Regulatory Aspects of Cell and Gene Therapy Products: The Japanese Perspective.

Regulations for regenerative medicine for human use, such as cell and gene therapy (CGT), have evolved in accordance with advancements in clinical experience, scientific knowledge, and social acceptance of these technologies. In November 2014, two acts, "The Act on the Safety of Regenerative Medicine" (ASRM) and the "Pharmaceuticals, Medical Devices, and Other Therapeutic Products Act" (PMD Act), came into effect in Japan. The responsibilities of medical institutions in ensuring the safety and transparency of such medical technologies are described under ASRM. The PMD Act provides the option of a new scheme for obtaining conditional and time-limited approval for CGT products. Overall, research and development on CGT products, especially gene therapy products, is progressing. New legislative frameworks have been designed to promote the timely development of new technologies and safe and effective CGT products for Japanese patients.

Japanese Laws and the Current Status of Regenerative Medicine in the Tohoku Region.

AIM: The aim of this study was to review Japanese laws regarding regenerative medicine and the current status of clinical application of regenerative medicine, to learn about the advantages and problems, and to thereby serve as a reference for measures necessary for the development of regenerative medicine. BACKGROUND: Regenerative medicine started in 1957 with the transplantation of hematopoietic stem cells, followed by the establishment of embryonic stem cells in 1981 and induced pluripotent stem cells in 2006, and continues to evolve progressively. At the same time, however, problems have emerged due to lax legal regulations, such as the use of treatments that lack scientific evidence. REVIEW RESULTS: The Japanese government enacted two laws to regulate regenerative medicine: the Law to Ensure the Safety of Regenerative Medicine and the Amend the Pharmaceutical Affairs Law in 2013. These laws were enacted with the aim of providing safe regenerative medicine promptly and smoothly and developing many regenerative medicine products. In these laws, regenerative medicine is defined as medical treatment that restores lost functions of damaged organs and tissues with the help of cellular and tissue-based products. Nowadays, there are two major methods of regenerative medicine. One representative method involves the transplantation of devices that activates self-regenerative ability by introducing living cells into patients' body. The other method is the activation and differentiation of endogenous stem cells with cell growth and differentiation factors. CONCLUSION: The current status of regenerative medicine in the Tohoku region after the enactment of these laws is described in detail. This clarified the advantages and disadvantages associated with regenerative medicine as it is currently practiced in Japan. CLINICAL SIGNIFICANCE: Development of regenerative medicine in dentistry will be advanced by learning about its clinical application in medicine.

Unproven stem cell interventions: A global public health problem requiring global deliberation.

The unproven stem cell intervention (SCI) industry is a global health problem. Despite efforts of some nations, the industry continues to flourish. In this paper, we call for a global approach and the establishment of a World Health Organization (WHO) Expert Advisory Committee on Regenerative Medicine to tackle this issue and provide guidance. The WHO committee can harmonize national regulations; promote regulatory approaches responsive to unmet patient needs; and formulate an education campaign against misinformation. Fostering an international dialog and developing recommendations that can be adopted by member states would effectively address the global market of unproven SCIs.

Reflection on the enactment and impact of safety laws for regenerative medicine in Japan.

Japan's Act on the Safety of Regenerative Medicine (ASRM) created an innovative regulatory framework intended to safely promote the clinical development of stem cell-based interventions (SCBIs) while subjecting commercialized unproven SCBIs to greater scrutiny and accountability. This article reviews ASRM's origins, explains its unprecedented scope, and assesses how it envisions the regulation of SCBIs. This analysis is used to highlight three key insights that are pertinent to the current revision of the ASRM: clarifying how the concept of safety should be defined and assessed in research and clinical care settings; revisiting risk criteria for review of SCBIs; and taking stronger measures to support the transition from unproven interventions to evidence-based therapies. Finally, the article reflects on lessons drawn from Japanese experiences in dealing with unproven SCBIs for international endeavors to regulate SCBIs.

Regulatory considerations for developing a phase I investigational new drug application for autologous induced pluripotent stem cells-based therapy product.

Induced pluripotent stem cells (iPSC)-based therapies have been hailed as the future of regenerative medicine because of their potential to provide treatment options for most degenerative diseases. A key promise of iPSC-based therapies is the possibility of an autologous transplant that may engraft better in the longer-term due to its compatibility with the patient's immune system. Despite over a decade of research, clinical translation of autologous iPSC-based therapies has been slow-partly due to a lacking pre-defined regulatory path. Here, we outline regulatory considerations for developing an autologous iPSC-based product and challenges associated with the clinical manufacturing of autologous iPSCs and their derivatives. These challenges include donor tissue source, reprogramming methods, heterogeneity of differentiated cells, controls for the manufacturing process, and preclinical considerations. A robust manufacturing process with appropriate quality controls and well-informed, prospectively designed preclinical studies provide a path toward successful approval of autologous iPSC-based therapies.

Promoting the ethical use of safe and effective cell-based products: the Andalusian plan on regenerative medicine.

With regard to regenerative medicine, the expectations generated over the last two decades and the time involved in developing this type of therapies, together with the availability of devices that allow point-of-care treatments through the rapid isolation of cellular or plasma products from patients in the operating theater, represent the perfect breeding ground for the offering of unproven or unregulated therapies on a global scale. A multidisciplinary approach-one based on the collaboration of institutions that, from the perspective of their area of competence, can contribute to reversing this worrying situation-to this problem is essential. It is a priority for local health authorities to take measures that are adapted to the particular situation and regulatory framework of their respective territory. In this article, the authors present the regenerative medicine action plan promoted by the Andalusian Transplant Coordination (i.e., the action plan for the largest region in Spain), highlighting the aspects the authors believe are fundamental to its success. The authors describe, in summary form, the methodology, phases of the plan, actions designed, key collaborators, important milestones achieved and main lessons they have drawn from their experience so that this can serve as an example for other institutions interested in promoting the ethical use of this type of therapy.

Governmental Regulations and Increasing Food and Drug Administration Oversight of Regenerative Medicine Products: What's New in 2020?

The United States Food and Drug Administration (FDA) is responsible for protecting and promoting public health through rules and regulations. Over the past few years, the field of regenerative medicine and cell therapy have garnered significant interest, and this evolving new biology is changing fast and challenging regulatory bodies. The FDA has published a series of guidance documents outlining steps to protect consumers against potentially dangerous and unproven treatments. The agency has offered a grace period for "stem cell clinics" until November 2020 to come into compliance by obtaining Investigational New Drug applications and working to secure premarket approval of their products. With the documentation of hundreds of "stem cell clinics," the FDA needs to enforce the adherence to their outlined standards to protect patients. The aim of this review was to provide an overview of these FDA regulations and some current issues within the industry. The purpose is to educate and inform the musculoskeletal community about the current government regulations of this new expanding biology. LEVEL OF EVIDENCE: Level V, expert opinion.

Reimbursement and pricing of regenerative medicine in South Korea: key factors for achieving reimbursement.

In the South Korean health technology assessment system, prices of alternative medicines, incremental cost-effectiveness ratios in pharmaco-economic evaluations and patient access improvement systems such as risk-sharing agreements are the most important factors concerning the reimbursement of regenerative medicine (RM). Research and development companies in RM should review the key features of these medicines throughout the product development cycle to increase the probability of successful reimbursement. In addition, the South Korean government should take steps to improve the system to reflect the unique characteristics and value of RM in the reimbursement and pricing policy, to revitalize research and development, and increase patient access.

The Progression of Regenerative Medicine and its Impact on Therapy Translation.

Despite regenerative medicine (RM) being one of the hottest topics in biotechnology for the past 3 decades, it is generally acknowledged that the field's performance at the bedside has been somewhat disappointing. This may be linked to the novelty of these technologies and their disruptive nature, which has brought an increasing level of complexity to translation. Therefore, we look at how the historical development of the RM field has changed the translational strategy. Specifically, we explore how the pursuit of such novel regenerative therapies has changed the way experts aim to translate their ideas into clinical applications, and then identify areas that need to be corrected or reinforced in order for these therapies to eventually be incorporated into the standard-of-care. This is then linked to a discussion of the preclinical and postclinical challenges remaining today, which offer insights that can contribute to the future progression of RM.

Cell and gene therapy manufacturing capabilities in Australia and New Zealand.

Cell and gene therapy products are rapidly being integrated into mainstream medicine. Developing global capability will facilitate broad access to these novel therapeutics. An initial step toward achieving this goal is to understand cell and gene therapy manufacturing capability in each region. We conducted an academic survey in 2018 to assess cell and gene therapy manufacturing capacity in Australia and New Zealand. We examined the following: the number and types of cell therapy manufacturing facilities; the number of projects, parallel processes and clinical trials; the types of products; and the manufacturing and quality staffing levels. It was found that Australia and New Zealand provide diverse facilities for cell therapy manufacturing, infrastructure and capability. Further investment and development will enable both countries to make important decisions to meet the growing need for cell and gene therapy and regenerative medicine in the region.

Regulatory brokerage: Competitive advantage and regulation in the field of regenerative medicine.

This article concerns the roles of entrepreneurial scientists in the co-production of life science research and regulation. Regulatory brokerage, defined as a mode of strategic planning and as the negotiation of regulation based on comparative advantage and competition, is expressed in scientific activities that take advantage of regulatory difference. This article is based on social science research in Japan, Thailand, India and the UK. Using five cases related to Japan's international activities in the field of regenerative medicine, I argue that, driven by competitive advantage, regulatory brokerage at lower levels of managerial organization and governance is emulated at higher levels. In addition, as regulatory brokerage affects the creation of regulation at national, bilateral and global levels, new regulation may be based on competition in regulatory advantage rather than on ethical and scientific values. I argue that regulatory brokerage as the basis for regulatory reform bypasses issues that need to be decided by a broader public. More space is needed for international and political debate about the socio-political consequences of the global diversity of regulation in the field of the life sciences.

Improving the biocompatibility of biomaterial constructs and constructs delivering cells for the pelvic floor.

PURPOSE OF REVIEW: Interactions between biomaterials and biomaterial-delivering cells and the host tissues are complexly affected by the material itself, the ultrastructure of the overall construct and cells and other bioactive factors involved. The aim of this review is to review the current understanding on the definitions of biocompatibility and current advances in improving biocompatability of tissue-engineered constructs. RECENT FINDINGS: Some synthetic materials are associated with more foreign body reactions compared with natural materials; however, they allow fabrication of materials with a great diversity of physical and mechanical properties. Material design strategies can be tailored to mimic the natural extracellular matrix topography. There are also advancements in the pharmacological functionalization of materials with improved angiogenic potential that can lead to better tissue response. Stem cells are also used to improve the tissue response of tissue-engineered materials; however, the recent regulations on regenerative medicine products necessitate significant regulatory approval processes for these. SUMMARY: The biggest challenge faced in translation of tissue-engineered constructs into clinical practice relates to their engraftment and poor tissue integration into the challenging wound bed of the pelvic floor. Biocompatibility of tissue engineered constructs can theoretically be improved by the incorporation of bioactive agents, such as vitamins C or oestradiol.