Regenerative Medicines: FDA Finalizes Guidance on Expedited Programs

Regulatory NewsRegulatory News | 18 February 2019 |  By 

With almost 80 regenerative medicine advanced therapy (RMAT) designation requests in 2017 and 2018, it’s clear that the US Food and Drug Administration’s (FDA) Center for Biologics Evaluation and Research (CBER) has been busy with RMATs, though only on Friday did the agency finalize guidance from 2017 on the designation.

Advantages of the RMAT designation, according to the guidance, include all the benefits of the fast track and breakthrough therapy designation programs (sponsors may apply for and receive more than one designation for a given product), including early interactions with FDA. Although, as opposed to breakthrough therapy, the RMAT designation “does not require evidence to indicate that the drug may offer a substantial improvement over available therapies,” the guidance explains.

FDA spells out precisely what constitutes a therapy that could qualify for an RMAT designation, which includes cell therapies, therapeutic tissue engineering products, human cell and tissue products and combination products using such therapies.

As far as what would constitute the necessary evidence to win an RMAT, FDA says that in some instances, 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 US,” the agency notes.

CBER also offered the following as hypothetical examples of preliminary clinical evidence 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 addition to noting that it will review preliminary clinical evidence in each request and make designation decisions on a case-by-case basis, CBER said it intends to consider certain 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.”

As far as changes between the draft and final version, FDA said it “received several comments on the draft guidance and those comments were considered as the guidance was finalized. In addition, editorial changes were made to improve clarity.”
In addition to the RMAT guidance, FDA also finalized a second guidance on Friday dealing with a wide range of devices that may be used in conjunction with an RMAT.

For example, the devices can be simple, low-risk devices, such as a manual surgical instrument (e.g., scalpel) for recovering cells and tissue, or complex, higher-risk devices, such as an automated cell collection system that selects and processes specific cells intended for immediate return to the patient. Additionally, devices can be constituent parts of an RMAT that is a combination product.

The 11-page guidance spells out the least burdensome principles, the available premarket pathways (510(k), De Novo, Premarket Approval Application and Humanitarian Device Exemption) and when a device and RMAT may be considered a combination product.

The guidance also discusses factors to consider when a device may be intended for use with a particular type of cell-based RMAT or with more than one type of cell-based RMAT.

Cumulative CBER Regenerative Medicine Advanced Therapy (RMAT) Designation Requests Received by Fiscal Year

Expedited Programs for Regenerative Medicine Therapies for Serious Conditions

Evaluation of Devices Used with Regenerative Medicine Advanced Therapies


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