Unapproved Stem Cell Therapies Remain Top FDA Priority | Hogan Lovells

This follows the agency’s official end of the discretionary enforcement period for developers of human cells, tissues, or cell-based or tissue-based (HCT/Ps) products, and foreshadows enhanced enforcement after years of industry monitoring and advice by the FDA’s Center for Biologics Evaluation and Research (CBER) to stem cell clinics and other HCT/P facilities that it considers to be illegally marketing products. This summer and beyond, we anticipate increased agency enforcement action against parties marketing unapproved stem cell products, especially as the FDA regains full operational capacity and barriers to inspections resulting from the COVID-19 pandemic are reduced.

This article is the sixth in our 2022 series, “Trends in Cell, Tissue, and Gene Therapies,” which aims to help you stay informed about the wide range of legal and regulatory issues affecting companies operating in the field of regenerative medicine.


In 2017, the FDA issued a new regenerative medicine policy frame consisting of four guidance documents, which provided a “grace period” of risk-based enforcement discretion for certain P/EHPs. This grace period was intended to give certain manufacturers time to assess whether they needed to file an IND or marketing application with the FDA, or if they met the four regulatory criteria to continue to market their products. products only under the authority of Section 361 of the Public Health Service Act (PHSA), which does not require premarket review and approval. However, this period of “enforcement discretion” ended on May 31, 2021, and the FDA began cracking down on companies operating in the space that do not comply with the agency’s regenerative medicine policy framework.

We recently analyzed (online here) the importance these warnings have for companies in the field of regenerative medicine and highlighted the potential risks of non-compliance. These risks go far beyond FDA enforcement and include the possibility of FTC action, False Claims Act liability, product liability claims, and susceptibility to private prosecutions. Previously summarized here, the crackdown on the illegal marketing of unapproved stem cell treatments continues with enhanced enforcement by the FDA, the US Department of Justice (DOJ), and the Federal Trade Commission (FTC). This application has included actions against clinics in California, Florida and New Jersey (these actions summarized here). Since December 2018, the FDA has issued at least 400 letters to manufacturers and healthcare providers who may offer non-compliant stem cell or related products. Additionally, since 2018, the FDA has issued 46 untitled letters involving violent HCT/Ps, with more than two dozen such shows occurring in 2020 and 2021.

Recent enforcement actions

In a untitled letter issued against the Regenerative Stem Cell Institute last April, the FDA reviewed the Institute’s website, Facebook page, and YouTube channel for advertising and promoting stem cell products marketed without an IND application. The FDA also suggested that the Institute’s assertion that its products are offered “under an IRB-approved research protocol” was an attempt to circumvent the submission of an IND. The FDA emphasized that “IRB approval is required in addition to, and not in lieu of, obtaining an effective IND from the FDA for the study of the investigational drug or biologic.”

In addition to focusing on advertising and promotion enforcement, FDA inspections have also targeted deviations from Good Manufacturing Practices (GMP) and Current Good Tissue Practices (CGTP) requirements. ). Another recent Warning letter published in February against Smart Surgical, Inc dba Burst Biologics demonstrates this trend, citing significant GMP and CGTP violations, including poor donor selection, inadequate aseptic practices, unvalidated manufacturing processes, and deficient environmental monitoring. For example, the company failed to effectively screen donors from areas considered to be at higher risk of Zika virus transmission and did not perform media fill simulations to validate that the aseptic manufacturing can “consistently produce products free of viable microorganisms”.

While factors such as limited personnel and resources continue to slow FDA enforcement goals, some have suggested that the FDA strengthen its coordination with other regulators such as the DOJ, FTC, state attorneys general, state legislatures, and medical boards.

Likely strengthening of law enforcement

Coming out of the COVID-19 pandemic, we expect to see more enforcement activity regarding claims/promotion of stem cell products and the compliance and manufacturing quality of these products, likely to focus on the scenarios that pose the highest or greatest potential risk to patients and consumers. During a recent webinar on regenerative medicine, CBER Office of Tissues and Advanced Therapies (OTAT) Director Wilson Bryan, MD, said his office has increasingly notified, warned, and taken enforcement action against manufacturers, clinics, and individuals administering unapproved regenerative medicine therapies. Indeed, in January 2022 reorganizationOTAT added another branch to handle gene therapies, as well as a new tissue engineering branch.

Speaking at the Food and Drug Law Institute’s (FDLI) annual conference on Tuesday, FDA Acting Chief Counsel Mark Raza discussed the investigative priorities of the Office of the Chief Counsel (OCC) of the FDA, including its focus on shutting down stem cell clinics that put patients at risk. Raza described how pleased the FDA was with several recent court rulings in favor of the agency, including the Eleventh Circuit upholding the Stem Cell Clinic USA ruling in favor of the FDA. Responding to the verdict, the agency said that while regenerative cell-based medicine offers a significant medical opportunity, the FDA “cannot license unproven products that harness the hope of patients and their loved ones”; we have previously summarized this case online here.

Next steps

Companies that currently market HCT/Ps without a license or other marketing authorization from the FDA are required to meet the criteria set forth in section 1271.10(a) of title 21 of the Code of Federal Regulations; those who do not face limited options if they wish to legally market these products. Of course, the FDA would like to see companies in this situation submit an IND, initiate controlled clinical studies, and ultimately submit a marketing application. However, for many companies in this situation, the prospect of opening an IND and initiating registration-grade clinical studies is daunting. A number of important questions arise in the context of companies seeking FDA approval for their HCT/Ps. For instance:

  • Will the FDA require companies in this situation to conduct preclinical animal studies before initiating human clinical trials?

  • Will companies be able to persuade the FDA to accept data from previous human experiences with their products to support going straight to subsequent clinical studies (rather than being forced to start with conventional phase 1 trials? )?

  • If companies have previously conducted open-label, uncontrolled studies with their products, will the FDA be willing to accept data from those studies in support of a marketing application?

  • If a company legally markets an HCT/P in other countries, could the company submit patient data from those countries to the FDA as real-world evidence in support of regulatory approval?

  • Will companies in this situation be able to qualify for one of the FDA’s accelerated programs for serious conditions, such as Fast Track, Breakthrough Therapy, Accelerated Approval, or Regenerative Medicine Advanced Therapy?

The FDA remains committed to strengthening cell and gene therapy approvals. The agency recently said at the Association for Cellular and Gene Therapies that it plans to undertake a series of internal measures to broaden its messaging by using more “group communications” through advice, workshops and webinars. Still, it remains to be seen how flexible the FDA will be in working with companies that are trying in good faith to secure regulatory approvals for their HCT/Ps.

This article is the sixth in our 2022 series, “Trends in Cell, Tissue, and Gene Therapies,” which aims to help you stay informed about the wide range of legal and regulatory issues affecting companies operating in the field of regenerative medicine. From clinical studies to obtaining patents to scaling up manufacturing, our global team will discuss emerging issues arising in all regions of the world, including the unique issues of negotiation, litigation and inspections for CTGT companies.

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