Following the court’s decision in United States Stem Cell Clinic, CBER Director Peter Marks, MD, said in a The voices of the FDA blog post that the agency will continue to crack down on unapproved products marketed as regenerative medicine therapies, citing how the American stem cell The move is “a victory for public health and an endorsement of the FDA’s work to shut down stem cell clinics that put patients at risk by marketing products that violate the law.” Dr Marks also referred to a second injunction case, United States v. Cellular Surgical Network et al., which is currently the subject of litigation in the United States District Court for the Central District of California, and a third enforcement action sued by the FDA involving the seizure of vials of Vaccinia Virus Vaccine, Live , which was resolved in March 2018.
Background on United States Stem Cell Clinic
Since 2015, the FDA has documented violations of current Good Manufacturing Practices (cGMP) requirements for tissue products by the US Stem Cell Clinic. The agency sent a warning letter to the clinic in August 2017, which we analyzed here. The clinic claimed that the FDA’s cGMP regulations were not applicable because the treatment fell under the FDA “same surgical procedure” and “361 HCT / P” exceptions to regulations under the Federal Food Act, Medicines and Cosmetics (FDCA) and the Public Health Services Act. (PHSA). In June 2019, a Florida district court ruled in favor of the FDA and banned the clinic from offering its stem cell therapy to patients.
As we have summarized (here), the district court found that the population of stromal and vascular cells in the therapy of the US Stem Cell Clinic, known as the stromal-vascular fraction (SVF), requires the FDA approval of a New Drug Application (NDA) or biologic. Apply for a license (BLA) before it can be marketed. The court also found that the therapy was falsified and mislabelled due to the clinic’s manufacturing procedures and that its promotion violated legal requirements.
Exception “same surgical intervention”
On appeal to the Eleventh Circuit, the US Stem Cell Clinic again argued that it was exempt from regulation under the FDCA because the procedure fell under the “same surgical procedure” exception in 21 CFR § 1271.15 (b). This provision states that FDA regulations do not apply if “you are an establishment that removes HCT / Ps from an individual and implants these HCT / Ps in the same individual during the same surgical procedure”. Arguing in the district court, the FDA successfully asserted that the FCS implanted into the patients at the clinic does not constitute an “such HCT / P” removed from the patient due to the treatment steps applied to the FCS in this case. which means the US Stem Cell Clinic was not covered by this exception.
As a preamble to its analysis, the Eleventh Circuit explained in particular that it was not simply offering judicial deference to the FDA, asserting that it “did not give any particular weight to the agency’s point of view.” The court said that although “[t]there was a time when a court faced with a rule that seemed “impenetrable on first reading” could simply “wave the flag of ambiguity” and defer to the agency’s interpretation, “it is the case “[n]o longer. On the contrary, the court “carefully examines[ed] the text, structure, history and purpose of [the] regulation ”, and resolved the apparent ambiguity in favor of the FDA.
First, the court considered the clinic’s argument that cells or tissues can only be HCT / Ps if they are “intended to be implanted” into a patient, and that is FVS – not adipose tissue – which is ‘intended for implantation’. The court rejected this defense, explaining that because adipose tissue contains FCS and because HCT / Ps are “articles containing or made up of human cells or tissues intended to be implanted” in a patient, adipose tissue and the SVF are both HCTs. / Ps subject to regulation.
Second, the US Stem Cell Clinic argued that an HCT / P reimplanted in a patient meets the regulatory definition of “such HCT / P” if it is “similar or similar” to the HCT / P removed from the patient. The Eleventh Circuit disagreed. Instead, the court adopted the FDA’s interpretation that “such HCT / P” refers to “the history of HCT / P removed from the patient in its original form.” The Eleventh Circuit agreed with the FDA and the district court that the SVF procedure did not fall under the “same surgical procedure” exception “because the biological material implanted in the patient is not the same as that removed. “. The court cited an FDA history of “such HCT / P” to mean HCT / Ps in their original form that have not been subjected to significant processing.
Exception “361 HCT / P”
The clinic also argued on appeal that it is exempt from regulation under the FDCA and PHSA because the procedure falls under the “361 HCT / P” exception, whereby an HCT / P responding to four criteria (set out in 21 CFR § 1271.10 (a)) is considered a “361 HCT / P”, meaning that it is regulated only under Section 361 of the Public Health Service Act (PHSA) and its implementing regulations in 21 CFR Part 1271. Being considered a “361 HCT / P” is subject to therapy at a lighter regulatory burden. However, the Eleventh Circuit ruled that the 361 HCT / P exception does not apply because the HCT / P in this case is not “intended for peer use only”.
“Homologous use” is “the repair, reconstruction, replacement or supplementation of cells or tissues of a recipient with an HCT / P which performs the same basic function (s) in the recipient as in the donor” . 21 CFR § 1271.3 (c). The US Stem Cell Clinic argued that the SVF meets the criteria for “homologous use” of a “361 HCT / P” because the SVF was intended to perform the same basic regenerative function before and after the procedure. However, the district court determined that the clinic intended the SVF to treat a “litany of recipient illnesses,” which is not the “same core function” that the SVF performed before the procedure.
The Eleventh Circuit agreed with the district court that the clinic intends the stem cells to perform post-procedure functions that go beyond the basic functions the stem cells performed before the procedure. The court stated that “promoting an HCT / P for an unproven therapeutic use, such as curing cancer” would be a non-homologous use, and therefore exception 361 HCT / P does not apply in that case. In making this decision, the court said it relied on labeling, advertising and other indications of the objective intent of the manufacturer. Because the defendants had marketed their FCS therapy to treat a range of illnesses, the court ruled that the clinic could not argue that the pre-procedural FCS cells were believed to have the same function as the reimplanted FCS cells.
In rendering its opinion, the court permanently banned the US Stem Cell Clinic from offering its fat stem cell therapy until several conditions were met, including FDA approval of a new application for drug or a biologics license application for the SVF solution.
CBER quotes American stem cell victory to warn again of the end of the “grace period” for HCT / P compliance
In 2017, the FDA released a new Regenerative Medicine Policy Framework consisting of four guidance documents, which provided for a risk-based enforcement discretion “grace period” for certain HCT / Ps, which ended on May 31, 2021. This grace period was meant to give some manufacturers time to assess whether they should file an IND or marketing application with the FDA, or whether they meet the four regulatory criteria to continue to market their products only under the authority of Section 361 of the PHSA, which does not require market review and approval.
Following the government’s victory in this legal battle, CBER Director Peter Marks, MD, posted a blog on June 3 warning the FDA to crack down on unapproved products marketed as regenerative medicine therapies, citing how the Eleventh Circuit upheld the lower court judgment. in American stem cell as the reason for the renewed warning. Marks wrote that “the US stem cell decision is a victory for public health and an endorsement of the FDA’s work to shut down stem cell clinics that put patients at risk by marketing products that violate the law.”
More recently, on July 9, CBER added a question-and-answer page to its website about the end of the HCT / P discretionary enforcement period, drawing a clear line in the sand to indicate that the FDA is serious about the end of the discretionary period of execution. Notably, the Q&A page instructs physicians not to administer an HCT / P that does not qualify for 361 HCT / P status, until HCT / P has a BLA, unless that physician is studying the HCT / P as a clinical investigator in a trial under an IND. It also appears to be saying that there is no grace period for products that entered interstate commerce before May 31, 2021 and are still on the market.
This was not the first time that CBER had warned of the imminent application of its policy framework for regenerative medicine; In an April 21 FDA “Voices” blog post, Marks wrote that the agency would not further extend the “grace period” for HCT / P companies to comply with its regenerative medicine policy framework. In this article and in the June 3 post, Marks pointed out that the FDA has taken – and will continue to take – action regarding illegally traded HCT / Ps. More recently, Marks wrote that, since December 2018, the FDA has sent 400 letters to manufacturers and healthcare providers who may suggest infringing stem cells or related products. Additionally, since 2017, the FDA has issued 14 warning letters and 24 untitled letters involving offending HCT / Ps, Marks wrote.
We recently analyzed (online here) the importance of these warnings to companies in the regenerative medicine field 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 the susceptibility to private lawsuits.