Impact of genetically modified organism requirements on gene therapy development in the EU, Japan, and the US.

Advanced therapies are emerging as an important class of medicinal products; among these, gene therapies are advancing at an exceptional rate. However, one of the major challenges for gene therapies relates to the additional regulatory requirements for genetically modified organisms. In this paper, we provide an overview of the regulatory requirements for genetically modified organisms in the European Union, Japan, and the United States. We share our experience in managing these requirements and their impact on the adeno-associated virus gene therapies that are under development at Pfizer. Specifically, we discuss the relative complexity of the approval process and the impact of risk assessment expectations on the clinical development of genetically modified organisms. We also compare the regulatory processes and timelines of various regions based on our experience with adeno-associated viral vectors. Finally, we propose that genetically modified organisms, for which pathogenicity and replication competency are well controlled, should be regulated solely under medicinal product regulations and be exempt from additional requirements for genetically modified organisms. Even if an exemption is not implemented, it should still be possible to significantly reduce the sponsor and agency burden by simplifying and harmonizing documentation and data requirements as well as timelines for applications for genetically modified organisms.

Global regulatory progress in delivering on the promise of gene therapies for unmet medical needs.

The rapid expansion of the gene therapy pipeline in recent years offers significant potential to treat diseases with great unmet medical need. However, the unique nature of these therapies poses challenges to regulating them within traditional frameworks, even when developing in a single country. Various factors exacerbate the issues in commercializing products across regions, including the lack of established regulatory frameworks for developing gene therapy products in many jurisdictions. While some countries have established separate regulatory frameworks for advanced therapies/regenerative medicine products, differences exist between them. Recommended solutions to overcome these hurdles include fostering convergence among countries with separate regulatory frameworks for these products and utilizing reliance and recognition for countries without such frameworks. Additionally, regulators who choose to establish new dedicated frameworks for regulating gene therapies should consider the inclusion of key elements such as expedited regulatory pathways that offer early engagement with regulators, innovative clinical trial design, and adequate post-market confirmatory studies. Increasing the alignment of regulatory pathways across countries will be crucial to facilitating the development of, and access to, gene therapies on a global scale.

Global Manufacturing of CAR T Cell Therapy.

Immunotherapy using chimeric antigen receptor-modified T cells has demonstrated high response rates in patients with B cell malignancies, and chimeric antigen receptor T cell therapy is now being investigated in several hematologic and solid tumor types. Chimeric antigen receptor T cells are generated by removing T cells from a patient's blood and engineering the cells to express the chimeric antigen receptor, which reprograms the T cells to target tumor cells. As chimeric antigen receptor T cell therapy moves into later-phase clinical trials and becomes an option for more patients, compliance of the chimeric antigen receptor T cell manufacturing process with global regulatory requirements becomes a topic for extensive discussion. Additionally, the challenges of taking a chimeric antigen receptor T cell manufacturing process from a single institution to a large-scale multi-site manufacturing center must be addressed. We have anticipated such concerns in our experience with the CD19 chimeric antigen receptor T cell therapy CTL019. In this review, we discuss steps involved in the cell processing of the technology, including the use of an optimal vector for consistent cell processing, along with addressing the challenges of expanding chimeric antigen receptor T cell therapy to a global patient population.

MSC-based product characterization for clinical trials: an FDA perspective.

Proposals submitted to the FDA for MSC-based products are undergoing a rapid expansion that is characterized by increased variability in donor and tissue sources, manufacturing processes, proposed functional mechanisms, and characterization methods. Here we discuss the diversity in MSC-based clinical trial product proposals and highlight potential challenges for clinical translation.

Regulation of xenogeneic porcine pancreatic islets.

The use of xenogeneic porcine pancreatic islets has been shown to be a potentially promising alternative to using human allogeneic islets to treat insulin-dependent type 1 diabetes (T1D). This article provides an overview of the existing FDA regulatory framework that would be applied to the regulation of clinical trials utilizing xenogeneic porcine pancreatic islets to treat T1D.

Considerations for tissue-engineered and regenerative medicine product development prior to clinical trials in the United States.

Tissue-engineered and regenerative medicine products are promising innovative therapies that can address unmet clinical needs. These products are often combinations of cells, scaffolds, and other factors and are complex in both structure and function. Their complexity introduces challenges for product developers to establish novel manufacturing and characterization techniques to ensure that these products are safe and effective prior to clinical trials in humans. Although there are only a few commercial products that are currently in the market, many more tissue-engineered and regenerative medicine products are under development. Therefore, it is the purpose of this article to help product developers in the early stages of product development by providing insight into the Food and Drug Administration (FDA) process and by highlighting some of the key scientific considerations that may be applicable to their products. We provide resources that are publically available from the FDA and others that are of potential interest. As the provided information is general in content, product developers should contact the FDA for feedback regarding their specific products. Also described are ways through which product developers can informally and formally interact with the FDA early in the development process to help in the efficient progression of products toward clinical trials.

Update on regulatory issues in pancreatic islet transplantation.

Over the past 12 years, the US Food and Drug Administration (FDA) has reviewed more than 40 investigational new drug applications for the use of allogeneic pancreatic islets to treat type 1 diabetes mellitus. Recent advances in islet cell isolation, transplantation, and immunosuppressive maintenance have led to multiple centers reporting promising results in the treatment of type 1 diabetes with allogeneic islet cells. The FDA held an advisory committee meeting on October 9-10, 2003, to explore the potential for licensing allogeneic islets as a therapy for severe type 1 diabetes. This article highlights the manufacturing challenges, discussed by the FDA advisory committee, that remain to be resolved before allogeneic islets can be approved for treatment of type 1 diabetes. This article also briefly addresses the challenges facing the clinical trial design of studies that could be used to support licensure.

The effects of stress on memory cytotoxic T lymphocyte-mediated protection against herpes simplex virus infection at mucosal sites.

Psychological stress has been shown to affect many components of the innate and adaptive immune responses to a variety of pathogens including herpes simplex virus (HSV). Mucosal tissues are clinically relevant sites of infection with HSV as well as with many other common pathogens. However, there is a scarcity of experimental evidence that stress affects mucosal immunity. We have taken advantage of a murine model of HSV-specific immune protection that is mediated by only memory cytotoxic T lymphocytes (CTLm) specific for a single CTL recognition epitope within glycoprotein B of HSV-1 (gB498-505). This CTLm population is elicited by vaccination with a recombinant vaccinia virus, which expresses this epitope in the absence of any other HSV-encoded antigens. We report here that stress reduces the ability of gB498-505-specific CTLm to protect against a lethal intranasal or intravaginal HSV infection. Also, stress decreases the ability of these CTLm to limit virus levels at the mucosal site of infection but does not have a significant effect on the levels of virus in the innervating sensory ganglia. Finally, stress decreases protection against HSV-mediated pathology of the vaginal epithelium. These studies are the first to examine the effects of stress on CTLm activation and function in vivo.