Key Takeaways
- The U.S. Food and Drug Administration (FDA) recently issued three draft guidances concerning development of cell and gene therapy (CGT) products. The guidances provide advice concerning qualifying CGTs for expedited review, alternative clinical trial designs for small populations, and post-approval confirmatory data.
- All three guidance documents stress the importance of early interaction with the FDA, and the need for long-term planning with regulatory requirements throughout a CGT product’s lifecycle. This collaborative approach is essential for avoiding regulatory delays, particularly for CGTs that treat rare disease or pediatric patients.
In a coordinated release last week, the FDA issued three draft guidance concerning development of cell and gene therapy (CGT) products. The guidances focus on different but related aspects of CGT development:
- Expedited Programs for Regenerative Medicine Therapies for Serious Conditions1
- Innovative Designs for Clinical Trials of Cellular and Gene Therapy Products in Small Populations2
- Postapproval Methods to Capture Safety and Efficacy Data for Cell and Gene Therapy Products3
Expedited Programs for Regenerative Medicine Therapies for Serious Conditions
The draft guidance Expedited Programs for Regenerative Medicine Therapies for Serious Conditions updates the FDA’s 2019 final guidance on the same topic. The guidance reaffirms that CGTs can qualify for any of the FDA’s expedited programs to treat serious or life-threatening conditions and address an unmet medical need.
This includes eligibility for Fast Track designation, Breakthrough Therapy designation, Priority Review, Accelerated Approval, and the Regenerative Medicine Advanced Therapy (RMAT) designation.4 While each designation has its own criteria and benefits, RMAT designation is intended specifically for CGTs and similar products.5 The designation provides intensive FDA-sponsor interaction, potential approval based on surrogate or intermediate clinical endpoints, and flexibility in post-approval requirements.
The guidance emphasizes that expedited review must be matched with Chemistry, Manufacturing, and Controls (CMC) readiness. Sponsors are encouraged to engage the FDA early in the development process to ensure product quality and manufacturing standards keep pace with clinical development. For example, a sponsor should establish controls for critical quality attributes well in advance of submitting a Biologics License Application (BLA). The FDA encourages sponsors to raise CMC questions early in development to prevent BLA delays.
Innovative Designs for Clinical Trials of Cellular and Gene Therapy Products in Small Populations
The second draft guidance, Innovative Designs for Clinical Trials of Cellular and Gene Therapy Products in Small Populations, describes methods to collect reliable effectiveness data in small populations. Recognizing that traditional randomized controlled trials may not be feasible for rare diseases, the guidance outlines a more flexible approach.
The guidance several innovative alternatives, such as single-arm trials using patients as their own control, disease progression modeling, externally controlled studies, adaptive and Bayesian methods, and master protocols.6 Sponsors must still demonstrate substantial evidence of effectiveness, the guidance acknowledges that alternative designs may be necessary for ultra-rare diseases.7
The FDA also provides practical advice for participant selection. Sponsors are encouraged to ensure that study populations reflect the broader target patient group, avoid symptom-based enrollment biases, and pay special attention to pediatric inclusion and assent.8 The guidance recommends that sponsors request early feedback from the FDA concerning the suitability and rigor of alternative trial designs.
Postapproval Methods to Capture Safety and Efficacy Data for Cell and Gene Therapy Products
The third draft guidance, Postapproval Methods to Capture Safety and Efficacy Data for Cell and Gene Therapy Products, addresses CGT development after marketing approval. For example, how real-world data (RWD) can provide confirmatory evidence to support an accelerated approval.
The guidance describes several potential sources of confirmatory RWD, such as electronic health records, insurance claims, mortality databases, and disease and product-specific registries.9 Decentralized data collection through telemedicine is encouraged, particularly over extended follow-up periods. The FDA places heightened importance on long-term follow-up because of the potential for delayed adverse events from durable or one-time treatments.
The agency also reminds sponsors that post-approval data collection must comply with human subject protection requirements. Sponsors should plan for continuity of these requirements during long-term follow-up, which can be particularly challenging with pediatric trials where follow-up extends into adulthood.10
This guidance complements the FDA’s emphasis on using real-world evidence to support regulatory decision-making and underscores sponsors’ continuing responsibilities through years of post-approval monitoring.
Conclusion
All three guidances are currently open for public comment. Taken together, they provide planks for different stages of CGT product development—from streamlined access to expedited programs, through flexible yet rigorous trial designs for small populations, to long-term post market monitoring strategies.
Sponsors and investors in the CGT space should view these guidances as a roadmap through the different stages of CGT development. Early planning, transparent interaction with the FDA, and a commitment to quality and compliance remain essential.
For additional information regarding development of CGT products and other FDA programs, please contact Wilson Sonsini attorneys Eva F. Yin or Daniel E. Orr.
[1] U.S. Food and Drug Administration, Expedited Programs for Regenerative Medicine Therapies for Serious Conditions: Draft Guidance for Industry (Sept. 2025), https://www.fda.gov/regulatory-information/search-fda-guidance-documents/expedited-programs-regenerative-medicine-therapies-serious-conditions-0.
[2] U.S. Food and Drug Administration, Innovative Designs for Clinical Trials of Cellular and Gene Therapy Products in Small Populations: Draft Guidance for Industry (Sept. 2025), https://www.fda.gov/regulatory-information/search-fda-guidance-documents/innovative-designs-clinical-trials-cellular-and-gene-therapy-products-small-populations.
[3] U.S. Food and Drug Administration, Postapproval Methods to Capture Safety and Efficacy Data for Cell and Gene Therapy Products: Draft Guidance for Industry (Sept. 2025), https://www.fda.gov/regulatory-information/search-fda-guidance-documents/postapproval-methods-capture-safety-and-efficacy-data-cell-and-gene-therapy-products.
[4] Expedited Programs, note 1 above, at 3-10.
[6] Innovative Designs, note 2 above, at 3-6.
