Implications of FDA’s New Draft Guidance on Innovative Trial Design for Rare-Disease CGTs

In September 2025, FDA, through the Center for Biologics Evaluation and Research, issued a new draft guidance titled Innovative Designs for Clinical Trials of Cellular and Gene Therapy Products in Small Populations, which provides nonbinding recommendations to sponsors that are developing cell and gene therapy (CGT) products intended for conditions affecting small populations—typically those defined as rare diseases. The importance of this draft guidance to CGT developers and manufacturers lies in the fact that it promotes efficient and rigorous clinical trial design (1).

FDA created this guidance in response to the commitment outlined in the Prescription Drug User Fee Act VII (2) to enhance the efficiency of CGT development. Developing biological products for rare diseases faces major hurdles, including extremely limited patient numbers, sparse data to support regulatory decisions, and unique challenges related to product manufacturing and generation of nonclinical evidence. By recommending innovative trial designs, the agency aims to help sponsors leverage every collected data point, which expedites development while still generating substantial evidence of efficacy, which is necessary for product licensure.

What parameters are encouraged in the design of advanced clinical trials for CGTs aimed at treating rare diseases?

For sponsors working in CGT development, the core of this new guidance lies in the discussion of novel trial methodologies designed to succeed despite small patient populations. The document addresses several approaches that reduce the need for large, concurrent control groups, a critical factor when treating rare diseases. These approaches include single-arm trials in which participants act as their own control, comparing outcomes to a reliable baseline status. This design is particularly persuasive if the condition is universally degenerative and the intervention is expected to show improvement.

Another key concept is the use of externally controlled studies, which utilize historical or real-world data from patients who did not receive the investigational treatment as the comparator. Success in using this method depends on ensuring the external control and trial populations are highly similar regarding baseline characteristics and disease severity. Furthermore, Bayesian trial designs (3) are highlighted for their ability to explicitly incorporate clinical data external to the trial in analyses.

With this capability, researchers are allowed to augment concurrent control groups, thus potentially reducing the overall sample size needed for the study. The guidance also details adaptive clinical trial designs, which permit prospectively planned modifications—such as sample size reassessment or adaptive enrichment—based on accumulating data. According to FDA, these methods improve the chance of trial success when pre-trial clinical data is limited, which is often the case for novel CGT products (1).

How does this new guidance streamline product development and regulatory submission?

The implications of this new draft guidance are profound for the CGT sector. Given the complexity and cost associated with manufacturing CGT products, maximizing the data generated from each patient encounter is crucial. By providing pathways to utilize efficient designs, such as master protocols—which study multiple interventions or disease subtypes concurrently—or externally controlled studies, FDA acknowledges the urgent need for safe and effective therapies for severely debilitating diseases.

The guidance also provides specific considerations for participant selection, which directly affects development strategies. Under the guidance, sponsors are encouraged to carefully assess the current treatment landscape and note that trial entry criteria requiring participants to exhaust all available therapies may be unnecessarily restrictive when there is a significant unmet medical need. For diseases that may be asymptomatic early on, sponsors should consider incorporating surrogate endpoints, biomarkers, or intermediate clinical endpoints—which are often measurable using digital health technologies—to capture meaningful changes prior to full symptom onset.

In addition, encouraging broad representativeness in early trials is also recommended to increase the available participant pool for safety evaluation and potentially allow for data extrapolation to wider populations upon approval. Ultimately, these recommendations from FDA encourage sponsors to discuss innovative trial designs with the agency early in development to optimize the quality and interpretation of data for regulatory assessment.

References

1. FDA. Draft Guidance for Industry, Innovative Designs for Clinical Trials of Cellular and Gene Therapy Products in Small Populations (CBER, OTP, September 2025).
2. FDA. PDUFA VII: Fiscal Years 2023 – 2027. FDA.gov. Current as of April 24, 2023 (accessed Sept. 30, 2025).
3. Berry Consultants. A Bayesian Framework for Modern Trial Design. Blog post, berryconsultants.com. Aug. 9, 2025.