With the emergence of cell-based therapies as viable treatment options readily accessible to patients, the scientific community and public have raised concerns regarding consumer accessibility and regulation enforcement. Opposing viewpoints regarding regulation have emerged, and efforts to maintain the balance between promoting scientific innovation and ensuring public safety has proved challenging. To further complicate matters, there is contradictory information regarding the clinical safety and efficacy of cell-based treatments. Herein, we outline the FDA’s regulatory framework for cell-based therapies and describe what we term the cutting edge, bleeding edge, and off the edge interventions. We conclude with a new classification system for regenerative cell-based therapies intended to further aid in delineating between the clinically and scientifically sound therapies to those that compel further scientific investigation.
There is controversy surrounding cell-based therapies. Patients have broad access to risky and unregulated stem cell therapies and this has raised concerns regarding regulation enforcement. Furthermore, there is contradictory evidence describing the clinical usefulness and safety of current therapies. Herein, we outline the FDA's regulatory framework for cellular therapies and describe what we define as the cutting edge, bleeding edge, and off the edge cell-based therapies. We describe a new classification system for regenerative cell-based therapies that stratifies interventions based on the supporting evidence and risk for harm. We intend to provide the scientific community with a systematic strategy to assess cell-based therapies and to further inform patients.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Price includes VAT (USA)
Tax calculation will be finalised during checkout.
Cyranoski D. Stem cells in Texas: cowboy culture. Nature. 2013;494(7436):166–8.
Turner L, Knoepfler P. Selling stem cells in the USA: assessing the direct-to-consumer industry. Cell Stem Cell. 2016 Aug;19(2):154–7.
Fu W, Smith C, Turner L, Fojtik J, Pacyna JE, Master Z. Characteristics and scope of training of clinicians participating in the US direct-to-consumer marketplace for unproven stem cell interventions. JAMA. 2019;321(24):2463–4.
Knoepfler PS, Turner LG. The FDA and the US direct-to-consumer marketplace for stem cell interventions: a temporal analysis. Regen Med. 2018;13(1):19–27.
Friedmann T. Lessons for the stem cell discourse from the gene therapy experience. Perspect Biol Med. 2005;48(4):585–91.
Bipartisan Policy Center. Advancing regenerative cellular therapy: medical innovation for healthier Americans [Internet]. 2015 [cited 2019 Aug 27]. Available from: https://bipartisanpolicy.org/report/advancing-regenerative-cellular-therapy-medical-innovation-for-healthier-americans/
U.S. Congress. S.2689-REGROW Act [Internet]. Senate, 114th Congress; 2016 [cited 2019 Aug 30]. Available from: https://www.congress.gov/bill/114th-congress/senate-bill/2689
U.S. Food and Drug Administration. Right to Try [Internet]. 2019. [cited 2019 Aug 30]. Available from: https://www.fda.gov/patients/learn-about-expanded-access-and-other-treatment-options/right-try
Yano K, Speidel A, Yamato M. Four Food and Drug Administration draft guidance documents and the REGROW act: a litmus test for future changes in human cell- and tissue-based products regulatory policy in the United States? J Tissue Eng Regen Med. 2018;12:1579–93.
Food and Drug Administration. Tissue and tissue product questions and answers [Internet]. [cited 2019 Jun 27]. Available from: https://www.fda.gov/vaccines-blood-biologics/tissue-tissue-products/tissue-and-tissue-product-questions-and-answers
Chirba, Mary Anne; Garfield SM FDA Oversight of Autologous Stem Cell Therapies: Legitimate Regulation of Drugs and Devices or Groundless Interference with the Practice of Medicine J Heal Biomed Law 2011;233–272.
Food and Drug Administration. Proposed approach to regulation of cellular and tissue-based products. [Internet]. Rockville, MD; 1997 [cited 2019 Jun 27]. Available from: https://www.fda.gov/media/70704/download
Food and Drug Administration. Code of Federal Regulations, Title 21, Part 1271 [Internet]. 2018 [cited 2019 Jul 30]. Available from: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=1271-.
Marks P, Gottlieb S. Balancing safety and innovation for cell-based regenerative medicine. N Engl J Med. 2018;378(10):954–9.
Food and Drug Administration. Suitability determination for donors of human cellular and tissue-based prodcuts [Internet]. Rockville, MD; 1999 [cited 2019 Jun 27]. Available from: https://www.govinfo.gov/content/pkg/FR-1999-09-30/pdf/99-25378.pdf
Food and Drug Administration. Current good tissue practice for manufacturers of human cellular and tissue-based products; inspection and enforcement [Internet]. Rockville, MD; 2001 [cited 2019 Jun 27]. Available from: https://www.federalregister.gov/documents/2001/01/08/01-447/current-good-tissue-practice-for-manufacturers-of-human-cellular-and-tissue-based-products
Food and Drug Administration. Regulation of human cells, tissues, and cellular and tissue-based products [Internet]. 2007 [cited 2019 Jun 27]. Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/regulation-human-cells-tissues-and-cellular-and-tissue-based-products-hctps-small-entity-compliance
Food and Drug Administration. FDA warns about stem cell therapies [Internet]. 2017 [cited 2019 Jul 1]. Available from: https://www.fda.gov/consumers/consumer-updates/fda-warns-about-stem-cell-therapies
Food and Drug Administration. FDA announces comprehensive regenerative medicine policy framework [Internet]. 2017 [cited 2019 Jun 12]. Available from: https://www.fda.gov/news-events/press-announcements/fda-announces-comprehensive-regenerative-medicine-policy-framework
Food and Drug Administration. Same surgical procedure exception under 21 CFR 1271.15(b) [Internet]. 2017 [cited 2019 Jun 30]. Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/same-surgical-procedure-exception-under-21-cfr-127115b-questions-and-answers-regarding-scope
Food and Drug Administration. Regulatory considerations for human cells, tissues, and cellular and tissue-based products: minimal manipulation and homologous use [Internet]. 2017 [cited 2019 Jun 20]. Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/regulatory-considerations-human-cells-tissues-and-cellular-and-tissue-based-products-minimal
Food and Drug Administration. Expedited programs for regenerative medicine therapies for serious conditions [Internet]. 2019 [cited 2019 Jul 2]. Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/expedited-programs-regenerative-medicine-therapies-serious-conditions
Food and Drug Administration. Federal court issues decision holding that US Stem Cell clinics and owner adulterated and misbranded stem cell products in violation of the law [Internet]. 2019 [cited 2019 Aug 13]. Available from: https://www.fda.gov/news-events/press-announcements/federal-court-issues-decision-holding-us-stem-cell-clinics-and-owner-adulterated-and-misbranded-stem
Food and Drug Administration. Statement on stem cell clinic permanent injunction and FDA’s ongoing efforts to protect patients from risks of unapproved products [Internet]. 2019 [cited 2019 Jul 15]. Available from: https://www.fda.gov/news-events/press-announcements/statement-stem-cell-clinic-permanent-injunction-and-fdas-ongoing-efforts-protect-patients-risks
United States of America v. US Stem Cell Clinic, LLC, et al. [Internet]. [cited 2019 Aug 30]. Available from: https://www.casewatch.net/fda/court/us_stem_cell/order_2019.pdf
Food and Drug Administration. Warning Letter US Stem Cell Clinic, LLC [Internet]. 2017 [cited 2019 Jun 25]. Available from: https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/us-stem-cell-clinic-llc-524470-08242017
Kuriyan AE, Albini TA, Townsend JH, Rodriguez M, Pandya HK, Leonard RE, et al. Vision loss after intravitreal injection of autologous “stem cells” for AMD. N Engl J Med. 2017;376:1047–53.
Daley G. Polar extremes in the clinical use of stem cells. N Engl J Med. 2017;367(11):1075–7.
Mandai M, Watanabe A, Kurimoto Y, Hirami Y, Morinaga C, Daimon T, et al. Autologous induced stem-cell-derived retinal cells for macular degeneration. N Engl J Med. 2017;376:1038–46.
Hiltzik M. U.S. judge rejects FDA bid to shut down stem cell clinics, dealing blow to regulators [Internet]. Los Angeles Times. 2020 [cited 2020 Jan 29]. Available from: https://www.latimes.com/business/story/2020-01-28/judge-fda-stemcell-clinics
Rodriguez RL, Frazier T, Bunnell BA, Mouton CA, March KL, Katz AJ, et al. Arguments for a Different Regulatory Categorization and Framework for Stromal Vascular Fraction. Stem Cells Dev. 2020; [Epub ahead of print]
Food and Drug Administration. Approved cellular and gene therapy products [Internet]. 2019. [cited 2019 Aug 20]. Available from: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-products
National Cancer Institute. CAR T cells: engineering patients’ immune cells to treat their cancers [Internet]. 2019 [cited 2019 Aug 1]. Available from: https://www.cancer.gov/about-cancer/treatment/research/car-t-cells
Kochenderfer J, Wilson W, Janik J, Dudley M, Stetler-Stevenson M, Feldman S, et al. Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. Blood. 2010;116(20):4099–102.
Food and Drug Administration. FDA approval brings first gene therapy to the United States [Internet]. 2017 [cited 2019 Aug 20]. Available from: https://www.fda.gov/news-events/press-announcements/fda-approval-brings-first-gene-therapy-united-states
Food and Drug Administration. Kymriah [Internet]. 2019 [cited 2019 Aug 20]. Available from: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/kymriah-tisagenlecleucel
Food and Drug Administration. Yescarata [Internet]. 2018 [cited 2019 Aug 20]. Available from: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/yescarta-axicabtagene-ciloleucel
National Heart Lung and Blood Institute. Cord blood transplantation study (COBLT) [Internet]. [cited 2019 Aug 1]. Available from: https://biolincc.nhlbi.nih.gov/studies/coblt/
Kurtzberg J. Update on umbilical cord blood transplantation. Curr Opin Pediatr. 2009;21(1):22–9.
Strauer B, Brehm M, Zeus T, Kostering M, Hernandez A, Sorg R, et al. Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation. 2002;106(15):1913–8.
Fisher S, Doree C, Mathur A, Taggart D, Martin-Rendon E. Stem cell therapy for chronic ischaemic heart disease and congestive heart failure. Cochrane Database Syst Rev. 2014;12.
Clifford D, Fisher S, Brunskill S, Doree C, Mathur A, Watt S, et al. Stem cell treatment for acute myocardial infarction. Cochrane Database Syst Rev. 2012;2.
Gyongyosi M, Haller P, Blake D, Rendon E. Meta-analysis of cell therapy studies in heart failure and acute myocardial infarction. Circ Res. 2018;123:301–8.
Fernandez-Aviles F, Sanz-Ruiz R, Climent AM, Badimon L, Bolli R, Charron D, et al. Global position paper on cardiovascular regenerative medicine. Eur Heart J. 2017;38(33):2532–46.
Whittle S, Johnston R, McDonald S, Worthley D, Campbell T, Buchbinder R. Stem cell injections for osteoarthritis of the knee. Cochrane Database Syst Rev 2019. 2019;(5).
Xia P, Wang X, Lin Q, Li X. Efficacy of mesenchymal stem cells injection for the management of knee osteoarthritis: a systematic review and meta-analysis. Int Orthop. 2015;39:2363–72.
Pas H, Winters M, Haisma H, Koenis M, Tol J, Moen M. Stem cell injections in knee osteoarthritis: a systematic review. Br J Sports Med. 2017;51:1125–33.
Yubo M, Yanyan L, Li L, Tao S, Bo L, Lin C. Clinical efficacy and safety of mesenchymal stem cell transplantation for osteoarthritis treatment: a meta-analysis. PLoS One. 2017;12(4):e0175449.
Jevotovsky D, Alfonso A, Einhorn T, Chiu E. Osteoarthritis and stem cell therapy in humans: a systematic review. Osteoarthr Cartil. 2018;26:711–29.
Browne J, Nho S, Goodman S, Della VC. American Association of hip and Knee Surgeons, hip society, and knee society position statement on biologics for advanced hip and knee arthritis. J Arthroplast. 2019;34:1051–2.
Sun Z, Li F, Zhou X, Chung K, Wang W, Wang J. Stem cell therapies for chronic obstructive pulmonary disease: current status of pre-clinical and clinical trials. J Thorac Dis. 2018;10(2):1084–98.
Moura M, Novaes MR, Zago Y, Eduardo E, Casulari L. Efficacy of stem cell therapy in amyotrophic lateral sclerosis: a systematic review and meta-analysis. J Clin Med Res. 2016;8(4):317–24.
Abdul Wahid S, Law Z, Ismail N, Azman Ali R, Lai N. Cell-based therapies for amyotrophic lateral sclerosis/motor neuron disease. Cochrane Database Syst Rev. 2016;11.
ISCT. Consumer Alert! ISCT Issues Patient Advice and Concern on Unproven Car-T-Cell preservation services [Internet]. 2019 [cited 2019 Aug 7]. Available from: https://www.worldstemcellsummit.com/2019/08/07/isct-issues-patient-advice-and-concern-on-unproven-t-cell-preservation-services/
Srivastava A, Mason C, Wagena E, Cuende N, Weiss DJ, Horwitz EM, et al. Part 1: defining unproven cellular therapies. Cytotherapy. 2016;18:117–9.
Chan S. Current and emerging global themes in the bioethics of regenerative medicine: the tangled web of stem cell translation. Regnerative Med. 2017;12(7):839–51.
Food and Drug Administration. Q9 Quality Risk Management [Internet]. 2006 [cited 2019 Nov 15]. Available from: https://www.fda.gov/regulatory-information/search-fda-guidancedocuments/q9-quality-risk-management
Food and Drug Administration. Code of Federal Regulations, Title 21, Volume 5, 21CFR312.32 [Internet]. 2019 [cited 2019 Nov 15]. Available from: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=312.32
Food and Drug Administration. Patient-reported outcome measures: use in medical product development to support labeling claims [Internet]. 2009 [cited 2019 Nov 15]. Available from: https://www.fda.gov/media/77832/download
ClinicalTrials.gov. Non-randomized, open-labeled, interventional, single group, proof of concept study with multi-modality approach in cases of brain death due to traumatic brain injury having diffuse axonal Injury [Internet]. 2016 [cited 2019 Nov 27]. Available from: https://clinicaltrials.gov/ct2/show/NCT02742857
Lewis A, Caplan A. Response to a trial on reversal of death byneurologic criteria. Critical Care. 2016.
Park G-Y, Kwon DR, Lee SC. Regeneration of Full-Thickness Rotator Cuff Tendon Tear After Ultrasound-Guided Injection With Umbilical Cord Blood-Derived Mesenchymal Stem Cells in a Rabbit Model. Stem Cells Transl Med. 2015;4(11):1344–51.
Marks P, Witten C, Califf R. Clarifying stem-cell therapy’s benefits and risks. N Engl J Med. 2017;376:1007–9.
Stadtmauer EA, O’Neill A, Goldstein LJ, Crilley PA, Mangan KF, Ingle JN, et al. Conventional-dose chemotherapy compared with high-dose chemotherapy plus autologous hematopoietic stem-cell transplantation for metastatic breast cancer. N Engl J Med. 2000;342:1069–76.
Laurencin CT, Nair LS. Regenerative Engineering: Approaches to Limb Regeneration and Other Grand Challenges. Regen Eng Transl Med. 2015;1(1):1–3.
Narayanan G, Bhattacharjee M, Nair LS, Laurencin CT. Musculoskeletal Tissue Regeneration: the Role of the Stem Cells. Regen Eng Transl Med. 2017;3(3):133–65.
Tang X, Daneshmandi L, Awale G, Nair LS, Laurencin CT. Skeletal Muscle Regenerative Engineering. Regen Eng Transl Med. 2019;5(3):233–51.
Kasir R, Vernekar VN, Laurencin CT. Regenerative Engineering of Cartilage Using Adipose-Derived Stem Cells. Regen Eng Transl Med. 2015;1:42–9.
Otsuka T, Phan AQ, Laurencin CT, Esko JD, Bryan SV, Gardiner DM. Identification of Heparan-Sulfate Rich Cells in the Loose Connective Tissues of the Axolotl (Ambystoma mexicanum) with the Potential to Mediate Growth Factor Signaling during Regeneration. Regen. Eng. Transl. Med. 2020. https://doi.org/10.1007/s40883-019-00140-3
Tang X, Saveh-Shemshaki N, Kan H-M, Khan Y, Laurencin CT. Biomimetic Electroconductive Nanofibrous Matrices for Skeletal Muscle Regenerative Engineering. Regen Eng Transl Med. 2019. https://doi.org/10.1007/s40883-019-00136-z
Barajaa MA, Nair LS, Laurencin,CT. Bioinspired Scaffold Designs for Regenerating Musculoskeletal Tissue Interfaces. Regen Eng Transl Med. 2019. https://doi.org/10.1007/s40883-019-00132-3
Nelson C, Khan Y, Laurencin CT. Nanofiber/Microsphere Hybrid Matrices In Vivo for Bone Regenerative Engineering: A Preliminary Report. Regen Eng Transl Med. 2018;4(3):133–41.
Ogueri KS, Escobar Ivirico, JL, Nair LS, Allcock HR, Laurencin CT. Biodegradable Polyphosphazene-based Blends For Regenerative Engineering. Regen Eng Transl Med. 2017;3(1):15–31.
Support from NIH DP1 AR068147 and the Raymond and Beverly Sackler Center for Biomedical, Biological, Physical, and Engineering Sciences is gratefully acknowledged.
Conflict of Interest
The authors declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human participants or animals performed by and of the authors.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Laurencin, C.T., McClinton, A. Regenerative Cell-Based Therapies: Cutting Edge, Bleeding Edge, and Off the Edge. Regen. Eng. Transl. Med. 6, 78–89 (2020). https://doi.org/10.1007/s40883-020-00147-1
- Stem cells
- Classification system
- Regenerative engineering