Cell & Gene Therapies: Will 2025 Represent A Continuation Of FDA's 2024 Developments?

By Emily Marden and Kelly Cho, Sidley Austin

In recent years, the FDA has communicated a focus on advancing the development of cell and gene therapies (CGT), mirroring industry’s optimism that these therapies can potentially offer durable and targeted treatment options. Such therapies are regulated in the U.S. as biological products by FDA’s CBER and require approval of a biologics license application (BLA) under Section 351 of the Public Health Service Act prior to being marketed.

FDA’s attention to CGTs is reflected in the pace of recent approvals: in 2024, there were eight novel CGT approvals and at least six new indications approved for existing CGTs. This is an increase from prior years and an encouraging signal that FDA is poised to meet its previous projection of approving 10 to 20 CGTs a year by 2025.¹ Even as the pace of approvals appears to be increasing, however, FDA has made clear that it will continue to be very focused on the safety of these products.

In this article, we recap the significant FDA regulatory considerations for CGTs in 2024 and offer a preview of potential developments for 2025.

Robust Pipeline Of CGT Products

In 2023–2024, there were reported to be more than 2,500 active INDs for CGTs and around 1,300 active INDs for gene therapies on file with the Office of Therapeutic Products (OTP), the “super office” in CBER established to oversee such products.² For gene therapies, there are at least six candidates in preregistration phase in the United States and 35 in Phase 3 trials globally,³ signaling a robust pipeline that bodes well for the years ahead.  

CGTs For Rare Disease

CGTs continue to play a critical role in the treatment of rare disease — given that as much as 80% of rare disease is caused by single-gene defects — with seven out of eight (88%) novel CGTs approved last year with Orphan Drug designations.⁴

CBER has recently launched a number of initiatives focused on rare disease with CDER. These include the Rare Disease Innovation Hub, which is intended to serve as a point of collaboration and connectivity between the two centers. While there has been discussion in the past whether this initiative would come in the form of a separate center of excellence (akin to the Oncology Center of Excellence), it was finalized in the form of a hub co-led by the two center directors.⁵ A new senior leadership position, director of strategic coalitions, accountable to both center directors, was also created to promote collaboration between the centers and serve as the hub’s primary point of engagement for parties external to FDA.⁶ The hub structure will preserve application review decisions within the review divisions but leverage cross-agency expertise to address common scientific, clinical, and policy issues related to rare disease product development, particularly for products intended for smaller populations or for diseases where the natural history is variable and not fully understood.⁷

In 2024, CBER also chose four investigational CGTs for its Support for clinical Trials Advancing Rare disease Therapeutics (START) program, which is intended to accelerate the development of the chosen products by providing frequent access and enhanced communication with FDA staff.⁸

Notably, it remains uncertain whether rare disease treatments (that are also for a pediatric disease and meet other qualifying criteria) will continue to receive a highly sought-after rare pediatric disease priority review voucher, as the voucher program sunset in late 2024 without being renewed by Congress. The program is intended to incentivize the development of novel therapies for rare pediatric disease by providing a voucher that can be redeemed or sold to receive priority review for a different product. Under the current statutory provisions, FDA is not able to award a priority review voucher unless the drug was granted designation as a drug for a rare pediatric disease — generally known as the first step to receiving a voucher — before December 20, 2024.⁹

Currently, gene therapy products account for more than a quarter (28%) of all designations.¹⁰ Given their market value of approximately $100 million,¹¹ CBER Director Peter Marks has acknowledged that these vouchers may serve as a significant financial incentive for smaller gene therapy companies, for a voucher is “the one thing that makes it worthwhile to get that gene therapy for 20 or 30 people across the finish line,” and “otherwise, it’s completely non-viable.”¹²

International Harmonization

In 2024, CBER also took proactive steps to advance global regulatory convergence for gene therapies, including the Collaboration on Gene Therapies Global Pilot (CoGenT Global), which promises to advance the potential for collaborative review of gene therapy applications with other international regulators. The program, modeled after the Oncology Center of Excellence’s Project Orbis, would allow foreign regulators to participate in internal FDA meetings, share applications and supporting information, and collaborate on regulatory reviews.¹³

While CoGenT will initially launch with the European Medicines Agency (EMA) and focus on submission and review of gene therapy applications, it may be expanded to include chemistry, manufacturing, and controls (CMC) and nonclinical issues from earlier in the development cycle.¹⁴ CBER leadership has indicated that it is hopeful that the program will reduce duplication of efforts and facilitate global harmonization of regulation of gene therapies, ultimately expediting patient access to these products.

Mitigating Safety Considerations

Importantly, even as FDA works to advance CGT, the agency remains cautious about potential safety risks.

During a public listening meeting with patients and caregivers of CGT in September 2024, OTP identified a list of safety considerations and noted that the “newness” of these therapies and their use in small rare disease populations increase uncertainty about risk. OTP’s list of potential shorter-term risks from therapy administration included liver toxicity, hematologic toxicity, infection, and immune responses, as well as more delayed reactions, such as secondary cancer or malignancy, infection (e.g., potentially increased susceptibility to infections from CAR T cell therapies), immune responses (e.g., development of antibodies that decrease the effectiveness of the gene therapy or affect future treatments), reproductive or fertility effects, and off-target effects.¹⁵ As seen in 2024, when FDA becomes aware of any such risks, it may require a boxed warning or evaluate the need for further regulatory action.¹⁶ Accordingly, it is important to be aware of FDA’s specific safety focus and to continue to monitor how FDA reacts to signals going forward.

In addition, FDA currently continues to adhere to its recommendation for 15 years of long-term follow-up (LTFU) after gene therapy administration.¹⁷ Notably, however, the director of OTP has indicated that the agency is considering potential changes to the LTFU requirements and that “everything is on the table for revisiting and reassessing,”¹⁸ suggesting that there may be changes in this regard in the future.

CBER’s Guidance Agenda

CBER’s guidance agenda for 2025 — which we note was issued before the change in administrations — contains as many as 14 guidances geared toward CGTs and highlights the Center’s ongoing commitment to advancing these therapies.¹⁹ These guidances touch upon topics such as platform technologies in gene therapy products incorporating genome editing, post-approval methods to capture safety and efficacy data, and safety testing of human allogeneic cells expanded for use in cell-based products.

Of particular note, CBER indicates that it is planning to issue draft guidance on “Accelerated Approval of Human Gene Therapy Products for Rare Diseases,” a document that is likely to reflect the agency’s recent strategic emphasis of accelerated approval for this therapeutic category.

It remains to be seen if and how Marks’ past statements about accelerated approval for CGT will be reflected in the planned draft guidance. Marks has previously suggested that the guidance would divide accelerated approval for gene therapy products into three major categories, identifying two of these as appropriate for accelerated approval: (1) when sponsors can measure the gene therapy product (e.g., hemoglobin for hemophilia or beta thalassemia) and this correlates with an aspect of health, and (2) when the product itself may not be measurable but an upstream or downstream marker can be used as a proxy.²⁰ Marks has noted a caveat that accelerated approval could be more challenging for the more complex genetic diseases where there is no easily measurable marker that is directly associated with clinical benefit.

It will also be interesting to see whether the planned draft guidance reiterates that flexibility will be granted to therapies with Regenerative Medicine Advanced Therapy (RMAT) designations for verification of clinical benefit. Marks has previously stated that for these therapies, the center would consider accepting continued follow-up of subjects from the pivotal trial to provide the confirmatory evidence, rather than the conventional approach of requiring sponsors to conduct an additional clinical study.²¹ 

It will be important to monitor these and other CBER priorities as they continue to evolve under the new administration, particularly once a new Commissioner is confirmed at the FDA.

References

1. See FDA Statement, Statement from FDA Commissioner Scott Gottlieb, MD, and Peter Marks, MD, 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 (current as of January 15, 2019), https://www.fda.gov/news-events/press-announcements/statement-fda-commissioner-scott-gottlieb-md-and-peter-marks-md-phd-director-center-biologics.
2. See Anne Rowzee, Assoc. Dir. for Policy, OTP, CBER, RegenMedEd: Empowering Patients and Advocates to Advance Rare Disease Research (March 1, 2024), https://www.fda.gov/media/176632/download; Thousands of Gene and Cell Therapies are Inundating FDA Reviewers as the Agency Tries to Keep Up, Endpoints News (February 15, 2023), https://endpts.com/thousands-of-gene-and-cell-therapies-are-inundating-fda-reviewers-as-the-agency-tries-to-keep-up/.
3. See American Society of Gene & Cell Therapy, Gene, Cell & RNA Therapy Landscape Report, Q4 2024 Quarterly Data Report at 18, https://www.asgct.org/global/documents/asgct-citeline-q4-2024-report.aspx.
4. See supra, Anne Rowzee at n.2; FDA CBER OTP Listening Meeting Methods and Approaches for Capturing Post-Approval Safety and Efficacy Data on Cell and Gene Therapy Products (April 27, 2023), https://www.fda.gov/media/173146/download.
5. See FDA Official Discusses Agency’s New Rare Disease Innovation Hub, RAPS (September 26, 2024), https://www.raps.org/news-and-articles/news-articles/2024/9/fda-official-discusses-agency-s-new-rare-disease-i.
6. See FDA, FDA Rare Disease Innovation Hub Q&A (current as of January 15, 2025), https://www.fda.gov/industry/fda-rare-disease-innovation-hub/fda-rare-disease-innovation-hub-qa.
7. See FDA, FDA Rare Disease Innovation Hub (current as of January 15, 2025), https://www.fda.gov/industry/medical-products-rare-diseases-and-conditions/fda-rare-disease-innovation-hub.
8. See FDA, Support for Clinical Trials Advancing Rare Disease Therapeutics (START) Pilot Program (current as of June 27, 2024), https://www.fda.gov/science-research/clinical-trials-and-human-subject-protection/support-clinical-trials-advancing-rare-disease-therapeutics-start-pilot-program.
9. See 21 U.S.C.§ 360ff(b)(5)(A).
10. Mease et al., Analysis of the First Ten Years of FDA’s Rare Pediatric Disease Priority Review Voucher Program: Designations, Diseases, and Drug Development, Orphanet Journal of Rare Diseases 19:86 (2024), https://pmc.ncbi.nlm.nih.gov/articles/PMC10895788/pdf/13023_2024_Article_3097.pdf.
11. See id.
12. FDA Leadership Changes Tune on Pediatric Priority Review Voucher Benefit, Pink Sheet (July 24, 2024), https://insights.citeline.com/PS155019/FDA-Leadership-Changes-Tune-On-Pediatric-Priority-Review-Voucher-Benefit/.
13. See FDA’s START and CoGenT Pilot Programmes: Streamlining Rare Disease Drug Approvals (January 20, 2025), https://www.pharmaceutical-technology.com/analyst-comment/fda-start-cogent-pilot-programmes/.
14. See Gene Therapies: CoGenT Pilot Could Help With Regulatory Convergence Earlier In Development, Pink Sheet (September 25, 2024), https://insights.citeline.com/PS155279/Gene-Therapies-CoGenT-Pilot-Could-Help-With-Regulatory-Convergence-Earlier-In-Development/.
15. See Shelby Elenburg, M.D., OTP, CBER, Perspectives on Safety Considerations for Gene Therapies for Rare Diseases (September 20, 2024), https://fda.zoomgov.com/rec/play/TaCkPhf4h623CJ1KhKq9C1dNxrmwCYGo_cVJE66jzqUC4CX1
    VM-92MASxXhoKm6WqTolvZKsUyfdKsq-.V8BqsGqoK7Gwaqez?canPlayFromShare=true&from=share_recording_detail&continueMode=true&componentName=rec-play&originRequestUrl=https%3A%2F%2Ffda.zoomgov.com%2Frec%2Fshare%2F0RyJFN7cmkxd
    RDFJDCv8-0cerztjMPdR_RBJJ816Tqmub90QI22ICMjR1iqQ79pO.GTAUAM27q3-Qi0VJ.
16. See, e.g., FDA Requires Boxed Warning for T cell Malignancies Following Treatment with BCMA-Directed or CD19-Directed Autologous Chimeric Antigen Receptor (CAR) T cell Immunotherapies (current as of April 18, 2024), https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/fda-requires-boxed-warning-t-cell-malignancies-following-treatment-bcma-directed-or-cd19-directed.
17. See supra, Shelby Elenburg, at n.15.
18. See Shorter Gene Therapy Postmarket Studies ‘On The Table,’ Pink Sheet (January 9, 2025), https://insights.citeline.com/pink-sheet/advanced-technologies/cell-and-gene-therapies/shorter-gene-therapy-postmarket-studies-on-the-table-7472BU2NKZBRJIIZ6TEUGDGX4M/.
19. See FDA, Guidance Agenda: Guidance Documents CBER is Planning to Publish During Calendar Year 2025 (current as of January 2, 2025), https://www.fda.gov/media/120341/download.
20. See US FDA Gene Therapy Accelerated Approval Guidance Will Describe ‘Buckets’ Of Use Scenarios, Pink Sheet (April 23, 2024), https://insights.citeline.com/PS150140/US-FDA-Gene-Therapy-Accelerated-Approval-Guidance-Will-Describe-Buckets-Of-Use-Scenarios/.
21. See FDA 'Leans In' to Accelerated Approval for Rare Disease Drugs, MedPage Today (May 19, 2023), https://www.medpagetoday.com/special-reports/exclusives/104594.

About The Authors:

Emily Marden is senior counsel in law firm Sidley Austin's Global Life Sciences practice group. Her legal regulatory practice involves counseling clients at the cutting edge of technology, including cell and gene therapies, regenerative medicine, complex drugs and biologics, genomics and synthetic biology, as well as innovations in food and agriculture. In addition to her regulatory practice, Marden is an adjunct professor of law at New York University School of Law, where she co-teaches food and drug law and policy. She divides her time between Sidley’s New York and San Francisco offices and can be reached at emarden@sidley.com.

Kelly Cho is a senior managing associate in law firm Sidley Austin's Global Life Sciences practice group. She advises clients on a wide range of FDA regulatory and compliance matters affecting drugs, biological products, medical devices, and other regulated products. This assistance extends to marketing authorization pathways, FDA review and approval processes, regulatory exclusivities, postmarket compliance, advertising, registration and listing, and supply chain matters. She is located in Washington, D.C. and can be reached at kcho@sidley.com.