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Volume 25, Issue 1
  • ISSN: 1566-5232
  • E-ISSN: 1875-5631

Abstract

Recent decades have seen advancements in the management and treatment of difficult- to-treat diseases such as cancer. A special class of therapeutics called cell and gene therapy has been introduced in the past 10 years. Cell and gene therapy products have strengthened the treatment options for life-threatening diseases with unmet clinical needs and also provided the possibility of a potential cure for the disease in some of the patients. Cell and gene therapy products are gaining recognition, and the interest in clinical development of cell and gene therapy products is increasing. Moreover, as the class of cell and gene therapy products is relatively new, there is a limited regulatory experience in the development, and the developers of the cell and gene therapy products can often be puzzled with an array of questions on regulations. The current review intends to provide a basic understanding of regulatory guidelines from the FDA and EMA that are applicable to cell and gene therapy products. Essentials such as which office is responsible for the evaluation of applications, which regulatory class/pathway is appropriate for development, and what are the quality, nonclinical and clinical studies that are needed to support the application are discussed in the article. In addition, a summary of regulatory designations and the post-approval requirements, such as Risk Evaluation and Mitigation Strategies (REMS) and long-term follow-up, is included in the article. Developers (referred to as ‘sponsors’ in this article) of cell and gene therapies can use the respective guidance documents and other specific review articles cited in this review for detailed information on the topics.

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2025-02-01
2024-11-22

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References

  1. FarkonaS. DiamandisE.P. BlasutigI.M. Cancer immunotherapy: The beginning of the end of cancer?BMC Med.20161417310.1186/s12916‑016‑0623‑527151159
     [Google Scholar]
  2. LazzariC. KarachaliouN. BulottaA. ViganóM. MirabileA. BrioschiE. SantarpiaM. GianniL. RosellR. GregorcV. Combination of immunotherapy with chemotherapy and radiotherapy in lung cancer: Is this the beginning of the end for cancer?Ther. Adv. Med. Oncol.201810175883591876209410.1177/175883591876209429662546
     [Google Scholar]
  3. RotteA. Combination of CTLA-4 and PD-1 blockers for treatment of cancer.J. Exp. Clin. Cancer Res.201938125510.1186/s13046‑019‑1259‑z31196207
     [Google Scholar]
  4. TohH.C. Cancer immunotherapy—the end of the beginning.Chin. Clin. Oncol.2018721210.21037/cco.2018.04.0329764157
     [Google Scholar]
  5. RotteA. Predictive models for response and survival in patients treated with anti-PD-1 monotherapy or with anti-PD-1 and ipilimumab combination: Editorial commentary.Ann. Transl. Med.202311522710.21037/atm‑22‑656437007583
     [Google Scholar]
  6. WhitesideT.L. DemariaS. RuizR.M.E. ZarourH.M. MeleroI. Emerging opportunities and challenges in cancer immunotherapy.Clin. Cancer Res.20162281845185510.1158/1078‑0432.CCR‑16‑004927084738
     [Google Scholar]
  7. ChristofiT. BaritakiS. FalzoneL. LibraM. ZaravinosA. Current perspectives in cancer immunotherapy.Cancers20191110147210.3390/cancers1110147231575023
     [Google Scholar]
  8. RotteA. SahasranamanS. BudhaN. Targeting TIGIT for immunotherapy of cancer: Update on clinical development.Biomedicines202199127710.3390/biomedicines909127734572463
     [Google Scholar]
  9. LiuM. GuoF. Recent updates on cancer immunotherapy.Precis. Clin. Med.201812657410.1093/pcmedi/pby01130687562
     [Google Scholar]
  10. LemaireV. ShemeshC.S. RotteA. Pharmacology-based ranking of anti-cancer drugs to guide clinical development of cancer immunotherapy combinations.J. Exp. Clin. Cancer Res.202140131110.1186/s13046‑021‑02111‑534598713
     [Google Scholar]
  11. SinghP. RotteA. GolsorkhiA.A. GirishS. Optimizing outcomes and managing adverse events in locally advanced or metastatic urothelial cancer: A clinical pharmacology perspective.Expert Rev. Clin. Pharmacol.202316653354810.1080/17512433.2023.221944637282597
     [Google Scholar]
  12. RohaanM.W. WilgenhofS. HaanenJ.B.A.G. Adoptive cellular therapies: The current landscape.Virchows Arch.2019474444946110.1007/s00428‑018‑2484‑030470934
     [Google Scholar]
  13. HoangD.M. PhamP.T. BachT.Q. NgoA.T.L. NguyenQ.T. PhanT.T.K. NguyenG.H. LeP.T.T. HoangV.T. ForsythN.R. HekeM. NguyenL.T. Stem cell-based therapy for human diseases.Signal Transduct. Target. Ther.20227127210.1038/s41392‑022‑01134‑435933430
     [Google Scholar]
  14. FrigaultM. RotteA. AnsariA. GlinerB. HeeryC. ShahB. Dose fractionation of CAR-T cells. A systematic review of clinical outcomes.J. Exp. Clin. Cancer Res.20234211110.1186/s13046‑022‑02540‑w36627710
     [Google Scholar]
  15. RotteA. FrigaultM.J. AnsariA. GlinerB. HeeryC. ShahB. Dose–response correlation for CAR-T cells: A systematic review of clinical studies.J. Immunother. Cancer20221012e00567810.1136/jitc‑2022‑00567836549782
     [Google Scholar]
  16. RotteA. HeeryC. GlinerB. TiceD. HilbertD.M. BCMA targeting CAR T cells using a novel D-domain binder for multiple myeloma: Clinical development update.Immuno Oncology Insights202231132410.18609/ioi.2022.003
     [Google Scholar]
  17. SternerR.C. SternerR.M. CAR-T cell therapy: current limitations and potential strategies.Blood Cancer J.20211146910.1038/s41408‑021‑00459‑733824268
     [Google Scholar]
  18. RafiqS. HackettC.S. BrentjensR.J. Engineering strategies to overcome the current roadblocks in CAR T cell therapy.Nat. Rev. Clin. Oncol.202017314716710.1038/s41571‑019‑0297‑y31848460
     [Google Scholar]
  19. BonifantC.L. JacksonH.J. BrentjensR.J. CurranK.J. Toxicity and management in CAR T-cell therapy.Mol. Ther. Oncolytics201631601110.1038/mto.2016.1127626062
     [Google Scholar]
  20. MohantyR. ChowdhuryC. AregaS. SenP. GangulyP. GangulyN. CAR T cell therapy: A new era for cancer treatment (Review).Oncol. Rep.20194262183219510.3892/or.2019.733531578576
     [Google Scholar]
  21. RathJ.A. ArberC. Engineering strategies to enhance TCR-based adoptive T cell therapy.Cells202096148510.3390/cells906148532570906
     [Google Scholar]
  22. BauluE. GardetC. ChuvinN. DepilS. TCR-engineered T cell therapy in solid tumors: State of the art and perspectives.Sci. Adv.202397eadf370010.1126/sciadv.adf370036791198
     [Google Scholar]
  23. DunbarC.E. HighK.A. JoungJ.K. KohnD.B. OzawaK. SadelainM. Gene therapy comes of age.Science20183596372eaan467210.1126/science.aan467229326244
     [Google Scholar]
  24. SchellerE.L. KrebsbachP.H. Gene therapy: Design and prospects for craniofacial regeneration.J. Dent. Res.200988758559610.1177/002203450933748019641145
     [Google Scholar]
  25. UddinF. RudinC.M. SenT. CRISPR gene therapy: Applications, limitations, and implications for the future.Front. Oncol.202010138710.3389/fonc.2020.0138732850447
     [Google Scholar]
  26. LiT. YangY. QiH. CuiW. ZhangL. FuX. HeX. LiuM. LiP. YuT. CRISPR/Cas9 therapeutics: progress and prospects.Signal Transduct. Target. Ther.2023813610.1038/s41392‑023‑01309‑736646687
     [Google Scholar]
  27. KeelerA.M. ElMallahM.K. FlotteT.R. Gene therapy 2017: Progress and future directions.Clin. Transl. Sci.201710424224810.1111/cts.1246628383804
     [Google Scholar]
  28. MunisA.M. Gene therapy applications of non-human lentiviral vectors.Viruses20201210110610.3390/v1210110633003635
     [Google Scholar]
  29. JieX.L. YingH.X. PingZ.K. LianJ.C. JuanL.J. CRISPR-Cas9: A new and promising player in gene therapy.J. Med. Genet.201552528929610.1136/jmedgenet‑2014‑10296825713109
     [Google Scholar]
  30. HuangJ. ZhouY. LiJ. LuA. LiangC. CRISPR/Cas systems: Delivery and application in gene therapy.Front. Bioeng. Biotechnol.20221094232510.3389/fbioe.2022.94232536483767
     [Google Scholar]
  31. GhalehG.H.E. BolandianM. DorostkarR. JafariA. PourM.F. Concise review on optimized methods in production and transduction of lentiviral vectors in order to facilitate immunotherapy and gene therapy.Biomed. Pharmacother.202012811027610.1016/j.biopha.2020.11027632502836
     [Google Scholar]
  32. ManillaP. RebelloT. AfableC. LuX. SlepushkinV. HumeauL.M. SchonelyK. NiY. BinderG.K. LevineB.L. MacgregorR.R. JuneC.H. DropulicB. Regulatory considerations for novel gene therapy products: A review of the process leading to the first clinical lentiviral vector.Hum. Gene Ther.2005161172510.1089/hum.2005.16.1715703485
     [Google Scholar]
  33. MaC-C WangZ-L XuT The approved gene therapy drugs worldwide: From 1998 to 2019.Biotechnology Adv.202040107502
     [Google Scholar]
  34. TakefmanD. BryanW. The state of gene therapies: the FDA perspective.Mol. Ther.201220587787810.1038/mt.2012.5122549801
     [Google Scholar]
  35. ElverumK. WhitmanM. Delivering cellular and gene therapies to patients: Solutions for realizing the potential of the next generation of medicine.Gene Ther.2020271253754410.1038/s41434‑019‑0074‑731024072
     [Google Scholar]
  36. MarksP. The FDA’s regulatory framework for chimeric antigen receptor-T cell therapies.Clin. Transl. Sci.201912542843010.1111/cts.1266631328862
     [Google Scholar]
  37. EisenmanD. SwindleS. FDA guidance on shedding and environmental impact in clinical trials involving gene therapy products.Appl. Biosaf.202227319119710.1089/apb.2022.002036779200
     [Google Scholar]
  38. LockeF.L. DavilaM.L. Regulatory challenges and considerations for the clinical application of CAR-T cell anti-cancer therapy.Expert Opin. Biol. Ther.201717665966110.1080/14712598.2017.132295328454503
     [Google Scholar]
  39. WillsC.A. DragoD. PietruskoR.G. Clinical holds for cell and gene therapy trials: Risks, impact, and lessons learned.Mol. Ther. Methods Clin. Dev.20233110112510.1016/j.omtm.2023.10112537886603
     [Google Scholar]
  40. DasguptaA. HerzeghK. SpencerH.T. DoeringC. DayE. SwaneyW.P. Regulatory framework for academic investigator-sponsored investigational new drug development of cell and gene therapies in the USA.Curr. Stem Cell Rep.20217412913910.1007/s40778‑021‑00196‑434608428
     [Google Scholar]
  41. GalaroK.A. SaeuiC. FDA perspective on the preclinical development of cell-based immunotherapies.Cell Gene Ther. Insights2020691381139010.18609/cgti.2020.148
     [Google Scholar]
  42. Approved cellular and gene therapy products (Internet).Available from: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-products 2023
  43. Statement from FDA Commissioner Scott Gottlieb, M.D. and Peter Marks, M.D., Ph.D Director of the Center for Biologics Evaluation and Research on new policies to advance development of safe and effective cell and gene therapies (Internet).Available from: https://www.fda.gov/news-events/press-announcements/statement-fda-commissioner-scott-gottlieb-md-and-peter-marks-md-phd-director-center-biologics 2019
  44. SchettG. MackensenA. MougiakakosD. CAR T-cell therapy in autoimmune diseases.Lancet2023402104162034204410.1016/S0140‑6736(23)01126‑137748491
     [Google Scholar]
  45. ZmievskayaE. ValiullinaA. GaneevaI. PetukhovA. RizvanovA. BulatovE. Application of CAR-T cell therapy beyond oncology: Autoimmune diseases and viral infections.Biomedicines2021915910.3390/biomedicines901005933435454
     [Google Scholar]
  46. PapaioannouI. OwenJ.S. MuñozY.R.J. Clinical applications of gene therapy for rare diseases: A review.Int. J. Exp. Pathol.2023104415417610.1111/iep.1247837177842
     [Google Scholar]
  47. BuerenJ.A. AuricchioA. Advances and challenges in the development of gene therapy medicinal products for rare diseases.Hum. Gene Ther.20233417-1876377510.1089/hum.2023.15237694572
     [Google Scholar]
  48. KallandM.E. BoirazianP.T. PalomoG.M. WinterN.F. CostaE. MatuseviciusD. DuarteD.M. MalikovaE. VitezicD. LarssonK. MagrelliA. BeninskaS.V. MarizS. Advancing rare disease treatment: EMA’s decade-long insights into engineered adoptive cell therapy for rare cancers and orphan designation.Gene Ther.2024202410.1038/s41434‑024‑00446‑038480914
     [Google Scholar]
  49. FDA Human gene therapy for rare diseases.Research CfBEa2020
     [Google Scholar]
  50. KohlerM. Regulatory pathways in the European Union.MAbs20113324124210.4161/mabs.3.3.1547421487236
     [Google Scholar]
  51. FontanaS.L.I. A regulatory risk-based approach to ATMP/CGT development: Integrating scientific challenges with current regulatory expectations.Front. Med.2022985510010.3389/fmed.2022.85510035646952
     [Google Scholar]
  52. FDA Formal meetings between the FDA and sponsors or applicants.CDER, CBER2009
     [Google Scholar]
  53. FDA M4 organization of the common technical document for the registration of pharmaceuticals for human use guidance for industry.(CDER) CfDEaR, (CBER) CfBEaR2017
     [Google Scholar]
  54. FDA Guidance-for-industry-providing-regulatory-submissions-in-electronic-format-—-human-pharmaceutical-product-applications-and-related-submissions-using-the-eCTD.(CDER) CfDEaR, (CBER) CfBEaR2008
     [Google Scholar]
  55. FDA Chemistry, manufacturing, and control (CMC) information for human gene therapy investigational new drug applications (INDs).Research CfBEa2020
     [Google Scholar]
  56. Manufacturing ChangesFDA. Manufacturing changes and comparability for human cellular and gene therapy products (Draft guidance).Research CfBEa2023
     [Google Scholar]
  57. FDA M3(R2) nonclinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals.(CDER) CfDEaR, (CBER) CfBEaR2010
     [Google Scholar]
  58. ICH ICH guideline M3(R2) on non-clinical safety studies for the conduct of human clinical trials and marketing authorisation for pharmaceuticals.European Medicines Agency2009
     [Google Scholar]
  59. FDA S12 nonclinical biodistribution considerations for gene therapy products guidance for industry.(CDER) CfDEaR, (CBER) CfBEaR2023
     [Google Scholar]
  60. EMA Guideline on the Non-Clinical Studies Required Before First Clinical Use of Gene Therapy Medicinal Products.Use CftMPfH2008
     [Google Scholar]
  61. MoffitJ.S. BlansetD.L. LynchJ.L. MacLachlanT.K. MeyerK.E. PonceR. WhiteleyL.O. Regulatory Consideration for the Nonclinical Safety Assessment of Gene Therapies.Hum. Gene Ther.20223321-22hum.2022.09010.1089/hum.2022.09035994386
     [Google Scholar]
  62. GeeA.P. How to design a cell or gene therapy clinical trial: Advice from the FDA.Mol. Ther.20132191639164010.1038/mt.2013.17224008615
     [Google Scholar]
  63. F.D.A. Considerations for the Design of Early-Phase Clinical Trials of Cellular and Gene Therapy ProductsResearch CfBEa2015
     [Google Scholar]
  64. ICH ICH guideline E8 (R1) on general considerations for clinical studies.(CHMP) CfHMP2021
     [Google Scholar]
  65. FDA E6(R2) Good Clinical Practice: Integrated Addendum to ICH E6(R1).(CDER) CfDEaR, (CBER) CfBEaR2018
     [Google Scholar]
  66. FDA. Establishment and Operation of Clinical Trial Data Monitoring Committees.(CBER) CfBEaR, (CDER) CfDEaR, (CDRH) CfDaRH2006
     [Google Scholar]
  67. PacudZ.Ż. LenarczykG. Clinical trial data transparency in the EU: Is the new clinical trials regulation a game-changer?IIC Int. Rev. Ind. Prop. Copyr. Law202354573276310.1007/s40319‑023‑01329‑437215361
     [Google Scholar]
  68. DragoD. CampbellF.B. WonnacottK. BarrettD. NduA. Global regulatory progress in delivering on the promise of gene therapies for unmet medical needs.Mol. Ther. Methods Clin. Dev.20212152452910.1016/j.omtm.2021.04.00133997101
     [Google Scholar]
  69. FDA Guidance for Industry: Expedited Programs for Serious Conditions.(CDER) CfDEaR, (CBER) CfBEaR2014
     [Google Scholar]
  70. FDA Guidance for industry: Expedited programs for regenerative medicine therapies for serious conditions.(CBER) CfBEaR2019
     [Google Scholar]
  71. EMA PRIME: priority medicinesAvailable from: https://www.ema.europa.eu/en/human-regulatory-overview/research-and-development/prime-priority-medicines [cited on: 2023]2023
  72. EMA PRIME: Analysis of the first 5 years’experienceFindings, learnings and recommendations2022
     [Google Scholar]
  73. LomashR.M. ShchelochkovO. ChandlerR.J. VendittiC.P. PariserA.R. OttingerE.A. Successfully navigating food and drug administration orphan drug and rare pediatric disease designations for AAV9-hPCCA gene therapy: The national institutes of health platform vector gene therapy experience.Hum. Gene Ther.2023345-621722710.1089/hum.2022.23236694456
     [Google Scholar]
  74. FDA Long term follow up after administration of human gene therapy products.Research CfBEa2020
     [Google Scholar]
  75. EMA Guideline on follow-up of patients administered with gene therapy medicinal products.CHMP2009
     [Google Scholar]
/content/journals/cgt/10.2174/0115665232306205240419091414
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Development of Cell and Gene Therapies for Clinical Use in the US and EU: Summary of Regulatory Guidelines
Curr. Gene Ther. 25, 10 (2025); https://doi.org/10.2174/0115665232306205240419091414
/content/journals/cgt/10.2174/0115665232306205240419091414
/content/journals/cgt/10.2174/0115665232306205240419091414
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  • Article Type:     Review Article
Keyword(s): cell therapy; DNA; EMA; FDA; gene therapy; Regulatory affairs; RNA

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