FDA’s Center for Biologics Evaluation and Research (CBER) is overcoming daunting challenges in its enforcement of laws and regulations in the area of human cells, tissues, and cellular and tissue-based products (HCT/Ps) that are being sold without the required FDA approval.

While some companies are submitting applications to CBER seeking agency approval for marketing HCT/Ps, others are marketing and administering products they claim will treat various diseases and life-threatening conditions—including cancer, amyotrophic lateral sclerosis (ALS), Alzheimer’s, autism, arthritis, stroke, Multiple Sclerosis (MS), macular degeneration, Parkinson’s disease, chronic obstructive pulmonary disease (COPD), and many others—without proof of the claims and without agency approval.

At the Food and Drug Law Institute (FDLI) Enforcement, Litigation, and Compliance Conference held in Washington, DC in December 2019, CBER Office of Compliance and Biologics Quality Deputy Office Director Melissa Mendoza reviewed the challenges her office is facing and the enforcement and litigation actions the center took in 2019.

The intention, she said, is for compliance and enforcement efforts to be impactful. Enforcing the regulations against the bad actors is “critical to the legitimacy of the entire field. We want to encourage those who follow the rules to keep following them. And we want patients who are considering enrolling in a clinical trial to not be swayed by the allure of an unsubstantiated claim that they could be cured right now. We certainly want those clinical studies to be under FDA’s oversight.”

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Enforcement Discretion Ends November 2020

FDA defines HCT/Ps in 21 CFR Part 1271 as “articles containing or consisting of human cells or tissue that are intended for implantation, transplantation, infusion, or transfer into a human recipient.” There are two broad categories of HCT/Ps with very different regulatory requirements, defined under sections 351 and 361 of the Public Health Services Act (PHSA).

Which section a product falls under can be a source of confusion, specifically regarding the interpretation of the terms “minimal manipulation” and “homologous use.” An HCT/P regulated solely under Sec. 361 has very specific properties and does not require an IND or pre-market approval—the company or individual simply needs to declare that they meet the description of a 361 product.

Firms are getting creative, and we are in hot pursuit of them

There are those who think they meet the 361 requirements and market a product without agency approval but find out later that the agency disagrees. [Editor’s Note: The requirements for a section 361 product are included in 21 CFR 1271.10.]

To better define the 361 and 351 requirements, CBER released a guidance in November 2017, “Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use.”

In order to allow manufacturers of products time to comply with new requirements for HCT/Ps introduced in 2017, for the first 36 months following issuance of the final guidance document FDA has exercised “enforcement discretion” for certain products that are subject to the agency’s premarket review under the existing regulations but are not currently meeting those requirements. FDA does not exercise that discretion for products that pose a potentially significant safety concern.

Regarding products that require FDA approval but are being sold without it sometimes quietly and locally, at the FDLI meeting Mendoza commented, “It is unfortunate, but firms are getting creative, and we are in hot pursuit of them.”

In November 2019 CBER issued 20 of what it is referring to as “It’s Come to Our Attention” letters. These letters inform various healthcare practitioners, clinics, and others that its “enforcement discretion” for certain HCT/Ps is coming to an end in November 2020. The letters also highlight CBER’s regenerative policy framework and provide links to some information and ways to engage with FDA. The Center has issued more than 80 of these letters since December 2018 and another 50 letters to affiliates of the Untitled Letter recipients as another means of getting the word out.

Mendoza explained that when CBER issues an Untitled Letter to a cellular therapy company it is usually based on a website review. In most instances, a warning letter results from an inspection, which may result from whatever prompted the Untitled Letter.

A Two-Month Microcosm

The CBER deputy office director explained that a review of the final two months of the calendar year 2019 would provide “a good glimpse” into CBER’s work for all that year. Actions during that time included the issuance of Untitled Letters, Warning Letters, and an administrative action to cease manufacturing.

On December 5, 2019, CBER issued a warning letter to Liveyon Labs and Liveyon LLC. The firm was marketing a cellular product derived from umbilical cord blood intended to treat orthopedic conditions. The labeling indicated that it should be administered intraarticularly. It is not approved by FDA for any use. CBER believes the product should be regulated as a drug and biological product.

The Office of Biological Products Operations conducted an inspection of Liveyon in May 2019 and documented Current Good Manufacturing Practices (CGMP) violations as well as Current Good Tissue Practice (CGTP) violations, which were conveyed to Liveyon in the warning letter. Liveyon also had a first-generation product that was the subject of a warning letter in 2018 that was being processed by Genentech.

Liveyon’s first-generation product was the subject of a CDC Morbidity and Mortality Weekly Report, on December 21, 2018. It documented the bloodstream infections that Liveyon’s first-generation product was linked to in over 12 patients across multiple states.

Liveyon is currently being featured in a popular podcast called Bad Batch. The company also has a video podcast through which it markets its products as being not drugs and biological products, but the lesser-regulated human cellular and tissue-based section 361 products. “We, of course, disagree as evidenced by our letter,” Mendoza said. CBER also issued a safety notification to Liveyon on December 6.

On November 27, 2019, CBER issued an administrative order against Gynecology, Reproductive Endocrinology and Fertility Institute (GREFI) of San Juan, Puerto Rico, and its Medical Director and Owner, Dr. Rosa I. Cruz, to immediately cease manufacturing due to significant violations of FDA regulations.

An FDA inspection and subsequent record review revealed that GREFI was not testing for relevant communicable diseases for its reproductive tissues, including for HIV, hepatitis, syphilis, chlamydia, and gonorrhea. They were also not properly screening donors.

“We took swift action involving a firm for which we had reasonable grounds to believe their products posed a danger to health,” Mendoza emphasized. The clinic’s actions put patients at risk for exposure to the communicable diseases it was not testing for.

CBER issued an untitled letter to Chara Biologics in California on November 25, 2019, based on a review of its website. “The best I can tell, the product is umbilical cord tissue and amniotic membrane,” Mendoza explained. “Sadly, they are offering it to parents of children with autism, claiming that these children will speak more as a result of having the product, especially in higher doses. They are also offering it to autistic children in hopes that they will do things such as use the bathroom or no longer need diapers. They are also marketing the product to adults suffering from traumatic brain injury.”

Chara states that its products are “suitable for all forms of injection, to assist the body’s ability to repair and regenerate.” CBER notified Chara that these products are regulated as drugs and biological products and they are not approved for any use.

It issued a similar letter a week earlier to RichSource Stem Cells, another combination product described as a combination of amniotic fluid and membrane, Wharton’s jelly, and placental tissue. The product is called RichGen, and it is claimed to treat cancer, tumors, diabetes, Lyme’s disease, asthma, COPD, various orthopedic conditions, and topical wound healing. It is not approved by FDA for any use.

In High Profile Cases, Courts Agree with CBER

Mendoza reviewed some high profile cases CBER has been involved in that ended up in federal court, and the outcomes.

In June 2019, in the United States District Court for the Southern District of Florida, the government prevailed in a landmark case against US Stem Cell Clinic and another corporate entity and the Chief Scientific Officer for both of those entities.

The court in this case agreed with the government and what we have been saying for years—that the defendant’s establishment is subject to FDA’s jurisdiction, that the products are regulated as drugs and biological products, and must adhere to all the requirements that come with that, from pre-market review and approval to CGMP requirements and others

The case involved the defendants’ adulteration and misbranding of a cellular product that is derived from adipose tissue (body fat). The product was referred to as a stromal vascular fraction (SVF) product. These were cells taken from human fat tissue and extensively processed.

The clinic was administering the product both intravenously or directly into the spinal cord of patients to treat a variety of serious diseases or conditions, including Parkinson’s disease, ALS, COPD, heart disease, and pulmonary fibrosis. FDA has not reviewed or approved any biological products manufactured by US Stem Cell Clinic for any use.

“The court, in this case, agreed with the government and what we have been saying for years,” Mendoza explained, “that the defendant’s establishment is subject to FDA’s jurisdiction, that the products are regulated as drugs and biological products, and must adhere to all the requirements that come with that, from pre-market review and approval to CGMP requirements and others.”

The court enjoined the companies and their Chief Scientific Officer. The case is currently on appeal before the 11th Circuit Court.

Mendoza also described a similar case that she referred to as a “sister action” in the Central District of California against the California Stem Cell Treatment Center, the Cell Surgical Network, and the responsible individuals involved. The defendants are also offering multiple SVF products for the treatment of a variety of diseases. Like the product in the US Stem Cell Clinic, these SVF products are not approved for any use. CBER is seeking a permanent injunction against the entities.

Those two cases continue the trend of active litigation involving HCT/Ps and articles related to HCT/Ps. “There is still a lot of active litigation. Last year, we took aggressive enforcement action against Five Articles of Drug—specifically, ACAM 2000, which is a licensed biological product that is intended to immunize those at high risk of smallpox infection. This would include certain members of the military.”

However, it was not intended to be used for that purpose. Rather, it was intended to be mixed with an SVP product to be administered, for example, to advanced-stage cancer patients.

Exosomes Remain Undefined but Used in Unapproved Marketed Products

Mendoza explained CBER is “attempting to keep up with the new unapproved products that are regulated as drugs, devices and/or biological products. One of those are products marketed as exosome products.” She pointed out that exosomes have not been defined by the agency.

“It is unclear exactly what is being marketed as exosomes. Some market their product as an ‘exo shot’ that is administered in combination with other HCT/P products or for additional therapeutic benefit. Again, all outside of FDA’s review and oversight.”

According to a Q&A in BCM Biology, “Since the original description of exosomes over 30 years ago, the term has been loosely used for various forms of extracellular vesicle, muddying the field and contributing to the skepticism with which the research has sometimes been met. Exosomes are best defined as extracellular vesicles that are released from cells upon fusion of an intermediate endocytic compartment, the multivesicular body (MVB), with the plasma membrane. This liberates intraluminal vesicles (ILVs) into the extracellular milieu and the vesicles thereby released are what we know as exosomes.”

They deceive patients with unsubstantiated claims about the potential for these products to prevent, treat or cure various diseases and conditions

The agency used a public safety notification on December 6, 2019, to warn the public about exosome products.

The Safety Notification said in part, “Certain clinics across the country, including some that manufacture or market violative ‘stem cell’ products, are now also offering exosome products to patients. They deceive patients with unsubstantiated claims about the potential for these products to prevent, treat, or cure various diseases or conditions. He may claim that these products do not fall under the regulatory provisions for drugs and biological products—that is simply untrue.”

It includes questions for patients to ask clinics, manufacturers, or health care professionals about the products. It also sheds light on some serious recent adverse events that have been brought to the agency’s attention—patients who have been seriously adversely affected by exosome products in Nebraska. The intention of the notice is “to bring some public attention to the issue so people will recognize that the risks related to all these unapproved products that should be under FDA’s oversight are real and patients are being harmed.”

Cell and Gene Therapies are the Future of Medicine

Mendoza commented that her office is seeing new trends and products they have never seen before. “As a lawyer at CBER I can tell you that I repeatedly ask my product office colleagues and agency experts whether what I am seeing is actually the case and for an explanation of some products and technologies that are fairly remarkable.”

In addition to releasing guidance and performing enforcement activities, CBER is also working to promote innovation. “We are poised and ready to do whatever we can within the bounds of the law to do that. Cell and gene therapies are the future of medicine, in some respects, and that is beyond dispute. We are seeing more approvals all the time. We hope to see many more. It is exciting for us in the Office of Compliance to see all this innovation.”

Links

Liveyon Labs 2019 Warning Letter
Genentech 2018 Warning Letter Mentioning Liveyon
CDC Morbidity and Mortality Weekly Report December 21, 2018
GREFI Order to Cease Manufacturing
Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use
Q&A on Exosomes in BCM Biology
21 CFR Part 1271