee review Oversight: TBD (where committee is housed) Key Question: Is study worth doing?

Donor Intervention Research ACOT Work Group: Potential Protocol Process (c ont.) Resource RISK: Description of levels of risk to recipient Human Subjects Review Input: Guidance from OHRP, DIRB requirements Responsibility: Researcher submitted; DIRB review Oversight: DIRB, OHRP Key Question: Does study demonstrate protection of human subjects? Allocation: Impact of allocation on protocol design and implementation; impact on non-targeted organs Resource DIRB/DSMB: Model elements for DIRB review and DSMB monitoring; centralized versus regional Data and Safety Monitoring Input: Standardized reporting process Responsibility: Research team reporting; Board monitoring and action Oversight: DSMB, OHRP Key Questions: Does study protect subject? Are adverse events identified and mitigated?

Donor Intervention Research ACOT Work Group Processes  Subcommittee Meetings-May, July, September  Representation (ACOT, HRSA, UNOS, Transplant clinicians)  Identify what role ACOT can play in this process  Recommendation development

Topics Addressed  Donor-focused issues – Standards for OPO review and participation – Donor hospital considerations  Transplant-focused issues – Quantifying risk – Communicating info about protocol to accepting team – required elements – Informed consent of recipient or possible waiver of documentation of informed consent

DRAFT ACOT Recommendation WHEREAS, the Committee finds that: 1. Clinical innovation through deceased donor intervention research has the potential to substantially increase both the quantity and quality of organs to mitigate the increasing gap between the number of available organs (supply) and the number of patients with end stage organ failure waiting for transplantation (demand); 2.Donor intervention research creates multiple considerations for transplant candidates on the waiting list, transplant recipients of such organs and the outcomes of such organs; 3.A number of unique and substantial ethical, logistical and regulatory barriers and challenges at multiple levels in the field of deceased donor intervention research has stifled clinical innovation and progress; 4.Conducting donor intervention research impacts the process at the deceased donor level (involving all OPOs and thousands of donor hospitals nationwide) and also at the transplant recipient level (involving thousands of transplant candidates and recipients at hundreds of transplant centers nationwide ) annually;

DRAFT ACOT Recommendation Continued 5.Only centralized oversight of deceased donor intervention research with a single consistent review process can effectively address the complex existing barriers and facilitate deceased donor intervention research while providing a mechanism to assure reasonable protections for potential (waitlisted candidates) and actual transplant recipients of such organs and maintaining the public trust in organ donation and transplantation; 6.The Institute of Medicine completed a planning meeting on July 14, 2015 with respect to undertaking a study on issues in deceased organ donation research; and 7.There are regulatory disincentives in the performance measures for transplant centers and OPOs that create barriers to participating in innovative deceased donor research protocols.

The Committee RECOMMENDS that the Secretary: 1.Take timely action to establish a nationwide centralized oversight mechanism to facilitate deceased donor (and organ) intervention research; 2.Support and facilitate as appropriate the planned study by the Institute of Medicine on issues in deceased organ donor research; and 3.Direct the relevant stakeholders (e.g. CMS, OPTN, SRTR, et al) to evaluate and implement mechanisms for risk-adjusting outcome measures and center-specific reports which would eliminate barriers for broader participation in donor intervention research thus potentially increasing both the quantity and quality of organs available for transplantation.