1. HRSA’s Role in Pancreas and Islet Transplantation
James Burdick, M.D.
Director
Health Resources and Services Administration
Division of Transplantation
BRMAC Meeting October 9, 2003

2. Statutory Authority
National Organ Transplant Act (NOTA) of 1984 (42 U.S.C. § 273, et seq.)
Section 1138 of the Social Security Act
(42 U.S.C § 1320b-8(a)(1)(B) )
Statutory authority for Federal regulation of organ transplantation rests on two key pieces of legislation: the National Organ Transplant Act and Section 1138 of the Social Security Act.
Division of Transplantation/OSP/HRSA

3. National Organ Transplant Act (NOTA)
Passed in 1984; amended 1988 and 1990
Created Task Force on Organ Transplantation
Created Organ Procurement and Transplantation Network (OPTN)
Created Scientific Registry of Transplant Recipients (SRTR)
Grants to organ procurement agencies
Prohibited purchase of transplantable organs
NOTA created the national organ transplantation system—the OPTN.
Division of Transplantation/OSP/HRSA

4. Organs Covered by NOTA Kidney, Liver, Heart, Lung, Pancreas
Any other human organ specified by the Secretary
NOTA specifically covers the kidney, liver, heart, lung, and pancreas, but also any other human organ the Secretary specifies.
Division of Transplantation/OSP/HRSA

5. NOTA Establishment of the OPTN
NOTA authorized HHS to contract with non-profit entity with expertise in organ procurement and transplantation
United Network for Organ Sharing (UNOS) has been the OPTN contractor since 1986
Established requirements for organ procurement organization (OPO) participation
The OPTN is operated by the United Network for Organ Sharing under contract to HRSA.
Division of Transplantation/OSP/HRSA

6. NOTA Framework for OPTN
Responsibilities of OPTN outlined by NOTA
Select a Board of Directors
Establish a national organ sharing system
Maintain a list of individuals who need organs
Develop a system to match donor organs with individuals in need of transplants
Increase the supply of donated organs
Collect, analyze and publish data
Responsibilities of the OPTN under NOTA include maintaining a national organ sharing system capable of matching donated organs with individuals on a waiting list.
Division of Transplantation/OSP/HRSA

7. Section 1138 of the Social Security Act
Hospital must have written protocols for the identification of potential donors
A hospital that performs organ transplants must be member and abide by the rules of the OPTN
Hospital must have agreement with assigned OPO [waivers may be approved by CMS]
Requirements for receipt of reimbursement under Medicare for organ procurement costs
Section 1138 of the Social Security Act requires that a transplant center must be a member and abide by the rules of the OPTN. It also set forth requirements for Medicare reimbursement for organ procurement costs.
Division of Transplantation/OSP/HRSA

8. Structure for HHS Oversight
Office of the Secretary Tommy G. Thompson
Centers for Medicare and Medicaid Services (CMS)
Tom Sculley
Health Resources and Services Administration
Elizabeth Duke
Other HHS Agencies
National Institutes of Health
Food & Drug Administration
Centers for Disease Control & Prevention
Other agencies..
Federal involvement in organ transplantation is spread across multiple HHS agencies. For example, CMS handles reimbursement and OPO certification. Other HHS agencies have roles in transplantation research; regulation of products, devices, and tests; and development of guidance documents.
* HIV/AIDS Bureau
* Bureau of Primary Health Care
* Bureau of Health Professions
* Maternal & Child Health Bureau
* Office of Special Programs
- Division of Transplantation
Division of Transplantation/OSP/HRSA

9. Structure for HHS Oversight (Cont.)
Health Resources and Services Administration (HRSA) – Office of Special Programs – Division of Transplantation
OPTN [UNOS]
SRTR [URREA]
National Bone Marrow Donor Registry [NMDP] Contract
Coordination of Organ and Tissue Donor Activities including Secretary’s Initiative
HRSA is responsible for oversight of the OPTN.
Division of Transplantation/OSP/HRSA

10. Regulatory Framework for HRSA Oversight of OPTN
Organ Procurement and Transplantation Network (OPTN) Final Rule[42 CFR Part 121] – effective March 16, 2000
OPTN board configuration
OPTN membership requirements
OPTN policies
Designated transplant program requirements
Reviews, evaluation and enforcement
Data collection and reporting
Advisory Committee on Organ Transplantation
The OPTN Final Rule sets forth requirements for OPTN membership and establishes goals for OPTN policy development.
Division of Transplantation/OSP/HRSA

11. OPTN Contract UNOS as the OPTN Contractor must:
Maintain organ waitlist and match patients to donor organs 24 hours/day, 365 days/year
Facilitate policy development by the OPTN
Administer the OPTN Board and Committees
Collect, maintain pre- and post-transplant data and data on organ donors
Review and evaluate OPTN member compliance
Maintain website [
UNOS maintains the computer matching system and facilitates OPTN policy development by the OPTN.
Division of Transplantation/OSP/HRSA

12. OPTN Policy 2.0 Minimum Procurement Standards for an OPO
The OPO is responsible for:
Identifying, evaluating and maintaining the donor;
Obtaining consent for the removal of organs;
Verifying pronouncement of death;
Ensuring the approved organ allocation computer program is executed for each donor organ;
Ensuring appropriate preservation and packaging of the organs, proper packaging of donor documentation, and adequacy of tissue typing material.
Under OPTN Policy 2.0 Minimum Procurement Standards for an Organ Procurement Organization, the OPO is responsible for…
Division of Transplantation/OSP/HRSA

13. Evaluation of Potential Donors
For all potential donors:
CBC
Electrolytes
ABO typing
Chest x-ray
All potential organ donors must have a CBC, electrolytes, ABO typing, and chest x-ray.
Division of Transplantation/OSP/HRSA

14. Evaluation of Potential Donors (Cont.)
Hepatitis (incl. HBsAg, HBcAb, and Anti-HCV)
VDRL or RPR
FDA licensed Anti-HIV I/II
Anti-HTLV I/II
Anti-CMV
Blood & urine cultures (donor hospitalized 72 hrs)
Donor blood sample for EBV testing provided to transplant program if requested
These are the infectious disease tests required for all potential donors; OPOs may do additional tests based on donor risk factors, local disease prevalence, and other considerations.
Division of Transplantation/OSP/HRSA

15. Evaluation of Potential Donors (Cont.)
For all potential pancreas donors:
Serum amylase
Serum lipase (if requested)
Glucose
Division of Transplantation/OSP/HRSA

16. Issues in Pancreas Procurement for Islet Transplantation
Under-procurement of pancreata
Limited availability of surgeons with expertise to recover the pancreas in some areas
Placement can be difficult
OPOs do not get credit for recovery of pancreas if discarded
Reimbursement for pancreas allocated for research is lower than for clinical use
What are the driving forces behind pancreas procurement? According to OPTN data, 63% of all pancreata were not recovered between
Several factors may contribute to under-procurement of pancreata…
Division of Transplantation/OSP/HRSA

17. Disposition of Pancreata
Of 18,249 deceased donors recovered :
4142 (22.7%) recovered/used for whole transplant
582 (3.2) recovered/used for islet transplant
243 (1.3%) recovered for whole, used for islets
248 (1.4%) recovered for whole, used for research
787 (4.3%) recovered for research
773 (4.2%) discarded
11473 (62.9%) not recovered
Data Analysis by UNOS
Majority of donors recovered for whole pancreas transplant were age That is 2562 donors (39.8%).
76% of donors age years, and 82% of donors age did not have the pancreas recovered.
Division of Transplantation/OSP/HRSA

18. Issues in Pancreas Procurement for Islet Transplantation (Cont.)
Islet transplantation may require more than one donor to treat a patient
Pancreas is offered for whole organ transplantation nationally, then for islet transplantation; may be less than ideal (e.g. cold ischemia, donor factors)
Facilitated placement if unable to place after 5 hours or if anticipate retrieval within 1 hour
At this time, the priority is to procure pancreata for established utility in whole organ transplantation.
Scarcity of organs further drives preference for use of the pancreas as a whole organ rather than 2-3 donors per recipient for islet transplantation.
A pancreas that is finally offered for islet transplantation has been refused for whole organ transplantation nationally, and probably is not the best quality pancreas. There is a mechanism for facilitated placement if pancreas has not been accepted after 5 hours, or if retrieval is anticipated within 1 hour. Pancreas will be offered to programs that have agreed to participate in the facilitated system, and will accept pancreata procured outside of their OPO service area.
The challenge is to encourage and increase procurement of pancreata, rather than divert pancreata from whole organ to islet transplantation.
Division of Transplantation/OSP/HRSA

19. Issues in Pancreas Procurement for Islet Transplantation (Cont.)
Avoid procurement standards that may lead to decreased pancreas utilization or increased cost
Criteria that may exclude reasonable islet donors (limits on donor age or BMI, cold ischemic time)
Standardized preservation method without data to support superiority (OPTN has no requirement for standardized preservation method for any organ)
Division of Transplantation/OSP/HRSA

20. Contact Information
James Burdick, M.D.
(301)
DoT Website [
OPTN Final Rule
OPTN Website [
SRTR Website [
Division of Transplantation/OSP/HRSA

21. Allocation of Pancreata for Whole Organ and Islet Transplantation
James Burdick, M.D.
Director
Health Resources and Services Administration
Division of Transplantation
BRMAC Meeting October 10, 2003

22. National Organ Transplant Act (NOTA) of 1984
Created Organ Procurement and Transplantation Network (OPTN)
Prohibited purchase of transplantable organs (Section 301)
As a reminder…
Division of Transplantation/OSP/HRSA

23. Section 1138 of the Social Security Act
A hospital that performs organ transplants must be a member and abide by the rules of the OPTN
Section 1138 of the Social Security Act requires that a transplant center must be a member and abide by the rules of the OPTN.
Division of Transplantation/OSP/HRSA

24. Transplant Programs 246 kidney 124 liver 139 pancreas
37 pancreas islet cell
44 intestine
139 heart
73 heart/lung
70 lung
There are 254 OPTN-member transplant centers in the U.S. These are the transplant programs represented by those 254 transplant centers.
Division of Transplantation/OSP/HRSA

25. Islet Program Membership
Currently, there are no OPTN membership criteria for islet programs
The OPTN Kidney-Pancreas Transplantation Committee has developed criteria
Public comment period closed October 4, 2003 for most recent proposal on islet program membership
Proposed criteria will be submitted to the OPTN Board of Directors for final approval in November
(The next Board of Directors meeting is scheduled for November )
Division of Transplantation/OSP/HRSA

26. Proposed Islet Program Membership Criteria
Must be located in a hospital at a center approved to perform whole pancreas transplants
Must provide data on patients transplanted
Must report the disposition of the islets (transplanted, discarded, other use)
Must have a qualified surgeon, physician, and radiologist
Must have access to ancillary personnel
This is a summary of the proposed islet program membership criteria. Of significance is the requirement that an islet program must be located at a transplant center that also performs whole pancreas transplants. This requirement attempts to address the concern that patients may not be informed about the option of whole organ transplantation if the transplant center does not offer that option. Also, the requirement attempts to ensure that there is appropriate expertise to handle complications of the procedure and to manage immunosuppression.
There is an exceptions pathway for an islet program not located at a center with a whole pancreas program. The exceptions pathway requires documentation of affiliation with a whole pancreas transplant program and an interview. The islet center still must be in a hospital
Division of Transplantation/OSP/HRSA

27. OPTN Policy 3.2 Waiting List
All patients who are potential recipients of deceased organ transplants must be listed on the computer Waiting List
OPTN Members shall not provide organs to non-member transplant centers
All transplant candidates must be listed on the national waiting list. This includes candidates for islet transplants.
Non-OPTN members should not receive organs for clinical transplantation.
Division of Transplantation/OSP/HRSA

28. Waiting List Size Candidates waiting as of September 19, 2003:
1445 pancreas
2418 kidney/pancreas
164 islet
As of September 19, there were 164 candidates waiting for islet transplants.
(NOTE: candidates are only counted once; there is no duplication in the other counts)
Division of Transplantation/OSP/HRSA

29. Allocation of Pancreata for Islet Transplantation
Current OPTN allocation algorithm for pancreata gives priority for whole organ transplantation
OPTN has approved requests for variances giving higher priority for allocation of pancreata for use in islet transplantation locally
Approved variances generally limit the number of pancreata diverted for use in islet transplantation
Division of Transplantation/OSP/HRSA

30. Variances Under Final Rule
Experimental policies that test methods of improving allocation
Accompanied by a research design
Include plans for data collection and analysis
Time limited
Subject to same approval process as standard policies
The OPTN Final Rule defines variances as experimental policies designed to test methods of improving allocation.
Division of Transplantation/OSP/HRSA

31. Current Pancreas Allocation Algorithm
Candidates ranked by length of time on the waiting list
Current algorithm gives highest priority to:
0-mismatch and highly sensitized candidates
Isolated and combined whole pancreas transplantation
Efforts are made to place the pancreas locally, regionally, then nationally for whole pancreas transplantation before offering it for clinical islet transplantation
If a pancreas still is not accepted, it is offered for research use (not clinical research)
Note that a pancreas allocated for research use is not intended for use in clinical transplantation.
Division of Transplantation/OSP/HRSA

32. Proposed Pancreas Allocation Algorithm
Donor age  50 years AND BMI  30 kg/m²
Local isolated or combined whole pancreas, or combined solid organ-islet; then
Regional then national isolated or combined whole pancreas; then
Local, regional, then national islet; then
Research
The OPTN Kidney-Pancreas Transplantation kidney has proposed modifying the allocation algorithm to improve availability of pancreata for use in islet transplantation. The proposed algorithm is based on data that pancreata from older donors and donors with high BMI may have better islet yields. Also, older and high BMI donor pancreata are sometimes difficult to place for whole organ transplantation.
This is a somewhat simplified summary of the algorithm. Highest priority for zero mismatches would be preserved.
Pancreata from younger, low BMI donors would be preferentially allocated for whole pancreas transplantation.
Division of Transplantation/OSP/HRSA

33. Proposed Pancreas Allocation Algorithm (Cont.)
Donor age > 50 years OR BMI > 30 kg/m²
Local isolated or combined whole pancreas, or combined solid organ-islet; then
Local, regional, then national islet; then
Regional then national isolated or combined whole pancreas; then
Research
Pancreata from older or high BMI donors would receive higher priority for islet transplantation.
Majority of Kidney-Pancreas Committee felt very strongly that a pancreas always should be offered for whole organ transplantation before offered for islet transplantation, since islet transplantation is experimental.
Division of Transplantation/OSP/HRSA

34. Issues/Concerns Non-OPTN member institutions doing islet transplants
FDA IND does not take into account that non-OPTN member institutions can not receive pancreata for clinical transplantation
Pancreata allocated for research being used for clinical islet transplantation
FDA does not require OPTN membership for islet IND, and apparently some institutions that are not OPTN members have INDs in effect.
It has come to the OPTN’s attention that some institutions have received pancreata allocated for research, isolated the islets, and transplanted those islets into patients not on the OPTN Waiting List.
Division of Transplantation/OSP/HRSA

35. OPTN Response Proposal by the Kidney-Pancreas Committee
All pancreata for clinical islet transplantation must be allocated through the OPTN/UNOS allocation system
Pancreata initially allocated for research cannot be used for clinical transplantation unless re-allocated through the system
To address this concern, the OPTN Kidney-Pancreas Committee has The islet product would re-enter the allocation system if the pancreas was not initially allocated for use in islet transplantation.
The recipient of the islet product would have to be on the OPTN Waiting List.
Division of Transplantation/OSP/HRSA

36. Issues/Concerns (Cont.)
Allocation of pancreas for islets
Pancreas is allocated to a specific patient on waiting list, not an institution
Allocation based on need, equitable access
Any difference in cost/reimbursement for licensed product vs IND product?
Is it possible to ensure that access to islet products is equitable, and not limited to those who can pay for the product if it costs more than the product under IND?
Division of Transplantation/OSP/HRSA

37. Issues/Concerns (Cont.)
Islets as a licensed/commercial product
May shift procurement focus towards ideal islet donors
May shift a center’s listing focus
Dual regulation (HRSA & FDA)
NOTA section 301 implications?
Is there a danger that procurement efforts will shift from a focus on whole pancreas transplantation to islet transplantation—older, high BMI donors?
Will require dual regulation--HRSA regulates the allocation while FDA regulates the safety and efficacy.
Are there any NOTA section 301 implications (transfer for valuable consideration), particularly if HRSA regards islet as organs or subparts for the purpose of allocation? Needs further exploration.
Division of Transplantation/OSP/HRSA

38. Issues/Concerns (Cont.)
Whole pancreas transplantation is a proven therapy—how does islet transplantation compare
Patients adequately informed about both options (whole pancreas vs. islet transplant)
Transplant program expertise
Surgical management of complications of islet transplant procedure
Management of immunosuppression
FDA licensure does not require comparison of efficacy of whole pancreas transplantation vs. islet transplantation.
Again, the proposed islet program membership criteria attempt to address the concerns about informing patients about their options and ensuring availability of appropriate expertise.
On-site qualified transplant physician and surgeon
Available operating and recovery room resources
evidence of collaborative involvement with specialists
immediate access to clinical support services and capacity to monitor treatment with immunosuppressive drugs, and
available psychiatric and social support services for candidates, recipients and families
Division of Transplantation/OSP/HRSA

39. Contact Information
James Burdick, M.D.
(301)
DoT Website [
OPTN Final Rule
OPTN Website [
SRTR Website [
Division of Transplantation/OSP/HRSA