FDA, industry look to revisit regulatory framework for HCT/Ps

The US Food and Drug Administration (FDA) is exploring a new regulatory framework for human cells, tissues, and cellular and tissue products (HCT/Ps) in response to the growing variety and complexity of these products, which can no longer easily be categorized into broad classifications.

One industry proposal would aim to establish new low- and moderate-risk categories for Section 351 tissue products to facilitate their development.

The plans were discussed during a meeting convened by the FDA’s Center for Biologics Evaluation and Research (CBER) and the Office of Therapeutic Products (OTP) on February 25, where industry officials also spoke about recent developments in cell therapy.

Top FDA officials seemed open to rethinking the framework for such products. “We are revisiting the regulatory framework for cell and tissue products,” said CBER Director Peter Marks.

Marks added that human cell and tissue products are a “fairly diverse array of products ranging from single skin grafts to artificial organs … [the] remarkable breadth of these products makes it challenging and quite stimulating to regulate.”

Marks noted that the current regulatory framework for cell and tissue products has evolved over the past three decades, and it was based on the agency’s understanding of cell and tissue-based products at that time of its introduction.

Since then, he stated that "science has greatly evolved," leading to a more complex array of products; some of which require relatively small amounts of data, while others necessitate more extensive information.

OTP Director Nicole Verdun said that there are over 3,000 active investigational new drug applications (INDs) for cellular, tissue, and gene therapy products. “It has been an exciting time and an exciting year for us last year in this space.”

Two different pathways

Julie Tierney, CBER’s deputy center director, said FDA has two different pathways for regulating HCT/Ps, which are codified under Sections 351 and 361 of the Public Health Service Act (PHS Act). Section 361 governs HCT/Ps that are regulated as human cell and tissue products and do not require premarket approval.

The regulations under 21 CFR 1271.10(a), which were finalized in 2004, further define the scope of these HCT/P regulations and lists the criteria for when a human cell or tissue products should be regulated under Section 361, spelling out that these products can only be minimally manipulated and intended for homologous use without requiring extensive premarket review by FDA. The regulation defines the terms minimal manipulation, homologous use, and autologous use.

Section 351 defines products that do not meet all the criteria outlined in 21 CFR 1271.10(a). Products in this category are regulated as " drugs, devices, or biological products” under the Federal Food, Drug, and Cosmetic Act (FDCA). These products require clinical trials to determine safety and efficiency.

Tierney acknowledged that products don’t always fall neatly into these two buckets.

“Given the broad spectrum of cell theory products and given the differing amounts of evidentiary questions that we may have that we talked about through the day, it is not surprising that they don’t fall into these two buckets very neatly.”

Tierney said that these products include mesenchymal stem cells for orthopedic use, allogenic pancreatic islets, and genetically modified autologous stem cells.

Revision proposed

Melissa Greenwald, chief medical officer for the American Association of Tissue Banks (AATB), agreed that the growing complexity of these products necessitates a new way of regulating them.

AATB is proposing two new categories of section 351 HCPs: low-risk and medium-risk HCPs that do not require premarket approval, and higher-risk HCPs that would require premarket approval.

Examples of low-risk products include minimally manipulated tissue products for nonhomologous use that have preclinical or real-world evidence of safety. This can include epidermal or amniotic tissue grafts intended for wound healing, or dermal or epidermal grafts intended to reduce pain in patients. For these products, the submission process would resemble the current 510(k) notifications for devices.

Examples of medium risk products include HCT/Ps for homologous use used in combination with another article that raises moderate safety concerns; these products are more than minimally manipulated HCT/Ps for nonhomologous use. Products in this category would be submitted in a PMA-like process and provide evidence of safety through one clinical trial, instead of two.

“It’s an issue that this organization has been thinking about for many years; I believe the agency has been as well. We believe that such a framework has the potential to increase the development of lower risk but innovative HCT/Ps and reduce the costs of a biologics license application. It would increase the number of acceptable claims for approval for certain products and certainly the potential to facilitate reimbursements,” said Greenwald. She said that FDA would also benefit from a more efficient review process.

Growing array of products

Sally Temple, the scientific director and co-founder of the Neural Stem Cell Institute, further detailed the growing number and increasing complexity of HCP/T products.

There are new treatments in clinical development for various conditions, ranging from neurodegenerative diseases, epilepsy, heart disease, spinal cord injury, type 1 diabetes, cancer, autoimmune diseases, blindness, epidermolysis bullosa, and Duchenne muscular dystrophy. Additionally, there have been recently approved treatments for graft-versus-host disease and sickle cell disease.

As of December 2024, Temple said there were 116 clinical trials in the United States testing 83 human pluripotent stem cell (hPSC) products. Most of these trials focus on conditions affecting the eyes, central nervous system, and cancer.

FDA, industry look to revisit regulatory framework for HCT/Ps

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