FDA issues guidances on CGT, regenerative medicine development

The US Food and Drug Administration (FDA) has published three draft guidances on developing cell and gene therapies (CGT) to treat rare diseases, conducting postapproval CGT studies, and using the agency's expedited programs to get regenerative medicine advanced therapies (RMAT) to market.

Trial designs for rare disease CGTs

FDA published draft guidance on innovative clinical trial designs for developing CGTs for small populations. The agency noted that while CGTs are particularly promising for rare diseases and conditions, proving the safety and efficacy of treatments with a limited patient pool is particularly difficult.

“FDA recognizes the significant challenges in developing drug and biological products for rare diseases, including small population sizes where limited data exist to support regulatory decision-making, sparse natural history knowledge, incompletely understood molecular pathogenetic mechanisms, and molecular and phenotypic heterogeneity,” said FDA. “These development challenges are further compounded by unique considerations for product manufacturing and the generation of nonclinical evidence to support a product’s pharmacology and toxicology profile for CGT products.”

To address the challenges associated with designing and conducting clinical trials for CGTs for rare diseases, FDA proposed that sponsors consider a non-exhaustive list of clinical trial designs, including single-arm trials in which the participants are their own control. The agency noted that the trial design uses an internal, baseline control strategy where patient response to a therapeutic measure is compared to their baseline status on that measure.

“When considering such a study design, sponsors should account for the overall course of the illness and goal of treatment,” said FDA. “Self-controlled studies can be particularly persuasive when a condition is universally degenerative in all affected individuals, and the intervention is expected to lead to improvement.

“However, in conditions that have waxing and waning course, or when the CGT is intended to slow rather than reverse progression, it can be challenging to demonstrate effectiveness without a concurrent control,” the agency added. “For such conditions, it is important to ensure that enrollment criteria do not lead to subjects beginning the trial with unusually severe symptoms.”

The guidance also proposes that sponsors consider trial designs such as disease progression modeling, externally controlled studies, adaptive trials, Bayesian trials, and master protocol designs that use multiple substudies.

Another major challenge in developing CGTs for rare diseases for unmet needs is that trial participation often requires patients to have exhausted all other possible treatments. However, FDA notes that such a requirement may not be appropriate or may be unnecessarily exclusive. Instead, the agency said sponsors should fully consider what treatments are available to patients before enrolling them in clinical trials.

“Sponsors are encouraged to carefully consider the treatment landscape and the effectiveness of available therapies prior to determining whether restriction of the trial to those who are no longer responding to available treatments is appropriate, and whether such an approach would facilitate generalizability of study results should the product be approved,” said FDA.

FDA also said sponsors should consider the patient’s symptom status and how well they represent the disease population. The agency said that in most cases, it is appropriate to enroll patient who are broadly representative of the disease as it can help increase the pool of trial participants.

“Broad representativeness in the enrolled population may also permit the collection of data that may be relied upon to extrapolate to populations beyond those enrolled in pivotal study(ies),” said FDA. “When appropriate, generally based on the product’s mechanism of action, broad representation of those with common genetic variants and phenotypes should be allowed to enroll.”

Stakeholders can comment on the guidance on www.regulations.gov through 23 November under docket no. FDA-2025-D-3403.

Draft guidance

Postapproval CGT evaluation

FDA also published a draft guidance on capturing CGT post-approval safety and efficacy data. The agency noted that CGT confirmatory clinical trials tend to have a limited number of participants before they are approved, so it is crucial to gather long-term postmarket data to monitor the products for safety and efficacy.

“Postapproval methods that capture safety and efficacy data can help balance premarket and postmarket data, including for CGT products approved under accelerated pathways,” said FDA. “The postapproval collection of real-world evidence (RWE) can add additional data to studies with small sample sizes, lack of comparators, and low completion rates.”

The agency also proposed postapproval methods in the guidance that may help researchers identify subgroup differences and adverse events. More specifically, it proposed four data sources that can help researchers gather postapproval information to understand the treatments better.

FDA proposed that sponsors look at real-world data (RWD) and real-world evidence (RWE). However, the agency also cautioned that sponsors should establish robust data governance structures to ensure data integrity and confidentiality. It also said electronic health records, medical claims and vital statistics data may be useful sources of information.

“Administrative medical claims, vital statistics, and electronic health records (EHRs) are not typically designed to collect data for evaluation of safety or effectiveness of medical products,” said FDA. “Therefore, sponsors should consider several important constraints when assessing fitness for use of these RWD sources for approved CGTs, especially in rare disease settings where patient numbers are limited, diagnosis is delayed, and clinical presentations are heterogeneous.”

FDA also said sponsors may want to consider decentralized data collection from clinical trials where at least some trials are conducted at locations other than the traditional clinical site and patient registries.

Stakeholders can comment on the guidance on www.regulations.gov through 23 November under docket no. FDA-2023-D-5365.

Draft guidance

Expediting RMATs

FDA issued draft guidance on how regenerative medicine advanced therapies (RMAT) sponsors can use the agency's expedited programs to get their products to market. The guidance will replace the agency’s 2019 guidance on the topic when finalized. The agency noted that RMATs are a subset of regenerative medicine therapies that are intended to treat life-threatening diseases or conditions.

Under the 21st Century Cures Act, RMATs were granted the use of FDA's accelerated approval pathway. The proposed guidance outlines the agency's thinking on qualifying for the pathway, considerations when developing RMATs, and opportunities for interacting with agency staff when developing the treatments.

“The programs described in this guidance are intended to facilitate development and review of regenerative medicine therapies intended to address an unmet medical need in patients with serious conditions,” said FDA. “In addition to the programs described in this guidance, regenerative medicine therapies may also be eligible for FDA’s Platform Technology Designation Program.

“Sponsors may be able to leverage information and relevant prior knowledge, when scientifically justified and legally permissible, outside of the platform technology designation program,” the agency added.

Stakeholders can comment on the guidance on www.regulations.gov through 23 November under docket no. FDA-2017-D-6159.

Draft guidance

FDA issues guidances on CGT, regenerative medicine development

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