Islets 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

Clinical islet allotransplantation has been successfully regulated as tissue/organ for transplantation in number of countries and is recognized as a safe and efficacious therapy for selected patients with type 1 diabetes mellitus. However, in the United States, the FDA considers pancreatic islets as a biologic drug, and islet transplantation has not yet shifted from the experimental to the clinical arena for last 20 years. In order to transplant islets, the FDA requires a valid Biological License Application (BLA) in place. The BLA process is costly and lengthy. However, despite the application of drug manufacturing technology and regulations, the final islet product sterility and potency cannot be confirmed, even when islets meet all the predetermined release criteria. Therefore, further regulation of islets as drugs is obsolete and will continue to hinder clinical application of islet transplantation in the US. The Organ Procurement and Transplantation Network together with the United Network for Organ Sharing have developed separately from the FDA and BLA regulatory framework for human organs under the Human Resources & Services Administration to assure safety and efficacy of transplantation. Based on similar biologic characteristics of islets and human organs, we propose inclusion of islets into the existing regulatory framework for organs for transplantation, along with continued FDA oversight for islet processing, as it is for other cell/tissue products exempt from BLA. This approach would reassure islet quality, efficacy and access for Americans with diabetes to this effective procedure.

BEPU Analysis in LBLOCA Safety Review Calculation

Deterministic safety analysis (DSA) is essential for nuclear power plant licensing. The conservative method followed CFR50 Appendix K, which will lead to a large margin. As one of the DSA methodologies, best estimate plus uncertainty (BEPU) generates more realistic results that can be used in the license application of nuclear power plants (NPPs). However, uncertainty evaluation of parameters is needed in BEPU. In this article, the safety regulatory focuses on the large break loss of coolant accident (LBLOCA) of an advanced PWR. The BEPU analysis is mainly performed by TRACE V5.0 patch 4 code, and the uncertainty analysis is conducted based on DAKOTA code. For correlation coefficients analysis, the sample size is enlarged reasonably. According to the results, this NPP meets the acceptance criteria effectively in LBLOCA with enough margin. By statistic assessment, the set of PCTs calculated has typical normal distribution characters. Based on BEPU, the uncertainties of parameters are studied. Additionally, the influence of sample size on the correlation of parameters is considered too. It could be seen that more samples could permit a more accurate estimation for Spearman partial correlation coefficient (abbreviated as SPCC). The conclusions of this article can provide technical support for the subsequent review of the safety analysis report and the design changes of NPPs.

Comparison of regulatory approval process for vaccines development and manufacturing in India & USA

The Vaccine Development is a complex and time-consuming process because of stringent quality assessment procedures. The vaccine is approved for release into the market, a stringent regulatory procedure to assess quality, efficacy and safety must be maintained. The regulation of vaccine in India with the licensing and GMP is controlled by the drug controller general of India (DCGI). The USA regulation was controlled by the USFDA in center biologics evaluation and research committee (CBER) and Biologics license application (BLA). These Authorities are responsible for vaccine regulations in India & USA. The current review articles highlight the comparison of registration process of vaccines in INDIA and USA.

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

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.

Inebilizumab-cdon: USFDA approval for the treatment of NMOSD (neuromyelitis optica spectrum disorder)

: Inebilizumab-cdon (Uplizna™) was currently approved by the United States Food and Drug Administration (USFDA) for the treatment of NMOSD (neuromyelitis optica spectrum disorder). It was developed by Viela Bio (Nasdaq: VIE) USA. Inebilizumab-cdon (formerly MEDI-551) is a humanized antibody, which induces CD19 + B cell depletion by increasing antibody-dependent cell cytotoxicity (ADCC) and cell phagocytosis (ADCP) of effector cells. Various clinical trials exhibit its safe and effective pharmacokinetic and pharmacodynamic profile. In June 2019, Viela Bio submitted Biologics License Application (BLA) to the FDA based on the findings obtained from the N-Momentum trial. This article summarizes the milestones in the development of Inebilizumab-cdon leading to approval for the treatment of advanced NMOSD.

Regulatory Prototype for Biological Products in the United States

Biological products are used for the treatment of many disease, so the biological application submitted for the approval of products are also increasing. The progress of a biosimilarproduct is more difficult and expensive than a small molecule generic product. Biosimilars are not true generic drugs, but demonstrate a high degree of similarity to the reference biological product. In order to improve access to costly biological treatments, a biosimilar pathway in the US was established under the Biologics Price Competition and Innovation Act of 2009. The study highlighted the “Regulatory prospective for the registration of Biological products in US” and a brief description about the development, Manufacturing and approval process of biosimilar products. This article is also focused on the regulatory framework, Biological License Application, Purple book, and Pharmacovigilance of biological products.

A Comparative Study for License Application Regulations on Proprietary Chinese Medicines in Hong Kong and Canada

Ethnopharmacological Relevance: Chinese Medicine plays a symbolic role among traditional medicines. As Chinese Medicine products are widely used around the globe, regulations for Chinese Medicine products are often used as models for the efficient regulation of natural products that are safe, and high-quality.Aim of the Study: We aimed to compare the regulatory registration requirements for Proprietary Chinese Medicines in Hong Kong and Canada.Materials and Methods: We compared registration requirements for Proprietary Chinese Medicine in Hong Kong and Canada based on publicly available information provided by the respective Regulators. A marketed product, Zhizhu Kuanzhong Capsule (SFDA approval number Z20020003; NPN approval number 80104354), was used as a case study to demonstrate the similarities and differences of the requirements in both Hong Kong and Canada.Results: There were similarities and differences between the two regulatory systems in terms of the quality, safety and efficacy requirements. Despite the superficial appearance of similar categories and groups/classes, Hong Kong requires significantly more primary test data compared to Canada's reliance on attestation to manufacturing according the standards outlined in approved reference pharmacopeias/texts.Conclusion: Improved understand of the similarity and differences will enable applicants to plan appropriate strategies for gaining product approval. Exploring ways to harmonize the regulatory process has the potential to benefit manufacturers, regulators, and patients by increasing efficiency and decreasing costs.

Research On Optimization Method of Fatigue Analysis for Nuclear Pipeline

The initial design life of nuclear power plant is 40 years. In 60 year life extending license application, the fatigue of component should be evaluated under the influence of the fatigue factors of the pressurized water reactor coolant environment. Because the original design used a more conservative analysis method, the result could not meet the requirement of Cumulative usage fatigue factor of RCC-M. An optimizing analysis method is studied, and as an example of application, optimizing fatigue analysis of Safety Injection Nozzle of Main Coolant Line is performed. The evaluation results show that the optimized fatigue analysis results meet the requirements of RCC-M.