FDA’s regulations set forth criteria for determining when particular products are regulated merely as transplanted human cells or tissues subject only to the authority of Section 361 of the Public Health Service Act to prevent the transmission of communicable diseases. Such products, referred to as 361 HCT/Ps or 361 products, may be sold without prior FDA review. The regulation also sets forth several exceptions where an HCT/P is exempt from FDA regulation altogether, such as when a physician removes an HCT/P from an individual and implants the HCT/P into the same individual during the same surgical procedure (known as the “same surgical procedure” exception). When an HCT/P neither meets the 361 HCT/P criteria nor qualifies for an exception, the product requires either FDA licensure as a biological product under Section 351 of the Public Health Service Act (PHSA), or approval or clearance under the Federal Food, Drug, and Cosmetic Act (FDCA) as a new drug or a medical device.

In United States v. California Stem Cell Treatment Center, a stem cell clinic challenged FDA’s determination that its products were subject to premarket review, and the court agreed with the stem cell clinic. It held that: (1) autologous stromal vascular fraction cells (SVF Cells) were not “new drugs” and were created and implanted during the “same surgical procedure,” exempting them from FDA oversight altogether; and (2) expanded mesenchymal stem cells (MSC Cells) were also not “drugs” and are not subject FDA’s premarket review and approval. The district court decision threatens to undermine FDA’s efforts to enforce its standards against unapproved regenerative medicines since FDA lifted a grace period against such enforcement last year. Furthermore, this decision conflicts with two other decisions in the Eleventh and DC Circuits. On October 26, 2022, FDA filed a notice of its intent to appeal to the Ninth Circuit. According to the scheduling order in that appeal, initial briefing will be completed March 8, 2023, with an optional reply brief from the Government due by the end of March. Hogan Lovells will continue to monitor updates to the briefing schedule.

Background

FDA sued the stem cell center alleging that its two products – SVF Cells and MSC Cells – failed to meet the requirements for qualifying as 361 HCT/Ps, specifically that they were: (1) more than minimally manipulated; (2) not intended for homologous use; and (3) combined with articles other than those permitted by regulation (water, crystalloids, and sterilizing, preserving, or storage agents). FDA has provided guidance about factors that would lead it to conclude that a product was more than minimally manipulated and not intended for homologous use in a 2020 guidance document. FDA has also provided guidance on when an HCT/P qualifies for the “same surgical procedure” exception. Specifically in a 2017 guidance, FDA interpreted the exception as being met only when "autologous cells or tissues … are removed … and [reimplanted] … without intervening processing steps beyond rinsing, cleansing, sizing, or shaping.”

In California Stem Cell Treatment Center, the SVF therapy involved (1) extracting adipose tissue through a process called “miniliposuction via subdermal local anesthesia;” (2) isolating SVF Cells from the adipose tissue through mechanical and chemical processes; and (3) administering the SVF cells into the same patient. During the procedure, SVF Cells are isolated from adipocytes using a centrifuge device and an enzyme called Liberase. After separation, the SVF Cells are filtered through a hundred-micron filter, viewed through a special micrograph to ensure they are free from impurities and then suspended in a sterile saline solution. The SVF Cells are then injected into the patient.

The MSC therapy also involves the extraction of adipose tissue via liposuction, but the tissue is then transported to a third party good manufacturing practices (GMP) compliant lab to isolate MSC Cells, which are a subset of the cells in stromal vascular fraction. The third party lab suspends the MSC Cells in a culture where the cells replicate. The expanded MSC Cells are then bottled in sterile, labeled vials, and are sent back to the stem cell center to be injected into the same patient, sometimes weeks, months, or even years later.  

District Court rejects FDA’s interpretation of “same surgical procedure”

Judge Bernal found that the SVF therapy was provided during the “same surgical procedure” and was thus exempt from the requirements applying to HCT/Ps – not simply rejecting FDA’s request that the products were regulated as drugs, but holding that they were not even regulated under 21 CFR Part 1271 as tissue products. A critical finding was Judge Bernal’s interpretation of the exception. The regulation exempts from FDA oversight any “establishment that removes HCT/Ps from an individual and implants such HCT/Ps into the same individual during the same surgical procedure.” FDA interprets that language to mean that the implanted HCT/P must remain “such” HCT/P as the establishment originally removed from the patient. In FDA’s view, any change to the initial HCT/P – other than “rinsing [and] cleansing” or “sizing and shaping,” including “dilation,” “cutting,” “meshing” – disqualifies the procedure from meeting the exception. Other courts have adopted FDA’s interpretation.

In contrast, Judge Bernal found that the regulation must be read to focus on the cells or tissues targeted for transplantation, rather than the largest tissue system removed. He rested this interpretation on the regulatory definition of HCT/P in two ways. First, HCT/Ps are defined as limited to articles intended for implantation, transplantation, or infusion into a human recipient. He reasoned that any portions of the harvested adipose not intended to be implanted do not meet the definition of HCT/P.

Second, Judge Bernal also pointed out that the definition of HCT/P includes both “cells” and “tissues.” He found that cells can only be removed from patients along with larger systems, such as the tissues or organs they comprise. Consequently, he held that the Government’s interpretation, in reality, improperly narrowed the definition of HCT/P to tissues, excluding cells. Thus, Judge Bernal rejected the Government’s position that only “such” tissues that are removed from the donor, in their entirety, may be re-implanted, and that any material change to the full tissue removed disqualifies the article from meeting the same surgical procedure exception.

Expanded MSC surgical procedure

Judge Bernal also rejected FDA’s position that the expanded MSC Surgical Procedures constituted the manufacture of drugs. He recognized that the same surgical procedure exception did not apply to the MSC Cells because their extraction and subsequent implantation back into the patient involved more than one procedure, by more than a single HCT/P establishment, rather being part of the same surgical procedure. Nevertheless, he found that FDA lacked jurisdiction over MSC Cells altogether on the ground that the Expanded MSC Procedure that produced the MSC Cells constituted the practice of medicine, not the manufacture of pharmaceuticals.

Judge Bernal based this conclusion of law in part on section 1006 of the FDCA, which states that the Act “shall not be construed to limit or interfere with the authority of a health care practitioner to prescribe or administer any legally marketed device . . . .” He failed to address, however, how that provision applies to cells that are neither devices nor were purported to be legally marketed as devices. Judge Bernal also cited the Supreme Court case Buckman Co. v. Plaintiffs’ Legal Comm. for the position that Congress rejected “any intent to directly regulate the practice of medicine.” But he failed to show how that case about a device which FDA had cleared for marketing has any bearing on cells that FDA had never cleared for marketing, or how the specific quote in Buckman about off-label use of legally marketed devices (at n.5) was relevant. Moreover, he overlooked the long-held judicial interpretation of the statute that “‘[W]hile the [FDCA] was not intended to regulate the practice of medicine, it was obviously intended to control the availability of drugs for prescribing by physicians.’”

Judge Bernal also rested his conclusion on a finding that the line between “drug” and “procedure” was indecipherably blurred by the Expanded MSC Procedure. He did not explain, however, how nevertheless, elsewhere in the decision, he was able to define and describe the output of the procedure as “MSC Cells.” Nor did he address the logic of the D.C. Circuit Court of Appeals in the Regenerative Sciences case distinguishing between regulation of procedures used to administer cells and regulation of the administered stem cells themselves. The court in Regenerative Sciences wrote:

“Notwithstanding appellants' attempt to characterize this case as an effort by the FDA to ‘restrict[] the use of an autologous stem cell procedure,’ . . . the focus of the FDA's regulation is the Mixture. That is, the FDA does not claim that the procedures used to administer the Mixture are unsafe; it claims that the Mixture itself is unsafe. Appellants' arguments about the practice-of-medicine exemption are therefore wide of the mark.”

Finally, Judge Bernal found that expanded MSCs resulting from the procedures were not drugs based on a 2013 Supreme Court decision on pharmaceutical patents, Ass'n for Molecular Pathology v. Myriad Genetics, Inc., which held that naturally-occurring human body parts are a “product of nature and not patent eligible merely because it has been isolated.” He did not explain how this law on patent eligibility has any bearing on the FDCA or on what products FDA has authority to regulate.

FDA notice of intent to appeal to the Ninth Circuit

An appeal to the Ninth Circuit could usher in a period of protracted litigation for FDA’s stem cell regulation or it could strengthen the deference given to the agency in regulating regenerative medicine. Although the Eleventh Circuit's decision, United States v. Cell Surgical Network et al., and DC Circuit's 2014 decision, United States v. Regenerative Sciences, LLC found that FDA has authority to regulate very similar stem cells, a Ninth Circuit decision in favor of California Stem Cell Treatment Center would call into question FDA’s authority to enforce in a large swath of the U.S.

FDA has yet to comment publicly on how the California Stem Cell Treatment Center decision will impact enforcement. At the Perinatal Stem Cell Society Conference on November 3, 2022, CBER Director, Peter Marks declined to comment on pending litigation.

Hogan Lovells has previously analyzed the significance of FDA’s HCT/P warning letters in the regenerative medicine space and outlined potential risks of noncompliance, which can be accessed here. There are numerous other risks, including FTC action, False Claims Act liability, product liability claims, and susceptibility to private lawsuits.

If you have any questions on responding to the uncertainty around HCT/P FDA enforcement, or if you need to evaluate whether your products and facilities comply with FDA’s regenerative policy framework, please contact the authors or the Hogan Lovells lawyer with whom you regularly work.

Authored by Michael N. Druckman, Meredith Manning, and Ashley Grey