Why is islet transplantation
still not available to the patients with Type 1 Diabetes in the US?
Islet transplantation is approved for clinical use worldwide...
... Why not yet in the US?
"...because, human islets have been regulated as drugs,
instead of being regulated as organs for transplantation as in all other developed countries worldwide..."
...scientific evidence strongly supports need for the urgent regulatory update in the US, and the need for the islet regulation 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
"...anyone who is involved in the science, to say: "you should never change your mind", does not understand what science is..."
Director of National Institute for Allergy and Infectious Disease
Pancreatic islets are micro-organs, yet
FDA has been regulating human islets for transplantation as drugs
Pancreatic islets are located in the human pancreas surrounded by the exocrine tissue.
Islets are micro-organs, with own unique anatomy, structure and function, they are made of many different type of cells.
They have own blood vessels and nerves.
They are retrieved (isolated from the pancreas) and transplanted while their structure and function remain preserved- exactly like for 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 deeply concern about over 20-year lack of the 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 the islets in the US, which lead to the imminent demise of the entire field of islet transplantation, or alternatively to unsafe and detrimental for the field and patients, commercialization of the human pancreas and islets for clinical transplantation.
3. Based on our analysis, we identified a key elements critical of 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, with components of the FDA regulations for human cel and tissue for transplantation exempt from the drug regulations, which can be easy implemented by the decision of the Secretary of the HHS.
5. Unfortunately, despite our call, no need for the regulatory update has 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 position during the FDA Experts Advisory Committee Meeting in April 2021 and during the Scientific Sessions of the American Diabetes AssociationCongress in June 20021. (see below)
Key negative consequences of the deficiencies in the current islet regulations
Imminent demise of islet transplantation in the US
Over last 10 years, we have witnessed a decline of islet transplantation in the US, as the procedure remained limited only to experimental settings due to outdated islet regulations, Regulations of human islets as drugs preclude safe transition of the islet transplantation to the standard of care procedure available to diabetic patients in the US. Lack of finacial support system and reimbursment precludes any 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 and FDA's own report clearly indicate that the current regulation of human islets as drugs does not reassure safety and effectiveness of the therapy as intended to. Islet sterility and quality prior to transplant cannot be reassured despite the application of the drug manufacturing procedures and regulations during 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 above, the FDA still considers granting a Biological License to a single for-profit company to market human islets for transplantation in the US, which would further compromise patient safety, lead to unsafe and detrimental commercialization of human pancreas and islets for clinical transplantation in the US .
The continuation the islet regulation as drugs has multiple negative consequences for the future of islet and organ transplantation and diabetes 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, why this is an urgent problem
and need to be addressed immediatelly:
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 life is severely compromised. They are afraid to drive, work and live independently.
They develop severe anxiety and depression.
2. Islet Transplantation can save those patients and prevent from
low blood sugars
watch Stacy' story below
Islet transplantation restores normal blood glucose control. eliminates dangerous low blood sugars and allows patients to resume fully independent personal and professional life.
3. FDA’s outdated regulations have created unnecessary barriers to access to islet transplantation and need to be updated
Letter to the Secretary of Health and Human Services with
the request to regulate human islets as organs for transplantation
May 4, 2021
In other countries Islet Transplantation has become a standard of care but this treatment is still not available in the USA
To educate about the negative consequences of the current regulations of the pancreatic islet for transplantation in the US and
To promote an appropriate regulatory update for safe and effective islet transplantation in the US
To stimulate 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 preventing from unsafe and detrimental commercialization of human islet transplantation.
It sounds ambitious but in reality we are just playing catch 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 any other organ for transplantation instead of as biologic drugs
Not only pancreas 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). FDA's position is in conflict with that law, since it mandates conversion of the human organ (pancreas), or subparts of human pancreas (pancreatic islets), into a biologic drug for the purpose of the transplantation. FDA position would allow commercial, for profit manufactures of the human islets to benefit from altruistic human organ donation.
Based on the same act, allogeneic islets as subpart for human pancreas for transplantation should be regulated not by 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 any other organ 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.
Introduction of 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 the current scientific knowledge and clinical practice in regard to allogeneic islets for transplantation. Unfortunately, the FDA has been reluctant and again, only the Secretary of the Department of Health and Human Services may direct the FDA to pursue the updates.
Specifically, experts call on FDA 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 justified by the science and is not necessary to protect patients, but serves only to prevent patients from accessing this treatment in the U.S.
Specifically, 21 CFR 1271.10(a)(4)(ii)(b), which currently states: “Is for allogeneic use in a first-degree or second-degree blood relative” should be revised to state: “Is 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, 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 neither 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 will happen after proposed regulatory update?
Experts highlight the numerous predicted positive effects of updating the regulation including:
Unnecessary and outdated regulatory requirements will be removed, but regulations necessary to protect patient safety will remain in place.
Main regulatory barrier will be eliminated for the implementation of the 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 the procedure.
Islet transplantation would be more affordable by eliminating need for redundant and unnecessary costly processing systems related to drug manufacturing control.
As more transplant centers would be able to meet the requirements, islet transplantation will be much more accessible for the patients.
Human pancreas and islet for transplantation remain public resources which will promote organ donation and life-saving transplantation.
Research being more affordable will lead to further progress not only in islet transplantation but in cellular therapies and regenerative medicine overall.
Executive action required
The FDA has refrained from the required regulatory update, exemption of the allogeneic islets from drug related regulations
Therefore in our opinion, the shortest route to changing FDA’s current outdated policy is through the decision of the Secretary of the Health and Human Services to include and reinforce regulation of the allogeneic islets as subparts of human organ for transplantation under the National Organ Transplantation Act, and not 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 islet transplantation clinical trial so others Americans could get access to this treatment one day too.
Some patients still do not need any insulin injections (off insulin) more than 7 years later