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.

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.

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.

Mapping and driving the stem cell ecosystem.

The stem cell and regenerative medicine arena has become increasingly complicated in recent years with thousands of people involved. There are as many as a dozen or more main groups of stakeholders, who together may be viewed as one ecosystem that is now rapidly evolving. The nature of the ecosystem and its evolution have major implications for not just those within it, but also for medicine and society at large. Here, I describe this ecosystem and its evolution, as well as the negative impacts within the ecosystem of a constellation of hundreds of unproven for-profit clinics and related businesses. Finally, I propose approaches for how to positively influence and drive the future of the global stem cell ecosystem.

Regulation of Regenerative Medicine Products.

Cellular therapies have moved to the forefront based upon promising results from clinical trials using both chimeric antigen receptor T lymphocytes to treat leukemia and other cell types to restore structure and function to tissues that have been damaged by disease or physical injury. The pace at which these treatments have evolved has posed a regulatory challenge to agencies, such as the Food and Drug Administration (FDA). This chapter describes how a specific regulatory strategy was developed and how it has evolved in response to the demand for these new therapies.

Texas H.B. 810: Increased Access to Stem Cell Interventions or an Increase in Unproven Treatments?

Born of the expectations and hype associated with regenerative medicine, there are now numerous clinics around the world selling stem cell-based interventions (SCBI) that have yet to be proven effective or safe, with little to no accounting of the outcomes being collected. In the United States, SCBI are overseen by the U.S. Food and Drug Administration (FDA), but several SCBI clinics have been pushing for policies to expand access and circumvent FDA oversight. Related to this effort, in 2017, Texas passed a bill, HB 810, which allows clinics to provide "investigational stem cell treatments to patients with certain severe chronic diseases or terminal illnesses." In this article, we describe how the new law relates to another deregulation movement, state and federal, the Right to Try laws, the content of HB 810, and the state legislators' intent in passing HB 810.

Regenerative Medicine in Orthopaedics and Trauma: Challenges, Regulation and Ethical Issues.

The ability of stem cells to self-renew and differentiate into cell types of different lineages forms the basis of regenerative medicine, which focuses on repairing or regenerating damaged or diseased tissues. This has a huge potential to revolutionize medicine. It is anticipated that in future, stem cell therapy will be able to restore function in all major organs. Intensive research has been on-going to bring stem cell therapy from bench to bedside as it holds promise of widespread applications in different areas of medicine. This is also applicable to orthopaedics, where stem cell transplantation could benefit complications like spinal cord injury, critical bone defects, cartilage repair or degenerative disc disorders. Stem cell therapy has a potential to change the field of orthopaedics from surgical replacements and reconstructions to a field of regeneration and prevention. This article summarizes advances in stem cell applications in orthopaedics as well as discussing regulation and ethical issues related to the use of stem cells.

Between the Local and the Global: Evaluating European regulation of stem cell regenerative medicine.

Current European regulations hinder the compilation of the evidence that would be required to bring safe and effective autologous stem cell-based interventions (SCBIs) into standard clinical care. European agencies have expanded their regulations to cover all new SCBIs and research. They establish demanding conditions for cell retrieval, processing, and application. Drawing on empirical sociological findings from the implementation of the first phase III stem cell clinical trial in Europe, this article examines ethical problems effected by that policy, such as that the costs of bringing treatments to market means new autologous SCBIs may remain untested and that this plays in favor of the growing direct-to-consumer market, and that the research pathways in regenerative medicine and the role of clinician-scientists in developing new treatments are restricted, because the regulations are biased to enable specific SCBIs that are of interest to industry. This situation contradicts the moral and social concerns in favor of new treatments and patient interests, which the regulations supposedly safeguard. To align the aims and effects of policy better, European regulatory authorities should reconfigure their regulations to advance a fair and effective governance regime that allows pursuit of all promising SCBIs.

Workshop to address gaps in regulation of minimally manipulated autologous cell therapies for homologous use in Canada.

In Canada, minimally manipulated autologous cell therapies for homologous use (MMAC-H) are either regulated under the practice of medicine, or as drugs or devices under the Food and Drugs Act, Food and Drug Regulations (F&DR) or Medical Device Regulations (MDR). Cells, Tissues and Organs (CTO) Regulations in Canada are restricted to minimally manipulated allogeneic products for homologous use. This leaves an important gap in the interpretation of existing regulations. The purposes of this workshop co-organized by the Stem Cell Network and the Centre for Commercialization of Regenerative Medicine (CCRM) were to discuss the current state of regulation of MMAC-H therapies in Canada and compare it with other regulatory jurisdictions, with the intent of providing specific policy recommendations to Health Canada. Participants came to a consensus on the need for well-defined common terminology between regulators and stakeholders, a common source of confusion and misinformation. A need for a harmonized national approach to oversight of facilities providing MMAC-H therapies based on existing standards, such as Canadian Standards Association (CSA), was also voiced. Facilities providing MMAC-H therapies should also participate in collection of long-term data to ensure patient safety and efficacy of therapies. Harmonization across provinces of the procedures and practices involving administration of MMAC-H would be preferred. Participants felt that devices used to process MMAC-H are adequately regulated under existing MDR. Overly prescriptive regulation will stifle innovation, whereas insufficient regulation might allow unsafe or ineffective therapies to be offered. Until a clear, balanced and explicit approach is articulated, regulatory uncertainty remains a barrier.