Regenexx: Recipe for Controversy?

With stem cell therapies changing and morphing at an increasing rate, FDA appears more than ever open to interpretation. Clinics that offer up novel and sometimes controversial stem cell treatments may be on a collision course in fact with the agency. Some worry about the efficacy of such treatments and protecting the patient from slickly marketed innovations that lack results. Others are concerned with clinics being able to dodge regulation and review. At the same time physician-led clinics see stem cell advancements as holding a promise to patients, once removed from pharmaceutical companies and long, drawn-out trials.

Lab-Cultured Stem Cell Therapy in Colorado

Drs. Chris Centeno and John Schultz operate the only U.S.-based clinic/lab (that we are aware of) that offers lab-cultured mesenchymal stem cell (MSC) therapies to patients suffering from joint pain. Because of that, the team is raising both eyebrows and hope for orthopedic patients. The pair incorporated their clinic as Regenerative Sciences Inc. (RSI) some years back and are based in Broomfield, Colorado. Their specific technique, which is branded Regenexx, uses patient-derived (autologous) mesenchymal stem cells to treat various orthopedic indications including maladies of the hands, hips, knees, shoulders, back (non-spinal cord injury), ankles, and even bone fractures.

Before and after knee MRIs courtesy of the Centeno/Shultz Clinic“We have seen the best results with partial tendon and ligament tears which are non-retracted, ” explains Dr. Christopher Centeno, “such as partial rotator cuff and partial ankle ligament tears. We have also seen good one-year follow-up data on knees with moderate OA [osteoarthritis] (knee replacement candidates) and will be publishing on a dataset of about 200 patients soon.”

The Regenexx procedure is comparatively straightforward. It begins with the extraction of a sample of the patient’s bone marrow, from which stem cells are isolated, cultured and then combined with the patient’s own blood and re-injected into the treatment area.

Since the start of this year, Centeno’s clinic has treated 333 patients with a total of 754 Regenexx injections. While other clinics may employ, for example, allograft forms of bone material which contain MSCs, the RSI clinic is the only one that cultures the patient’s own MSCs into an expanded number, up to 10 million, of MSCs before injecting them back into the patient.

As for his background, Dr. Centeno is board certified in physical medicine, rehabilitation medicine, and pain management through the American Board of Anesthesia. He is the founding member of the International Cellular Medicine Society and the Spinal Injury Foundation and completed a residency at the Baylor College of Medicine and training at the Texas Medical Center and the Institute for Rehabilitation Research.

Okay, but Is It Safe and Does It Work?

Dr. Centeno has published a number of papers in peer review journals including, recently, a paper titled “Safety and complications reporting on the re-implantation of culture-expanded mesenchymal stem cells using autologous platelet lysate technique” in Current Stem Cell Research & Therapy, March 2010.

The study looked at patients who were treated at Centeno’s clinic for a variety of orthopedic conditions using his Regenexx culture-expanded, autologous, bone marrow-derived MSCs. As described in his paper, the cells were cultured in monolayer culture flasks using an autologous platelet lysate technique and then re-injected into the subject’s peripheral joints or intervertebral discs. Follow-up MRIs over the course of two years failed to demonstrate any tumor formation at the re-implant sites. That is, incidentally, consistent with other research which has found no evidence of malignant cellular change due to and after implantation of expanded MSCs.

Another paper, a review, was published in Medical Hypotheses, in September 2008 titled “Regeneration of meniscus cartilage in a knee treated with percutaneously implanted autologous mesenchymal stem cells”. The paper, which was authored by Dr. Centeno, presents his experience using his techniques with autologous MSC therapy and, no surprise, reports that it was a “successful harvest, expansion, and transplant of autologous mesenchymal stem cells into an adult human knee that resulted in an increase in meniscal cartilage volume.”

Lab Tech / Wikimedia CommonsRSI charges between $7, 000-$8, 500 for the treatment—depending on indication. This price includes the marrow and blood draw, lab expansion of the cells, pre-injection, re-injection of cells, and post injection(s). The procedure is not covered by insurance, something Centeno hopes will change soon. “There are about 11, 000 published articles on autologous mesenchymal stem, so yes, with that type of publishing activity (several thousand papers a year), it’s likely to be a foregone conclusion that at some point, in my opinion, this type of stem cell therapy will get insurance approval.”

Table 1 – Cartilage Volume Analysis in mm³ from the case report: Increased knee cartilage volume in degenerative joint disease using percutaneously implanted, autologous mesenchymal stem cells, platelet lysate and dexamethasone

Image	Area of Measurement	Volume (N=3)	STDEV	SE	% Change from Pre-Injection
	Cartilage surface	2227	115.82	66.95
Pre-Injection	Meniscus	1533	13	7.51
	Defect	20.7	1.53	0.88
	Cartilage surface	2216	150.7	87.11	-0.49
6 Months	Meniscus	1545	35.1	20.29	0.78
	Defect	14.7	1.15	0.67	-28.99

Source:  RSI

“The Regenexx procedure is needle based, so it’s less invasive than traditional surgery, ” says Centeno. “There is also opportunity to provide MSCs with traditional or minimally invasive orthopedic surgery techniques. MSCs have been shown to aid in cartilage, meniscus, ligament, tendon, and bone healing. In addition, they also seem to improve osteointegration of grafts. For example, we have worked with local surgeons to inject cells after knee micro fracture procedures.”

The FDA Conundrum

Walter Gardner, Chief of the Consumer Affairs Branch at the Center for Biologics Evaluation and Research at FDA says “Currently there are no autologous stem cell therapies licensed for use in the United States. Stem cells are regulated by Center for Biologics Evaluation and Research (CBER) as human cells, tissues and cellular and tissue-based products (HCT/Ps). Under the authority of Section 361 of the Public Health Service (PHS) Act, FDA established regulations for all HCT/Ps to prevent the transmission of communicable disease.” Under these well established and carefully monitored rules, tissues based products must be used only for homologous purposes and during processing be “minimally manipulated”. Culturing is not minimal manipulation according to the FDA.

There are a fair number of stem cell based products working their way through the FDA clinical study process in order to demonstrate to a statistically significant degree that they are safe and efficacious. Most of these products are based on cultured stem cells. But not all. Some are based on autologous products and others are based on systems that allow physicians to harvest the patient’s own stem cells.

It would appear that RSI’s approach is either in a gray area or fits into one corner of the regulations where, so long as the cultured MSCs are used in the clinic and for its own patients and not sold to other clinics, they are inside the bounds of the law.

Then there is the fact that these are autologous materials. Autologous stem cell therapies use a patient’s own bone marrow, blood, adipose tissues or even tooth enamel to collect MSCs. According to Dr. Centeno, using autologous source material brings the risk of disease transmission to virtually zero.

Said Dr. Centeno, “We began this procedure in 2005 as part of a bigger two-year research study that went through IRB approval [Institutional Review Board]. We asked regulatory counsel if we needed FDA approval and received the opinion that we didn’t require that approval since there was no intent to make this a product, just simply use this procedure as part of our medical practice in Colorado.”

He cites the example of a surgeon in his garage formulating a new surgical instrument, which he then sterilizes and uses in surgery the next day. Since the FDA only regulates drugs and devices sold in interstate commerce, Centeno says that surgeon is under no obligation to seek FDA approval for his custom surgical instrument. “However, if that surgeon started taking orders from other surgeons around the country for that device and began shipping devices ‘interstate’, he would then require FDA approval on the device.” He says the same holds true for stem cells. FDA approval he adds, would only be needed if donor stem cells were shipped in a vial “interstate.”

Centeno says that upon receiving an “untitled letter” from the FDA questioning parts of their practice, the clinic responded and in the summer of 2009, “They visited our Colorado site, ” explains Centeno “and declared that since we were culturing cells, we were manufacturing a biologic drug. We again asked for them to support their position that they had regulatory authority with some logical argument, again they declined to comment.” At that point the doctors filed a lawsuit but a ruling came down stating that “we couldn’t file against them until they did something. We filed a notice of appeal and asked to have a court enforced mediation started, ” says Centeno.

For their part, Drs. Centeno and Schultz now sit on the Board of Directors of the International Cellular Medicine Society and have established a three-point process which takes a note from the IVF (in vitro fertilization) community to create safety guidelines for physicians interested in offering this therapy.

“The fertility specialists have formed professional organizations that have established professional guidelines, lab guidelines with third party audits, and a re-implantation registry. We’ve done the same. We have worked with physicians and scientists to establish professional guidelines for safe autologous stem cell use, lab guidelines with a third party auditor (Reglera), and a third party non-profit re-implantation registry. There are now about 250 physicians and scientists that have joined this organization.”