The successful translation of a stem cell-derived product from the laboratory into an approved medicine requires specific scientific, technical, and regulatory understanding. Since this knowledge base is fragmented across websites and publications, the ISSCR has developed a new resource, The Best Practices for the Development of Pluripotent Stem Cell-Derived Therapies. This comprehensive, interactive document, designed for academia and industry, addresses critical areas of the translational pipeline and key decision points for the successful translation to a licensed therapy. Uniquely, it provides a global perspective of the regulatory landscape while providing resources for critical processes and links to jurisdictional regulatory information.

Over the last 25 years, there has been tremendous progress in human pluripotent stem cell (hPSC) technology and clinical trials testing hPSC-derived products. The development of these hPSC-derived products requires the selection of a suitable hPSC line as the starting material for product manufacturing. The bespoke development of an hPSC line for product development can require significant time and resources. Given the acceleration of clinical trials testing hPSC-derived products, there is a growing need for available clinically and commercially suitable “off-the-shelf” hPSC lines. We have identified 166 clinical hPSC lines that are currently available for licensing and distribution. This paper provides details regarding these lines that may assist developers in preliminary evaluation of lines for use in clinical development.

Developing cellular therapies is not straightforward. This Perspective summarizes the experience of a group of academic stem cell investigators working in different clinical areas and aims to share insight into what we wished we knew before starting. These include (1) choosing the stem cell line and assessing the genome of both the starting and final product, (2) familiarity with GMP manufacturing, reagent validation, and supply chain management, (3) product delivery issues and the additional regulatory challenges, (4) the relationship between clinical trial design and preclinical studies, and (5) the market approval requirements, pathways, and partnerships needed.

The ability to generate cell therapies from pluripotent stem cells is changing the way we think about diseases and how to treat them. Regenerative medicines derived from pluripotent stem cells have the potential to treat a large number of diseases, many of which currently lack efficacious therapies, by identifying the deficient or non-functional cell type involved in the disease and generating the corresponding healthy cell type from pluripotent stem cells. However, like other cell and gene therapy products, pluripotent stem cell-based regenerative medicines face development challenges that must be solved before we can deliver on their promise to patients.

The International Society for Stem Cell Research has updated its Guidelines for Stem Cell Research and Clinical Translation in order to address advances in stem cell science and other relevant fields, together with the associated ethical, social, and policy issues that have arisen since the last update in 2016. While growing to encompass the evolving science, clinical applications of stem cells, and the increasingly complex implications of stem cell research for society, the basic principles underlying the Guidelines remain unchanged, and they will continue to serve as the standard for the field and as a resource for scientists, regulators, funders, physicians, and members of the public, including patients. A summary of the key updates and issues is presented here.

Stem cell-based clinical interventions are increasingly advancing through preclinical testing and approaching clinical trials. The complexity and diversity of these approaches, and the confusion created by unproven and untested stem cell-based "therapies,'' create a growing need for a more comprehensive review of these early-stage human trials to ensure they place the patients at minimal risk of adverse events but are also based on solid evidence of preclinical efficacy with a clear scientific rationale for that effect. To address this issue and supplement the independent review process, especially that of the ethics and institutional review boards who may not be experts in stem cell biology, the International Society for Stem Cell Research (ISSCR) has developed a set of practical questions to cover the major issues for which clear evidence-based answers need to be obtained before approving a stem cell-based trial.

Beta cell replacement has the potential to restore euglycemia in patients with insulin-dependent diabetes. Although great progress has been made in establishing allogeneic islet transplantation from deceased donors as the standard of care for those with the most labile diabetes, it is also clear that the deceased donor organ supply cannot possibly treat all those who could benefit from restoration of a normal beta cell mass, especially if immunosuppression were not required. Against this background, the International Pancreas and Islet Transplant Association in collaboration with the Harvard Stem Cell Institute, the Juvenile Diabetes Research Foundation (JDRF), and the Helmsley Foundation held a 2-day Key Opinion Leaders Meeting in Boston in 2016 to bring together experts in generating and transplanting beta cells derived from stem cells. The following summary highlights current technology, recent significant breakthroughs, unmet needs and roadblocks to stem cell-derived beta cell therapies, with the aim of spurring future preclinical collaborative investigations and progress toward the clinical application of stem cell-derived beta cells.

Regenerative MedicineVol. 10, No. 5 EditorialFree AccessCell Therapy Regulatory Toolkit: an online regulatory resourceEmily J Culme-Seymour, James Lawford Davies, Julian Hitchcock, Julian Mason, Melissa K Carpenter & Chris MasonEmily J Culme-Seymour London Regenerative Medicine Network, MedCity, 2 Royal College Street, London NW1 0NH, UK, James Lawford Davies Hempsons, 40 Villiers Street, London WC2N 6NJ, UK, Julian Hitchcock Denoon Legal, 14a Clerkenwell Green, London, EC1R 0DP, UK, Julian Mason Faculty of Science, Engineering and Computing, Kingston University, Penrhyn Road, Kingston upon Thames, Surrey, KT1 2EE, UK, Melissa K Carpenter Carpenter Group Consulting Inc., 28870 237th Place Se, Black Diamond, WA 98010, USA & Chris Mason*Author for correspondence: E-mail Address: chris.mason@ucl.ac.uk Advanced Centre for Biochemical Engineering, University College London, Bernard Katz Building, Gordon Street, London, WC1H 0AH, UKPublished Online:3 Aug 2015https://doi.org/10.2217/rme.15.33AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit Keywords: cell therapyregulationtranslationFigure 1. The UK Cell Therapy Regulatory Toolkit homepage, from where information on banking, consent, licensing, developing cells as therapeutic products, 'incentives', and resources can be accessed.Data taken from [2].Figure 2. The 'Expedited Programs' section within the USA Cell Therapy Regulatory Toolkit, which details the various alternative regulatory pathways available to those developing cell therapies in the USA.Data taken from [3].Cell therapy has recently boomed with dramatic increases in investment, clinical efficacy, deals and partnerships, and government support. A requirement to focus on successful translation remains, with numerous groups dedicating research efforts toward novel business models, manufacturing solutions and regulatory strategies. With these latter considerations in mind, the Cell Therapy Regulatory Toolkit has been put together and is now available free of charge to use at [1].The Cell Therapy Regulatory Toolkit was devised by the London Regenerative Medicine Network (LRMN; London, UK), and developed with assistance from Lawford Davies Denoon (London, UK) and Carpenter Group Consulting, Inc. (WA, USA). The toolkit is designed to inform users about licensing, consent and banking requirements associated with different types of cellular products. It also provides details about applicable regulations, product classifications, manufacturing requirements, possible exemptions and available incentives. It is intended to be informative and educational, rather than providing tailored regulatory guidance, and was developed as an online capability in the first instance to ensure ease of access.Due to the challenges of creating a globally relevant 'generic' tool, there are two different sections to the toolkit: one pertaining to the UK and EU regions, and the other covering the USA. Each section can be accessed from the other, or from the LRMN holding page.The UK and EU site contains information in five main sections: banking, consent, licensing, therapy and incentives. The fourth section, therapy, incorporates a comprehensive plan for informing those developing cells as therapeutic products, covering the relevant directives, regulations and classifications – all of which is easily navigated to from the home page (Figure 1). Users are taken through a series of questions designed to guide them to useful information relevant to their product, including a number of options to 'see more', where further background and supporting information relating to any complexities of the question asked is provided. In some cases, further clarification is also attained by viewing the 'unsure'? option provided with a question or answer. There is additional guidance on manufacturing requirements for specific product classes, potential exemptions that might be available for certain medicines in accordance with their particular manufacture and use and the process of EMA approval of a marketing authorisation for a product. A sixth section entitled resources contains further supporting information, such as the composition and tasks of the EMA's Committee for Advanced Therapies (CAT), other tools that are available for users (see below) and links to the main statutes and regulations relevant to these medicinal products, along with the applicable UK and EU regulatory authorities.The USA site is built around a standard clinical trial pathway from the research stage through to commercialization. Information is then set out in three sections: Steps to Product, Manufacturing and Expedited Programs, each of which is aligned with the clinical pathway displayed on the left hand side of the pages. This ensures clarity for the user on where the specific information included within each section is applicable in relation to product development. The first section covers the various meetings and applications required by US FDA, as well as the information and documents required for submissions, where relevant. The second section looks at the manufacturing requirements for each stage of product development, detailing information included within investigational new drug (IND) applications, as well as requirements on product potency assays and compliance with current good manufacturing practices (cGMP). The third section details the various expedited programs available to those developing cell therapies in the USA, which may be requested at various times during product development (Figure 2). These include fast track designation, breakthrough therapy designation, special protocol assessment, orphan status, humanitarian use device designation, accelerated approval and priority review designation. This section contains information on qualifying criteria, when to submit the request, the timelines for FDA response and the corresponding benefits for each program detailed. Across all three sections, further supporting information is contained within the 'Find out more…' options displayed within the text, as well as 'links to other websites' options, which the user can click on to be directed toward useful FDA Guidance for Industry documents, website pages or publications. A fourth section, 'resources', briefly details the specific Code of Federal Regulations (CFR) that apply to the IND application process.The toolkit was constructed using information available in 2014. It is inevitable that regulatory requirements will change over time, and looking ahead, users should therefore check whether there have been any subsequent changes introduced by the relevant regulatory bodies.We would seek to encourage anyone interested in cell therapy translation to use the Cell Therapy Regulatory Toolkit. The information within the site should provide useful regulatory education about what to expect further down the line of development pipelines, as well as informing users of classification differences or consenting requirements, which would be helpful if you are at an earlier stage of development. Currently, the content is appropriate for those looking at the UK/EU and USA regions for product development; in due course, additional capability exploring other regulatory environments for cell therapies may be incorporated into the toolkit, including Canada, Japan and India.Alternative toolkits are indeed available to other UK users seeking regulatory information for cell therapies. Consulting on Advanced Biologicals (UK) have previously published a set of tools covering product development, characterization, comparability, reference materials and agency advice [4]. In addition, the UK Stem Cell Tool Kit was initially developed around 2009 by the UK's Department of Health in order to inform individuals conducting human stem cell research in the UK about the regulatory requirements [5]. A related initiative is the NIHR's Clinical Trials Toolkit, which was initially developed in 2004 by the Medical Research Council and the Department of Health, and provides information about the legal and regulatory requirements in setting up and managing a clinical trial of an Investigational Medicinal Product (IMP) in the UK [6]. These are complementary to the Cell Therapy Regulatory Toolkit, and indeed all the resources work together to inform users seeking to understand locally relevant regulatory pathways.AcknowledgementsThe authors are grateful to K Rowland for design and creative concept for the toolkit.Financial & competing interests disclosureThe Cell Therapy Regulatory Toolkit was developed within the British Regen Industry Tool Set (BRITS) project (2010–2014) funded by Innovate UK (then the Technology Strategy Board) under their Regenerative Medicine Program: Value Systems and Business Modelling. C Mason was the Principle Investigator and EJ Culme-Seymour was an investigator on the project. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.References1 LRMN – Cell Therapy Regulatory Toolkit. www.lrmn.com/regs.html.Google Scholar2 LRMN – Cell Therapy Regulatory Toolkit – UK. lrmn.com/toolkit/uk/uk-regs.html.Google Scholar3 LRMN – Cell Therapy Regulatory Toolkit – US. lrmn.com/toolkit/us/us-regs.html.Google Scholar4 Consulting on Advanced Biologicals. advbiols.com/Resources.php.Google Scholar5 UK Stem Cell Tool Kit. www.sc-toolkit.ac.uk/home.cfm.Google Scholar6 Clinical Trials Toolkit. www.ct-toolkit.ac.uk/routemap.Google ScholarFiguresReferencesRelatedDetailsCited BySTEM CELL TECHNOLOGY IN PERIPHERAL NERVE RESTORATION29 June 2020 | Eastern Ukrainian Medical Journal, Vol. 8, No. 2Orthobiologics: Regulation in Different Parts of the World27 May 2017Large-Scale Mesenchymal Stem/Stromal Cell Expansion: A Visualization Tool for Bioprocess ComparisonTissue Engineering Part B: Reviews, Vol. 22, No. 6CLINICAL TRANSLATION OF TISSUE ENGINEERED MEDICINAL PRODUCTS1 January 2016 | Journal of Stem cell & Regenerative Biology, Vol. 2, No. 1 Vol. 10, No. 5 Follow us on social media for the latest updates Metrics History Published online 3 August 2015 Published in print August 2015 Information© Future Medicine LtdKeywordscell therapyregulationtranslationAcknowledgementsThe authors are grateful to K Rowland for design and creative concept for the toolkit.Financial & competing interests disclosureThe Cell Therapy Regulatory Toolkit was developed within the British Regen Industry Tool Set (BRITS) project (2010–2014) funded by Innovate UK (then the Technology Strategy Board) under their Regenerative Medicine Program: Value Systems and Business Modelling. C Mason was the Principle Investigator and EJ Culme-Seymour was an investigator on the project. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.PDF download

Several human embryonic stem cell (hESC)-derived cell therapeutics have entered clinical testing and more are in various stages of preclinical development. The U.S. Food and Drug Administration (FDA) regulates these products under existing regulations and has stated that these products do not constitute a new class of biologic. However, as human tissue, hESCs are subject to regulations that were developed before hESCs were first described. The regulations have not been revised since 2005, well before the first hESC-derived product entered clinical studies. The current regulations require donors of hESCs to be tested in the same manner as donors of tissues intended for transplantation. However, because hESC-derived cell products are more than minimally manipulated, they are also subject to the same end-of-production release testing as most other biologic agents. In effect, this makes hESC products subject to redundant testing. No other biologic is subject to a similar testing requirement. Furthermore, the regulations that require donor testing are specifically applicable to hESC cells harvested from donors after a date in 2005. It is unclear which regulations cover hESCs harvested before 2005. Ambiguity in the guidelines and redundant testing requirements have unintentionally created a burdensome regulatory paradigm for these products and reluctance on the part of developers to invest in these promising therapeutics. We propose a simple solution that would address FDA safety concerns, eliminate regulatory uncertainty and risk, and provide flexibility for the FDA in the regulation of hESC-derived cell therapies. STEM CELLS TRANSLATIONAL MEDICINE 2015;4:1097-1100

The field of pluripotent stem cells (PSCs) is in a state of dynamic flux driven by significant advances in the derivation of specific phenotypes from embryonic stem cells, breakthroughs in somatic cell nuclear transfer, and dramatic improvements in generating induced PSCs using zero footprint methods. Spurred by these technological advances, companies have begun to plan clinical studies using human PSC derivatives manufactured in current Good Manufacturing Practice-compliant conditions. In the present review, we discuss the challenges in making these biological products, starting from tissue sourcing to the processes involved in manufacture, storage, and distribution. Additional challenges exist to meeting the regulatory requirements and keeping costs affordable. A model is described that has been proposed by the U.S. National Institutes of Health for reducing the costs and permitting flexibility and innovation by individual investigators. This model, combined with small adjustments in the regulatory processes tailored to address the unique properties of PSCs, has the potential of significantly accelerating the implementation of PSC-based cell therapy.

Because of their remarkable proliferative capacity and differentiation potential, human pluripotent stem cells (hPSCs) may provide a cell source for cell replacement therapies, drug screening, and disease modeling. The use of hPSCs in these applications requires a scalable, reproducible and controlled process. An adherent cell culture using cell feeder layers has been traditionally employed for the growth of human embryonic stem cells (hESCs). The utilization of defined culture components allows for reagent standardization, consistent cultures, and reduces risks from undefined components or undetectable animal pathogens. We firstly demonstrated that hESCs could be maintained on Matrigel or laminin-coated plates in serum-free medium conditioned by mouse feeders. We later developed culture techniques using defined media. Cells maintained in these culture systems show stable karyotype and proliferation rates, express pluripotency markers and differentiate into all three germ layers. In this chapter, we present culture methods for hPSC cultures and an approach for their characterization.

Suspension bioreactors are an attractive alternative to static culture of human embryonic stem cells (hESCs) for the generation of clinically relevant cell numbers in a controlled system. In this study, we have developed a scalable suspension culture system using serum-free defined media with spinner flasks for hESC expansion as cell aggregates. With optimized cell seeding density and splitting interval, we demonstrate prolonged passaging and expansion of several hESC lines with overall expansion, yield, viability and maintenance of pluripotency equivalent to adherent culture. Human ESCs maintained in suspension as aggregates can be passaged at least 20 times to achieve over 1×10(13) fold calculated expansion with high undifferentiation rate and normal karyotype. Furthermore, the aggregates are able to differentiate to cardiomyocytes in a directed fashion. Finally, we show that the cells can be cryopreserved in serum-free medium and thawed into adherent or suspension cultures to continue passaging and expansion. We have successfully used this method under cGMP or cGMP-equivalent conditions to generate cell banks of several hESC lines. Taken together, our suspension culture system provides a powerful approach for scale-up expansion of hESCs under defined and serum-free conditions for clinical and research applications.

Human pluripotent stem cell (hPSC) lines have been considered to be homogeneously euploid. Here we report that normal hPSC - including induced pluripotent - lines are karyotypic mosaics of euploid cells intermixed with many cells showing non-clonal aneuploidies as identified by chromosome counting, spectral karyotyping (SKY) and fluorescent in situ hybridization (FISH) of interphase/non-mitotic cells. This mosaic aneuploidy resembles that observed in progenitor cells of the developing brain and preimplantation embryos, suggesting that it is a normal, rather than pathological, feature of stem cell lines. The karyotypic heterogeneity generated by mosaic aneuploidy may contribute to the reported functional and phenotypic heterogeneity of hPSCs lines, as well as their therapeutic efficacy and safety following transplantation.

Kelly et al . describe antibodies for purifying two progenitor populations that arise during the differentiation of human embryonic stem cells to pancreatic beta cells: pancreatic endoderm and polyhormonal endocrine cells. After transplantation into mice, only pancreatic endoderm cells differentiate into glucose-responsive insulin-producing cells.

The last decade has seen a dramatic rise in the development of new cellular therapeutics in a wide range of indications. There have been acceptable safety profiles reported in early studies using blood-derived and adherent stem cell products, but also an inconsistent efficacy record. Further expansion has been hindered in part by a lack of capital (both private and public) and delayed entry into the cell therapy space by large healthcare and pharmaceutical companies, those members of the industry most reliably able to initiate and maintain advanced-phase clinical trials. With recognition that the International Society for Cellular Therapy (ISCT) is uniquely positioned to serve the global translational regenerative medicine research community as a network hub for scientific standards and policy, the ISCT commissioned the establishment of an Industry Task Force (ITF) to address current and future roles for industry. The objectives of the ITF were to gather information and prioritize efforts for a new Commercialization Committee (CC) and to construct innovative platforms that would foster constructive and synergistic collaborations between industry and ISCT. Recommendations and conclusions of the ITF included that the new CC: (1) foster new relationships with therapeutic and stem cell societies, (2) foster educational workshops and forums to cross-educate and standardize practices, (3) create industry subcommittees to address priority initiatives, with clear benchmarks and global implementation, and (4) establish a framework for a greater industry community within ISCT, opening doors for industry to share the new vision for commercialization of cell therapy, emphasizing the regenerative medicine space.