In 2003, I did my first stem cell case, and it was, as far as I know, the first time the Feds investigated a physician for the clinical use of stem cells. Mitch Ghen had treated a couple of dozen ALS patients with umbilical cord blood. He obtained the material from a Florida cord blood bank. The Feds found out and were not happy. So a half dozen agents raided his clinic in 2003.  After the raid, they threatened to indict the Florida cord blood bank unless it stopped selling Mitch cord blood. It did and that pretty much put Mitch out of the stem cell business. The Feds kept investigating Mitch; calling his patients and former employees all to try to build a case against him. They wanted him to plead to a few minor felonies with probably only a scant few years of actual jail time. I made my arguments and we went round-and-round. In law, sometimes you have to know when to holdem and know when to foldem.  I advised Mitch not to plead guilty to anything. He followed my advice. After more saber rattling, the Feds backed down and moved on to some easier targets. Mitch learned his lesson and his next forays into allogenic (other people’s) stem cell therapy were done abroad. Since that time, it has been clear that allogenic stem cell transplants can only be performed under FDA approved clinical trials. (Galileo’s Lawyer contains a chapter on Mitch Ghen and his run-in with the FDA.  http://www.amazon.com/Galileos-Lawyer-Alternative-Complementary-Experimental/dp/0980118301

However, the allure of stem cells was irresistible to many medical mavericks and they started thinking about autologous stem cell transplants. This had been done legally for decades as part of oncology procedures (bone marrow/stem cell recovery as part of high dose chemotherapy) and other reasons. They focused on the extraction of mesenchymal cells from fat, maybe because it was relatively easy to remove belly fat and liposuction was common and safe. There were various techniques for separating the mesenchymal stem cells from the fat, some chemical and some mechanical via centrifuge.

I believe I wrote the first opinion clearing the use of these cells for transplant in US patients. But there was a rub or a couple rubs. First, the removal and reinjection of the material has to take place during the “same surgical procedure.” But back then, there were no guidelines as to what that meant. There were noises about “homologous,” use, meaning for the same type of thing the cell was made for. But that was also vague (or vague enough for me) and that the material couldn’t be materially altered, or in FDA parlance, the cells couldn’t be “more than minimally manipulated.” Back then, separation either by physical or chemical means was not considered “more than minimally manipulated,” at least by me because there was no specific language so indicating.  (This exemption from full drug regulation for stem cells and tissue (in FDA parlance “HCT/P’s”) is found at 21 CFR 1271.15.  https://www.law.cornell.edu/cfr/text/21/1271.15).

On the other hand, it seemed pretty clear to me (and I assume to others knowledgeable in the field) that the one thing stem cell transplanters couldn’t do was culture stem cells because of two of the above FDA restrictions: First, expanding the original cells over many days or weeks sure seemed like the original cells were being “more than minimally manipulated.”   Second, it would be hard to argue that reinjecting all those expanded cells a week or two after removal was during the same surgical procedure.

By the late mid to late 2000’s stem cells became a big thing.  Of course, there were many clinical studies, but the private clinical practice of stem cells really took off. Organizations like A4M were doing modules and training on clinical stem cell use. All kinds of physicians were offering stem cell treatment for many medical conditions, especially muscle, joint and ligament problems. Even then Texas Governor Rick Perry received stem cell treatment, illegally I might add, as his cells were expanded.

And the clinics kept pushing the envelope.  The folks who (in my view) pushed it too far was the Colorado clinic (Regenerative Sciences) that treated orthopedic patients with cultured stem cells.

That was a bridge too far. The FDA had enough of the Wild West stem cell medicine business. The proponents made too many unsubstantiated claims and were using stem cells as therapeutic drugs without going through the FDA drug testing program (INDs or Investigational New Drug Applications).

In 2008 the FDA sent Regenerative Sciences a warning letter telling the company that what it was doing was illegal. Specifically, it was violating the FDA drug trifecta: the material was an unapproved new drug, it was misbranded and adulterated. The Feds also had problems with the company’s non-compliance with cGMP standards.  http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/ComplianceActivities/Enforcement/UntitledLetters/ucm091991.htm

Yes, the material started out and ended up as the person’s own stem cells (the new ones were daughter cells), and yes the original cells were originally part of the person’s body.  So how could that material be a drug?   Logic is logic, and fair is fair, but FDA law and regulations have a logic unto itself, and as unintuitive as it seemed, under FDA law, something that was literally removed from a person’s body could be converted by regulatory definitional magic into an adulterated, misbranded, unapproved and legally dangerous new drug.

The Company had two arguments. First, the FDA didn’t have jurisdiction over the practice of medicine because only the states can regulate medical practice. Second, the company argued that there was no jurisdiction because the treatment was given in Colorado, so there was no interstate commerce which is a requisite for the FDA to act.

After receiving the warning letter which told the company to stop violating federal law, it followed the usually wise precept that the best defense is offense. The company sued the FDA in Colorado federal court for declaratory and injunctive relief using the two argument.

What did the court say about these arguments?  Nothing. The court only decided that the company didn’t have a right to bring a lawsuit. And herein lies the unfair federal government sleight-of-hand. Even though the FDA told the company that what it were doing was illegal; the feds did it via a “warning letter.” In a move only a regulator would have the temerity to concoct, the feds argued that a warning letter is not “final agency action” and “confers no rights.” It’s just the agency’s current informal thinking on the matter, and that the agency’s thinking could change. The federal courts have accepted this nonsense before, and the Colorado district court did so in this case. So like in other cases, the judge dismissed the company’s lawsuit on jurisdictional grounds.

But the FDA didn’t change its mind, it just wanted to have the case heard in the DC circuit. It didn’t take the FDA long to file an action against the company in DC federal court, seeking basically the opposite of what the company sought, a declaration that what the company was doing was illegal and an injunction stopping the treatment.  But this time the FDA was the plaintiff and the case was in the court which spends much of its time on administrative law cases.

Litigating in court against an administrative agency is sometimes a frustrating exercise. In a regular civil or criminal case, the judge decides the law and how it is interpreted. This gives both parties an equal shot at convincing the judge what a law means. It doesn’t work that way when one of the parties is an administrative agency. Both federal and state courts stack the deck in the agency’s favor in a variety of ways. One way is that when an agency is a party and the case involves the interpretation of a statute or regulation which the agency oversees or enforces, the judge does not have the latitude to make independent and neutral rulings concerning the meaning or interpretation of the statutes or rules. Instead, an administrative agency’s interpretation of its own statute and rules is given deference (The Feds call it the Chevron doctrine). Unless an agency’s interpretation is self-contradictory, makes no sense or is irrational, the agency’s interpretation of its laws and rules will be followed by the court.

This sort of takes the desire out of litigating against an agency, which is probably the point or goal.  Long story short, the district court agreed with the FDA on basically everything and entered an injunction against the clinic barring it from doing the procedure. The judge’s decision was affirmed on appeal by the DC Court of Appeals.https://www.cadc.uscourts.gov/internet/opinions.nsf/947528CDDA0B9A5A85257C7500533DF4/$file/12-5254-1478137.pdf

Enough is enough

The FDA had enough of the autologous clinical stem cell transplanters, so they did what comes naturally to regulators, they (belatedly) asserted jurisdiction and regulated the stem cell clinics, which in all practicality means the Feds are trying to put a stop to the therapeutic use of autologous stem cell transplant outside of clinical trials. They did it (or are in the process of doing it) via two administrative vehicles, warning letters and industry guidance documents.

In 2012, the FDA sent a warning letter to a New York company extracting stem cells (stromal vascular fraction) from fat and promoting their use for a wide variety of medical conditions.http://www.fda.gov/iceci/enforcementactions/warningletters/2012/ucm297245.htm).

In December 2015, the FDA sent a similar warning letter to a physician doing the same things in California and Florida. http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2015/ucm479837.htm

Same basic contention/finding in both instances: the cells were an unapproved new drug because the use was not homologous, the cells were more than manipulated (“your processing alters the original relevant characteristics of the adipose tissue” yada, yada) and of course the obligatory cGMP (current good manufacturing procedures) violations relating to the manufacture of the material.

Apart from lobbing warning letters at the unlucky who hit its radar screen, between late 2014 and 2015, the FDA also circulated specific draft industry guideline documents on the key regulatory points, basically making formal the principles and interpretations of the regulations set forth in the warning letters. Thus, there are draft guidelines on:

What constitutes the same surgical procedure.http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Tissue/UCM419926.pdf

What is a homologous use of stem cells. (not much)http://www.fda.gov/downloads/biologicsbloodvaccines/guidancecomplianceregulatoryinformation/guidances/tissue/ucm469751.pdf

And most importantly, what constitutes more than minimal manipulation. This was the biggest blow since the FDA is taking the position (or trying to) that separating the stem cell from its fat structure is more than minimal manipulation, and this pretty much kills the whole therapeutic use of stem cells outside of clinical trials, at least according to the FDA. http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/ucm427692.htm

And in case the adipose stem cell transplanters had any doubts that the FDA  were serious about stopping all the fat-based stem cell therapeutics, the FDA even put out a draft guidance specifically on   HCT/P’s from adipose tissue. http://www.fda.gov/biologicsbloodvaccines/guidancecomplianceregulatoryinformation/guidances/tissue/ucm427795.htm

Note, these are just “draft” guidelines (“guidance documents”). Under the arcane rules of administrative agencies, the agency publishes draft guidances and the public gets to comment on them.  Then there is public hearing where stakeholders can comment to the agency face-to-face. The public hearing on these guidance documents was set for April 2016, but the FDA adjourned the hearing because of the intense public reaction to the guidelines. Supposedly the FDA wanted to give more time for stakeholders to comment. We’ll see, and we’ll also see if the public hearing will be longer than the one day previously scheduled.  The FDA received over seventy written comments about these guidelines so far.  But don’t count on the FDA changing its mind, on any of the big issues anyway. Is it still worth submitting public comments? For sure. You never know. Maybe some congressional muscle might help as well. Ditto for a public ground swell, if such could be managed.

What can stakeholders do if the FDA adopts the draft guidance documents? Not much. But more of that once the guidelines are in final form.  More to come.

 

Rick Jaffe Esq.