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

Abstract

The Food and Drug Administration (FDA) has been regulating human islets for allotransplantation as a biologic drug in the US. Consequently, the requirement of a biological license application (BLA) approval before clinical use of islet transplantation as a standard of care procedure has stalled the development of the field for the last 20 years. Herein, we provide our commentary to the multiple FDA’s position papers and guidance for industry arguing that BLA requirement has been inappropriately applied to allogeneic islets, which was delivered to the FDA Cellular, Tissue and Gene Therapies Advisory Committee on 15 April 2021. We provided evidence that BLA requirement and drug related regulations are inadequate in reassuring islet product quality and potency as well as patient safety and clinical outcomes. As leaders in the field of transplantation and endocrinology under the “Islets for US Collaborative” designation, we examined the current regulatory status of islet transplantation in the US and identified several anticipated negative consequences of the BLA approval. In our commentary we also offer an alternative pathway for islet transplantation under the regulatory framework for organ transplantation, which would address deficiencies of in current system.

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“…As leaders in the field of islet transplantation, we repeatedly requested the regulatory updates and re-evaluation of the need for BLA from the FDA and HHS. A working group of over 40 leaders and experts in the field as Islets for US Collaborative (www.isletsforus.org) performed a detailed analysis and published several articles to provide scientific evidence and promote the need for regulatory updates for allogeneic islets to the regulatory authorities in the US (1,2,4,5). However, the FDA maintains its rigid position regarding BLA requirements for allogeneic islets.…”

“…1) Islets are human micro-organs and should thus be regulated along with other human organs, which are not regulated by the FDA, and for which a BLA is not required (5)(6)(7)(8). Islets are comprise of many different types of cells with well-integrated functions, have their own internal vascular and neural network Islets maintain their own morphology and structure during processing and in the recipient after the transplantation.…”

“…However, such quality assessments are ineffective, thus inappropriate for human organs used for organ transplantation ( 4 , 5 ). Human organs including islets are not created in a laboratory or factory, but rather naturally developed in the human body with wide variability of characteristics, especially when retrieved from a deceased donor.…”

“…Thus, human organs and islets require a different quality reassurance system than the FDA applies to drugs/biologics. Such regulatory framework has been developed and optimized over decades under HRSA, an agency of the Department of Health and Human Services (HHS); and successfully implemented by the Organ Procurement and Transplantation Network (OPTN) and the United Network for Organ Sharing (UNOS) ( 5 ) ( Figure 1B ).…”

“…A recent FDA’s analysis of data submitted by the sponsor to support the BLA, uncovered in our opinion, major deficiencies in current regulations of human islets of deeply concern regarding patient safety and efficacy ( 4 , 5 ). In contrast to other approved biologics and cell therapies, and despite application of drug manufacturing principles, technology, and regulations, the sterility and potency of islets cannot be verified prior to clinical use.…”