Future Approaches to Organ Donor Intervention Research Study Design. Bertram Kasiske, MD Project Director, SRTR December 14, 2016

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1 Future Approaches to Organ Donor Intervention Research Study Design Bertram Kasiske, MD Project Director, SRTR December 14, 2016

2 Disclosures and Disclaimers I have no conflicts pertinent to this topic. The views expressed here are my own and not necessarily those of the US Government.

3 About the SRTR The HRSA-SRTR contract is currently administered by the Minneapolis Medical Research Foundation, located at Hennepin County Medical Center, Minneapolis, MN. SRTR maintains a national database for solid organ transplantation including data on organ donation, candidates waiting for transplant, and transplant recipients.

4 SRTR Roles and Responsibilities Provide research support to the OPTN Board of Directors, OPTN Committees, HRSA, and the transplant community. Perform ongoing evaluations of the status of solid organ transplantation: Transplant Program-Specific Reports Organ Procurement Organization-Specific Reports Annual report on trends in organ transplantation Facilitate outside research by releasing data to researchers. Disseminate information through reports and publications.

5 SRTR Could Support Pragmatic Trials in Organ Allocation & Preservation Most data are already collected: Donor & organ characteristics Recipient characteristics Outcomes o Discards o Patient survival o Graft survival A study could randomly allocate: Preservation methods Organ allocation protocols

6 Overcoming Barriers to the Use of SRTR in Clinical Research Time Required to Approve New Data Elements. New data elements must be approved by the OMB Paperwork Reduction Act requirement Process may take up to 1-2 years Data collected for a clinical trial Would not cause extra burden on programs Could be directly transmitted to the SRTR

7 Recipient Protections in 13 Donor Intervention Studies First author, publication year Donor Intervention Org. RCT Site(s) Number of Recipients IRB Recipient Consent Niemann, 2015 Hypothermia K Yes 2 OPOs 572 Yes No Ware, 2014 Albuterol Neb All Yes 1 OPO 796 No No Oniscu, 2014 Regional perf All No 3 49 No No D Amico, 2013 NAC Li Yes Yes Yes Guarrera, 2010 HMP Li No 1 20 Yes Yes Watson, 2010 HMP v cold K Yes 5 45/45 Yes Yes Jochmans, 2010 HMP v cold K Yes? 82/82 Yes No Schnuelle, 2009 Dopamine K Yes Yes No Moers, 2009 HMP v cold K No /336 Yes No Venkateswaran, 2008 MP +/- T3 Lu Yes 1 48 No No Kotsch, 2008 MP Li Yes Yes No Perez-Blanco, 2005 T3 All Yes 1 52 donors Yes No Koneru, 2005 Isch. Precon. Li Yes 1 62 Yes Yes HMP, hypothermic machine perfusion; MP, methylprednisolone; NAC, N-Acetylcysteine; T3, triiodothyronine;

8 What is needed to move organ donor intervention & allocation research forward? All research should have central IRB oversight. Some research could & should require consent from potential recipients. The need for consent could be determined by the feasibility and the balance between: Potential benefit to the recipient Potential risk to the recipient

9 Defining Donor Intervention Risk to Recipients Characteristic Low Risk Mod. Risk High Risk Accepted drug or procedure Experimental drug or procedure but with some preliminary data Experimental drug or procedure with little/no preliminary data

10 Level of Review & Consent Could Be Determined by Risk to the Recipient Low risk: central IRB only Mod risk: central IRB + local IRBs High risk: central IRB + local IRBs + recipient consent

11 Example: Low Risk to Recipients

12 A Randomized Trial of the Effects of Nebulized Albuterol on Pulmonary Edema in Brain-Dead Organ Donors Aerosolized albuterol (5mg q4h) v. placebo during active donor management in 506 organ donors No institutional IRBs No recipient consent LB Ware, et al. Am J Transplant 2014; 14: 621

13 Example: Low Risk to Recipients Donor Intervention Commonly used medication or procedure Preliminary data suggest safety Yes/No Yes Yes Local IRB approval may not be needed Recipient consent may not be needed

14 Example: Moderate Risk to Recipients

15 Machine Perfusion or Cold Storage in Deceased- Donor Kidney Transplantation International RCT 1 kidney from 336 consecutive deceased donors had machine perfusion & the other cold storage. 672 recipients were followed for 1 year. Approval obtained from IRBs in each trial region & from the Eurotransplant Ethical Advisory Committee. No informed consent from recipients. C Moers, et al. N Engl J Med 2009;360:7

16 Example: Moderate Risk to Recipients Donor Intervention Commonly used medication or procedure Preliminary data suggest safety Yes/No No Yes Obtain local IRB approvals Recipient consent may not be needed

17 Example: High Risk to Recipients

18 Hypothermic Machine Preservation (HMP) in Human Liver Transplantation: The First Clinical Series Prospective cohort study of liver HMP in 20 undergoing liver transplant at a single center versus 20 who received static cold stored livers. IRB-approved Recipients gave informed consent JV Guarrera, et al. Am J Transplant 2010; 10: 372

19 Example: High Risk to Recipients Donor Intervention Commonly used medication or procedure Preliminary data suggest safety Yes/No No No Obtain local IRB approvals Recipient consent required

20 Future Approaches to Organ Donor Intervention Research Include research risk in a standardized (dichotomous) risk acceptance for consenting candidates at the time of listing. Consent donor surrogates but not necessarily recipients at the time of organ offer Base need to consent recipients on risk Establish a National Oversight Board as recommended by the Donor Intervention Research Expert Panel Workgroup Approve study protocols Provide ethical oversight Monitor safety

21 Summary The OPTN/SRTR data collection and analysis infrastructure provide an excellent opportunity to conduct pragmatic trials in organ preservation and allocation. For multiple reasons this opportunity has yet to be exploited. A central IRB could assess risk of donor interventions to recipients and assess the need for local IRB and recipient consent.

22 Thank you!