Non-clinical,quality and environmental impact assessments of cell and gene therapy products: Report on the 5th Asia Partnership Conference of Regenerative Medicine - April 7, 2022

The 5th Asia Partnership Conference of Regenerative Medicine (APACRM) was held online on April 7, 2022 to promote regulatory harmonization of regenerative medicine products throughout Asia. The recognition of domestic regulatory guidelines within each country and region and the underpinning rationales are important initial steps toward the harmonization of regulations. The 5th APACRM featured open dialog regarding non-clinical, quality and environmental impact assessment settings for cell and gene therapy products through presentations from the industry and panel discussions with regulatory agencies. The latest updates on regenerative medicine fields in each country and region were also introduced. This paper summarizes the proceedings of the 5th APACRM for public dissemination to foster future discussion.     

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.     

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.     

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.     

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,...     

Experience of reviewing the follow-on biologics including Somatropin and erythropoietin in Japan

To share the experience of reviewing clinical data required for the licensing of follow-on biologic products (biosimilar products and similar biotherapeutical products as EU and WHO terminology, respectively) in Japan, the data packages of two follow-on biologics, "Somatropin BS s.c. [Sandoz] (Omnitrope?)" and "Epoetin alfa BS [JCR]", which have been recently approved in Japan according to the "Guidelines for the Quality, Safety and Efficacy Assurance of Follow-on Biologics" published on March 4th 2009, are described. The clinical data package and indication of Somatropin BS/Omnitrope(?) were different in each country. In case of Epoetin alfa BS [JCR], non-clinical and clinical data-package was different from those of erythropoietin biosimilar products approved in EU. Submission of post-marketing surveillance plans for both products was required. Even though there seem to be differences in data requirements by each national regulatory authority, the accumulation of experience will provide the rationale and consensus on how to design the clinical trials for follow-on biologics.     

Standards efforts and landscape for rapid microbial testing methodologies in regenerative medicine

The Standards Coordinating Body for Gene, Cell, and Regenerative Medicines and Cell-Based Drug Discovery (SCB) supports the development and commercialization of regenerative medicine products by identifying and addressing industry-wide challenges through standards. Through extensive stakeholder engagement, the implementation of rapid microbial testing methods (RMTMs) was identified as a high-priority need that must be addressed to facilitate more timely release of products. Since 2017, SCB has coordinated efforts to develop standards for this area through surveys, weekly meetings, workshops, leadership in working groups and participation in standards development organizations. This article describes the results of these efforts and discusses the current landscape of RMTMs for regenerative medicine products.Based on discussions with stakeholders across the field, an overview of traditional culture-based methods and limitations, alternative microbial testing technologies and current challenges, fit-for-purpose rapid microbial testing and case studies, risk-based strategies for selection of novel rapid microbial test methods and ongoing standards efforts for rapid microbial testing are captured here. To this end, SCB is facilitating several initiatives to address challenges associated with rapid microbial testing for regenerative medicine products. Two documentary standards are under development: an International Organization for Standardization standard to provide the framework for a risk-based approach to selecting fit-for-purpose assays primarily intended for cell and gene therapy products and an ASTM standard guide focused on sampling methods for microbial testing methods in tissue-engineered medical products. Working with the National Institute of Standards and Technology, SCB expects to facilitate the process of developing publicly available microbial materials for inter-laboratory testing. These studies will help collect the data necessary to facilitate validation of novel rapid methods. Finally, SCB has been working to increase awareness of, dialog about and participation in efforts to develop standards in the regenerative medicine field.     

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.     

An iterative method to protect the type I error rate in bioequivalence studies under two‐stage adaptive 2×2 crossover designs

Bioequivalence studies are the pivotal clinical trials submitted to regulatory agencies to support the marketing applications of generic drug products. Average bioequivalence (ABE) is used to determine whether the mean values for the pharmacokinetic measures determined after administration of the test and reference products are comparable. Two‐stage 2×2 crossover adaptive designs (TSDs) are becoming increasingly popular because they allow making assumptions on the clinically meaningful treatment effect and a reliable guess for the unknown within‐subject variability. At an interim look, if ABE is not declared with an initial sample size, they allow to increase it depending on the estimated variability and to enroll additional subjects at a second stage, or to stop for futility in case of poor likelihood of bioequivalence. This is crucial because both parameters must clearly be prespecified in protocols, and the strategy agreed with regulatory agencies in advance with emphasis on controlling the overall type I error. We present an iterative method to adjust the significance levels at each stage which preserves the overall type I error for a wide set of scenarios which should include the true unknown variability value. Simulations showed adjusted significance levels higher than 0.0300 in most cases with type I error always below 5%, and with a power of at least 80%. TSDs work particularly well for coefficients of variation below 0.3 which are especially useful due to the balance between the power and the percentage of studies proceeding to stage 2. Our approach might support discussions with regulatory agencies.     

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.     

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.     

Comparison of new Brazilian legislation for the approval of advanced therapy medicinal products with existing systems in the USA,European Union and Japan

Background aimsAdvanced therapy medicinal products (ATMPs) are a class of biological products for human use that are based on genes, cells and tissues. The first ATMP received marketing authorization in Europe in 2009, whereas Brazil granted the first authorization in 2020. The objective of this study was to compare the regulatory models adopted by Brazil, the USA, Japan and the European Union, which comprise the member countries of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, with regard to the marketing authorization of ATMPs.MethodsThe authors performed a review of the scientific literature and official documents of the regulatory agencies in the aforementioned countries.ResultsThe legislation and regulatory guidelines adopted by the regulatory agencies exhibit similarities and differences. It was not possible to assess whether these differences can be translated into divergent final recommendations by regulatory authorities upon a request for marketing authorization.ConclusionsIn the future, it will be appropriate to start a progressive process of harmonization between these agencies in terms of terminology, legal recommendations and characterization requirements. This is particularly important for emerging countries such as Brazil. In this sense, some measures can be taken to achieve alignment between regulators.     

Manufacture of a human mesenchymal stem cell population using an automated cell culture platform

Tissue engineering and regenerative medicine are rapidly developing fields that use cells or cell-based constructs as therapeutic products for a wide range of clinical applications. Efforts to commercialise these therapies are driving a need for capable, scaleable, manufacturing technologies to ensure therapies are able to meet regulatory requirements and are economically viable at industrial scale production. We report the first automated expansion of a human bone marrow derived mesenchymal stem cell population (hMSCs) using a fully automated cell culture platform. Differences in cell population growth profile, attributed to key methodological differences, were observed between the automated protocol and a benchmark manual protocol. However, qualitatively similar cell output, assessed by cell morphology and the expression of typical hMSC markers, was obtained from both systems. Furthermore, the critical importance of minor process variation, e.g. the effect of cell seeding density on characteristics such as population growth kinetics and cell phenotype, was observed irrespective of protocol type. This work highlights the importance of careful process design in therapeutic cell manufacture and demonstrates the potential of automated culture for future optimisation and scale up studies required for the translation of regenerative medicine products from the laboratory to the clinic.     

US regulatory system for genetically modified [genetically modified organism (GMO), rDNA or transgenic] crop cultivars

This paper reviews the history of the federal regulatory oversight of plant agricultural biotechnology in the USA, focusing on the scientific and political forces moulding the continually evolving regulatory structure in place today. Unlike most other jurisdictions, the USA decided to adapt pre-existing legislation to encompass products of biotechnology. In so doing, it established an overarching committee (Office of Science and Technology Policy) to study and distribute various regulatory responsibilities amongst relevant agencies: the Food and Drug Administration, Environmental Protection Agency and US Department of Agriculture. This paper reviews the history and procedures of each agency in the execution of its regulatory duties and investigates the advantages and disadvantages of the US regulatory strategy.     

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.     

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.     

China's perspective on similar biotherapeutic products

In order to ensure most Chinese patients, particularly in the population with relatively low incomes, have access to safe, low cost, effective and quality-assured medicines, a number of "stand-alone" biological products, which have good quality, safety and efficacy have been marketed in China. Many countries and regions' regulatory agencies are actively engaging in the development of bio-similar guidance and documents, which is being coordinated by WHO. As a major developing country of new drug development, China is now working hard to promote the process of new similar biotherapeutic products (SBPs) approval and also actively involved in developing and updating technical documents.