On November 16, in the context of announcing a comprehensive regenerative medicine policy framework (discussed here), FDA released a draft guidance document that describes the expedited programs available for the development and review of certain regenerative medicine therapies. Importantly, the draft guidance clarifies important aspects of the Regenerative Medicine Advanced Therapy (RMAT) designation established by the 21st Century Cures Act. In particular, the draft guidance expressly includes “gene therapies, including genetically modified cells, that lead to a durable modification of cells or tissues” in FDA’s interpretation of a “regenerative medicine therapy” that may be eligible for RMAT designation.
The RMAT program builds on prior statutory changes that created programs for expedited product development and review, including fast track designation, accelerated approval, and breakthrough therapy designation. Although RMAT designation requires preliminary clinical evidence that indicates that the therapy has the potential to address unmet medical needs, RMAT does not require evidence to indicate that the drug may offer a substantial improvement over available therapies, as breakthrough designation requires. The draft guidance states that it is possible that the preliminary evidence needed for RMAT designation could come from clinical trials with “appropriately chosen” historical controls, well-designed retrospective studies, or even “clinical case series that provide data systematically collected by treating physicians.” If an RMAT-designated product also receives an accelerated approval based on a surrogate endpoint, FDA could accept “patient registries, or other sources of real world evidence, such as electronic health records” to satisfy post-approval requirements. In addition, CBER Center Director, Peter Marks, has highlighted the great value of early interactions provided under the RMAT program to address the unique manufacturing challenges associated with regenerative medicine products.
The interpretation in the draft guidance for gene therapies is significant because there has been uncertainty about the scope of RMAT eligibility. One of the criteria for RMAT eligibility is that the drug must be a “regenerative medicine therapy,” which “includes cell therapy, therapeutic tissue engineering products, human cell and tissue products, and combination products using any such therapies or products.” 21 USC 356(g)(8). Because the term “gene therapy” was not expressly included in the regenerative medicine therapy definition, some feared that gene therapies may have been excluded. Perhaps adding to the confusion, a related bill that was never enacted, known as the REGROW Act, S. 2689, 114th Cong. (2016), did expressly exclude cells or tissues that were “genetically modified.”
However, unlike most definitions in the Federal Food, Drug, and Cosmetic Act, which say that a term “means” something, the regenerative medicine therapy definition uses “includes.” The only express exclusion is for “products regulated solely under” 42 USC 361 and 21 CFR 1271. Therefore, Congress gave FDA discretion as to the meaning of a regenerative medicine therapy, as long as it included and excluded the items specified. The new draft guidance interprets the term “regenerative medicine therapy” to include “gene therapies … that lead to a durable modification of cells or tissues.” This interpretation should include both ex vivo gene therapies, in which genetically-modified cells are reintroduced into the body, as well as in vivo gene therapies, in which a non-cellular vector or substance is introduced into the body to initiate the genetic modification of cells.
The regenerative medicine therapy interpretation in the draft guidance is also significant because it builds on the language that Dr. Gottlieb used in August. Dr. Gottlieb had said that RMAT could be available to “certain” gene therapies that “permanently alter tissue and produce sustained therapeutic benefit,” but the draft guidance allows for gene therapy products that “lead to a durable modification of cells or tissues.” Allowing for a “durable” modification should be easier for gene therapy products to demonstrate than “permanently” altering tissue, although the draft guidance does not explain how FDA will draw the line between durable and more transient effects. The draft guidance also clarifies Dr. Gottlieb’s prior reference to altering ‘tissue” and states that the modification could also apply to “cells.”
So far, we are aware of at least two RMAT designations that have been announced (here and here) for gene therapy products. However, a large number of applications involving gene therapies have been submitted for FDA review: In September, FDA disclosed that it already had 550 active investigational new drug applications (INDs) related to gene therapies, including 76 active INDs related to CAR-T cellular therapies. As of November 9, it has been reported that a total of 11 RMAT designations have been granted out of 31 requests. We expect that the greater clarity and broadened scope provided by the draft guidance will lead more sponsors of gene therapies to seek RMAT designation, which should encourage further development and expedite review of future gene therapy innovations. FDA is seeking comments on the draft guidance through February 15, 2018.