Pancreatic islet transplantation has effectively halted in the United States while the procedure has become standard of care in much of the rest of the world. The University of Miami Miller School of Medicine is the only U.S. center where more than 100 islet transplants were performed between 2000 and 2020.

“We have not done a single procedure in the past two years,” said Camillo Ricordi, MD, FNAI, the Stacy Joy Goodman Professor and Director, Diabetes Research Institute and Cell Transplant Center, University of Miami, and a member of the Supreme Council of Health in Italy. “The challenge is how to cross the barrier imposed by the FDA of treating islet transplantation like a pharmaceutical due to outdated regulation.”

Meanwhile, the number of countries that allow and reimburse islet transplantation for type 1 diabetes is growing. At least 11 centers in Canada, Europe, Australia, and Asia passed the 100-procedure mark in 2020.

“After being a U.S.-led field in the 20th century, expertise in islet allograft transplantation has moved to other countries,” said Thierry Berney, MD, Professor of Surgery and Chief of Transplantation, University of Geneva, Switzerland. “The high-activity centers are overwhelmingly located in countries in which islet allograft transplantation benefits from health care coverage.”

Drs. Berney and Ricordi were two of the four presenters in the Scientific Sessions symposium Clinical and Regulatory Hurdles Facing Islet Transplantation, which was originally presented Monday, June 28. The session can be viewed by registered meeting attendees at ADA2021.org through September 29, 2021. If you haven’t registered for the Virtual 81st Scientific Sessions, register today to access all of the valuable meeting content.

The U.S. Food and Drug Administration regulates islet transplants the way it regulates chimeric antigen receptor (CAR) T and other cell-based therapies, said symposium moderator A.M. James Shapiro, MD, PhD, Professor of Surgery and Medicine, University of Alberta, Canada.

“The FDA has demanded that islets be regulated as a drug,” he said. “Other countries have taken a broader view of islet transplantation (as organ transplantation) and provided government funding to drive toward success.”

U.S. regulatory roadblocks date back to the 1980s, explained Piotr Witkowski, MD, PhD, Associate Professor of Surgery and Director, Pancreatic Islet Transplantation Program, University of Chicago. The National Organ Transplantation Act of 1983 (NOTA) defines the human organ, the distribution and regulation of organs, and protections from commercialization. A 1989 NOTA amendment added subparts of organs, such as islets, to the definition.

However, the Organ Procurement and Transplantation Network (OPTN) Final Rule was never updated to include the new definition. That lapse means the United Network for Organ Sharing (UNOS) and transplantation programs accredited by OPTN and UNOS cannot transplant islets outside of clinical studies.

Failing to update the OPTN Final Rule allowed the FDA to regulate islet transplantation under the same Biologics License Application (BLA) requirements used to regulate human cells, tissues, and products (HCT/Ps).

HCT/Ps that are more than minimally manipulated—meaning that their biological characteristics are substantially altered—are subject to BLA requirements, including clinical trials and FDA approval. That includes stem cells, regulatory T cells, CAR T cells, and allogeneic islets isolated from unrelated deceased donor pancreas.

A consortium of medical groups with an interest in type 1 diabetes, including the ADA, unsuccessfully petitioned the U.S. Department of Health and Human Services to update the OPTN Final Rule earlier this year, Dr. Witkowski reported.

“Defining the appropriate drug or biologic identity, strength, quality, and purity which has been proven to be responsible for clinical outcome is a cornerstone for the drug and biologic quality assurance system,” he said. “But the FDA drug and biologic quality assurance system does not work for human organ transplantation.

“Human organs are naturally highly variable, and the characteristics required for clinical outcomes cannot be defined and verified prior to transplant,” Dr. Witkowski continued. “Full control over all elements of organ transplantation, and the ultimate responsibility for outcomes, is a cornerstone of human organ quality assurance as part of the organ transplantation quality, safety, and effectiveness assurance system implemented by OPTN and UNOS.”

Academic centers, including the University of Chicago, have successfully completed clinical trials showing clinically significant benefits for allogeneic islet transplantation that clearly outweigh the risks in type 1 diabetes, Dr. Witkowski said. But none have the resources to submit a BLA.

Without an approved BLA, islet transplantation is an unapproved investigational product and is not eligible for reimbursement.

Other jurisdictions took a different approach.

The European Medicines Agency (EMA) regulates cell and tissue products as Advanced Therapeutic Medicinal Products. Islet transplants are exempt because the islets are not substantially manipulated, they are used for the same essential function, and they cannot be commercialized or manufactured on an industrial scale for ethical and legal reasons under the framework of transplant laws.

Most European Union countries reimburse islet procedures as they do any other organ transplant, Dr. Berney said.

“The path followed in Europe, Australia, and other countries has led to successful delivery of islet transplantation to patients with type 1 diabetes,” he added. “The path followed in the United States has so far led to a failure to deliver islet transplantation to patients with type 1 diabetes. It is time to learn from the evidence generated by your own academics.”