Challenges to Research and Innovation to Optimize Deceased Donor Organ Quality and Quantity

Peter Abt, MDSandy Feng, MD PhDAmerican Society of Transplant Surgeons

August 28, 2012

Organ Quantity Limits Transplant Opportunities

Primary limitation to transplantation

•Motivates living donor transplantation

Engenders waitlist morbidity and

mortality

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

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

Donor

RecipientsThe 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

Obstacles to Research and Innovation in Deceased (Brain Dead) Donors

Scientific

Ethical

Logistical

Regulatory

Investigator

Donor / Donor hospitals

OPOs

Waitlist candidates

Transplant recipients / centers

ProblemCurrent 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.

7/10 7/11 7/12

Initiative advanced by the Scientific Studies

Committee

Form working group to write Working Document

in conjunction with Ethics and Standards/Quality Committees

1st F2F Meeting ATC 2011

ASTS, AOPO, ODRC

Share and Revise Working Document

AST, AOPO, SCCM, ASBH

2nd F2F Meeting ATC 2012

ASTS, AST, AOPO, SCCM, ODRC, and ODTA

Discussions with Key Stakeholders

Timeline of ASTS Efforts

Donor-based Issues

Peter Abt

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

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

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

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

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

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

Recipient-based Issues

Sandy Feng

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

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

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?

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

The Need for Communication Mechanisms

A single repository that provides standardized information

related to all donor-based studies (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

Safety and Efficacy Assessment

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

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

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

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

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

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.

Acknowledgements

ASTS• Scientific Studies, Ethics, and Standards

and Quality Committees

ASTAOPO/ODRCSCCMASBHODTA