Richard Poling was a 77-year-old from Indiana who suffered from pulmonary hypertension and pulmonary fibrosis.  His family sought out different options for health improvements so he could enjoy what little he had left in life. Their search led them to a little stem cell clinic in south Florida owned by Dr. Zannos Grekos.  The cardiologist specialized in stem cell therapy and had developed a busy stem cell practice. With staff, operations, a web site and the promise of almost miraculous results—the family was excited about what the huge promise of stem cell treatments.  Although the patient was required to sign a consent form acknowledging the procedures’ risks (including death) according to Poling’s daughter Gina Adams, Dr. Grekos confidently expressed that her father “would be back on the golf course the next day” after a procedure intended to treat the lung condition that made breathing difficult. The cost was $8,000.  Mr. Poling and family were convinced that Dr. Grekos was on to a game-changing medical breakthrough via stem cell therapy.  After all there were major breakthroughs with stem cells happening everywhere.  In the scientific news researchers were forging ahead with new investigational approaches—based on stem cells. The time seemed right; Dr. Grekos was extremely knowledgeable and the medical condition and associated symptoms only worsened. It was time to go for it. Poling was eventually treated by Grekos who harvested the fat frorm Poling’s abdomen and sent it to an off-site processing facility to isolate the stem cells.  Later in the day, Dr. Grekos instructed an assistant to infuse the processed mixture into Richard Poling’s bloodstream.  As a result of the infusion, Poling body went into a shocking reaction and suffered cardiac arrest. He was rushed to a local emergency room and pronounced dead.

Just a couple years earlier 69-wheel chair bound Domenica Fitzgerald visited Dr. Grekos in the hopes of being able to walk again.  Dr. Grekos treated Fitzgerald with a stem cell cocktail derived from unfiltered bone marrow-derived stem cells into the arteries of her brain.  According to the press, the state produced a report and concluded “it was virtually inevitable that the procedure would clog blood vessels in the brain and cause a major and very possibly fatal stroke.”  Consequently, Mrs. Fitzgerald suffered severe brain damage and was taken off life support just days later.

After two deaths in two years the Florida Board of Medicine finally voted to revoke Grekos’ license.  Critics wondered what took so long.

Not able to practice his investigational stem cell work stateside—and convinced that despite the deaths his procedures were on the right track–Dr. Grekos moved to the Dominican Republic and set up a stem cell company on that Caribbean island nation.  Through the new venture Regenocyte, Grekos could continue the investigational stem cell practice—but now more freely marketing to a global audience of the sick and vulnerable. Regenocyte markets treatments for autism, dementia and many other diseases.  Of course, Dr. Grekos argues that the deaths were not related to his specific care.  After all in legitimate FDA or EMA-regulated and approved clinical trials deaths do occur at times when investigational medicine is involved. Grekos dedicates his life to the stem cell treatments because he believes they work. Moreover, he considers that there was a state agenda against him—selecting him out as an example; to make a statement—a warning to other doctors against working with stem cells.   Some industry critics believe that regulation should come from the FDA and not state level boards.  The reality is that Dr. Grekos is conducting investigational research under the auspices of a stem cell clinic. Throughout the world investigational research falls under the regulatory control of the FDA.

In 2016 another Florida physician received a warning letter from the FDA.   In the warning letter, the FDA noted that he was violating federal public health laws.  At the time of this action in 2016, Dr. Gionis’ clinic was one of more than 170 clinics across the country that were selling experimental stem cell procedures for dozens of diseases and conditions—a growing industry that thrives despite minimal evidence of safety or effectiveness. After all, based on TrialSite News perspective stem cell activity is investigational in nature and must be held accountable to scientific-driven regulatory body.

Fast forward just a couple years to today and there are nearly triple the number of stem cell clinics since 2016- the industry is booming.  With aging baby boomers and a quest for pain relief and possibly a cure vver 500 specialty stem cell clinic operations market and sell what are in many cases investigational medicine services directly to patients across the United States.  Calculated in how they set up and market via website search engine optimization (SEO), they aggressively target those searching key terms online–the sick; the desperate; folks’ that have given up and will try anything to heal.  They often utilize questionable marketing tactics to lure in patients (customers).  They seek easy targets; where the pain is known, and the hope of a cure is greatest.  Thanks to the research of Leigh Turner and Paul Knoepfler health researchers that seek to understand how these stem cell clinics are operating have a good resource reference. For example, the researchers identified the marketed therapy conditions most exploited by these stem cell clinics which included the following:

  • Orthopedic (over 300 clinics)
  • Pain (over 150 clinics)
  • Sports (approx. 80 clinics)
  • Neuro (between 50 and 70)
  • Immune (between 50 and 70)
  • Lung/Resp (between 50 and 70)

There were many marketed therapies under 50 clinics. Note that there were approximately 500 clinics identified in this research and that clinics would market and promote multiple therapeutic treatments. For example, there might be a sports therapy-focused stem cell clinic that covers orthopedic, pain and neurology. Not by any means do all of these clinics represent bad actors. In many cases they are legitimate, reputable—even brilliant physicians—doing caring and attentive work and following the letter of the law. However, the evidence exists that healthcare consumers must be careful. They must educate and empower themselves to make wise choices.

The FDA clearly understands the magnitude of the growing problem—an under-regulated stem cell medicine market—or put another way, an investigational research market posing as a proper medical market—and is making moves to strengthen oversight of this flourishing industry.  For example, regulators are issuing warning letters to multiple stem cell clinics for violating laboratory and manufacturing standards and in one case ordered a company, Amniotic Therapies, LLC,  to stop selling stem cell-based products.  

Moreover, the FDA now invests considerable time in terms of funding, resources and information about stem cell treatments.  They note that stem cell treatments hold great promise but that healthcare consumers must be very careful.  The federal agency recently warned:

“Stem cells have been called everything from cure-alls to miracle treatments. But don’t believe the hype. Some unscrupulous providers offer stem cell products that are both unapproved and unproven. So beware of potentially dangerous procedures—and confirm what’s really being offered before you consider any treatment.”

It is imperative that those struggling with illness don’t fall prey to what amount to con artists out in the marketplace.  The consequences are too high. The FDA recommends that patients (and their loved ones) do their part and make sure that any stem cell treatment is either 1) FDA-approved or 2) Currently being studied under an Investigational New Drug Application (IND), which is a clinical investigational plan submitted and allowed to proceed by the FDA.

The FDA now has the authority to regulate stem cell use in the United States. https://www.fda.gov/BiologicsBloodVaccines/TissueTissueProducts/RegulationofTissues/ucm150485.htm  They note that doctors often use stem cells that come from bone marrow or blood in transplant procedures to treat patients with cancer and disorders of the blood and immune system.  The FDA is concerned that there are clinics inappropriately advertising stem cell clinical trials without submitting an Investigatory New Drug Application (IND). Much like was the case with Dr. Grekos earlier on in this story. If a clinical trial is conducted without an IND that means that the FDA has not reviewed the experimental therapy and TrialSite News cautions readers to not participate with any stem cell research that is not FDA approved. And even FDA approved trials need patient and family scrutiny—there are documented risks.

Presently the only stem cell-based products in the United States that are FDA-approved include blood-forming stem cells (hematopoietic cells) derived from blood cord. This class of stem cell product has been approved for limited use in patients with disorders that affect the body system involved in the production of blood (the “hematopoietic” system).

These products are approved for limited use in patients with disorders that affect the body system that is involved in the production of blood (called the “hematopoietic” system). These FDA-approved stem cell products are listed on the FDA web site. Bone marrow also is used for these treatments but is generally not regulated by the FDA for this use.

The following stem cell products are approved according to the FDA

ALLOCORD (HPC Cord Blood): SSM Cardinal Glennon Children’s Medical Center

LAVIV (Azficel-T): Fibrocell Technologies

MACI (Autologous Cultured Chondrocytes on a Porcine Collagen Membrane): Vericel Corp

CLEVECORD (HPC Cord Blood) Cleveland Cord Blood Center

GINTUIT (Allogeneic Cultured Keratinocytes and Fibroblasts in Bovine Collagen) Organogenesis Inc.

HEMACORD (HPC, Cord Blood): New York Blood Center

Ducord, HPC Cord Blood: Duke University School of Medicine

HPC, Cord Blood: Climmune Labs, University of Colorado Blood Bank                                                                                    

HPC Cord Blood —MD Anderson Core Blood Bank: MD Anderson Cord Blood Bank

HPIC Cord Blood-Life South: LifeSouth Community Blood Centers

HPC Cord Blood, Bloodworks: Bloodworks

IMLYGiC (talimogene Iaheparepvec): BioVex Inc.

KYMRIAH (tisagenlecleucel): Novartis Corp

LUXTURNA: Spark Therapeutics, Inc.

PROVENGE (sipuleucel-T): Dendreon Crop

YESCARTA https://www.fda.gov/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/ucm581222.htm (axicatagene ciloleucel): Kite Pharma Inc.

On August, 2017, the FDA announced its enforcement policies concerning stem cell clinics and research operations.  TrialSite News sought it appropriate to include in the hopes that those seeking more information have a reference. The federal regulatory agency notes that stem cells represent

“One of the most promising new fields of science and medicine is the area of cell therapies and their use in regenerative medicine. These innovative technologies, most of which are in early stages of development, hold significant promise for transformative and potentially curative treatments for some of humanity’s most troubling and intractable maladies. Recent advances in our basic knowledge of the pathways involved in tissue damage and regeneration have combined with remarkable progress in adult stem cell biology to put us at a genuine inflection point in the history of medicine. The prospect of clinical tissue repair strategies is a tangible reality. This promise is reinforced by the strong commitment of the investment and scientific communities in exploring the potential applications across a wide range of vexing diseases and conditions, such as cancer, Parkinson’s disease, and diabetes, among many others.”

However, raising the specter of imminent concern:

“However, with all of the medical potential, also comes novelty and uncertainty as this field matures. There are a small number of unscrupulous actors who have seized on the clinical promise of regenerative medicine, while exploiting the uncertainty, in order to make deceptive, and sometimes corrupt, assurances to patients based on unproven and, in some cases, dangerously dubious products. These dishonest actors exploit the sincere reports of the significant clinical potential of properly developed products as a way of deceiving patients and preying on the optimism of patients facing bad illnesses. This puts the entire field at risk. Products that are reliably and carefully developed will be harder to advance if bad actors are able to make hollow claims and market unsafe science. In such an environment a select few, often motivated by greed without regard to responsible patient care, are able to promote unproven, clearly illegal, and often expensive treatments that offer little hope, and, even worse, may pose significant risks to the health and safety of vulnerable patients. These so-called treatments run afoul of the FDA’s legal and regulatory framework governing this new field.”

The FDA stem cell research committee mission:

  • Stepping up enforcement
    • Maintain efficient regulation
    • Collaborate closely with industry—examples of FDA embracing innovation is the Regenerative Medicine Advanced Therapy (RMAT) Designation

In March 2017, the FDA published a perspective article in the New England Journal of Medicine with a focus on the benefits and the risks of stem cell therapy.

The FDA recommends that for patients seeking stem cell treatments in the United States:

  1. Ask if the FDA has reviewed the treatment.  Ask your health care provider to confirm this information. Patients (or loved ones) can ask the clinical investigator to give them the FDA-issued Investigational New Drug Application number and the chance to review the FDA communication acknowledging the IND. Ask for this information BEFORE seeking treatment—even if the stem cells are their own.
  2. Request the facts and ask questions if the patient doesn’t understand.  To participate in a clinical trial that requires an IND application, the patient must sign a consent form that explains the experimental procedure. The consent form also identifies the Institutional Review Board (IRB) that assures the protection of rights and welfare of human subjects.  Make sure that they understand the entire process and known risks before they sign. The patient can also ask the study sponsor for the clinical investigator’s brochure, which includes a brief description of the product and information about its safety and effectiveness.

In other countries do the following:

  1. Learn about regulations that cover products in that country
  2. Know that the FDA does not have oversight of treatments done in other countries.
  3. Be cautious
  4. Do the necessary research and homework

A key recommendation for any individual patient or patient family member interested in stem cell treatments is to ensure the treatment is either A) FDA approved or B) part of an FDA approved clinical trial. 

TrialSite News Clinical Pipeline Including Stem Cell Research

Given FDA recommendations for importance of considering stem cell treatments presently undergoing FDA approved clinical trials, TrialSite News ran a sample search in government-sponsored website www.Clinicaltrials.gov to identify existing trials.  We organized the search by the following attributes:

  • Stem Cell Product
    • Phases 1, 2, 3 4
    • Commercial and other which included government, academic and other third party
    • Active Trials

What follows is a breakdown of results. 

Active Trials by Phase Commercial Government/Academic
Phase 1 18 34
Phase 2 24 34
Phase 3 5 3

What follows is a breakdown of commercially-sponsored, Phase 3 clinical trials.

Disease: β-thalassemia

β (beta)-thalassemia is a genetic disease characterized by reduced or absent production of functional β-globin, a key component of adult hemoglobin, which carries oxygen to all parts of the body. Lack of sufficient β-globin leads to chronic anemia and other serious complications. Transfusion-dependent β-thalassemia (TDT) is a severe, progressive type of β-thalassemia characterized by severe anemia, lifelong transfusion dependence, unavoidable iron overload, serious comorbidities, and shorter lifespan compared with the general population.

Sponsor: Bluebird Bio

Study Description:

A single-arm, multi-site, single-dose, Phase 3 study in approximately 23 subjects ≤50 years of age with transfusion-dependent β-thalassemia (TDT), also known as β-thalassemia major, who do not have a β0 mutation at both alleles of the hemoglobin β (HBB) gene. The study will evaluate the efficacy and safety of autologous hematopoietic stem cell transplantation (HSCT) using LentiGlobin BB305 Drug Product.

Disease:  Adrenoleukodystrophy (ALD)

A rare, genetic, X-linked metabolic disorder caused by mutations in the ABCD1 gene that result in a deficiency in a peroxisomal protein called adrenoleukodystrophy protein (ALDP). This leads to the accumulation of very–long chain fatty acids (VLCFA) in various parts of the body, including the adrenal cortex and white matter of the brain and spinal cord, leading to a range of symptoms. Males who inherit the ALD mutation will typically develop one or more of three sets of ALD symptoms. These are: primary adrenal insufficiency (where the body doesn’t make enough of certain key hormones), a progressive nervous system disorder called adrenomyeloneuropathy, and a severe, rapidly progressive degenerative brain disease called cerebral ALD (CALD).

Sponsor: Bluebird Bio

Study Description:

This trial will assess the efficacy and safety of autologous CD34+ hematopoietic stem cells, transduced ex-vivo with Lenti-D lentiviral vector, for the treatment of cerebral adrenoleukodystrophy (CALD). A subject’s blood stem cells will be collected and modified (transduced) using the Lenti-D lentiviral vector encoding human adrenoleukodystrophy protein. After modification (transduction) with the Lenti-D lentiviral vector, the cells will be transplanted back into the subject following myeloablative conditioning.

Disease: β-thalassemia

β (beta)-thalassemia is a genetic disease characterized by reduced or absent production of functional β-globin, a key component of adult hemoglobin, which carries oxygen to all parts of the body. Lack of sufficient β-globin leads to chronic anemia and other serious complications. Transfusion-dependent β-thalassemia (TDT) is a severe, progressive type of β-thalassemia characterized by severe anemia, lifelong transfusion dependence, unavoidable iron overload, serious comorbidities, and shorter lifespan compared with the general population.

Sponsor: Bluebird Bio

Study Description:

A Phase 3 Single Arm Study Evaluating the Efficacy and Safety of Gene Therapy in Subjects With Transfusion-dependent β-Thalassemia, Who Have a β0/β0 Genotype, by Transplantation of Autologous CD34+ Stem Cells Transduced Ex Vivo With a Lentiviral βA-T87Q-Globin Vector in Subjects ≤50 Years of Age

Disease:  Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Myelodysplastic Syndrome, Chronic Myeloid Leukemia or Lymphoma—all with required disease features rendering them eligible for allogeneic transplant.  In an allogeneic transplant, stem cells are collected from a matching donor and transplanted into the patient to suppress the disease and restore the patient’s immune system.

Sponsor: Gamida Cell Ltd.

Study Description:

This study is an open-label, controlled, multicenter, international, Phase III, randomized study of transplantation of NiCord® versus transplantation of one or two unmanipulated, unrelated cord blood units in patients with acute lymphoblastic leukemia or acute myeloid leukemia, myelodysplastic syndrome, chronic myeloid leukemia or lymphoma, all with required disease features rendering them eligible for allogeneic transplantation.

Disease:   FLT3-ITD (+) Acute Myeloid Leukemia (AML)

Sponsor: Daiichi Sankyo, Inc.

Study Description:  

This is a phase 3, randomized, double-blind, placebo-control global study. The purpose of this study is to compare the effect of quizartinib versus placebo (administered with standard induction and consolidation chemotherapy, then administered as maintenance therapy for up to 12 cycles) on event-free survival in subjects with FLT3-internal tandem duplication (ITD) positive AML.

TrialSite News On-Demand Research

TrialSite News research on-demand is available to support readers’ due diligence efforts into stem cell clinics. This is a topic of great interest to our group. Research services includes stem cell clinic operation; physician and staff background check; stem cell therapeutic focus area (e.g. orthopedic, etc.); whether the clinic has submitted to FDA regulatory oversight; and any evidence of litigation or any other troubles. This article was a result of a research request by a TrialSite News reader. Regardless, before signing up for any experimental stem cell treatment do your homework.  Seek out a second and a third opinion. 

Conclusion

The stem cell medical industry has exploded over the past several years.   The treatment breakthrough represents great promise for the development of new advancement treatments and possibly even cures someday.  This promise is evidenced by 1) growing number of FDA approved stem cell products and 2) budding number of FDA approved clinical trials. Consumers should be weary of any stem cell clinic either 1) not marketing an FDA approved treatment or 2) not participating in an FDA approved investigatory new drug investigation.  The stem cell clinic should also include on their website a description of what needs to be FDA approved. Patients have died from stem cell treatments not approved by the FDA. The implications for stem cell research are big. To all– understand the stem cell promise and avoid any current peril.

About the Author

Daniel O’Connor 

Mr. O’Connor has spent nearly 20 years providing technology and services to the clinical trials and health technology industry. An entrepreneur, he has been instrumental in building different ventures focusing on FDA 21 Part 11 enterprise document management, technology-enabled patient recruitment services, clinical document and safety data exchange, as well as population health and community care coordination for at-risk populations with Eccovia Solutions. He is a co-founder of a group launching of a global clinical research site accreditation standard–ACRES ReServ. Mr. O’Connor has built a comprehensive research site data base and intelligent clinical research site news curation engine with TrialSite News. He earned his combined MA and JD from the University of California (Los Angeles and Hastings College of the Law) and undergraduate from San Francisco State University.

Source: TrialSite News

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