Nature abhors a vacuum, and in the absence of evidence-based therapies to treat or prevent COVID-19, stem cell clinics with a menu of unsubstantiated direct-to-consumer therapies are more than willing to fill the gap.

Ambitious claims are not out of place in the realm of stem cell marketing, in which hundreds of U.S. businesses aggressively pitch unproven stem cell products to treat a variety of conditions, ranging from autism to Parkinson’s disease to macular degeneration. It is a gray area of regenerative medicine that rheumatologists and orthopedic providers are typically familiar with, as the promise of stem cell injections to relieve joint pain or bypass invasive surgeries often resonates among patients with osteoarthritis.

Although much of the attention surrounding unproven regenerative medicine has focused on the significantly flashier claims, it is the relatively lowkey promises related to arthritis and other orthopedic conditions that remain the industry’s main source of revenue.

“A lot of the times when people talk about this market, they are interested in the really far out claims, such as that they treat ALS or spinal cord injuries or Alzheimer’s Disease,” Leigh Turner, PhD, of the University of Minnesota Center for Bioethics and School of Public Health, told Healio Rheumatology. “While that is important and the misrepresentations are extreme, individuals with arthritis and similar conditions are really the bread and butter of this marketplace. It is a lot more common.”

In the United States, more than 27 million people are affected by OA, with an estimated 9.9 million adults exhibiting OA of the knee. It is to this population that regenerative medicine companies, through hundreds of sports medicine and pain management clinics across the country, direct their most enticing promises — that all patients have to do is take cells from bone marrow or blood, process it, and inject them back into the body, and it will have a variety of anti-inflammatory therapeutic effects.

“These are widespread advertising claims,” Turner said. “It’s almost so widespread that their existence has kind of been normalized and routinized. When you think about regulatory activity with the FDA and the Federal Trade Commission, much of it has not been in the orthopedic or pain management space; the focus instead has been on the companies making the especially egregious claims.”

In 2015, platelet injections for arthritis alone generated more than $93 million in revenue in the United States, according to a 2018 article in The Journal of Knee Surgery. Globally, the regenerative medicine market, including direct-to-consumer stem cell therapy, is expected to reach $5.6 billion by 2025, according to a 2019 report from the market research firm ReportLink.

“Many businesses [involved in direct-to-consumer stem cell therapies] appear to be violating federal law — and generating a lot of money by doing it — but are not really drawing the attention of investigators, regulators or journalists, and remain such a fundamental part of the marketplace,” Turner said. “It deserves to have a light shown on it.”

But now, many of the same regenerative medicine companies offering unproven treatments are adding a new promise to their advertising copy: the prevention and/or treatment of COVID-19.

In a statement published this year in JAMA, Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, warned physicians of this new development, and asked for their help in cracking down on these clinics.

Proven vs. Unproven Products
When it comes to evidence-based, FDA-approved stem-cell therapies, the list of indications is short. According to Turner, these include stem-cell transplants for blood-related cancers and sickle cell maladies.

Outside the stem-cell arena, the FDA in 2018 approved the regenerative medicine advanced therapy designation to MiMedx Group’s AmnioFix Injectable — an allogeneic micronized dehydrated human amnion/chorion membrane — for use in the treatment of OA of the knee.

“Beyond that, there are credible clinical trials taking place, where you have individuals with relevant training and legitimate credentials doing the kind of research genuinely intended to get at these questions for stem cell use in orthopedic diseases and injuries,” Turner said. “I would say that some of these preliminary studies are certainly encouraging enough to suggest the merits of further research.”

In addition, according to Shane A. Shapiro, MD, medical directors for the Regenerative Medicine Therapeutics Program at the Mayo Clinic, the science of cell-based, or cell-derived, therapies for musculoskeletal disorders has made promising progress over the last decade.

“We have given this subset of treatments the moniker ‘orthobiologics’ to help separate these types of treatments from pure mesenchymal stem cell treatments, which are still in various phases of research, and quite far from ready to market or FDA approval,” Shapiro told Healio Rheumatology. “Additionally, we need to draw the distinction between orthobiologics and ‘biologic’ agents used as treatments in inflammatory arthritic diseases, which modulate the immune system and have been approved for use in several arthritis and systemic inflammatory diseases.”

Among these orthobiologic agents being translated into occasional practice include blood-based therapies, such as platelet rich plasma (PRP), as well as a similar product concentrated from bone marrow product called BMAC, and some fat-based therapies. All of these have begun testing in clinical trials, with some early use in clinical practice to treat arthritis, or to help augment surgical procedures, Shapiro said.

“We have the most experience — about 15 years — with PRP for osteoarthritis and the literature, via several randomized controlled trials at this point, is quite supportive of PRP as a treatment for arthritic pain,” he said. “However, it is not a ‘cure.’ PRP has been successful as a cure in a few, but certainly not all, chronic tendinopathies. The other cell-based therapies are further behind in our understanding of how they work and need more research. Still, we try very hard not to call any of these ‘stem cell’ treatments, because it leads to greater patient confusion.”

Moreover, most of this work has been focused in orthopedic and sports medicine, with very little known about their application in rheumatic diseases.

“Given that OA and rheumatoid arthritis are different diseases with differing etiology, it would be hard to recommend any of these treatments in routine rheumatologic practice outside of a clinical trial,” Shapiro said. “Only a few stem-cell therapies have been approved worldwide and the few U.S. approvals treat hematologic malignancies. No other cell therapy product — stem cell treatment — has been adequately studied for use in rheumatology practice.”

Baseless Claims
In stark contrast to the work of the Mayo Clinic and other institutions focusing on evidence-based research, treatment claims commonly seen in the direct-to-consumer marketplace have gone well beyond the confines of credibly-designed clinical trials or generating meaningful data, according to Turner.

“The businesses that I am concerned the most about are the ones that are about just hanging out a shingle on the internet and making advertising claims about having stem cell therapies for arthritis and a litany of other diseases and injuries,” he said. “Sure, there are credible studies taking place, but these are businesses that have leaped beyond that. Instead, these businesses are making claims to prospective clients that what they are advertising is safe, and that it will help them with pain relief or pain mitigation — or even stronger claims.”

A 2016 study co-authored by Turner and published in Cell Stem Cell found 351 U.S. businesses engaged in direct-to-consumer marketing of stem cell interventions offered at 570 American-based clinics.

These businesses, according to Turner, persuade people to spend thousands, or even tens of thousands, of dollars based on amorphous claims — often relating to the mechanics of medicinal signaling cells — that they are safe, robust and reliable.

“What I would say is that it is not a hypothesis that should be dismissed out of hand, but we also shouldn’t walk around as though this is all established fact,” Turner said. “And to their credit, the FDA and the FTC have gradually over the past decade, especially in the last few years, stepped up their enforcement activities against these claims and the businesses that make them.”

Typically, such enforcement actions from the FDA come in the form of a warning letter or, more recently, untitled letters — used for violations that may not meet the threshold of regulatory significance for a warning letter — requesting that a company correct their behavior.

According to Turner, recent warning and untitled letters from the FDA have resulted in some companies scaling back their claims regarding stem-cell therapies. However, as not all of these letters have been made public, it is difficult to know the extent of their use and which companies have received them.

Federal authorities have also sought and obtained permanent injunctions against companies and clinics for making unsubstantiated stem cell claims. The FDA and the U.S. Department of Justice in June 2019 successfully obtained a permanent injunction in a Florida federal court that stopped U.S. Stem Cell Clinic LLC and U.S. Stem Cell Inc., as well as their chief scientific officer, from manufacturing or distributing any and all stromal vascular fraction products, which are fat-tissue derived stem cell products.

However, Turner cautioned, such victories come with an important caveat.

“The interesting thing there is that it was a specific stem cell product that the FDA wanted to get a permanent injunction on,” Turner said. “I think some people assume that if a company gets a warning letter, then it’s the end of the line, but my understanding with U.S. Stem Cell is that it resulted in a rebranding of the business. They still market stem cell treatments, but they have moved away from fat-derived products. So, it’s kind of a success for the FDA and the Department of Justice, but also maybe not such a dramatic success if the company can keep on marketing supposed stem cell therapies.”

Cracking Down in the Age of COVID
In his statement in JAMA, Marks wrote that some of the same clinics that have been advertising unproven regenerative therapies are “now offering similarly unproven products for the treatment of complications of COVID-19, and are making claims that are simply not supported by compelling clinical data.”

Turner, from his perspective, said the vast majority of these clinics have been largely unaffected by the emergence of COVID-19, with most boasting the same claims as before the pandemic.

However, there are those who have pivoted to take advantage of the spreading coronavirus, he added.

“There is an interesting development in the marketplace, having to do with the companies that have seen the pandemic as a marketing opportunity, and are now advertising their stem cell products as treatments or preventive measures for COVID-19,” Turner said. “Now, I am not seeing that across hundreds of businesses, but it is an activity that is out there in the marketplace. Some of it is being picked up by the FDA and the FTC, and some of it continues to happen, but it hasn’t appeared to have attracted the attention of regulators yet.”

That may be changing, though. According to Turner, recent unproven claims regarding COVID-19 could give regulators a renewed focus and provide a clear target for corrective actions.

“There is a kind of crispness, or a clarity to it, when companies make claims on their website, Facebook page or YouTube video that they have stem cells that are immune-system boosters, or that they will prevent individuals from getting COVID-19,” he said. “The FDA, the FTC and the Department of Justice have all indicated that they are going to be very aggressive in terms of pursuing businesses that are engaging in misrepresentations about treatment and preventive measures about COVID-19.”

“Not in every case, because you can still find some of these businesses, but I would say that they have been as active as I have ever seen them, not just in terms of responding, but responding speed as well, to these misleading claims,” he added.

In addition, Marks called on clinicians and patients alike to help federal authorities catch these clinics and companies, by coming forward and reporting any unproven claims or advertisements that they see.

However, that kind of work would require substantial communication between patient and physician regarding the large amount of medical and scientific material surrounding cell therapies circulating around the internet, in clinical practice and elsewhere.

And that, according to Shapiro, is exactly what the Mayo Clinic’s Regenerative Medicine Therapeutics Program, and its consulting service, have set out to do.

Harnessing Expertise
Speaking as director of the program, Shapiro said the Mayo Clinic’s Regenerative Medicine Therapeutics Program, and its consult service, can help patients understand the available treatment options and provide answers about unmet clinical needs.

“In most cases, that means having a conversation about the patient’s diagnosis, reviewing the standard of care treatment for their diagnosis, and then discussing available regenerative treatment options — if there are any — or alternatively, helping the patient find a clinical trial they might be a candidate for,” Shapiro said.

“Important, for patients with arthritis, is to clear up any misconceptions about what the cell therapies can and cannot do in current medical practice,” he added. “We also help patients understand the drug approval process and why stem cell therapies for arthritis might still need further research before they can be used to treat inflammatory conditions.”

According to Shapiro, rheumatologists can help patients avoid unproven therapies by taking the time to explain all legitimate treatment options.

“Rheumatologists are the experts in inflammatory arthritis conditions,” he said. “Patients look to their expertise for guidance. Rheumatologists should be providing patients with all legitimate treatment options, partnering with patients to decide on the best treatment option for their diagnosis, offering reassurance that patients are being presented with all scientifically-validated options, and engaging in a respectful but evidenced-based conversation about the current state of practice when it comes to regenerative therapeutics for inflammatory arthritis.”

“We can also provide them hope that legitimate scientific research is making great strides when it comes to regenerative treatments for such conditions,” he added. “There are legitimate scientific reports of bone-marrow stem-cell transplants for severe rheumatoid arthritis offering cures in small studies.”

Turner agreed, adding that clinicians and rheumatologists should also help their patients who have been taken in by false claims to report such activities, as well as any adverse events they experience as a result. This, he said, would provide regulators with a better sense of the illicit direct-to-consumer marketplace, and how people are being taken advantage of.

“I suspect there is substantial underreporting because the businesses themselves don’t really report these kinds of problems, and when patients go to these clinics, they can feel embarrassed that they lost money or were harmed by it, so there can be some hesitancy in coming forward,” Turner said.

“I think part of it is the difficult work of trying to help patients understand where the current state of research is, and what kinds of treatment exist and which ones should we really be talking about as established, evidence-based therapies,” he added. “Those kinds of sober, cautious conversations help people sort out credible, evidence-base claims from what we might think of as scams or outright fraud.”

the article is originally published at healio.