In September 2025, the Food and Drug Administration (FDA) issued three draft guidance documents designed to facilitate the continued development of novel cell and gene therapies. The recommendations include guidance regarding innovative trial designs, expediting programs for regenerative therapies and post-approval recommendations. Comments on the first two guidance documents are due to the FDA by Nov. 24, 2025, and comments on the post-approval recommendation guidance are due Dec. 24, 2025.
Innovative Trial Designs
The innovative trial design guidance outlines the FDA recommendations for innovative clinical trial designs for cellular and gene therapy products, particularly those aimed at small populations, targeting those with rare diseases. Sponsors are encouraged to engage with the FDA early in the process to discuss trial design options and ensure compliance with regulatory expectations.
The recommendations expand on existing FDA guidance by providing recommendations for trial design, endpoints and data generation to support product licensure, especially for rare diseases These include:
- Single Arm Trials: These trials use participants as their own controls, comparing their responses to therapy against their baseline data.
- Disease Progression Modeling: This quantitative approach characterizes disease progression over time, incorporating various factors to inform trial design.
- Externally Controlled Studies: These studies utilize historical or real-world data as a comparator group instead of a concurrent control arm.
- Adaptive Clinical Trial Designs: These allow for modifications based on accumulating data, including group sequential designs, sample size reassessment, adaptive enrichment and adaptive dose-selection.
- Bayesian Trial Designs: These designs incorporate external clinical data to enhance analyses, potentially reducing sample size requirements and improving estimates of treatment effects in subgroups.
- Master Protocol Designs: These involve multiple sub-studies under a single protocol, allowing concurrent evaluation of various interventions or conditions, which can address heterogeneity in clinical presentations.
Expedited Programs for Regenerative Medicine Therapies
The expedited programs guidance reviews five FDA expedited programs—Fast Track designation, Breakthrough Therapy (BT) designation, Regenerative Medicine Advanced Therapy (RMAT) designation, accelerated approval, and priority review designation—as they apply to regenerative medicine therapies.
Regenerative medicine therapies include allogenic and autologous cell therapies, human gene therapies, therapeutic tissue engineering products and human cell and tissue products. For regenerative medicine therapies, the guidance emphasizes flexibility, especially with increasing rarity of the disease, in clinical trial design, and it provides two examples of novel endpoints. The guidance encourages sponsors to engage early with the FDA.
Important takeaways from this guidance include:
- RMAT designation provides cell and gene therapies (and regenerative therapies more generally) with the benefits of BT designation with a lower evidentiary standard.
- It is important to pursue more rapid manufacturing development and use CMC quality product if a product is to take advantage of BT or RMAT designations or even approval using early clinical data because FDA expects early clinical evidence to be generated using the same or “comparable” product to what will be approved.
Post-Approval Study Guidance
This draft guidance outlines methods for capturing post-approval safety and efficacy data for cell and gene therapy products. The guidance emphasizes the importance of post-approval monitoring for cell and gene therapy (CGT) products due to their potential long-lasting effects and the limited number of participants in premarket clinical trials. It highlights the need for additional data to understand long-term safety and effectiveness, particularly for pediatric patients who may require extended follow-up. The guidance is part of the FDA’s commitment under the Prescription Drug User Fee Act (PDUFA VII) and reflects input from stakeholders on various data collection methods.
The guidance aims to facilitate the collection of comprehensive post-approval data for CGT products, enhancing understanding of their long-term safety and effectiveness. By employing diverse methodologies and ensuring robust data governance, sponsors can contribute valuable insights that inform regulatory decisions and improve patient outcomes.
