Why is islet transplantation
still not available to patients with Type 1 Diabetes in the US?
Islet transplantation is approved for clinical use worldwide...
... But why not in the US?
"...this is because, human islets have been regulated as drugs,
instead of as organs for transplantation like in all other developed countries worldwide..."
...scientific evidence strongly supports the need for an urgent update in the US, regarding the regulation of islets as organs...
Professor of Surgery, Medicine, Biomedical Bioengineering, Immunology at University of Miami
Director of the Diabetes Research Institute (DRI) and the Cell Transplant Center
expert, inventor and "father" of the field of islet transplantation
Pancreatic islets are micro-organs, yet
the FDA has been regulating human islets for transplantation as drugs
Pancreatic islets are located in the human pancreas and are surrounded by exocrine tissue.
Islets are micro-organs with their own unique anatomy, structure and function, and they are made of many different type of cells.
They have their own blood vessels and nerves.
They are retrieved (isolated from the pancreas) and transplanted while their structure and function remains preserved- exactly like in whole organ transplantation.
The Human Islet: Mini-Organ With Mega-Impact. Endocr Rev. 2021, 42:605–657.
Why pancreatic islets should be regarded and regulated like organs. CellR4, 2021, 9.
The pancreatic islet: a micro-organ in control. CellR4, 2021 9.
The "Islets for US" Collaborative
Our collaborative is composed of over 50 experts and leaders in the field of islet and pancreas transplantation . We are deeply concern about the over 20-year lack of access to life saving islet transplantation for Americans with type 1 diabetes, severe hypoglycemic episodes and hypoglycemia unawareness.
2. We have identified major deficiencies in the current regulatory approach to islets in the US, which is leading to the imminent demise of the entire field of islet transplantation, or alternatively to unsafe and detrimental for the field and patients, and to potentially unsafe and detrimental commercialization of the human pancreas and islets for clinical transplantation.
3. Based on our analysis, we have identified a key elements that would be critical in the regulatory update, which we propose to the FDA and HHS for considerations.
4. We propose islet regulation under the existing regulatory framework for organ transplantation in the US under UNOS and OPTN. Several FDA regulatory components concerning human cel and tissue for transplantation is exempt from the drug regulations under this proposal. This can be easy implemented by the decision of the Secretary of the HHS.
5. Unfortunately, despite our efforts, the need for the regulatory update has not been recognized by the regulators.
We wrote several letters to the FDA, HHS, HRSA, CMS, UNOS and published 6 articles in peer -reviewed scientific journals voicing our concerns and need for regulatory update.
We presented our proposition at the FDA Experts Advisory Committee Meeting in April 2021 and during the Scientific Sessions of the American Diabetes AssociationCongress in June 20021. (see below)
The detrimental effects of regulating islets as drugs in the US
Over the last 10 years, we have witnessed a decline of islet transplantation in the US, given that as the procedure remained limited to experimental settings due to outdated islet regulations, The regulation of human islets as drugs precludes safe transition of the islet transplantation to the standard of care procedure available to diabetic patients in the US. The lack of financial support also precludes islet transplantation activity.
The demise of islet allotransplantation in the United States: A call for an urgent regulatory update. Am J Transplant, 2021, 21:1365–1375.
Recent scientific evidence along with the FDA's own report clearly indicate that the current regulation of human islets as drugs do not reassure safety and effectiveness of the islet transplantation therapy. Islet sterility and quality prior to transplant cannot be reassured despite the application of the drug manufacturing procedures and regulations during the islet preparation for the transplantation.
Pancreatic Islets Quality and Potency Cannot be Verified as Required for Drugs. Transplantation 2021, Dec 1;105(12):e409-e410.Jul
Despite this safety concerns, the FDA still considers granting a Biological License to a single for-profit company to market human islets for transplantation in the US. This would further compromise patient safety and lead to unsafe and detrimental commercialization of human pancreas and islets for clinical transplantation in the US .
The continuation the islet regulation as it is a drug, has multiple detrimental effects for the future of islet and organ transplantation and diabetic care for the US public.
Regulatory updates are needed to prevent the commercialization of islet transplantation in the United States. Am J Transplant (2021) 21:2620–2622.
Islet transplantation in the United States – Quo Vadis? An interview with Camilo Ricordi (CR), Ali Naji (AN), Peter Stock (PS), Piotr Witkowski (PW). Transpl Int 2021, 34:1177–1181.
Arguments against the Requirement of a Biological License Application for Human Pancreatic Islets: The Position Statement of the Islets for US Collaborative Presented during the FDA Advisory Committee Meeting. J Clin Med 2021, Jun 29;10(13):2878.
Islet Transplantation at a Crossroads - Need for Urgent Regulatory Update in the United States: Perspective Presented During the Scientific Sessions 2021 at the American Diabetes Association Congress" Frontiers in Endocrinology, 2022 in press.
These are the reasons for why this is an urgent problem
and needs to be addressed immediately:
Patients with type 1 diabetes mellitus can die suddenly due to low blood sugar despite modern insulin therapy
Some diabetic patients and their families live in constant fear of sudden death due to low blood sugar. Their daily lives are severely compromised. They are afraid to drive, work and live independently.
They are especially susceptible to development of severe anxiety and depression.
2. Islet Transplantation can save those patients and resolve their issues with low blood sugars
watch Stacy' story below
Islet transplantation restores normal blood glucose control, eliminates dangerously low blood sugar and allows patients to resume fully independent personal and professional lives.
3. The FDA’s outdated regulations have created unnecessary barriers to the accessibility to islet transplantation and need to be updated
the request to regulate human islets as organs for transplantation
May 4, 2021
Islet Transplantation at a Crossroads - Need for Urgent Regulatory Update in the United States: Perspective Presented During the Scientific Sessions 2021 at the American Diabetes Association Congress
Frontiers in Endocrinology.
To educate the regulators about the negative consequences of the current regulations strategy of the pancreatic islet for transplantation in the US
To promote an appropriate regulatory update for safe and effective islet transplantation in the US
To inspire the FDA and the U.S. Government to introduce appropriate
regulatory update regarding islets for transplantation under the regulatory framework developed for organ transplantation in the US.
allow for safe and effective islet transplantation in the US
promote safe, effective, and affordable access to islet transplantation for millions of Americans with diabetes.
preserve the human pancreas and islets as public resources for the public good while preventing unsafe and detrimental commercialization of human islet transplantation.
It sounds ambitious but in reality we are merely catching up to other developed countries, such as Canada, Europe, Japan, and Australia, which already offer clinical islet transplantation to their patients !
Regulation of allogeneic islets (micro organs) as organs for transplantation instead of as biologic drugs
Not only whole organs but also allogeneic islets as subparts of human organs are protected from the commercialization by the law in the US ( 1984 National Organ Transplantation Act, 42 U.S. Code § 274e (Prohibition of organ purchase). TheFDA's position is in conflict with this law, as it mandates conversion of the human organ (the pancreas), or subparts of human pancreas (pancreatic islets), into biologic drugs for the purpose of the transplantation. The FDA possess the authority to for the allow commercialization of human islets to benefit from altruistic human organ donation.
Based on the same act, allogeneic islets as subparts of human pancreas for transplantation should be regulated not by the FDA but by the HRSA/OPTN/UNOS as other organs for transplantation in the US.
The Department of Health and Human Services may introduce reinforcement of the regulation of human pancreatic islets as organs and its parts for transplantation by the HRSA/OPTN in the next two of months, before a biological license for islets as a drug is issued by the FDA.
There is potential in proposing the regulation of allogeneic islets as a tissue for transplantation solely under the Section 361 of the Public Health Service (PHS) Act with the exemption from the Section 351 of the PHS.
This would require the FDA to update the interpretation of the regulations based on current scientific knowledge and clinical practice concerning allogeneic islets for transplantation. Unfortunately, the FDA has been reluctant ate processing this change. To reiterate, it is only the Secretary of the Department of Health and Human Services who may direct the FDA to pursue updates.
The experts are calling on the FDA specifically to:
1. Recognize that short-term incubation of islet allografts prior to infusion does not alter their relevant
biological characteristics and that these cells are therefore not “more than minimally manipulated”;
2. Update its regulations to allow islet allografts from suitably-matched unrelated donors to be regulated in the same manner as autologous or related-allogeneic donor cells.
The substantially higher burden for unrelated islet allografts is not scientifically justified and is not necessary to for patient protection. It is only serves to prevent patients from accessing this treatment in the U.S.
Specifically, 21 CFR 1271.10(a)(4)(ii)(b), which describes conditions for exemption from drug regulations currently states: “...for allogeneic use in a first-degree or second-degree blood relative” should be revised to state: “..,for use in immunologically-compatible donors and recipients.” This language is more consistent with current clinical standards.
Contrary to the United States, many other countries regulate allogeneic islet cells as minimally-manipulated human tissue for transplantation . In particular, according to the European Medicines Agency:
"...If the enzymatic digestion leads to isolation of functionally intact tissue units (e.g. pancreatic islets) or there is scientific evidence that the original structural and functional characteristics are maintained, the procedure is NOT considered substantial manipulation..." (EMA ref)
Moreover, in 2011, the European Committee for Advanced Therapies (CAT) considered that
autologous/allogeneic human islets of Langerhans were not an ATMP but are considered to fall under the provisions of the Tissues and Cells legislation.
Under this legislation, islet cells are not considered a medicinal product, since the active substance, i.e., human tissues, cannot be commercialized or manufactured on an industrial scale for ethical and legal reasons. (ref)
What are the benefits behind this regulatory update?
Experts highlight the numerous predicted positive effects of updating the regulation including:
Unnecessary and outdated regulatory requirements will be removed, but the regulations necessary to protect patient safety will remain in place.
The main regulatory barrier will be eliminated for the implementation of islet transplantation as a standard of care procedure.
Clinical oversight by the OPTN/UNOS as for any other organ transplantation would be implemented improving overall safety and efficacy of procedure.
Islet transplantation would be more affordable by eliminating the need for redundant and unnecessary costly processing systems related to drug manufacturing control.
As more transplant centers become able to meet the requirements, islet transplantation will be made much more accessible to patients.
Human pancreas and islet for transplantation shall remain public resources, which will promote organ donation and life-saving transplantation.
The increasing affordability of research will lead b to further progress not only in islet transplantation, but also in cellular therapies and regenerative medicine as a whole.
Executive action required
The FDA has refrained from making the required regulatory update, which constitutes the exemption of the allogeneic islets from drug related regulations
Therefore, we believe that he shortest route to changing the FDA’s current outdated policy is by influencing the decision of the Secretary of the Health and Human Services to include and enforce regulation of the allogeneic islets as subparts of human organ for transplantation under the National Organ Transplantation Act. This cannot be by the FDA but by the HRSA/OPTN/UNOS as any other organ transplantation in the US.
2015 University of Chicago
14 patients participated in an islet transplantation clinical trial so the others Americans could get one day also access to this treatment.
Post -procedure, many patients remain no longer in need any insulin injections (off insulin) more than 7 years later