Commenters seek details on RMAT designation

Commenters responding to the US Food and Drug Administration’s (FDA) draft guidance on the development of regenerative medicine therapies for serious or life-threatening diseases want more details from the agency on which products qualify for regenerative medicine advanced therapy (RMAT) designation. They also want FDA to provide more flexibility in clinical trial design, provide examples of rejected applications, and describe situations in which an application might be withdrawn.

FDA’s draft guidance, which, when finalized, will replace a February 2019 final guidance with the same title, includes information on how sponsors can bring regenerative medicine therapy products for serious conditions to market using the agency’s expedited programs, including the RMAT designation. RMATs may qualify for the accelerated approval pathway if they achieve a previously agreed-upon surrogate endpoint likely to result in clinical benefit and have data from a “meaningful number of sites.” The draft guidance also contains information on clinical development considerations for these therapies and how to engage with the Center for Biologics Evaluation and Research (CBER) staff (RELATED: FDA issues guidances on CGT, regenerative medicine development, Regulatory Focus, 25 September 2025).

Stakeholders were generally supportive of FDA’s recommendations for its expedited programs, preliminary clinical evidence, and a mention in the draft guidance that regenerative medicine products may also be eligible for the agency’s platform technology designation program. However, the draft guidance has raised questions about which products now fall under its purview, clinical trial design considerations, and how products intended to treat rare diseases can meet accelerated approval expectations based on data obtained from a meaningful number of study sites.

PhRMA

The Pharmaceutical Research and Manufacturers of America (PhRMA) asked FDA in its comment to specify which products are included in the draft guidance, including human gene therapies. “PhRMA asks that FDA explain when a human gene therapy might not meet the definition of a regenerative medicine therapy, if any such case exists,” according to the comment.

PhRMA also recommended FDA highlight whether the draft guidance should apply to cellular therapies, noting that language in a footnote on exclusions to the definition of regenerative medicine therapy includes “products that are genetically modified but do not express a foreign transgene,” which could be interpreted as excluding genetically modified cellular therapies.

The organization also recommended that FDA consider offering greater flexibility for the development of critical quality attributes (CQAs), pointing out that development can be iterative, and is often “poorly understood and/or composed of multiple attributes.” They suggested that the agency allow sponsors to use data from other products they own or other reference products to develop a CQA or analytical platform.

What may also be useful to include in the draft guidance provide are issues that are associated with a denial in an RMAT designation, a clarification of preliminary clinical evidence that can be generated with a comparable product, a cross-reference to specific portions of relevant guidelines to explain FDA’s definition of significant improvement of safety and effectiveness, and more information on how RMAT designation compares to breakthrough and fast track designation.

One area where the draft guidance appears to contradict the Federal Food, Drug, and Cosmetic Act is in the use of real-world evidence (RWE) for postmarketing requirements, PhRMA wrote. Although the text of the draft guidance notes real-world evidence can fill “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 some circumstances, the statute states that RWE may be used to meet postapproval requirements of regenerative medicine advanced therapy accelerated approval products.

ACRO

In its comment, the Association of Clinical Research Organizations (ACRO) agreed with FDA that some regenerative medicine therapies that are intended to treat conditions with unmet needs have small patient populations where prospective randomized clinical trials may not be feasible early in development, and described the agency’s inclusion of external controls and alternative study designs as potentially acceptable preliminary clinical evidence as useful.

However, this small patient population may be a potential impediment to the collection of data from a “meaningful number of study sites,” which is not elaborated on in the draft guidance, they explained.

“Given the very small numbers of patients and sites in ultra-rare indications, lack of clarity on the interpretation of ‘meaningful number’ may impact the ability to design feasible studies in ultra-rare indications,” they wrote. “Further clarification and interpretation of ‘meaningful number’ in different contexts and on acceptable alternatives would be welcome.”

FDA noted in the draft guidance that if a product no longer meets the qualifying criteria for an RMAT designation, the agency may rescind that designation. “We believe the draft guidance could be strengthened by further discussion and elaboration about the circumstances under which RMAT designation can be withdrawn,” ACRO wrote.

The agency could include scenarios in the draft guidance that describe a product that has had its RMAT designation rescinded alongside processes and expectations.

“We would also welcome recommendations for planning in order to help mitigate that risk” in addition to more information about whether the RMAT designation could be remediated or reconsidered with submission mitigation or corrective actions, ACRO said.

Other comments

The Alliance for Regenerative Medicine highlighted the removal of a line from the 2019 final guidance that sponsors could use INitial Targeted Engagement for Regulatory Advice on CBER producTs (INTERACT) to receive early advice from CBER on their products.

“Because INTERACT meetings are now a formal meeting type, reinstating reference to them would emphasize the value of early engagement, clarify FDA’s formal meeting structure, and help sponsors use these meetings effectively to support efficient development of regenerative medicine therapies,” they said.

The Institute for Gene Therapies noted that FDA’s draft guidance, while useful, is diverging from commentary outside the agency about these products. “While greater structure is welcome, unstable expectations around manufacturing comparability, novel endpoints, and real-world evidence threaten to impede rather than accelerate innovation,” they wrote.

“Looking ahead, we encourage the FDA to build on the logical architecture laid out in this draft guidance by further clarifying how sponsors may prospectively engage with critical manufacturing and quality control issues, how surrogate and intermediate endpoints may be used with confidence, and how real-world evidence may satisfy confirmatory requirements without undermining rigor,” they added.

Draft guidance

Commenters seek details on RMAT designation

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