US vs Regenerative Sciences Comes to End

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A court case we blogged a fair amount about even before it started (see the first post in 2008) appears to have finally come to an end in the DC Circuit Court's decision to uphold the ruling in favor of the FDA.

United States Court of Appeals 
FOR THE DISTRICT OF COLUMBIA CIRCUIT 

Decided February 4, 2014 

No. 12-5254 

UNITED STATES OF AMERICA, 
APPELLEE 

v. 

REGENERATIVE SCIENCES, LLC, A CORPORATION, ET AL., 
APPELLANTS 

Appeal from the United States District Court 
for the District of Columbia 
(No. 1:10-cv-01327) 

It has been an interesting ride.  Chris Centeno and his partners (and investors) have been the lightning rod for a lobby and debate around the right way to regulate the use of cells therapeutically - particularly one's one cells.  The arguments became more sophisticated as the case wore on and, as so often happens, the ground shifted considerably while the case was ongoing.  The case and Chris Centeno's unparalleled commitment to the cause has contributed significantly to a debate that is important to have and I suspect is not over simply because the case is done.

Dr. Centeno and I have had our differences but now is the time to recognize his contributions to the debate and, more importantly, to the field. We look forward to his future contributions to developing robust, cell-based treatments for patients.

FDA 1. RSI 0. Regenerative Sciences (Regenexx) vs FDA (2012)

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As followers of this blog will know I've been blogging about Regenerative Sciences and predicting their eventual run-in with the FDA since my first post in September 2008 (Cell Therapy is Not the Practice of Medicine) and again in February 2009 (Regenexx vs the FDA 2009).  When the FDA finally proceeded with an injunction against RSI in August 2010,I helped spread the news (here).

I've watched the development of the fight between RSI and the FDA with interest.  In September 2001 I posted a rather lengthy commentary about the potential impact of the case (Potential far-reaching implications of the ongoing fight over point-of-care autologous cell therapy.

Since then I have welcomed other bloggers and commentators who are now following and commenting on the case much more closely and frequently than I including @LeighGTurner (on Twitter) and Paul Knoepfler (@PKnoepfler on Twitter and his Knoeplfer Lab Stem Cell Blog).  Recently I enjoyed being interviewed by Paul on the issue of unregulated stem cell activity and touched on the case for his blog.

Consequently I read with interest yesterday's federal court ruling upholding the FDA's injunction against RSI and the immediate commentary from the New Scientist, Stanford's Scope Blog and Knopfler's multiple posts (here and here). As a long-term follower of this case, I've been asked to comment.  Here is my brief reaction:

This is a case that was always destined for the appellate courts regardless of which way the initial court ruled.    The fact the federal court ruled in the FDA's favor certainly now sets the onus on RSI and what is anticipated to be a gamut of intervenors but taking this case to the appellate courts is what the legal team have anticipated and legal arguments designed for all along.

This is just the beginning of what will be a long and interesting battle.  The ruling was nothing more than the granting of an injunction in response to the government's motion for summary judgement.  In granting the injunction the court  agreed with the government's position that it was acting under the authority given it under the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. § 321(g) but it provided little-to-no rationale for its ruling.

The court chose, in its wisdom, not to address the bulk of the RSI's legal arguments which are largely jurisdictional in nature. These are the kinds of arguments which the lower courts prefer be dealt with by appellate courts and frankly the judge did us all a favor by ruling quickly, succinctly and punting the case where we all knew it was inevitably headed.

In my opinion, other than chalking one up in the government's win column there is little to be gleaned from this ruling in terms of how RSI's arguments will be received in appellate court.  The interesting day is yet to come.

In terms of a short-term practical impact, frankly I see very little.  RSI has already ceased distributing Regenexx within the US so there will be little-to-no impact there.  As for the potential impact on other companies or clinics who might be operating on the fringes of FDA regulation within the US, I suspect it will be business as usual.

Most of the clinics/companies offering cell-based treatments/products which are arguably in contravention of FDA regulation are operating under the clear knowledge of what they are doing and where the FDA stands with respect to the treatments/products they offer and yet they persist and continue.


 For the truly fraudulent there is the risk of criminal charges and/or litigation but for those companies or practitioners who are operating in this shade of grey which are not shady (and they do exist), the  risks associated with this practice are barely higher than in the routine practice of medicine. 


In reality, with the exception of the most fraudulent examples, it takes a fair long-time for the FDA to catch up with these folks and there is good money to be made in the interim.  When they get caught, they will stop. If they've recouped their initial investment (which is nominal and the margins are high) there is very little penalty to this course of action.  Perhaps they set up shot elsewhere or simply enjoy the proceeds.  I doubt we will see much of a slow-down of this kind of activity.  Indeed it may strengthen the resolve of those committed to the cause.

In my opinion yesterday's ruling was in interesting and important milestone in a continuing evolution in the debate of how best to regulate the use of cells in treating people but I'm not sure it's the seminal pivot point that some believe.  I suspect we will not see any radical shift in terms of FDA or industry activity until (if then) the appellate courts rule.

Just my two cents....

--Lee

Potential far-reaching implications of the ongoing fight over point-of-care autologous cell therapy

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The FDA recently issued an untitled letter to Parcell Laboratories and its contract manufacturing organization, New England Cryogenic Center (NECC), pertaining to the product PureGen™ Osteoprogenitor Cell Allograft intended for the "repair, replacement, reconstruction of musculoskeletal defects". The letter stated:

"The PureGen™ Osteoprogenitor Cell Allograft is not the subject of an approved biologics license application (BLA) nor is there an IND in effect. Based on this information, we have determined that your actions have violated the Act and the PHS Act."

This would appear to be an indicator that the FDA does not intend to relax enforcement of its view of how autologous cell therapies are to be regulated despite its ongoing litigation on this very subject with RSI.

As followers of this blog know, since the battle's inception in 2008 I have followed the case of Regenerative Sciences, Inc and their war with the FDA over their right to provide certain autologous cell therapy treatments to patients in certain circumstances without FDA approval. My first blog entry on the topic was in September 2008 in which I pointed out that the FDA had written a letter to RSI that July taking issue with some of their practices.

My next blog on the subject was February 2009 in which I concluded "I think the FDA is building its case and a showdown is on its way to Denver-town."

At the advice of legal counsel, I pointed out in a March 2010 blog entry that my reference to FDA's July 2008 letter to RSI was not officially a "warning letter" as that is defined and as I had referred to it but rather an "untitled letter". I also commented that FDA's lack of enforcement action against RSI to-date was emboldening medical practitioners into thinking FDA was reconsidering their position on the legality of providing autologous, expanded cells to patients outside of an FDA-cleared IND or BLA.

I took some satisfaction in announcing on my blog in August 2010 that the FDA had finally taken action against RSI. My satisfaction was not rooted in a belief that the FDA is right (I've always been agnostic as to which side is right) but in the sense that things had occurred as I had predicted they would.

The action the FDA chose to take against RSI was to seek an injunction against RSI from continuing to provide the "offending" treatment - a version of the Regenexx™ procedure using mesenchymal stem cells (“MSCs”) grown outside the body after harvest for the later infusion back into the donor-patient for the treatment of various orthopedic conditions - which the FDA alleges is a "product" falling under its regulatory authority but for which RSI has never received any FDA clearance to provide to patients.

RSI counterclaimed against the United States, challenging the FDA’s authority to regulate the Regenexx™ Procedure in question and challenging certain FDA regulations. The United States moved to dismiss Defendants’counterclaims and for summary judgment.

I have continued to follow the case relatively closely through a number of source (see this sample media coverage in OthosSpineNews) as it continued to progress. Last month, for example, a blog I follow posted an eloquent case in support of RSI's position with the help of Mary Ann Chirba, J.D., D.Sc., M.P.H. of Boston College Law School.

So it was with much interest that I was recently notified of an order issued by the court which appears to have the potential to take the case in a very unexpected direction with enormous potential ramifications.

The context is that the judge was reviewing the FDA's motion for summary judgment, RSI's response, and FDA's reply when the judge issued this order to show cause.

At its essence the Judge has ordered the FDA to file a brief no later than 26 September showing the court why the term “chemical action” applies to stem cells. It is is a short Order the core of which reads as follows:

The Government finds its definition for a “drug” in the FDCA: “The term ‘drug’means . . . articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals” and “articles (other than food) intended to affect the structure or any function of the body of man or other animals.” 21 U.S.C. § 321(g)(1)(B)&(C).

This definition, at least as to subsection (C), would be broad enough to encompass a boot on a patient’s ankle to hold it secure after ankle surgery. The Court doubts that was Congress’s intent.

Neither party references the definition for “device,” found in the statute at 21 U.S.C. § 321(h). A “device,” is a certain kind of “article” used in diagnosis, cure, mitigation, treatment or prevention of disease, 21 U.S.C. § 321(h)(2), but which, presumably unlike a drug, “does not achieve its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of its primary intended purposes.” 21 U.S.C. § 321(h).

These contrasting definitions immediately raise the question of why the Court should not interpret the meaning of the word “drug” to include not only an article for use in diagnosis, etc., and intended to affect the structure or function of a patient, but also an article that “achieve[s] its primary intended purposes through chemical action” and which is “dependent upon being metabolized for the achievement of its primary intended purposes.” Id.

The United States is ORDERED TO SHOW CAUSE why the Court should not read the definition of “device” at 21 U.S.C. § 321(h) as informing and restricting the definition of “drug” at 21 U.S.C. § 321(g)(1)(B)&(C).

It will be most curious to see how the FDA argues out of the corner that many believe the Judge has painted the agency. The FDA recently defined “chemical action” in its draft "Guidance for Industry and FDA Staff: Interpretation of the Term “Chemical Action” in the Definition of Device under Section 201(h)of the Federal Food, Drug, and Cosmetic Act". What is curiously absent from the document is any mention of cells or HCT/P’s despite CBER’s approval stamp on the document.

Another line of argument centers around whether cells - notably 'stem' cells - are “metabolized" as that term is defind.

If one extrapolates the ramifications of where the court appears to be currently leaning, the implications of this judgment may have far-reaching implications for biologics in general well beyond cell therapy and certainly well beyond autologous cell therapy.

As some quite logically argue, one potential scenario is that this judge rules all biologics fail to fall within the legislative "drug" definition. The argument goes like this. The drug regulations live under title 21, which has narrow definitions for what constitutes a drug. The FDA’s authority over biologics comes from title 42, which is merely to control communicable disease transmission in transplants, with no authority to take the drug provisions from title 21 and apply them to title 42. So the agency is risking a loss of control over all biologics.

What’s curious here - and perhaps somewhat ironic for RSI at this stage - is that they only ever set out to challenge their ability to regulate autologous cells used by a physician as part of his or her medical practice yet now the FDA's authority to govern all biologics is currently under question.

The fact that I cannot fathom the courts striking FDA's jurisdiction over all biologics when the dust settles on this case does not make the arguments any less compelling and it does leave open the possibility that a lower court Judge such as the one presiding over this case may be inclined to make a ruling which essentially ensures the issues are punted to the appellate courts for a more considered ruling. In such circumstances, even if the FDA were to prevail at the end of the day (perhaps a decade down road) the uncertainty such a ruling would rain down on the sector would be commercially stifling - even if if were just limited to autologous cell therapy let alone if were any broader.

My dated and unpolished law degree can only take this analysis so far and anyone interested in some further but delightfully light and practical reading on the potential ramifications of the case could do no better than read a paper published recently by the relevant practice groups at the law firm K&L Gates entitled "Cultured Stem Cells for Autologous Use:Practice of Medicine or FDA Regulated Drug and Biological Product in which they review the case and its potential implications - the latter of which the authors are not guilty of underestimating in the following concluding sentence of their analysis:

The court’s decision will, to a large degree, dictate the types of legal strategies and business models that will be necessary to successfully perform stem cell procedures in the future.

_____________

post-script: The potential stink of commercial uncertainty wafting from this case is even more egregious when combined with the uncertainty around what to expect from the FDA in its much-anticipated and typically overdue guidance on adipose-derived cell therapies.

Rumor has it that the FDA is leaning toward considering most (if not all) means of deriving cell populations from adipose tissue (typically lipoaspirate) to be governed as what we colloquially refer to as a '351' thus taking it out of the purview of the practicing physician and into the hands of companies prepared to follow the traditional "drug development' model for new medicines. The rationale here is that the mechanical and/or enzymatic digestion required to separate the desired cell populations from the stroma take the process beyond "minimal manipulation'.

Watch for this guidance from CBER OCTGT in the weeks to come and/or any relevant rulings by the Tissue Reference Group. This would be a serious blow to those building business models around point-of-care, autologous adipose-derived cell therapy treatments.

What makes this even more interesting is the pace of which US-based medical practitioners (and/or companies supporting them) are adopting and selling autologous cell-based products, services and/or treatments for sundry indications in ways which many would argue are apparently in obvious and flagrant disregard for the FDA's regulatory authority over such treatments. Included for consideration on such a list would be the following:

IntelliCell Biosceinces

eternaMD

Arizona Stem Cell Center

.

FDA files injunction again Regenerative Sciences citing Regenexx violates regulations

For those of you who follow this blog, you'll imagine my surprise to wake up the morning to the following announcement from the FDA:

_____________________________________________________________

FDA NEWS RELEASE

For Immediate Release: August 6, 2010

Media Inquiries: Shelly Burgess, 301-796-4651, shelly.burgess@fda.hhs.gov

Consumer Inquiries: 888-INFO-FDA

FDA Seeks Injunction Against Colorado Manufacturer of Cultured Cell Product

Violations of current good manufacturing practice and labeling requirements cited

The U.S. Food and Drug Administration is seeking an injunction in federal court against Regenerative Sciences LLC, of Broomfield, Colo., citing violations of current good manufacturing practice (cGMP) that cause its cultured cell product to be adulterated. The product is also misbranded due to the lack of adequate directions for use and the failure to bear the “Rx only” symbol.

The company’s cultured cell product is derived from a patient’s bone marrow or fluid surrounding the patient’s joints (synovial fluid). The cells are grown, processed, and mixed with drug products outside the body before being injected back into the patient.

Regenerative Sciences’ cultured cell product is not approved by the FDA, and no adequate and well-controlled studies have been done to demonstrate its safety or effectiveness for any indication.

“FDA recognizes the importance of the development of novel and promising new therapies,” said Karen Midthun, M.D., acting director of FDA’s Center for Biologics Evaluation and Research. “However, when companies like Regenerative Sciences fail to comply with FDA laws and regulations, they put the public’s health at risk.”

The complaint for the injunction was filed Aug. 6, 2010, by the Justice Department on behalf of the FDA in the U.S. District Court for the District of Columbia, against Regenerative Sciences and three of its employees, Christopher J. Centeno, M.D., John R. Schultz, M.D., and Michelle R. Cheever. The injunction would permanently prevent the company and cited individuals from adulterating and misbranding the cultured cell product while the product, or one or more of its components, is held for sale after shipment in interstate commerce.

Regenerative Sciences has agreed to cease production of the cultured cell product while the case is pending.

The FDA warned Regenerative Sciences about its cGMP violations as recently as June 2010. The company failed to make sufficient corrections, and the conduct of the individuals cited in the complaint demonstrates refusal to comply with the law.

Regenexx vs the FDA 2009

Last year I blogged a couple times about Dr. Christopher "the renegade" Centeno from Regenerative Sciences, Inc (aka "Regenexx"). He's in Colorado collecting, growing, and re-administering stem cells for now a growing list of orthopedic-related conditions.

As previously discussed on this blog, FDA CBER's Mary Malarkey sent a warning letter in July 2008 to Dr. Christopher J. Centeno, Medical Director of Regenerative Sciences, Inc (RSI), doing business as Regenexx. The company responded on its website that they do not fall under FDA jurisdiction. One of the reasons cited is that their entire procedure occurs within the state ergo no interstate commerce ergo no federal jurisdiction.

The good doctor (aka @stemcelldoc on Twitter) is not only rapidly expanding the indications for which he'll pump you up with stem cells, he is really ramping up his marketing. He is actively promoting his services on the internet (blogging, a Twitter stream, etc) encouraging people to come from all over god's green earth to visit Colorado and get shot up with a dose of their own stem cells.

Now I know that archaic legal paradigms weren't designed for this new-fangled world but according to a good ole fashioned sniff test many would say that smells a lot like interstate commerce to them.

This is not a critique of the Regenexx therapy, Dr. Centeno, or the company. I'm not saying the Regenexx therapy doesn't work. I'm betting it does. I'm not saying I wouldn't be tempted to go if I had joint problems. I likely would. I'm not saying what they're doing is wrong or even illegal - sometimes it takes a gutsy cowboy/girl or two to change the rules for good. BUT if the FDA lets this happen in Colorado it seems to me a slippery slope to letting all autologous cell therapies go unregulated. And I don't see that happening any time soon.

Rumor has it Regenexx is planning to open a new clinic in Florida. There's the slope in clear sight.

On other fronts, there have been reports of the Regenexx therapy being reimbursed by at least one insurer. Aside from the FDA, this is quickly gaining all the hallmarks of a legitimate medical procedure. As of November, they had performed 250 procedures.

In September last year Dr. Centeno posted on an online discussion board:, "To set the record straight, we have been working with regulatory council for 3 years on our needle based, surgical procedure. We have responded to the FDA unititled [sp]letter and we believe we have answered all of their questions. This is a surgical procedure and not a new biologic drug. We have been communicating with the FDA and they have had no response, so we assume that we have answered their questions."

The FDA may not have any more questions but unfortunately I doubt that ends the issue.

Interstate commerce aside, Regenexx appears to be manufacturing a biological therapeutic. While they appear to have taken references to cell expansion or manipulation off their website, according to a recent blogger allegedly quoting from a letter from the company, the stem cells are collected, expanded (at minimum) and reinjected. The letter apparently stated: "The procedure involves drawing our patient’s blood and bone marrow, growing their stem cells in our laboratory for approximately 3 weeks and then injecting the stem cells into the affected joint".

If this is true, it seems to me this is not just a doctor doing his doctor thing and the big, bad FDA should let a doc be a doc. This would be a doctor manufacturing a biologic without any of the manufacturing controls created by regulatory agencies and industry to keep such things safe - safe, for instance, from contamination.

If there are no such controls in place god only knows what kind of back-alley operations might come to town selling stem cells from basement labs. It is not far-fetched. If this is allowed to continue, other docs will get in this business. Some will decide they just want to run the clinic not grow the cells. They outsource that to company X which is being run by some half-baked science dropout who decided this is probly better money than making meth so let's start a stem cell grow-op! Ok, that's the extreme but you see my point.

I've got a lot of sympathy for people who push against the rules. I believe Dr. Centeno and his company are doing what they believe is right and I'm sure they are doing everything they can to ensure their product is safe and efficacious. I also believe that in years to come we may well be comfortable enough with these types of products that this may well be as commonplace as Dr. Centeno would have it but I don't think it will be in his lifetime. At least not in the US. I kinda hope I'm wrong.

We can't simply let the market decide which therapies will succeed. We need a minimum level of safety assurance and oversight by an agency like the FDA and without any controls how long is it before someone perhaps not as diligent or trained as Dr. Centeno makes a product that does more harm than good?

I think the FDA is building its case and a showdown is on it's way to Denver-town.

Cell therapy is not the practice of medicine

I have several doctor friends who in the early days of cell therapy years ago argued that autologous cell therapies should be considered the practice of medicine - like stem cell transplants - and not require regulatory approval like drugs or devices. Indeed some of the motivation for the creation of industry self-accreditation bodies like FACT was to attempt to convince regulatory agencies that cell therapy products were best regulated by medical industry bodies. The FDA and other regulatory agencies were engaged in this discussion - they heard, they listened...and in large part they disagreed. My doctor friends came to grips with that reality and worked with the FDA to help create a regulatory framework that they now work within.

Even under the strictest regulatory frameworks there are some types of products which do not require formal approval. This blog will not be an overview of the regulatory distinctions between - for instance - s.351 and s.361 products (per FDA) but suffice it to say the differences between the products which do and do not require formal approval are, by now, fairly well defined in both US and Europe (albeit the latter only more recently). Furthermore, the regulatory agencies are eager to engage in dialogue with anyone who has questions about the proper regulatory pathway for their product.

And yet...there are those even now in the US and Europe who attempt to skirt the regulatory framework by conducting unauthorized and/or non-compliant clinical research and/or offering for sale commercial products without regulatory approval despite them falling clearly under the rubric of the regulatory requirements that such products be approved for such purposes.

It's one thing to be offering clinical products in unregulated markets that would would be or are regulated in other markets. I've previously opined here about the medical tourism industry and the issues it raises. But trying to conduct clinical research or sell clinical therapies that are not approved, in markets where there are clear rules governing the authorization to do so? Really?

Regrettably, yes. Two recent examples are described below. I'm not here to cast aspersions, don't want to spark any skirmishes, and certainly have no basis for suggesting impropriety on the part of those involved in these examples. I refer to these examples because they are recent, part of the public record, and, in my opinion, exemplify actions which should justifiably be called out and discouraged (if not penalized).

1. The first example comes out of Europe as described in recent reports in Science, MedPage Today, etc where the Lancet recently retracts a published article stating "... the editors rejected Dr. Strasser's assertion that products of tissue engineering are not medical products and therefore not subject to the Good Clinical Practice requirements."

Following is the report from MedPage Today (5 Sept 2008) :


Lancet Retratct Article on Incontinence Cell Therapy - Free Legal Forms

2. The second example comes from the US. Below is a copy of a recent letter sent to Regenerative Sciences, Inc (doing business as Regenexx) by the FDA .


FDA Warning Letter to Regenexx (Regenerative Sciences Inc - RSI) - Free Legal Forms

There are only three possible explanations I can come up with for why anyone would act as these two teams of people have done in clear contravention of the guidelines regulating their actions: (a) they simply don't understand, (b) they are looking to wage a fight or make a point, and/or (c) they believe their license to practice medicine supersedes regulatory authority (an argument long-ago tried, tested, and proven a loser). None of those reasons are justifiable in the circumstances.


In some instances, those who push the envelope help to shift the paradigm and improve the system they buck against. Even civil disobedience can - at least in retrospect - be occasionally justified if not even heralded as the impetus for positive change. This is not that.

This is playing with people's lives in clear contravention of the rules. That's not to say the FDA always has it right or that there are not issues to discuss or changes to make. The fact that neither of these treatments appear to pose any real risk to patient safety is certainly part of the argument for relaxed regulatory controls - I understand. But does that justify flagrant contravention of the guidelines as they exist using patients as pawns in the argument?

There are other ways to make this case. Go to a jurisdiction where the treatment is permitted, employ patient groups to lobby or litigate, engage industry and FDA in discussions to affect change in the regulatory regime.

Dear Doctor. The fact these therapies may be relatively harmless is no excuse for acting outside the regulatory framework and guidelines created to protect those people you're treating - agree with it or not, like it or not. Thanks.

--Lee