Will the FDA Kill Adult Stem Cell Medicine?

Within the next five years, it’s quite possible that physicians will come into routine possession of a remarkable set of tools   — a brand new way of dealing with the frailty and disabilities of aging.  The tool kit is autologous stem cells derived from the patients themselves, amplified in culture, and infused back into the patient according to a precise protocol.  It would be such a leap from today’s medical diagnostics and treatments; it could only be called revolutionary.

The purpose of employing autologous cells is to prevent rejection of histo-incompatible cells by the patient’s immune system.  But it’s also possible that these new therapies could slip from our grasp, at least in the US. If we’re not careful, these therapies could become the exclusive domain of the pharmaceutical industry, as regulated by the Federal Food and Drug Administration  (FDA). This could push the availability of this tool kit 15 to 20 years into the future. The opportunity-cost in terms of morbidity and mortality could be catastrophic.

Dr. Christopher J. Centeno, M.D., is an expert in this field, having spent four years performing an autologous, minimal culture-expansion technique in orthopedics that use adult mesenchymal stem cells.  Known as the Regenexx™ procedure, it uses a patient’s own stem cells and hematogenous growth factors to regenerate bone and cartilage. At Regenerative Sciences, Inc. (where he also serves as Lab Director) and CentenoSchultz Clinic in Broomfield, CO (run with Co-Medical Director John R. Schultz, M.D.), the focus is on development of this non-surgical option for people suffering from a variety of orthopedic conditions. L. Stephen Coles spoke with Dr. Centeno for h+.

“The cell-therapy industry right now is very nascent; it’s where age-management was ten years ago,” he told me. Dr. Centeno has established an organization to define guidelines and standards called The American Stem Cell Therapy Association (ASCTA). “We’re trying to develop physician guidelines in the U.S. for the safe use of stem cells, similar to the way fertility clinics operate. We’ve got an organization to formulate guidelines, and we’ve got clinicians working to form a stem-cell registry. But the FDA doesn’t appreciate that. We only do adult cells from the same person. But the FDA contends that if one cultures stem cells at all, regardless of the use of those cells, then it’s a prescription drug.” He points out that the age-management community has seen many instances where the FDA has tried to insert itself into the practice of medicine — although this has been strictly prohibited by Congress — and this is just the latest. “Compounding pharmacies have been coming under FDA pressure for a long time, and have now organized and set up their own standards and guidelines as a way to combat that interference.”

Dr. Centeno compares the current state of stem-cell medicine to that of fertility treatments. “If you’re an infertility specialist, you have to grow a woman’s fertilized oocytes at least to the blastocyst stage before implanting them, and the FDA has no control over that. If the FDA had gained control, you wouldn’t have individual fertility practices — instead you’d have just a few big labs across the country.” Instead of being regulated by the FDA, fertility doctors are regulated state-by-state. The reason, says Dr. Centeno, is simple: “They organized, put their own standards in place, and created a case, saying, ‘Listen, this is the practice of medicine, and you, by charter, are not allowed to regulate the practice of medicine.’”

Prior to becoming involved in stem-cell research, Dr. Centeno was already an international expert and specialist in musculoskeletal, spinal, and neurologic injury. Having trained at the Baylor College of Medicine, Texas Medical Center, and the Institute for Rehabilitation Research, he is an M.D. who is double-boarded in Physical Medicine and Rehabilitation as well as Pain Medicine. Dr. Centano has seen the results that are achievable in an orthopedic context. “We’ve done this for four years for patients with orthopedic conditions. So, as a test case, we know it can work safely and effectively.”

To Dr. Centeno, it is inconceivable that a person’s own cells could be classified as a drug —  but that’s exactly what the FDA wants to do. “The FDA is working to protect the interests of Big Pharma,” he says. “If we wanted to insert some kind of new genes into these cells, we might all agree that could be a drug  — a new entity. But what we’re doing is simply culturing a person’s own cells. Most of the cells are bone-marrow derived; you can get them from synovial fluid in the knee or from other locations.” Basically, there are three main types of adult stem cells:

1. Mesenchymal stem cells are commonly found in the bone marrow. These cells can differentiate into multiple orthopedic, neural, organ, and other lineages.
2. Very Small Embryonic Like Cells (VSEL) are a newer stem-cell line and more likely to have the ability to differentiate into multiple cell types and lineages.
3. CD34+ heme progenitors are usually derived from bone marrow and can be mobilized into the bloodstream. They have been used commonly in vascular and cardiac applications.

Most importantly, the mesenchymal cell line alone  —  the one Regenexx has been using —  has more than 8,000 peer-reviewed citations showing its wide application in age-management medicine, including the treatment not just of orthopedic conditions, but of Type-II Diabetes, stroke, and cardiovascular disease. “It can be used to treat everything from cardiac disease after a heart attack, to vascular disease, to orthopedic injuries,” notes Dr. Centeno.

As we move beyond “Regenerative Medicine 1.0” ­- which is where Dr. Centeno sees things currently: “I suspect what will happen, in 2.0, is that you’ll see some age-management-medicine doctors start their own regenerative stem-cell lab, take cells derived from a patient, minimally culture them, and then they can be deployed.” For instance, in cases of diabetes, the cultured cells would be injected under CT or ultrasound guidance directly into the Islets of Langerhans in the pancreas. There, according to Dr. Centeno, “in animal models, they routinely cure diabetes.”

It’s important to note that, while the recently lifted ban on embryonic stem-cell research federal-funding by President Obama on March 9th has helped to focus attention to the whole subject of stem-cell-based therapies, including iPSC’s (induced Pluripotent Stem Cells derived from a skin biopsy), the work that ASCTA does is exclusively linked to ‘adult’ stem cells… and the patient’s own stem cells at that. “A large number of diseases have already been looked at,” notes Dr. Centeno;  “The basic research is already in place.” As presented in a “list-in-progress” on the ASCTA website, areas involved in ongoing research on the use of adult stem cells in disease treatment clearly overlap with areas of embryonic stem-cell research:

• ALS (Amyotrophic Lateral Sclerosis) or Lou Gehrig’s Disease
• Alzheimer’s Disease
• Parkinson’s Disease
• Multiple Sclerosis
• Muscular Dystrophy
• Osteoarthritis
• Rheumatoid Arthritis
• Spinal-Cord Injury
• Stroke

In terms of treating age-related conditions, Dr. Centeno sees stem-cell therapies as an entirely new level of medicine. “In 1.0, we use hormones,” he explains. “Treating using hormones is great, but at some point the parts wear out and that’s where 2.0 comes in.” As an example, Dr. Centeno cites a study that was just presented at the American College of Cardiology Conference in Orlando, FL, showing a dose-response relationship on repairing the heart after an Acute Myocardial Infarction, with improved heart function after stem-cell injection.

On March 31, 2009 HealthDay News reported on a U.S. study that found that "treating a heart attack with the patients own bone-marrow stem cells boosts blood flow within the heart and may help reduce long-term complications." The study included 31 patients who underwent angioplasty and stent placement after a heart attack. Within one week of the attacks, 16 of the patients received infusions of their own bone-marrow cells into the coronary artery in which a blockage had caused the event. 

The 16 patients received different amounts of bone marrow stem cells — 5 million, 10 million, and 15 million cells. The 15 patients in the control group received standard medication only. All the patients were followed for up to five years. "After three to six months, patients who received higher doses of bone-marrow stem cells showed greater improvement in blood flow within the heart than patients who received lower doses and those in the control group," the researchers said.

In a news release, Principal Investigator Dr. Arshed Quyyumi, a Professor of Medicine at Emory University School of Medicine said: "This is critical information for future study design — the more cells a patient receives, the more beneficial effect we see in the heart," The researchers also found that higher doses of bone-marrow stem cells appeared to help cardiac function, as determined by measuring the percentage of blood pumped out with each heartbeat (Ejection Fraction), and by measuring the amount of tissue death (infarction) due to inadequate blood supply. However, these results were not considered statistically significant, the researchers stressed.

"These results show that treatment with a patient’s own bone-marrow stem cells has the potential to reduce long-term complications after a heart attack. We are encouraged by these results and are planning to conduct a more extensive study," Quyyumi said.

“Until now there was no way to treat that,” observes Dr. Centeno. “Obviously, if you are a heart specialist or cardiologist this is of big interest to you.”

One key to treatments using a patient’s own stem cells is to gather and bank those cells in advance. “The number available for treatment declines with age,” Dr. Centeno points out.

“In a 60-year-old person we might get 60,000; we can grow that in a lab to a million, which is enough to treat a condition.  It’s what the body does, but the body can’t always get a sufficient number to the right place at the right time. If someone enters your practice at 40, just starting to see the consequences of aging, you would remove those cells and freeze them.” Though this sounds relatively simple, the prospects for such treatments in the future rest squarely on developing industry standards in the near term. “There are already companies doing that stem-cell freezing,” Dr. Centeno notes. “The problem is that if the FDA has its way, nobody will be able to use those cells because they will be considered a prescription drug. You won’t be able to use them in any meaningful way; you must incubate them to get them out of the cryogenic state because it’s a delicate process” ­- and that’s what the FDA considers ‘turning the cells into a drug’.

Thus, while development of stem-cell standards and guidelines is a work in progress, it is one about which there is a real sense of urgency. “All of this could be done within the next 12 months; we could have hundreds of people across the country doing this work under the ASCTA Guidelines,” explains Dr. Centeno. “We could get out of the starting gate very quickly if everyone gets on board; otherwise, the window is going to shut and it will never happen.”

The stakes for the pharmaceutical industry are obviously also high. “You’re talking about replacing $60 billion in drug- and device-care with $6 billion in stem-cell care,” Dr. Centeno observes. The end result will either be individual physicians owning and controlling labs, or, says Dr. Centeno, “It will all be controlled by Big Pharma, and innovation will move at a snail’s pace.”

Interview with Dr. Christopher J. Centeno, M.D
By L. Stephen Coles, M.D., Ph.D., Visiting Professor of Computer Science UCLA School of Engineering for h+ Los Angeles, California

Dr. Centeno is an international expert and specialist in musculoskeletal, spinal, and neurologic injury. He is an M.D. who is double-boarded in both Physical Medicine and Rehabilitation, and in Pain Medicine. He trained at the Baylor College of Medicine, Texas Medical Center, and the Institute for Rehabilitation Research. Dr. Centano utilizes a traditional medical approach blended with alternative and research-based treatments. He is Medical Director of The Centeno-Schultz Clinic and the Spinal Injury Foundation, and Scientific Co-chair of the International Whiplash Trauma Congress, which draws scientists together from all over the world. He is Co-Editor-in-Chief of the new peer reviewed medical journal, Whiplash and Related Disorders published by Haworth Medical Press, as well as the author of the medical text, The Spine Dictionary. Dr. Centano practices in Denver, North Denver, and Boulder, Colorado.

L. Stephen Coles, M.D., Ph.D., is Co-Founder 
Los Angeles Gerontology Research Group


h+: When did you begin your clinical work on adult stem-cell therapeutics?

CHRISTOPHER CENTENO: I started in 2005, and the very first question I had to address was whether I needed approval from the FDA to infuse autologous culture-expanded stem cells derived from patient tissue back into that same patent or whether such procedures ought to be considered part of the normal practice of medicine. We obtained opinions from three different attorneys. Their opinion was that what we’re doing was, in fact, "the practice of medicine," so the FDA had no jurisdiction.  The FDA recently has asserted that it’s their belief that autologous stem cells are the equivalent of a prescription drug. But this is a position we dispute.

h+:  Does that mean that the FDA could consider a patient’s own cells — when infused back into the patient — as a "prescription drug" that would fall under their regulatory guidelines, requiring a full set of Phase-I, -II, and -III Clinical Trials that could take five years or more and cost millions of dollars?

CC: Yes, that’s right. And it’s even more complex than that. If the procedure were done in the physician’s office, but done over more than one day, then the FDA could claim that they should have jurisdiction, since the cells would then be considered a drug according to their perspective. When a federal agency is looking to expand its charter (the scope of activities it seeks to regulate), it may well infringe on the practice of medicine unless doctors stand up for what is rightfully their practice.

h+:  Has the FDA issued any draft guidelines regarding their intention to regulate autologous stem-cell therapies that take place in a doctor’s office?

CC:  Not with regard to "the practice of medicine," just with regard to drugs. The FDA website concerning this topic is "Eligibility Determination for Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps)" (see "Resources" below).

h+: Has your own organization American Stem Cell Therapy Association (ASCTA) issued similar guidelines?

CC: Yes, and they are even more specific to autologous stem-cell therapy than the FDA’s own guidelines, which derive from a 50-year tradition of drug regulation.

h+: Have you worked with animal models to provide the safety component of a pre-clinical trial? 

CC: There are hundreds of animal model studies with mesenchymal stem cells. There is published research on rats, dogs, and pigs to demonstrate the safety of autologous mesenchymal stem cells infused into the lumbar spine, so we know that they are safe for these animals. Furthermore, veterinarians have been using these treatments for expensive racehorses afflicted with arthritis or inflamed ligaments to positive effect. Nevertheless, there is no substitute for human studies, as compared with animal models, for patient treatment.  Each species presents unique problems in terms of calculating the dose of cells, route of administration, and establishing the optimal time for treatment-onset following trauma or a chronic condition.

Calculating the treatment regimen over several months is also species specific. We hope to establish our guidelines in collaboration with a community of stem-cell physicians who are working in this area.