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Cell, tissue and gene products with marketing authorization in 2018 worldwide

  • NATIVIDAD Cuende
    Correspondence
    Correspondence: Natividad Cuende, MD, MPH, PhD, Andalusian Initiative for Advanced Therapies/Iniciativa Andaluza en Terapias Avanzadas, Junta de Andalucía, C/ Algodón s/n (Esq. Avd. Hytasa), 41006 Sevilla, Spain.
    Affiliations
    Andalusian Initiative for Advanced Therapies, Junta de Andalucía, Seville, Spain

    Andalusian Transplant Coordination, Servicio Andaluz de Salud, Seville, Spain
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  • JOHN E.J. RASKO
    Affiliations
    Sydney Medical School, University of Sydney, Sydney, Australia

    Gene and Stem Cell Therapy Program, Centenary Institute, Sydney, Australia

    Department of Cell and Molecular Therapies, Royal Prince Alfred Hospital, New South Wales, Australia

    International Society for Cell & Gene Therapy (ISCT) President
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  • MICKEY B.C. KOH
    Affiliations
    Department of Haematology, St George's Hospital and Medical School, London, UK

    Blood Services Group, Health Sciences Authority, Singapore
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  • MASSIMO DOMINICI
    Affiliations
    Division of Oncology, Laboratory of Cellular Therapy, University of Modena & Reggio Emilia, Modena, Italy

    Chair, ISCT Presidential Task Force on the Use of Unproven Cellular Therapies
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  • LAERTIS IKONOMOU
    Correspondence
    Correspondence: Laertis Ikonomou, PhD, Center for Regenerative Medicine of Boston University and Boston Medical Center, 670 Albany St Biosquare III, Boston, MA 02118, USA.
    Affiliations
    The Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts, USA

    Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, Massachusetts, USA
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Open AccessPublished:October 24, 2018DOI:https://doi.org/10.1016/j.jcyt.2018.09.010

      Abstract

      Cell and gene therapies (CGTs) are progressively entering into clinical practice in different parts of the world. The International Society for Cell & Gene Therapy (ISCT), a global scientific society, has been committed since 1992 to supporting and developing knowledge on clinical applications of CGTs. Considering the number of products that have been progressively approved and, in some cases, withdrawn in recent years, the ISCT would like to present a brief annual report on CGTs with marketing authorization (MA) in different regions. This article reflects the dynamic momentum around authorized CGTs coinciding with the parallel increase of unproven approaches where cells are delivered without appropriate and rigorous scientific and regulatory assessment and authorization. This is intended to be a living document with a yearly update linked to a dedicated section of the ISCT website for faster adjustments. The aim is to ultimately inform, by periodic snapshots, the scientific community, healthcare stakeholders and patient associations on authorized CGT products as a way to increase communication around the approved therapeutic approaches charged with heightened expectations.

      Introduction

      The International Society for Cell & Gene Therapy (ISCT) is committed to translating cellular therapy into safe and effective treatments to improve patients’ lives while minimizing and balancing risks for patients. Being aware that many unproven or insufficiently proven cell-based treatments are commercially available for hopeful individuals seeking cures or health improvement for a variety of conditions, the ISCT created the ISCT Presidential Task Force (PTF) on the Use of Unproven Cellular Therapies (UCT) in 2014. The PTF-UCT strives to characterize unproven cellular interventions and promote safe and effective practices worldwide [
      • Dominici M
      • Nichols K
      • Srivastava A
      • Weiss DJ
      • Eldridge P
      • Cuende N
      • et al.
      Positioning a Scientific Community on Unproven Cellular Therapies: The 2015 International Society for Cellular Therapy Perspective.
      ,
      • Srivastava A
      • Mason C
      • Wagena E
      • Cuende N
      • Weiss DJ
      • Horwitz EM
      • et al.
      Part 1: Defining unproven cellular therapies.
      ].
      In line with the above goals, the PTF-UCT has launched several initiatives including providing updated information on approved cellular therapies. For a list of PTF-UCT–authored resources visit http://www.celltherapysociety.org/page/UCT. In this document the PTF-UCT has summarized cell, tissue and gene medicinal products authorized for commercialization by regions/countries, to help patients seeking safe and effective treatments. We have not included any products that are categorized as medical devices, even if they are cell-based. If a patient lives in one of the regions/countries included in the document and a healthcare professional or a business is offering a cell-based treatment not listed, they should ask whether they are going to receive the treatment as part of a clinical trial. If not, the ISCT recommends asking for more information about the “regulatory status” of the treatment they are going to receive to make an informed decision.

      Definitions and principles

      Human cell– or tissue-based products are highly heterogeneous and regulatory authorities will always apply their rulings on a case-by-case basis. Nevertheless, at present, most of the cell- and tissue-based products are considered biological medicinal products in those countries with more developed regulatory structures. The development of safe and effective “proven” cell therapies requires testing these medicinal products according to some general principles [
      • Cuende N
      • Izeta A
      Clinical translation of stem cell therapies: a bridgeable gap.
      ]. Before administration into humans, both biological activity and toxicity of the investigational medicinal product must be tested in relevant animal model(s). Researchers must then seek approval of an institutional review board (IRB) for all centers involved in the clinical trial as well as an authorization from the national regulatory agencies of the countries where patients will be recruited, irrespective of their nationalities. The sponsor's duties also include ensuring: (i) that there is an insurance policy in place to cover any liability, (ii) that recruitment of subjects is done after appropriate informed consent and (iii) that medicinal product batches for release conform to specifications. If the regulatory bodies determine that quality, safety and efficacy of a cell- or tissue-based medicinal product are sufficiently established through successful clinical phases (clinical trial phase 1, 2 and 3), then the next step is to apply for marketing authorization (MA). After that, the company that holds the MA can commercialize the medicinal product in the countries in which the product has been granted MA. In some cases, MA is provisional and post-marketing surveillance studies are required. Of note, some countries permit exceptions to this authorization rule depending on the nature of the medicinal product, be it industrial or otherwise. In any case, the use of a medicinal product has to be supervised by a regulatory body.

      Identified cell and gene therapies with MA

      We have identified and listed cell and gene therapies (CGTs) with MA based on available information, considering as a source of trustworthy information the regulatory body web resources, official press release by the interested companies or other source of data as indicated in Table I, Table II, Table III, Table IV, Table V, Table VI, Table VII, Table VIII, Table IX, Table X where countries/regions are listed in alphabetical order. The list has been updated as of September 15, 2018, unless otherwise specified.
      Table IList of cell/tissue/gene products with MA in Australia by TGA.
      Name (MA holder)Product description and indication(s)Product categoryDate of MACurrent statusAdditional information
      Chondrocytes - T - Ortho-ACI (Orthocell Pty Ltd)Autologous cultured chondrocytes for use in treatment of cartilage lesions associated with the knee, patella and ankleCell therapy product26-Mar-2017Still in marketClick here for link to TGA website
      TGA, Therapeutic Goods Administration.
      Table IIList of cell/tissue/gene products with MA in Canada by Health Canada (March 2018).
      Name (MA holder)Product description and indication(s)Product categoryDate of MACurrent statusAdditional information
      KYMRIAH (NOVARTIS PHARMACEUTICALS CANADA INC)CD19-directed genetically modified autologous T-cell immunotherapy indicated for the treatment of pediatric and young adult patients 3–25 y with B-cell ALL who are refractory, have relapsed after allogeneic SCT or are otherwise ineligible for SCT, or have experienced second or later relapse and for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy including DLBCL not otherwise specified, high-grade B-cell lymphoma and DLBCL arising from follicular lymphoma.Gene therapy product05-Sep-2018In marketClick here for link to Health Canada website
      Prochymal (MESOBLAST INTERNATIONAL SARL)Allogeneic ex vivo–cultured adult human mesenchymal stromal cells for the management of aGvHD in pediatric patientsCell therapy product02-May-2015The product was never marketed in CanadaClick here for link to Health Canada website
      ALL, acute lymphoblastic leukemia; SCT, stem cell transplantation; DLBCL, diffuse large B-cell lymphoma; aGVHD, acute graft-versus-host disease.
      Table IIIList of cell/tissue/gene products with MA in China by CSFDA.
      Name (MA holder)Product description and indication(s)Product categoryDate of MACurrent statusAdditional information
      Gendicine (Shenzhen SiBiono GeneTech Co. Ltd.)Recombinant adenovirus expressing p53 for treatment of head and neck squamous cell carcinomaGene therapy productOct-2003Still in marketClick here
      CSFDA, Chinese Food and Drug Administation.
      Table IVList of Cell/Tissue/Gene Products with MA in the European Union by EMA.
      Name (MA holder)Product description and indication(s)ATMPDate of MACurrent statusAdditional information
      YESCARTA (Kite Pharma EU B.V.)CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of adult patients with relapsed or refractory DLBCL and PMBCL, after two or more lines of systemic therapyGTMP23-Aug-2018Details of MA conditions not displayed at EMA website as of 31-Aug-2018Click here for link to EMA website
      KYMRIAH (Novartis Europharm Limited)CD19-directed genetically modified autologous T-cell immunotherapy indicated for the treatment of pediatric and young adult patients up to 25 y of age with B-cell ALL that is refractory, in relapse post-transplantation or in second or later relapse, and for the treatment of adult patients with relapsed or refractory DLBCL after two or more lines of systemic therapyGTMP27-Aug-2018Details of MA conditions not displayed at EMA website as of 31-Aug-2018Click here for link to EMA website
      ALOFISEL (Takeda Pharma A/S)Expanded allogeneic adipose stem cells as a suspension for injection for the treatment of complex perianal fistulas in patients with Crohn's diseaseSCTMP27-Mar-2018The company will complete a study to continue to collect information on the effectiveness and safetyClick here for link to EMA website
      SPHEROX (CO.DON AG)Spheroids of human autologous matrix-associated chondrocytes for knee-repairing cartilage defectsTEP10-Jul-2017MA under several obligations (post-authorization long-term efficacy and safety study, prospective process validation study and re-validation of the potency assay)Click here for link to EMA website
      ZALMOXIS (MolMed SpA)Donor's T lymphocytes genetically modified with a suicide gene as a control mechanism for GVHD after haploidentical bone marrow transplantationGTMP18-Aug-2016Granted MA under conditional approvalClick here for link to EMA website
      STRIMVELIS (GSK Trading Services Limited)Autologous CD34+ cells transduced with a retroviral vector that encodes for the human ADA cDNA sequence for severe combined immunodeficiency due to ADA deficiencyGTMP26-May-2016Granted MA under additional monitoring until 2037Click here for link to EMA website
      IMLYGIC (Amgen Europe B.V.)Oncolytic immunotherapy derived from a herpex simplex virus-1 genetically engineered to infect and replicate within melanoma cells and to produce GM-CSF for unresectable melanomaGTMP16-Dec-2015Granted MA under additional monitoringClick here for link to EMA website
      HOLOCLAR (Chiesi Farmaceutici S.p.A.)Ex vivo–expanded autologous human corneal epithelial cells containing stem cells for severe limbal stem cell deficiencySCTMP17-Feb-2015Granted MA under conditional approvalClick here for link to EMA website
      EMA, European Medicines Agency; ATMP, Advanced Therapy Medicinal Product; PMBCL, primary mediastinal large B-cell lymphoma; ADA, Adenosine deaminase; cDNA, complementary DNA; TEP, Tissue Engineered Product; GTMP, Gene Therapy Medicinal Product; SCTMP, Somatic Cell Therapy Medicinal Product; EC, European Commission.
      Table VList of cell/tissue/gene products with MA withdrawn or suspended in the European Union by EMA.
      Name (MA holder)Product description and indication(s)ATMPDate of MACurrent statusAdditional information
      PROVENGE (Dendreon)Autologous peripheral-blood mononuclear cells activated with prostatic acid phosphatase granulocyte-macrophage colony-stimulating factor for metastatic prostate cancerSCTMP6-Sep-2013Granted MA under additional monitoring. Withdrawn: company announced bankruptcy in 2015Click here for link to EMA website
      MACI (Aastrom Biosciences, Inc.)Matrix applied characterized autologous cultured chondrocytes for repairing knee cartilage defectsTEP27-Jun-2013Granted MA under additional monitoring. MA suspended: 25-Sep-2014Click here for link to EMA website
      GLYBERA (uniQure biopharma BV)Alipogene tiparvovec (human lipoprotein lipase gene variant in a adeno-associated viral vector) for adult patients with familiar lipoprotein lipase deficiencyGTMP25-Oct-2012Granted MA under additional monitoring. Withdrawn: MA expired on 25-Oct-2017. The company did not apply for renewal due to the lack of demandClick here for link to EMA website
      CHONDROCELECT (TiGenix NV)Characterized viable autologous cartilage cells expanded ex vivo for repairing knee cartilage defectsTEP5-Oct-2009The product was reimbursed in 3 countries. Withdrawn: 30-Nov-2016. Requested by the company for commercial reasonsClick here for link to EMA website
      Table VIList of cell/tissue/gene products with MA in India by DCGI.
      Name (MA holder)Product description and indication(s)Product categoryDate of MACurrent statusAdditional information
      CARTIGROWTM (Chondron ACI) (RMS Regrow)Autologous cultured cartilage cells for treatment of articular cartilage defectsCell therapy productApr-2017Conditional approval, post-market surveillance study required (50 subjects)Click here
      OSSGROWTM (Ossron ABI) (RMS Regrow)Autologous cultured osteoblasts for avascular necrosis of hipCell therapy productApr-2017Conditional approval, post-market surveillance study required (50 subjects)
      APCEDEN (APAC Biotech)Autologous monocyte-derived mature dendritic cells for treatment of prostate, ovarian, colorectal and non-small cell lung carcinomaCell therapy productMar-2017Conditional approval, post-market surveillance study requiredClick here
      Stempeucel® (Stempeutics Research)Ex vivo–cultured adult allogeneic mesenchymal stromal cells for treatment of critical limb ischemia due to Thromboangiitis Obliterans (Buerger's disease)Cell therapy productMay-2016In market, limited release (200 patients on a cost recovery basis), post-market surveillance study requiredClick here
      DCGI, Drug Controller General of India.
      Table VIIList of cell/tissue/gene products with MA in Japan by PMDA.
      Name (MA holder)Product description and indication(s)Product categoryDate of MACurrent statusAdditional information (In Japanese)
      Temcell HS (JCR Pharmaceuticals Co. Ltd.)Allogeneic mesenchymal stromal cells for treatment of aGVHDCell therapy productSep-2015In marketClick here for link to PMDA website
      HeartSheet (Terumo Corporation, Ltd.)Autologous skeletal myoblast sheet product for the treatment of severe heart failureTissue engineered productSep-2015Conditional approvalClick here for link to PMDA website
      JACC (J-TEC)Autologous cultured cartilageTissue engineered productJul-2012Still in market, previous authorization was as medical deviceClick here for link to PMDA website
      JACE (J-TEC)Autologous cultured epidermis for treatment of severe burnsTissue engineered productOct-2007Still in market, previous authorization was as medical deviceClick here for link to PMDA website
      PMDA, Pharmaceuticals and Medical Devices Agency.
      Table VIIIList of cell/tissue/gene products with MA in New Zealand by MEDSAFE.
      Name (MA holder)Product description and indication(s)Product categoryDate of MACurrent statusAdditional information
      Prochymal (Osiris Therapeutics Incorporated)Allogeneic ex vivo–cultured adult human mesenchymal stromal cells indicated for the rescue of patients NLT 6 mo to 17 y of age with aGVHD, refractory to treatment with systemic corticosteroid therapy or other immunosuppressive agentsCell therapy product14-Jun-2012Approval lapsedClick here for link to MEDSAFE website
      MEDSAFE, Medicines and Medical Devices Safety Authority; NLT, Not Lower Than.
      Table IXList of cell/tissue/gene products with MA in South Korea by MFDS.
      Name (MA holder)Product description and indication(s)Product categoryDate of MACurrent statusAdditional information
      KeraHeal-Allo™ (Biosolution Co., Ltd.)Composite cell product (allogeneic skin-derived keratinocytes suspended in a thermosensitive hydrogel) for deep 2nd degree burnsCell therapy product16-Oct-2015Still in marketClick here for link to MFDS website
      NEURONATA-R® (Corestem, Inc.)Autologous bone marrow mesenchymal stromal cell therapy for Amyotrophic Lateral SclerosisCell therapy product30-Jul-2014Orphan productClick here for link to MFDS website
      Cupistem® (Anterogen)Autologous adipose tissue–derived mesenchymal stromal cell for Crohn's fistulaCell therapy product18-Jan-2012Covered by insurance as of Jan-2014, orphan productClick here for link to MFDS website
      CARTISTEM® (Medipost Co., Ltd.)Human umbilical cord blood–derived mesenchymal stromal cells for the treatment of knee articular cartilage defects in patients with osteoarthritis (ICRS grade IV)Cell therapy product18-Jan-2012Still in marketClick here for link to MFDS website
      Cellgram®-AMI (Pharmicell Co., Ltd.)Autologous bone barrow–derived mesenchymal stromal cells for acute myocardial infarction patients (improvement of LVEF)Cell therapy product1-Jul-2011Name at time of approval was Hearticellgram®-AMI, still in marketClick here for link to MFDS website
      CureSkin Inj. (S.Biomedics Co., Ltd.)Autologous dermal fibroblasts (depressed acne scar)Cell therapy product11-May-2010Still in marketClick here for link to MFDS website
      Queencell® (Anterogen)Autologous adipose tissue–derived adipose cell by minimal manipulation for subcutaneous tissue defectCell therapy product26-Mar-2010Still in marketClick here for link to MFDS website
      Kaloderm® (Tego Science, Inc)Allogeneic keratinocytes (cell sheet) for deep 2nd degree burn or diabetic foot ulcerTissue engineered product21-Mar-2005 (2nd degree burn) 24-Jun- 2010 (Diabetic foot ulcer)Still in marketClick here for link to MFDS website
      RMS OssronTM (Sewon Cellontech Co., Ltd.)Cultured autologous osteoblasts for focal bone formation, can be used with or without fibrin glueCell therapy product26-Aug-2009Still in marketClick here for link to MFDS website
      Immuncell-LC (GC Cell Corp.)Autologous activated T cell for liver cancer (hepatocellular carcinoma)Cell therapy product6-Aug-2007Currently in market for hepatocellular carcinoma and in clinical trials for newly diagnosed glioblastoma (phase 3, completed) advanced pancreatic cancer (phase 2, completed)Click here for link to MFDS website
      CreaVax-RCC® (JW CreaGene Corporation)Autologous dendritic cells for metastatic renal cell carcinomaCell therapy product15-May-2007Received tentative approval in 2007 and product manufacture license as export product in 2013 from MFDSClick here for link to MFDS website
      KeraHeal® (Biosolution Co., Ltd.)Autologous skin-derived keratinocytes for deep 2nd degree burns that cover >30% of TBSA and 3rd degree burns that cover >10% of TBSACell therapy product3-May-2006Still in marketClick here for link to MFDS website
      Holoderm® (Tego Science, Inc)Autologous keratinocytes for deep 2nd degree burns that cover >30% of TBSA and 3rd degree burns that cover >10% of TBSATissue engineered product10-Dec-2002Still in market, reimbursed by insuranceClick here for link to MFDS website
      ChondronTM (Sewon Cellontech Co., Ltd.)Cultured autologous chondrocytes for focal cartilage defect of knee, can be used with or without fibrin glueCell therapy product30-Jan-2001Still in marketClick here for link to MFDS website
      MFDS, Ministry of Food and Drug Safety; ICRS, International Cartilage Regeneration & Joint Preservation Society; LVEF, left ventricular ejection fraction; TBSA, Total Burn Surface Area.
      Table XList of cell/tissue/gene products with MA in the United States by USFDA.
      Name (MA holder)Product description and indication(s)Product categoryDate of MACurrent statusAdditional information
      HPC, Cord Blood (MD Anderson Cord Blood Bank)For use in unrelated donor hematopoietic progenitor cell transplantation procedures in conjunction with an appropriate preparative regimen for hematopoietic and immunologic reconstitution in patients with disorders affecting the hematopoietic system that are inherited, acquired or result from myeloablative treatmentCell therapy product06-Jun-2018Still in marketClick here for link to FDA website
      LUXTURNA (voretigene neparvovec-rzyl) (Spark Therapeutics, Inc.)Adeno-associated virus vector-based gene therapy indicated for the treatment of patients with confirmed biallelic RPE65 mutation-associated retinal dystrophyGene therapy product19-Dec-2017Still in marketClick here for link to FDA website
      YESCARTA (axicabtagene ciloleucel) (Kite Pharma, Incorporated)A CD19-directed genetically modified autologous T-cell immunotherapy indicated for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including DLBCL not otherwise specified, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma and DLBCL arising from follicular lymphomaGene therapy product18-Oct-2017Still in marketClick here for link to FDA website
      KYMRIAH (tisagenlecleucel) (Novartis Pharmaceuticals Corporation)CD19-directed genetically modified autologous T-cell immunotherapy indicated for the treatment of patients up to 25 y of age with B-cell precursor ALL that is refractory or in second or later relapseGene therapy product30-Aug-2017Still in marketClick here for link to FDA website
      MACI (Vericel Corporation)Autologous cultured chondrocytes on a porcine collagen membrane for the repair of single or multiple symptomatic, full-thickness cartilage defects of the knee with or without bone involvement in adultsTissue engineered product13-Dec-2016Still in marketClick here for link to FDA website
      Clevecord (HPC, Cord Blood) (Cleveland Cord Blood Center)For use in unrelated donor hematopoietic progenitor cell transplantation procedures in conjunction with an appropriate preparative regimen for hematopoietic and immunologic reconstitution in patients with disorders affecting the hematopoietic system that are inherited, acquired or result from myeloablative treatmentCell therapy product1-Sep-2016Still in marketClick here for link to FDA website
      HPC, Cord Blood (Bloodworks)For use in unrelated donor hematopoietic progenitor cell transplantation procedures in conjunction with an appropriate preparative regimen for hematopoietic and immunologic reconstitution in patients with disorders affecting the hematopoietic system that are inherited, acquired or result from myeloablative treatmentCell therapy product28-Jan-2016Still in marketClick here for link to FDA website
      IMLYGIC (talimogene laherparepvec) (Amgen Inc.)Genetically modified oncolytic viral therapy indicated for the local treatment of unresectable cutaneous, subcutaneous and nodal lesions in patients with melanoma recurrent after initial surgeryGene therapy product27-Oct-2015Still in marketClick here for link to FDA website
      HPC, Cord Blood (LifeSouth Community Blood Centers, Inc.)For use in unrelated donor hematopoietic progenitor cell transplantation procedures in conjunction with an appropriate preparative regimen for hematopoietic and immunologic reconstitution in patients with disorders affecting the hematopoietic system that are inherited, acquired or result from myeloablative treatmentCell therapy product13-Jun-2013Still in marketClick here for link to FDA website
      ALLOCORD (SSM Cardinal Glennon Children's Medical Center)For use in unrelated donor hematopoietic progenitor cell transplantation procedures in conjunction with an appropriate preparative regimen for hematopoietic and immunologic reconstitution in patients with disorders affecting the hematopoietic system that are inherited, acquired or result from myeloablative treatmentCell therapy product30-May-2013Still in marketClick here for link to FDA website
      Ducord (HPC, Cord Blood) (Duke University School of Medicine)For use in unrelated donor hematopoietic progenitor cell transplantation procedures in conjunction with an appropriate preparative regimen for hematopoietic and immunologic reconstitution in patients with disorders affecting the hematopoietic system that are inherited, acquired or result from myeloablative treatmentCell therapy product4-Oct-2012Still in marketClick here for link to FDA website
      HPC, Cord Blood (Clinimmune Labs, University of Colorado Cord Blood Bank)For use in unrelated donor hematopoietic progenitor cell transplantation procedures in conjunction with an appropriate preparative regimen for hematopoietic and immunologic reconstitution in patients with disorders affecting the hematopoietic system that are inherited, acquired or result from myeloablative treatmentCell therapy product24-May-2012Still in marketClick here for link to FDA website
      GINTUIT (Organogenesis, Inc.)Allogeneic cultured keratinocytes and fibroblasts in bovine collagen (cellular sheets) for topical (non-submerged) application to a surgically created vascular wound bed in the treatment of mucogingival conditions in adultsTissue engineered product9-Mar-2012Still in marketClick here for link to FDA website
      Hemacord (HPC, Cord Blood) (New York Blood Center, Inc.)For use in unrelated donor hematopoietic progenitor cell transplantation procedures in conjunction with an appropriate preparative regimen for hematopoietic and immunologic reconstitution in patients with disorders affecting the hematopoietic system that are inherited, acquired or result from myeloablative treatmentCell therapy product1-Nov-2011Still in marketClick here for link to FDA website
      Laviv® (Azficel-T) (Fibrocell Technologies, Inc.)Autologous fibroblasts for improvement of the appearance of moderate-to-severe nasolabial fold wrinkles in adultsCell therapy product21-Jun-2011Still in marketClick here for link to FDA website
      PROVENGE (sipuleucel-T) (Dendreon Corporation)Autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate-resistant (hormone refractory) prostate cancerCell therapy product29-Apr-2010Still in marketClick here for link to FDA website
      In Figure 1, we present the distribution of authorized CGT products by region. In addition, we have listed (Table XI) the CGT approaches that have received a Regenerative Medicine Advanced Therapy (RMAT) designation by the United States Food and Drug Administration (USFDA) [
      • Marks P
      • Gottlieb S
      Balancing safety and innovation for cell-based regenerative medicine.
      ] but have not been approved as of September 2018. In Figure 2, we have categorized CGT products with MA worldwide in three different ways, namely, by product, therapy and disease type. Finally, in Figure 3 we present CGT products according to the year in which they received MA.
      Figure 1.
      Figure 1Number of cell, tissue and gene products with MA per region. *Eight products based on cord blood hematopoietic progenitors for unrelated donor hematopoietic progenitor cell transplantation have been included in the US's total number. These hold a MA license only in the US. Similar products are available in most countries as cell transplants and not as marketed products. The number of products presented in this figure does not include either products with Regenerative Medicine Advanced Therapy (RMAT) designation (United States Food and Drug Administration [USFDA]) or products with suspended MA.
      Table XIList of cell/tissue/gene products with RMAT Designation
      • Marks P
      • Gottlieb S
      Balancing safety and innovation for cell-based regenerative medicine.
      in the United States by USFDA (Sep-2018).
      Name (MA holder)Product description and indication(s)Product categoryDate of RMAT designationAdditional designationsAdditional information
      AT132 (Audentes Therapeutics, Inc.)AAV-mediated gene therapy for the treatment of XLMTM, a rare monogenic disease caused by mutations in the MTM1 geneGene therapy product21-Aug-2018Rare pediatric disease; fast track; orphan drugPress release
      Romyelocel-L (Cellerant Therapeutics, Inc.)Off-the-shelf human myeloid progenitor cells for the prevention of serious bacterial and fungal infections in patients with de novo AML undergoing induction chemotherapyCell therapy product02-Jul-2018Press release
      VY-AADC (Voyager Therapeutics, Inc.)AAV-mediated gene therapy for the treatment of Parkinson's disease in patients with motor fluctuations that are refractory to medical managementGene therapy product21-Jun-2018Press release
      CLBS14-RfA (Caladrius Biosciences, Inc.)CD34+ cell therapy program for the treatment of refractory anginaCell therapy product19-Jun-2018Press release
      NSR-REP1 (Nightstar Therapeutics plc)AAV-mediated gene therapy for the treatment of choroideremia, a rare, degenerative, genetic retinal disorder that leads to blindnessGene therapy product14-Jun-2018Press release
      ABO-102 (Abeona Therapeutics Inc.)AAV-mediated gene therapy for the treatment of Sanfilippo syndrome Type A (MPS IIIA), a rare autosomal-recessive lysosomal storage diseaseGene therapy product23-Apr-2018Press release
      AmnioFix® (MiMedx)Allogeneic micronized dehydrated human amnion/chorion membrane for use in the treatment of OA of the kneeTissue engineered product9-Mar-2018Press release
      CAP-1002 (Capricor Therapeutics)Allogeneic cell therapy (cardiosphere-derived cells) that is currently in clinical development for the treatment of Duchenne muscular dystrophyCell therapy product5-Feb-2018Orphan drug; rare pediatric diseasePress release
      EB-101 (Abeona Therapeutics Inc.)Gene-corrected autologous cell therapy product for patients with RDEBGene therapy product29-Jan-2018Breakthrough therapy; orphan drug; rare pediatric diseasePress release
      MPC therapy (Mesoblast Limited)MPC therapy in the treatment of patients with heart failure with left ventricular systolic dysfunction and LVADsCell therapy product21-Dec-2017Press release
      CEVA101 (Cellvation)Autologous bone marrow–derived stem cells for the treatment of traumatic brain injuryCell therapy product8-Nov-2017Press release
      Multistem (Athersys)Proprietary stem cell product for the treatment of ischemic strokeCell therapy product5-Oct-2017Press release
      AST-OPC1 (Asterias Biotherapeutics)Oligodendrocyte progenitor cells manufactured from pluripotent embryonic stem cells for treatment of patients with spinal cord injuryCell therapy product2-Oct-2017Press release
      LentiGlobin® BB305 (Bluebird Bio)Ex vivo modified autologous hematopoietic stem cells for treatment of transfusion-dependent β-thalassemia (also known as β-thalassemia major) and severe SCDGene therapy product1-Oct-2017Press release
      ATIR101™ (Kiadis Pharma)Adjunctive immunotherapeutic on top of allogeneic HSCTCell therapy product20-Sep-2017Press release
      StrataGraft (Mallinckrodt plc)Autologous skin cell product for the treatment of deep partial thickness burnsTissue engineered product18-Jul-2017Press release
      Ixmyelocel-T (Vericel)Autologous expanded multicellular (mesenchymal cells, monocytes and alternatively activated macrophages) product for the treatment of patients with advanced heart failure due to ischemic dilated cardiomyopathyCell therapy product10-May-2017Press release
      jCell (jCyte)Adult retinal progenitor cells for the treatment of RPCell therapy product2-May-2017Press release
      RVT-802 (Enzyvant)Allogeneic thymic tissue for the treatment of primary immune deficiency resulting from cDGSCell therapy product17-Apr-2017Breakthrough therapy, rare pediatric disease, orphan drugPress release
      HUMACYL® (Humacyte)HAV for patients undergoing hemodialysisTissue engineered product20-Mar-2017Press release
      JCAR017 (Juno Therapeutics)Treatment of r/r aggressive large B-cell non-Hodgkin lymphomaCell therapy product
      AAV, adeno-associated virus; XLMTM, X-linked Myotubular Myopathy; AML, acute myeloid leukemia; OA, osteoarthritis; RDEB, recessive dystrophic epidermolysis bullosa; MPC, mesenchymal precursor cell; LVADs, left ventricular assist devices; SCD, sickle cell disease; HSCT, hematopoietic stem cell transplantation; RP, retinitis pigmentosa; cDGS, complete diGeorge Syndrome; HAV, human acellular vessel.
      Figure 2.
      Figure 2Cell, tissue and gene products with MA worldwide (44 unique products) organized by (A) product type, (B) therapy type and (C) disease type. “Cell Therapy” products in (B) also include tissue engineered products. Eight products based on cord blood hematopoietic progenitors for unrelated donor hematopoietic progenitor cell transplantation have been included in the total number. These hold a MA license only in the US. Similar products are available in most countries as cell transplants and not as marketed products. The number of products presented in this figure does not include either products with RMAT designation (USFDA) or products with suspended MA. GVHD, graft-versus-host disease.
      Figure 3.
      Figure 3Cell, tissue and gene products with MA worldwide (44 unique products) organized by year of MA. Eight products based on cord blood hematopoietic progenitors for unrelated donor hematopoietic progenitor cell transplantation have been included in the total number. These hold a MA license only in the US. Similar products are available in most countries as cell transplants and not as marketed products. The number of products presented in this figure does not include either products with RMAT designation (USFDA) or products with suspended MA.
      Several products are currently available in different regions but have the same MA holder (YESCARTA, KYMRIAH, IMLYGIC, RMS Ossron/OSSGROW and Chondron/CARTIGROW). These products are taken into account only once in Figures 2 and 3, leading to a total number of 44 unique products.

      Discussion and conclusions

      The goal of this article is to provide a quick reference for anyone interested in a snapshot, to be updated annually, of the CGT landscape worldwide. This list may not be exhaustive and additional CGT products with MA will be included in future updates. To our knowledge, no cell/tissue/gene products have been authorized for marketing in Brazil, Hong Kong, Israel, Malaysia, Singapore and Taiwan as of September 2018.
      We have identified 44 unique products, 37 of them are cell and tissue therapies (84%) and mainly autologous (55%) (Figure 2). As far as targeted diseases are concerned, more than one third of the products are intended for the treatment of oncological or hematologic diseases.
      As shown in Figure 3, the number of products with MA has increased in recent years. For example, those authorized from 2015 to September 2018 represent 45%. Unfortunately, there has been a parallel increase in the number of businesses offering unproven and unlicensed cell-based interventions [
      • Berger I
      • Ahmad A
      • Bansal A
      • Kapoor T
      • Sipp D
      • Rasko JEJ
      Global distribution of businesses marketing stem cell-based interventions.
      ,
      • Knoepfler PS
      • Turner LG
      The FDA and the US direct-to-consumer marketplace for stem cell interventions: a temporal analysis.
      ].
      Even though the distribution of authorized CGTs shows important differences among countries or regions, it is not our intention to debate the complex financial, societal and scientific reasons behind these differences or the impact of different regulatory systems on the number of marketed products. As members of the ISCT PTF-UCT, our main objective is to help patients make informed decisions before receiving a cell or gene treatment so that they can avoid being exposed to unproven and unlicensed cell interventions. For that purpose, we aim to provide a reliable, up-to-date resource where patients or professionals can check whether a cell or gene therapy has been approved by a regulatory/medicine agency.
      As mentioned before, the ISCT recommends asking for information about the “regulatory status” of the treatment patients are going to receive to make an informed decision. This is particularly relevant for patients living in one of the regions/countries included in the document who seek safe and effective treatments, should a healthcare professional or a business offer a CGT that is neither listed nor part of a clinical trial.

      Acknowledgments

      Authors are grateful to the entire PTF-UCT for the fruitful suggestions and to the ISCT Head Office in Vancouver, in particular to Iulia Dude and Sophie Bockhold, for the support in completing the project. We are grateful to Doug Sipp (RIKEN, Kobe, Japan) for his help with MA status of cell, gene and tissue products in East Asia.

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