When Matthew Feshbach, then an investor, first heard about a California company developing treatments for a variety of diseases using stem cells derived from a patient’s own fat cells (autologous adipose-derived cells), he thought, That’s the biggest idea I’ve ever heard. Stem cells, which have the potential to differentiate into many types of cells, are a type of regenerative medicine with the promise of repairing damaged tissues and organs.
He was onboard. However, the Food and Drug Administration (FDA) rejected the company’s 510(k) application, which states that if a device is similar enough to something already on the market, it can be approved without new trials. Feshbach, unable to offer the treatments legally in the US without undertaking expensive, lengthy clinical trials to get FDA approval, opened his own cell therapy center, Okyanos, in the Bahamas, where he wrote the framework for the act that eventually regulated stem cell treatments while he built his facility.
It seems now, though, that the FDA’s regulations hadn’t deterred many others. It’s estimated that the U.S. has more regenerative medicine clinics than anywhere else in the world. Around the time that Feshbach went to the Bahamas, the number of clinics here was doubling each year.
Where Do Regenerative Medicines Come From?
Isolation Kits and All-In-One Treatment Systems
Many therapies use cells from a patient’s own body, but that doesn’t mean the cells are extracted and then immediately injected in another body part as-is. The provider will likely use a kit, a collection of plastic containers, chemicals to process cells and other tools, developed to isolate or process those cells before injecting them back into the patient’s body. Many providers purchase these kits from other companies. Feshbach’s Ambrose Cell Therapy, for example, uses the Celution System, a cGMP lab in a box made by Cytori Therapeutics, to isolate, process and re-inject or infuse adipose-derived regenerative cells in a single treatment.
Harvested and Packaged Cells or Exosomes
Some regenerative medicines are grown from bought or donated stem cells and harvested in labs before being sent to providers for use. For example, Kimera Labs uses stem cells to produce exosomes, which it then harvests, analyzes and sells to other doctors and researchers for use in their own practices or labs.
Birth Tissue and Cord Blood Banks
Mothers can choose to donate birth tissues like umbilical cord blood, which contains stem cells, after giving birth. The cord blood is then frozen and preserved in a cord blood bank. If donated, it may be used for research or to treat patients with blood disorders in an FDA-approved procedure. Others may choose to send the cord blood to a private bank, where they pay for its storage, in case they want to use it later for medical procedures on themselves or relatives.
Stem cell therapies started gaining traction in the 1990s, as scientists learned more about these cells. The researchers developed techniques to isolate them from embryos donated after in vitro fertilization efforts in 1998. Soon, researchers created cell lines, cultures of cells derived from a single cell — meaning the genetic makeup remains consistent across all cells — that can grow continuously for use in research and treatment. In the 2000s, scientists learned that even adults harbored some functional stem cells in their fat and bone marrow.
These discoveries all meant that the stem cell therapies were able to grow more varied and more complicated. Researchers developed protocols to isolate the stem cells from neighboring tissue by spinning them in centrifuges or adding certain chemicals to them. Others used cell lines to produce products that could sit in a freezer and be ready to inject into any patient. Some doctors injected cells into patients in hopes that those cells would fulfill functions completely different from those they had performed naturally. For example, stem cells destined to become fat or bone were used in attempts to restore function in the brain or treat diseases like diabetes.
It became clear that more regulations would be needed to keep patients safe from the unexpected risks of the expanding list of procedures, but it wasn’t obvious exactly which category these products fell into. Were they drugs? Were they medical devices? Additionally, “some individuals who were concerned that the regulations would constrain what were already evidence-based interventions. . . there was already substantial evidence that stem cells for leukemia could help individuals” explains Leigh Turner, PhD, a bioethicist at the University of Minnesota, referring to bone marrow transplants, which have become standard care for several blood disorders since the 1970s.
The FDA developed a new framework to regulate the use of what it now calls “human tissue/cell products,” based on how much risk each product was thought to carry, while allowing bone marrow transplants to continue uninterrupted.
Qualifying as “low-risk” hinged on two broadly defined terms. One, the product had to be “minimally manipulated,” signifying that scientists didn’t meaningfully change or combine the cells with other chemicals or products, and, two, designed for homologous use, meaning the cells would perform the same function in the body after implantation as they did before. For example, using bone marrow in hopes of healing bone is a homologous use; using it to treat Alzheimer’s is not. These low-risk products did not require FDA approval. Companies making or using them simply needed to show that the products weren’t contaminated with disease-causing microbes, like any other donated blood or organ used for transplants.
Any use of stem cells or human tissue that did not meet the above criteria would be subject to the usual FDA approval process for drugs. By 2005, the framework was finalized.
Stem Cell Clinics Start to Proliferate
After these regulations were published, stem cell clinics proliferated throughout the US. Facilities claimed to offer the low-risk services that allowed them to bypass cumbersome, expensive clinical trials to prove their safety and efficacy
As of May 2017, there were 716 known stem cell clinics in the U.S., many providing treatments that did not met the FDA’s regulatory guidelines. In August of that year, Sean Morrison, a stem cell researcher at the University of Texas Southwestern, told Time, “At some point, people made the calculation that the FDA didn’t seem to be enforcing these laws. [Their profit] margins are huge. They charge people tens of thousands of dollars.”
Many clinics found patients through advertising online. The FDA forbids companies from claiming that their procedures treat or cure specific injuries or diseases unless they’ve been proven to do so through clinical trials. The firms often rely on testimonials from previous patients to recruit new ones.
In a YouTube video, a woman who suffered from a traumatic brain injury, after which she couldn’t utter more than a simple “yes” or “no,” tells us in fully constructed sentences about her harrowing journey from weekslong hospital stays to physical therapy to outfitting her home with a hyperbaric chamber for hours of daily use in futile efforts at recovery. Finally, she says, she found U.S. Stem Cell. Now she has no trouble with day-to-day functioning and communicating.
Another patient, personal trainer Lem Brown, says his hip hurt so much from arthritis and a torn labrum, that “you name it, I was miserable doing it.” All it took to get him to U.S. Stem Cell was a hip surgeon not returning his calls. Now, he says “I jump rope. I can jog. I can do lunges. I can do squats. I’m just a new person.”
In a patient outcome on Feshbach’s Ambrose Cell Therapy website, a young woman named Amy tells readers that she suffered from diabetic neuropathy in her feet so severe that she could barely function. On bad days, she says, she would spend hours soaking in the bathtub. After having her own adipose-derived cells injected directly into her feet in 2014, she says she gradually improved. The severity of her diabetes declined, and the neuropathy in her feet was gone, according to tests run by her endocrinologist and shared on Ambrose’s website. With less pain, she’s now traveling the world, exploring mountains and canyons on foot.
The industry gains additional credibility from elite athletes, like basketball champion Kobe Bryant and hockey star Gordie Howe, who have undergone stem cell procedures in hopes of expediting the healing of sports injuries.
With reported success stories like these, it’s easy to imagine why people might seek out stem cell therapy whether they had exhausted all other treatment options or just hoped for a more permanent solution to their ills than drugs or other therapies provide.
But Then, a Flurry of High-Profile Failures
A Pew report published in 2019 suggests that adverse effects of stem cell therapies are likely underreported. As clinics sprung up around the country, a few high-profile events made headlines. In 2012, a cosmetic surgeon extracted a woman’s fat cells and injected them into her eyelids as a part of a face-lift. She and the provider believed the stem cells would rejuvenate her skin and restore a youthful appearance. But stem cells weren’t the only product added to her face that day; the surgeon also injected fillers made of calcium hydroxylapatite to restore volume lost due to aging.
Three months later, the woman struggled to open her eyes and reported a loud “clicking” sound when she tried. Another cosmetic surgeon ended up surgically removing chunks of bone from the woman’s eyelids and surrounding area. Scientists suspected that instead of forming fresh, new skin cells, the adipose-derived cells matured into bone cells, influenced by the calcium they sensed in the neighboring fillers. The incident demonstrated that scientists still had more to learn about how stem cells behave in different parts of the body.
A Canadian patient developed a tumor on his spinal cord 12 years after he had had stem cells injected there. The cells in the tumor were traced back to the ones injected during the treatment. To add insult to injury, the treatment hadn’t worked. The man, who had been paralyzed in an accident, remained so and reported additional pain after the injection.
Duncan Ross, PhD, CEO of Kimera Labs, notes that the cells used in this scenario were embryonic stem cells, and shouldn’t be compared to adult stem cells, “which shouldn’t be called a stem cell. The person who named it a ‘mesenchymal stem cell’ now calls it a ‘medicinal signaling cell’ because we’re really just using it for the growth factors,” found in exosomes.
While few tumors have been reported as the result of stem cell injections, the presence of tumors is a concern for regulators. Stem cells can multiply and grow, says Richard Bosshardt, MD, a plastic surgeon who doesn’t use stem cells. “If you can’t control that process, there’s a name for that; it’s called cancer.”
In another incident in 2018, 12 people were hospitalized with severe bacterial infections after they were injected with contaminated cord blood in hopes of treating pain related to joint disease and injuries.
The pressure was mounting for the FDA to do more to control the hundreds of providers offering treatments in the US. In 2017, the agency announced updates to the guidelines developed in 2005. The new guidance documents give more concrete explanations for what constitutes a “minimally manipulated” product, describe an exemption for certain products that are extracted from a patient and re-injected in the same surgical procedure, and outline how the FDA intends to enforce its regulatory framework.
Those rules didn’t go into effect right away. Companies have until May 31, 2021 to align their products with FDA recommendations. The FDA has offered to guide companies that requested help in filing the necessary paperwork and updating protocols.
At the same time, the FDA has vowed to crack down on those companies conducting the riskiest procedures or making unproven claims in their marketing materials, which were already considered against the existing rules. For the most part, this crackdown consisted of the FDA sending more than 350 letters informing companies that they were not in compliance with the agency’s standards.
The new guidelines are a big deal for Kimera Labs. Initially, the company’s products, exosomes, packages of molecular signals stem cells produced to communicate with other cells around them, weren’t subject to FDA oversight. But under the new guidance, they’ll be within the FDA’s regulatory purview. To prepare, Ross says he’s submitted an investigational new drug (IND) application, a set of paperwork outlining manufacturing standards, data from preclinical studies in animals and a proposed trial protocol to the FDA to test exosomes in the treatment of patients with COVID symptoms. Ross has several other applications in mind.
He says he’s been working on the IND for six years, and that “the regulation is good for me, because it’s really hard to hit all of these milestones you’re supposed to hit.” Ross adds, his competitors won’t be able to keep up.
While working on the IND, he’s continued to provide exosomes to doctors and researchers. In April 2020, Ross received a letter from the FDA, because, he says, one doctor to whom he had sent exosomes had advertised them on his website, writing, “COVID-19 is here. Is Kimera the cure?” The letter also cites claims that the doctor, and others associated with Kimera, have made in a series of YouTube videos.
Now that Ross is hoping to start clinical trials, he says he’s being more careful who he sends his products to. “I’m a lot more stringent about getting IRBs [institutional review boards], working with specific physicians that I know are going to collect that data, having a clinical research group out in L.A. that can collect that data in a fashion that the FDA is going to approve.”
Those he’s supplied in the past, he says, often didn’t return data on how the products performed. “I just make the products. It goes out and then the physicians use it however the physicians are going to. And I’m not usually updated on that. In fact, it’s really hard for me to get the data back from them because they’re worried about handing that information over.”
Another company that got a letter from the FDA is U.S. Stem Cell, one of the most influential companies in the industry, which stated that the adipose-derived stem cell treatments the clinic provided did not meet the low-risk criteria and thus were considered an unapproved drug. The company also failed to meet standards for preventing contamination. But when U.S. Stem Cell continued to provide the procedure in question — the one in which several patients were rendered blind in 2015 — the FDA sued the company. In the case, the judge ruled that the agency had the right to force U.S. Stem Cell to stop providing the procedure, confirming the FDA’s role in regulating adipose-derived stem cell products as drugs.
When the FDA guidelines go into effect at the end of May 2021, the agency will have the right to go after any company that’s not in compliance. Still, some experts worry that no matter how stringent the rules are, the FDA won’t have the resources or staffing power to enforce them. Its efforts so far have been described as a game of whack-a-mole, in that no matter how many dangerous clinics it knocks down, more just keep popping up.