Wednesday, February 26, 2014

Education (Law) - Court Rules Autologous Stem Cells Are Drugs—Final Ruling?

This article is published in Orthopedics This Week - Link

A “Mixture” processed from a patient’s own mesenchymal stem cells (MSCs), placed in a solution to culture and then combined with an antibiotic doxycycline and injected back into the patient, is a drug and therefore subject to FDA regulation.

But scientifically, that is a very difficult position to support. Which begs the question: Does bad science make good law?

On February 4, 2014 the U.S. District Court of Appeals for the District of Columbia in the case of United States of America v. Regenerative Sciences, LLC ruled that Dr. Chris Centeno was indeed making a “Mixture” of autologous MSCs and that is a “drug” and therefore subject to FDA regulation.

Chris Centeno, M.D. and his partners at Regenerative Sciences argued long and hard that their process did NOT create a “Mixture” but rather simply expanded the patient’s own cells and was, therefore, the practice of medicine and regulated by individual state medical boards. Not the FDA.
Chris Centeno, M.D.

In point of fact, Dr. Centeno had fully complied with the FDA ruling several years ago and was pursuing this very expensive litigation simply for the principal of the matter. His practice is unaffected by either the FDA’s previous ruling or this court’s ruling.

In view of what is scientifically correct and best for his patients, Centeno made the decision to use an antibiotic (doxycycline) during the culturing of the patient’s own cells.

Most doctors’ office in the U.S. have items that are combined with other items (mixtures) for injection that have travelled from another state to that doctor’s office.

So, in Centeno’s view, the principle at stake here is whether the FDA can regulate such common medical activities—especially if they are based on the physician’s own medical and scientific training and judgment. The D.C. court may well have opened the door wide to just such micro-regulation.

FDA Warning and Physician Challenge

At a huge cost in time and dollars, Dr. Centeno fought his battle all the way up to the D.C. Circuit. He is not a wealthy man and this appeals court ruling may be the last stop of a journey that started in 2008 when the FDA sent a Warning Letter to Regenerative.

The FDA charged that Regenerative’s procedure violated 21 CFR 1271.1—FDA’s human cell, tissue and tissue-based products (HCT/P) regulation—by running afoul of its “minimal manipulation” provisions and because the resulting stem cells were not “intended for homologous use only.” Of course, it was a bit of a head scratcher to say that using a patient’s own cells was not homologous use. But, given that interpretation, the procedure did not qualify as an HCT/P product and was therefore a drug.

The physicians of Regenerative disagreed and filed a lawsuit against the FDA in 2010 challenging the characterization of its Regenexx procedure. A July 2012 decision by the U.S. District Court sided with the FDA’s interpretation of the regulations.

Centeno’s Battle

Dr. Centeno and his partners appealed that decision.

“Since 2008, we have been challenging the FDA on whether a physician creating autologous, more than minimally manipulated cells (>MM) for his or her own patients was creating a drug or practicing medicine. This has always been an uphill battle, but one we felt was worth it as physicians do things everyday which should be regulated by FDA (if they weren’t physicians). For example, if you mix drug A and B, technically you need an IND (Investigational New Drug Application) for a combination product. If you alter an existing surgical tool, you would need an IDE (Investigational Device Exemption),” Dr. Centeno told OTW.

He added, “Despite all of our efforts, the D.C. Circuit ruled that your little medical practice can be regulated like a Pfizer drug factory if you use more than minimally manipulated autologous cells. While we’re not happy about their ruling, we fully accept that this is the law now that has been vetted by the courts and will do our best to follow it to the letter.”

Centeno made it clear that not much changes for his practice as a result of this ruling since they haven’t used >MM cells since 2010, the moment FDA took a formal position that the cells were a drug.

“This doesn’t impact PRP (platelet-rich plasma) or BMC (bone marrow cells) right now, as these fall squarely into the <MM rubric. However, if you’re creating adipose SVF (stromal vascular fraction) by using any method (ultrasound, collagenase, trypsin, etc.) that dissociates cells from tissue, it does apply. The D.C. Circuit opinion means that the novel theories about why many physicians believe their use of SVF isn’t FDA regulated no longer hold water,” said Centeno.

The Decision

Specifically, said the court, two statutes were violated, the Federal Food, Drug & Cosmetic Act (FDCA), 21 U.S.C. § 301 et seq., and the Public Health Service Act (PHSA), 42 U.S.C. § 201. The Regenexx “Mixture” did not satisfy the requirements of those laws and was therefore deemed “adulterated” or “misbranded.” “The text of those statutes forecloses” the argument that the Mixture is not subject to regulation said the court.

Defining Drugs and Biological Products

The FDCA defines a “drug” as any “article intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease” or “intended to affect the structure or any function of the body.” The PHSA defines biological product” in similarly broad terms as any “virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative…or analogous product…applicable to the prevention, treatment, or cure of a disease or condition of human beings.”

“Both of these wide-ranging definitions clearly apply to the Mixture, an article derived mainly from human tissue and intended to treat orthopedic diseases and to affect musculoskeletal function. Indeed, appellants do not actually dispute that the plain language of the statutes compels this conclusion,” wrote the court.

The court said Regenerative was urging it to construe the FDCA “in light of purported federalism concerns.” But, said the court, that lacked merit and Regenerative’s arguments boiled down to the following syllogism: “the FDCA was not intended to infringe on states’ traditional role in regulating the practice of medicine; the Procedure fits Colorado’s statutory definition of the ‘practice of medicine’; therefore, the FDA’s regulation of the Procedure exceeds the FDA’s authority under the FDCA. This syllogism is flawed twice over.”

Practice of Medicine v Regulating Drugs

First, said the court, Regenerative’s legal argument “misapprehends what this case is about,” by attempting to characterize this case as an effort by the FDA to “restrict the use of an autologous stem cell procedure.” However, said the court, the focus of the FDA’s regulation is the Mixture. “The FDA does not claim that the procedures used to administer the Mixture are unsafe; it claims that the Mixture itself is unsafe. Appellants’ arguments about the practice-of-medicine exemption are therefore wide of the mark.”

Second, the court added that Regenerative is, “wrong to suggest that the scope of the FDCA depends on state-by-state definitions of the ‘practice of medicine.’”

“While the FDCA was not intended to regulate the practice of medicine, it was obviously intended to control the availability of drugs for prescribing by physicians.” Regenerative’s legal construction of the FDCA, added the court, by contrast, “would allow states to gut the FDCA’s regulation of doctors, and thereby create an enormous gap in the FDCA’s coverage, by classifying the distribution of drugs by doctors as the practice of medicine. Such a construction is not tenable.”

Equally untenable, said the court, is Regenerative’s contention that because the procedure occurs entirely within the state of Colorado, the Mixture lacks a sufficient connection to interstate commerce to permit federal regulation under the Commerce Clause.

Citing precedents dealing with the growing of marijuana and wheat for personal consumption, the court said the Mixture does “undoubtedly have effects on interstate markets for orthopedic care, [and] actually includes an article shipped in interstate commerce, namely, doxycycline.”

“We therefore hold that, by virtue of its use of doxycycline, the Mixture is within the scope of drugs—and, by extension, biological products.”

Failing the Minimal Manipulation Test

The court dismissed Regenerative’s arguments that the Mixture is exempt from the FDCA’s manufacturing and labeling requirements even if it is otherwise subject to federal regulation.

The FDA promulgated regulations to ensure the safety of [HCT/Ps] used for therapeutic purposes in 2001. Those regulations define HCT/Ps, as “articles containing or consisting of human cells or tissues that are intended for implantation, transplantation, infusion, or transfer into a human recipient.”

“HCT/Ps may qualify as drugs or biological products, and when they do, the FDA generally regulates them accordingly.” However, noted the court, there is an exemption from regulation for any HCT/P that is no more than “minimally manipulated.”

“Minimal manipulation” of cells means “processing that does not alter the relevant biological characteristics.”

Regenerative claimed the exemption applied to the Mixture, while the FDA said culturing MSCs alters the genes and proteins they express.

To be fair, that notion that culturing MSCs alters genes and proteins is also scientifically difficult to support. Indeed, at OTW’s annual New York Stem Cell Summit, literally dozens of papers are presented annually which directly contradict the FDA’s position.

Issues of Fact

The court gave Regenerative credit for creating a “genuine issues of fact” by submitting expert affidavits arguing that the government’s views are based on scientific studies that do not apply to Regenerative’s culturing process.

But, why let facts get in the way of an intended ruling. According to the court, Regenerative gave no response to other reasons offered by the government. “For example, appellants admit that the culturing process is designed to ‘determine the growth and biological characteristics of the resulting cell population.’”

And in some cases, said the court, Regenerative added substances to the cell culture that “affect the differentiation of bone marrow cells.”

“These concessions are fatal to appellants’ attempt to claim refuge.”

The court also claimed that Regenerative conceded that culturing MSCs affects their characteristics and offered no evidence that those effects constitute only minimal manipulation. Said the court; “they fail to carry that burden as a matter of law.”


Regenerative argued that the Mixture is exempt from the FDCA’s manufacturing and labeling requirements because it is a compounded drug.

“A compounded drug must be produced using certain types of ‘bulk drug substances,’ one of which is ‘bulk drug substances…that…are components of drugs approved by the [government]. Appellants assert that the Mixture meets this definition because cultured MSCs are a component of the FDA-approved drug Carticel.”

But even if that were the case, the court said it would not be enough to meet the law. “To qualify as a ‘bulk drug substance,’ an item must be ‘represented for use in a drug, and appellants point to no evidence in the record even suggesting that MSCs are held out for use in Carticel. Appellants therefore fail to establish that the Mixture is exempt from the FDCA’s manufacturing and labeling requirements.”

Adulterated or Not?

The FDCA provides that a drug “shall be deemed to be adulterated…if…the methods used in, or the facilities or controls used for, its manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with current good manufacturing practice.”

The court concluded, “It is undisputed that appellants’ facilities, methods, and controls for processing the Mixture violated federal manufacturing standards in numerous respects. Therefore, the Mixture is per se adulterated, regardless of any other safety protocols appellants happen to use.”

Civics Lesson

Is this the end of a very expensive civics lesson for Dr. Centeno? The court’s ruling is still open to interpretation but initial word coming from the Centeno team is that they will not appeal any further. If this is the end of the legal fight, then perhaps it becomes a civics lesson. The courts, after all, only interpret the law, not make it. The court was very clear that they were not interested in making law in this case and that if a remedy exists, it lies with lawmakers in Congress.

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