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Regulatory Focus™ > News Articles > 2020 > 7 > US regulations for regenerative medicine advanced therapies

US regulations for regenerative medicine advanced therapies

Posted 24 July 2020 | By Siegfried Schmitt, PhD 

US regulations for regenerative medicine advanced therapies

This article examines US regulations and guidance documents for regenerative medicine advanced therapies (RMATs). The author describes the field of regenerative medicine, noting that it is expanding at an accelerated pace, and outlines some of the common terms associated with it. He also addresses the application process for these therapies, accelerated regulatory pathways, market access, and the outlook for RMATs. The author cautions that, as exciting as these therapies are, they require a rigorous and carefully planned approach to ensure a seamless progression to regulatory approval and commercial success.
Regenerative medicine is a rapidly expanding field, offering the potential to treat serious and life-threatening conditions by replacing, or “regenerating,” human cells, tissues, or organs that have been damaged by disease, trauma, or congenital defects.1 With more than 200 investigational new drug (IND) applications anticipated by the US Food and Drug Administration (FDA) in 2020,2 regenerative medicine should yield many new therapies with enormous benefits to patients, especially those with unmet medical needs.
Navigating the complex regulatory environment of regenerative medicine requires companies to engage with the FDA early and often throughout the drug development process to identify and overcome potential obstacles to approval. Many of these therapies are developed by scientific institutions and medical research groups with limited inhouse regulatory resources, so it is advisable to seek external regulatory support early in the planning process.
Regenerative medicines defined
Regenerative medicines, as defined by the FDA, include cell therapies (non- and genetically modified), therapeutic tissue-engineering products, human cell and tissue products, and combination products using these biologic components, which lead to a sustained effect on cells and tissues.
In addition, a combination product (biologic device, biologic drug, or biologic device-drug) can be eligible for regenerative medicine advanced therapy (RMAT) designation when the biological product constituent part is a regenerative medicine therapy and provides the greatest contribution to the overall intended therapeutic effects of the combination product (i.e., the primary mode of action of the combination product is conveyed by the biological product constituent part). In January 2020, the FDA released six final guidances on gene therapy manufacturing and clinical development of products and a draft guidance.3
The FDA’s policy to advance the development of safe and effective cell and gene therapies can be found here.4 This article explains some of the terminology and covers the key US regulations and guidance documents. Discussions of a select number of these documents will be published in separate articles in Regulatory Focus.
Cellular & gene therapy products5
Cellular therapy products include cellular immunotherapies, cancer vaccines, and other types of autologous and allogeneic cells, including hematopoietic stem cells and adult and embryonic stem cells, for certain therapeutic indications. Human gene therapy seeks to modify or manipulate the expression of a gene or to alter the biological properties of living cells for therapeutic use. The FDA’s Center for Biologics Evaluation and Research (CBER) has approved both cellular and gene therapy products.5
Gene therapy6
Gene therapy is a technique that modifies a person’s faulty genes treat or cure disease and is most often applied to cancer, genetic diseases and infectious diseases. Gene therapies can work by several mechanisms:
  • Replacing a disease-causing gene with a healthy copy of the gene
  • Inactivating a disease-causing gene that is not functioning properly
  • Introducing a new or modified gene into the body to help treat a disease
The regulations
The FDA provides several guidance documents:
  • ANDAs for Certain Highly Purified Synthetic Peptide Drug Products That Refer to Listed Drugs of rDNA Origin, Guidance for Industry, October 20177
  • Appropriate Use of Voluntary Consensus Standards in Premarket Submissions for Medical Devices Guidance for Industry and Food and Drug Administration Staff, 14 September, 20188
  • Changes to an Approved Application: Biological Products, Guidance for Industry, July 19979
  • Clinical Considerations for Therapeutic Cancer Vaccines, Guidance for Industry, October 201110
  • Comparability Protocols for Human Drugs and Biologics: Chemistry, Manufacturing, and Controls Information, Guidance for Industry, April 201611
  • Considerations for the Design of Early-Phase Clinical Trials of Cellular and Gene Therapy Products Guidance for Industry, June 201512
  • Evaluation of Devices Used with Regenerative Medicine Advanced Therapies Guidance for Industry, February 201913
  • FDA announces comprehensive regenerative medicine policy framework, 15 November, 201714
  • Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products, Draft Guidance for Industry, December 201715
  • Guidance for FDA Reviewers and Sponsors Content and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Somatic Cell Therapy Investigational New Drug Applications (INDs), April 200816
  • Human Gene Therapy for Hemophilia, Guidance for Industry, January 202017
  • Human Gene Therapy for Rare Diseases, Guidance for Industry, January 202018
  • Human Gene Therapy for Retinal Disorders, Guidance for Industry, January 202019
  • Important Information for Human Cell, Tissue, and Cellular and Tissue-Based Product (HCT/P) Establishments Regarding Zika Virus Transmission Risk in the World, March 1, 201920
  • INTERACT Meetings - (Initial Targeted Engagement for Regulatory Advice on CBER Products)21
  • Interpreting Sameness of Gene Therapy Products Under the Orphan Drug Regulations, Draft Guidance for Industry, January 20203
  • Long Term Follow- Up After Administration of Human Gene Therapy Products, Guidance for Industry, January 202022
  • OTAT Learn23
  • Patient Listening Sessions24
  • References for the Regulatory Process for the Office of Tissues and Advanced Therapies25
  • Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use Guidance for Industry and Food and Drug Administration Staff, Corrected December 201726
  • Standards Development and the Use of Standards in Regulatory Submissions Reviewed in the Center for Biologics Evaluation and Research Guidance for Industry, March 2019 27
  • Testing of Retroviral Vector‐Based Gene Therapy Products for Replication Competent Retrovirus (RCR) during Product Manufacture and Patient Follow‐up, Guidance for Industry, January 202028
  • Updated Information for Human Cell, Tissue, or Cellular or Tissue-based Product (HCT/P) Establishments Regarding the COVID-19 Pandemic, 2 July 202029
Consensus standards
  • ASTM F2312‐11: Standard Terminology Relating to Tissue-Engineered Medical Products
  • ASTM F2383‐11: Standard Guide for Assessment of Adventitious Agents in Tissue-Engineered Medical Products
  • ASTM F2315 Standard Guide for Immobilization or Encapsulation of Living Cells or Tissue in Alginate Gels
  • ISO 13022:2012: Medical Products Containing Viable Human Cells ‐ Application of risk Management & Requirements for Processing Practices
  • ISO 20387:2018: Biotechnology ‐ Biobanking ‐ General requirements for biobanking
  • ISO 10993: Biocompatibility
Application process
The FDA approved the first gene therapy product on 30 August 2017. Guidance on the chemistry, manufacturing, and controls section of an application was updated only recently.30 This guidance applies to human gene therapy products and to combination products that contain a human gene therapy in combination with a drug or device. The FDA has established several accelerated approval pathways for regenerative medicines (see Table 1).31-34


The following figure shows CBER’s organisation for pre‐ and postmarket regulation35

Market access and outlook
As of May 2019, the FDA had granted 34 products FDA regenerative medicine advanced therapy designations.36 In all, 68 of the 100 designation applications were cell therapy products, 20 of the 34 RMAT granted products have orphan product designation, and 11 of the 34 have fast track designation. While the promise of regenerative medicines to cure disease is driving the field forward at an accelerated pace, developing these therapies require a rigorous and carefully planned approach to ensure a seamless progression to regulatory approval and commercial success.
ANDA, abbreviated new drug application; CBER, Center for Biologics Evaluation and Research; FDA, Food and Drug Administration; HCT/P, human cell, tissue, and cellular and tissue-based product; IND, investigational new drug; PDUFA, Prescription Drug User Fee Act; rDNA, ribosomal DNA; RMAT, regenerative medicine advanced therapy.
All references were accessed 23 July 2020.
  1. Food and Drug Administration. Expedited Programs for Regenerative Medicine Therapies for Serious Conditions. Guidance for industry. https://www.fda.gov/media/120267/download. Dated February 2019. Accessed 23 July 2020.
  2. Food and Drug Administration. Statement from FDA Commissioner Scott Gottlieb, MD and Peter Marks, MD, PhD, Director of the Center for Biologics Evaluation and Research, on new policies to advance development of safe and effective cell and gene therapies. https://www.fda.gov/news-events/press-announcements/statement-fda-commissioner-scott-gottlieb-md-and-peter-marks-md-phd-director-center-biologics. Dated 15 January 2019. Accessed 23 July 2020.
  3. Food and Drug Administration. Interpreting sameness of gene therapy products under the orphan drug regulations. Draft guidance for industry. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/interpreting-sameness-gene-therapy-products-under-orphan-drug-regulations. Dated January 2020.
  4. Food and Drug Administration. Approved cellular and gene therapy products. https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-products. Last updated 29 March 2019.
  5. Food and Drug Administration. Cellular & Gene Therapy Products. https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products. Last updated 20 June 2019.
  6. Food and Drug Administration. What is gene therapy? https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/what-gene-therapy. Last updated 25 July 2018.
  7. Food and Drug Administration. ANDAs for certain highly purified synthetic peptide drug products that refer to listed drugs of rDNA origin. Guidance for industry: Draft guidance. https://www.fda.gov/media/107622/download. Dated October 2017.
  8. Food and Drug Administration. Appropriate use of voluntary consensus standards in premarket submissions for medical devices. Guidance for industry and Food and Drug Administration Staff. https://www.fda.gov/media/71983/download. Dated 14 September 2018.
  9. Food and Drug Administration. Guidance for industry. Changes to an approved application: Biological products https://www.fda.gov/media/77277/download. Dated July 1997.
  10. Food and Drug Administration. Guidance for industry. Clinical considerations for therapeutic cancer vaccines. https://www.fda.gov/media/82312/download. Dated October 2011.
  11. Food and Drug Administration. Comparability protocols for human drugs and biologics: Chemistry, manufacturing, and controls information. Guidance for industry: Draft guidance. https://www.fda.gov/media/97148/download. Dated April 2016.
  12. Food and Drug Administration. Considerations for the design of early-phase clinical trials of cellular and gene therapy products. Guidance for industry. https://www.fda.gov/media/106369/download. Dated June 2015.
  13. Food and Drug Administration. Evaluation of devices used with regenerative medicine advanced therapies. Guidance for industry. https://www.fda.gov/media/120266/download. Dated February 2019.
  14. Food and Drug Administration. FDA announces comprehensive regenerative medicine policy framework. https://www.fda.gov/news-events/press-announcements/fda-announces-comprehensive-regenerative-medicine-policy-framework. Dated 22 February 2018.
  15. Food and Drug Administration. Formal meetings between the FDA and sponsors or applicants of PDUFA products. Guidance for industry. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/formal-meetings-between-fda-and-sponsors-or-applicants-pdufa-products-guidance-industry. Dated December 2017.
  16. Food and Drug Administration. Guidance for FDA reviewers and sponsors content and review of chemistry, manufacturing, and control (CMC) information for human somatic cell therapy investigational new drug applications (INDs). https://www.fda.gov/media/73624/download. Dated April 2008.
  17. Food and Drug Administration. Human gene therapy for hemophilia. Guidance for industry. https://www.fda.gov/media/113799/download. Dated January 2020.
  18. Food and Drug Administration. Human gene therapy for rare diseases. Guidance for industry. https://www.fda.gov/media/113807/download. Dated January 2020.
  19. Food and Drug Administration. Human gene therapy for retinal disorders. Guidance for industry. https://www.fda.gov/media/124641/download. Dated January 2020.
  20. Food and Drug Administration. Important information for human cell, tissue, and cellular and tissue-based product (HCT/P) Establishments Regarding Zika virus transmission risk in the world. https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/important-information-human-cell-tissue-and-cellular-and-tissue-based-product-hctp-establishments-1. Dated 1 March 2019.
  21. Food and Drug Administration. INTERACT meetings. (Initial targeted engagement for regulatory advice on CBER products). https://www.fda.gov/vaccines-blood-biologics/industry-biologics/interact-meetings. Dated 9 July 2020.
  22. Food and Drug Administration. Long term follow-up after administration of human gene therapy products. Guidance for industry. https://www.fda.gov/media/113768/download. Dated January 2020.
  23. Food and Drug Administration. OTAT learn. https://www.fda.gov/vaccines-blood-biologics/news-events-biologics/otat-learn. Dated 23 March 2018.
  24. Food and Drug Administration. Patient Listening Sessions. https://www.fda.gov/patients/learn-about-fda-patient-engagement/patient-listening-sessions. Dated 22 January 2020.
  25. Food and Drug Administration. references for the regulatory process for the office of tissues and advanced therapies. https://www.fda.gov/vaccines-blood-biologics/other-recommendations-biologics-manufacturers/references-regulatory-process-office-tissues-and-advanced-therapies. Dated 23 March 2018.
  26. Food and Drug Administration. Regulatory considerations for human cells, tissues, and cellular and tissue-based products: minimal manipulation and homologous use. Guidance for industry and Food and Drug Administration Staff. https://www.fda.gov/media/124138/download. Dated December 2017.
  27. Food and Drug Administration. Standards development and the use of standards in regulatory submissions reviewed in the center for biologics evaluation and research. Guidance for industry. https://www.fda.gov/media/124694/download. Dated March 2019.
  28. Food and Drug Administration. testing of retroviral vector-based human gene therapy products for replication competent retrovirus during product manufacture and patient follow-up. Guidance for industry. https://www.fda.gov/media/113790/download. Dated January 2020.
  29. Food and Drug Administration. Updated Information for human cell, tissue, or cellular or tissue-based product (HCT/P) establishments regarding the COVID-19 pandemic. https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/updated-information-human-cell-tissue-or-cellular-or-tissue-based-product-hctp-establishments. Dated 2 July 2020.
  30. Food and Drug Administration. Chemistry, manufacturing, and controls (CMC) information for human gene therapy investigational new drug applications (INDs). Guidance for industry.  https://www.fda.gov/regulatory-information/search-fda-guidance-documents/chemistry-manufacturing-and-control-cmc-information-human-gene-therapy-investigational-new-drug. Dated 31 January 2020.
  31. Food and Drug Administration. Cellular & gene therapy guidances. https://www.fda.gov/vaccines-blood-biologics/biologics-guidances/cellular-gene-therapy-guidances. Dated 14 February 2020.
  32. Food and Drug Administration. Expedited programs for regenerative medicine therapies for serious conditions. Guidance for industry. https://www.fda.gov/media/120267/download. Dated February 2019.
  33. Food and Drug Administration. Guidance for industry. Expedited programs for serious conditions - drugs and biologics. https://www.fda.gov/media/86377/download. Dated May 2014.
  34. Vatsan R. Regulatory review programs for CAR T-cell biological license applications. Presentation at RAPS Regulatory Convergence, September 2016.
  35. Eacho M. Presentation at CASSS Cell and Gene Therapy Products Symposium, June 12, 2019.
  36. Witten CM. FDA’s approach to the development of cell and gene therapy products. Presentation at CASSS Cell and Gene Therapy Products Symposium, June 10, 2019.
About the author
Siegfried Schmitt, PhD, is vice president, technical at Parexel International, providing strategic
compliance and consulting services to the regulated healthcare industries. Before joining Parexel,
he worked for major pharmaceutical and medical device companies, and for engineering and
compliance consulting firms. Schmitt is member of the editorial advisory committee for Regulatory
Focus. He can be reached at siegfried.schmitt@parexel.com.
Citation Schmitt S. US regulations for regenerative medicine advanced therapies Regulatory Focus. July 2020. Regulatory Affairs Professional Society.


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