Regulate human pancreatic islets for transplantation as organs, not drugs
On April 15, an FDA advisory committee concluded that the islet cell therapy donislecel demonstrated a favorable risk-benefit profile for certain patients with difficult-to-control type 1 diabetes.
Donislecel (Lantidra, CellTrans) has been shown to lead to insulin independence and decrease the number of severe hypoglycemic events among patients with difficult-to-control type 1 diabetes, based on pooled results of two open-label studies. The therapy comprises islet cells isolated from a deceased donor pancreas. The final cultured cell product is transplanted through infusion in the portal vein going to the liver via percutaneous, laparoscopic or open surgical access. The FDA is expected to render a decision soon as to whether to approve a biologics license application (BLA) for the islets.
This therapy is promising. I congratulate the team behind the company and recognize the effort and considerable resources invested to bring this treatment before the FDA. However, if this treatment is approved under the current BLA pathway, the consequences for the field of islet transplantation in the U.S. will be detrimental.
Pancreatic islets are not drugs
FDA regulates pancreatic islets as drugs, rather than as human organs. There is plenty of evidence documenting pancreatic islets are not just cells, but rather small organs, and should be regulated as such. In addition, the great variability of pancreas donor factors, islet cellular composition and potency, make it impossible to try to fit islets into the requirements rightly set for advanced cell therapies, or other biologics, where the source material and the final product can be controlled and standardized.
The BLA pathway works for drug manufacturing. The principle of the FDA safety and efficacy reassurance system is based on the final product being well defined with specific product characteristics, produced with consistency and correlating with clinical effects and outcomes.
Human islets are highly variable. They cannot be perfectly defined. Their specific characteristics cannot be ensured with consistency, and most importantly, there are no tests to provide specific characteristics that correlate with clinical outcomes. Once a BLA is approved, we physicians would have to buy islets from a private company and transplant them, without any assurance they work. Even worse, if they do not work, there is no way to verify if this was a problem with the islets, medical management or the patient. This is why Australia, Canada, the Czech Republic, France, Italy, Japan, Norway, Poland, Sweden and Switzerland do not regulate islets as drugs but rather as organ/tissue for transplantation.
A different regulatory pathway
Now, FDA has three options. First, approve the BLA, and in doing so, provide false reassurance that the islet product provided by the commercial BLA-holder is consistently safe and potent. Second, FDA can reject the BLA and continue to require it for anyone desiring to process islets for transplantation outside clinical studies. This will lead to the complete demise of the field and a lack of therapy in use, as medical insurance companies would not pay for unproved islet transplantation.
Third — the most rational option — FDA can reject the BLA, acknowledge the scientific evidence of the last 20 years, and allow islets to be regulated as organs for transplantation.
Human islets should instead be regulated under the Health Resources and Services Administration (HRSA) and submitted to the Organ Procurement and Transplantation Network (OPTN) and the United Network for Organ Sharing (UNOS) — all, notably, outside the drug regulations of the FDA. This proposed framework was designed and developed to ensure human organ quality and potency, as well as safety and effectiveness of transplantation.
How would this ensure islet quality? The HRSA, through OPTN and UNOS, regulate every element involved in organ transplant therapy, including the organizational structure, personnel, quality and safety measurements, monitoring and control. Transplant programs obtain and maintain accreditation to perform transplantation based on rigorous criteria and are able to provide preset clinical outcomes. Transplant programs can control and take full responsibility for organ/islet quality and clinical outcomes only if they control the entire process, starting with donor selection, organ procurement, preservation, processing, transplantation and posttransplantation care.
The biggest worry is that a BLA approval falsely reassures islet safety by allowing for islet transplantation without the appropriate clinical oversight. Continuous clinical evaluation is the only reliable method that can ensure islet safety. One cannot do it by simply testing islets or by monitoring islet isolation. These are unreliable and thus unsafe ways to evaluate islet quality and quantity without oversight of the transplant program responsible for clinical application and outcomes. To expect that a BLA will help ensure the standardization and safety of islet transplantation is erroneous. It endangers our patients and will lead to the demise of the field.
It is important to note that the FDA advisory committee did not recommend BLA approval, as some journalists have reported; most members voted “yes” to a question asking if the benefit of islet transplant treatment outweighed the risks. Panelists were not specifically asked if the BLA should be approved, so they could not even express their thinking on this issue.
In the U.S., we have been transplanting islets for 20 years under research protocols and funding without a BLA, and it has been working fine. Insurance companies see the great benefits for Americans with type 1 diabetes and want to reimburse it, but according to law, islets are still an unapproved drug and cannot be used as a standard of care therapy.
As physicians, experts and leaders of the American Society of Transplant Surgeons, American Society of Transplantation and the American Diabetes Association, we have joined our efforts as the Islets for US Collaborative to point out an imminent threat resulting from outdated regulations. We also urge FDA and HRSA to support the inclusion of human islets on the list of human organs allowing regulation under OPTN and UNOS, as it is the only way to ensure safety and future progress. We ask the secretary of HHS to take action to ensure this happens before it is too late.
At the end of the day, we all hope FDA will do the right thing.
For more information:
Piotr Witkowski, MD, PhD, is associate professor of surgery and director of the Pancreatic and Islet Transplant Program at The University of Chicago. He is a leader of the Islets for US Collaborative and member of the Pancreas and Islet Transplantation Committee at the United Network for Organ Sharing. Reach him at email@example.com.