Nonclinical and quality assessment of cell therapy products: Report on the 4th Asia Partnership Conference of Regenerative Medicine,April 15, 2021

The 4th Asia Partnership Conference of Regenerative Medicine (APACRM) was held online on April 15, 2021, to promote regulatory harmonization of regenerative medicine products throughout Asia. Recognizing domestic regulatory guidelines within each country and region, and their underpinning rationales, is an important initial step toward a convergence of regulations. The 4th APACRM consisted of an open dialog with regulatory agencies regarding nonclinical and quality settings for cell therapy products (CTPs) through industry presentations and panel discussions with regulatory agencies. The latest updates on regenerative medicine fields in each country and region, and specific regulatory schematics in Japan, were also introduced. The objective of this paper is to summarize the proceedings of the 4th APACRM for public dissemination and to foster further discussion in the future.     

Non-clinical assessment of cell therapy products: the perspective from five Asian countries/regions based on regulatory guidelines and the underpinning rationales

Background aimsCell-based regenerative medicine is an innovative field that can potentially alter the overall survival and quality of life of patients with devastating diseases. Several cell therapy products (CTPs) have been approved within the last two decades, and more are under development. The establishment of an effective developmental strategy in accordance with the regulatory bodies of each country/region is crucial for fast delivery of each respective CTP. In particular, facilitating investigational new drug (IND) approval is important for accelerating the transition from non-clinical to clinical research/trial phases.MethodsHere the authors compared the non-clinical prerequisites for initiating clinical studies in five Asian countries/regions (India, China, Korea, Taiwan and Japan) from an industry viewpoint. The authors first identified the differences and tried to clarify the perspectives/considerations underpinning the different requirements.ResultsThe authors’ findings revealed that differences in regulations and development experiences, especially with CTPs, have led to clear differences in the non-clinical study package and its corresponding study design.ConclusionsBy sharing experiences of the research and development of CTPs among Asian countries/regions and including not only industry but also regulatory authorities, we will be able to expedite cross-border IND approval and eventually contribute to the early delivery of innovative CTPs to many Asian patients.     

Regenerative medicine's historical roots in regeneration, transplantation, and translation

Regenerative medicine is not new; it has not sprung anew out of stem cell science as has often been suggested. There is a rich history of study of regeneration, of development, and of the ways in which understanding regeneration advances study of development and also has practical and medical applications. This paper explores the history of regenerative medicine, starting especially with T.H. Morgan in 1901 and carrying through the history of transplantation research in the 20th century, to an emphasis on translational medicine in the late 20th century.     

FDA and NIST collaboration on standards development activities supporting innovation and translation of regenerative medicine products

The development of standards for the field of regenerative medicine has been noted as a high priority by several road-mapping activities. Additionally, the U.S. Congress recognizes the importance of standards in the 21st Century Cure Act. Standards will help to accelerate and streamline cell and gene therapy product development, ensure the quality and consistency of processes and products, and facilitate their regulatory approval. Although there is general agreement for the need of additional standards for regenerative medicine products, a shared understanding of standards is required for real progress toward the development of standards to advance regenerative medicine. Here, we describe the roles of standards in regenerative medicine as well as the process for standards development and the interactions of different entities in the standards development process. Highlighted are recent coordinated efforts between the U.S. Food and Drug Administration and the National Institute of Standards and Technology to facilitate standards development and foster science that underpins standards development.     

European regulation of herbal medicinal products on the border area to the food sector

This article summarizes the regulation of herbal medicinal products in the EU with emphasis on traditional herbal medicinal products (THMP) and provides an evaluation of the borderline between medicine and food. Differences in the regulation of THMP with influence on the harmonization are revealed. With regard to the borderline between medicine and food, THMP may not be medicinal products by function but by presentation. The thesis is established that depending on the presentation, the product can be medicine (THMP) as well as food. To avoid shifting into the food sector the regulatory system of THMP is evaluated with regard to its attractiveness to applicants. Recommendations to achieve a better harmonization of THMP in the EU and to increase the attractiveness of the simplified registration procedure are given.     

Material Flows and Material Productivity in China,Australia, and Japan

This article presents material flows and material productivity data and indicators for Australia, China, and Japan for the period 1970 to 2005. The main data used come from a new material flows database for the Asia‐Pacific region that was assembled using up‐to‐date standardized methodologies of material flow accounting and significantly extends the knowledge base available for studies on resource use dynamics in the region. We show that the three nations studied here have diverging patterns of resource use, and that these patterns can be linked to interdependencies between them and the very different roles each nation plays within a globalized system of natural resource exploitation. We also conduct a brief analysis of the most important drivers of changes in their resource use over the period, using an IPAT framework (Impact = Population × Affluence × Technology). The fundamentally different economic structures and trading roles of each country, that is, primary resource provider (Australia), mature and advanced manufacturer (Japan), and rapidly industrializing developing country (China), lead to starkly different contexts in which appropriate policies to encourage sustainable resource use must be formulated.     

干细胞与再生医学研究进展

干细胞具有分化成为体内所有类型细胞的能力,因此,其在再生医学治疗、体外疾病模拟、药物筛选等方面具有广阔的应用前景。干细胞技术在近些年取得了突飞猛进的发展,特别是诱导多能性干细胞的出现使干细胞领域经历了一场巨大的变革。我国干细胞研究在这场干细胞技术变革中取得了多项重大成果,逐渐成为了世界干细胞研究领域中的重要力量。本综述着重介绍近几年来,主要是诱导多能性干细胞技术出现之后,我国在干细胞和再生医学领域取得的重要进展,主要涵盖诱导多能性干细胞、转分化、单倍体干细胞以及基因修饰动物模型和基因治疗等方面。     

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.     

Quantifying the biophysical and socioeconomic drivers of changes in forest and agricultural land in South and Southeast Asia

South and Southeast Asia (SSEA) has been a hotspot for land use and land cover change (LULCC) in the past few decades. The identification and quantification of the drivers of LULCC are crucial for improving our understanding of LULCC trends. So far, the biophysical and socioeconomic drivers of forest change have not been quantified at the regional scale, particularly for SSEA. In this study, we quantify the biophysical and socioeconomic drivers of forest change on a country‐by‐country basis in SSEA using an integrated quantitative methodology, which systematically accounts for previously published driver information and regional datasets. We synthesize more than 200 publications to identify the drivers of the forest change at different spatial scales in SSEA. Subsequently, we collect spatially explicit proxy data to represent the identified drivers. We quantify the dynamics of forest and agricultural land from 1992 to 2015 using the Climate Change Initiative (CCI) land cover data developed by the European Space Agency (ESA). A geographically weighted regression method is employed to quantify the spatially heterogeneous drivers of forest change. Our results show that socioeconomic drivers are more important than biophysical drivers for the conversion of forest to agricultural land in South Asia and maritime Southeast Asia. In contrast, biophysical drivers are more important than socioeconomic drivers for the conversion of agricultural land to forest in maritime Southeast Asia and less important in South Asia. Both biophysical and socioeconomic drivers contribute approximately equally to both changes in the mainland Southeast Asia region. By quantifying the dynamics of forest and agricultural land and the spatially explicit drivers of their changes in SSEA, this study provides a solid foundation for LULCC modeling and projection.     

Regenerative medicine for diseases of the head and neck: principles of in vivo regeneration

The application of endogenous regeneration in regenerative medicine is based on the concept of inducing regeneration of damaged or lost tissues from residual tissues in situ. Therefore, endogenous regeneration is also termed in vivo regeneration as opposed to mechanisms of ex vivo regeneration which are applied, for example, in the field of tissue engineering. The basic science foundation for mechanisms of endogenous regeneration is provided by the field of regenerative biology. The ambitious vision for the application of endogenous regeneration in regenerative medicine is stimulated by investigations in the model organisms of regenerative biology, most notably hydra, planarians and urodeles. These model organisms demonstrate remarkable regenerative capabilities, which appear to be conserved over large phylogenetical stretches with convincing evidence for a homologue origin of an endogenous regenerative capability. Although the elucidation of the molecular and cellular mechanisms of these endogenous regenerative phenomena is still in its beginning, there are indications that these processes have potential to become useful for human benefit. Such indications also exist for particular applications in diseases of the head and neck region. As such epimorphic regeneration without blastema formation may be relevant to regeneration of sensorineural epithelia of the inner ear or the olphactory epithelium. Complex tissue lesions of the head and neck as they occur after trauma or tumor resections may be approached on the basis of relevant mechanisms in epimorphic regeneration with blastema formation.     

Tissue banking in Asia Pacific region: past,present and future

Tissue banking in the Asia Pacific regions is driven by two main forces—firstly the International Atomic Energy Agency (IAEA) via Regional Co-operative Agreement projects and secondly by the Asia Pacific Association of Surgical Tissue Banking (APASTB). This overview is written in three sections: (1) History of tissue banking in individual country in the region. (2) History of APASTB. (3) History of IAEA programme in Asia Pacific region. The current status and future of the tissue banking programme in the region will be discussed.     

Regulatory approaches for genome edited agricultural plants in select countries and jurisdictions around the world

Transgenic Research - Genome editing in agriculture and food is leading to new, improved crops and other products. Depending on the regulatory approach taken in each country or region,...     

Control of the Asian tiger mosquito: technical and administrative aspects

The Community legislator, through Directives 2004/17/CE and 2004/18/CE, wanted dictate to the Member States some "guidelines" to be used in the field of public procurement of services, in order to promote, through an inner market growth, developing appropriate operational protocols to document in the race; that, has the aim at testify the consolidated technical capacity of Company which conferred the health reclamation provided by the "Plans to put public health emergencies". By its nature, the legislative regulatory act which is capable of directing the gradual harmonization of national laws, giving also each state full autonomy on the form and means to be taken. Therefore, the objectives of the Community directives must be properly incorporated and interpreted, including the legislative adaptation about the regulation of the disinfestations Enterprises.     

Role of the blood service in cellular therapy

Cellular therapy is a novel form of medical or surgical treatment using cells in place of or in addition to traditional chemical drugs. The preparation of cellular products - called advanced therapy medicinal products - ATMP in Europe, requires compliance with good manufacturing practices (GMP). Based on long-term experience in blood component manufacturing, product traceability and hemovigilance, selected blood services may represent ideal settings for the development and experimental use of ATMP. International harmonization of the protocols and procedures for the preparation of ATMP is of paramount importance to facilitate the development of multicenter clinical trials with adequate sample size, which are urgently needed to determine the clinical efficacy of ATMP. This article describes European regulations on cellular therapy and summarizes the activities of the 'Franco Calori' Cell Factory, a GMP unit belonging to the department of regenerative medicine of a large public university hospital, which acquired a certification for the GMP production of ATMP in 2007 and developed nine experimental clinical protocols during 2003-2011.     

Survey of the differences between regenerative and non-regenerative animals

To investigate the boundaries between regenerative and non-regenerative animals, we first survey regenerative ability across animal phyla from sponges to chordates (including mammals). There are both regenerative and non-regenerative animals in each phylum. The cells participating in regeneration also vary among different species. Thus, it is hard to find clear rules concerning regeneration ability across the animal kingdom, suggesting that it is not useful to compare the difference of regenerative ability across phyla to seek the boundary between regenerative and non-regenerative animals. Instead, if we carefully compare the differences of regenerative ability between closely related species within each phylum and accumulate these differences at the cellular molecular levels, we may be able to clarify the boundary between regenerative and non-regenerative animals. Here we introduce our comparative analysis of cellular events after amputation of lower jaws between frogs and newts. Then we propose that such comparative analyses using closely related species within the same phylum should be accumulated to understand the boundary between regenerative and non-regenerative animals in order to apply this understanding for realizing regenerative medicine in the future.     

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.     

Biomaterials as carrier,barrier and reactor for cell-based regenerative medicine

Cell therapy has achieved tremendous success in regenerative medicine in the past several decades. However, challenges such as cell loss, death and immune-rejection after transplantation still persist. Biomaterials have been designed as carriers to deliver cells to desirable region for local tissue regeneration; as barriers to protect transplanted cells from host immune attack; or as reactors to stimulate host cell recruitment, homing and differentiation. With the assistance of biomaterials, improvement in treatment efficiency has been demonstrated in numerous animal models of degenerative diseases compared with routine free cell-based therapy. Emerging clinical applications of biomaterial assisted cell therapies further highlight their great promise in regenerative therapy and even cure for complex diseases, which have been failed to realize by conventional therapeutic approaches.     

Where and How Are Roads Endangering Mammals in Southeast Asia's Forests?

Habitat destruction and overhunting are two major drivers of mammal population declines and extinctions in tropical forests. The construction of roads can be a catalyst for these two threats. In Southeast Asia, the impacts of roads on mammals have not been well-documented at a regional scale. Before evidence-based conservation strategies can be developed to minimize the threat of roads to endangered mammals within this region, we first need to locate where and how roads are contributing to the conversion of their habitats and illegal hunting in each country. We interviewed 36 experts involved in mammal research from seven Southeast Asian countries to identify roads that are contributing the most, in their opinion, to habitat conversion and illegal hunting. Our experts highlighted 16 existing and eight planned roads - these potentially threaten 21% of the 117 endangered terrestrial mammals in those countries. Apart from gathering qualitative evidence from the literature to assess their claims, we demonstrate how species-distribution models, satellite imagery and animal-sign surveys can be used to provide quantitative evidence of roads causing impacts by (1) cutting through habitats where endangered mammals are likely to occur, (2) intensifying forest conversion, and (3) contributing to illegal hunting and wildlife trade. To our knowledge, ours is the first study to identify specific roads threatening endangered mammals in Southeast Asia. Further through highlighting the impacts of roads, we propose 10 measures to limit road impacts in the region.