There are several expedited development and review alternatives for novel therapies for serious conditions. The Regenerative Medicine Advanced Therapy (RMAT) designation is for advanced therapies where preliminary clinical evidence indicates the therapy has the potential to address the unmet medical need. RMAT designation makes innovative products eligible for quicker development and review of a marketing application.

In recognition of the growing importance of regenerative therapies, RMAT designation was enacted in the 21^st Century Cures Act in December 2016, and the initiative aims to facilitate and expedite the development and review of regenerative medicines. During 2022 a total of 30 requests for RMAT were received by the FDA and 14 of them were granted.

The Regenerative Medicine Advanced Therapy (RMAT) designation is for advanced therapies intended to treat life-threatening conditions and preliminary clinical evidence indicates the therapy has the potential to address unmet medical need.

An investigational drug is eligible for RMAT designation if:

• it meets the definition of regenerative medicine therapy i.e., cell therapies, therapeutic tissue engineering products, human cell and tissue products, and combination products using any such therapies or products. (See guidance for more detailed definition).
• it is intended to treat, modify, reverse, or cure a serious condition; AND
• preliminary clinical evidence indicates that the regenerative medicine therapy has the potential to address unmet medical needs for such condition.

If RMAT designation is granted, the FDA will notify no later than 60 calendar days after submission. Failure to meet the qualifying criteria can also lead to the withdrawal of the RMAT designation.

The RMAT designation offers important benefits to drug sponsors. Requests for RMAT designation can be made at the same time as the submission of the IND or later. Requests should be submitted to the FDA's Center for Biologics Evaluation and Research (CBER) in the IND or an amendment to the IND. As RMAT designation requires preliminary clinical evidence, many requests will be submitted as amendments. According to FDA guidance, the requests should be submitted no later than the end of phase 2. The request should contain:

• A description of the product and the rationale for how it meets the definition of regenerative medicine therapy.
• A discussion backing the severity of the disease or condition that the therapy intends to treat. The risks and benefits of any currently available therapies.
• How the unmet medical needs are being addressed.
• The preliminary clinical evidence supporting the designation.

When determining whether the preliminary clinical evidence is sufficient to support RMAT designation, CBER consider factors, including but not limited to: the rigor of data collection; the consistency and persuasiveness of the outcomes; the number of patients or subjects, and the number of sites, contributing to the data; and the severity, rarity, or prevalence of the condition.

The regulators expect the preliminary clinical evidence showing the potential of the therapy to address unmet medical needs to be obtained from clinical investigations. In early development, this evidence may not come from prospective clinical trials with a concurrent control. Data can be provided from clinical investigations with appropriate historical controls or well-designed retrospective studies.  CBER will review the preliminary clinical evidence in each designation request and will make decisions on a case-by-case basis.

As regenerative therapies are right at the front line of medical innovation, the regulatory considerations may be addressed for the very first time, therefore there may be no best practice for what evidence is necessary to demonstrate safety while proving efficacy for each of these new therapies. Qualifying for RMAT designation conveys significant regulatory benefits and allows for potential regulatory challenges to be identified and addressed early in the development process. 

Advantages of the RMAT designation include:

• Activities to expedite development and review.
• Rolling review
• Intensive guidance on efficient drug development, beginning as early as Phase 1
• Organizational commitment involving senior managers.
• Early interactions with FDA

RMAT offers further accessibility to FDA guidance including early interactions to discuss surrogate or intermediate endpoints. By maintaining regular and timely interactions with the agency to receive their advice and feedback, drug development programs can be optimized for efficiency, resulting in faster access to safe medicines for patients. To effectively obtain valuable input from regulators, it is essential to communicate the narrative behind your data and ask well-defined and clear questions. Adhering to the advice provided by the agency will yield the best results.

RMAT's primary objective is to expedite the drug development and approval timeline, thereby enabling quicker access to new regenerative therapies. For drugs that show promise in treating a serious condition, the program offers closer collaboration with the Agency to provide more detailed feedback and a smoother track to the marketing application submission.  By optimizing every regulatory interaction through clear and well-prepared communication, a more direct path to approval can be established.