The burgeoning U.S. stem cell therapy industry was delivered a setback last month in the form of a U.S. District Court injunction against use of the “Regenexx™ Procedure,” which purports to treat joint, muscle, tendon or bone pain due to injury or other conditions. The court agreed with the FDA that the cell product used in the procedure is both a drug and a “biological product” subject to FDA regulation. Because a similar process is used in other stem cell therapies the decision increases the possibility that the FDA will take a like position in other cases.
The general term “stem cell therapy” comprises an array of treatments which range from the clinically proven to quackery. On one end of the spectrum is blood stem cell transplantation to treat diseases and conditions of the blood and immune system. On the other lies the kind of stem cell therapy tourism addressed by both Steve Novella (here and here) and Orac (here and here), which involves the injection of what may, or may not be, stem cells from what may, or may not be, humans. In between fall therapies which are plausible and have promise but have not been adequately tested in clinical trials. There is a concern that these therapies are being oversold by clinics which charge thousands of dollars (not reimbursed by insurance) to treat conditions including multiple sclerosis, musculoskeletal pain, and cardiac disease.
Here’s how the district court described the procedure it enjoined from further use, quoting from a document filed by its manufacturer, Regenerative Sciences, LLC, a Colorado company, and three of its officers (two of them physicians who developed the procedure), co-defendants in the case:
The Regenexx™ Procedure begins with a licensed physician taking a small bone marrow sample from the back of a patient’s hip though a needle. Blood samples are also taken from a vein in the patient’s arm. These samples are then sent to the Regenrative laboratory . . . where the mesenchymal stem cells (MSCs) are isolated from the bone marrow and then grown to greater numbers. This process uses the natural growth factors found in the patient’s blood to grow the MSCs. . . .
Once the cells pass quality assurance testing [about 2 weeks later], they are placed back in to the patient’s injured area (i.e. knee, hip, rotator cuff), typically 4-6 weeks after they were removed. The stem cells then begin to repair the patient’s degenerated or injured area.
The FDA notified Regenerative Sciences in 2008 that the FDA believed the cell product used in the Regenexx™ Procedure constituted a drug under the Federal Food Drug and Cosmetics Act (FFDCA) and a biological product under the Public Health Service Act (PHSA). In 2009 and 2010, the FDA investigated a Regenerative Sciences laboratory and determined that it did not operate in conformity with current good manufacturing practices. In 2010, the FDA filed suit to enjoin further use of the Regenexx™ Procedure claiming that it constitutes the manufacturing and holding for sale an unapproved biological drug product and that it violated the FFDCA’s prohibition on adulteration and misbranding a drug.
The main defense centered on the argument that this procedure is not a drug, but rather the practice of medicine as defined by Colorado law, over which the state, not the federal government, has exclusive regulatory jurisdiction. In this argument the defendants were joined by the Association of American Physicians and Surgeons and the American Association of Orthopaedic Medicine both of whom the district court allowed to file amicus curiae (“friend of the court”) briefs.
The Association of American Physicians and Surgeons (AAPS) has appeared on SBM before. The title of David Gorski’s post alone tells you a lot: The Journal of the American Physicians and Surgeons: Ideology trumps science-based medicine. For an even closer look, Kathleen Seidel posted an extensive review on the neurodiversity weblog. Among other eye-popping positions, the AAPS warns that “physicians must beware of accepting the concept of a standard of care that is itself evidence-based, threatening the autonomy of physicians and subjugating the patient’s interest to that of the collective.” (What must they think of science-based medicine?) It’s no fan of the FDA either and regards its existence as unconstitutional.
The American Association of Orthopaedic Medicine describes “orthopaedic medicine” on its website as
. . . a specialty devoted to the evaluation, diagnosis and non-operative treatment of painful musculoskeletal diseases. Diagnostic modalities include a comprehensive history, a detailed and specific physical examination, radiologic evaluations and local anesthetic blocks. Therapeutic modalities encompass manipulations, corticosteroid or proliferant injections [also known as prolotherapy] with and without fluoroscopic guidance, therapeutic exercise and use of pharmaceutical, nutriceutical, herbal and/or homeopathic based treatment.
That’s likely all you need to know to draw your own conclusions.
The FDA filed a motion for summary judgment in the case, arguing that based on the record before it the court could find that there were no material questions of fact and that the FDA was entitled to judgment in its favor as a matter of law. The FDA won its motion, and thereby won the lawsuit without having to go to trial.
“The question here,” the court said in its opinion granting the FDA’s motion, “is whether the Regenexx™ Procedure constitutes a drug (or biologic product) subject to FDA regulation or whether it is merely an intrastate method of medical practice subject only to the laws of the State of Colorado.” The court continued
The FFDCA defines ‘drug’ to mean ‘articles intended for use in the diagnosis, cure mitigation, treatment, or prevention of disease’ or ‘articles (other than food) intended to affect the structure or any function of the body of man or other animals.’ . . . Based on this definition, whether an ‘article’ is a ‘drug’ depends on its ‘intended use’ . . . [which turns on] the nature of the claims advanced on its behalf.
In addressing the “intended use,” the court found that
Defendants’ website and pleadings describe their ‘intended use’ for Regenexx™ Procedure. Defendants promote the Regenexx™ Procedure to treat a variety of orthopedic conditions and injuries. . . . Defendants describe the Regenexx™ Procedure as ‘an Alternative to Traditional Surgery’ that can treat ‘[f]ractures that have failed to heal, joint cartilage problems, partial tears of tendons, muscles, or ligaments, chronic bursitis, avascular necrosis of the bone, and lumbar disc bulges. . . .
Defendants’ pleadings confirm their intentions to use the Regenexx™ Procedure for ‘mitigation’ and ‘treatment,’ among others, of disease and injury. They explain how the ‘stem cells . . . begin to repair the patient’s degenerated or injured area.’ . . . how [it] is ‘for the treatment of orthopedic injuries and arthritis,’ [and] . . . ‘for the treatment of musculoskeletal and spinal injury.’ These statements of ‘intended use’ fully satisfy the statutory definition for a ‘drug.’ Similarly, Defendants’ admissions that the Regenexx ™ Procedure is based on mesenchymal stem cells derived from the patient’s bone marrow . . . and that it is intended to treat orthopedic conditions fully satisfy the definition of ‘biological product’ under the PHSA . . . .
The court also found that because the cells used in the procedure were more than “minimally manipulated” the defendants could not claim an exemption from regulation under FDA rules.
Among other issues, as noted above, the court also had to determine whether defendants’ actions were subject to federal regulation at all, or whether they were simply the practice of medicine subject solely to regulation by the state of Colorado, an issue hotly contested by the AAPS and AAOM. Here, the court determined that defendants’ combination of an antibiotic, doxycycline, with the cell product before it is administered to patients was sufficient, as doxycycline is shipped through interstate commerce prior to its administration.
One of the principals in Regenerative Sciences and a defendant in the case, Chris Centeno, M.D., told the journal Nature that the company plans to appeal. It has already moved the procedure enjoined in the U.S. to a clinic in the Cayman Islands, an action taken when the FDA ordered the company to stop using the product in 2010. The company will continue to offer three other stem cell products for joint pain in the U.S. based on its contention these products do not fall within FDA’s jurisdiction. Dr. Centeno told Nature that the FDA sees these other procedures as the practice of medicine and “has no issues” with them. Nature reported that until July 25th the Regenerative Sciences website claimed the three procedures were “FDA approved.” However, Nature determined that this was not the case and the claim was removed after its further inquiries to the company.
Interestingly, the safety and efficacy of the Regenexx™ Procedure was not at issue in the district court case, although those certainly will be issues now that it’s been deemed a drug should the defendants choose to pursue its use in the U.S. The Regenerative Sciences website lists some journal publications and other data which the company apparently feels support the safety and efficacy of its procedures. It also provides a number of testimonials. I do not have sufficient education and training to evaluate those claims. However, the International Society for Stem Cell Research (ISSCR), which describes itself as “an independent, nonprofit organization formed in 2002 to foster the exchange of information on stem cell research. . . . [w]ith more than 3,500 members worldwide” has this to say:
Other stem cell treatments, while promising, are still at very early experimental stages. For example, the mesenchymal stem cell, found throughout the body including in the bone marrow, can be directed to become bone, cartilage, fat and possibly even muscle. In certain experimental models, these cells also have some ability to modify immune functions. These abilities have created considerable interest in developing ways of using mesenchymal stem cells to treat a range of musculoskeletal abnormalities, cardiac disease and some immune abnormalities such as graft-versus-host disease following bone marrow transplant.
I’ll take this opportunity to plug the ISSCR website as a wonderful resource for anyone interested in stem cell research, including those contemplating any sort of stem cell therapy. In addition to information for scientists and physicians it has easily understandable information and advice directed to the layperson.
While the district court’s injunction puts stem cell clinics on notice that some of their procedures may fall within the FDA’s jurisdiction, what of other stem cell procedures which, like those still offered in the U.S. by Regenerative Science, might not be classified as drugs? Who is protecting the public’s health and safety in those cases? This task would appear to fall to the state medical boards, which, depending on factors such as budget, interest and politics, may not be up to the task.
Texas governor Rick Perry, himself a recipient of stem cell therapy for a back problem, has heavily promoted the stem cell therapy industry in Texas and millions of state funds are available for research. But criticism from bioethicists and others about promotion of unproven therapies and the lack of patient protection led the Texas Medical Board to adopt new rules in April governing their use, as reported in The Texas Tribune (here and here) and Science Insider, a publication of the American Association for the Advancement of Science. The rules require that stem cell treatments either be part of an NIH or FDA-approved protocol or study, or have approval from a local Institutional Review Board (IRB), which need not be affiliated with a hospital or academic institution. The response to the new rules seems to run the gamut from “it’s better than nothing” to concerns that the rules will fail to protect patients. Critics noted the opportunity for lax oversight by private, for-profit IRBs, which have financial incentives to approve procedures. William Smyth, a Medical Board member who voted against the rules, told the Tribune that, “if Texas wants to be a leader in this area, there are other ways to do this. You want to add a layer of protection? Put a moratorium on the use of these agents until they are proven.”
But that would require expensive, time-consuming clinical trials. And the companies who market stem cell therapies apparently don’t want to spend that kind of time or money.