The demise of islet allotransplantation in the United States: A call for an urgent regulatory update.

Islet allotransplantation in the United States (US) is facing an imminent demise. Despite nearly three decades of progress in the field, an archaic regulatory framework has stymied US clinical practice. Current regulations do not reflect the state-of-the-art in clinical or technical practices. In the US, islets are considered biologic drugs and "more than minimally manipulated" human cell and tissue products (HCT/Ps). In contrast, across the world, human islets are appropriately defined as "minimally manipulated tissue" and not regulated as a drug, which has led to islet allotransplantation (allo-ITx) becoming a standard-of-care procedure for selected patients with type 1 diabetes mellitus. This regulatory distinction impedes patient access to islets for transplantation in the US. As a result only 11 patients underwent allo-ITx in the US between 2016 and 2019, and all as investigational procedures in the settings of a clinical trials. Herein, we describe the current regulations pertaining to islet transplantation in the United States. We explore the progress which has been made in the field and demonstrate why the regulatory framework must be updated to both better reflect our current clinical practice and to deal with upcoming challenges. We propose specific updates to current regulations which are required for the renaissance of ethical, safe, effective, and affordable allo-ITx in the United States.

Assessment of simple indices based on a single fasting blood sample as a tool to estimate beta-cell function after total pancreatectomy with islet autotransplantation - a prospective study.

We investigated six indices based on a single fasting blood sample for evaluation of the beta-cell function after total pancreatectomy with islet autotransplantation (TP-IAT). The Secretory Unit of Islet Transplant Objects (SUITO), transplant estimated function (TEF), homeostasis model assessment (HOMA-2B%), C-peptide/glucose ratio (CP/G), C-peptide/glucose creatinine ratio (CP/GCr) and BETA-2 score were compared against a 90-min serum glucose level, weighted mean C-peptide in mixed meal tolerance test (MMTT), beta score and the Igls score adjusted for islet function in the setting of IAT. We analyzed values from 32 MMTTs in 15 patients after TP-IAT with a follow-up of up to 3 years. Four (27%) individuals had discontinued insulin completely prior to day 75, while 6 out of 12 patients (50%) did not require insulin support at 1-year follow-up with HbA1c 6.0% (5.5-6.8). BETA-2 was the most consistent among indices strongly correlating with all reference measures of beta-cell function (r = 0.62-0.68). In addition, it identified insulin independence (cut-off = 16.2) and optimal/good versus marginal islet function in the Igls score well, with AUROC of 0.85 and 0.96, respectively. Based on a single fasting blood sample, BETA-2 score has the most reliable discriminant value for the assessment of graft function in patients undergoing TP-IAT.

Voluntary organ donation system adapted to Chinese cultural values and social reality.

Organ donation and transplant systems have unique characteristics based on the local culture and socioeconomic context. China's transplant and organ donation systems developed without regulatory oversight until 2006 when regulation and policy were developed and then implemented over the next several years. Most recently, the pilot project of establishing a voluntary citizen-based deceased donor program was established. The pilot program addressed the legal, financial, and cultural barriers to organ donation in China. The pilot program has evolved into a national program. Significantly, it established a uniquely Chinese donor classification system. The Chinese donor classification system recognizes donation after brain death (category I), donation after circulatory death (category II), and donation after brain death followed by circulatory death (category III). Through August 2014, the system has identified 2326 donors and provided 6416 organs that have been allocated though a transparent organ allocation system. The estimated number of donors in 2014 is 1147. As China's attitudes toward organ donation have matured and evolved and as China, as a nation, is taking its place on the world stage, it is recognizing that its past practice of using organs from executed prisoners is not sustainable. It is time to recognize that the efforts to regulate transplantation and provide voluntary citizen-based deceased organ donation have been successful and that China should use this system to provide organs for all transplants in every province and hospital in China. At the national organ transplant congress on October 30, 2014, the Chairman of the China's national organ donation and transplantation committee, Jeifu Huang required all hospitals to stop using organs from executed prisoners immediately and the civilian organ donation will be sole source for organ transplant in China starting January 2015.

A pilot programme of organ donation after cardiac death in China.

China's aims are to develop an ethical and sustainable organ transplantation system for the Chinese people and to be accepted as a responsible member of the international transplantation community. In 2007, China implemented the Regulation on Human Organ Transplantation, which was the first step towards the establishment of a voluntary organ donation system. Although progress has been made, several ethical and legal issues associated with transplantation in China remain, including the use of organs from executed prisoners, organ scarcity, the illegal organ trade, and transplantation tourism. In this Health Policy article we outline the standards used to define cardiac death in China and a legal and procedural framework for an organ donation system based on voluntary donation after cardiac death that adheres to both China's social and cultural principles and international transplantation standards.

Summary report of a national conference: Evolving concepts in liver allocation in the MELD and PELD era. December 8, 2003, Washington, DC, USA.

A national conference was held to review and assess data gathered since implementation of MELD and PELD and determine future directions. The objectives of the conference were to review the current system of liver allocation with a critical analysis of its strengths and weaknesses. Conference participants used an evidence-based approach to consider whether predicted outcome after transplantation should influence allocation, to discuss the concept of minimal listing score, to revisit current and potential expansion of exception criteria, and to determine whether specific scores should be used for automatic removal of patients on the waiting list. After review of data from the first 18 months since implementation, association and society leaders, and surgeons and hepatologists with wide regional representation were invited to participate in small group discussions focusing on each of the main objectives. At the completion of the meeting, there was agreement that MELD has had a successful initial implementation, meeting the goal of providing a system of allocation that emphasizes the urgency of the candidate while diminishing the reliance on waiting time, and that it has proven to be a powerful tool for auditing the liver allocation system. It was also agreed that the data regarding the accuracy of PELD as a predictor of pretransplant mortality were less conclusive and that PELD should be considered in isolation. Recommendations for the transplant community, based on the analysis of the MELD data, were discussed and are presented in the summary document.

The sickest first? Disparities with model for end-stage liver disease-based organ allocation: one region's experience.

February 27, 2002, allocation of cadaver livers for transplantation changed from a waiting-time-based system to an evidence-based system referred to as the Model for End-Stage Liver Disease (MELD). We reviewed data from 1 of the 11 United Network for Organ Sharing regions to determine the impact of the MELD on the allocation of cadaver livers for transplantation in that region. The region of interest (study region) consists of three distinct geographic areas (referred to as Transplant Service Areas [TSAs]). Based on information obtained from the Organ Procurement and Transplantation Network for the United States and for the study region, the following observations were made: (1) study region patients who received a cadaver liver had higher mean and median MELD scores than cadaver liver recipients in the United States (study region mean score, 25.1; median, 26.0; US mean score, 23.9; median, 24.0); (2) within the study region, TSAs with competing liver transplant programs performed transplantation on patients at a significantly higher mean MELD score than TSAs dominated by a single center (TSA-1 mean score, 27.3; TSA-2 mean score, 26.6; TSA-3 mean score, 21.3); this disparity persisted when transplantations for hepatocellular carcinoma (HCC) were excluded; and (3) study region patients removed from the waiting list because of death or being too sick for transplantation have higher MELD scores than the national average (study region mean score, 25.4; US mean score, 23.8). Overall, implementation of the MELD resulted in a substantial increase in the number of transplantations performed for HCC, and MELD exceptions for all reasons were more common in TSAs that have multiple centers. Despite the MELD, there remains disparity in organ allocation within the study region. The MELD may accurately predict pretransplantation mortality, but it does not ensure equitable organ distribution. We propose that intraregional sharing of cadaver livers based on the MELD may help limit disparities in organ allocation.