There are no specific regulations directed toward stem cells. Instead, there is a complex framework governing the use of any cell therapy in plastic surgery patients. The FDA has a tiered regulatory approach aimed at making sure any cells or tissues intended for human use are properly vetted.
UNDERSTANDING SECTION 361 OF THE PHS ACT
For starters, the FDA regulates cell and tissue therapies through two major sets of regulations. Each set was developed under authority granted to the FDA by federal law. One set is based upon Section 361 of the PHS act. It empowers the FDA to enact regulations to control the spread of communicable diseases. A second set of regulations is based on section 351 of the PHS act, and gives the FDA the power to enact regulations to oversee the introduction of prescription drugs and cells with drug-like consequences.
Materials governed under section 361 of the PHS act are generally considered to be lower risk.
In the case of cells and tissues that are removed from a patient and transplanted into a patient for largely structural purposes and regulated under Section 361 for autologous or allogenic use, the FDA has published a set of regulations found in 21 Code of Federal Regulations (CFR) 1271. These rules govern “human cell and tissue products (HCT/P)” These rules do not cover blood and blood products, which are regulated elsewhere. Examples of HCT/P include:
- human acellular dermal matrix
- bone allograft
Xenograft tissue products, such as porcine acellular dermal matrix, are not regulated under 21 CFR 1271, but instead fall under device regulations.
WHAT IS AN HCT/P?
HCT/P products do not undergo the same FDA approval process required for active biologic products, which require phase I, II, and III clinical trials. However, they must adhere to a rigorous set of guidelines in 21 CFR 1271 that cover donor-selection criteria, manufacturing standards, product labeling and storage requirements, requirements for facility inspections, and registration of the facility and all products with the FDA. These regulations described in 21 CFR 1271 essentially cover any cells or tissue removed from a human body and intended for therapeutic use in patients.
There is a stipulation that these cells and tissues fulfill the criteria that the HCT/P must:
- be minimally manipulated;
- be intended for homologous use only, as reflected in the labeling, advertising, or other indications of the manufacturer’s objective intent;
- not be combined with a drug or device, except for water, crystalloids, or a sterilizing, preserving, or storage agent, provided that the addition of the water, crystalloids, or sterilizing, preserving, or storage agent does not raise new clinical safety concerns with respect to the HCT/P; and
- not have a systemic effect and not be dependent on the metabolic activity of living cells for its primary function except if for autologous use, allogeneic use in a first-degree or second-degree blood relative, or reproductive use.
All the surgeons reading these guidelines would be prompted to ask the question, “Well, does that mean that the FDA regulates all of my free flaps, skin grafts, and fat transfers, since these are cells and tissues removed from a patient and intended for therapeutic use?” The answer to this is that the FDA does not actually regulate the practice of medicine; that is done at the level of the state medical board and accreditation bodies for the hospitals. There is language in 21 CFR 1271 that gives an exception to cells and tissues that would otherwise fit the requirements for HCT/P products, but are removed and reimplanted in the same procedure. Additionally, for commercial HCT/P products, it is the manufacturer that holds the responsibility for following the guidelines and maintaining compliance with the FDA. The operating surgeon and the health care facility stocking the product are considered end users and not subject to the regulations.
The regulations governing HCT/P products generally cover therapies that fall into a lower risk category. Most of the regulations surrounding these “361” products ensure safety of the recovery and processing procedures. Cells and tissues that do not fit the definition of an HCT/P product, as defined in 21 CFR 1271, are regulated under another rule, found in section 351 of the PHS act. This regulation gives the FDA the authority to license biologic products. Cells and tissue products such as somatic cell therapy and gene therapy products regulated under section 351 of 21 CFR 1271 are considered higher-risk products and are regulated as “biologic drugs.” This means that safety and efficacy must be proven in phase I, II, and III clinical trials. This creates a much higher barrier to market entry and can involve hundreds of millions of dollars in development costs.
A key differentiating factor determining whether human cells and tissues are regulated under 21 CFR 1271 (HCT/P) guidelines is whether the product is “minimally manipulated.” This is determined on an individual basis for each product. The FDA can render an opinion through inquiry with the tissue reference group (TRG). In general, cultured cell products and genetically manipulated cells are regulated as biologic drugs. Investigational trials of such products require an investigational new drug (IND) application and approval from the FDA. After successful completion of clinical trials, the manufacturer may apply to the FDA for a biologic license.
DEVICES, SCAFFOLDS, AND COMBINATION PRODUCTS
A very interesting development in plastic surgery has been the evolution of devices which can separate stem cells from fat tissue in an automated fashion. These portable “cell factories” have the practical advantage of allowing point-of-care cell processing in the operating room for innovative regenerative therapies. These devices, however, are still considered investigational in the United States and are not approved for general clinical use. The FDA has determined that these devices are class III medical devices, and must be evaluated in clinical trials before approval.
Cell populations that are seeded onto scaffold materials add another level of complexity. These “combination products” must take into consideration the safety of the cell populations and the scaffold material, as well as the interaction between the cells and scaffold and the resultant tissue that is formed in a living system. Depending on the scaffold material and whether any pharmacologic agents are also involved, these combination products are evaluated by multidisciplinary teams at the FDA with expertise in cell therapy, pharmacology, and device manufacturing.
Ernest K. Manders, MD, is Professor of Plastic Surgery and Medical Director of the Facial Nerve Center, University of Pittsburgh.
J. Peter Rubin, MD, is Chair and UPMC Endowed Professor, Department of Plastic Surgery, and Professor of Bioengineering, at the University of Pittsburgh.