On March 1, 2023, the Center for Biologics Evaluation and Research (CBER) at the U.S. Food and Drug Administration (FDA) published its first untitled letter of the year to Thomas Advanced Medical LLC (Thomas)[1] for marketing human cells, tissues, or cellular or tissue-based products (HCT/Ps)[2] without FDA premarket review. The letter described Thomas’ marketing of products derived from human umbilical cord, umbilical cord blood and amniotic tissue as “regenerative therapy solutions” or “stem cell derived biological product” to treat various diseases and conditions including cardiac disease, Alzheimer’s, Parkinson’s, lung disease, diabetes and COVID-19.

HCT/Ps are regulated under 21 CFR Part 1271, which classifies HCT/Ps into one of two categories. HCT/Ps that meet the following criteria are regulated solely under Section 361 of the Public Health Service (PHS) Act and are commonly known as “361 HCT/Ps”:

• The HCT/P is minimally manipulated;

• The HCT/P is intended for homologous use only;

• The HCT/P is not combined with another article (with some limited exceptions); and

• The HCT/P does not have a systemic effect and is not dependent upon the metabolic activity of living cells for its primary function; or, the HCT/P has a systemic effect or is dependent upon the metabolic activity of living cells for its primary function, and is for autologous use; for allogeneic use in a first or second degree blood relative; or for reproductive use.[3]

In order to assist manufacturers in determining whether their HCT/P fits these criteria, FDA issued the guidance document Regulatory Considerations for Human Cell, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use.[4] HCT/Ps that do not meet the above criteria are considered to be drugs, devices and biological products regulated under Section 351 of the Public Health Service (PHS) Act and the Federal Food, Drug, & Cosmetic Act (FDCA).

While 361 HCT/Ps are not required to undergo any FDA review or approval before being brought to market, HCT/Ps considered to be drugs, devices and biological products must meet FDA requirements for premarket notification or approval. These requirements include the submission of new drug application (NDA) or biologics license application (BLA) for drugs or biologics and premarket notification 510(k) or premarket approval (PMA) for devices, depending on the class.

In the 2017 HCT/P guidance[5] described above, FDA stated that they would not enforce these premarket review and approval requirements for HCT/Ps considered to be drugs, biologics or devices for a period of thirty-six (36) months in order to give manufacturers time to complete the appropriate submissions. This enforcement discretion period was later extended through May 2021.

Since the end of enforcement discretion, FDA has begun issuing warning and untitled letters to manufacturers for not complying with HCT/P regulations and premarket review and approval requirements. FDA has announced that it would prioritize enforcement for products that presented the greatest safety risks based on the following:

• The route and site of administration (e.g., those administered by intravenous injection or infusion, aerosol inhalation, intraocular injection, or injection or infusion into the central nervous system present a higher risk); and

• Whether the product was intended to treat a serious and/or life-threatening disease or condition. [6]

Based on a review of Thomas’ website and other online information, including the firm’s LinkedIn profile, FDA found that:

• The marketed HCT/Ps were intended to treat serious or life-threatening diseases and conditions, such as Alzheimer’s, Parkinson’s, lung disease, cardiac disease and diabetes, and included some products administered by intravenous injection;

• The marketed HCT/Ps should not be regulated solely under Section 361 of the PHS Act because they failed to meet the required criteria, including being intended for non-homologous uses and therefore would be regulated as drugs and biologics; and

• Thomas did not possess either biologics license or investigational new drug application (IND) for its products, in violation of the FDCA and the PHS Act.

In its letter to Thomas, FDA directs the firm to its comprehensive regenerative medicine policy framework[7] intended to support and expedite the development of regenerative medicine products, including HCT/Ps. The framework consists of four guidance documents, including:

• Regulatory Considerations for Human Cell, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use,[8] intended to help clarify whether HCT/Ps are subject to FDA’s premarket review requirements;

• Same Surgical Procedure Exception: Questions and Answers Regarding the Scope of the Exception,[9]intended to help clarity as to whether an establishment may qualify for an additional exception for HCT/Ps removed and implanted into the same individual during the same surgical procedure;

• Expedited Programs for Regenerative Medicine Therapies for Serious Conditions,[10]describing programs, such as Fast Track designation and Breakthrough Therapy designation, for sponsors of regenerative medicine therapies; and

• Evaluation of Devices Used with Regenerative Medicine Advanced Therapies,[11]describing FDA’s current thinking about devices used in the recovery, isolation and delivery of regenerative medicine advanced therapies (RMATs). 

FDA’s decision to make HCT/P promotion the subject of their first untitled letter of 2023 signals the agency’s continued push to keep a close eye on HCT/Ps and regenerative medicine in general. As this field continues to advance and more products begin to hit the market, it appears FDA will not be shy about making sure HCT/Ps are properly classified and undergo appropriate premarket review. Manufacturers developing products in this area should take care to properly follow FDA’s regenerative medicine guidance when determining an approval and marketing strategy for their product. 

FOOTNOTES

[1] Untitled letter available here: March 1, 2023 Untitled Letter – Thomas Advanced Medical LLC (fda.gov).

[2] See 21 CFR 1271.3(d).

[3] See 21 CFR 1271.10(a)

[4] Guidance available here: Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use; Guidance for Industry and Food and Drug Administration Staff, (fda.gov).

[5] Id.

[6] Id.

[7] Framework available here: Framework for the Regulation of Regenerative Medicine Products | FDA

[8] Guidance available here: Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use; Guidance for Industry and Food and Drug Administration Staff, (fda.gov).

[9] Guidance available here: Same Surgical Procedure Exception under 21 CFR 1271.15(b): Questions and Answers Regarding the Scope of the Exception; Guidance for Industry (fda.gov)

[10] Guidance available here: Expedited Programs for Regenerative Medicine Therapies for Serious Conditions; Guidance for Industry (fda.gov)

[11] Guidance available here: Evaluation of Devices Used with Regenerative Medicine Advanced Therapies; Guidance for Industry (fda.gov)