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

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

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

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

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

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

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

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

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

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

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 [www.optn.org] UNOS maintains the computer matching system and facilitates OPTN policy development by the OPTN. Division of Transplantation/OSP/HRSA

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

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

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

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

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 2000-2002. Several factors may contribute to under-procurement of pancreata… Division of Transplantation/OSP/HRSA

Disposition of Pancreata Of 18,249 deceased donors recovered 2000-2002: 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 18-40. That is 2562 donors (39.8%). 76% of donors age 50-55 years, and 82% of donors age 56-60 did not have the pancreas recovered. Division of Transplantation/OSP/HRSA

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

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

Contact Information James Burdick, M.D. (301) 443-7577 jburdick@HRSA.gov DoT Website [www.hrsa.gov/osp/dot] OPTN Final Rule OPTN Website [www.optn.org] SRTR Website [www.ustransplant.org] Division of Transplantation/OSP/HRSA

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

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

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

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

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 20-21.) Division of Transplantation/OSP/HRSA

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

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

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

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

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

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

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

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

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

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

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

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

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

Contact Information James Burdick, M.D. (301) 443-7577 jburdick@HRSA.gov DoT Website [www.hrsa.gov/osp/dot] OPTN Final Rule OPTN Website [www.optn.org] SRTR Website [www.ustransplant.org] Division of Transplantation/OSP/HRSA