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Replies to post #105424 on Creative Medical Technology Holdings Inc (CELZ)
Regenerative Medicine Advanced Therapy Designation
An investigational drug is eligible for RMAT designation if:
• It meets the definition of regenerative medicine therapy (see section II of this document);
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• It is intended to treat,9 modify, reverse, or cure10 a serious condition; and
• Preliminary clinical evidence indicates that the regenerative medicine therapy has the potential to address unmet medical needs for such condition.
Advantages of the RMAT designation include all the benefits of the fast track and breakthrough therapy designation programs, including early interactions with FDA (see Comparison of Breakthrough Therapy Designation and Regenerative Medicine Advanced Therapy Designation table, which sets forth key similarities and differences between breakthrough therapy designation and RMAT designation). Section 506(g)(5) of the FD&C Act specifies that these early interactions may be used to discuss potential surrogate or intermediate endpoints to support accelerated approval (see section III.E. in this guidance).
Regarding the preliminary clinical evidence to demonstrate the potential of a regenerative medicine therapy to address unmet medical needs, we generally expect that such evidence would be obtained from clinical investigations specifically conducted to assess the effects of the therapy on a serious condition. Such clinical investigations, particularly at the initial stages of product development, may not always be prospective clinical trials with a concurrent control. In some cases, clinical evidence obtained from clinical investigations with appropriately chosen historical controls may provide sufficient preliminary clinical evidence of the potential to address an unmet medical need. In other cases, preliminary clinical evidence could come from well-designed retrospective studies or clinical case series that provide data systematically collected by treating physicians. Such clinical evidence may be from studies conducted outside of the United States (Ref. 3). In any case, it is essential that the preliminary clinical evidence be generated using the product11 that the sponsor intends to use for clinical development.
When determining whether the preliminary clinical evidence is sufficient to support RMAT designation, CBER intends to 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. In addition, CBER intends to consider the potential that bias (e.g., bias in the study design, treatment assignment, or outcome assessment) may be a factor in the evidence provided in support of RMAT designation. CBER will review the preliminary clinical evidence in each designation request, and will make designation decisions on a case-by-case basis. As opposed to breakthrough therapy
9 As described in section III.A.2 of the Expedited Programs Guidance (Ref. 2), FDA considers a drug to be intended to treat a serious condition when the drug is intended to have an effect on a serious condition, or a serious aspect of a condition, such as a direct effect on a serious manifestation or symptom of a condition.
10 This guidance uses the term “treat” to refer to the terms treat, modify, reverse, and cure, as used in section 506(g) of the FD&C Act.
11 FDA acknowledges that the issue of manufacturing changes is complex; however, manufacturing changes and product comparability are beyond the scope of this guidance. Manufacturing changes made to products during the development program would not necessarily preclude initial RMAT designation or cause RMAT designation to be rescinded. Such considerations will be made on a case-by-case basis.
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designation, the RMAT designation does not require evidence to indicate that the drug may offer a substantial improvement over available therapies. As with breakthrough therapy designation, an RMAT designation is not the same as an approval and does not change the statutory standards for demonstration of safety and effectiveness needed for marketing approval.12
The following are hypothetical examples of preliminary clinical evidence that CBER would consider sufficient to demonstrate a product has the potential to address unmet medical needs in those with a serious condition:
• In a single-arm, open-label study conducted in a center treating patients with severe and extensive skin burns, use of allogeneic keratinocyte- and fibroblast-based cell therapy is associated with rapid and substantial wound re-epithelialization of deep partial thickness burns in the majority of treated wounds.
• In a phase 2, dose-finding study, intra-myocardial administration of allogeneic human mesenchymal precursor cells to patients with advanced chronic heart failure refractory to available medical therapies is associated with dose-dependent improvement in several physiological measurements of left ventricular performance.
In order to apply for RMAT designation, a sponsor should submit a request to CBER either with a new investigational new drug application (IND) or in an IND amendment. CBER will not accept requests for RMAT designation for INDs that are inactive or on clinical hold. Additionally, FDA will not further process a pending RMAT designation request for an IND that is placed on inactive or hold status while the designation request is under review. If you submit an RMAT designation request as an amendment to your IND, the cover letter should specify that the submission contains an RMAT designation request. The request should be in bold, uppercase letters as follows: REQUEST FOR REGENERATIVE MEDICINE ADVANCED THERAPY DESIGNATION. If the request is submitted with an initial IND, the cover letter should specify that the submission contains both an initial IND and a request for RMAT designation. The request should be in bold uppercase letters as follows: INITIAL INVESTIGATIONAL NEW DRUG SUBMISSION and REQUEST FOR REGENERATIVE MEDICINE ADVANCED THERAPY DESIGNATION.
In general, such a request should contain a concise summary of information that supports the RMAT designation, including:
12 FDA’s SOPP (Standard Operating Policy and Procedure) 8212, entitled “Management of Breakthrough Therapy-Designated Products: Sponsor Interactions and Status Assessment Including Rescinding” (Ref. 4), explains that breakthrough therapy designation is not the same as an approval and does not change the statutory standards for marketing approval.
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• A description of the investigational product, including a rationale for the investigational new drug meeting the definition of a regenerative medicine therapy;
• A discussion to support that the disease or condition, or the aspect of the disease or condition, that the product is intended to treat is serious;
• A summary of the risks and benefits associated with the therapies, if any, currently available for this condition;
• A description of the unmet medical need that the product has the potential to address; and
• The preliminary clinical evidence that the product has the potential to address the specified unmet medical need for this serious condition.
A request for designation as an RMAT should describe the preliminary clinical evidence supporting designation. A description of the preliminary clinical evidence should include, for example, the conditions for product administration, outcome assessment, and patient monitoring; a description of the patients and their outcomes, including the number of patients who have received the drug; and the design, conduct, and analyses of any clinical investigations.
No later than 60 calendar days after receipt of the designation request, CBER will notify the sponsor as to whether the regenerative medicine therapy has received the RMAT designation. If CBER determines that the regenerative medicine therapy does not meet the criteria for RMAT designation, CBER will include a written description of the rationale for the determination. As with other expedited development programs, if RMAT designation has been granted but, later in development, the product no longer meets the qualifying criteria, then CBER may rescind the RMAT designation. This is because FDA needs to focus its resources on RMAT product development programs that continue to meet the program’s qualifying criteria.
