It seemed like good news: Years after it became available in other countries, a powerful cell therapy for type 1 diabetes was approved in the United States in June. It will offer the first way for American patients to receive transplants of insulin-producing islet cells outside of the confines of a clinical trial, a therapy that in some cases can lead to insulin independence.
But the experts who helped to invent and develop islet transplant surgery aren’t celebrating. Instead, they are criticizing the U.S. Food and Drug Administration (FDA) for opting to regulate transplanted islet cells as drugs rather than as organs. As a result, a single private company will become the only approved American supplier of islets for transplantation.
“I don’t understand what the rationale is,” says Camillo Ricordi, MD, director emeritus of the Diabetes Research Institute, concerning the decision to regulate islets as drugs rather than organs. “There is no scientific rationale for it.”
Piotr Witkowski, MD, PhD, the director of UChicago’s pancreatic and islet transplantation program, says, “The transplant community has one voice. No one who understands transplant regulation is supporting this [regulation], in the States or anywhere in the world.”
In a comment to Diabetes Daily, the FDA stood behind its decision to approve the therapy, though it did not address the larger issue of whether or not islets should be regulated as drugs. CellTrans, the business that received the FDA’s approval to distribute islets for transplant, did not respond to multiple requests for comment.
Islet Cell Transplants
Islet cell transplantation is an advanced treatment for type 1 diabetes. Briefly, doctors take a donor’s islets of Langerhans (the clusters of cells in the pancreas that contain the insulin-producing beta cells) and inject them into patients with diabetes, typically into the liver. When successful, patients can discontinue insulin use altogether, or greatly reduce their reliance on insulin.
Some transplant recipients have remained free of insulin therapy for many years following the procedure, though anti-rejection drugs that carry serious risks of their own are required to protect the new cells from the body’s immune system.
Experiments are underway to evaluate the use of lab-grown islet cells, but today the islet cells for these transplants must be harvested from the pancreases of deceased organ donors. Such donor cells are scarce, limiting the number of surgeries that can be performed. But for patients with a dire need — for example, those with extreme glucose management challenges or hypoglycemia unawareness — islet transplantation can be a lifesaver.
Regulatory Confusion
Soon after the first successful islet transplants were performed in 1993, the FDA announced that it would treat transplanted pancreatic islets as if they were medicines rather than organs or organ subparts. The decision confounded experts. “We’re the only country that imposes this kind of regulation,” says Dr. Ricordi, who in 1988 developed the islet cell isolation technique that made transplantation feasible.
The problem, Ricordi explains, is that islets from the body of an organ donor cannot possibly meet the standards of precision and consistency expected of drug ingredients. Like other organs, islet cells can’t be accurately assessed for sterility, purity, or potency before transplantation. Even if it were possible, the nonprofit research hospitals that developed the therapy simply do not have the resources to meet the FDA’s expectations.
“No academic institution could invest millions of dollars and years of work to go through a BLA [biologics license application],” says Ricordi.
For years, Dr. Witkowski, Ricordi, and many of their colleagues have led a campaign named the “Islets for US Collaborative” to change the FDA’s thinking. “We’ve been telling the FDA that the safety of patients is endangered if islets are approved as a drug and distributed exclusively by a for-profit company. Islets should be regulated like any other organ for transplantation,” Witkowski says.
Though university and nonprofit hospitals couldn’t justify the expense, a biotech firm named CellTrans raised enough funding to jump through the FDA’s hoops. Initially, however, it was unclear whether CellTrans could surmount the unavoidable consistency issues inherent in human organs.
During an April 2021 hearing, an FDA advisory panel evaluated CellTrans’ clinical trial results. The presentation, says Witkowski, confirmed what transplant experts already knew: that islet cells harvested from a beating-heart cadaver simply cannot meet the FDA’s stated criteria for drug manufacturing. Unsurprisingly, the FDA found no correlation between measures of islet quality and clinical effectiveness, an unpredictability that would be considered unacceptable in most other drugs.
“The FDA clearly outlined why CellTrans failed,” Ricordi contends. Even so, a majority of the independent experts on the panel agreed that the therapy had “an overall favorable benefit-risk profile for some patients with type 1 diabetes.”
The panel’s endorsement didn’t fast-track CellTrans’ therapy toward approval. The procedure sat in regulatory limbo for about two years.
A Surprise Approval
Witkowski felt like the Islets for US Collaborative was finally getting somewhere in June, when Sen. Mike Lee (R-Utah) authored a legislative effort to fix the regulations and pave the way for legal islet cell transplantation in America. The ISLET Act promised to “move islets to a more appropriate regulatory framework.” But Witkowski’s optimism was short-lived.
One week after Sen. Lee unveiled his bill, the FDA announced that it had approved CellTrans’ cadaveric islets. The new islet source will be named donislecel (Lantidra). The Islets for US Collaborative responded with suspicion, stating that the move “substantially complicated the path for passing the ISLET Act and the implementation of the critical regulatory update.”
Though CellTrans had to spend millions to file its successful BLA, critics allege that the business didn’t actually develop anything new. A 2021 letter in Transplant International stated that Lantidra “is nothing more than a new name for pancreatic islet allotransplantation.”
Witkowski agrees: “They didn’t invent anything; they didn’t modify anything. It’s an unmodified human organ, but they’re calling it a drug and selling it as a drug.”
Lantidra is now the only FDA-approved source of islets for transplantation for the treatment of type 1 diabetes.
Islet Transplants and Risk
Islet cell transplants have great potential to treat type 1 diabetes. In Lantidra’s most important trials, conducted in an academic transplant center following all known protocols, 30 percent of participants achieved insulin independence of at least five years.
Islet transplants do, however, entail a concerning side effect profile, largely due to the powerful immunosuppressive drugs required to protect the new cells. A whopping 87 percent of Lantidra’s trial participants experienced at least one “severe” reaction, and 27 percent experienced at least one life-threatening adverse reaction. In 30 patients there were 211 separate incidents of infection. One subject died when an infection caused sepsis, leading to multiorgan failure, and another suffered a life-threatening liver laceration.
Witkowski says, “This was not a shock to us.” The risks inherent in islet transplants are significant, which is part of the reason that the procedure is limited to patients with the most profound glucose management challenges.
But Witkowski is worried that Lantidra’s risk profile could get even worse in the real world, because distributing it as a drug upends the chain of responsibilities that helps to keep organ transplants safe.
Traditionally, islet transplant surgeons take ownership of every aspect of a procedure — selecting and evaluating the organ, performing the surgery, and monitoring the patient on an ongoing basis.
“I take my own responsibility for doing everything,” Witkowski says. “Selecting the donor and everything. If there’s something wrong, it’s on me and my transplant center, and we have to disclose the results.”
By distributing Lantidra as a drug, however, “surgeons lose control of the product. They have no option; they have to take what they’re given.”
CellTrans could choose to sell Lantidra only to nonprofit transplant centers, putting it in the hands of the most qualified surgeons. But it could also ignore the traditional transplant center network and sell its islets to private facilities. Witkowski is especially worried about this latter possibility. In a private clinic, with no requirement to disclose outcomes, there might be “no responsibility … no oversight afterward.”
“They can choose to do it the right way, but they’re not obligated to do it the right way.”
Ethical Concerns
The authors of the 2021 Transplant International letter, a constellation of European endocrinologists, immunologists, and transplant surgeons, decried the ethical implications of approving Lantidra as a drug:
Conferring to a private, for-profit company the marketing rights for the isolation of allogenic islets could foreshadow the commercialization of human organs and their subparts … [raising] significant legal and ethical issues, since these products are obtained on ‘a philosophy of voluntary and unpaid donation, altruism of the donor and solidarity between donor and recipient.’
The experts outlined other problems. Lantidra’s approval, they argued, would discourage competition and likely limit the therapy to the wealthiest of patients: “Excessive regulatory burden, unjustified by scientific evidence, could irreversibly block its application and further development by increasing the costs and limiting the accessibility.”
Witkowski shares the same concerns. Organ transplant waiting lists, he explained, are dynamically managed by the United Network for Organ Sharing (UNOS), a nonprofit that is committed to distributing organs equitably, based on patient need. But CellTrans, as a private firm, “can choose the people they want to give it to.” The islets will be eligible for insurance reimbursement, but the business will have a strong incentive to attach a high price to Lantidra, likely putting it out of reach of some patients in need.
Though CellTrans was granted seven years of exclusivity under the Orphan Drug Act, the business has officially pledged to waive its exclusivity, allowing other businesses to submit BLAs and join them as approved islet suppliers. Witkowski, however, noted that CellTrans could easily revoke its exclusivity.
‘Very Disappointing’
Lantidra’s approval as a drug seems to fly in the face of the tradition of nonprofit collaboration that helped develop islet transplantation in the first place.
When Ricordi invented his technique to isolate islet cells — a technique that CellTrans requires for Lantidra — he shared it freely: “I released all of my intellectual property to the rest of the world. I was proud to have developed it and shared it worldwide, with the objective of curing type 1 diabetes in the fastest and most efficient way possible, renouncing any royalties, and making available equipment, drawings, and training.”
Saying that he hoped he didn’t sound immodest, Ricordi explained that he was inspired by the scientists who discovered insulin. Nobel Prize winner Frederick Banting and his colleagues sold their insulin patents for $1.00 each in the 1920s to allow the life-saving medicine to be distributed as quickly and as affordably as possible.
In a cruel irony, Ricordi’s innovation is now basically reserved in America for the exclusive use of a for-profit business to which he has no connection.
“To see so much effort to keep it nonprofit, to see it all swept to a commercial entity because of this outdated FDA regulation … it’s very disappointing. I’m happy for CellTrans; I’m not criticizing them. They played by the rules. … But I wish that the FDA would concentrate on more serious problems.”
Witkowski is unsure what will happen next. He’s hopeful that Sen. Lee and the other legislators who pledged to back the ISLET Act won’t back down.
“But I don’t know what will happen. I don’t think they were expecting this reaction from the FDA. I’m waiting for them to let us know if they will give up or if they’ll keep fighting.”
To pass, the act will require bipartisan cooperation. That’s been in short supply in our fractured political environment.
Witkowski says, “If we pass this ISLET Act, islets will be national resources just like every other organ, protected by the law.”
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