Stem Cell Therapy Blinds Three Patients at Florida Clinic

Ricki Lewis, PhD

March 15, 2017

Three women with non-neovascular ("dry") age-related macular degeneration (AMD) experienced profound visual loss after receiving bilateral intravitreal injections of autologous adipose tissue-derived stem cells at a Florida clinic, according to a report published online today in the New England Journal of Medicine.

"After 1 year, the patients' visual acuity ranged from 20/200 to no light perception," write Ajay E. Kuriyan, MD, from the Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami, Florida, and colleagues. These outcomes are "dramatically worse" than those of standard care for dry AMD, which is associated with moderate visual loss in 3.3% of patients in a year.

First One Patient, Then Two

The first patient arrived at the Bascom Palmer Eye Institute 2 days after undergoing the procedure at an unnamed Florida clinic in June 2015. She was 78 years old, and before the injections she had a visual acuity of 20/50 in the right eye and 20/100 in the left.

"Immediately after [the procedure], she had pain in both eyes and developed hemorrhaging in both retinas. Her vision dropped dramatically in both eyes to the point that she had become legally blind when we saw her," Thomas Albini, MD, associate professor of clinical ophthalmology at the University of Miami and the Bascom Palmer Eye Institute and the corresponding author on the article, told Medscape Medical News.

"She didn't require urgent intervention, but by 2 months postprocedure, both retinas had detached," he continued.

On talking with the patient and her family, Dr Albini and colleagues learned that she had paid $5000 for the treatment, which was administered to both eyes on the same day. Documents given to her at the clinic, which she shared with Dr Albini and colleagues, indicated the putative stem cells were isolated from adipose tissue aspirated from her abdomen and resuspended in autologous platelet-rich plasma.

Later the same week, a second patient arrived at the Bascom Palmer Eye Institute in even worse shape, requiring immediate treatment. She too reported that she had received stem cell injections at the same clinic 3 days before.

"She came in with dislocated lenses that pushed into the anterior chamber and were blocking the trabecular meshwork, elevating pressure. She required surgery to get the lenses out as fast as possible," Dr Albini said. "At the same time, we could see hemorrhage at the backs of the eyes and a retinal detachment in one eye that we fixed. She developed corneal edema and ultimately had bilateral retinal detachment and no light perception in both eyes over the course of a year."

That patient was 72 years old at the time of treatment, and prior to the stem cell injections had had visual acuity of 20/60 in the right eye and 20/30 in the left eye. She too had paid $5000 for the procedure. She "reported that she was under the impression that she was participating in a clinical trial and that she had met the criteria of the trial," the researchers write. The consent form included the possibility of blindness.

"When we saw the first two patients, we thought they had an alarming presentation, and we informed the Florida Department of Health, [the US Food and Drug Administration (FDA)], and the Research and Safety in Therapeutics (ReST) committee of the American Society of Retina Specialists. The society then sent an email blast to its 5000 members to see if anyone else knew of a case," said Dr Albini. (The ReST committee works with the Centers for Disease Control and Prevention and the FDA to identify and investigate adverse events in all retina drugs and devices.)

A third case quickly emerged after the ReST message. The patient was 88 years old and had presented at the Dean McGee Eye Institute in Oklahoma City 1 week after having flown to the Florida clinic for treatment. Her visual acuity before the procedure was 20/40 in the right eye and 20/200 in the left. A year after the procedure, retinal damage was extensive. She had perception of hand motion in the right eye and light perception in the left.

"So there was definitely a pattern, and not just one bad outcome. We decided to publish because we were amazed that this type of procedure, which had never been proven effective or safe with any studies, was being offered to patients and was being done in such a cavalier way as to offer injections into both eyes simultaneously," Dr Albini said.

A Clinical Trial by Listing Only

In each of the first two cases, the patient or a family member had found the procedure described in a listing on ClinicalTrials.gov. The entry, NCT02024269, is for a "study to assess the safety and effects of cells injected intravitreal in dry macular degeneration" (sic) and is described as open-label, nonrandomized, interventional, and stated under Study Design: "primary purpose: treatment" (https://clinicaltrials.gov/ct2/show/NCT02024269, accessed March 15, 2017).

"The family thought the protocol sounded like a legitimate study, and the woman got treatment," Dr Albini said, referring to the first patient.

On closer examination, however, none of the women would have qualified for the trial, as eligibility criteria required visual acuity in the study eye "equal to or worse than 20/200." Only 1 of 6 eyes treated had such poor visual acuity before the procedure.

Dr Albini told Medscape Medical News that it is not really clear what happened, "but the 2 patients [seen at Bascom] thought they were in a study, but they were not really. They'd never signed informed consent for a clinical trial, nor did they meet the criteria as outlined. But it was a misunderstanding. They thought they were in a study."

He continues, "The company didn't file an [investigational new drug application] with the FDA and didn't consider this to be experimental therapy, and it was being offered outside of the standard practice of medicine. Patients have grown accustomed to expect clinics and hospitals will live up to standards and expect a treating clinician will use common sense and ethical guidelines in treatment, such as not doing both eyes at the same time for a treatment that does not have a proven track record of safety."

The listing on ClinicalTrials.gov also suggests that the patients were not treated in the trial, even if that was how they initially heard about the procedure. The status of the trial listing states the trial was withdrawn with no patients enrolled as of September 15, 2015, which was months after the women were treated.

The sponsoring company included in the ClinicalTrials.gov listing when it was first filed in late 2013 was Bioheart, which in November 2015 became part of US Stem Cell Inc, a company founded in 1999.

Kristin Comella, chief science officer at US Stem Cell, declined to comment on the three women because of a legal settlement of a civil suit. However, she reinforced in an interview with Medscape Medical News that the trial never enrolled any patients and that all patients receiving treatments from the company sign informed consent forms, including the three women. She would not comment about the treatment of two eyes at once, nor clarify who actually performed the procedure.

Stem Cell Tourism

The report on the three women blinded by experimental stem cell therapy will not come as a surprise to many. "A whole cottage industry of stem cell clinics in the US is proliferating and is very profitable, for everything from chronic pain and joint disease to male pattern baldness. You can get stem cell treatments for any condition, especially those that don't have acceptable therapy," warned Dr Albini.

In fact, just a few months after the three women were treated, the FDA began to investigate another company (the Miami Stem Cell Treatment Center) for the use of adipose-derived stem cells to treat AMD. That company claims to have halted its use of "stromal vascular fraction (SVF) product" as of September 20, 2015, but the FDA sent a harsh warning letter dated December 30, 2015, reiterating that the product must be regulated as a drug because it is intended to treat and is also a biological product and a human-cell-based product.

"This little niche of stem cell therapies took off because somebody decided there's a loophole called the Public Health Services Act from 1944," explained Dr Albini. The intent was to cover autologous skin and vein grafts, but that's skin-to-skin and vein-to-vein — not fat to eye.

"If the cells are more than minimally manipulated, they require FDA approval before they can be marketed," Timothy Caulfield, LLM, research director, Health Law Institute, University of Alberta, Canada, who publishes frequently on stem cell tourism, told Medscape Medical News.

However, many of the companies claim minimal manipulation, and thereby avoid FDA oversight, according to George Daley, MD, PhD, who authored an editorial that accompanies the account of the patients. A study published last year and reported by Medscape Medical News, identified 351 businesses in the US marketing stem cell procedures direct to consumer at 570 clinics.

In his discussion, Dr Daley, from the Division of Pediatric Hematology-Oncology, Boston Children's Hospital, Massachusetts, contrasts the "stem cell tourism" of an unregulated experiment with participating in a well-designed clinical trial based on sound preclinical data. (Dr Daley calls the material injected into these three patients "a poorly defined slurry.")

Caulfield too argues for stricter oversight. "I would like to see more aggressive regulation of providers, particularly in for-profit clinics. Professional regulatory bodies should monitor their physician members more closely."

Dr Albini and colleagues hope their article will prevent future victimization. "This report joins a small but growing medical literature highlighting the risks of such wanton misapplication of cellular therapy," writes Dr Daley. He led development of the International Society for Stem Cell Research's guidelines for clinical use of stem cells.

"The guidelines highlight the stark distinction between the innovative treatments that are founded on methodical preclinical evidence, proven in rigorous clinical trials, and approved for marketing after regulatory review and the unproven interventions that are offered by practitioners who are naive regarding the biologic complexities of stem cells or by charlatans peddling the modern equivalent of snake oil," Dr Daley concludes.

Dr Albini consults for J&J/Janssen Cell Therapy, Genentech, and eight vision-related companies. Three coauthors have licensed patents on RPE cells and sheets to Healios. Dr Daley holds patents on derivation of iPSC products, reprogramming methods, and stem cell characterization and developed the international guidelines on quality control of stem-cell-based therapies. Comella and Caulfield have disclosed no relevant financial relationships.

N Engl J Med. 2017;376:1038-1046, 1047-1053, 1075-1077.

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