The US Food and Drug Administration has released three comprehensive draft guidances designed to streamline the development and approval process for cell and gene therapies, with particular emphasis on innovative clinical trial designs for small patient populations. The guidance documents, published on September 24, 2025, represent a significant regulatory milestone in the agency's commitment under the Prescription Drug User Fee Act (PDUFA) VII to increase efficiency in CGT product development.
Innovative Trial Design Framework
The centerpiece guidance, titled "Innovative Designs for Clinical Trials of Cellular and Gene Therapy Products in Small Populations," addresses the urgent need for safe and effective products to treat serious and severely debilitating diseases in small populations. The FDA acknowledges the importance of innovative and efficient trial designs, including selection of appropriate endpoints that are feasible and capable of generating the necessary evidence for approval.
The agency has identified six specific trial design approaches for CGT sponsors:
- Single-arm trials utilizing participants as their own control
- Disease progression modeling
- Externally controlled studies
- Adaptive clinical trial designs
- Bayesian trial designs
- Master protocol designs
The FDA emphasizes that this list is not exhaustive and encourages sponsors to engage with the agency early in the development process to discuss additional innovative approaches.
Patient Selection and Endpoint Considerations
The guidance addresses critical considerations for patient selection in CGT trials, noting that sponsors should carefully evaluate patients' previous treatment histories before enrollment to ensure studies would facilitate generalizable results upon product approval. This approach recognizes the complex treatment landscapes often encountered in rare disease populations.
For endpoint selection, the FDA acknowledges unique challenges in CGT development where patients' symptoms may be mild or absent in certain cases. This uncertainty regarding symptom development timing and progression may require sponsors to consider trial designs that "incorporate surrogate endpoints, biomarkers, or intermediate clinical endpoints prior to symptom onset," potentially utilizing digital health technologies to capture meaningful changes in clinical function.
Post-Approval Data Collection Strategies
The second guidance, "Postapproval Methods to Capture Safety and Efficacy Data for Cell and Gene Therapy Products," focuses on methods for monitoring postapproval safety and efficacy data. The document promotes several strategies for capturing post-approval data:
- Real-world evidence (RWE) and real-world data (RWD)
- Electronic Health Records (EHRs), medical claims, and vital statistics data
- Registries that collect clinical and other data in standardized formats
- Decentralized data collection to reduce travel time and improve patient retention
This guidance builds on input solicited at an April 2023 Office of Tissue Products listening meeting and provides sponsors with greater flexibility in demonstrating ongoing product safety and efficacy.
Enhanced RMAT Program Guidelines
The third guidance, "Expedited Programs for Regenerative Medicine Therapies for Serious Conditions," updates and replaces the February 2019 final guidance of the same name. The updated document describes FDA programs available to sponsors of regenerative medicine therapies intended for serious or life-threatening diseases, including products designated as "regenerative medicine advanced therapies" (RMATs).
Key enhancements in the updated guidance include:
- Emphasis on real-world evidence, which "may be used to fulfill gaps in confirmatory evidence to verify and describe the clinical benefit of a regenerative medicine therapy granted RMAT designation and approved via accelerated approval"
- Integration with FDA's Platform Technology Designation Program for products using well-understood and reproducible technologies
- Exclusion of certain products from the regenerative medicine therapy definition, including "products that are genetically modified but do not express a foreign transgene and peptide therapeutic vaccines"
- Enhanced focus on long-term safety monitoring requirements
Pediatric Population Considerations
The guidance addresses specific requirements for pediatric studies, stating that sponsors must "address requirements for permission by parents/guardians and, where appropriate, assent by children, the level of risk posed to children as subjects, and additional safeguards."
When planning CGT clinical development programs, sponsors should consider whether the disease affects pediatric populations differently than adults, whether adult data would be relevant to pediatric patients, and what available data can support assessment of clinical benefit prospects in children.
Digital Health Technology Integration
The updated guidance encourages CGT sponsors to explore the feasibility of leveraging digital health technologies "for collecting the safety information necessary for achieving the goals of monitoring and follow up," referencing the agency's 2023 DHT guidance. This recommendation reflects the FDA's recognition of technology's potential to enhance data collection efficiency and patient experience.
Regulatory Flexibility and Collaboration
The three guidances demonstrate the FDA's commitment to regulatory flexibility during development and approval of products addressing rare diseases and unmet medical needs. This approach builds on recent initiatives such as the "Rare Disease Evidence Principles" program, under which eligible drugs and biologics for ultra-rare diseases caused by known genetic defects receive assurance of FDA consideration of additional supportive data.
The agency acknowledges that case-specific factors will significantly affect evaluations of study designs and data, reinforcing the importance of early engagement with FDA during study design. If significant changes in the treatment landscape occur during trials, sponsors can request FDA meetings to determine optimal trial adaptations.
Industry Impact and Implementation
Analysis by Clinical Trials Arena in May 2024 found that single-group assignment trial designs were the most commonly used approach for cell and gene therapies, with trial type determination typically based on patient population and indication characteristics, as suggested by the new FDA guidance.
The FDA has invited public comments on all three guidance documents through November 24, 2025, providing stakeholders an opportunity to contribute to the final regulatory framework that will govern CGT development in the coming years.
