CDC: Patients Contaminated by Allograft Umbilical Cord Products

If your practice treated patients with certain allograft umbilical cord products which purport to have “stem cells” from a San Diego, California, company called Genetech, Inc.* in the past year, distributed through a Yorba Linda, California company called Liveyon, LLC, you stood a chance of unwittingly infecting them with dangerous pathogens.

*This is not the big San Francisco biotech company, Genentech, Inc. (with an “n” in the middle).

Now, the Food and Drug Administration (FDA) seems to be planning an aggressive, immediate crackdown on processors of human cells, tissues, and cellular and tissue-based products (HCT/Ps) to ensure that any company selling tissue products is not, in fact, selling biologics or drugs – which are regulated under either a BLA or IND protocol.

Here’s the story:

1. On June 18 and 22, FDA inspected the facility at which Genetech produced the human umbilical-cord-blood-derived cellular products called ReGen^®5, ReGen^®10, and ReGen^®30, distributed to orthopedists and other physicians through Liveyon.
2. Liveyon recalled the entire lot of products on or around September 27 amid rumors that someone had been infected with Escherichia coli.
3. On November 29, the FDA issued a harsh Warning Letter to Genetech alleging that the company was not only distributing human cells, tissues, and cellular and tissue-based products (HCT/Ps, a.k.a. stem cells) without adhering to proper FDA HCT/P processing rules and, as a result, Genetech’s collection, processing, and record-keeping methods create a serious danger of widely spreading many potentially deadly diseases.
4. The risk turned out to be more than theoretical. On December 21, the Centers for Disease Control (CDC) published a “Notes from the Field” saying that it had so far discovered 12 cases of Enterobacter cloacae, Citrobacter freundii, Escherichia coli, Enterococcus faecalis, and Proteus mirabilis from Genetech-processed HCT/Ps distributed through Liveyon.
5. On December 20, with the information about the 12 infections in hand, FDA sent an ominous letter to the entire HCT/P industry regarding the commercialization of living cell based tissue forms and any claims that these living cell-based forms provide regenerative medicine benefits.  The letter warned HCT/P processors to contact the FDA to find out what level of regulation their products require.
6. Also, on December 20, FDA issued a press release titled, “FDA sends warning to company for marketing dangerous unapproved stem cell products that put patients at risk and puts other stem cell firms, providers on notice.”
7. FDA’s use of the word “providers” seems to mean that the notice is intended for any clinic, physician’s office, or hospital which treats patients with stem cell or other HCT/P products. The release says FDA is “discouraged”—which is probably diplomatic code for “infuriated”—by the industry’s response to a 36-month period of relaxed enforcement granted in November 2017.

The CDC Report on the Infections: Up to 58 Days Hospitalized

All 12 infected patients discovered* by CDC had been treated with Genetech HCT/P cells for complaints including chronic pain, joint or back pain, rheumatoid arthritis or osteoarthritis, and rotator cuff tears.

*In researching this report, we found comments online from other people saying they’d been made ill by these products.

CDC received the first reports from Texas health officials on September 17 and from Florida officials on September 22. CDC then issued a nationwide call for reports of culture-confirmed infections in patients who had received the Genetech/Liveyon products. One additional report has since been received from Arizona. The 12 reports received so far go back to infections as early as last February 21.

Every treatment involved injections into the patient’s knee, shoulder, or spine, or into more than one orthopedic treatment site. One case also involved intravenous infusion. The injections were done at orthopedic, spine, and pain clinics, and an ambulatory surgery center. None was done at a hospital, according to CDC records.

All 12 patients were hospitalized for their infections; the shortest stay was four days, the longest 30, 35, and 58 days. None died. In eight of the 12 cases, the infections were determined to have spread into the patients’ blood streams from injection sites.

In the 58-day hospitalization, the injection site is described in the CDC report as “Intra-articular injection, lumbar spine;” the patient ended up infected with Escherichia coli and Enterococcus faecalis at these sites: “bloodstream, lumbosacral epidural abscess, discitis, and vertebral osteomyelitis.”

The CDC investigators say that in one Texas clinic, the Enterococcus cloacae bacterium was found in all six vials containing the Genetech product. Similar results were found in vials tested at other clinics where injections were given. The source of the infections was apparently the manufacturer, not the clinics, CDC said.

The full “Notes from the Field” report, including the injection sites, pathogens, and subsequent infection sites, is in the December 21 issue of the CDC journal Morbidity and Mortality Weekly Report.

The CDC field report adds, “Health care professionals and consumers should report any adverse events related to treatment with the Genetech/Liveyon products or any unapproved stem cell therapies to FDA’s MedWatch Safety Information and Adverse Event Reporting Program.”

That comment raises this question: Are providers who treated patients with the Genetech/Liveyon products required, legally or ethically, to notify them of the danger?

Liveyon ceased distributing the Genetech products, CDC said. However, it did not shut down its marketing; the company appears to have said in an October 9 announcement (posted under a blog, not confirmed here) that it had a new supplier and was resuming deliveries October 8. Its website seems to indicate that it now calls the product “Liveyon Pure.”

Details in the FDA Warning Letter to Genetech

The November 19 FDA Warning Letter did mention the infections. It seems to arise solely from the June inspections, which were well before the CDC received the first disease report. Key points in the warning letter:

1. The Genetech-Liveyon products are drugs and biologics, not cosmetics or consumer products. However, Genetech has not submitted any kind of FDA application, not even for an investigational new drug (IND) or a biologics license application (BLA), much less received approval to sell them.
2. The collection and manufacturing processes FDA says it saw in its June 2018 Genetech inspections are shocking:

“Genetech’s deficient donor eligibility practices, unvalidated manufacturing processes, uncontrolled environment, lack of control of components used in production, such as the addition of [redacted as a trade secret], and lack of defined areas or a control system to prevent contamination and mix-ups, as described below, pose a significant risk that your products may be contaminated with microorganisms or have other serious product quality defects.”

“[S]ince operations began in mid-2017, Genetech has failed to document whether donors of umbilical cord blood are eligible. Neither you, Liveyon, nor your suppliers have determined donor eligibility for the umbilical cord blood used to manufacture your products.”

The letter goes on in 19 additional detailed paragraphs describing risky operations and operating controls, including failure to screen donors for Zika virus, using tests not approved by the FDA for a wide variety of other blood-borne diseases; inadequate cleaning, inadequate air controls in the manufacture and gowning rooms, and, “Your firm added non-sterile [redacted] to approximately [redacted] batches of your products between mid-2017 and June 2018. These [redacted] are labeled ‘For research use only.’”

The December 20 Letter to HCT/P Companies, the Press Release, and Their History

FDA’s December 20 letter called out “stem cell” companies (FDA’s language) among HCT/P processors and providers, and along with the press release that was also released that day, referred to a November 2017 policy announcement which included this paragraph:

“To give manufacturers time to determine if they need to submit an IND or marketing application in light of this guidance and, if such an application is needed, to prepare the IND or marketing application, for the first 36 months following issuance of this guidance FDA generally intends to exercise enforcement discretion … provided that use of the HCT/P does not raise … significant safety concerns.”

To benefit from “enforcement discretion,” HCT/P processors were supposed to meet with FDA to discuss whether their processed living cell tissues needed some type of application or approval, and if so, what data was needed to obtain it.

“However, thus far it does not appear as though many firms have taken FDA up on their offer,” said a January 16, 2019 article by attorney Mark. I. Schwartz in the FDA Law Blog published by the law firm Hyman, Phelps, & McNamara. Schwarz is a former Deputy Director for Compliance in the Center for Biologics Evaluation and Research (CBER), the office which enforces compliance with these products.

FDA Commissioner Scott Gottlieb, M.D. said in the December 20 announcement that FDA is still “committed to advancing the field of cell-based regenerative medicine,” but “At the same time, we’re also focusing more resources on enforcement when we see companies skirt safety measures and put patients at risk.”

“The letters we’re issuing today to manufacturers, health care providers and clinics around the country are a reminder that there’s a clear line between appropriate development of these products and practices that sidestep important regulatory controls needed to protect patients. Time is running out for firms to come into compliance during our period of enforcement discretion. We’ll be increasing our oversight related to cell-based regenerative medicine as part of our comprehensive plan to promote beneficial innovation while protecting patients,” Gottlieb said.

The November 2017 FDA “Framework for the Regulation of Regenerative Medicine Products” includes two guidance documents. The main document, “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” covers human tissue from a donor, or human tissue extracted from a patient and later reintroduced into the same patient in a subsequent surgical procedure.

The second document, “Same Surgical Procedure Exception under 21 CFR 1271.15(b): Questions and Answers Regarding the Scope of the Exception Guidance for Industry” is brief guidance setting the conditions under which autologous use—that is, taking tissue from the patient and reintroducing it in the same procedure—is permitted.

In an interview, Schwartz said, “It is unclear whether the products that Liveyon is referencing on their website are the same ones that Genetech received its Warning Letter for. That said, it is likely that FDA would argue that any umbilical cord stem cells used for these indications violate at least two of the four criteria for regulation solely as a 361 HCT/P (i.e., that they are intended for a non-homologous use and that they are dependent on the metabolic activity of living cells for their primary function), thereby rendering the product an unapproved drug and biological product.”

The State of the Science (and the Profiteering) of Living Cell Implants

The state of the science in the use of stems cells in orthopedics is covered in depth in two recent Orthopedics This Week articles, “Mixed Cells, Not Stem Cells,” Tuesday, November 6, 2018, and “The Wild West of “Stem Cells: Updated,” Thursday, October 11, 2018.

We’ll have more on the prices and profits in: Upcoming in Part 2: Liveyon Markets On