1. Challenges to Research and Innovation to Optimize Deceased Donor Organ Quality and Quantity Peter Abt, MD Sandy Feng, MD PhD American Society of Transplant Surgeons August 28, 2012

2. Organ Quantity Limits Transplant Opportunities  Primary limitation to transplantation Motivates living donor transplantation  Engenders waitlist morbidity and mortality

3. Organ Quality Limits Transplant Outcomes  Decrease in ideal donors; increase in marginal or 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

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

5. Donor Recipients The Long Pathway for Donor-based Research Authorization/Consent IRB Approval Donor hospital “approval” Protocol dissemination Waitlist candidate / recipient consent Impact on allocation and distribution Recipient and transplant center outcomes Dissemination of study outcomes Safety and efficacy analyses Impact on donation

6. Obstacles to Research and Innovation in Deceased (Brain Dead) Donors  Scientific  Ethical  Logistical  Regulatory Investigator Donor / Donor hospitals OPOs Waitlist candidates Transplant recipients / centers

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

8. 7/107/117/12 Initiative advanced by the Scientific Studies Committee Form working group to write Working Document in conjunction with Ethics and Standards/Quality Committees 1 st F2F Meeting ATC 2011 ASTS, AOPO, ODRC Share and Revise Working Document AST, AOPO, SCCM, ASBH 2 nd F2F Meeting ATC 2012 ASTS, AST, AOPO, SCCM, ODRC, and ODTA Discussions with Key Stakeholders Timeline of ASTS Efforts

9. Donor-based Issues Peter Abt

10. The Legal Basis for Research Authorization in Deceased (Brain Dead) Donors  Organ donation and associated research is based on gift law Donation is viewed as gifting, not as an informed decision regarding healthcare by the deceased or his / her next of kin

11. Specific Circumstances that Require Full Informed Consent  Genetic studies that risk Identification of the donor or Bears implications for the donor family  Precedent established by the National Disease Research Interchange Detailed informed consent related to genomics testing

12. Does Authorization Achieve Maximal Transparency?  Public perception of donation The importance of trust in the process Lack of awareness that donation may be associated with research Potential risk for research to alter the intention of the gift Varies with specific risk posed by each specific study

13. Donor Hospitals  All hospitals are potential donor hospitals There may, however, be as few as a single donor participating in any particular donor study  Donor hospitals have a vested interest in the appropriate assessment and conduct of research in deceased donors Public relations and perception Financial

14. Regulatory and Logistical Challenges Posed by Donor Hospitals  Most lack a policy for assessing clinical trial protocols in deceased donors Precedent of hospital DCD policy  If an investigator must approach each hospital on an individual basis – the current approach – donor-based research would be unfeasible

15. Regulatory Vacuum Related to Research in Deceased (Brain Dead) Donors  Federal regulations governing research in human subjects do not apply  The role of the institutional review board, if any, in the evaluation of donor intervention / treatment trials is unclear. Investigator OPO Donor hospital

16. Recipient-based Issues Sandy Feng

17. Potential Impact of Donor-based Research on Waitlist Candidates  Organ offers are made to waitlist candidates through their transplant physicians  Transplant physicians, in conjunction with candidates, must decide whether to accept or decline any / all organ offers  The exposure of an organ to an investigational intervention or treatment may impact the decision regarding acceptance or declination  The refusal of an organ secondary to concerns regarding donor research may lead to waitlist morbidity and / or mortality

18. Issues Related to Informed Consent in the Recipient  Receiving an organ that has been involved in a donor-based research protocol does NOT obligate the recipient to participate in the research  Donor-based research questions the necessity of recipient consent under specific circumstances Research with endpoints that relate solely to data derived from the deceased donor Research limited to the use of data submitted to the United Network for Organ Sharing and obtained without identifiers

19. Issues Related to Recipient Informed Consent  The necessity for informed consent depends on whether a person is a research subject Will there be interaction between the investigator and the organ recipient related to an investigational treatment? Will identifiable data be collected and/or analyzed for research purposes?  What might be the implications for donor intervention / treatment trials if organ recipients frequently decline consent to participate in research?

20. Logistical Challenges Related to Informed Consent for the Transplant Physician and Transplant Center  Transplant physicians will need to participate in and take responsibility for obtaining informed consent from the recipient for research participation Imposes an additional burden  The research protocol must be approved by the transplant center IRB Need for “IRB exemption” if center is not participating in the specific trial

21. The Need for Communication Mechanisms  A single repository that provides standardized information related to all donor-based studies (www.clinicaltrials.gov)www.clinicaltrials.gov  A mechanism to expeditiously distribute detailed information about study interventions / treatments to the physicians of all candidates offered an organ from a donor that has participated in an intervention or treatment trial Essential for final decision regarding organ acceptance Essential to support informed consent discussion with the recipient regarding research participation  A mechanism to optimally and safely provide data regarding the recipient and/or transplant outcomes to the investigator

22. Safety and Efficacy Assessment

23. Impact on Organ Donation  Donor-based intervention and/or treatment trials may impact organ donation Negative impact if public perception views research as compromising the intent of the donor/donor family to bestow a gift through transplantation

24. Impact on Organ Allocation and Distribution  Declining to consider or accept organ offers secondary to donor-based research would alter organ allocation or distribution, respectively  The impact on individual and overall waitlist morbidity and mortality for all exposed organs must be assessed

25. Impact on Transplant Outcomes for All Exposed Organs  Donor intervention and treatment trials will likely be designed with a focus on collecting and analyzing data related to the outcome of a single organ However, multiple organs will likely have been exposed in the donor  The impact on the transplant outcomes of all exposed organs should be examined

26. Impact on Recipient-based Studies  Participation in a donor-based trial may exclude recipients of exposed organs from participation in other trials designed for transplant recipients  Transplant physicians and programs may harbor concerns about the imposition of these restrictions

27. Impact on Transplant Center Outcome Metrics  Donor intervention and treatment trials can impact statistics related to waitlist and transplant outcomes for transplant centers Performance metrics for OPOs and transplant centers are currently misaligned  These publicly available statistics, in turn, may risk a center’s reputation, accreditation, insurance contracting position, transplant volume, and revenue

28. What does the Organ Donation and Transplant Recipient Community Need? The ASTS requests that ACOT recommend to the Secretary that HRSA leadership work with the donation and transplantation community to provide recommendations that address the complex and multi-disciplinary challenges that obstruct the safe and optimal design and execution of innovative clinical trials in deceased brain dead organ donors.

29. Acknowledgements  ASTS Scientific Studies, Ethics, and Standards and Quality Committees  AST  AOPO/ODRC  SCCM  ASBH  ODTA