Cell & gene therapy clinical trials, development promoted in three new FDA guidance documents

Innovative clinical trial designs

In recent years, we have seen FDA increasingly promote innovative clinical trial designs. Most notably, the agency has issued guidances and recommendations on the use of decentralized clinical trials (DCTs) and global studies in efforts to promote development of rare disease treatments, help expedite drug development, and substantially increase the body of clinical evidence for new and approved drugs, as we previously analyzed online here.

Now, FDA has issued draft guidance entitled “Innovative Designs for Clinical Trials of Cellular and Gene Therapy Products in Small Populations,” which describes FDA requirements for the use of various clinical trial designs and endpoints to generate evidence to support licensure for CGT products, aimed at helping sponsors leverage the use of innovative trial designs that can simultaneously expedite drug development and generate data necessary to demonstrate substantial evidence of effectiveness.

In this new draft guidance, FDA recommends that sponsors discuss options for innovative clinical trial designs with the agency as early as possible, including:

• Single arm trials utilizing participants as their own control
• Disease progress modeling
• Externally controlled studies
• Adaptive clinical trial designs
• Bayesian trial designs
• Master protocol designs

The guidance also describes how considerations for participant selection include treatment landscape concerns, symptom status considerations, and study population representativeness.

Post-approval studies

The new draft guidance “Postapproval Methods to Capture Safety and Efficacy Data for Cell and Gene Therapy Products” also recommends methods of data generation, with a focus on postapproval data. The draft guidance discusses approaches for monitoring postapproval safety and efficacy data for CGT products and describes concerns that CGT sponsors should keep in mind when utilizing those methods. FDA solicited input on this topic at an April 2023 Office of Tissue Products (OTP) listening meeting, which the agency discussed at a separate listening meeting last week.

This guidance promotes the use of the following 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 a standardized format for a population defined by a particular disease, condition, or drug exposure
• Decentralized data collection, which FDA says can reduce travel time to the clinical study sites and thereby improve patient retention

While focused on postapproval data, the guidance nonetheless is a step forward in providing more flexibility to sponsors of these complex CGT products, including those intended for rare disease and those that qualify as regenerative medicine therapies and that are permitted to leverage a range of postapproval data sets to confirm the relationship between a surrogate endpoint on which an accelerated approval is granted and clinical benefits (more below).

RMAT expedited programs

The draft guidance “Expedited Programs for Regenerative Medicine Therapies for Serious Conditions” describes FDA programs available to sponsors of regenerative medicine therapies intended for serious or life-threatening diseases or conditions, including products that FDA has designated as “regenerative medicine advanced therapies” (RMATs). In the draft guidance, FDA’s Center for Biologics Evaluation and Research (CBER):

• encourages flexibility in clinical trial design to facilitate the development of data to demonstrate the safety and effectiveness of regenerative medicine therapies that are being developed to address unmet needs in patients with serious conditions;
• provides additional thinking on post-approval requirements and on approaches and processes relating to chemistry, manufacturing, and controls (CMC); and,
• describes opportunities for sponsors of regenerative medicine therapies to interact with CBER review staff.

When finalized, this will replace a February 2019 final guidance of the same name. Although largely similar to the 2019 version, the new draft guidance:

• emphasizes the importance of real-world evidence (RWE), describing how it “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,” in certain circumstances, and
• points out that RMAT-eligible products may also apply for FDA’s Platform Technology Designation Program, about which FDA issued draft guidance in June 2024, as we described online here. A Platform Technology is “a well-understood and reproducible technology, which may include a nucleic acid sequence, molecular structure, mechanism of action, delivery method, vector, or a combination of any such technologies that [FDA] determines to be appropriate.” The platform program described in the RMAT draft guidance aims to streamline drug development, manufacturing, and review for products using a platform technology.
• adds in a footnote excluding “products that are genetically modified but do not express a foreign transgene (e.g., an adenovirus vector that has been genetically modified with a deletion), and peptide therapeutic vaccines” from the definition of regenerative medicine therapy.
• stresses the importance of long-term safety monitoring for CGTs, clarifying that sponsors should “include in their specific monitoring plans both short-term and long-term safety monitoring, where the duration of long-term safety monitoring should be based on the type of the regenerative medicine therapy product.”
• encourages CGT sponsors to explore the feasibility of leveraging digital health technologies (DHTs) “for collecting the safety information necessary for achieving the goals of monitoring and follow up,” citing its 2023 DHT guidance.

Next steps

Across the three new draft guidances, it is clear that FDA is focused on using regulatory flexibility during the development and approval of products to treat rare diseases and unmet need, committing to a more collaborative approach than sponsors have historically experienced. This builds on efforts such as FDA’s recently announced “Rare Disease Evidence Principles” (RDEP), under which eligible drugs and biologics for ultra-rare diseases caused by known genetic defects will receive assurance of FDA consideration of additional supportive data that may be used to meet regulatory approval standards. We outlined the RDEP program announcement online here.

Another key theme we observed is the agency’s acknowledgment that many case-specific factors will affect their evaluations of study designs and data. Therefore, as always, early engagement with FDA is recommended during study design. In addition, if significant changes in the treatment landscape occur during a trial, sponsors can request an FDA meeting to determine how best to adapt the trial accordingly.

FDA invites comments on the guidance documents through November 24, 2025. If you may wish to submit a comment to any of the guidances, or have any questions on developing CGT products, innovative clinical trial designs, or post-approval studies, please contact any of the authors of this alert or the Hogan Lovells attorney with whom you regularly work.

Authored by Robert Church, Michael Druckman, and Bryan Walsh