On Dec. 20, 2018, the Food and Drug Administration (FDA) issued a warning letter to Genetech Inc., citing numerous deviations from current good manufacturing and tissue practices discovered during a June 2018 facility inspection. The agency found that the company was engaged in the manufacturing and distribution of umbilical cord blood products that had not been cleared for use under an approved biologics license application (BLA) nor an investigational new drug (IND) application—thereby violating the Federal Food, Drug, and Cosmetic Act and Public Health Service Act.
The letter followed a recall of all ReGen Series products, manufactured by Genetech Inc., and distributed by Liveyon, of Yorba Linda, Calif. On Sept. 28, 2018, the FDA’s Center for Biologics Research and Evaluation (CBER) notified the distributor of reports of possible adverse reactions. Liveyon subsequently suspended all shipments of the products while CBER conducted an investigation into reported adverse events. The agency worked with Liveyon on a strategic recall action plan and immediately initiated a voluntary recall of the products.
Compliance and enforcement policy reminder
At the same time the FDA issued the warning, the agency reiterated its compliance and enforcement policy in letters to other manufacturers and healthcare providers who may be offering stem cell treatments. The letters reminded recipients of the FDA’s November 2017 guidance documents that reflect the agency’s comprehensive regenerative medicine policy framework. The documents also included changes to the regulatory status of adipose-derived stem cells, ending their exempt status and requiring compliance with IND and premarket approval.
The agency’s recall and warning letters included a statement from FDA Commissioner Scott Gottlieb, MD, signaling the agency’s intent to increase oversight of cell-based regenerative medicine. The FDA offered a period of enforcement discretion after release of the guidance documents to allow time for manufacturers to file the necessary applications to achieve compliance with the new regulations.
The FDA also intends to exercise enforcement discretion for certain products until November 2020, with respect to its IND application and premarket approval requirements when the use of the product does not raise reported or potential safety concerns. However, for products that do pose potential safety concerns for patients, the agency will employ the risk-based approach to enforcement outlined in its comprehensive regenerative medicine policy framework.
Impact on orthopaedics
Surgeons must be familiar with the regulatory status of therapies they offer, especially in the rapidly changing regulatory environment for regenerative medicine products. The final FDA guidance documents released in November 2017 changed the regulatory status of some cell therapies commonly used in orthopaedics. Previously, stem cells derived from adipose tissue were exempt from FDA regulation, provided they met all four exemption criteria:
- intended for homologous use only
- minimally manipulated
- not combined with cells and other agents
- no systemic effect, or systemic effect and intended for autologous use, for allogeneic use in a first- or second-degree blood relative, or for reproductive use
The revised guidance related to minimal manipulation and homologous use clarified the agency’s approach to structural and cellular/nonstructural tissues, stating that under the regulations, “human cells, tissues, and cellular and tissue-based products are considered either structural tissues or cells/nonstructural tissues.” In the question and answer section of the guidance, the FDA explicitly categorizes adipose tissue as structural. This characterization effectively negates the exemption because adipose-derived stem cells do not meet the requirement for homologous use (not structural), nor would processing meet the minimal manipulation definition for structural tissue to “not alter the original relevant characteristics of the tissue relating to the tissue’s utility for reconstruction, repair, or replacement.”
Although there are many arguments in opposition to the FDA’s position, the agency has not indicated any plans to change this interpretation. As such, surgeons planning to use adipose-derived stem cells for orthopaedic applications must comply with these regulations through the submission of a BLA or work with an industry sponsor of such an application.
A list of all currently approved cellular and gene therapy products is available on the FDA website.
Katherine Sale is a senior manager in the AAOS Office of Government Relations.
Questions to ask your product reps
- What is the regulatory status of this product? If it is approved by the Food and Drug Administration (FDA), it should be found on the FDA website. If it is exempt, it must meet all four criteria described in the regulation. There should be a clear, well-documented history of the source of the tissue/cells from an American Association of Tissue Banks member tissue bank.
- What is the evidence of its safety and effectiveness for my patient? If the product has been through a clinical trial, there should be clear indications for intended use. For exempt products, there should be literature to support its use in orthopaedic patients.
- Have there been adverse events (AEs) reported? Even use of the most thoroughly tested products may result in AEs. This information should be made available.
- Food and Drug Administration: Genetech Inc 11/29/18. Available at: https://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm628019.htm. Accessed January 18, 2019.
- Food and Drug Administration: Recall Notification to Clients with Possible Product On-Hand, Effective 9/28/18. Available at: https://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/Recalls/ucm622190.htm. Accessed January 18, 2019.
- Food and Drug Administration: Letter. Available at: https://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/UCM628912.pdf. Accessed January 18, 2019.
- Food and Drug Administration: 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. Available at: https://www.fda.gov/downloads/biologicsbloodvaccines/guidancecomplianceregulatoryinformation/guidances/cellularandgenetherapy/ucm585403.pdf. Accessed January 18, 2019.
- Food and Drug Administration: Biologics License Applications (BLA) Process (CBER). Available at: https://www.fda.gov/BiologicsBloodVaccines/DevelopmentApprovalProcess/BiologicsLicenseApplicationsBLAProcess/default.htm. Accessed January 18, 2019.
- Food and Drug Administration: Approved Cellular and Gene Therapy Products. Available at: https://www.fda.gov/biologicsbloodvaccines/cellulargenetherapyproducts/approvedproducts/default.htm. Accessed January 18, 2019.
- Food and Drug Administration: Framework for the Regulation of Regenerative Medicine Products. Available at: https://www.fda.gov/BiologicsBloodVaccines/CellularGeneTherapyProducts/ucm585218.htm. Accessed January 18, 2019.
- AAOS: Position Statement: Use of Emerging Biologic Therapies. Available at: https://www.aaos.org/uploadedFiles/PreProduction/About/Opinion_Statements/position/1187_Use%20of%20Emerging%20Biologic%20Therapies.pdf. Accessed January 18, 2019.