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The U.S. Department of Health and Human Services (HHS) has opened a public docket to solicit input, supporting data, and comments as it considers how best to regulate deceased-donor islet cells and/or deceased-donor islet cell products for the treatment of Type 1 diabetes (T1D).

Electronic or written comments must be submitted by November 9, 2026.

Below, we present our response to the questions posed by HHS, providing data, scientific evidence, and regulatory arguments supporting the reclassification of unmodified human pancreatic islets from a biologics/drug regulatory framework to the regulatory framework established for human organs.

We encourage clinicians, researchers, patients, transplant professionals, and other stakeholders to review the evidence and participate in this important public discussion about the future of islet transplantation and patient access.

-> https://www.regulations.gov/document/FDA-2026-N-10738-0001

PUBLIC COMMENT

Islets for US Collaborative Response to HHS Request for Public Comment

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SUMMARY

Re: Docket FDA-2026-N-10738 — Improving Patient Access to Deceased Donor Islet Cells and Cell Products

We urge HHS to recognize unmodified deceased-donor pancreatic islets as organs and to regulate their transplantation under the HRSA/OPTN framework, not as FDA biologics.

1. Islets are organs, not manufactured products. Each islet is a naturally formed 3D micro-organ comprise of multiple cell types with its own vascular and neural components, functioning as an integrated unit. Islets are recovered from a pancreas procured by an OPO through standard multiorgan recovery; isolation separates them from exocrine tissue in the same sense that surgical recovery separates any organ from surrounding tissue. Just as every pancreas is different from different donors, every batch of islets is different. Islets are not expanded, differentiated, or engineered, and perform in the recipient the same function as in the donor. The term "islet cell transplantation" is a misnomer that has driven the regulatory mismatch.

2. The drug/biologic framework cannot assure islet quality. No manufacturing process "creates" an islet. The FDA review of Lantidra confirmed that no in-vitro potency assay or combination of release criteria predicts clinical graft function, and that Gram stain alone cannot assure sterility. A BLA therefore creates an appearance of product assurance without the ability to predict outcomes — the problem the organ framework addresses through donor screening, procurement standards, traceability, center accreditation, and outcome monitoring. Donor-to-donor variability is intrinsic to organs, not a manufacturing defect.

3. The evidence base is extensive. CITR (NIDDK, since 2001) holds data on 1,517 recipients and 3,557 islet preparations from 47 programs; a worldwide survey identified 4,321 allogeneic transplants in 2,149 patients across 25 countries (2000–2020); the international Edmonton Protocol trial and 12-year follow-up document durable function. Immunosuppressive agents and the transhepatic portal route have >25 years of clinical experience; repeat reproductive, carcinogenicity, or route-specific animal studies should be waived. International RWE is highly fit for clinical outcomes and, where processing practices are comparable, informative for quality standards.

4. Precedent exists and is narrow. Canada (CTO Regulations), the UK, France, Italy, Switzerland, Australia, Japan and others regulate islets as organ/tissue transplants; EMA does not classify unmodified islets as substantially manipulated. Reclassification should apply only to unmodified deceased-donor islets. Stem cell-derived islets, encapsulated, expanded, or otherwise substantially manipulated products remain appropriately under FDA biologics oversight.

5. The BLA requirement is the central access barrier. After NIH-funded trials ended, the absence of a reimbursement pathway without a BLA caused most U.S. programs to close, while Edmonton alone performed >700 procedures under provincial coverage. Today intraportal transplantation is available only under IND at a few U.S. centers. Over 3,000 patients have applied recently for few open positions in the current trials. Tens of thousands of U.S. patients with hypoglycemia unawareness have no practical access to a therapy that is standard of care abroad.

6. Implementation is feasible within existing OPTN infrastructure. The Pancreas and Islet Transplantation Committee of the OPTN can set standards for program certification, pancreas allocation (donor BMI ≥32 pancreata are preferred for islets and rarely used for whole-pancreas transplant, so there is no competition with other waiting patients), isolation under GTP-based controlled/clean-room conditions with FDA-informed sterility and quality-system standards, release assessment (count, viability, purity, Gram stain, endotoxin) as quality-control tools rather than potency assays, and prospective outcome reporting through OPTN/SRTR (one-year patient and graft survival, primary nonfunction by C-peptide, Igls classification, complications). Transplant centers are accountable for the entire chain, from donor selection to follow-up, as for other organs. No new provider category is needed; existing pancreas programs suffice, with 8–10 centers likely initially. Islet transplantation is less invasive and comparable or lower in cost than whole-pancreas transplantation.

Reclassification would correct decades-long regulatory mismatch, restore U.S. competitiveness in a field it pioneered, and give patients access to an established, life-changing transplant. We respectfully request that HHS proceed. Detailed responses to each question in the RFI and supporting references are provided in the attached document.

On behalf of Islet for US Collaborative

Piotr Witkowski M.D. Ph.D

Camillo Ricordi M.D

Jon S Odorico M.D.

Fouad Kandeel M.D. Ph.D.

Islets for US Collaborative Detailed Response to HHS Questions

for Public Comment

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Introduction

Human Islets Are Organs and Should Be Regulated as Organs, Not as Drugs or Biologics

Human islets are anatomically and physiologically human organs with a complex structure created naturally within the human body. They are not manufactured in a laboratory. Therefore, attempts to control, characterize, and measure islet or organ quality using tools and methods developed for the manufacture and quality control of drugs or biologics are fundamentally inappropriate and cannot reliably establish the safety, quality, or clinical effectiveness of transplanted islets.

This became evident during the regulatory review and registration of human islets under the name Lantidra. In a public presentation, the FDA acknowledged that the characteristics used in the released product criteria, which were developed according to a drug/biologic manufacturing framework, did not correlate with clinical function. Such correlation is a critical consideration for any biological product intended for clinical use. In other words, the characteristics used to establish the quality of human islets could not reliably confirm their clinical function or predict clinical outcomes in the manner expected for a drug or biologic.

Nevertheless, the FDA approved the BLA for Lantidra for clinical use. This approval created an unjustified perception that the product's quality, safety, and effectiveness have been adequately established under a conventional drug or biologic regulatory framework. Moreover, significant questions remain regarding whether Lantidra can be demonstrated to meet the level of sterility and pathogen safety ordinarily expected for a product administered by intravenous infusion. Yet the product has been approved for clinical use as a biological product.

Under the current regulatory framework, Lantidra is therefore presented as an approved product without the type of quality assurance that can reasonably be established for a naturally occurring human organ. This creates significant safety concerns and illustrates a fundamental regulatory problem: applying a drug/biologic manufacturing framework to a human organ.

Because the quality of human organs cannot be adequately assured through manufacturing standards and testing paradigms developed for drugs or biologics, a specialized regulatory framework for human organ transplantation has been developed under the Health Resources and Services Administration (HRSA) and the Organ Procurement and Transplantation Network (OPTN). This framework recognizes the fundamental biological differences between naturally occurring human organs and manufactured pharmaceutical products.

Human islets are small organs and should therefore be incorporated into an organ-based regulatory framework rather than regulated as conventional drugs, biologics, or dissociated cellular products. Such an approach would provide a more scientifically appropriate mechanism for assuring the safety, quality, and effectiveness of human islet transplantation. For this reason, we urge the Secretary of Health and Human Services to establish a regulatory pathway that recognizes human islets as organs and subjects them to the appropriate organ-transplantation regulatory framework.

Detailed Evidence That Human Islets Are Organs and Should Be Regulated as Organs, Not as Drugs or Biologics

1. Human islets are not single-cell or conventional cellular products Human islets are small, highly organized endocrine organs with a defined anatomical architecture. Each islet contains thousands of cells of multiple specialized types arranged in an integrated three-dimensional structure. Islets also contain their own vascular and neural components and function through coordinated interactions among different cell populations.The function of an individual islet is therefore not simply the function of an isolated cell or collection of cells. Rather, it is the result of highly integrated and coordinated activity among multiple cell types, regulated by hormonal, vascular, and neural mechanisms, as occurs in other organs of the human body.Accordingly, treating human islets as conventional cellular products fails to recognize their fundamental anatomical and physiological characteristics as organs.

2. Human islets are not manufactured in a laboratory Human islets are naturally developed within the human body, like all other human organs. They are not created, assembled, or manufactured through a laboratory production process.For clinical transplantation, islets originate from a human pancreas that is surgically recovered from a deceased donor in the same organ-recovery system used for other transplantable organs. The pancreas is recovered together with the surrounding anatomical structures, including the duodenum and spleen, as appropriate for organ procurement and preservation.The islets therefore originate as naturally occurring structures within a human organ. They are not a manufactured biological product created through a standardized laboratory production process.

3. Islet isolation is analogous to the retrieval of an organ from surrounding tissueDuring islet isolation, the islets are separated from the surrounding exocrine pancreatic tissue. This process is analogous, in principle, to separating a transplantable organ from the surrounding tissues during surgical organ recovery.Importantly, the objective of islet isolation is not to manufacture a new biological product. The naturally occurring islets are recovered from the pancreas while preserving their essential anatomical structure and biological function.Unlike conventional cellular therapies, in which cells may be dissociated, expanded, genetically modified, or otherwise manufactured into a therapeutic product, human islet transplantation preserves the islet as an intact biological unit.

4. Human islets are preserved prior to transplantation in the same fundamental manner as other transplantable organsLike other organs, human islets must be preserved after recovery and before transplantation for logistical and clinical reasons.Islets are generally maintained under controlled conditions, including incubation at approximately room temperature, while other transplantable organs may be preserved under hypothermic conditions or through normothermic perfusion. These differences in preservation conditions do not change the fundamental nature of the biological material: the islet remains an intact organ.Human islets are not routinely dissociated into individual cells during clinical transplantation. Their three-dimensional structure is preserved, and their biological function depends on the continued interaction of the different cellular components within the intact islet.

5. Human islets cannot be treated as conventional frozen cellular productsHuman islets intended for clinical transplantation cannot simply be frozen, stored, and later administered in the same manner as conventional cellular therapy products.Their viability and function depend on preservation of the intact islet structure and the complex interactions among its cellular components. This further distinguishes human islets from conventional manufactured cellular products.

6. The quality of human islets cannot be reliably established using drug or biologic manufacturing standardsBecause human islets are naturally occurring organs rather than manufactured biological products, their quality cannot be adequately established through the same manufacturing controls and release-testing paradigms used for drugs or biologics.For a manufactured pharmaceutical product, quality can be controlled by standardizing the manufacturing process, raw materials, formulation, manufacturing conditions, and release specifications. The product is created through a defined process, and consistency between batches is a fundamental component of quality assurance.This paradigm does not apply to a naturally occurring human organ.There is no laboratory process that "creates" the human islet. Standardization of the isolation or processing procedure cannot, by itself, guarantee the biological quality or clinical effectiveness of the naturally occurring organ obtained from a particular donor.This limitation is evident in the case of Lantidra. Although Lantidra may satisfy specified release criteria, there was no demonstrated set of measured islet characteristics that could consistently predict clinical function or clinical outcome. Consequently, a product can satisfy predefined release criteria while still having variable biological quality and potentially poor clinical performance.The distinction is fundamental: meeting manufacturing release criteria is not equivalent to demonstrating the quality or clinical effectiveness of a naturally occurring human organ.

7. Sterility and pathogen safety present additional regulatory challengesThe same problem applies to sterility and pathogen safety. Human organs cannot necessarily be rendered sterile through manufacturing processes in the manner of conventional pharmaceutical products. Instead, organ transplantation relies on donor screening, testing, procurement procedures, preservation standards, traceability, and risk-management systems specifically designed for human organs.This distinction is particularly important for human islets because they are administered clinically, including by intravenous infusion. If conventional pharmaceutical sterility standards cannot be applied or conclusively demonstrated, the regulatory framework must instead provide an appropriate organ-based system for assessing and managing infectious risks.The regulatory treatment of Lantidra demonstrates the concern. If sterility is not directly and conclusively established before transplantation, approval of the product under a drug/biologic framework may create a false impression that the same level of sterility assurance has been established as would ordinarily be expected for a manufactured pharmaceutical product.

8. Human islets should therefore be regulated within the existing organ-transplantation frameworkThe fundamental characteristics of human islets demonstrate that they are organs:•They are naturally developed within the human body.•They possess a defined three-dimensional anatomical structure.•They contain multiple specialized cell types that function together as an integrated unit.•They have vascular and neural components.•They are recovered from a human pancreas obtained through organ procurement.•They are isolated from surrounding pancreatic tissue rather than manufactured in a laboratory.•Their clinical function depends on preservation of their intact biological architecture.•Their quality cannot be reliably established through conventional pharmaceutical manufacturing and release-testing paradigms.•Their infectious and other safety risks require donor screening, recovery, preservation, traceability, and transplantation controls rather than conventional pharmaceutical manufacturing controls.For these reasons, human islets should not be regulated as conventional drugs, biologics, or manufactured cellular products. They should be recognized and regulated as human organs intended for transplantation.A specialized organ-transplantation regulatory framework has already been developed and refined over decades for precisely this purpose. The HRSA/OPTN system provides a framework designed to address the unique biological, logistical, safety, allocation, procurement, preservation, and transplantation issues associated with human organs.Because human islets are small organs, they should be incorporated into an appropriate organ-transplantation regulatory framework rather than forced into a regulatory model designed for manufactured drugs or biologics. Recognizing this distinction would provide a scientifically sound basis for improving the safety, quality assurance, and effectiveness of human islet transplantation.

Reference

1.Abdulreda MH, et al. The pancreatic islet: a micro-organ in control. CellR4 Repair Replace Regen Reprogram. 2021;9. doi:10.32113/cellr4_20213_3093.
Monserrat N. Islet transplantation in the US-quo vadis? An interview with Camillo Ricordi (CR), Ali Naji (AN), Peter Stock (PS), Piotr Witkowski (PW). Transplant Int. 2021;34. doi:10.1111/tri.13931.
United States Food and Drug Administration. Cellular, Tissue, and Gene Therapies Advisory Committee April 15, 2021 meeting announcement. Available at: FDA meeting announcement. Accessed May 20, 2021.
Walker JT, et al. The human islet: mini-organ with mega-impact. Endocr Rev. 2021;42:605-657. doi:10.1210/endrev/bnab010.
Weir GC, et al. Why pancreatic islets should be regarded and regulated like organs. CellR4 Repair Replace Regen Reprogram. 2021;9. doi:10.32113/cellr4_20213_3083.
Witkowski P, et al. 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. Front Endocrinol (Lausanne). 2022;12:789526. doi:10.3389/fendo.2021.789526.
Witkowski P, et al. 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;10(13):2878. doi:10.3390/jcm10132878. PubMed.
Witkowski P, et al. Regulatory updates are needed to prevent commercialization of islet transplantation in the US. Am J Transplant. 2021;21(7):2620-2622. doi:10.1111/ajt.16555.
Witkowski P, et al. Pancreatic islets quality and potency cannot be verified as required for drugs: reflection on the FDA review of a biological license application for human islets. Transplantation. 2021;105(12)-e410. doi:10.1097/TP.0000000000003880. PubMed Central (PMC).
Witkowski P, et al. The demise of islet allotransplantation in the United States: a call for an urgent regulatory update. Am J Transplant. 2021;21(4):1365-1375. doi:10.1111/ajt.16397. OpenAlex.
Witkowski P, et al. Demise of cadaveric islet transplantation in the USA: quo vadis, 1 year after BLA approval and 24 years after the Edmonton breakthrough? Front Transplant. 2025;4:1491568. doi:10.3389/frtra.2025.1491568.

IV.A Questions for Consideration Regarding Food and Drug Administration Regulation

A. General

What publicly available data sources/information demonstrate quality source material for creation of deceased donor islet cellular products? Elements include, but are not limited to, donor eligibility, pancreas procurement parameters, organ quality acceptance criteria, and infectious disease testing. Information might include donor health status, donor age, donor body mass index for organ quality acceptance criteria, donor screening and testing records equivalent to the information required by 21 CFR part 1271, subpart C for donor eligibility; data on organ procurement procedures, ischemia time (warm/cold), preservation methods, shipping containers and conditions for organ procurement parameters; predefined acceptance criteria for organ or deceased donor islet cell quality: size, fibrosis extent, and results of all required communicable disease tests using FDA-licensed, -approved, or-cleared test kits; performed by Clinical Laboratory Improvement Amendments-certified laboratory for infectious disease testing.

Pancreas donor characteristics

As outlined in the introduction, deceased-donor islet transplantation does not involve the creation of a cellular product from a separate or independently manufactured “source material.” Rather, human pancreatic islets are isolated from the pancreatic tissue of an eligible deceased organ donor and subsequently transplanted into the recipient. The donor pancreas itself is therefore the source of the transplanted islets.

The quality and suitability of a deceased-donor pancreas for islet transplantation have historically been assessed using the same established organ-donor evaluation and allocation framework used for other solid-organ transplantation, supplemented by criteria that are specific to successful islet isolation and transplantation. These assessments include the donor's medical history and clinical characteristics, laboratory and infectious-disease testing, hemodynamic status, cause of death, age, body mass index (BMI), history of diabetes or impaired glucose metabolism, and direct visual and anatomic assessment of the pancreas during organ recovery.

Over several decades of clinical experience, both individual transplant centers and multicenter groups have identified donor characteristics associated with successful islet isolation and transplantation. Donor-selection scoring systems have also been developed to provide an objective framework for pancreas acceptance and to optimize islet isolation efficiency and clinical outcomes. For example, a history of diabetes and elevated donor HbA1c (e.g., >6.0%) are generally considered unfavorable characteristics and may constitute exclusion criteria in islet-transplant protocols. Persistent hemodynamic instability requiring substantial pharmacologic cardiovascular support is another unfavorable factor. In contrast, donor BMI in the higher range (including BMI >32 kg/m²) has been associated in published studies with greater pancreatic islet yield and successful islet transplantation. Importantly, donor suitability is not determined by any single characteristic; rather, the overall constellation of donor factors is considered when determining whether a pancreas is suitable for islet isolation.

Published donor-selection and scoring systems provide publicly available evidence supporting these criteria and can be used to establish objective donor-acceptance parameters. It is also important to recognize that the optimal donor characteristics for whole-pancreas transplantation are not necessarily identical to those associated with optimal islet isolation and transplantation. The donor-selection process for islet transplantation therefore incorporates criteria specifically developed from the clinical experience of islet-transplant programs. For optimal allocation and utilization, pancreata from donors with BMI<32 are primarily allocated for whole-pancreas transplantation and pancreata from donors with BMI of 32 and over, for islet transplantation.

Assessment of the pancreas also includes direct visual and anatomic evaluation at the time of organ recovery. The recovering surgeon communicates the condition and appearance of the pancreas to the accepting transplant center, and significant abnormalities are documented. When appropriate, photographic documentation can supplement the operative assessment. These established organ-recovery practices provide direct documentation of the quality of the pancreas before it is accepted for islet transplantation.

Reference

Wang LJ, et al. A multicenter study: North American Islet Donor Score in donor pancreas selection for human islet isolation for transplantation. Cell Transplant. 2016;25(8):1515–1523. doi:10.3727/096368916X691141.
Gołębiewska JE, et al. Validation of a new North American Islet Donor Score for donor pancreas selection and successful islet isolation in a medium-volume islet transplant center. Cell Transplant. 2019;28(2):185–194. doi:10.1177/0963689718816989. PMID: 30520321.
O'Gorman D, et al. The standardization of pancreatic donors for islet isolations. Transplantation. 2005;80(6):801-806. doi:10.1097/01.tp.0000172216.47547.d5. PMID: 16210968.

With respect to prevention of transmission of donor-derived infection or malignancy, deceased donors for islet transplantation undergo the same fundamental donor-screening and infectious-disease evaluation required for deceased-donor organ transplantation, with additional restrictions where required by the applicable islet-transplant protocol. Historically, FDA-approved clinical protocols for islet transplantation have generally excluded donors with certain active infections, bacteremia, malignancy, or other conditions considered to present an unacceptable risk of donor-derived disease transmission. In addition, increased-risk donor categories have historically been excluded from many islet-transplant protocols.

Donor screening, infectious-disease testing, and associated documentation are performed and maintained through the Organ Procurement Organization (OPO) responsible for donor evaluation and organ allocation. This system provides a standardized, regulated framework for donor eligibility assessment and documentation that is already used nationally for deceased-donor organ transplantation. The relevant donor records therefore provide the information necessary to evaluate donor eligibility and communicable-disease risk before the pancreas is accepted for islet transplantation.

Pancreas procurement

Pancreas procurement for islet transplantation is performed as part of a deceased-donor multiorgan recovery coordinated by the local Organ Procurement Organization (OPO) under the regulatory framework of HRSA and the OPTN.

The surgical recovery of the pancreas for islet transplantation is essentially the same as pancreas procurement for whole-organ transplantation. The principal technical difference is that iliac vessels are generally not recovered as vascular conduits because vascular anastomosis is not required for subsequent islet transplantation. Surgeons trained and credentialed in pancreas recovery for whole-organ transplantation are therefore appropriately qualified to recover pancreata intended for islet isolation.

Following procurement, the pancreas is preserved using established abdominal-organ preservation solutions and transported under the established organ-transport system used for deceased-donor organs. Typically, the pancreas is placed in a sterile organ container, maintained under cold preservation conditions, and transported on ice in a standard organ-transport container. Transportation is coordinated and documented by the OPO and/or the receiving transplant program in accordance with established organ procurement and transplantation procedures. Preferably time of transportation should remain below 12 hours for optimal outcomes of islet isolation and transplantation.

Consequently, the relevant quality parameters for a deceased-donor pancreas intended for islet transplantation—including donor eligibility, donor medical and infectious-disease evaluation, pancreas acceptance criteria, procurement procedures, ischemia and preservation parameters, and transportation conditions—are already captured within the established deceased-donor organ procurement and transplantation infrastructure. These data are generated contemporaneously during the donor evaluation, organ recovery, allocation, preservation, and transportation processes rather than through creation of a separate cellular-source-material record.

The subsequent isolation of pancreatic islets does not change the underlying origin or eligibility of the donor material. Rather, it constitutes processing of the donated pancreas to recover the naturally occurring pancreatic islets that are subsequently transplanted into the recipient.

Reference

Kneteman NM, Lakey JR, Kizilisik TA, Ao Z, Warnock GL, Rajotte RV. Cadaver pancreas recovery technique. Impact on islet recovery and in vitro function. Transplantation. 1994;58(10):1114-1119. PMID: 7974719.
Lee TC, Barshes NR, Brunicardi FC, Alejandro R, Ricordi C, Nguyen L, Goss JA. Procurement of the human pancreas for pancreatic islet transplantation. Transplantation. 2004;78(3):481-483. doi:10.1097/01.TP.0000128910.41921.4B. PMID: 15316380.
Lakey JRT, Kneteman NM, Rajotte RV, Wu DC, Bigam D, Shapiro AMJ. Effect of core pancreas temperature during cadaveric procurement on human islet isolation and functional viability. Transplantation. 2002;73(7):1106-1110. doi:10.1097/00007890-200204150-00016. PMID: 11965040.

2. What publicly available data sources/information demonstrate control of the manufacturing? Elements might include summary of control strategy, process validation data and facility and Current Good Manufacturing Practice (CGMP) compliance.

The Collaborative Islet Transplant Registry (CITR) provides an important publicly available source of evidence regarding the consistency, quality, and safety of human pancreatic islet isolation and transplantation. CITR has collected standardized clinical and processing data from islet-transplant centers in the United States, Canada, and other countries, encompassing more than 2,000 islet-processing procedures. These data provide a substantial longitudinal clinical experience with human islet isolation and transplantation across multiple institutions and processing facilities.

Importantly, the CITR experience demonstrates that clinically suitable human islets can be consistently isolated, characterized, and transplanted using established islet-processing procedures without requiring that every processing facility operate under a commercial biologics-license application (BLA) framework.

It is a multicenter registry designed specifically to aggregate standardized clinical data across islet-transplant programs. Data from CITR provide evidence that outcomes, safety, donor characteristics, and graft function can be evaluated using an established transplant-registry framework rather than treating every islet preparation as a newly manufactured biological product.

A substantial portion of the international CITR experience has been generated at centers operating under Good Tissue Practice (GTP)-equivalent or similarly controlled conditions. In the United States, islet preparations used in clinical trials have been produced under institutionally controlled processing and quality systems appropriate for investigational clinical use, including facilities operating under INDs. These clinical experiences provide extensive evidence regarding the reproducibility, safety, and clinical suitability of the islet-isolation process in the absence of a commercially licensed BLA manufacturing framework.

The processing itself is also highly standardized. It consists of established and reproducible steps including pancreas receipt and inspection, enzymatic digestion, mechanical dissociation, tissue separation, islet assessment and counting, determination of purity and viability, culture when applicable, formulation, and preparation for transplantation. Critical process parameters and product-release characteristics can be defined and monitored at each stage. These include, as applicable, pancreas transport and ischemia times, digestion parameters, tissue processing conditions, islet yield, purity, viability, cellular composition, sterility, endotoxin, and other relevant product-quality attributes.

Clinical experience accumulated through CITR and through individual and multicenter clinical trials demonstrates that these established processes can produce islet preparations of sufficient and reproducible quality for clinical transplantation. The extensive international experience is particularly relevant because it demonstrates that the fundamental manufacturing process and associated quality-control measures are not dependent upon a single facility, institution, or proprietary manufacturing system.

The available evidence should therefore be considered in the context of the proposed regulatory classification. The question is not whether deceased-donor islet transplantation has been manufactured under the same commercial CGMP/BLA framework used for an FDA-approved biologic product. Rather, the relevant question is whether there is established evidence that human pancreatic islets can be recovered from appropriately screened deceased donors, processed under controlled and standardized conditions, subjected to appropriate quality-control and release criteria, and safely administered to patients. More than two decades of clinical experience and over 3,000 reported islet-processing procedures provide substantial evidence addressing these questions.

Accordingly, publicly available CITR data, together with published clinical-transplantation experience and data from U.S. clinical trials conducted under INDs, provide an extensive evidence base for the control, reproducibility, and clinical safety of human islet processing. These data support the conclusion that the established organ/tissue procurement and processing framework can provide appropriate control of deceased-donor islet transplantation without requiring the additional regulatory framework applicable to commercial BLA-manufactured biologic products.

Reference

The CITR Coordinating Center and Investigators. 12th Collaborative Islet Transplant Registry 2025 Annual Report. Available at: https://citregistry.org/system/files/CITR%2012th%20Allograft%20Report_2025_Final.pdf.
Barton FB, et al. Improvement in outcomes of clinical islet transplantation: 1999-2010. Diabetes Care. 2012;35(7):1436-1445. doi:10.2337/dc12-0063. PMID: 22723582.
Barton FB, et al. Islet product characteristics and factors related to successful human islet transplantation from the Collaborative Islet Transplant Registry (CITR) 1999-2010. Am J Transplant. 2014;14(11):2595-2606. doi:10.1111/ajt.12872. PMID: 25278159.
Marfil-Garza BA, et al. Pancreatic islet transplantation in type 1 diabetes: 20-year experience from a single-centre cohort in Canada. Lancet Diabetes Endocrinol. 2022;10(7):519-532. doi:10.1016/S2213-8587(22)00114-0.
Lablanche S, et al. Islet transplantation versus insulin therapy in patients with type 1 diabetes with severe hypoglycaemia or poorly controlled glycaemia after kidney transplantation (TRIMECO): a multicentre, randomised controlled trial. Lancet Diabetes Endocrinol. 2018;6(7):527-537. doi:10.1016/S2213-8587(18)30078-0. PMID: 29776895.

3. What publicly available data sources/information demonstrate product quality and potency? Elements include characterization, release tests, validated potency assays and lot-to-lot consistency data, and other quality parameters..

Extensive clinical-trial and published clinical experience has evaluated different release criteria for human pancreatic islets intended for transplantation. These studies have established a set of commonly used quality and functional assessments that provide complementary information about the islet preparation at the time of transplantation.

Commonly used release and quality-control assessments include:

islet number and/or islet equivalent (IEQ) count;
islet purity and composition;
cellular viability;
glucose-stimulated insulin secretion (GSIR), including stimulation indices;
Gram stain; and retrospective microbiological culture and
endotoxin testing

These parameters provide information about different aspects of the islet preparation, including the quantity of transplanted tissue, cellular viability, functional insulin secretory capacity, and potential microbiological contamination. However, all those parameters together and individually have been unable to fully characterize the quality or clinical potency of a deceased-donor human islet preparation.

The clinical experience leading to and including the FDA review of Biological License Application (BLA) for human islets under the commercial name Lantidra, is particularly informative in this regard. The available FDA review demonstrates inability to establish a conventional in-vitro potency assay or combination of release characteristics that reliably predicts clinical graft function following transplantation of donor-derived human islets. In other words, measured characteristics of an islet preparation at the time of release do not correlate directly with the subsequent clinical outcome in the recipient. Similarly, the FDA review identified limitations of relying on Gram staining alone as a method for assuring sterility and demonstrated substantial variability among individual islet preparations.

These observations are not unexpected and reflect an important biological characteristic of deceased-donor human islet transplantation: human islets are not a conventionally manufactured, compositionally uniform biological product. They are naturally occurring small organ structures recovered from individual deceased-donor pancreata. Consequently, substantial biological variability between preparations is intrinsic to the donor as a “source material”. Donor age, BMI, metabolic characteristics, cause of death, hemodynamic stability, pancreas quality, ischemia and preservation conditions, and other donor-specific factors can all influence islet yield, composition, viability, and functional capacity.

This variability is analogous to the biological variability inherent in other deceased-donor organs used for transplantation. A kidney or liver is not expected to be identical from donor to donor, nor is its suitability determined by a single laboratory measurement. Instead, the transplant physician integrates donor characteristics, organ appearance and quality, preservation and procurement information, and available functional assessments when determining whether the organ is suitable for a particular recipient.

The same principle is applicable to deceased-donor pancreatic islets. Assessment of the islet preparation should therefore incorporate the characteristics of the donor and pancreas, the quality of the recovered organ, the technical characteristics of the isolation procedure, direct assessment of the isolated islets, and available laboratory release-testing results. These may include islet count, viability, purity, GSIR/stimulation index, Gram stain, endotoxin, and microbiological testing, among other parameters.

Importantly, these measurements should be understood as complementary quality attributes rather than as independent surrogates for clinical potency. The transplant physician does integrate these findings with the overall clinical and biological context to determine whether a particular organ or islet preparation is appropriate for transplantation into a particular recipient.

Ultimately, the clinically meaningful measure of islet graft potency is the ability of the transplanted islets to provide durable endocrine function in the recipient. Accordingly, longitudinal clinical outcomes provide an essential component of the evidence for quality and potency of deceased-donor islet transplantation. Relevant outcomes include graft function and insulin independence or reduced insulin requirements, HbA1c and glucose control, stimulated C-peptide production, incidence of primary graft dysfunction or graft failure, procedure-related complications, and longer-term graft and patient outcomes.

At the programmatic level, outcomes such as one-year graft function and survival, frequency of primary graft failure, and procedure-related complications can provide meaningful evidence of the effectiveness and consistency of an islet-transplant program. These clinical outcomes are ultimately more relevant to the biological function of the transplanted human islets than any single in-vitro release assay.

Thus, the publicly available clinical literature and registry experience demonstrate that quality assessment of deceased-donor islets is feasible and has been performed for decades using a combination of standardized laboratory assessments, donor and organ characteristics, processing parameters, and clinical outcomes. At the same time, the available evidence demonstrates the limitations of applying a conventional pharmaceutical-product model of a single validated potency assay and strict lot-to-lot uniformity to naturally occurring human islets obtained from individual deceased donors.

Reference

United States Food and Drug Administration. Cellular, Tissue, and Gene Therapies Advisory Committee April 15, 2021 meeting announcement. Available at: FDA meeting announcement. Accessed May 20, 2021.
Witkowski P, et al. 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. Front Endocrinol (Lausanne). 2022;12:789526. doi:10.3389/fendo.2021.789526.
Witkowski P, et al. 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;10(13):2878. doi:10.3390/jcm10132878. PubMed.
Witkowski P, et al. Regulatory updates are needed to prevent commercialization of islet transplantation in the US. Am J Transplant. 2021;21(7):2620–2622. doi:10.1111/ajt.16555.
Witkowski P, et al. Pancreatic islets quality and potency cannot be verified as required for drugs: reflection on the FDA review of a biological license application for human islets. Transplantation. 2021;105(12)–e410. doi:10.1097/TP.0000000000003880. PubMed Central (PMC).
Witkowski P, et al. The demise of islet allotransplantation in the United States: a call for an urgent regulatory update. Am J Transplant. 2021;21(4):1365–1375. doi:10.1111/ajt.16397. OpenAlex.
Witkowski P, et al. Demise of cadaveric islet transplantation in the USA: quo vadis, 1 year after BLA approval and 24 years after the Edmonton breakthrough? Front Transplant. 2025;4:1491568. doi:10.3389/frtra.2025.1491568.
Hering BJ, et al. Phase 3 trial of transplantation of human islets in type 1 diabetes complicated by severe hypoglycemia. Diabetes Care. 2016;39(7):1230–1240. doi:10.2337/dc15-1988.
Hering BJ, et al. Phase 3 trial of human islet-after-kidney transplantation in type 1 diabetes. Diabetes Care. 2016;39(7):1230–1240.

4. What publicly available nonclinical toxicology data supports use of existing immunosuppressive regimens?.

The immunosuppressive agents currently used in islet transplantation have extensive nonclinical pharmacology and toxicology experience supporting their use in humans, including their use in solid-organ transplantation. These agents are not novel drugs developed specifically for islet transplantation; rather, they are established immunosuppressive medications with well-characterized pharmacologic, toxicologic, dosing, and safety profiles.

The relevance of these nonclinical data to islet transplantation is further supported by more than 26 years of clinical experience with human islet transplantation. During this period, calcineurin inhibitors, mTOR inhibitors, antimetabolites, corticosteroids, induction agents, and other immunomodulatory agents have been used in numerous clinical trials and routine clinical practice. Published clinical experience, including data reported through the Collaborative Islet Transplant Registry (CITR), the Collaborative Islet Transplant Study (CIT), and the FDA-reviewed Lantidra clinical development program, provides extensive evidence regarding the safety and effectiveness of these established immunosuppressive regimens in islet-transplant recipients.

The risk-benefit profile of immunosuppression in islet transplantation is also well established. The principal purpose of immunosuppression is to prevent alloimmune-mediated destruction of the transplanted islets and thereby preserve graft function. Without adequate immunosuppression, allogeneic islet grafts are subject to immune-mediated rejection and loss of function. Consequently, the potential toxicities of immunosuppressive medications must be evaluated against their demonstrated benefit in maintaining islet graft survival and function.

Some immunosuppressive agents have recognized effects that may be potentially detrimental to pancreatic β-cell or islet function. Tacrolimus, for example, has been associated in experimental and clinical studies with effects on β-cell function and insulin secretion. These potential effects are well recognized and have contributed to efforts to develop calcineurin-inhibitor-sparing or calcineurin-inhibitor-free regimens. Nevertheless, tacrolimus and other established immunosuppressive agents have been successfully used in islet transplantation for many years, and their immunoprotective effect can outweigh these potential adverse effects when the overall objective is preservation of the transplanted islet graft.

Importantly, the clinical experience provides an opportunity to evaluate the net effect of these medications in the actual islet-transplant population. The relevant question is therefore not whether any individual immunosuppressive agent is completely free of toxicity—which none of these agents is—but whether the established regimen provides an acceptable balance between immunosuppressive efficacy, preservation of islet graft function, and systemic toxicity. More than two decades of clinical experience provides substantial evidence supporting that risk-benefit assessment.

Thus, the existing immunosuppressive regimens used for deceased-donor islet transplantation are supported by a combination of extensive nonclinical pharmacology and toxicology data for the individual agents, their established use in transplantation, and more than 26 years of clinical experience specifically in islet-transplant recipients. The totality of this evidence supports continued use of established immunosuppressive agents when clinically indicated, while also supporting ongoing investigation of less toxic and immunosuppression-sparing approaches.

Reference

The CITR Coordinating Center and Investigators. 12th Collaborative Islet Transplant Registry 2025 Annual Report. Available at: https://citregistry.org/system/files/CITR%2012th%20Allograft%20Report_2025_Final.pdf.
Barton FB, et al. Improvement in outcomes of clinical islet transplantation: 1999–2010. Diabetes Care. 2012;35(7):1436–1445. doi:10.2337/dc12-0063. PMID: 22723582.
Barton FB, et al. Islet product characteristics and factors related to successful human islet transplantation from the Collaborative Islet Transplant Registry (CITR) 1999–2010. Am J Transplant. 2014;14(11):2595–2606. doi:10.1111/ajt.12872. PMID: 25278159.
Liu Y, et al. The direct effects of tacrolimus and cyclosporin A on isolated human islets: a functional, survival and gene expression study. Diabetes Metab. 2011. PMID: 21099257.
Marfil-Garza BA, et al. Pancreatic islet transplantation in type 1 diabetes: 20-year experience from a single-centre cohort in Canada. Lancet Diabetes Endocrinol. 2022;10(7):519–532. doi:10.1016/S2213-8587(22)00114-0.
Lablanche S, et al. Islet transplantation versus insulin therapy in patients with type 1 diabetes with severe hypoglycaemia or poorly controlled glycaemia after kidney transplantation (TRIMECO): a multicentre, randomised controlled trial. Lancet Diabetes Endocrinol. 2018;6(7):527–537. doi:10.1016/S2213-8587(18)30078-0. PMID: 29776895.
Hering BJ, et al. Phase 3 trial of transplantation of human islets in type 1 diabetes complicated by severe hypoglycemia. Diabetes Care. 2016;39(7):1230–1240. doi:10.2337/dc15-1988.
Hering BJ, et al. Phase 3 trial of human islet-after-kidney transplantation in type 1 diabetes. Diabetes Care. 2016;39(7):1230–1240.

a) Reproductive, developmental, and carcinogenic risk studies: Should these studies be waived for sponsors using conventional allogeneic islet products manufactured by methods frequently reported in the scientific literature for these endpoints, as considered by FDA.

For conventional allogeneic islet transplantation using immunosuppressive medications that are already FDA-approved for use in solid-organ transplantation, additional reproductive, developmental, or carcinogenicity studies should generally not be required solely because the same medications are being used in islet transplantation.

These medications have already undergone the applicable nonclinical reproductive, developmental, and carcinogenic risk assessments as part of their original development and regulatory approval. Their pharmacology, toxicology, dosing, safety profile, and known reproductive and carcinogenic risks are well characterized through their established use in transplantation.

If deceased-donor islet transplantation is regulated within the same organ-transplantation framework as other deceased-donor organ transplantation, the selection and use of an already approved immunosuppressive regimen should be guided by the treating transplant physician, based on the individual patient's characteristics, the islet graft, the anticipated benefits and risks of immunosuppression, and the established prescribing information for the medication.

For a new immunosuppressive medication or a medication being used outside the scope of its existing regulatory characterization, previously conducted reproductive, developmental, and carcinogenicity studies should be leveraged to the greatest extent possible. Additional studies should be considered only when there is a scientifically justified knowledge gap that is specific to the proposed use in islet transplantation.

Requiring repetition of reproductive, developmental, or carcinogenicity studies solely because the transplanted tissue is pancreatic islets, rather than another solid organ, would duplicate substantial existing nonclinical and clinical evidence without necessarily providing additional information relevant to the safety of the transplantation procedure.

Accordingly, the regulatory framework should distinguish between established immunosuppressive medications with extensive transplantation experience and novel agents for which relevant safety information has not yet been established. For established medications, existing regulatory and scientific evidence should generally be considered sufficient, with clinical use determined by the transplant physician according to the patient's individual risk-benefit profile.

b) Novel route-of-administration safety data: Should animal model safety studies for the delivery route be waived where sponsors propose the standard percutaneous transhepatic portal vein delivery route?

Yes. Additional animal-model safety studies specifically evaluating the route of administration should generally be waived when sponsors propose the standard percutaneous transhepatic portal vein delivery route for allogeneic islet transplantation.

Percutaneous transhepatic portal vein infusion is an established clinical route for delivery of pancreatic islets and has been used extensively in human islet transplantation for more than two decades. The procedure, including percutaneous hepatic access, portal venous catheterization, and infusion of the islet preparation into the portal circulation, has been extensively described in the scientific literature and evaluated in clinical practice.

The safety of this route is therefore supported by substantial human clinical experience, including experience reported through the Collaborative Islet Transplant Registry (CITR), the Collaborative Islet Transplant Study (CIT), and numerous published clinical trials and clinical series. Known procedure-related risks, such as bleeding, portal vein thrombosis, hepatic complications, and other procedural adverse events, are well characterized and can be appropriately assessed through established clinical monitoring.

Requiring additional animal studies solely to demonstrate the safety of a standard percutaneous transhepatic portal vein delivery procedure would provide limited additional information when the same route has already been extensively evaluated in humans. Such studies should instead be reserved for novel routes of administration, substantially different delivery devices or procedures, or circumstances in which the proposed approach introduces new or previously uncharacterized risks.

Therefore, when the proposed islet transplantation procedure uses the established percutaneous transhepatic portal vein route without introducing a materially novel delivery approach, additional route-specific animal safety studies should not be required.

5. What impact, if any, could reclassification of deceased donor islet cells as ‘‘organs’’ have on the existing regulatory framework for biological products regulated by FDA? What factors distinguish deceased donor islet cells from other biological products that justifies different regulatory treatment?

Reclassification of deceased-donor pancreatic islets as organs would not undermine the existing FDA regulatory framework for biological products. Rather, it would clarify that deceased-donor islets represent a fundamentally different category of biological material from conventionally manufactured biological products and should therefore be regulated under the established organ-transplantation framework applicable to other human organs obtained from deceased donors.

The fundamental distinction is that human pancreatic islets are naturally occurring, highly organized multicellular endocrine micro-organs obtained directly from a human donor pancreas. They are not conventionally manufactured cellular products.

Several characteristics distinguish deceased-donor islets from biological products manufactured as therapeutic products.

Human islets are multicellular organs, not single-cell products. Each pancreatic islet is a highly organized multicellular structure containing multiple specialized cell types, including insulin-producing β-cells, glucagon-producing α-cells, somatostatin-producing δ-cells, pancreatic-polypeptide-producing cells, endothelial cells, immune and supporting cells, and other cellular components. Their physiological function results from the coordinated interaction of these different cell populations rather than from the activity of an isolated or homogeneous cell population.

Islets are obtained directly from a human donor organ. The islets originate within the donor pancreas and are recovered from the pancreatic tissue by an established isolation process. They are not created de novo through cell culture, differentiation, expansion, genetic engineering, or other manufacturing processes used to generate many modern cellular or biological products.

Islets retain their intrinsic anatomical organization and biological identity. Unlike products consisting of dissociated or substantially modified cells, pancreatic islets retain their characteristic three-dimensional architecture and multicellular organization after isolation. Their biological activity depends on the integrated function of the cells within this structure.

Islets have an organ-like physiological function. The endocrine function of an islet depends on coordinated and regulated secretion of multiple hormones and interactions among its constituent cell types. Following transplantation, the islets respond dynamically to the recipient's metabolic environment and regulate insulin and other hormone secretion in response to changes in blood glucose and other physiological signals.

The biological material is not substantially altered before transplantation. The purpose of the isolation process is to recover the naturally occurring islets from the donor pancreas while preserving their viability, integrity, and function. The process does not ordinarily involve genetic modification, expansion, differentiation, coating, encapsulation, or other substantive alteration of the biological identity of the islets.

The transplanted islets perform the same fundamental biological function they performed in the donor. Following transplantation, the islets retain their endocrine identity and physiological function. They respond to the recipient's metabolic environment and produce insulin and other hormones through the same fundamental biological mechanisms present in the donor.

Islet transplantation involves biological integration with the recipient. Following transplantation, the islets establish a functional relationship with the recipient's circulation. The transplanted tissue receives blood supply from the recipient and undergoes revascularization, allowing oxygen, nutrients, glucose, and other circulating signals to reach the islet cells and permitting their secreted hormones to enter the recipient's circulation.

Preservation is intended to maintain, rather than manufacture, biological function. During procurement, preservation, transportation, and processing, the objective is to maintain the viability, structural integrity, and physiological function of the naturally occurring donor islets until transplantation. The preservation process does not create a new biological product.

These characteristics are fundamentally different from conventional biological products in which cells or biological molecules are manufactured, expanded, differentiated, genetically modified, engineered, formulated, or otherwise substantially manipulated to create a therapeutic product with predefined manufacturing specifications.

There is also an important regulatory consequence of this distinction. The principal risks associated with deceased-donor islet transplantation arise from the same fundamental issues that are addressed in other organ transplantation: donor eligibility, communicable-disease transmission, organ quality, procurement, preservation, ischemia, transportation, surgical delivery, immune rejection, and recipient-specific compatibility and risk. These risks are already addressed through the established deceased-donor organ procurement and transplantation system operated through Organ Procurement Organizations, HRSA, and the OPTN, together with clinical oversight by transplant physicians.

By contrast, applying a biologics-manufacturing framework designed for manufactured cellular products creates requirements based on characteristics that are inherently difficult or biologically inappropriate to standardize for deceased-donor islets, such as strict lot-to-lot uniformity and a single validated potency assay. Individual deceased-donor pancreata naturally differ in cellular composition, islet yield, viability, and functional characteristics, just as kidneys, livers, hearts, and other donor organs differ from donor to donor. Such biological variability does not represent a manufacturing defect; it is an intrinsic characteristic of transplantation using human donor organs.

Reclassification would therefore not eliminate appropriate FDA oversight of biological products. Rather, it would establish a scientifically appropriate boundary between manufactured biological products and naturally occurring human organs or organ-derived tissues intended for transplantation. Novel cellular therapies involving substantial manipulation—such as genetic modification, extensive ex-vivo expansion, differentiation of stem cells,

encapsulation, or other engineering—could remain subject to the appropriate FDA biologics framework.

For conventional deceased-donor pancreatic islets, however, the organ-transplantation framework is better aligned with the biological nature of the material, the established clinical practice, and the actual risks that must be controlled. Reclassification would recognize that the central regulatory objective should be to ensure appropriate donor eligibility, procurement, processing, quality assessment, transplantation, and patient safety without imposing manufacturing requirements designed for fundamentally different types of biological products.

Reference

Abdulreda MH, et al. The pancreatic islet: a micro-organ in control. CellR4 Repair Replace Regen Reprogram. 2021;9. doi:10.32113/cellr4_20213_3093.
United States Food and Drug Administration. Cellular, Tissue, and Gene Therapies Advisory Committee April 15, 2021 meeting announcement. Available at: FDA meeting announcement. Accessed May 20, 2021.
Walker JT, et al. The human islet: mini-organ with mega-impact. Endocr Rev. 2021;42:605–657. doi:10.1210/endrev/bnab010.
Weir GC, et al. Why pancreatic islets should be regarded and regulated like organs. CellR4 Repair Replace Regen Reprogram. 2021;9. doi:10.32113/cellr4_20213_3083.
Witkowski P, et al. 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. Front Endocrinol (Lausanne). 2022;12:789526. doi:10.3389/fendo.2021.789526.
Witkowski P, et al. 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;10(13):2878. doi:10.3390/jcm10132878. PubMed.
Witkowski P, et al. Regulatory updates are needed to prevent commercialization of islet transplantation in the US. Am J Transplant. 2021;21(7):2620–2622. doi:10.1111/ajt.16555.
Witkowski P, et al. Pancreatic islets quality and potency cannot be verified as required for drugs: reflection on the FDA review of a biological license application for human islets. Transplantation. 2021;105(12)–e410. doi:10.1097/TP.0000000000003880. PubMed Central (PMC).
Witkowski P, et al. The demise of islet allotransplantation in the United States: a call for an urgent regulatory update. Am J Transplant. 2021;21(4):1365–1375. doi:10.1111/ajt.16397. OpenAlex.
Witkowski P, et al. Demise of cadaveric islet transplantation in the USA: quo vadis, 1 year after BLA approval and 24 years after the Edmonton breakthrough? Front Transplant. 2025;4:1491568. doi:10.3389/frtra.2025.1491568.

B. Data Sources

6. What types of information and data would be necessary to show that publicly available real-world evidence (RWE) is relevant to deceased donor allogeneic islet transplantation for the noted indication:

a. FDA welcomes data and information on the volume and duration of international clinical trial data.

There is a substantial body of international clinical-trial and real-world clinical experience demonstrating the safety, feasibility, and clinical effectiveness of deceased-donor allogeneic islet transplantation. The most comprehensive source is the Collaborative Islet Transplant Registry (CITR), supplemented by international multicenter clinical trials, national and regional registries, and published long-term follow-up studies.

The CITR was established in 2001 with support from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and has collected standardized information on islet transplantation for more than two decades. CITR data include donor characteristics, pancreas procurement, islet processing and product characteristics, transplantation procedures, immunosuppressive regimens, adverse events, and longitudinal recipient outcomes.

The most recent CITR Allograft Report provides particularly strong evidence of the volume and duration of this experience. From 1999 through 2023, 28 North American and 12 international Eurasian and Australian centers contributed data, representing 1,477 allogeneic human islet-transplant recipients. This included 1,134 islet-transplant-alone recipients and 337 recipients undergoing islet-after-kidney or simultaneous islet-kidney transplantation, as well as six kidney-after-islet recipients.

The experience continues to accumulate. In its September 2025 request for continuation of the CITR program, NIDDK reported that the Registry had pooled data from 47 programs, including 1,517 allograft recipients and 3,557 islet preparations through 2025. CITR has therefore accumulated more than two decades of longitudinal experience with deceased-donor human islet transplantation.

The international Edmonton Protocol trial provides an additional important source of prospective clinical-trial evidence. This NIH-sponsored multicenter trial enrolled 36 patients at nine international centers in North America and Europe and used deceased-donor pancreata for islet transplantation. The participating centers followed a common islet-preparation protocol and standardized criteria for islet enumeration and product release.

Importantly, the duration of the international clinical experience extends well beyond the initial treatment period. Long-term follow-up of participants in the Edmonton Protocol demonstrated sustained islet function for more than a decade in all seven subjects included in that analysis, with follow-up extending to 12 years. No patient experienced severe hypoglycemia, opportunistic infection, or lymphoma during the reported long-term follow-up.

CITR does not capture the entire worldwide experience. A separate international survey of islet-transplant programs identified 94 centers in 25 countries that reported allogeneic islet-transplant activity between 2000 and 2020. These centers performed 4,321 allogeneic islet transplants in 2,149 patients, including 2,608 procedures in Europe and 1,475 in North America. This broader dataset demonstrates that the international clinical experience substantially exceeds the experience captured by CITR alone.

These data sources provide the characteristics necessary to establish the relevance of international RWE to deceased-donor allogeneic islet transplantation:

Large clinical experience: More than 1,500 allogeneic recipients are currently represented in CITR, with thousands of individual islet preparations and transplant procedures documented.

Long duration of experience: Clinical experience extends from the first Edmonton-era transplants in the late 1990s through the present, providing approximately 25 years of follow-up and experience.

International multicenter experience: The data encompass numerous centers across North America, Europe, Australia, and other regions, demonstrating that the clinical experience is not dependent on a single institution or geographic location.

Deceased-donor source material: The relevant datasets specifically include islets isolated from deceased-donor pancreata and therefore directly address the proposed indication.

Standardized clinical and processing data: CITR collects information regarding donor characteristics, pancreas procurement, islet processing and testing, islet product characteristics, transplantation procedures, immunosuppression, adverse events, and clinical outcomes.

Longitudinal safety and efficacy outcomes: Available data include graft function, insulin independence, HbA1c, C-peptide, severe hypoglycemia, adverse events, graft failure, and patient outcomes, allowing assessment of both short- and long-term safety and effectiveness.

Prospective clinical-trial confirmation: The international Edmonton Protocol and Clinical Islet Trial sponsored by NIH provides prospective, multicenter evidence using standardized procedures in addition to the retrospective and prospective registry experience.

Taken together, these data demonstrate that deceased-donor allogeneic islet transplantation is supported by an unusually extensive body of international clinical experience for a relatively specialized transplantation procedure. The duration, geographic breadth, number of recipients and islet preparations, standardized data collection, and availability of long-term follow-up provide a strong foundation for evaluating publicly available RWE as relevant evidence for the safety and effectiveness of conventional deceased-donor allogeneic islet transplantation.

The RWE should therefore be evaluated according to the characteristics of the underlying clinical practice—namely, deceased-donor pancreas procurement, established islet isolation and processing methods, conventional transplantation techniques, and established immunosuppressive regimens—rather than applying evidentiary requirements designed for a newly manufactured biological product with no prior clinical experience.

References

Collaborative Islet Transplant Registry (CITR). 12th Allograft Network Data Report. 2025. CITR. The report includes data from 1999–2023 and 1,477 allogeneic islet-transplant recipients across 40 centers. CIT Registry CITR Network Data Reports and Bibliography.
Shapiro AMJ, et al. International trial of the Edmonton protocol for islet transplantation. N Engl J Med. 2006;355(13):1318–1330. doi:10.1056/NEJMoa061267. This prospective international multicenter trial included 36 recipients at nine centers using deceased-donor pancreata and a common islet-preparation protocol. PubMed.
Brennan DC, et al. Long-Term Follow-Up of the Edmonton Protocol of Islet Transplantation in the United States. Am J Transplant. 2016;16(2):509–517. doi:10.1111/ajt.13458. Reports follow-up of Edmonton Protocol recipients for up to 12 years, with continued islet function beyond a decade in all seven subjects studied. PubMed.
Rickels MR, et al. Collaborative Islet Transplant Registry — successive Allograft Network Data Reports. CITR has published longitudinal reports documenting the expanding international experience with allogeneic islet transplantation. CIT Registry.
Bosi E, et al. A worldwide survey of activities and practices in clinical islet of Langerhans transplantation. Transpl Int. 2022;35:10507. doi:10.3389/ti.2022.10507. The survey identified 94 institutions/networks in 25 countries with allogeneic islet-transplant activity and reported 4,321 allogeneic islet transplants in 2,149 patients between 2000 and 2020. PubMed Central (PMC).
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Continuation of the Collaborative Islet Transplantation Registry (CITR). 2025. This provides the most recent federal description of the registry and its accumulated U.S. and international experience.
Collaborative Islet Transplant Registry (CITR). CITR Bibliography. Contains the published literature generated from the registry and is useful for documenting the breadth and duration of the clinical experience.
Hering BJ, et al. Phase 3 trial of transplantation of human islets in type 1 diabetes complicated by severe hypoglycemia. Diabetes Care. 2016;39(7):1230–1240. doi:10.2337/dc15-1988.
Hering BJ, et al. Phase 3 trial of human islet-after-kidney transplantation in type 1 diabetes. Diabetes Care. 2016;39(7):1230–1240.
Marfil-Garza BA, et al. Pancreatic islet transplantation in type 1 diabetes: 20-year experience from a single-centre cohort in Canada. Lancet Diabetes Endocrinol. 2022;10(7):519–532. doi:10.1016/S2213-8587(22)00114-0.
Lablanche S, et al. Islet transplantation versus insulin therapy in patients with type 1 diabetes with severe hypoglycaemia or poorly controlled glycaemia after kidney transplantation (TRIMECO): a multicentre, randomised controlled trial. Lancet Diabetes Endocrinol. 2018;6(7):527–537. doi:10.1016/S2213-8587(18)30078-0. PMID: 29776895.

b). Established and consistent clinical endpoints. Should FDA continue to apply the same primary endpoint in evaluating RWE that FDA considered in the 2009 Islet Guidance—composite HbA1c 6.5% and elimination of severe hypoglycemia to facilitate direct comparison with endpoint routinely applied in Collaborative Islet Transplant Registry (CITR) and international registries?

If deceased-donor allogeneic islets are appropriately regulated as organs, rather than as FDA-regulated biological products, the FDA endpoint framework described in the 2009 Islet Cell Guidance should not be required as the primary regulatory endpoint.

Instead, clinical outcomes should be established and monitored within the HRSA/OPTN organ-transplantation framework, consistent with the approach used for other transplanted human organs. The relevant OPTN committees, in collaboration with the islet-transplantation community, could establish standardized outcome measures and reporting requirements for accredited islet-transplant programs. This approach would also facilitate direct comparison of islet transplantation with other organ-transplantation procedures with respect to patient and graft safety and effectiveness.

Clinical outcomes should be collected prospectively and longitudinally through the OPTN/UNOS infrastructure and used for verification of the safety and effectiveness of islet transplantation at accredited transplant centers.

Appropriate core outcome measures should include:

a) One-year islet graft survival/function-Islet graft function could be assessed using the Igls classification, an internationally developed and widely used framework for standardized assessment of islet-transplant outcomes. The classification incorporates clinically meaningful measures of glycemic control, insulin requirements, and stimulated C-peptide;

b) One-year patient survival;

c) Primary graft nonfunction- which could be defined using objective measures of graft endocrine function, including serum C-peptide. For example, a serum C-peptide <0.3 ng/mL at one month after transplantation could be used as a criterion for primary nonfunction, subject to final consensus definition and validation by the relevant transplant community;

d) Graft failure and loss of function over time. Longitudinal assessment should capture subsequent loss of graft function, changes in insulin requirements, HbA1c, and C-peptide levels.

e) Procedure- and transplant-related complications- These should include clinically important adverse outcomes such as portal-vein thrombosis, bleeding, infection, and other serious complications associated with islet procurement, processing, transplantation, and immunosuppression.

Patient safety outcomes- These should include severe hypoglycemia, serious infections, malignancy, and other clinically significant complications related to transplantation and immunosuppression.

The composite endpoint of HbA1c ≤6.5% together with elimination of severe hypoglycemia, as used in the 2009 FDA Islet Cell Guidance, remains a clinically meaningful measure and has value for comparison with historical clinical-trial and registry data. However, it should not necessarily be mandated as the sole or primary regulatory endpoint for conventional deceased-donor islet transplantation if the product is reclassified as an organ.

The advantage of the OPTN approach is that it would allow outcomes to evolve as clinical experience increases. Initial certification criteria could focus on objective and clinically meaningful measures such as one-year patient survival, one-year graft survival/function, and primary graft nonfunction. Additional measures could subsequently be incorporated based on accumulated registry data, international experience, and consensus among islet-transplantation experts.

This approach would also provide a mechanism for continuous quality improvement. Similar to other organ-transplant programs, outcomes could be collected at the center level, monitored longitudinally, and used to identify meaningful differences in safety and effectiveness among programs.

Accordingly, the appropriate regulatory endpoint for deceased-donor islet transplantation should be durable patient and graft outcomes, rather than a surrogate endpoint designed for evaluation of a newly manufactured biological product. The existing Igls classification, CITR outcomes, international registry data, and established pancreas-transplantation outcome frameworks provide a strong foundation for developing standardized OPTN outcomes criteria.

c) Well-defined patient population with robust natural history as control: Should FDA apply criteria such as persistent, life-threatening hypoglycemia, poor glycemic control despite intensive insulin management and education, or hypoglycemia unawareness, as enrollment criteria?

Islet transplantation should be regulated under the HRSA/OPTN organ-transplantation framework rather than as an FDA-regulated biological product. Accordingly, patient selection and inclusion criteria should be established within the organ-transplantation system, rather than dictated by FDA criteria developed for clinical trials of a biological product.

The OPTN Pancreas and Islet Transplantation Committee, in collaboration with the clinical islet-transplantation community, could establish standardized indications and eligibility criteria for islet transplantation. At the current stage of clinical experience, these criteria would most likely continue to include patients with persistent, life-threatening severe hypoglycemia; hypoglycemia unawareness; and/or inadequate glycemic control despite optimized intensive insulin therapy, appropriate diabetes education, and use of available diabetes-management technologies.

These criteria appropriately identify patients in whom the risks and burdens of transplantation and lifelong immunosuppression may be justified by the potential clinical benefit. They also provide a well-defined population for assessment of outcomes through prospective OPTN data collection and longitudinal follow-up.

Importantly, eligibility criteria should not be considered static. As clinical experience and scientific evidence evolve—including evidence regarding newer insulin-delivery technologies, stem-cell-derived cell therapies,

immunomodulatory approaches, and long-term outcomes—the OPTN could periodically review and update the indications for islet transplantation. This approach would allow patient selection to evolve with medical knowledge while maintaining consistent, transparent, and evidence-based criteria for transplantation.

d) Should FDA consider a robust external control, consistent with the ‘historical control arm’ design FDA’s 2009 Islet Guidance referred to as sufficient for clinical trials?

As highlighted above, islet transplantation should be regulated under HRSA/OPTN as organ transplantation, rather than under FDA as a biologic or drug product. Therefore, clinical trials evaluating the safety and efficacy of islet transplantation itself should not require an FDA-defined external control or historical control arm.

For the development and licensing of new immunosuppressive medications specifically intended for use in islet transplantation, however, an appropriate controlled study design could be considered by FDA. In that setting, a control arm using currently FDA-approved immunosuppressive medications would provide an appropriate comparator for evaluating the safety and efficacy of the investigational immunosuppressive therapy.

e) Are there additional reasons to support or limit RWE-supported deceased donor islet cell transplantation for the noted indication?

Deceased-donor islet transplantation has been demonstrated to be safe and effective through extensive clinical experience and real-world evidence. It is an established standard-of-care procedure in multiple countries, including Canada, countries in Europe, and Australia, where it is regulated within established organ and tissue transplantation frameworks.

In the United States, deceased-donor islet transplantation has also been performed successfully in clinical trials for patients with type 1 diabetes who have hypoglycemia unawareness and recurrent, life-threatening severe hypoglycemic episodes, with substantial evidence supporting its safety and clinical effectiveness. Importantly, the procedure has been performed in the U.S. for many years without requiring a BLA for the transplantation procedure itself.

Given the extensive international and U.S. clinical experience, the existing body of real-world evidence, and the serious risks faced by patients with severe hypoglycemia and hypoglycemia unawareness, there is strong justification for supporting RWE-based access to deceased-donor islet transplantation. This therapy should be made broadly available to appropriate patients in the United States as soon as possible, within an appropriate organ and tissue transplantation regulatory framework.

7. What real-world data (RWD) sources would be acceptable? Could available registries such as CITR, UK Transplant Registry/National Health Service Blood and Transplant (NHSBT), Edmonton Protocol cohort (University of Alberta), published peer-reviewed literature, or data generated from a sponsor-held U.S. investigational new drug (IND) be considered as data sources? What are the limitations and advantages of each category?

All of the above sources should be considered acceptable and used collectively to evaluate the safety and effectiveness of deceased-donor islet transplantation.

International registries and cohorts, including CITR, the UK Transplant Registry/NHSBT, and the Edmonton Protocol cohort, provide extensive longitudinal clinical experience demonstrating that islet transplantation can be performed safely and effectively within established organ and tissue transplantation regulatory frameworks. Data from countries outside the United States are particularly important because they demonstrate that deceased-donor islet transplantation can be appropriately regulated as transplantation rather than as a drug or biologic product. The primary limitation is that practices, patient selection, immunosuppression protocols, and regulatory requirements may differ among countries and centers.

Published peer-reviewed literature provides an additional large body of evidence from multiple institutions and countries, allowing consistency of outcomes to be evaluated across different settings, protocols, and patient populations. Its limitations include heterogeneity in study design, patient selection, follow-up duration, and reporting standards, as well as the potential for publication bias.

U.S. clinical-trial data, including data generated under sponsor-held INDs, are particularly valuable because they demonstrate the safety and effectiveness of islet transplantation in the U.S. patient population and under U.S. clinical practice conditions. These data provide direct evidence that deceased-donor islet transplantation can be performed safely and effectively in the United States without requiring a BLA for the transplantation procedure itself. The principal limitation is that clinical-trial populations may be relatively small and highly selected compared with the broader population that could benefit from transplantation.

Importantly, these limitations should not be viewed in isolation. The different RWD sources are complementary, and their consistency provides a much stronger evidence base than any individual source alone. The totality of evidence from international transplantation programs, U.S. clinical trials, registries, established cohorts, and peer-reviewed literature is reassuring and supports the safety and effectiveness of deceased-donor islet transplantation.

The unnecessary requirement for a BLA has been a major roadblock to the broader implementation of islet transplantation in the United States. Academic institutions preparing islets for transplantation are not structured to function as pharmaceutical companies, prepare and submit Biologics License Applications (BLAs), or operate pharmaceutical-grade manufacturing facilities. Nevertheless, under the current regulatory framework, they are effectively being asked to assume the legal, regulatory, financial, and operational burdens associated with such activities.

It has substantially restricted access for appropriate patients, limited reimbursement and clinical availability, and contributed to the decline of islet transplantation programs and expertise in the U.S. Despite the extensive evidence supporting the procedure, U.S. patients continue to face barriers to receiving a therapy that is routinely available in other countries under organ and tissue transplantation frameworks. Three years after the FDA granted a BLA to CellTrans, the company has not provided islets for transplantation to patients. As a result, Americans with diabetes continue to face severely limited access to this potentially life-changing therapy, placing the United States at a disadvantage compared with other countries where islet transplantation is more readily available under organ and tissue regulations.

Therefore, the existing RWD should be considered collectively as compelling evidence supporting the regulation and broad clinical availability of deceased-donor islet transplantation under the appropriate organ and tissue transplantation framework in the United States.

8. What are the criteria to determine the RWD fitness? Should criteria such as: data completeness, endpoint consistency, manufacturing comparability, confounding and bias, and generalizability to U.S. patients be included? What are their limitations and advantages?

RWD from countries outside the United States should be critically assessed for data completeness, endpoint consistency, islet processing and manufacturing practices, potential confounding factors and bias, and generalizability to U.S. patients. These criteria are appropriate for evaluating the quality and relevance of the available evidence. However, they should be applied within the framework of organ and tissue transplantation rather than using criteria designed for evaluation of a drug or biologic product.

The appropriate body to evaluate the international evidence and incorporate it into U.S. standards should be the OPTN transplantation community, including the relevant OPTN committees and experts in islet transplantation. This process can be used to establish appropriate patient-selection criteria, islet-processing standards, outcome measures, quality requirements, and reporting requirements for U.S. islet transplant programs.

Data generated from U.S. clinical trials should similarly be evaluated for completeness, consistency, bias, and generalizability. These data have particular value because they reflect U.S.-specific clinical conditions, including the U.S. organ procurement and allocation system, donor organ distribution, islet isolation and transplantation practices, immunosuppression protocols, and patient populations.

The advantages of combining international RWD with U.S. clinical-trial data are that international experience provides a large and mature evidence base, while U.S. data provide confirmation that the procedure is safe and effective within the U.S. transplantation system. Differences in islet-processing methods, patient selection, immunosuppression, and transplantation practices should be recognized as potential limitations, but they can be addressed through appropriate standards and oversight rather than being used as a reason to exclude otherwise highly relevant RWD.

Overall, RWD fitness should be determined by the totality, quality, consistency, and clinical relevance of the evidence, with the evaluation and regulatory standards established through the appropriate organ and tissue transplantation framework.

C. Manufacturing Data

9. How should Product Standards Derivation be addressed? Should FDA, based on RWE review, establish product standards (potency specifications, viability thresholds, etc.), that individual sponsors must demonstrate their product meets?

Islets for transplantation should not be regulated as a drug or biologic product but as an organ or tissue intended for transplantation. Accordingly, there should not be individual “sponsors” responsible for an islet product. Instead, islet transplantation should be performed by OPTN-accredited transplant centers that are responsible for the entire process of deceased-donor pancreas selection, procurement, preservation and transportation, islet isolation and preservation, recipient selection and preparation, transplantation, and post-transplant medical management.

This integrated model is analogous to the current approach to whole-organ transplantation. The transplant center would have responsibility for maintaining appropriate standards at every step of the process and would ultimately be accountable for islet quality, patient safety, and clinical outcomes. Appropriate national standards for islet processing, quality assessment, viability, potency, sterility, and release for transplantation could be established within the organ and tissue transplantation framework and overseen through OPTN and the transplant community.

The current drug-based regulatory framework creates a separation between islet processing and clinical

transplantation that is not well suited to a transplanted organ. The transplant center may have limited control over the manufacturing and release of the islet product, while the clinical outcome depends on multiple interconnected factors, including donor and pancreas quality, procurement and preservation, islet isolation, islet quality, recipient characteristics, immunosuppression, and post-transplant medical management.

In particular, when primary islet nonfunction or early graft failure occurs, it may be difficult under the current framework to determine whether the outcome resulted from the quality of the islet product, donor and procurement factors, the transplantation procedure, or recipient medical management. Separating responsibility for these interconnected components does not facilitate systematic quality improvement.

An organ-transplantation framework would allow the transplant center to control and continuously improve the entire process, from donor selection through transplantation and post-transplant care. Outcomes could then be systematically monitored, and quality standards could be refined based on accumulated clinical experience and RWE.

Therefore, FDA should not establish a drug-style product specification framework requiring individual sponsors to demonstrate that each islet product meets FDA-defined potency or viability specifications. Instead, appropriate standards for islet procurement, processing, quality assessment, and transplantation should be developed within the established organ and tissue transplantation framework, with transplant centers responsible for compliance and for the overall safety and clinical outcomes of their patients.

This approach would provide greater accountability and transparency across the entire transplantation process and would better align regulation with the clinical reality that islets are transplanted cells derived from a donor organ rather than a conventional manufactured drug product.

D. Clinical Data

10. Should manufacturers or health care facilities be required to submit postmarketing data? Should the following be incorporated:

Islets should not be regulated as drugs but as organs or tissues intended for transplantation. Therefore, the concept of “postmarketing” surveillance by manufacturers is not appropriate for deceased-donor islet transplantation.

Under an organ transplantation framework, each OPTN-accredited islet transplant center should be required to prospectively report standardized clinical and outcome data to OPTN, as is done for other organ transplantation procedures. These data should include relevant measures of patient safety, graft function, insulin independence, complications, graft failure, and long-term patient and graft outcomes.

OPTN should use these data to monitor outcomes, establish and continuously improve standards for islet transplantation, identify variation in outcomes among centers, and determine whether centers continue to meet the requirements for accreditation and authorization to perform islet transplantation.

Appropriate aggregate outcomes should also be made publicly available to provide transparency and allow independent evaluation of the safety and effectiveness of islet transplantation. Public reporting would provide an additional mechanism for accountability and quality improvement.

This approach would provide continuous real-world surveillance of islet transplantation while placing responsibility with the transplant centers that control the entire transplantation process, rather than creating a manufacturer-based postmarketing surveillance system designed for drugs or biologic products.

a). Clinical outcome data collection: Manufacturers required to collect and report product-related clinical outcomes from transplant centers (e.g., graft failure, delayed engraftment, infusion reactions, infection transmission)

Islets should not be regulated as drugs but as organs or tissues intended for transplantation. Therefore, manufacturers should not be responsible for collecting and reporting clinical outcomes of deceased-donor islet transplantation.

As described above, clinical outcomes should be systematically collected and reported by each OPTN-accredited islet transplant center to OPTN. Standardized reporting should include graft failure, delayed or inadequate engraftment, infusion-related complications, infection transmission, other significant adverse events, graft function, insulin independence, and long-term patient and graft outcomes.

This approach is preferable because the transplant center is responsible for the entire transplantation process, including donor selection, organ procurement and preservation, islet isolation and processing, recipient selection, transplantation, immunosuppression, and post-transplant care. The OPTN can therefore evaluate outcomes in the context of the entire transplantation process rather than attributing outcomes to an isolated “product.”

The resulting data should be used for ongoing quality assurance, center accreditation, development of transplantation standards, and public reporting of aggregate outcomes, just as is done for other deceased donor organ transplants in the United States.

b). Adverse experience reporting: Mandatory reporting of serious and unexpected adverse experiences of the type currently required by 21 CFR 600.80, including toxicity associated with islet infusion and immunosuppressive regimens.

Islets should not be regulated as drugs but as organs or tissues intended for transplantation. Therefore, drug-specific adverse-event reporting requirements under 21 CFR 600.80 should not be applied to deceased-donor islet transplantation.

Islet transplantation should be performed as a standard-of-care transplantation procedure under the oversight of OPTN. Islet transplant centers should be required to report standardized clinical outcomes and significant adverse events to OPTN for ongoing safety monitoring, verification of outcomes, quality assurance, and maintenance of accreditation. Reporting should include serious complications associated with the transplantation procedure, islet infusion, graft function or failure, infection transmission, and immunosuppressive therapy.

In addition, payers and insurance companies will have access to clinical outcomes through their routine claims and contracting processes. Payer evaluation of outcomes and quality can provide an additional mechanism for accountability and may further incentivize transplant centers to maintain high-quality outcomes.

This multi-level oversight—OPTN regulatory and accreditation requirements, center-level quality monitoring, and payer-based outcome assessment—would provide robust ongoing surveillance without applying a drug-manufacturer adverse-event reporting system to an organ transplantation procedure.

c). Biological product deviation reporting: Required reporting of deviations from CGMP, applicable regulations, or established specifications that may affect safety, purity, or potency of a distributed product, within 45 calendar days of acquiring information reasonably suggesting that a reportable event has occurred, as is currently submitted on Form FDA 3486 as required by 21 CFR 600.14.10

As described above, deceased-donor islets for transplantation should not be regulated by FDA as a biological drug product subject to CGMP requirements or biological product deviation reporting under 21 CFR 600.14.

Instead, the quality and safety of islets should be regulated within the organ and tissue transplantation framework. The OPTN-accredited transplant program performing the islet isolation and transplantation should have primary responsibility for ensuring the quality, safety, and appropriate processing of the islet graft. The transplant center should maintain appropriate records of donor selection, pancreas procurement and preservation, islet isolation and processing, quality assessment, preservation, and transplantation, and should report significant deviations or adverse outcomes through the OPTN oversight and quality-assurance system.

This approach places responsibility with the transplant center that controls the entire process and is directly accountable for the quality of the transplanted islets and the clinical outcome, rather than imposing a drug-manufacturer reporting system that is not appropriate for an organ transplantation procedure.

d). Annual product quality review: Annual review of production and control records to evaluate product quality and determination of the need for changes in specifications or manufacturing controls.

Annual review of islet processing, quality-control measures, and transplantation outcomes should be performed within the OPTN organ transplantation regulatory and quality-assurance framework rather than as an FDA-required annual product quality review.

OPTN-accredited islet transplant centers should maintain appropriate records of islet procurement, processing, quality assessment, transplantation, and patient and graft outcomes. These data should be reviewed regularly to identify opportunities for improvement, ensure compliance with established transplantation standards, and determine whether changes in islet processing or quality-control procedures are warranted.

This approach would allow islet quality to be evaluated together with transplantation outcomes and would support continuous quality improvement while maintaining accountability of the transplant center for the entire islet transplantation process.

e). Postmarketing Registry contribution: Should manufacturers contribute standardized outcome data to CITR or a designated FDA registry supporting ongoing RWE generation for the U.S. patient population.

There is no need to create a new FDA postmarketing registry for deceased-donor islet transplantation. Islet transplantation should be regulated as organ transplantation under the OPTN framework, using the existing infrastructure for collection and monitoring of transplantation outcomes.

OPTN-accredited islet transplant centers should report standardized islet transplantation outcomes at regular intervals through the appropriate transplantation registry and reporting system, including the Scientific Registry of Transplant Recipients (SRTR), as is done for other organ transplantation procedures in the United States.

This established system would provide ongoing, standardized, and independently monitored real-world outcome data for the U.S. patient population, including patient survival, graft function and failure, insulin independence, complications, and other relevant outcomes. It would also allow comparison of outcomes among transplant centers and support continuous quality improvement and maintenance of center accreditation.

Therefore, manufacturer contributions to a separate FDA postmarketing registry should not be required for deceased-donor islet transplantation. The existing OPTN/SRTR transplantation infrastructure provides a more appropriate and comprehensive mechanism for ongoing generation and oversight of U.S. real-world evidence.

11.. List additional data sources to address clinical risks associated with deceased donor islet cell transplantation. Risks include but are not limited to bleeding, blood clots, allograft rejection, immunosuppression related risks, graft function loss, and long-term burden of lifelong immunosuppression on patients who receive these transplants.

The available data from the Collaborative Islet Transplant Registry (CITR), together with data from U.S. and international clinical trials and the extensive peer-reviewed literature, provide a comprehensive assessment of the clinical risks and benefits of deceased-donor islet transplantation.

These sources collectively provide substantial information regarding procedural complications, bleeding and thrombotic events, allograft rejection and graft loss, immunosuppression-related complications, loss of graft function, and the long-term risks associated with immunosuppressive therapy. Longitudinal data from established islet transplantation cohorts are particularly valuable for assessing outcomes and risks that may not be fully captured in shorter clinical trials.

Additional U.S. real-world outcome data collected through the OPTN and SRTR transplantation infrastructure, once islet transplantation is incorporated into the organ transplantation framework, would further strengthen ongoing safety monitoring in the U.S. patient population.

Taken together, these existing data sources provide a sufficiently comprehensive evidence base to characterize the risks and benefits of deceased-donor islet transplantation without requiring creation of a separate FDA-specific data collection system.

12.. What information on product quality and manufacturing is needed to allow HHS to evaluate available effectiveness data regarding donor islet therapies? For example, some RWE is generated under international regulatory frameworks that treat unmodified deceased donor islets as tissue/organ products rather than biological products. Clinical outcomes data (efficacy and safety endpoints) from these international cohorts could be relevant and informative. However, manufacturing quality data from these cohorts may not be directly translatable to current standards for biological products because they were generated under tissue/organ frameworks rather than CGMP-equivalent manufacturing oversight. What standards and supporting data would explicitly distinguish between the use of international RWE for clinical outcomes support (high fitness) versus manufacturing quality support (limited fitness; must be supplemented by the sponsor’s own CGMP data)?

This question highlights an important distinction between the regulatory classification of islets and the actual clinical evidence regarding their safety and effectiveness. Data from CITR and the extensive peer-reviewed literature demonstrate that deceased-donor islet transplantation performed in countries where islets are regulated as organs or tissues has produced clinical outcomes comparable to those reported by U.S. centers, despite differences in the regulatory framework.

Importantly, islet processing at established transplant centers is based on standardized principles and practices, including appropriate donor selection, pancreas procurement and preservation, islet isolation, purification, culture and preservation, and processing in controlled and appropriately monitored clean-room environments. The available clinical experience does not demonstrate that imposing pharmaceutical manufacturing requirements produces superior clinical outcomes compared with the established transplantation-based approach.

International RWE should therefore be considered highly relevant and highly fit for evaluating the clinical effectiveness and safety of deceased-donor islet transplantation. Differences in national regulatory frameworks should not, by themselves, diminish the value of clinical outcome data when the underlying transplantation procedure and islet-processing principles are comparable.

For purposes of manufacturing quality, international data should be evaluated based on the actual processing methods, quality-control procedures, environmental controls, sterility assurance, donor selection, and product-release criteria used by the contributing centers. Where these practices are comparable to the standards proposed for U.S. transplantation, the international experience should be considered directly informative rather than automatically classified as having limited fitness simply because it was not generated under pharmaceutical CGMP requirements.

Most importantly, deceased-donor islet transplantation does not involve the manufacture of a conventional biological drug. The pancreas is a donated human organ, and the islets are isolated, prepared, and preserved for transplantation. There is no expansion or pharmaceutical manufacturing of the cells. Appropriate controlled and monitored processing conditions, including suitable clean-room/GTP practices and validated quality-control procedures, can provide the necessary safeguards for safe transplantation.

Therefore, requiring pharmaceutical CGMP manufacturing standards and a BLA framework for deceased-donor islets is not supported by evidence that these additional requirements improve clinical outcomes. Rather than imposing drug-manufacturing requirements designed for manufactured biological products, HHS should establish appropriate, risk-based standards for islet procurement, processing, quality assessment, preservation, and transplantation within the organ and tissue transplantation framework.

International RWE should consequently be used as a major component of the evidence supporting both the clinical safety and effectiveness of deceased-donor islet transplantation and the development of appropriate U.S. transplantation standards. Any additional U.S.-specific quality requirements should be evidence-based and proportionate to the actual risks of islet transplantation, rather than automatically derived from pharmaceutical manufacturing regulations.

13.. What is the current data regarding long-term graft durability beyond 5 years, and how does it weigh against the risk of long-term immunosuppression use?

Long-term systematic data beyond 5 years remain more limited than short- and intermediate-term data. Nevertheless, available longitudinal experience demonstrates that islet grafts can provide durable insulin independence and protection from severe, life-threatening hypoglycemia for many years. There are individual patients with more than 10 years, and even 20 years, of continued insulin independence following islet transplantation, demonstrating the potential for very long-term graft function and clinical benefit.

An important advantage of islet transplantation compared with whole-pancreas transplantation is that the procedure is minimally invasive and can be safely repeated when graft function declines. Experience from the Edmonton program and other centers has demonstrated that patients who lose function of an initial graft can undergo subsequent islet transplantation, including third, fourth, or even fifth islet infusions in selected patients. Repeat transplantation can therefore extend insulin independence and continued protection from severe hypoglycemia without the surgical risks associated with repeat whole-organ pancreas transplantation.

The durability of clinical benefit should therefore not be assessed solely by the survival of an individual islet graft. A patient may receive substantial long-term benefit through sequential islet transplantation, with relatively low procedural risk compared with repeat whole-organ transplantation.

The major limitation to long-term outcomes is the need for chronic immunosuppression. Current tacrolimus-based regimens can have significant nephrotoxicity and other adverse effects and may contribute to declining graft function and patient adherence over time. In addition, long-term patient compliance with complex immunosuppressive regimens can affect durability of the clinical benefit.

Importantly, the field is rapidly developing less toxic immunosuppressive approaches, including calcineurin-inhibitor-free and co-stimulation blockade-based regimens. These approaches have the potential to reduce medication-related toxicity, improve long-term adherence, and ultimately improve graft durability and patient outcomes.

Therefore, although additional long-term prospective data are needed, the existing experience demonstrates substantial potential for durable benefit. The risks of chronic immunosuppression should be weighed against the serious and potentially life-threatening consequences of severe hypoglycemia in appropriately selected patients, as well as against the availability of repeat islet transplantation and increasingly less toxic immunosuppressive strategies.

14.. Please discuss the comparability of international RWE. How generalizable are the experiences of international cohorts to the U.S. T1D population? Are there differences in disease management practices, HbA1c targets, hypoglycemia thresholds and other factors that could significantly impact the interpretability and applicability of international RWE to the US T1D population?

In general, international RWE from established islet transplantation programs is highly applicable and generalizable to the U.S. type 1 diabetes population. The underlying disease, indications for transplantation, clinical objectives, and fundamental transplantation procedures are comparable across countries. Clinical protocols generally use similar inclusion and exclusion criteria, immunosuppressive medications, and approaches to islet isolation and transplantation. Islet isolation techniques are also well established and standardized across experienced centers.

There may be differences among countries in diabetes management practices, HbA1c targets, definitions or thresholds for severe hypoglycemia, continuous glucose-monitoring practices, patient selection, and access to advanced diabetes therapies. These differences should be considered when interpreting individual studies and can be addressed through appropriate subgroup analyses and adjustment for relevant clinical factors. However, such differences do not negate the substantial value or generalizability of the international RWE, particularly when consistent outcomes are observed across multiple countries and cohorts.

In fact, the U.S. transplantation system has several characteristics that could allow outcomes to be at least as good as, and potentially better than, those reported by international programs. The United States has a large donor pool, an established national organ procurement and allocation infrastructure, and highly developed organ preservation and transportation systems. These factors can facilitate more efficient donor pancreas allocation and transportation to experienced islet isolation centers.

The U.S. also has a mature organ transplantation regulatory and quality-assurance framework through OPTN, which can provide systematic monitoring of center performance, standardized outcome reporting, accreditation, and continuous quality improvement.

Moving deceased-donor islet transplantation from the current drug-based regulatory framework to an appropriate organ and tissue transplantation framework would facilitate broader implementation and appropriate reimbursement. Increased availability of transplantation at qualified centers, combined with standardized outcome reporting and OPTN oversight, would promote quality improvement and allow centers to learn from one another while maintaining accountability for patient outcomes.

Therefore, differences between international and U.S. clinical practice should be recognized and appropriately considered, but they should not be used to discount the extensive international RWE supporting the safety and effectiveness of deceased-donor islet transplantation. The existing international experience provides a strong foundation for implementation in the United States, while the U.S. transplantation infrastructure has the potential to further optimize the procedure and accelerate continued progress in the field.

IV.B Questions for Consideration Regarding HHS Oversight Framework

The OPTN framework, overseen by HRSA, is built on creating policy and equity for allocating scarce, life-saving resources to the many patients in dire medical need for a new organ. HRSA’s existing authorizing statute 12 and regulations 13 define the organs that the OPTN is responsible for, including the pancreas. Reclassifying deceased donor islet cells as ‘‘organs’’ would be a departure for this established oversight framework.

We respectfully suggest that the premise that reclassifying deceased-donor islets as organs would represent a departure from the established organ transplantation framework is based, in part, on a misconception arising from the terminology commonly used to describe the procedure.

The term “islet cell transplantation” may suggest that a suspension of individual cells is being transplanted. In reality, deceased-donor islet transplantation involves the transplantation of intact pancreatic islets, which are naturally occurring, highly organized multicellular endocrine micro-organs. Each islet contains multiple specialized cell populations organized into a complex three-dimensional structure with an intrinsic vascular network and coordinated endocrine function. The islet therefore functions as an integrated physiological unit rather than as a collection of isolated individual cells.

The fact that pancreatic islets are isolated from the donor pancreas before transplantation does not change their biological nature. The process is analogous to preparing an anatomical component of a donated organ for transplantation rather than manufacturing a new biological product. Islets are derived directly from a deceased-donor pancreas, undergo isolation and preservation, and are subsequently transplanted into a recipient to restore physiological endocrine function.

Accordingly, including deceased-donor islets within the established organ and tissue transplantation oversight framework would be consistent with their biological origin, anatomical organization, and clinical use. It would also allow islet transplantation to benefit from the existing OPTN infrastructure for donor allocation, transplant-center accreditation, quality assurance, outcome reporting, and continuous improvement.

We therefore respectfully submit that inclusion of deceased-donor islets within the established organ transplantation framework should not be viewed as an unprecedented departure from the current system. Rather, it would correct a regulatory mismatch that has persisted in part because of the terminology used to describe islet transplantation and would bring the regulatory framework into better alignment with the biological and clinical reality of the procedure.

In this context, extending the existing organ transplantation framework to deceased-donor pancreatic islets is not only appropriate but long overdue.

1. Existing shared oversight. The current framework divides responsibilities between FDA oversight of manufacturing and biological product regulation and HRSA’s oversight of the OPTN and its policies governing organ donation, procurement, and transplantation. Are there modifications to the existing shared oversight framework that could improve patient access to unmodified deceased donor islet cells and cell products without an alteration of FDA’s and HRSA’s current regulatory responsibilities? If so, please describe.

Yes. We believe that the current classification of unmodified deceased-donor pancreatic islets as FDA-regulated biological products is fundamentally mismatched to the biological nature and their clinical use. Deceased-donor islets are not manufactured as a conventional biological drug; they are naturally occurring; anatomically organized endocrine micro-organs derived from a donated human pancreas. They should therefore be regulated within the established organ and tissue transplantation framework.

The application of pharmaceutical CGMP requirements to islet isolation has created substantial barriers to the ability of academic and transplant centers to perform islet transplantation. Academic transplant programs are organized and equipped to procure, process, preserve, and transplant donated organs under transplantation quality and safety standards; they are not structured to operate as pharmaceutical manufacturers. Appropriate controlled processing under CGTP or comparable transplantation standards would provide a more appropriate framework for preparation of deceased-donor islets for transplantation.

The current FDA regulatory framework has also created a separation between islet processing and transplantation that does not exist for other donated organs. Under the organ transplantation model, the transplant center is responsible for the entire chain of care—from donor selection and pancreas procurement through preservation, transportation, processing, recipient selection and preparation, transplantation, and post-transplant medical management. This integrated responsibility allows the center to identify and address factors affecting graft quality and clinical outcomes.

Importantly, the experience with Lantidra illustrates the limitations of applying a conventional biological-product framework to deceased-donor islets. The product-release characteristics used under the current framework do not necessarily provide a reliable measure of the ultimate clinical quality or effectiveness of an individual islet preparation. Similarly, sterility of a human islet preparation cannot necessarily be established in the same manner as sterility of a conventional manufactured pharmaceutical product. These limitations raise the concern that a BLA designation may create an appearance of product assurance without necessarily providing a corresponding ability to predict clinical outcomes.

Organ transplantation has long operated under a different and appropriate concept of quality assurance. The quality of a donated organ cannot be completely established by laboratory testing before transplantation. Instead, safety and effectiveness are supported through a comprehensive system that includes donor screening, procurement standards, preservation and transportation requirements, transplant-center infrastructure, personnel training and experience, standardized clinical practices, and rigorous monitoring of patient and graft outcomes. Continued reporting of outcomes is an essential component of center accreditation and quality improvement.

The same principles can appropriately be applied to deceased-donor islets. Because islets are naturally occurring components of a donor organ and their ultimate quality cannot be completely established through pre-transplant laboratory release testing, the transplant center should have responsibility for the entire process and for the clinical outcome.

We therefore recommend maintaining FDA and HRSA responsibilities but modifying the regulatory pathway for unmodified deceased-donor islets so that their preparation and transplantation are governed primarily within the organ and tissue transplantation framework. FDA could continue to provide appropriate standards for sterile processing and environmental controls, using a risk-based framework such as CGTP or comparable requirements developed in coordination with HRSA and OPTN. OPTN would oversee transplant-center accreditation, personnel qualifications, processing standards, outcome reporting, and continuous quality improvement.

Such a framework would preserve appropriate federal oversight while eliminating the unnecessary application of pharmaceutical manufacturing requirements to a naturally occurring human organ. It would also place responsibility for islet quality where it can be most effectively exercised—the experienced transplant center that controls the entire process from donor organ selection through transplantation and long-term patient follow-up.

This approach would improve access to deceased-donor islet transplantation while maintaining rigorous standards for patient safety, quality control, accountability, and clinical outcomes.

2. Evidence of access barriers.

Stakeholders have expressed concern that the current regulatory structure, with most pancreatic islet cell transplants conducted under an IND, may have unintentionally limited the ability of providers to regularly or consistently perform islet cell therapies or infusions. Please provide RWD or documented delays in providing this care as clinically indicated for patients who would benefit from this therapy. Please provide quantitative data or documented evidence demonstrating that FDA regulatory requirements, rather than manufacturing capacity, reimbursement, clinical infrastructure, donor availability, or other factors, are the primary cause of limited patient access.

The history of islet transplantation in the United States provides strong evidence that the current FDA regulatory framework has been a major, and in our view fundamental, barrier to sustained clinical access. Importantly, the regulatory barrier has interacted with reimbursement and research-funding limitations rather than operating independently of them.

More than 20 years ago, NIH-sponsored Phase 1, 2, and 3 clinical trials provided substantial support to multiple U.S. centers to establish and perform islet transplantation. These programs demonstrated that islet transplantation could be performed successfully in the United States and generated substantial clinical evidence supporting its safety and effectiveness.

However, following completion of these federally supported trials, the absence of an approved BLA for deceased-donor islets created a major barrier to transitioning islet transplantation from a research procedure to routine clinical care. In the U.S. healthcare system, the lack of a conventional FDA-approved biological product created substantial uncertainty regarding insurance coverage and reimbursement. Without sustainable reimbursement, transplant centers could not maintain the personnel, facilities, islet-processing infrastructure, and clinical programs necessary to provide transplantation routinely. As research funding was exhausted, many U.S. programs discontinued or substantially reduced their islet transplantation activity.

This regulatory and reimbursement barrier is particularly apparent when the U.S. experience is compared with other countries. In Edmonton, Canada, more than 700 islet transplantation procedures have been performed under the provincial healthcare system, and additional Canadian centers, including programs in Toronto, Montreal, and Vancouver, have developed significant islet transplantation activity. The United Kingdom and France have established national islet transplantation programs alongside pancreas transplantation, while islet transplantation is also supported within national healthcare systems in Switzerland, Scandinavia, and the Netherlands.

The difference is therefore not explained by the absence of a suitable clinical procedure, lack of donor pancreata, or inability to isolate and transplant islets. The procedure has been performed successfully for many years in multiple healthcare systems. Rather, the U.S. regulatory and reimbursement structure has prevented the procedure from transitioning from federally supported research into sustainable routine clinical transplantation.

The current demand from U.S. patients further demonstrates the magnitude of the access problem. Following the highly encouraging results of the University of Chicago clinical trial evaluating Tegoprubart in 12 patients with type 1 diabetes, interest from patients seeking islet transplantation increased dramatically. More than 3,000 patients expressed interest in only three additional available trial positions. This level of demand illustrates the substantial unmet need among patients with severe type 1 diabetes and life-threatening hypoglycemia who are unable to access transplantation through routine clinical care.

At present, intraportal deceased-donor islet transplantation within clinical trials is available at only a very limited number of U.S. centers, including the University of Chicago and City of Hope. Consequently, the vast majority of U.S. patients who could potentially benefit from this therapy have no practical access to it. Estimates suggest that tens of thousands of patients with type 1 diabetes may have severe hypoglycemia and other clinical characteristics that could make them candidates for islet transplantation, while only a very small fraction can currently receive the procedure.

The interaction between regulation and reimbursement is critical. The requirement to treat deceased-donor islets as an FDA-regulated biological product has prevented routine transplantation outside an IND/BLA framework. This, in turn, has made reimbursement difficult, discouraged development and maintenance of transplant-center infrastructure, and limited the number of centers willing and able to offer the procedure. Thus, although reimbursement and infrastructure are proximate causes of limited access, the underlying regulatory classification contributes directly to both barriers.

Moving deceased-donor islet transplantation into the established organ transplantation framework would remove the requirement for a BLA for the transplantation procedure itself. Islet transplantation could then be performed by appropriately qualified OPTN-accredited transplant centers as a transplantation service, with outcomes reported through the established transplantation oversight system. This would create a pathway for appropriate reimbursement, allow centers to rebuild and maintain the necessary clinical infrastructure, and permit expansion of access to patients with the greatest medical need.

The international experience demonstrates that when islet transplantation is treated as an established transplantation procedure within a healthcare system, it can be sustained and expanded. The U.S. experience demonstrates the opposite: when the procedure remains dependent on research funding and an FDA drug-development pathway, clinical programs have difficulty achieving sustainable access.

Therefore, while manufacturing capacity, reimbursement, clinical infrastructure, and donor availability all influence access, the current FDA regulatory classification and resulting BLA requirement have been a central structural barrier to transitioning deceased-donor islet transplantation into routine clinical care in the United States. Removing this barrier and incorporating islet transplantation into the established organ transplantation framework would address the underlying regulatory problem and allow reimbursement, infrastructure, and clinical capacity to develop in response to the substantial unmet patient need.

3. Alternative approaches. Please provide publicly available examples of alternative approaches to regulating deceased donor islet cells for transplant (e.g., legal oversight frameworks implemented by other regulatory authorities).

There are numerous publicly available examples demonstrating that deceased-donor human pancreatic islets can be regulated and transplanted within organ and tissue transplantation frameworks rather than as conventional biological medicinal products. Such approaches have been implemented in Canada, the United Kingdom, France, the Netherlands, Poland, Italy, Sweden, Norway, Switzerland, Hungary, Australia, and Japan, among other countries.

In these systems, deceased-donor pancreatic islets are treated as a component derived from a donated human organ and are subject to transplantation-specific requirements governing donor selection, organ procurement, preservation and transport, islet isolation and processing, recipient selection, transplantation, clinical follow-up, and outcome reporting. This approach recognizes that the transplanted islets remain donor-derived human tissue and that their clinical quality and effectiveness depend on the entire transplantation process rather than on pharmaceutical-style manufacturing and product-release criteria alone.

Importantly, the European regulatory framework provides an additional example. European authorities have determined that unmodified cadaveric pancreatic islets prepared for transplantation are not considered advanced or substantially manipulated cellular products when the processing does not alter their relevant biological characteristics. Consequently, such islets do not automatically fall under the regulatory pathway applicable to conventional medicinal products/biologics. This reflects the principle that isolation and preparation of pancreatic islets for transplantation, when their essential biological characteristics are preserved, should not by itself transform a donor-derived transplant material into a manufactured medicinal product.

Health Canada explicitly states that minimally manipulated islet cells intended for homologous use are regulated under the Safety of Human Cells, Tissues and Organs for Transplantation Regulations (CTO Regulations), even though islets have a systemic metabolic function. The guidance specifically describes pancreatic digestion and purification of islets as processing within this transplantation framework.

These international approaches provide a strong precedent for a U.S. framework in which deceased-donor pancreatic islets are regulated as organs/tissues for transplantation under HRSA/OPTN oversight, with appropriate standards for donor screening, procurement, processing, quality control, transplantation, and longitudinal outcome monitoring. The existence of established transplantation systems in multiple countries also demonstrates that pharmaceutical-style BLA and CGMP requirements are not the only viable means of ensuring the safety and quality of deceased-donor islet transplantation.

Reference

Health Canada. Guidance on the Safety of Human Cells, Tissues and Organs for Transplantation Regulations: Classification of CTOs. Government of Canada; revised August 4, 2026.
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European Medicines Agency. Committee for Advanced Therapies (CAT). Reflection paper on classification of advanced therapy medicinal products. EMA/CAT/600280/2010 Rev.1. 21 May 2015.
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Lablanche S, Borot S, Wojtusciszyn A, et al. Islet transplantation versus insulin therapy in patients with type 1 diabetes with severe hypoglycaemia or poorly controlled glycaemia after kidney transplantation (TRIMECO): a multicentre, randomised controlled trial. Lancet Diabetes Endocrinol. 2018;6(7):527–537. doi:10.1016/S2213-8587(18)30104-8.

4. Implementation. What operational changes may be necessary to implement reclassification of deceased donor islet cell products as organs under the OPTN framework? Please identify any policy changes that would be required and discuss any implementation challenges..

Implementation could be accomplished largely by building on the existing OPTN pancreas transplantation infrastructure rather than creating a new regulatory system. The OPTN Pancreas and Islet Transplantation Committee already has experience developing policies and standards related to deceased-donor pancreas allocation and certification of islet transplantation programs.

The same committee could expand its existing responsibilities to establish and oversee standards specific to deceased-donor islet transplantation, including: a) Certification and accreditation of islet transplant programs, including appropriate institutional infrastructure, personnel, training, and experience; b) Standards for pancreas procurement, preservation, transport, and allocation for islet transplantation; c) Standards for islet isolation and processing, including appropriate controlled/sterile processing environments, quality control, documentation, and release criteria; d) Recipient selection and transplantation requirements, including appropriate clinical indications and contraindications; e) Standardized reporting of clinical outcomes, including islet graft function, insulin independence, severe hypoglycemia, complications, graft failure, and long-term outcomes; f) Performance-based accreditation and quality assurance, using prospectively collected outcomes to evaluate individual transplant programs and identify opportunities for quality improvement; and g) Periodic review and updating of standards as clinical experience, processing technology, and transplantation outcomes evolve.

The necessary policy changes would therefore primarily involve formally recognizing deceased-donor islet transplantation within the OPTN organ-transplantation framework and expanding the existing pancreas/islet policies to encompass the full pathway from donor pancreas allocation through islet processing, transplantation, and longitudinal outcome reporting. Coordination among HRSA, OPTN, transplant centers, organ procurement organizations, and relevant regulatory agencies would be important during the transition.

The principal implementation challenge would be establishing appropriate national standards for islet processing and quality assurance while avoiding the inappropriate application of pharmaceutical manufacturing requirements designed for manufactured biological products. These standards should be risk-based and transplantation-specific, with appropriate sterile processing, quality control, documentation, and accountability.

Importantly, this approach would place responsibility for the entire process within the transplant system. The transplant center would remain accountable for donor and pancreas selection, processing, transplantation, immunosuppression, and follow-up, while OPTN would provide standardized oversight, accreditation, outcome reporting, and performance monitoring.

We therefore believe that reclassification would be operationally feasible and could be implemented by expanding and adapting an existing national transplantation infrastructure, rather than establishing a new regulatory pathway from the ground up.

5. Precedential effects. If deceased donor islet cells were classified as organs for purposes of Federal oversight, what precedent could this establish for other donor-derived cellular products or future cell-based therapies? What factors should HHS consider in determining whether pancreatic islet cells are distinguishable from processed donor-derived cellular products?

Classification of deceased-donor, unmodified pancreatic islets as organs or tissues for transplantation should not establish a precedent requiring other donor-derived cellular products or future cell-based therapies to be regulated under the same framework. Indeed, this approach has already been implemented in multiple countries, including European countries, without resulting in automatic classification of other donor-derived cellular products as organs or tissues.

Reclassification of pancreatic islets would therefore not represent a broad exemption for cellular products. Rather, it would recognize that deceased-donor pancreatic islets have distinct biological and clinical characteristics and that their appropriate regulatory classification can be determined under existing principles governing human cells, tissues, and organs.

Under the existing PHS Act framework, donor-derived cellular products that are substantially manipulated or otherwise meet the criteria for regulation as biological products can appropriately remain subject to FDA oversight. The relevant distinction should be the nature and extent of manipulation and whether the essential biological characteristics and intended function of the donor-derived material are altered.

Deceased-donor pancreatic islets are fundamentally different from manufactured or engineered cellular products. During conventional islet isolation, enzymatic digestion is used primarily to dissociate the exocrine/acinar tissue surrounding the pancreatic islets and release the intact pancreatic islets. The islets themselves are not expanded, genetically modified, differentiated, engineered, or otherwise substantially altered. Short-term culture, including incubation for preservation for up to approximately 72 hours, is intended to maintain the viability and function of these naturally occurring pancreatic micro-organs rather than to manufacture a new cellular product.

Importantly, during this process the islets do not proliferate or undergo intentional changes in their phenotype, genotype, or fundamental biological function. The resulting transplant material remains the same donor-derived pancreatic islet tissue that was present in the donated pancreas. The processing therefore facilitates recovery and preservation of an anatomical and functional component of the donated organ rather than creating a substantially manipulated cellular product.

These characteristics provide a clear basis for distinguishing cadaveric pancreatic islets from other donor-derived cellular therapies involving substantial manipulation, expansion, genetic modification, differentiation, combination with synthetic materials, or other processes that materially alter the cells or their biological characteristics.

European regulatory authorities have already recognized this distinction in determining that appropriately prepared, unmodified cadaveric pancreatic islets do not constitute more-than-minimally manipulated cellular material when their relevant characteristics are not substantially changed during processing. Applying the same principle in the United States would therefore represent regulatory harmonization rather than creation of a new categorical precedent.

HHS should consider, at minimum: a) The biological origin of the product—whether it is a naturally occurring component of a donated human organ; b) The extent of manipulation during processing; c) Whether the essential biological characteristics, phenotype, genotype, and function are maintained; d) Whether the cells are expanded, genetically modified, differentiated, engineered, or otherwise intentionally altered; e) The intended clinical use—particularly whether the material is transplanted to replace the function of the corresponding tissue or organ from which it was derived; and f) Whether the transplantation process can be appropriately governed through an established organ/tissue transplantation framework, including donor screening, processing standards, transplant-center certification, and longitudinal outcome monitoring.

Applying these criteria would clearly distinguish conventional deceased-donor islet transplantation from substantially manipulated or engineered donor-derived cellular therapies. Recognition of pancreatic islets as organs/tissues for transplantation would therefore provide a specific, scientifically and legally grounded classification for pancreatic islets without establishing automatic precedent for other cellular products.

6. Suitability of the OPTN framework.

The OPTN framework was established primarily to oversee allocation of vascularized organs and transplant programs. What aspects of that framework are well suited—or not well suited—for oversight of processed cellular therapy products such as deceased donor islet cell products? Please identify any additional policies, expertise, or infrastructure that would be necessary.

We respectfully suggest that deceased-donor pancreatic islets should not be classified as a conventional “processed cellular therapy product.” Human pancreatic islets are naturally occurring, intact, multicellular endocrine micro-organs derived directly from a donated pancreas. Their isolation and preparation for transplantation does not create a new cellular product; rather, it makes a functional component of the donated organ available for transplantation.

Accordingly, the existing OPTN framework is well suited to oversee deceased-donor islet transplantation. OPTN already provides oversight of deceased-donor pancreas allocation and transplantation programs—the same clinical infrastructure within which deceased-donor islet transplantation should occur and remain regulated. The existing principles of donor selection, organ allocation, transplant-center certification, clinical expertise, recipient selection, outcome reporting, and performance-based quality oversight are directly applicable to islet transplantation.

Additional OPTN policies could be developed specifically for pancreas procurement and islet isolation/processing, including requirements for:

a) appropriate donor and pancreas selection;

b) validated and standardized islet isolation and processing procedures;

c) controlled and sterile processing environments;

d) appropriate personnel qualifications and training;

e) documentation and traceability throughout procurement, processing, preservation, and transplantation;

f) standardized quality-control measures for islet preparations, including assessment of viability, purity, quantity, and functional characteristics as appropriate;

g) defined criteria for suitability of an islet preparation for transplantation; and

h) prospective reporting of transplantation outcomes and processing-related complications.

These policies could incorporate appropriate principles and safeguards from existing Good Tissue Practice (GTP), current good manufacturing practice (CGMP), and other established sterile-processing and quality-control standards, where scientifically appropriate. Importantly, however, such standards should be adapted to the biological and clinical characteristics of donor-derived islets rather than applying pharmaceutical manufacturing requirements designed for manufactured biologic products.

The OPTN framework also has an important advantage over a product-centered regulatory model: the transplant center can remain accountable for the entire clinical pathway—from donor and pancreas selection through procurement, preservation, islet isolation and processing, transplantation, immunosuppression, and long-term follow-up. This integrated accountability allows processing quality to be evaluated together with actual clinical outcomes.

We therefore do not believe that a separate OPTN regulatory framework for “cellular therapy products” is necessary. Rather, deceased-donor islet transplantation should be incorporated into the existing pancreas and islet transplantation framework, with additional islet-specific policies, technical expertise, processing standards, and outcome-reporting requirements developed as needed.

The principal infrastructure already exists through OPTN, transplant centers, organ procurement organizations, and transplant outcome-reporting systems. Implementation would primarily require development of detailed, nationally standardized policies for islet isolation and processing and appropriate expertise within the existing Pancreas and Islet Transplantation Committee. This approach would provide appropriate safeguards while preserving the fundamental distinction between transplantation of donor-derived pancreatic micro-organs and manufacture of cellular therapy products.

7. Manufacturing and product quality oversight. FDA currently oversees manufacturing processes, quality systems, product release testing, potency, sterility, and other controls applicable to biological products. If regulatory oversight were transferred to HRSA, via its oversight of the OPTN, how should the full range of oversight functions across the products’ life cycle be executed? Are there aspects of the current FDA framework that should continue at FDA, versus moving to HRSA via its oversight of the OPTN, regardless of the regulatory classification?

If deceased-donor pancreatic islets are appropriately classified as organs/tissues for transplantation, oversight should focus on the quality and safety of the entire transplantation process, rather than applying the manufacturing and product-release framework used for conventional biological products.

We see two potential approaches for oversight of islet isolation and processing.

First, FDA could retain a limited role in establishing or overseeing appropriate processing standards, while recognizing that these standards should be based on Good Tissue Practice (GTP) or comparable transplantation-specific standards rather than CGMP requirements applicable to manufactured biologics. FDA could establish general requirements for controlled and sterile processing environments and appropriate quality systems, while allowing certified transplant centers to determine the technical details of their validated isolation procedures. The centers would be responsible for demonstrating and documenting appropriate processing conditions and the quality of the resulting islet preparation.

Alternatively, FDA could establish more specific minimum safeguards for islet-processing facilities, drawing selectively from existing CGMP principles where scientifically appropriate—for example, requirements for appropriately controlled clean-room or clean processing environments, environmental monitoring, contamination control, equipment qualification, personnel training, documentation, and quality-control procedures. These requirements should be proportionate to the actual risks of donor-derived islet transplantation and should not require transplant centers to operate as pharmaceutical manufacturing facilities.

In either approach, appropriate release assessment could include measures such as islet quantity, viability, purity, morphology, and other clinically relevant quality characteristics, with documentation of the processing history and suitability of the preparation for transplantation. Importantly, these measurements should be understood as quality-control tools rather than pharmaceutical-style potency assays intended to establish that a manufactured product will predictably produce a particular clinical outcome.

Second, equivalent oversight could be incorporated directly into the OPTN framework. OPTN, with appropriate technical expertise and informed by FDA recommendations and existing GTP/CGMP principles, could establish national standards for islet isolation and processing and incorporate them into certification requirements for islet transplant programs. OPTN could then oversee compliance through program certification, periodic review, documentation requirements, and performance-based outcome monitoring.

Regardless of which approach is selected, the transplant center should remain responsible for the complete chain of custody and clinical process—from donor and pancreas selection through procurement, preservation, isolation, processing, transplantation, and long-term follow-up. OPTN oversight could integrate processing quality with actual clinical outcomes, allowing standards to evolve based on real-world transplant experience.

We therefore believe that FDA expertise in sterile processing, contamination control, and quality systems could remain valuable, but a full FDA biologic-product regulatory framework, including BLA requirements and pharmaceutical CGMP manufacturing requirements, is not necessary for deceased-donor islet transplantation. The appropriate balance would preserve FDA or FDA-informed expertise where it adds value while placing primary oversight of the transplantation process, program certification, and clinical outcomes within the HRSA/OPTN organ-transplantation framework.

8. Patient safety. What patient safety risks should HHS consider when evaluating whether post-marketing products should remain within the FDA biological product regulatory framework or be wholly incorporated into the OPTN framework? Please address issues including communicable disease transmission, manufacturing variability, sterility, product potency, traceability, and post-market surveillance.

Patient safety should be fully incorporated into the HRSA/OPTN transplantation framework, consistent with the approach used for other deceased-donor organ transplantation. The relevant safety risks can be effectively addressed through donor screening, procurement and processing standards, transplant-center certification, traceability, quality control, and prospective clinical outcome monitoring.

Communicable disease transmission. OPTN and the existing organ-transplantation system already have established mechanisms for donor evaluation, communicable disease screening, donor testing, organ allocation, documentation, and traceability. These mechanisms can be applied directly to deceased-donor islet transplantation. Additional islet-specific requirements can be incorporated into OPTN policies where appropriate.

Processing variability. Islet isolation should not be considered conventional pharmaceutical manufacturing. Nevertheless, standardized processing requirements should be established for certified islet-processing laboratories, including validated procedures, qualified personnel, appropriate equipment, environmental controls, documentation, and quality-control testing. Processing variability can then be monitored together with clinical outcomes and addressed through center certification and performance-based quality improvement.

Sterility and contamination. Islet isolation and processing should occur under appropriately controlled and aseptic conditions in a dedicated clean-room or comparable controlled laboratory environment. Appropriate environmental monitoring and contamination-control procedures can be based on established GTP principles and, where appropriate, relevant elements of CGMP clean-room standards. Testing such as Gram stain and endotoxin assessment could be incorporated into release criteria or used to guide clinical decision-making, as appropriate, recognizing that some microbiological testing may not be available before transplantation and that clinical management must account for the timing of transplantation.

Islet quality and potency. Islet quality should be assessed using clinically relevant measures, including islet quantity, viability, purity, and morphology, with appropriate documentation before transplantation. Additional functional assessments may be incorporated as the field develops. However, the clinical effectiveness of an islet preparation cannot be determined solely by an in-vitro potency assay. As with organ transplantation, the ultimate assessment of graft quality and function is based on clinical outcomes following transplantation.

Traceability. Complete traceability should be maintained from donor identification and pancreas procurement through transportation, islet isolation and processing, preservation, transplantation, and recipient follow-up. OPTN infrastructure can provide the framework for standardized documentation and longitudinal tracking, with transplant centers maintaining detailed processing records.

Post-transplant surveillance. Rather than relying on a pharmaceutical-style post-marketing surveillance system, islet transplantation should use the established OPTN approach of prospective reporting of clinical outcomes. This should include graft function, insulin independence, severe hypoglycemia, graft failure, complications, infection transmission, and other clinically significant outcomes. Aggregate outcomes can be used for program certification, performance assessment, quality improvement, and development of future standards.

Importantly, islet quality and the quality of the entire transplantation process should ultimately be evaluated in conjunction with clinical outcomes, as is already done for vascularized organ transplantation under the OPTN framework. This integrated approach recognizes that outcomes depend not only on the characteristics of the isolated islets, but also on donor factors, pancreas procurement and preservation, isolation and processing, recipient characteristics, transplantation technique, immunosuppression, and post-transplant management.

Accordingly, we believe that the major patient-safety risks identified by HHS can be addressed through an appropriately designed OPTN/HRSA framework with islet-specific processing and quality standards, without requiring deceased-donor islets to remain regulated as conventional FDA biological products.

9. Provider implications. If deceased donor islet cell products were reclassified as ‘‘organs’’, would OPTN membership need to expand to include new types of providers (e.g., endocrinologists) to perform these treatments? Or would the existing pool of providers at OPTN member institutions perform these treatments if islet cells are classified as ‘‘organs’’?

a. What are the potential provider implications?

Deceased-donor islet transplantation should be performed within OPTN-accredited organ transplantation centers, particularly centers already accredited and experienced in pancreas transplantation. These centers are appropriately structured, staffed, and equipped to provide the complex medical care required for patients undergoing transplantation and subsequent chronic immunosuppression.

There is therefore no need to create a separate category of OPTN providers or substantially expand OPTN membership solely because pancreatic islets are classified as organs. The existing multidisciplinary transplant infrastructure is well suited to provide this therapy.

Endocrinologists are already an integral part of the multidisciplinary care of organ-transplant recipients and would remain essential members of the islet transplantation team, particularly for diabetes management, assessment of graft endocrine function, and post-transplant metabolic care.

Interventional radiology is also an important component of an islet transplantation program because intraportal islet infusion requires specialized image-guided access and because interventional radiologists may be needed to manage potential vascular or procedural complications. Interventional radiologists are already part of the multidisciplinary infrastructure at many transplant centers and provide important services to solid-organ transplant recipients.

The remaining members of the multidisciplinary transplant team—including transplant surgeons, transplant physicians/nephrologists, infectious disease specialists experienced in immunocompromised patients, pharmacists, social workers, dietitians, nurses, and other transplant professionals—are already integral to accredited transplantation programs and are essential for the safe management of patients receiving deceased-donor islets and chronic immunosuppression.

Accordingly, we do not anticipate a need to create a substantially different provider structure. Rather, existing OPTN-accredited pancreas transplantation programs can provide the appropriate clinical infrastructure, with islet-specific training and experience incorporated into program certification requirements as necessary.

This approach would also provide an important patient-safety advantage: patients receiving deceased-donor islets would be treated within established transplant programs with immediate access to the multidisciplinary expertise, emergency services, immunosuppression management, infectious disease care, interventional radiology, and surgical support required for transplantation.

In summary, reclassification of deceased-donor islets as organs would primarily require islet-specific competency and program requirements within existing pancreas transplantation programs, rather than expansion of OPTN membership to create a new category of providers.

b. What are the potential system costs and implications for each approach?

We anticipate that reclassification of deceased-donor islet transplantation within the organ-transplantation framework would facilitate insurance reimbursement and broader clinical access, given the substantial clinical evidence supporting the safety and effectiveness of islet transplantation in appropriately selected patients with type 1 diabetes and severe hypoglycemia.

The cost of an islet transplantation episode is expected to be broadly comparable to, and potentially lower than, the cost of whole-pancreas transplantation. Islet transplantation is minimally invasive, generally requires only a short hospital stay, and has a relatively low risk of major surgical complications. In contrast, whole-pancreas transplantation is a major abdominal operation associated with longer hospitalization, intensive care in some patients, risks of surgical complications, reoperation, and readmission.

These savings would be partially offset by the costs associated with establishing and maintaining specialized islet isolation and processing facilities, including dedicated laboratory infrastructure, qualified personnel, quality-control systems, and ongoing facility maintenance. Nevertheless, these costs should be considered in the context of the overall cost of transplantation and the potential reduction in surgical morbidity and hospitalization associated with islet transplantation.

Although we estimate that more than 40,000 patients in the United States may have clinical characteristics that could potentially make them candidates for islet transplantation, not all would ultimately be eligible. Patient comorbidities, ability to undergo chronic immunosuppression, psychosocial considerations, and other clinical factors would substantially limit the population appropriate for transplantation.

We therefore anticipate that, following reclassification and establishment of reimbursement, the initial volume would likely be in the range of several hundred procedures annually, rather than the entire potentially eligible population. As programs become established, some of these procedures would likely be performed in patients who otherwise might be considered for whole-pancreas transplantation.

Consequently, increased access to islet transplantation would not necessarily result in a proportional increase in overall healthcare expenditures. A portion of the cost of islet processing and transplantation would be offset by lower procedural morbidity, shorter hospitalization, fewer major surgical complications, and potentially reduced need for reoperation and readmission. In addition, replacing some whole-pancreas transplants with minimally invasive islet transplantation could provide a more efficient use of healthcare resources while offering an effective treatment for appropriately selected patients.

The principal near-term system costs would therefore be the re-establishment of islet-processing infrastructure, development of appropriately certified programs, training of personnel, and creation of sustainable reimbursement mechanisms. These investments should be viewed in the context of the potential long-term clinical and economic benefits of making an established transplantation therapy available to patients who currently have very limited treatment options.

Reference

Moassesfar S, Masharani U, Frassetto LA, Szot GL, Tavakol M, Stock PG, Posselt AM. A comparative analysis of the safety, efficacy, and cost of islet versus pancreas transplantation in nonuremic patients with type 1 diabetes. Am J Transplant. 2016;16(2):518–526. doi:10.1111/ajt.13536.
Guignard AP, Oberholzer J, Benhamou PY, et al. Cost analysis of human islet transplantation for the treatment of type 1 diabetes in the Swiss-French Consortium GRAGIL. Diabetes Care. 2004;27(4):895–900. doi:10.2337/diacare.27.4.895.

10. Patient access. If deceased donor islet cell products were reclassified as organs, what effect could that have on:

a). the number and geographic distribution of treatment centers;

Reclassification of deceased-donor pancreatic islets as organs/tissues would allow islet transplantation to be implemented relatively quickly within existing OPTN-accredited pancreas transplantation centers. Most of the necessary clinical infrastructure—including transplant surgeons and physicians, immunosuppression management, inpatient and outpatient transplant services, interventional radiology, infectious disease expertise, and multidisciplinary transplant support—is already available at these centers.

The principal limitation to rapid expansion would be the specialized infrastructure and expertise required for islet isolation and processing. Islet processing is a technically demanding procedure requiring an appropriately designed and controlled clean-room laboratory, specialized equipment, trained personnel, validated processing procedures, and sufficient experience to consistently produce high-quality islet preparations.

Based on the experience of U.S. multicenter islet transplantation clinical trials approximately 20 years ago, we anticipate that reclassification could initially result in approximately 8–10 active academic centers capable of performing both islet processing and transplantation. These centers would ideally be geographically distributed across the East Coast, West Coast, and central regions of the United States, providing access to major population centers while allowing sufficient procedure volume and expertise to maintain program quality.

As clinical demand increases, reimbursement becomes established, and additional transplant centers develop the necessary processing infrastructure and expertise, the number of certified centers could expand. OPTN program certification and performance-based outcome monitoring would provide an appropriate mechanism for ensuring that expansion occurs while maintaining adequate clinical and processing standards.

Thus, reclassification would not require creation of an entirely new network of treatment centers. Rather, it would allow the United States to reactivate and expand an infrastructure that previously existed through multicenter islet transplantation programs, using existing pancreas transplantation centers as the foundation for broader geographic access.

b). patient travel requirements;

Initially, patients who live outside the geographic areas served by certified islet transplantation centers would need to travel to an established islet transplantation center for the transplantation procedure and the early post-transplant period. This is appropriate given the specialized nature of islet isolation and transplantation and is similar to the current practice for patients requiring complex or highly specialized organ transplantation.

We anticipate that patients would remain closely followed by the islet transplantation center during the first year, when monitoring of graft function, immunosuppression, complications, and other transplant-related issues is most intensive. Once the patient is clinically stable, routine follow-up could increasingly be transitioned to a qualified local transplant center, with continued communication and coordination with the islet transplantation center.

This model would minimize the long-term travel burden while maintaining access to the specialized expertise required during the most critical period after transplantation. As the number of certified islet transplantation centers increases and geographic distribution improves, the need for long-distance travel should decrease further.

This approach is already consistent with the model used for other complex organ-transplant recipients, in which patients may initially receive care at a specialized transplant center and subsequently receive portions of their ongoing care closer to home in coordination with the transplant program.

c). provider participation;

Existing multidisciplinary transplant teams are well positioned to provide deceased-donor islet transplantation without major changes to their current clinical structure. The same transplant infrastructure, expertise, and multidisciplinary medical support used for whole-organ transplantation can be applied to islet transplantation.

Islet transplant recipients require many of the same services as other organ-transplant recipients, including transplant surgery, transplant medicine, endocrinology, immunosuppression management, infectious disease expertise, pharmacy, nursing, nutrition, psychosocial support, and interventional radiology.

The immunosuppressive medications and monitoring strategies used for whole-organ transplantation can also be utilized for islet transplantation, with regimen selection tailored to the individual patient and the specific islet transplantation protocol. Patients require the same careful monitoring for immunosuppression-related complications, infection, graft function, and other medical issues associated with transplantation.

Therefore, reclassification would not require creation of a new provider workforce or major restructuring of existing transplant programs. The principal additional requirement would be islet-specific training and experience in islet isolation, processing, transplantation, and assessment of graft function for centers seeking certification to perform the procedure.

d). waiting times;

At the University of Chicago, the current waiting time for an islet transplantation procedure is approximately 1–3 months. This relatively short waiting time reflects the highly limited number of islet transplantation procedures currently being performed in the United States, primarily because of limitations in research funding and the lack of sustainable reimbursement rather than an absence of clinical demand.

Following reclassification and broader insurance reimbursement, we anticipate that the number of patients seeking islet transplantation would increase substantially. At the same time, additional transplant centers would become capable of performing the procedure. Because islet transplantation relies on different deceased-donor pancreas pool as whole-pancreas transplantation, expansion of the number of centers would by itself increase the number of available donor pancreata (whole-pancreas transplantation favors donors with BMI<32, whole donors with BMI>32 are preferred for islet transplantation).

Consequently, as the field transitions from a highly restricted research-based model to routine clinical transplantation, waiting times would likely increase substantially from the current 1–3 months. If demand becomes comparable to that for other pancreas transplantation services, waiting times could potentially reach approximately 6 months-2 years, similar to the current time frame experienced by some patients awaiting whole-pancreas transplantation.

Actual waiting times would depend on several factors, including the number of certified centers, geographic distribution, allocation policies, donor availability, patient eligibility, and the development of appropriate allocation criteria for islet transplantation. An OPTN framework would provide the appropriate mechanism to monitor these factors and develop allocation policies that promote equitable access to available donor pancreata.

e). patient costs;

Reclassification of deceased-donor islet transplantation under the HRSA/OPTN organ-transplantation framework should substantially improve patients’ access to insurance coverage and reduce the financial burden associated with islet transplantation. At present, the lack of a sustainable reimbursement pathway can leave patients dependent on research funding, charitable support, or other exceptional arrangements to access a potentially life-changing treatment.

Islet transplantation is also substantially less invasive than whole-pancreas transplantation. Patients generally require a shorter hospitalization, have a faster recovery, and can return to normal activities and employment much sooner. These advantages can reduce not only direct medical expenses, but also indirect costs related to prolonged hospitalization, time away from work, caregiving, travel, and lost income.

Initially, patients may need to travel to one of a limited number of specialized islet-transplantation centers, which could create additional out-of-pocket costs. As additional OPTN-accredited centers develop islet-processing and transplantation capabilities, geographic access should improve and travel-related expenses should decrease.

Importantly, once islet transplantation is recognized and reimbursed as an organ-transplantation service, patients should be able to receive coverage under the same general insurance mechanisms used for other transplant procedures, subject to appropriate medical-necessity and eligibility criteria. This would replace the current highly restrictive, research-dependent model with a sustainable pathway to treatment and substantially reduce financial barriers for patients with severe, otherwise difficult-to-control diabetes.

f). insurance coverage

Given that islet transplantation at experienced centers can achieve safety and effectiveness comparable to whole-pancreas transplantation, while being substantially less invasive and associated with shorter hospitalization, faster recovery, and earlier return to work, it should represent an attractive and potentially more cost-efficient treatment option for both patients and insurers.

Reclassification of deceased-donor islet transplantation under the HRSA/OPTN organ-transplantation framework would remove the BLA requirement, which has been a critical structural barrier to routine insurance coverage and clinical access to islet transplantation in the United States. The absence of a sustainable reimbursement pathway following earlier U.S. clinical trials has contributed substantially to the decline of the U.S. islet-transplantation field.

Establishing islet transplantation as an organ-transplantation service, with appropriate OPTN standards, center certification, outcomes reporting, and payer reimbursement, would provide a sustainable pathway for coverage. Given the less invasive nature of islet transplantation and its potential to reduce hospitalization, postoperative morbidity, recovery time, and time away from employment compared with whole-pancreas transplantation, broader insurance coverage could also be economically favorable for the healthcare system.

g). donor willingness to participate in organ donation?

We believe that demonstrating that donated pancreata can directly help patients with severe diabetes achieve insulin independence and a substantially improved quality of life could further reinforce the altruistic purpose of organ donation and potentially strengthen public willingness to participate in organ donation. Families may find additional meaning in knowing that the pancreas of a deceased loved one can be used not only for whole-organ transplantation but also to provide life-changing treatment to patients with otherwise difficult-to-control diabetes.

Conversely, public perception may be negatively affected if donated pancreata are viewed primarily as a source of material for a private company with exclusive rights to manufacture and commercialize an islet product. Organ donation is fundamentally based on altruism and public trust. It is therefore important that the use of donated organs for islet transplantation remain transparent and clearly connected to the purpose of transplantation and patient benefit.

A regulatory framework that treats deceased-donor islets as an organ-derived transplant rather than as a commercially manufactured biological product would help preserve this distinction and reinforce the principle that donated organs are being used primarily to provide transplantation and life-saving or life-changing care to patients.

11. Operational and financial impact on OPTN. The OPTN is funded primarily through organ transplant patient registration fees. What operational, administrative, or financial impacts would reclassification have on the OPTN, its member organizations, and patients waiting for an organ transplant? Please comment on potential effects on policy development, Board of Directors and committee workload, information technology systems, membership requirements, patient registration processes, and overall program costs.

The operational impact on the OPTN should be relatively limited because the existing OPTN Pancreas and Islet Transplantation Committee is already fully operational and has experience developing and overseeing policies related to pancreas and islet transplantation. Reclassification would therefore primarily require expansion and refinement of the existing framework rather than creation of a new regulatory structure.

There would likely be a temporary increase in workload for the OPTN Board of Directors, the Pancreas and Islet Transplantation Committee, and relevant OPTN staff during the initial implementation period. This would include development of updated policies and standards for islet transplantation, program certification, patient registration, islet processing and quality requirements, data collection, outcome reporting, and allocation. Additional work may also be required to modify information technology systems and reporting infrastructure to accommodate islet-specific transplantation data.

These changes should be viewed as a one-time or transitional implementation effort, rather than a permanent major expansion of the OPTN's administrative burden. Much of the necessary infrastructure—including transplant-center membership, committee structure, pancreas allocation systems, patient registration, and outcome reporting—is already in place and can be adapted for islet transplantation.

In the longer term, reclassification would result in a substantial increase in the number of patients formally registered and followed within the OPTN system for islet transplantation. The associated registration and transplant-related fees would provide an additional source of funding to support the incremental administrative, information-technology, data-management, and oversight requirements. Thus, while some additional resources may be needed during implementation, the expanded islet-transplantation activity should provide a sustainable mechanism to support the corresponding OPTN workload.

For patients currently waiting for other organs, we would not anticipate a meaningful adverse effect. Islet transplantation uses pancreata that may otherwise be unsuitable or unavailable for whole-pancreas transplantation, and islet candidates would enter an islet-specific allocation and transplantation pathway rather than compete directly for organs allocated to patients awaiting other solid-organ transplants. The principal effect would therefore be an expansion of transplantation services and utilization of donated pancreatic tissue, rather than diversion of resources from patients waiting for other organs.

Overall, we anticipate modest short-term operational and implementation costs, followed by a sustainable long-term integration of islet transplantation into the existing OPTN infrastructure. Because the necessary expertise, committee structure, and much of the administrative infrastructure already exist, the incremental impact should be considerably smaller than creating a separate national regulatory system for islet transplantation.

Reference (all alphabetically)

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