Regenerative Medicine Therapies: Manufacturing Changes May Not Impact RMAT Designation
Executive Summary
Final guidance notes that preliminary clinical evidence may come from studies conducted outside the US, says historical controls may be considered in clinical trial designs.
The US FDA made minor tweaks to its draft guidance for development of regenerative medicine therapies, clarifying that historical controls may be considered in clinical trials, that sponsors may receive more than one regenerative medicine advanced therapy (RMAT) designation for a product, and that manufacturing changes to products would not necessarily preclude an initial RMAT designation or cause it to be rescinded.
The agency's final guidance, Expedited Programs for Regenerative Medicine Therapies for Serious Conditions, includes few changes to the draft guidance issued in November 2017. FDA addressed several recommendations made by industry with the addition of a few sentences and footnotes.
The draft guidance recommended the use of innovative trial designs, such as having multiple clinical sites sharing combined clinical trial data to support a biologics license application. It also provided examples of when products might qualify for expedited programs. (Also see "Regenerative Medicine Clinical Trials: US FDA Supports Studies Comparing Multiple Agents" - Pink Sheet, 16 Nov, 2017.)
The agency also released final guidance on Evaluation of Devices Used with Regenerative Medicine Advanced Therapies. It specifically addresses devices used in the recovery, isolation, or delivery of such therapies and is nearly identical to the agency's draft guidance. (Also see "Devices Addressed In US FDA's New Regenerative Medicine Framework" - Medtech Insight, 16 Nov, 2017.)
"When we first issued our comprehensive regenerative medicine policy framework in November 2017, our goal was to achieve a balanced and risk-based approach to support product development in cell-based therapies, while clarifying the FDA's authorities and enforcement priorities to make sure we were protecting patients," FDA Commissioner Scott Gottlieb said in a Feb. 15 release. "The final guidances issued today demonstrate our continued commitment to fulfilling this promise."
Clarifying Regenerative Medicine Therapy Definition
The guidance says that regenerative medicine therapies include cell therapies, therapeutic tissue engineering products, human cell and tissue products, and combination products using any such therapies or products, except for those regulated solely under Section 361 of the Public Health Service Act and part 1271 of Title 21 of the Code of Federal Regulations.
In comments on the draft guidance, Biocom, a group of biotech, pharma, medical device and genomics and diagnostic companies, recommended that the final guidance specifically state that "autologous" and "allogenic" therapies are included in the definition of regenerative medicine therapy.
FDA responded by adding a footnote in the final guidance that says FDA interprets cell therapies "to include both allogeneic and autologous cell therapies."
The agency added another footnote saying that based on its interpretation of the Food, Drug, and Cosmetic Act, microorganisms (e.g., viruses, bacteria, fungi) that are not genetically modified do not meet the definition of regenerative medicine therapy.
Biocom also requested that the final guidance provide greater clarity on the level of evidence required for RMAT designation and how it compares to breakthrough and fast track designations.
FDA added a sentence noting that regenerative medicine therapies receiving fast track designation, breakthrough therapy designation, and RMAT designation must meet the evidentiary standards for approval, including demonstrating effectiveness (regardless of whether the product receives accelerated or traditional approval). It said each of these designation programs have different programmatic requirements.
The RMAT designation was created by the 21st Century Cures Act as an expedited regulatory pathway for sponsors developing regenerative medicine therapies that are intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition, and for which preliminary clinical evidence indicates that the product has the potential to address unmet medical needs. Products with the designation may be eligible for accelerated approval and sponsors have the opportunity for early interaction with FDA.
As of Feb. 1, the agency had received 91 requests for RMAT designation, of which it had granted 30, and denied 51. Five requests were withdrawn.
Historical Controls, Multiple Indications
Biocom also asked FDA to specify that a study with an appropriate historical control could satisfy the burden of preliminary clinical evidence required for RMAT designation even if that historical control was chosen post hoc.
The agency added two sentences addressing historical controls. "Historical controls may be considered, if appropriate. Natural history data may provide the basis of a historical control, but only if the control and treatment populations are adequately matched, in terms of demographics, concurrent treatment, disease state, and other relevant factors," the guidance says.
The Biotechnology Innovation Organization proposed that FDA include an explicit statement in the guidance clarifying that a sponsor can submit a request for RMAT designation for multiple indications for the same product.
The agency added a statement addressing multiple RMAT designations. "Sponsors may apply for and receive more than one designation for a given product, but sponsors should apply for each designation separately. Information that supports more than one designation may be submitted in each separate designation request," the final guidance states.
Manufacturing Changes
Gilead Sciences Inc. asked the agency to provide examples of preliminary clinical evidence that would be suitable to support an RMAT designation. For example, Gilead asked, "would data from a similar product be acceptable?"
The final guidance states that it is "essential that the preliminary clinical evidence be generated using the product that the sponsor intends to use for clinical development."
However, the agency added a footnote to the final guidance addressing manufacturing changes: "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."
FDA has focused on the ability of regenerative medicine companies to manufacture products throughout their development and commercial lifecycle in a way that can satisfy regulatory requirements. At a BIO meeting last year, FDA Office of Tissues and Advanced Therapies Director Wilson Bryan noted that his office sometimes will deny RMAT designation requests, or ask a sponsor to provide additional information, due to uncertainties about the identity of the product studied in early trials. (Also see "RMAT Designation Requests May Rise Or Fall On Manufacturing Changes, Clinical Data Breadth" - Pink Sheet, 27 Jun, 2018.)