• Jacquie Mahon

2020: The Future of Cutting-Edge Medicines is Now

United States: Regenerative Medicine

The U.S. Food and Drug Administration (FDA) is currently reviewing more than 800 investigational new drug (IND) applications for gene and cell therapies.[1] (Box 1) The FDA predicts that by 2025, 10 to 20 cell- and gene-therapy products will be approved annually.[2] For gene therapy alone, the FDA foresees 40 to 60 product launches and >500,000 patients treated by 2030.[3] Cell therapy, while also surging, faces bioengineering challenges in reproducibly manufacturing and administering cells to thousands of patients.[4] Limitations in the manufacture of cell therapies include cell harvesting, expansion, manipulation, purification, preservation, and formulation.[4]

The combination gene/cell/immunotherapy called chimeric antigen receptor T-cell (CAR-T) therapy is the subject of 111 active investigations as of June 30, 2018.[5] Of note, 44% of these are CD-19 directed. Hematologic cancers comprise 68% of the CAR-T investigations; the rest are solid cancers.[5]

Expectations are high for gene and cell therapies because they have the potential to cure previously incurable diseases.[5] Regulatory bodies are scrambling to keep up with the pace of innovation. The FDA released six gene-therapy guidance documents[5] for comment in July 2018; all are still in draft form:

FDA’s Center for Biologics Evaluation and Research (CBER) is working to streamline the review and safety reporting requirements for gene-therapy protocols.[7] The agency plans to add about 50 clinical reviewers dedicated to oversight of cell and gene therapies,[2] doubling the current number of reviewers.[8] Accelerated product development pathways offered by the FDA now include the Regenerative Medicine Advanced Therapy (RMAT) designation, created as part of the 21st Century Cures Act in 2016 (Figure 1; Box 2). RMAT includes all the benefits of the Fast Track and Breakthrough Therapy designations, including early interactions with the agency.[1] It may allow regenerative therapy developers to conduct smaller, shorter trials.[9] As of September 2019, 44 RMAT designations have been granted,[10] most recently for CAR T-cell therapy CT053 for the treatment of relapsed/refractory multiple myeloma.[11]

Figure 1. FDA accelerated product-development pathways.[1,5]

In addition, CBER has implemented the Initial Targeted Engagement for Regulatory Advice on CBER products (INTERACT) program to facilitate communication with the FDA at an early developmental stage.[5] INTERACT will provide sponsors of innovative products with informal regulatory advice about preclinical requirements, manufacturing, and clinical development programs even before the start of any formal regulatory filings.[7]

The National Institutes of Health (NIH) has undertaken similar efforts. For example, the NIH’s Recombinant DNA Advisory Committee has transitioned to become the Novel and Exceptional Technology and Research Advisory Committee (NExTRAC). NExTRAC will facilitate transparent discussions about the scientific, safety, ethical, and social issues associated with emerging biotechnologies.[12] The inaugural meeting was held December 5–6, 2019.[12]

See Tables 1–3 for currently FDA-approved cell and gene therapies.

Europe: Advanced Therapy Medicinal Products

Europe has been a pioneer of what the European Medicines Agency (EMA) calls “advanced therapy medicinal products” (ATMPs) and was the first region to adopt specific regulation for their development and approval.[13] To date, the EMA has granted the most marketing authorizations for ATMPs worldwide. During 2014–2018, however, the number of advanced-therapy clinical trials in Europe has stalled, growing by only 2%. Comparatively, the number of these trials in North America and Asia rose by 36% and 28% in the same period.[13]

Key issues in Europe include the fragmentation of regulatory bodies and ethical committees and lack of process harmonization. In addition, gene therapies are classified as “genetically modified organisms” in Europe, requiring an extra approval and adding complexity to the clinical-trial authorization process.[13] Moreover, Clinical Trial Directive 2001/20/EC allows 90 days for the review of clinical-trial applications for ATMPs, with a possible 90-day extension. Other types of medicinal products require a decision within 60 days, and even with the longer timeline, ATMP decisions are often delayed beyond the extension period. A new Clinical Trial Regulation expected to be implemented by the end of 2020 offers streamlining, but does not substantially improve timelines.[13]

Several potentially remedial initiatives are underway.[14] For example, in 2014, a public-private partnership between the European Federation of Pharmaceutical Industries and Associations and the European Commission devised the “Medicine Adaptive Pathways to Patients” initiative. It facilitates up-front agreement with the EMA about the development plan across target populations and indications.[14]

The EMA launched Priority Medicines (PRIME) in 2016 specifically to optimize regulatory strategies and expedite pathways for ATMPs.[15] PRIME uses existing EU regulatory tools—such as scientific advice (formal dialogue with the EMA), conditional approval, and accelerated assessment—"to define and optimize the development pathway for priority medicines addressing high unmet medical need and/or demonstrating therapeutic innovation.”[15] Also, steps have been taken (eg, guidelines and a common application form) to begin harmonizing GMO authorizations across Europe.[15] Thus, after a slow start, gene and cell therapies in Europe are likely to advance rapidly in the coming years.

See Tables 4–6 for currently EMA-approved cell and gene therapies and tissue-engineering products.

Challenges with Rapid Development

The commercial market for regenerative medicines has grown fast. For example, in the US as of May 2017, at least 716 clinics offered stem-cell therapies.[9] Regrettably, unauthorized interventions that have not been submitted to the appropriate regulatory bodies for efficacy and safety review are directly marketed to consumers around the world as regenerative treatments and stem-cell therapies.[9,16,17] These unapproved treatments are concerning for public-health officials, hopeful patients, and many others.[9] The only stem cell-based products that are FDA-approved for use in the United States consist of blood-forming stem cells (hematopoietic progenitor cells) derived from cord blood (Box 3). These products are approved for patients with disorders that affect the hematopoietic (blood-production) system. Bone marrow also is used for these treatments, but is generally not regulated by the FDA for this use.[18]

FDA officials have used aggressive measures to remove high-risk treatments from the marketplace.[20] In June 2019, a federal judge ruled in favor of the FDA in a lawsuit against a Florida-based stem cell company, U.S. Stem Cell, whose treatments blinded at least four patients.[21] In Europe, despite clear EMA legislation regarding ATMPs, the regulation of unproven stem-cell therapies has been difficult to enforce and inconsistent across jurisdictions.[22]

Simultaneously, however, access to approved cutting-edge medicines continues to be a problem. One cause is the lack of international coordination in the harmonization of regulatory requirements for regenerative medicine clinical trials.[17] The FDA recently stated that reducing differences among European, US, and Canadian regulations and availability of a globally developed general regulatory framework would expedite patient access, since developing regulations from scratch is challenging.[3] The FDA’s practical next steps include[3]:

  • More actively seeking harmonization of regulatory approach in high-income countries

  • Scheduling meetings among US, EU, Canada, others

  • Encouraging sponsors that are considering global development programs that include the US to invite other regulators to early-stage meetings

  • Working with the World Health Organization to produce a white paper on a potential regulatory framework for cell and gene therapies for low- and middle-income countries

  • Promoting international collaboration on advancing methods for production of gene therapies

  • Developing public-private partnerships that can facilitate gene therapy for ultra-rare disorders

While efforts like the RMAT designation that facilitate expedited-development pathways are laudable, they also increase the burden on the FDA to enforce post-approval study requirements for confirmation of safety and efficacy. The agency has historically struggled to meet this responsibility.[9] The balance between timely patient access and the meeting of key protective standards is challenging.[1]

Coming To Market

Truly revolutionary cell and gene therapies have become available in many therapeutic areas. They have changed standards of care and modified or even cured diseases. While the number of approved advanced therapies is small, many more are in preclinical and clinical development. Global collaboration is important because the science is evolving rapidly, while manufacturing technology is lagging behind.[3] Current regulatory and policy initiatives seek to encourage innovation and expedite review. Global regulatory convergence among high-income countries could help with commercial availability of advanced medicines in low- and middle-income countries. In addition, innovative reimbursement models must be implemented; for example, to cover a one-time treatment curing a chronic disease. Vigilance is essential in all of these areas, and as our knowledge grows, so too will the availability, efficacy, and safety of these products.


1. Woodcock J, Marks P; for the US FDA. Delivering Promising New Medicines Without Sacrificing Safety and Efficacy. August 27, 2019. Accessed January 3, 2020 at www.fda.gov/news-events/fda-voices-perspectives-fda-leadership-and-experts/delivering-promising-new-medicines-without-sacrificing-safety-and-efficacy

2. US FDA. 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. January 15, 2019. Accessed January 3, 2020 at www.fda.gov/news-events/press-announcements/statement-fda-commissioner-scott-gottlieb-md-and-peter-marks-md-phd-director-center-biologics

3. Marks P, for the US FDA. The Relevance of Global Convergence to Accelerating the Availability of Gene Therapies. ASGCT Policy Summit on Global Regulatory Issues. November 4, 2019. Accessed January 3, 2019 at www.asgct.org/advocacy/policy-summit/regulatory-november-4-asgct-policy-summit

4. Aijaz A, Li M, Smith D, et al. Biomanufacturing for clinically advanced cell therapies. Nat Biomed Eng.2018;2(6):362-76.

5. Vatsan RS, for the US FDA Center for Biologics Evaluation and Research. Regulatory Expectations for Cell and Gene Therapies. Presentation at 4th PQRI/FDA Conference on Advancing Product Quality: Patient-Centric Product Design, Drug Development, and Manufacturing. April 9-11, 2019. Available at https://pqri.org/4th-fda-pqri-conference-on-advancing-product-quality-presentations/

6. American Society of Gene and Cell Therapy. Gene and cell therapy FAQs. 2020. Accessed January 15, 2020 at www.asgct.org/education/more-resources/gene-and-cell-therapy-faqs

7. Marks P; for the U.S. FDA. FDA's Efforts to Advance the Development of Gene Therapy. May 1, 2019. Accessed January 2, 2020 at www.fda.gov/news-events/fda-voices-perspectives-fda-leadership-and-experts/fdas-efforts-advance-development-gene-therapy

8. Usdin S; news release for BioCentury. FDA Promising Carrots and Sticks for Gene, Cell Therapy Developers. January 15, 2019. Accessed January 3, 2020 at www.pharmavoice.com/newsreleases/fda-promising-carrots-sticks-gene-cell-therapy-developers/

9. The Pew Charitable Trusts. Report: FDA’s Framework for Regulating Regenerative Medicine Will Improve Oversight. October 17, 2019. Accessed January 3, 2020 at www.pewtrusts.org/en/research-and-analysis/reports/2019/10/17/fdas-framework-for-regulating-regenerative-medicine-will-improve-oversight

10. US FDA. Cumulative CBER Regenerative Medicine Advanced Therapy (RMAT) Designation Requests Received by Fiscal Year, December 13, 2016 to September 30, 2019. Accessed January 2, 2020 at www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/cumulative-cber-regenerative-medicine-advanced-therapy-rmat-designation-requests-received-fiscal

11. Adis Insight. Drug profile: CT 053 CAR T-cell therapy. Accessed January 3, 2020 at https://adisinsight.springer.com/drugs/800050542

12. National Institutes of Health, Office of Science Policy. Introducing the NExTRAC. April 24, 2019. Accessed January 3, 2020 at https://osp.od.nih.gov/2019/04/24/introducing-the-nextrac/

13. Alliance for Regenerative Medicine. Clinical Trials in Europe: Recent Trends In ATMP Development. October 2019. Accessed January 2, 2020 at https://alliancerm.org/publications-presentations/

14. Corbett MS, Webster A, Hawkins r, Woolacott N. Innovative regenerative medicines in the EU: a better future in evidence? BMC Med. 2017;15:49.

15. Detela G, Lodge A. EU regulatory pathways for ATMPs: standard, accelerated and adaptive pathways to marketing authorisation. Mol Ther Methods Clin Dev.2019;13:205-32.

16. Bianco P, Barker R, Brüstle O, et al. Regulation of stem cell therapies under attack in Europe: for whom the bell tolls. EMBO J. 2013;32(11):1489-95.

17. Kleiderman E, Boily A, Hasilo C, Knoppers BM. Overcoming barriers to facilitate the regulation of multi-centre regenerative medicine clinical trials. Stem Cell Res Ther. 2018;9:307.

18. US FDA. FDA Warns About Stem-Cell Therapies. September 3, 2019. Accessed January 3, 2020 at www.fda.gov/consumers/consumer-updates/fda-warns-about-stem-cell-therapies

19. Seoane‐Vazquez E, Shukla V, Rodriguez‐Monguio R. Innovation and competition in advanced therapy medicinal products. EMBO Mol Med. 2019;11(3):e9992.

20. Richardson L, for The Pew Charitable Trusts. FDA and congress move to stop unproven stem cell interventions. August 22, 2019. Accessed January 5, 2020 at www.pewtrusts.org/en/research-and-analysis/articles/2019/08/22/fda-and-congress-move-to-stop-unproven-stem-cell-interventions

21. US FDA. Federal court issues decision holding that US Stem Cell clinics and owner adulterated and misbranded stem cell products in violation of the law. FDA News Release. June 4, 2019. Accessed January 10, 2020 at www.fda.gov/news-events/press-announcements/federal-court-issues-decision-holding-us-stem-cell-clinics-and-owner-adulterated-and-misbranded-stem

22. MacGregor C, Petersen A, Munsie M; for EuroStemCell. Regulation of unproven stem cell therapies – medicinal product or medical procedure? August 30, 2015. www.eurostemcell.org/regulation-unproven-stem-cell-therapies-medicinal-product-or-medical-procedure

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Jacqueline M. Mahon, MA
Medical/Health Writer & Communications Consultant
Clarifying complex ideas

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