• Cell therapy
• Gene therapy
• NAFLD
• Non-Alcoholic Fatty Liver Disease
• Stem cell
• Viral vectors

• Humans
• Non-alcoholic Fatty Liver Disease/therapy
• Non-alcoholic Fatty Liver Disease/genetics
• Non-alcoholic Fatty Liver Disease/immunology
• Genetic Therapy/methods
• Hepatocytes/metabolism
• Hepatocytes/cytology
• Animals
• Cell- and Tissue-Based Therapy/methods
• Endoplasmic Reticulum Stress
• Hepatic Stellate Cells/metabolism
• Liver/pathology

• Advanced therapy medicinal products
• Challenges
• Financial-based agreements
• Managed entry agreements
• Outcome-based agreements
• Reimbursement

• Humans
• Drug Costs

• ClinicalTrials.Gov
• cell and gene therapy
• investigational new drug
• investigator‐initiated trials
• quasi‐dual‐track regulatory

• Humans
• China
• Genetic Therapy/methods
• Genetic Therapy/trends
• Clinical Trials as Topic/legislation & jurisprudence
• Clinical Trials as Topic/statistics & numerical data
• Cell- and Tissue-Based Therapy/methods
• Cell- and Tissue-Based Therapy/trends
• Research Personnel
• Gene Therapy Agents

• Cell therapy
• Extracellular vesicles
• Mesenchymal stromal cell
• Sterility testing
• Validation

• acute kidney injury
• chronic kidney disease
• perinatal stem cell
• prevention

• Acute Kidney Injury/therapy
• Acute Kidney Injury/pathology
• Acute Kidney Injury/prevention & control
• Animals
• Renal Insufficiency, Chronic/therapy
• Renal Insufficiency, Chronic/pathology
• Humans
• Rats
• Mesenchymal Stem Cells/cytology
• Mesenchymal Stem Cells/metabolism
• Female
• Pregnancy
• Mesenchymal Stem Cell Transplantation/methods
• Placenta/cytology
• Reperfusion Injury/therapy
• Reperfusion Injury/prevention & control
• Reperfusion Injury/pathology
• Disease Models, Animal
• Kidney/pathology
• Rats, Sprague-Dawley
• Male
• Disease Progression

• bioinspired materials
• deep noncompressible wounds
• hemostatic materials
• self‐crosslinking pollen cryogel

• Cryogels/chemistry
• Animals
• Mice
• Pollen/chemistry
• Hemorrhage
• Hemostatics/chemistry

• 023126-00001 Minister of Education, MOE AcRF Tier 1
• 52303131 National Natural Science Foundation of China
• CHA-202300230001 CHA University
• 2042023kf0177 Fundamental Research Funds for Central Universities of the Central South University
• MOET32022-0008 Minister of Education, MOE AcRF Tier 3

• China
• Global benchmarking Tool (GBT)
• advanced therapy medicinal products
• drug regulatory authority
• regulatory science

• China
• World Health Organization
• Humans
• Benchmarking/methods

• CNN model
• Image classifier
• Machine learning
• Mesenchymal stem cells
• Quality assurance
• Single-cell analysis

• Humans
• Mesenchymal Stem Cells/cytology
• Machine Learning
• Single-Cell Analysis/methods
• Immunophenotyping/methods
• Flow Cytometry/methods
• Tooth, Deciduous/cytology
• Image Processing, Computer-Assisted/methods
• Wharton Jelly/cytology
• Cells, Cultured

• Cell therapy
• Drug delivery
• Extracelluar vesicle
• Nucleic acid

• Humans
• COVID-19 Vaccines
• Drug Delivery Systems
• Nucleic Acids/therapeutic use

• ATMPs in bone disorders
• bone regeneration
• cartilage regeneration
• cell-based therapy.
• mesenchymal stromal cell
• regenerative medicine

• Humans
• Tissue Engineering/methods
• Animals
• Cartilage Diseases/therapy
• Bone Diseases/therapy
• Cartilage/injuries
• Bone Regeneration/drug effects

• 075-15-2021-596 Ministry of Science and Higher Education of the Russian Federation
• 21-15-00339 Russian Science Foundation

• Biofabrication
• Bioglass
• Hydroxyapatite
• PLA
• Scaffold

• Tissue Scaffolds/chemistry
• Durapatite
• Tissue Engineering/methods
• Ceramics/chemistry

• biomarkers
• castration-resistant prostate cancer
• dendritic cell-based vaccines
• immunotherapy
• prostate cancer
• tumor microenvironment

• CAR-T
• acute lymphoblastic leukemia
• cost-effectiveness analysis
• tisagenlecleucel

• bioethics
• regenerative medicine
• responsible innovation
• scientific integrity
• social impact
• tissue engineering

• Animals
• Humans
• Tissue Engineering
• Regenerative Medicine
• Biocompatible Materials
• Induced Pluripotent Stem Cells
• Bioprinting

• BMSCs
• MSCs
• Osteonecrosis of the femoral head
• Regenerative medicine
• Treatment
• bone marrow aspirate concentrate (BMAC)
• cell-based therapy
• femoral head
• growth factors
• osteogenic cells
• osteonecrosis of the femoral head (ONFH)
• regenerative therapies
• stem cells

• conjunctiva
• goblet cells
• immunocytochemistry
• keratin
• mucin
• squamous epithelial cells

• Critical quality attributes
• Gene therapy
• Marketing approval
• Potency
• Product development
• Quality and regulatory compliance
• Somatic cell therapy
• Suitable potency assay
• Surrogate potency assay
• Tissue engineering products

• Approved ATMP
• CAR T-cell potency
• CAR T-cell therapy
• Cell therapies
• Compliance
• Epithelial stem cells
• Gene therapies
• Hematopoietic stem cells
• Immunotherapy
• Tissue engineering

• ATMP
• Advanced therapy medicinal products
• Analytical procedures
• Cell therapy
• Clinical trial
• Potency assay
• Smallpox
• Standard operating procedure
• Stem cell research
• Variolation

• Advanced therapies medicinal products
• Barriers
• Cell therapy
• Development cycle
• Gene therapy
• Tissue engineering

• Humans
• European Union
• Marketing

• VSV-GP
• cation-exchange chromatography
• cryo-EM of viruses
• downstream processing
• membrane adsorbers
• oncolytic viruses
• sartobind S
• virus analytics and characterization

• ATMP
• Ficoll
• GMP production
• PBMC
• cell therapy
• critical limb ischemia
• monocyte

• Humans
• Leukocytes, Mononuclear
• Monocytes
• Chronic Limb-Threatening Ischemia
• Biological Products
• Serum Albumin, Human
• Synthetic Drugs
• Nitrogen

Chondrogenic models utilizing human mesenchymal stromal cells (hMSCs) are often simplistic, with a single cell type and the absence of mechanical stimulation. Considering the articulating joint as an organ it would be beneficial to include more complex stimulation. Within this study we applied clinically relevant kinematic load to biphasic constructs. In each case, the upper layer consisted of fibrin embedded hMSCs retained within an elastomeric polyurethane (PU) scaffold. These were randomly assigned to five base scaffolds, a cell-free fibrin PU base, viable bone, decellularized bone, 3D printed calcium phosphate or clinically used cement. This allowed the study of cross talk between viable bone and chondrogenically differentiating MSCs, while controlling for the change in stiffness of the base material. Data obtained showed that the bulk stiffness of the construct was not the defining factor in the response obtained, with viable and decellularized bone producing similar results to the softer PU base. However, the stiff synthetic materials led to reduced chondrogenesis and increased calcification in the upper MSC seeded layer. This demonstrates that the underlying base material must be considered when driving chondrogenesis of human cells using a clinically relevant loading protocol. It also indicates that the material used for bony reconstruction of osteochondral defects may influence subsequent chondrogenic potential.

• cancer treatment
• gene delivery
• iron oxide nanoparticles
• tumor diagnosis
• tumor targeting

The development of cell-, gene- and tissue engineering (CGT)-based therapies must adhere to strict pharmaceutical quality management standards, as for any other biological or small-molecule drug. However, early developments often failed to fully comply with good laboratory practices (GLP) in non-clinical safety studies. Despite an upward trend of positive opinions in marketing authorization applications, evidence of adherence to the principles of GLP is not openly reported; therefore, their relative impact on the overall quality of the product development program is unknown. Herein we investigated the actual degree of GLP implementation and the underlying factors impeding full compliance in non-clinical developments of CGT-based marketed medicines in the EU and USA, including (i) the co-existence of diverse quality management systems of more strategic value for small organizations, particularly current Good Manufacturing Practices n(GMP); (ii) lack of regulatory pressure to pursue GLP certification; and (iii) the involvement of public institutions lacking a pharmaceutical mindset and resources. As a final reflection, we propose conformity to good research practice criteria not as a doctrinaire impediment to scientific work, but as a facilitator of efficient clinical translation of more effective and safer innovative therapies.

• advanced therapy medicinal products
• good laboratory practice
• non-clinical safety
• preclinical assessment
• product development
• quality compliance
• regulatory guidelines

Cell therapies are required to meet with compulsory regulations that co-exist with other optional standards and guidelines that together compose a complex quality management system. Indeed, reliable insights on the mechanisms of action and safety of novel cell-based therapies require adherence to solid quality management structures in all steps of the value chain, from early research and tissue procurement to clinical trials and biovigilance, thus guaranteeing reproducibility and solid foundations for better science and improved clinical practice. Herein we present the concept of the quality ecosystem as a tool to understand and assist all stakeholders involved in developing and structuring the integration of standards as novel developments are taking place. We conclude that the various quality management initiatives can all be thought about under the umbrella of an ecosystem.

• Ministerstvo Školství, Mládeže a Tělovýchovy

• ATMP
• India
• mesenchymal stem cell
• regulations
• stem cell

• NRF-2019R1I1A1A01061296 National Research Foundation of Korea
• NRF-2021R1I1A1A01040732 National Research Foundation of Korea

• Autologous cell therapy
• Castration-resistant prostate cancer
• Dendritic-tumor hybridoma vaccine
• Immunotherapy

• Mesenchymal Stem/Stromal Cells
• extracellular vesicles
• homing
• immunomodulation
• regenerative medicine
• secretome

• SFRH/BD/146172/2019 Fundação para a Ciência e Tecnologia
• SFRH/BD/146689/2019 Fundação para a Ciência e Tecnologia
• 2021.05265.BD Fundação para a Ciência e Tecnologia
• POCI-01-0247-FEDER-017771 Agencia de Inovacao
• POCI-01-0247-FEDER-033877 Agencia de Inovacao
• POCI-01-0145-FEDER-031146 Agencia de Inovacao
• PEst-OE/AGR/UI0211/2011 Fundação para a Ciência e Tecnologia

Human mesenchymal stem cells (MSC) are multipotent stem cells, which are isolated from various sources. Currently, there is a worldwide interest for dental MSC to be used against neurodegenerative diseases, since they derive from the neural crest and express embryonic stem cell markers. This fact prompted us to explore their potential for neural trans-differentiation in culture. We employed all-trans-retinoic acid (ATRA) and 2-(3-ethylureido)-6-methylpyridine (UDP-4) to induce neural differentiation of human MSC from the dental apical papilla (SCAP). The SCAP were exposed to either agent separately and assessed for proliferation, viability, morphology, and gene expression of the following neural-specific markers: neuron-specific enolase (ENO2), neurofibromin 1 (NF1), choline acetyltransferase (CHAT), tyrosine hydroxylase (TH), and the vesicular GABA transporter (SLC32A1). They were also assessed for the expression of glial fibrillary acidic protein (GFAP) and neuronal nuclear antigen (NeuN) by immunofluorescence. ATRA or UDP-4 treatment inhibited the cell growth and promoted limited cell death, but to a different extent. The addition of the neuroprotective agent recombinant human erythropoietin-alpha (rhEPO-α) enhanced the UDP-4-inducing capacity for more than three weeks. ATRA or UDP-4 treatment significantly upregulated ENO2 and NF1 expression, indicating neuronal differentiation. Moreover, the ATRA treatment significantly induced the upregulation of the GABAergic-specific SLC32A1, while the UDP-4 treatment led to the significant upregulation of the adrenergic-specific TH. The UDP-4 treatment induced the expression of NeuN and GFAP after four and three weeks, respectively, while the ATRA-treatment did not. Our findings indicate that SCAP can be differentiated into neural-like cells after treatment with ATRA or UDP-4 by exhibiting a disparate pattern of differentiation. Therefore, UDP-4 is suggested here as a new potent neural-differentiation-inducing compound, which, when combined with rhEPO-α, could lay the foundation for robust stem-cell-based therapies of neurodegeneration.

• Cell Differentiation
• Cells, Cultured
• Humans
• Mesenchymal Stem Cells
• Pyridines
• Tretinoin/metabolism
• Tretinoin/pharmacology
• Urea/analogs & derivatives
• Urea/metabolism

Advanced therapy medicinal products, considered special medications, requires Anvisa approval for use and commercialization in Brazil. They include the advanced cellular therapy products, tissue engineering products and gene therapy products, which due to their complexity involve innovation and risks, optimized regulatory channels for their development and life cycle monitoring. The scientific elements and the compliance with applicable regulatory aspects are fundamental pillars for the advancement of clinical trials, the positive evidence of the benefit-risk profile and the definition of the critical quality attributes, from the perspective of making safe, effective and high-quality products available to the population. The approval models of these products in Brazil adapt to the specificities and characteristics of the technology and the patient target population, with accelerated regulatory analyses, use in emergency situations by risk controls and specific monitoring mechanisms, principally those related to rare diseases without other therapeutic alternatives. The opportune access to the advance therapy product with safety, efficacy and quality involves innovative normative elements that include the long-term follow-up of the safety and efficacy and of the adaptive pharmacovigilance requisites, as well as the traceability mechanisms for the start-off materials, products and patients.

• Advanced therapy medicinal product
• Anvisa
• Clinical trials
• Gene therapy
• Regulatory approval

• chondrogenesis
• donor comparison
• osteochondral constructs
• osteogenesis

• Cell Differentiation/physiology
• Chondrogenesis/physiology
• Collagen Type I/metabolism
• Collagen Type II/metabolism
• Glycosaminoglycans/metabolism
• Humans
• Immunohistochemistry
• Mesenchymal Stem Cells/cytology
• Mesenchymal Stem Cells/metabolism
• Osteogenesis/physiology
• Tissue Engineering

• MR/R015635/1 Medical Research Council
• N/A AO Foundation
• 31003A_179438 Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung

Human erythropoietin (EPO) is an N-linked glycoprotein consisting of 166 aa that is produced in the kidney during the adult life and acts both as a peptide hormone and hematopoietic growth factor (HGF), stimulating bone marrow erythropoiesis. EPO production is activated by hypoxia and is regulated via an oxygen-sensitive feedback loop. EPO acts via its homodimeric erythropoietin receptor (EPO-R) that increases cell survival and drives the terminal erythroid maturation of progenitors BFU-Es and CFU-Es to billions of mature RBCs. This pathway involves the activation of multiple erythroid transcription factors, such as GATA1, FOG1, TAL-1, EKLF and BCL11A, and leads to the overexpression of genes encoding enzymes involved in heme biosynthesis and the production of hemoglobin. The detection of a heterodimeric complex of EPO-R (consisting of one EPO-R chain and the CSF2RB β-chain, CD131) in several tissues (brain, heart, skeletal muscle) explains the EPO pleotropic action as a protection factor for several cells, including the multipotent MSCs as well as cells modulating the innate and adaptive immunity arms. EPO induces the osteogenic and endothelial transdifferentiation of the multipotent MSCs via the activation of EPO-R signaling pathways, leading to bone remodeling, induction of angiogenesis and secretion of a large number of trophic factors (secretome). These diversely unique properties of EPO, taken together with its clinical use to treat anemias associated with chronic renal failure and other blood disorders, make it a valuable biologic agent in regenerative medicine for the treatment/cure of tissue de-regeneration disorders.

• bone marrow erythropoiesis
• bone remodeling
• endothelial transdifferentiation (angiogenesis)
• erythropoietin-alpha
• mesenchymal stem cells
• regenerative medicine

• Bone Remodeling/drug effects
• Bone Remodeling/physiology
• Cell Transdifferentiation/drug effects
• Cell Transdifferentiation/physiology
• Endothelial Cells/cytology
• Erythropoiesis/drug effects
• Erythropoiesis/physiology
• Erythropoietin/metabolism
• Erythropoietin/pharmacology
• Humans
• Mesenchymal Stem Cells/cytology
• Multipotent Stem Cells/cytology
• Receptors, Erythropoietin/metabolism
• Regenerative Medicine/methods

Advanced therapy medicinal products are human medical therapies based on genes, cells, or tissues, and due to their characteristics, they offer new innovative opportunities for the treatment of diseases and injuries, especially for diseases beyond the reach of traditional approaches. These therapies are at the forefront of innovation and have historically been very controversial, although in the last decade they have gained prominence while the number of new advanced therapies has increased every year. In this regard, despite the controversy they may generate, they are expected to dominate the market in the coming decades. Technologies based on advanced therapies are the present and future of medicine and bring us closer to the long-awaited precision medicine. Here we review the field as it stands today, with a focus on the molecular mechanisms that guided the different advanced therapies approved by the European Medicines Agency, their current status, and their legal approval.

• Advanced therapy
• Advanced therapy medicinal products
• Cell therapy
• Gene therapy
• Tissue therapy
• Chimeric antigen receptor T cell

Adoptive cancer immunotherapy using chimeric antigen receptor (CAR) engineered T-cells holds great promise, although several obstacles hinder the efficient generation of cell products under good manufacturing practice (GMP). Patients are often immune compromised, rendering it challenging to produce sufficient numbers of gene-modified cells. Manufacturing protocols are labour intensive and frequently involve one or more open processing steps, leading to increased risk of contamination. We set out to develop a simplified process to generate autologous gamma retrovirus-transduced T-cells for clinical evaluation in patients with head and neck cancer. T-cells were engineered to co-express a panErbB-specific CAR (T1E28z) and a chimeric cytokine receptor (4αβ) that permits their selective expansion in response to interleukin (IL)-4. Using peripheral blood as starting material, sterile culture procedures were conducted in gas-permeable bags under static conditions. Pre-aliquoted medium and cytokines, bespoke connector devices and sterile welding/sealing were used to maximise the use of closed manufacturing steps. Reproducible IL-4-dependent expansion and enrichment of CAR-engineered T-cells under GMP was achieved, both from patients and healthy donors. We also describe the development and approach taken to validate a panel of monitoring and critical release assays, which provide objective data on cell product quality.

• chimeric antigen receptor
• closed process
• good manufacturing practice
• interleukin-4
• retrovirus

• Cell Culture Techniques
• Cell Line, Tumor
• Cytokines/metabolism
• Cytotoxicity, Immunologic/immunology
• Humans
• Immunotherapy, Adoptive/methods
• Interleukin-4/metabolism
• Receptors, Chimeric Antigen/genetics
• Receptors, Chimeric Antigen/metabolism
• T-Lymphocytes/immunology
• T-Lymphocytes/metabolism
• Transduction, Genetic

• BB/D014301/1 Biotechnology and Biological Sciences Research Council
• BB/E005896/1 Biotechnology and Biological Sciences Research Council
• Cancer Research UK
• 104802/Z/14/Z Wellcome Trust

Multipotent mesenchymal stromal cells (MSCs) are currently the most extensively studied type of adult stem cells in advanced stages of development in the field of regenerative medicine. The biological properties of MSCs have generated great hope for their therapeutic use in degenerative and autoimmune conditions that, at present, lack effective treatment options. Over the last decades, MSCs have been typically obtained from adult bone marrow, but the extraction process is highly invasive and the quality and numbers of isolated cells is drastically influenced by patient age, medication and associated comorbidities. Therefore, there is currently an open discussion on the convenience of allogeneic over autologous treatments, despite potential disadvantages such as rejection by the host. This shift to the allogeneic setting entails the need for high production of MSCs to ensure availability of sufficient cell numbers for transplantation, and therefore making the search for alternative tissue sources of highly proliferative MSC cultures with low levels of senescence occurrence, which is one of the greatest current challenges in the scale up of therapeutic cell bioprocessing. Herein we (i) present the main isolation protocols of MSCs from bone marrow, adipose tissue and Wharton’s jelly of the umbilical cord; and (ii) compare their qualities from a bioprocess standpoint, addressing both quality and regulatory aspects, in view of their anticipated clinical use.

• Adipose tissue
• Bone marrow
• MSCs isolation protocols
• Multipotent mesenchymal stromal cells
• Umbilical cord
• Wharton’s jelly

Advanced therapy medicinal products (ATMPs) are a group of innovative and complex biological products for human use that comprises somatic cell therapy medicinal products, tissue engineered products, gene therapy medicinal products, and the so-called combined ATMPs that consist of one of the previous three categories combined with one or more medical devices. During the last few years, the development of ATMPs for the treatment of eye diseases has become a fast-growing field as it offers the potential to find novel therapeutic approaches for treating pathologies that today have no cure or are just subjected to symptomatic treatments. Therefore, it is important for all professionals working in this field to be familiar with the regulatory principles associated with these types of innovative products. In this review, we outline the legal framework that regulates the development of ATMPs in the European Union and other international jurisdictions, and the criteria that each type of ATMP must meet to be classified as such. To illustrate each legal definition, ATMPs that have already completed the research and development stages and that are currently used for the treatment of eye diseases are presented as examples.

• ATMP
• advanced therapy medicinal product
• cell therapy
• eye
• gene therapy
• marketing authorization
• ocular
• ophthalmology
• regulatory
• tissue engineering

• advanced therapy medicinal product
• investigational medicinal product
• investigational medicinal product dossier (IMPD)
• regulatory agency
• translational (regulation)

• Angiogenesis Inducing Agents
• Animals
• Biocompatible Materials
• Chitosan/pharmacology
• Ischemia
• Macrophages/metabolism
• Mice
• Neovascularization, Physiologic
• Polysaccharides/analysis
• Polysaccharides/pharmacology
• Sulfates
• Vascular Endothelial Growth Factor A/metabolism
• Vascular Endothelial Growth Factor Receptor-2/metabolism
• Vascular Endothelial Growth Factors

• bioreactors
• integration
• osteochondral
• tissue engineering

• N/A AO Foundation

Recently, the design and development of a modern health policy in the field of regenerative medicine leads to the formation of a new and integrated cognitive field, which requires systematic research and study in order to produce innovative answers and best practices. Advanced therapy medicinal products (ATMPs) is a new product category, which is at the heart of concern since it has to deal with diseases in which traditional medicine has proven to be ineffective so far. The aim of this review is to provide evidence for the state of the art ATMPs and their modern applications in the field of regenerative medicine. The ATMPs are characterized by a great heterogeneity and variation in methods of isolation, which cover the entire spectrum from a single intravenous injection to a surgical placement. Clinical development of ATMP encounters specific challenges due to the nature of the product and the limited availability of non-clinical data. The gold standard of a controlled, randomized, clinical trial may not be feasible or ethically justified for all indications, particularly in life-threatening diseases, where there is no satisfactory standard of care. Therefore, the European Commission (EC) took initiatives in order to set standards and operating rules concerning authorization and supervision of ATMPs and on pharmacovigilance in relation to them. The European Union (EU) Regulation 1394/2007 provides the possibility of exceptions. In particular, the “hospital exemption” allows for the administration of an ATMP without a license on certain conditions. Although the Regulation 1394/2007 has led to the commercial exploitation of ATMPs, the reality today, 11 years after its first implementation, is completely different. While the Committee for Advanced Therapies (CAT) has already registered 285 products as ATMPs, only 10 licenses were granted which only remained six (the rest related to products withdrawn). The key players in the development and delivery of ATMPs still remain the academic/research centers and small and medium-sized enterprises; while the involvement of pharmaceutical companies is focusing on recent developments in the treatment of oncological incidents with in vitro modified cytotoxic T lymphocytes, and chimeric antigen receptor (CAR)-T cells.

• Advanced therapy medicinal products
• CAT
• EU regulation
• Quality and safety standards
• Randomize clinical trial

• CAR T-cells
• bispecific antibodies
• immune checkpoint inhibitors
• immunomodulatory agents
• non-Hodgkin lymphomas

• Gene therapy
• advanced therapy medicinal product
• gene therapy medicinal product
• randomised clinical trial

• evidence map
• genetics
• therapeutics

Within the past few years, there has been tremendous growth in clinical trials of chimeric antigen receptor (CAR) T-cell therapies. Unlike those of many small-molecule pharmaceuticals, CAR T-cell therapy clinical trials are fraught with risks due to the use of live cell products. The aim of this study is to reach a consensus with experts on the most relevant set of risks that practically occur in CAR T-cell therapy clinical trials.

A Delphi method of consensus development was used to identify the risks in CAR T-cell therapy clinical trials, comprising three survey rounds. The expert panel consisted of principal investigators, clinical research physicians, members of institutional ethics committees, and Good Clinical Practice managers.

Of the 24 experts invited to participate in this Delphi study, 20 participants completed Round 1, Round 2, and Round 3. Finally, consensus (defined as >80% agreement) was achieved for 54 risks relating to CAR T-cell clinical trials. Effective interventions related to these risks are needed to ensure the proper protection of subject health and safety.

The Delphi method was successful in gaining a consensus on risks relevant to CAR T-cell clinical trials in a geographically diverse expert association. It is hoped that this work can benefit future risk-based quality management in clinical trials and can potentially promote the better development of CAR T-cell therapy products.

• CAR T-cell therapy
• Delphi study
• clinical trial
• risk identification
• subject protection