The US Food and Drug Administration (FDA) on Thursday launched a new policy framework for regenerative medicine, building off a previous framework from 2005, as part of efforts to bring new cell, stem cell and tissue products to patients as efficiently as possible while managing the proliferation of unscrupulous actors hawking unproven therapies.
FDA’s announcement included the release of two new draft guidance documents – one on ways to expedite approvals for regenerative medicines for serious conditions and one on medical devices used with regenerative therapies – and two final guidance documents offering clarity on when cell and tissue-based products would be excepted from the regulations and clarifying how the agency interprets the regulatory definitions of "minimal manipulation" and "homologous use."
"We’re adopting a risk-based and science-based approach that builds upon existing regulations to support innovative product development while clarifying the FDA’s authorities and enforcement priorities," FDA Commissioner Scott Gottlieb said in a statement. "This will protect patients from products that pose potential significant risks, while accelerating access to safe and effective new therapies."
But the new guidance documents were not released alongside any new warning letters or enforcement actions against a growing market of unapproved direct-to-consumer (DTC) stem cell products.
Leigh Turner, associate professor at the University of Minnesota Center for Bioethics and co-author of an article in Cell about DTC stem cell clinics, told Focus that FDA still has yet to crack down on these unscrupulous companies profiting off unproven treatments, noting the market is "quite large, quite active and there's been a long time without meaningful oversight."
Turner took issue with a provision in the "minimal manipulation" and "homologous use" final guidance that says FDA will use discretion in enforcement over the next 36 months. "To me, it’s a matter of what is the enforcement activity going to be over that time frame. If it’s a 3-year period where FDA won’t do much, that strikes me as a green light for the industry" selling unapproved products.
"If I ran one of these [DTC stem cell] clinics in Florida or California, I would see today’s action by FDA to mean business as usual," he added.
An FDA spokesperson clarified to Focus via email, "The FDA does not intend to exercise such enforcement
discretion for those HCT/Ps [human cells, tissues, and cellular and tissue-based products] that pose a potential significant safety concern.
Going forward, the FDA will apply a risk-based approach to enforcement taking
into account how products are being administered as well as the diseases and
conditions for which they are being used.
"Specifically, under limited conditions, when a product
requires an investigational new drug application (IND) or premarket approval
(biologics license applications or BLAs), the agency intends to focus its
enforcement actions on products that pose higher risks. For example,
actions related to products administered by higher-risk routes of
administration (e.g., those administered by intravenous injection or infusion,
aerosol inhalation, intraocular injection, or injection or infusion into the
central nervous system) will be prioritized over those associated with a lower
risk (e.g., those administered by intradermal, subcutaneous, or intra-articular
The 21st Century Cures Act (Cures Act) created what’s known as the Regenerative Medicine Advanced Therapy (RMAT) designation (previously known as the RAT designation), which can be used to speed the review of cell therapies, therapeutic tissue engineering products, human cell and tissue products or any combination product using such therapies or products.
Peter Marks, director of FDA's Center for Biologics Evaluation and Research (CBER), said on Tuesday that as of last Friday, the agency has received 34 RMAT designation requests, acted on 31 requests and granted 11 RMAT designations. Humacyte and Vericel are two examples of companies that have already received the RMAT designation.
Advantages of the RMAT designation include all the benefits of the fast track and breakthrough designations, including early interactions between the agency and sponsors.
But as opposed to the breakthrough designation, the RMAT designation does not require evidence to indicate that the drug may offer a substantial improvement over available therapies, according to one of the draft guidances released Thursday.
And like breakthrough designations, RMAT designations do not mean the product will be approved and do not change the statutory standards for demonstration of safety and effectiveness needed for approval.
In addition to creating the RMAT, Section 3034 of the Cures Act also mandates that FDA issue guidance clarifying how FDA will evaluate devices used in the recovery, isolation or delivery of RMATs, which also was released on Thursday.
Guidance and Examples
In spelling out how FDA determines what should be considered for an RMAT designation, one of the draft guidances notes that CBER intends to consider "the rigor of data collection; the nature and meaningfulness 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 draft offers two hypothetical examples of preliminary clinical evidence that CBER would consider sufficient, what an RMAT request should contain and considerations in clinical trial design.
The other draft guidance specifies that devices intended for use with a specific RMAT may be considered a combination product. It also addresses how FDA intends to simplify and streamline its application of regulatory requirements for combo devices and cell or tissue products; what, if any, intended uses or specific attributes would result in a device used with a regenerative therapy that would make it a Class III device; factors to consider in determining whether a device may be labeled for use with a specific RMAT or class of RMATs; when a device may be limited to a specific intended use; and application of the least burdensome approach to demonstrate how a device may be used with more than one cell type.
Both draft guidance documents will have 90-day comment periods.
The two final guidance documents together supersede a 2014 draft guidance related to adipose tissue and the one on defining homologous use and minimal manipulation finalizes a draft from December 2014 on minimal manipulation of human cells, tissues, and cellular and tissue-based products (HCT/Ps) and another draft from October 2015 on the homologous use of HCT/Ps.
In one finalized guidance, FDA says, "Homologous use means the repair, reconstruction, replacement, or supplementation of a recipient’s cells or tissues with an HCT/P that performs the same basic function or functions in the recipient as in the donor. This criterion reflects the Agency’s conclusion that there would be increased safety and effectiveness concerns for HCT/Ps that are intended for a non-homologous use, because there is less basis on which to predict the product’s behavior, whereas HCT/Ps for homologous use can reasonably be expected to function appropriately."
FDA also defines “minimal manipulation” as: “1) For structural tissue, processing that does not alter the original relevant characteristics of the tissue relating to the tissue’s utility for reconstruction, repair, or replacement; 2) For cells or nonstructural tissues, processing that does not alter the relevant biological characteristics of cells or tissues.”
The other guidance finalizes a draft from 2014 and offers seven questions and answers describing which establishments are not required to comply with certain requirements if they remove HCT/Ps from an individual and implant them into the same individual during the same surgical procedure.
In terms of the ways FDA has adapted its regulatory model to meet the "revolutionary nature of the products," Gottlieb pointed to the example of "how we’re considering innovative trial designs whereby individual academic investigators would follow the same manufacturing protocols and share combined clinical trial data in support of approval from the FDA. This is an innovative way of making sure that small investigators who are working with cells that are being manufactured in ways that render them subject to our current laws and regulations -- because the cells are, for example, more than ‘minimally manipulated.’"
FDA announces comprehensive regenerative medicine policy framework
Expedited Programs for Regenerative Medicine Therapies for Serious Conditions: Draft Guidance for Industry
Evaluation of Devices Used with Regenerative Medicine Advanced Therapies: Draft Guidance for Industry
Regulatory Considerations for Human Cell, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use Guidance for Industry and Food and Drug Administration Staff
Same Surgical Procedure Exception under 21 CFR 1271.15(b): Questions and Answers Regarding the Scope of the Exception Guidance for Industry
Editor's note: Story updated with comment from FDA.