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There are hundreds of clinics across the USA (and the rest of the world) offering stem cell treatment of dubious merit. The clinics in the USA operate in a somewhat gray area of regulation by the Food and Drug Administration (FDA). In this article I will focus on one particular for-profit stem cell clinic operated by U.S. Stem Cell Inc. The activities of this clinic came to my attention because a group of patients with macular degeneration suffered tragic outcomes as a result of treatment they received. U.S. Stem Cell has attracted particular scrutiny by the FDA, but has defied their regulatory authority, resulting in a legal standoff. The future of the commercial stem cell industry in the USA may rest on the result of a court battle between the FDA and U.S. Stem Cell.

A recap

An article in the prestigious New England Journal of Medicine described three patients who went to a clinic operated by U.S. Stem Cell and received putative stem cell treatment for macular degeneration. The three women began with relatively good vision and rapidly deteriorated to legal blindness, apparently as a result of the treatment they received. I wrote an article providing some background and analysis of the tragic loss of vision in the three women. There have been some recent events relevant to this sad story.

U.S. Stem Cell offers “stem cell” treatments for a variety of conditions. The three women reported in the NEJM article went to the U.S. Stem Cell clinic in Sunrise, Florida. For the cost of $5,000, each received stem cell treatment for macular degeneration in both eyes.

The treatment began with liposuction of fat from the lower part of the abdomen (see SBM guest poster Paul Knoepfler’s primer on stem cell therapy for more details). The liposuction material was processed and the part purportedly containing stems was suspended in platelet-rich plasma (isolated from the patients’ own blood). The resulting biological soup was then injected into both eyes. Things deteriorated quickly after that. Within a few weeks, all three of the patients became legally blind, with one of the patients losing all perception of light in both eyes.

A summary of my opinions about these tragic events:

  1. Treatment consisting of processed liposuction material and platelet-rich plasma injected into the eye is implausible as a treatment for any eye condition and had no record of safety testing.
  2. U.S. Stem Cell lacked experience and expertise in the invasive treatment of eye disease and may not have engaged outside experts. Someone with a competent understanding of the anatomy, physiology, and pharmacology of the eye would have likely raised concerns about the plan for treatment in these patients.
  3. The treatment involved the intravitreal injection of both eyes. This is a highly dubious decision for a treatment with no established record safety or efficacy, and likely contributed to the tragic outcomes of these patients.
  4. There was a body of prior research foreshadowing the outcomes in these patients. Platelet-rich plasma (one of the components of the biological soup injected into the eyes of these patients) was found to create complex retinal detachments in animal models.

An update: Another patient and another tragic outcome

Another case of vision loss from treatment by U.S. Stem Cell has emerged. This patient was not treated at a U.S. Stem Cell Clinic, but instead at the office of a doctor trained by U.S. Stem Cell. The Chief Scientific officer of U.S. Stem Cell is alleged to have participated in the treatment as well. Only one eye had the cells injected inside. The other eye was treated with an injection near, but not inside the eye. The fate of the eye treated with the intraocular injection was tragically similar to the patients reported in the New-England Journal of Medicine article. A lawsuit has been filed in this case. This is the third known lawsuit filed by a patient of U.S. Stem Cell treated for macular degeneration.

U.S. Stem Cell is apparently not the only clinic that has performed intravitreal adipose derived stem cell treatment for macular degeneration. A case-report recently appeared of a patient with exudative macular degeneration treated at a stem cell clinic in Georgia. Her clinical course and outcomes were very reminiscent of the patients treated at US Stem Cell. An article in The Washington Post refers to “at least half a dozen additional patients who suffered severe vision loss,” but no further details were disclosed.

Chief Scientific Officer gets a diploma

kristin-comella1
Kristen Comella is the Chief Scientific officer of U.S. Stem Cell. She is also very much the public face and voice of the company. U.S. Stem Cell website promotes her as a leader and innovator in stem cell therapies. Despite her many years as Chief Scientific Officer at a biology-based company, until recently she did not hold a degree in any biologic science. A prior version of her bio listed her highest degree as a Master’s in chemical engineering, and as a PhD candidate in Biomedical Engineering at Florida International University.

She has graduated, but oddly not from Florida International University. In an autobiographical post from the Academy of Regenerative Medicine (an organization she founded), she announced that she been awarded her PhD in Stem Cell Biology from Panama College of Cell Science. Never heard of it? According to their website:

This exciting, stand-alone biology doctoral program remains the only doctoral program in stem cell biology that can be completed entirely online.

The website lists four “Permanent Staff”. Noteworthy among them is Igneris Rosado-Erazo, M.S. PhD. Dr. Rosado-Erazo earned her PhD from…you guessed it…Panama College of Cell Science. Her PhD dissertation is entitled “How to treat patients with adult stem cells without FDA approval and without the necessity of conducting any prior clinical trial“.

Not to put too fine a point on it, this PhD dissertation for the Panama College of Stem Cell Science explains how to do stem cell therapies…without all that pesky science. You can read it in its entirety via the above link. It is 18 pages long (including a title page, a dedication page, an abstract page, and 3 pages of references). It includes no original science. The 25 references are mostly websites (including 2 Wikipedia entries). Apparently the dissertation was sufficient, because Dr Rosado-Erazo was awarded her PhD, and a “permanent staff” position at Panama College of Stem Cell Science.

Authors note: Some readers of this post may not understand the rigor associated with earning a PhD in an experimental science. I have not earned a PhD myself. I welcome those of you who have done so to provide some context in the comments.

You too might earn a diploma from this non-accredited virtual college in just 3 years for a $2,950/year ($2,700/year if paid in advance). Got a high school diploma? In 5 years you can earn a B.S. and a Ph.D degree.

Why did Dr. Comella divert her education (and degree) from a fully accredited, brick and mortar university to an off-shore, unaccredited, virtual college? One can only speculate.

A family affair and a callous assertion

According to an ABC news affiliate in Tampa, a company called Pavillion Foods Inc. has been linked to the lawsuit mentioned above. The company assembles medical kits used by U.S. Stem Cell. The suit alleges that the kits contained items that were inappropriate and potentially unsafe for clinical use. The CEO of Pavillion Foods is Bob Comella, father of Kristen Comella, and co-owner of a U.S. Stem Cell Clinic. In an interview, Mr. Comella discloses “We own the clinic, actually it’s owned by my son, my wife and U.S. Stem Cell Inc.”

In the same interview, Mr. Comella speaks of the thousands of patients treated and helped by U.S. Stem Cell. “We’ve cured thousands of people. Why are we not talking about the thousands of people that have been cured…?” In regards to the blinded women and lawsuits against U.S. Stem Cell, he said “We told them we were sorry and they got several million dollars and they were going to go blind anyway”.

Most patients with macular degeneration do not become blind. Very few experience vision loss at the pace and to the degree of the patients known to have been treated by U.S. Stem Cell. These women likely would have had functional vision for years, quite possibly the rest of their lives. One of the women lost all ability to perceive light in both her eyes. This virtually never happens in untreated or conventionally treated macular degeneration.

A video version of the article is here. The interview with Mr. Comella starts at 2:20.

A world leader in research and development?

According to the U.S. Stem Cell website, they are a “World leader in research and development of stem cell and regenerative medicine treatments for patients with degenerative conditions”.

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Screenshot from http://us-stemcell.com, accessed 4/23/2019

In 2013 U.S. Stem Cell (then known as Bioheart) announced intent to perform a clinical research trial investigating stem cell therapy for macular degeneration. In addition to the press release, the company opened an entry in the clinical trial registry Clinicaltrials.gov. Creating an entry for an anticipated clinical trial is something a responsible research organization would do. Registries such as clinicaltrials.gov are intended to improve the transparency in the conduct and reporting of clinical trials. Despite the fanfare, the trial was withdrawn, without enrolling a single patient. Instead, they went directly to a fee-for-service model for this implausible, completely untested treatment, with catastrophic results.

The study was never initiated but the clinicaltrials.gov registry listing lives on. Patients sometimes peruse Clinicaltrials.gov in search of experimental treatments, especially if they perceive that conventional options for their condition are undesirable. Because it is government-run website, people understandably assume that registration on clincaltrials.gov involves review and approval by the US government; it does not, and was never intended to do so! Even if unintentional, the clinicaltrials.gov registration for a withdrawn clinical trial was an effective marketing tool for U.S. Stem Cell. The clinicaltrials.gov website was allegedly the way patients learned of U.S. Stem Cell, and their program to treat macular degeneration. Some believed they were part of a clinical trial.

The omission of a clinical trial definitely contributed to the misery experienced by the women treated by U.S. Stem Cell. First of all, their vision was too good to qualify for the registered trial. Even if eligible, the study protocol mandated that only one eye be treated. The fact that both eyes were treated multiplied the poor outcomes of these patients. Another thing a responsible research organization would do is study the previous literature for an intervention they were contemplating. There was existing preclinical literature for at least one of the components of the intravitreal injections they performed, and it foreshadowed what happened to these patients.

So why did a world leader in research and development abandon a clinical trial and move directly to a fee-for-service treatment for an untested therapy? Let’s examine U.S. Stem Cell’s very frugal commitment to research and development. According to an SEC filing, US Stem Cell had total revenue of $5.5 million in 2017, with a nice boost to $6.7 million in 2018. In those years they spent $4.4 million and $5.5 million, respectively, on “marketing, general, and administrative” expenses, while investing $6,644 and $5,439, respectively, on research and development.

Who would have guessed that an investment of about $6,000 per year, accounting for .1% of operating expenses, earns you status as a “world leader in research and development”?

The FDA pays a visit

Between April and May 2017 representatives of the FDA inspected the U.S. Stem Cell Sunrise Florida facility and on 8/28/2017 issued a warning letter. The letter explicitly explains the conditions that place U.S. Stem Cell’s activity under the jurisdiction of the FDA as a drug, and therefore, that they were marketing an unapproved drug. In addition, the letter enumerates 14 deviations from current good manufacturing practice (CGMP) and current good tissue practice (CGTP).

A defiant reply

In an 8/29/2017 reply letter to the FDA, Kristen Comella explains all the ways the FDA was wrong in interpreting regulations about use of biologic tissues to treat patients. She asserts that the activities in which they are engaged are part of the practice of medicine and do not fall under the regulations for drugs. She does not define a plan for addressing the Warning Letter, but instead dismisses the FDA’s assertions as irrelevant and possibly unconstitutional.

We strongly believe that it is a violation of the rights of American citizens to prevent them from seeking alternative care for their conditions as long as it does not violate regulations or the law…Our clinic is not violating the law as it is currently written. We have previously described in detail why the FDA has wrongly defined these in clinic procedures as a drug and provided evidence…If the federal government were to interfere with a person’s ability to obtain and utilize their own cells in their body to heal themselves, this could be a gross violation of the constitution…Our clinic is simply providing medical treatments to consenting patients using cells from their own body during a medical procedure which does not invoke oversight by the federal government.

The FDA seeks legal action

Based on lack of response to their warning letter, on May 9 2018 the FDA went to federal court seeking permanent injunctions against U.S. Stem Cell (and also against a West Coast stem cell network), to stop them “…from marketing stem cell products without FDA approval and for significant deviations from current good manufacturing practice requirements.”

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screen shot from https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm607257.htm, accessed 4/23/2019

Ever defiant, U.S. Stem cell has vowed on their website: “USRM [U.S. Stem Cell Inc.] will vigorously defend medical freedom of Americans.” Further:

The lawsuit seeks to stop U.S. Stem Cell Clinic and related parties from performing a surgical procedure using stem cells from autologous adipose tissue, even when a physician and patient agree that such a procedure is in the best interest of the patient. USRM believes that the patient and physician have the right to decide whether or not to use a patient’s own cells for a therapeutic purpose without federal government interference.

Interview with a Chief scientific officer and stem cell advocate

For an in-depth peek into the mind of Dr. Comella check this “Healing Miracle” interview. It is part of a larger “docuseries” entitled “The Healing Miracle, The Truth About Stem Cells”. Note that you will have to “sign in” with a name and email address to watch the video. She is articulate, and personable. She is a true believer. Given her ebullient confidence in the “miracle” of stem cell treatment, her commitment to defend access to this treatment is understandable.

She endorses stem cell treatment for a diseases as diverse as arthritis, degenerative disc disease, type 1 and type 2 diabetes, Alzheimer, ALS, Parkinson disease, multiple sclerosis, stress incontinence, Lyme disease, autoimmune disease, COPD, myocardial infarction, and kidney disease. She discusses injecting into joints, intravenously, intrathecal (into the cerebrospinal fluid), into the face and into the vaginal wall. She proudly announces that she treated her teenage son’s acne with intravenous stem cells, as well as various other maladies among other family members and herself. She supports her assertions with mostly anecdotal evidence, including some highly emotional stories.

She extrapolates to endorse treatment of pretty much any disease in any organ: “Any organ or tissue inside the body that needs healing to have going on can be used with these cells because we are going to promote healing inside that tissue.”

She is very enthusiastic about stem cell treatment for traumatic brain injury, and makes some very specific claims. Regarding athletes subject to head trauma:

Every Monday morning after their game on Sunday they should be getting a stem cell treatment. This should be standard of care…it can prevent the damage and the scar tissue from forming in the brain.

At times she veers into more familiar alternative medicine language: toxins, the greed of big pharma, drugs only treats symptoms but we treat underlying causes, etc.

It is possible, even likely, that some form of stem cell treatments will be proven effective for one or more of these diseases…someday. It seems profoundly unlikely, however, that U.S. Stem Cell’s particular form of adipose-derived stem cell treatment is effective for all these conditions for which she advocates. The current evidence is quite thin that any of them are effective.

How should stem cells be regulated?

The argument that the government should not be regulating how people use their own cells is superficially compelling, and I suspect will resonate strongly with the public.

The question is not whether Americans have autonomy over their own bodies and their own cells. They do. There are many other questions that lie at the border between patient autonomy and commerce. Are vulnerable patients being exploited? Can practitioners can sell a procedure for which the risks and benefits are largely unknown? Can they market these procedures with the exuberance of a true believer, even when the belief far exceeds the evidence?

Yes, these are the patients’ own cells, but they are collected and administered using invasive procedures. They are handled in a manner that can hardly be considered “natural”. The cells are processed chemically and mechanically in ways that the tissues may become contaminated with reagents or infected with pathogens.

Does patient autonomy entitle a practitioner to inject fat-derived stem cells and platelet-rich plasma into the eyes of patients even when there is prior science demonstrating that at least one component of the treatment was harmful in animal models?

Are patients being given appropriate informed consent? How can meaningful informed consent even be given when there has been little rigorous collection of data regarding the safety or efficacy of these procedures? Can contributors to a docuseries entitled “Healing Miracle, The Truth About Stem Cells” be trusted to give objective counsel?

The FDA opines that the way these cells are collected, processed, and delivered place them under the regulatory category of a drug. Kristen Comella and U.S. Stem Cell disagree. FDA regulation is an existential threat to U.S. Stem Cell and much of the consumer stem cell industry in the USA. An important decision now lies in the hands of the courts. Stay tuned.

Additional resources

The International Society of Stem Cell Researchers (ISSCR) has some excellent content for consumers on their website.

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Posted by David Weinberg

David Weinberg is a full-time academic vitreoretinal surgeon, and professor of ophthalmology at the Medical College of Wisconsin, Milwaukee. His interest in the less-than-science-based aspects of medicine was sparked by inquiries from his patients. Investigation their questions led to his discovery of numerous grandiose claims for implausible, unproven treatments of potentially blinding eye diseases. All opinions expressed by Dr. Weinberg are his alone, and do not represent those of his employer or any other organization with which he is affiliated.