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FDA Regulates Stem Cells

Started By: TonyFrancis, MD, Orthopaedic Surgery, 11:20PM Oct 08, 2013

Our friends over at PointofLaw highlighted a position paper from the Manhattan Institute which is critical of the FDA's attempt to regulate a Colorado company that specializes in the injection of adult stem cells into arthritic joints and fracture non-unions.  The paper focuses on a case which is pending before the U.S. Court of Appeals for the D.C. Circuit.  In Regenerative Sciences, LLC v. United States, a federal court issued a permanent injunction against the company on the basis that it had violated FDA rules, inter alia, for not properly labeling a "drug" in interstate commerce and also presented a risk of spreading a communicable disease.  The appeal follows.  The Manhattan Institute believes this is an overreach on the part of the government.  One of the questions involves the distinction between a "drug" and "the practice of medicine." The FDA can regulate the former, but not the latter.   The doctors who own the company withdraw bone marrow from the patient, then manipulate it to produce stem cells.  These are quality checked by a Colorado genetics company.  Next, the regenerated mesenchymal cells are injected into arthritic joints, knees with meniscus tears and non-unions of bone fractures of the same patient.  The paper claims this is an example of the government stifling creative innovation.  Maybe so. 

The Manhattan Institute paper quotes a 10 year old anecdotal report from "Wired" magazine which claims stem cells saved a patient with a nail gun injury to the heart the necessity to get a heart transplant.  What that case has to do with the instant case remains to be demonstrated. 

The legal arguments concerning whether the FDA can call stem cells a "drug" and whether interstate commerce is involved are left to those who want to read them.  Appropriate links are provided infra.  Here's my beef:  I can't find anything in the literature showing this procedure actually works.  There are two  "case reports" from 2008 and 2006 stating two  patients with various arthritic conditions were "improved."  There are a couple of reports showing the procedure does not cause cancer.  I can't find any controlled studies demonstrating the benefits, if any.  Maybe they are there and I missed them.  A link to the relevant abstracts from the company is provided.   

We have decided that medical research in the US won't be done by individuals or small groups of individuals.  It is just the way things have gone.  Maybe someone could do that back in the 1940s, or even the 1960s.  But not now.  For better or worse, it isn't allowed.  Anymore than someone would cobble up an airliner in their barn that is better than the Boeing 777.  Those days are gone.  It also appears the company in question charges $5600 for the procedure.  There is an anecdotal website where a patient sings the praises of the procedure.  If 1100 procedures have been done for $5600 each (insurance does not pay so it is cash on the barrel head) - well, you do the math.    

Anyone who has practiced medicine knows that there are all kinds of treatment regimens.  Some are deliberate scams.  Others are done by well meaning doctors who really believe their procedure or treatment is useful.  The public is exceedingly gullible.  I don't have a pony in this race.  If there are any studies out there I missed, see if you can find them.  Please - prove me wrong. 

Regenexx has announced three controlled studies starting as of 5/22/13.  There are also links to various blogs with anecdotal success stories.  

From the order for a permanent injunction


Drs. Centeno and Schultz practice together and jointly own the Centeno-Schultz Clinic in Broomfield, Colorado. Drs. Centeno and Schultz are also the majority shareholders of Regenerative, which owns the Regenexx™ Procedure and exclusively licenses the Clinic to use it. Ms. Sheever serves as Regenerative's Laboratory Director. Regenerative and the Clinic are related companies and operate as one business. The Regenexx™ Procedure is a non-surgical procedure for patients suffering from moderate to severe joint, muscle, tendon or bone pain due to injury or other conditions. (commercials)

The Regenexx™ Procedure begins with a licensed physician taking a small bone marrow sample from the back of a patient's hip through a needle. Blood samples are also taken from a vein in the patient's arm. These samples are then sent to the Regenerative laboratory which is also in Broomfield, Colorado, just a few miles from the Clinic 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. After approximately 2 weeks, the expanded stem cells are sent to the University of Colorado affiliated Colorado Genetics Laboratory for testing.... Once the cells pass quality assurance testing, they are placed back into 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 repair process usually takes between 3-6 months but many patients demonstrate marked improvement within 1-3 months.

Of critical importance here is the process by which Regenerative expands the mesenchymal cells taken from a patient's bone marrow and delivers a syringe with the cells in solution to the Clinic.

1. A doctor at the Clinic obtains a tissue sample from the patient's bone marrow by inserting a needle into the hip bone and drawing a thick blood like liquid into a syringe; the sample is then sent to the laboratory.

2. The marrow sample is centrifuged to separate out fractions of the bone marrow and the middle layer ("buffy coat") is taken off with a pipette.

3. The cells from the buffy coat are placed in a plastic flask and kept in a warm environment to incubate with the patient's own blood platelets that contain growth factors, as well as a nutrient solution. Over a few days, the mesenchymal stem cells adhere to the plastic flask while the rest of the cells do not adhere. 4. The non-adherent cells are discarded and the mesenchymal stem cells are collected using Trypsin, an enzyme, to detach the cells from the plastic flask. 5. The process is repeated to grow the cells. 6. The cells undergo a visual inspection by the Colorado Genetics Laboratory to make sure that there are no genetic mutations or other genetic problems. The treating doctor then approves the cells.

In a letter dated July 25, 2008, the FDA notified Regenerative that the FDA believed that the cell product used in the Regenexx™ Procedure constituted a drug under the FFDCA and a biological product under the Public Health Service Act, 42 U.S.C. § 262 ("PHSA"). Further, the FDA stated that because Regenerative had not obtained the necessary approvals for the cell product, its actions in this regard were possibly unlawful.

FDA investigators inspected Regenerative between February 23, 2009 and April 15, 2009. That inspection showed that the laboratory did not operate in conformity with current good manufacturing practice ("CGMP"). When the 2009 inspection concluded, the FDA investigators issued a list of observations that identified a series of alleged CGMP violations.

FDA investigators again inspected Regenerative between June 2, 2010 and June 16, 2010. That inspection also revealed alleged CGMP violations, which the investigators catalogued in a list of observations.

While the initial FDA inspection was ongoing, Regenerative filed a complaint against the FDA in United States District Court for the District of Colorado, alleging that the FDA did not have the jurisdiction to regulate autologous3 use of stem cells. (Colo. Feb. 26, 2009) ("Regenerative I"). On March 26, 2010, the district court granted the FDA's motion to dismiss on ripeness grounds.  Regenerative then filed a notice of appeal with the United States Court of Appeals for the Tenth Circuit on March 29, 2010.

It is a close question but ultimately the Court concludes that the Regenexx™ Procedure is subject to FDA enforcement because it constitutes a "drug" and because a drug that has been shipped in interstate commerce is used in the solution through which the cultured stem cells are administered to patients. This acknowledged connection to interstate commerce renders the Regenexx™ Procedure subject to the FFDCA even though the doctors themselves are practicing medicine under Colorado law. Summary judgment will be granted to the United States and an injunction will be issued precluding the continued use of the Regenexx™ Procedure without compliance with the FFDCA.

Regenexx costs $5600 according to this blog entry from [2/18/12]:

At seven weeks the patient was satisfied.  He was undergoing physical therapy:

Two abstracts:

Increased knee cartilage volume in degenerative joint disease using percutaneously implanted, autologous mesenchymal stem cells.

Regenerative Sciences Inc (RSI), Centeno-Schultz Clinic, Westminster, CO 80020, USA.

Pain Physician. 2008 May-Jun;11(3):343-53.


BACKGROUND: The ability to repair tissue via percutaneous means may allow interventional pain physicians to manage a wide variety of diseases including peripheral joint injuries and osteoarthritis. This review will highlight the developments in cellular medicine that may soon permit interventional pain management physicians to treat a much wider variety of clinical conditions and highlight an interventional case study using these technologies OBJECTIVE: To determine if isolated and expanded human autologous mesenchymal stem cells could effectively regenerate cartilage and meniscal tissue when percutaneously injected into knees. DESIGN: Case Study SETTING: Private Interventional Pain Management practice. METHODS: An IRB approved study with a consenting volunteer in which mesenchymal stem cells were isolated and cultured ex-vivo from bone marrow aspiration of the iliac crest. The mesenchymal stem cells were then percutaneously injected into the subject’s knee with MRI proven degenerative joint disease. Pre- and post-treatment subjective visual analog pain scores, physical therapy assessments, and MRIs measured clinical and radiographic changes. RESULTS: At 24 weeks post-injection, the patient had statistically significant cartilage and meniscus growth on MRI, as well as increased range of motion and decreased modified VAS pain scores. CONCLUSION: The described process of autologous mesenchymal stem cell culture and percutaneous injection into a knee with symptomatic and radiographic degenerative joint disease resulted in significant cartilage growth, decreased pain and increased joint mobility in this patient. This has significant future implications for minimally invasive treatment of osteoarthritis and meniscal injury.

PMID: 18523506 [PubMed - indexed for MEDLINE]Free Article

Partial regeneration of the human hip via autologous bone marrow nucleated cell transfer: A case study.

The Centeno-Schultz Clinic, 11080 Circle Point Road, Building 2, Suite 140, Westminster, CO 80020, USA.

Pain Physician. 2006 Jul;9(3):253-6.


HISTORY: This is a case report of a 64-year-old white male with a 20 year history of unilateral hip pain that had become debilitating over the last several years. On intake, Harris hip score was rated as: Pain subscale = 10, Function subscale = 32, Deformity subscale = 4, Motions subscale = 4.775 with a total score of 50.8 out of 100. MRI of the affected hip showed severe degeneration with spurring, decrease in joint space, and several large subchondral cysts. The patient had been evaluated by an orthopedic surgeon and told he was a candidate for bipolar hip replacement. METHOD: Two autologous nucleated cell collections were performed from bone marrow with subsequent isolation and transfers into the intra-articular hip using a hyaluronic acid and thrombin activated platelet rich plasma scaffold. Marrow samples were processed by centrifugation and lysis techniques to isolate nucleated cells. CONCLUSION: This report describes partial by articular surface regeneration 8 weeks after intraarticular bone marrow transfer. Post-op 3.0T FGRE MRI showed neocortex formation when compared to immediate pre-op MRI and objective improvements were noted that coincided with subjective reports of improvement.

PMID: 16886034 [PubMed - indexed for MEDLINE]Free Article

Complete list of abstracts:

From the Manhattan Institute paper:

The FDA’s Misguided Regulation of Stem-Cell Procedures:

How Administrative Overreach Blocks Medical Innovation

Executive Summary

The current biomedical revolution has its most tangible application to ordinary people in the new cutting-edge techniques devised by individual physicians for the cure and palliation of chronic and degenerative diseases. The rate of advance in this area is a testimony to the creative forces unleashed by the decentralized control over medical procedures. But that progress is now threatened by the federal Food and Drug Administration (FDA), which seeks to extend its statutory authority to subject these practices to the same oversight that is given to large drug manufacturers in the design and production of new products for the mass market. One area over which the FDA has asserted its power is private adult stem-cell treatment, which has developed treatment protocols that were not possible a generation, or even a decade, ago.

The FDA has taken the aggressive position that it has oversight authority over any stem-cell procedure that reinjects harvested stem cells into the same person from whom they were removed, so long as those cells were grown and cultured outside the human body. Indeed, one promising use of this technique for heart-attack patients was scuttled after the FDA stepped in to require extensive clinical trials over a hospital that could not afford the high costs of FDA compliance. It is unclear how many promising similar avenues have been shut off by physicians who were unwilling to run the FDA gauntlet of initial approval and constant oversight to bring their techniques to the market in the United States without risk of regulatory censure. But two physicians utilizing one such approach are now challenging in federal court the FDA’s authority to regulate—and effectively prohibit—the use of adult stem cells to mitigate the effects of one widespread malady: degenerative joint conditions, including those caused by sports injuries.

Regenerative Sciences, LLC v. United States, now pending before the U.S. Court of Appeals for the D.C. Circuit, concerns a stem-cell procedure developed by Colorado doctors Christopher Centeno and John Schultz. The doctors’ procedure involves the patient-specific extraction of blood and bone marrow stem cells, centrifuged, grown, and sterilized in their in-house laboratory, and then reinjected into the patient’s own body. The FDA claims that the doctors’ procedure involves the manufacturing of “drugs” for sale in “interstate commerce” that falls within its statutory purview to prevent the spread of “communicable diseases.”

This paper analyzes the government’s position on legal and policy grounds. Legally, the government incorrectly reads the “interstate commerce” clause of the Federal Food, Drug and Cosmetic Act of 1938 (FFDCA) as identical to the broad authority that contemporary cases attach to the Commerce Clause in the U.S. Constitution. A close reading of the statutory text and history suggests that it is anything but that. Properly read, the clause clearly places the doctors’ procedure outside the FDA’s purview. Similarly, the government’s broad definition of the doctors’ procedure as a “drug” rather than the “practice of medicine” strains the ordinary meaning of both terms. Read as a whole, the government’s theory boils down to the proposition that its power to prevent the spread of “communicable diseases” applies to the doctors’ procedure because the patient’s own stem cells may become contaminated during the process, as could happen in all common forms of surgical procedures widely understood to fall outside FDA authority. This sweeping assertion of new statutory authority, if consistently applied, would grant the FDA broad powers to regulate common surgical practice, traditionally regulated by the states.

This paper reviews and rebuts specific arguments as they relate to these issues in more detail:

    1. Interstate Commerce. The FFDCA gives the FDA authority to regulate an act involving a drug if the act occurs “after shipment in interstate commerce and results in such article being adulterated or misbranded.” The government, as well as the district court that ruled on the government’s behalf below, has argued that the broad deference that the Supreme Court affords Congress’s constitutional power to regulate interstate commerce gives the FDA ample authority to oversee any local business that receives supplies or customers from out of state. What the government position misses is that the statutory authority does not extend as far as the constitutional authority. The FFDCA was enacted four years before the Supreme Court’s 1942 decision in Wickard v. Filburn, which expanded Congress’s power over interstate commerce to reach purely intrastate activities that influenced interstate commerce. It was only as late as 1964 in Katzenbach v. McClung that the Supreme Court held that Congress’s power over interstate commerce covered any business that received some of its supplies through the channels of interstate commerce. In context, the statutory definition of interstate commerce in the FFDCA—like the parallel language in the statute’s predecessor, the 1906 Pure Food and Drug Act—makes conscious and explicit reference to the pre-Wickard account of interstate commerce. The stem-cell procedure developed by doctors Centeno and Schultz clearly is not interstate commerce as defined in the statute.

    2. Drugs Versus the Practice of Medicine. The government and district court also misfire when they assume that the stem cells removed from and reinjected into patients are “drugs” subject to FDA regulation rather than the “practice of medicine,” the regulation of which Congress has traditionally left to the states. The traditional mass-production manufacturer that makes a drug that is sold downstream for physicians’ use has little in common with the physician who grows a patient’s own stem cells for reinjection into the same patient. Those differences all cut in favor of removing the FDA from a role of direct oversight over the physician’s practice. Although the government insists that the FDA should be afforded substantial deference in defining the meaning of the term “drug,” the Supreme Court has often cut back against FDA definitions that generate major extensions of the agency’s jurisdiction into areas already subject to alternative schemes of regulation, as in the Court’s 2000 decision in FDA v. Brown & Williamson Tobacco.

    3. Communicable Diseases. The government claims that the FDA may also regulate the Colorado doctors’ stem-cell procedures under the 1944 Public Health Service Act, which gives the agency authority “to make and enforce such regulations as … necessary to prevent the introduction, transmission, or spread of communicable diseases from foreign countries into the States or possessions, or from one State or possession into any other State or possession.” Whatever risks the stem-cell procedure developed by Centeno and Schultz might create for the doctors’ patients—and there are no documented cases of adverse side effects cited by the FDA—such risks would not involve “communicable diseases,” according to those words’ ordinary meaning, given that their procedure involves injecting not foreign stem cells but the patients’ own stem cells into their own bodies. The government’s fear that under the Colorado doctors’ procedure, “samples may be improperly labeled, mixed up with other cells, and contaminated or exposed to communicable disease agents,” is doubtless correct but only identifies risks routinely found in a clinical setting whenever a lab technician makes a similar error. These local issues should be, and typically are, regulated by local public health authorities. Such errors are far more likely to happen in routine hospital settings when blood, stool, or urine samples are taken from sick individuals who are known to carry various infectious agents than in the controlled process used in the Colorado doctors’ lab. Tellingly, the FDA’s own report asserting regulatory authority over stem-cell procedures of the sort developed by Centeno and Schultz impliedly claims the power to control any common form of surgery that requires drug use, which, in practice, is all surgeries.

To read the entire paper:

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