During the nearly four weeks that this blog was in limbo, as in the wake of Scienceblogs’ informing me that it was shutting down I was frantically trying to transfer nearly 12 years worth of content to a new host, a lot of things happened that I normally would have blogged about but didn’t. One of those things was that the FDA started to show some signs that it might actually do something that it should have done many years ago and crack down on dubious stem cell clinics. Actually, indications that the FDA had finally been moved to action by the egregious flouting of science and the law in the service of making money dated back before my enforced hiatus. Some of the offenses that might have pushed the FDA to action included abuses by a company called Stemedica exploiting the desperation of hockey legend Gordie Howe’s family in the wake of his stroke, stories about the dangers of stem cell tourism and how we have plenty of quack stem cell clinics right here in the USA, how they’re using hard sell techniques to promote unproven therapies, and how they’ve even started to emulate cancer quack Stanislaw Burzynski by charging patients to be on scientifically dubious clinical trials.
So back in August, I took note of an FDA news release FDA warns US Stem Cell Clinic of significant deviations, which provoked some news stories about the FDA cracking down on dubious (and unscrupulous) stem cell clinics:
The Food and Drug Administration announced a crackdown on dangerous stem cell clinics on Monday, while at the same time pledging to ease the path to approval for companies and doctors with legitimate treatments in the growing field.
The agency reported actions against two large stem cell clinics and a biotech company, saying that it was critical to shut down “unscrupulous actors” in regenerative medicine, a broad umbrella that includes stem cell and gene therapies and immunotherapies.
“The F.D.A. will not allow deceitful actors to take advantage of vulnerable patients by purporting to have treatments or cures for serious diseases without any proof that they actually work,” said Dr. Scott Gottlieb, the F.D.A. commissioner.
I had my doubts about Scott Gottlieb, and, quite frankly, I still do, but his actions with respect to dubious stem cell clinics have been a good first step. Don’t get me wrong, I’m still suspicious of his ideological drive to loosen drug approval standards, but at least he’s trying to get it right here. Indeed, the FDA letter to US Stem Cell Clinic in Sunrise, Florida is brutal. The clinic claimed that its stem cell produce could be used to treat Parkinson’s disease, amyotrophic lateral sclerosis, chronic obstructive pulmonary disease, heart disease, pulmonary fibrosis, Crohn’s disease, lupus, and diabetes. Of course, this is just one example, I’ve been writing extensively over the last couple of years how unscrupulous many of these stem cell clinics are and just how much they are quackery. Let’s just put it this way. If naturopaths are starting their own stem cell clinics, you know there’s a serious quackery problem.
I knew the doctors running quack stem cell clinics were worried. I could tell by a post by Stanislaw Burzynski’s former lawyer, Richard Jaffe, on his blog. Jaffe, you’ll recall, is basically the lawyer to the quacks, so to speak, and was the architect of Burzynski’s plan to get around FDA regulation through 70+ dubious and scientifically worthless clinical trials. Jaffe observed:
In late August, the FDA issued a trilogy of pubic actions and announcements advancing its goal of shutting down what I’ll call the practice of medicine stem cell clinics (“POM”). These clinics provide autologous stem cells and other autologous tissue or tissue based products which have not been approved by the FDA. These clinics have exploded in popularity over the past dozen years, which has caused the FDA and the stem cell institutional players much angst. The FDA’s efforts to close these clinics started a couple years ago when it sent warning letters and issued four draft stem cell guidance documents which, if followed, would all but eliminate the ability of patients to use their own stem cells for therapeutic purposes.
Gee. He wrote that as though it would be a bad thing.
Last week, the FDA finally issued its draft guidance on stem cell therapies, Human Cell, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use, as well as another guidance entitled Same Surgical Procedure Exception under 21 CFR 1271.15(b): Questions and Answers Regarding the Scope of the Exception. The intent is to clarify regulations with respect to “human cells, tissues, and cellular and tissue-based products” (HCT/P).
There are two issues relevant to stem cell “medicine” in these guidelines. The first is: How much are the cells manipulated? In other words, what constitutes “minimal manipulation.” Basically, the FDA has in the past ruled that autologous products, like blood transfusions, are not drugs, at least not in the same sense that other drugs are. The same is true of autologous tissue removed from the body and reimplanted elsewhere, as plastic surgeons do when they do liposuction and use the fat to sculpt the body elsewhere or, in fact, when surgeons remove a flap of muscle and reimplant it elsewhere or resect a section of bowel and sew it to somewhere else in the digestive tract (something general surgeons do all the time). Considering such autologous products to be drugs that need to be regulated would interfere with surgery and a lot of other well-accepted medical procedures. However, it’s different if the products are manipulated or changed somehow. Traditionally, the FDA has said that “minimal manipulation” of such products is acceptable; more than that and you’re looking at a drug or a product that needs to be regulated. The problem is that what constitutes “minimal manipulation” has never really been well-defined.
Second, is the use homologous or not? Homologous use basically involves using a like product only to treat a like tissue or organ (i.e., fat to treat fat; skin to treat skin; blood for blood or immune cells; etc.). Non-homologous use involves using HCT/P to treat organs not related to their origin or to carry out biological functions that they don’t normally do.
I’m going to deal with the second issue first because it is how stem cell clinics market their products. Here’s the sentence that most alarms Jaffe and that I find most promising. I include Jaffe’s commentary, because it explains quite well why this is one area where the FDA probably got it right:
If there is one sentence in the FDA guidance document which sums up the FDA’s position on the use of HCT/P’s by the heretofore unregulated clinics, this is it:
“If an HCT/P is intended for use as an unproven treatment for a myriad of diseases or conditions, the HCT/P is likely not intended for homologous use only.” (Page 15 of “Regulatory Considerations for Human Cell, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use”, here is the link again: https://pactgroup.net/system/files/GD_HCTs_20171116_UCM585403.pdf )
To remind you, if the use is non-homologous, (meaning not the same function as from where the HCT/P derived), it’s a drug, requiring the IND/NDA path, and the non-homologous use of which is a violation of the regulation, the law which leads to bad things.
Every unregulated stem cell clinic that I am aware of falls within this FDA statement, and I wouldn’t get my hopes up based on the FDA’s “likely” qualification. If you’re using an HCT/P to cure a disease and it’s not something like hematopoietic cells or bone marrow for blood conditions, blood related cancers, or immune system issues, your use is non-homologous according the guidance documents (draft and final).
Again, Mr. Jaffe says this as though it were a bad thing. Clearly, the FDA is targeting quack stem cell clinics of the very type that Mr. Jaffe defends, which is why Jaffe is so alarmed. (One can’t help but wonder, though, if he isn’t secretly happy, anticipating all the fees he can collect from stem cell clinic owners who find themselves targeted by the FDA under its new interpretation of the existing regulations.) These are the clinics whose websites claim they can cure autism, Alzheimer’s disease, diabetes, cancer, and a huge variety of diseases unrelated to the stem cells being used. I also at this point can’t help but point out that these clinics do this without anything resembling high quality evidence that their treatments can do what they claim, as in randomized clinical trials. I’ve documented over the years the special pleading and excuses that owners of these stem cell clinics use to try to explain away their lack of evidence, even as they not infrequently charge more than $10,000 a pop for their unproven treatments.
As for the issue of “minimal manipulation,” stem cell scientist Paul Knoepfler note that the FDA appears to be coming down strongly on the side of ruling that fat stem cells are a drug. Period. The FDA also appears to be assuming that stem cell products are default more than minimally manipulated, without strong evidence and arguments otherwise. Jaffe agrees and is very alarmed:
When is an HCT/P More than Minimally Manipulated? Answer: Every process used on an HCT/P unless there is scientific proof to the contrary
The nastiest thing in the final guidance document is that the FDA has created in effect an irrebuttable presumption that anytime you do anything to an HCT/P, it’s MMM unless there is information that that the process is minimal manipulation, or as the FDA puts it:
“Please note that if information does not exist to show that the processing meets the definition of minimal manipulation, FDA considers the processing of an HCT/P to be “more than minimal manipulation”, (which basically makes the HCT/P a drug)
Even Jaffe agrees that “when you separate the mesenchymal stem cell (“MSC”) from the adipose substrate, that’s MMM, let alone when the MSC is further processed into something like SVF or some other derivative product” but notes that prior to the draft guidance documents and under draft guidances quacks (OK, he didn’t use that word, but I do) were “more or less free to argue that what you were doing to the HCT/P was not changing its relevant characteristics or MMM (more than minimally manipulating it), and then presumably force the FDA to prove that you were.” No more. Now, the quacks have to prove that what they are doing is not “MMM.” Of course, I can’t help but chuckle at the irony. Stem cell clinic quacks attribute all sorts of miraculous healing properties to these stem cells that they claim to isolate. (Again, I’m often…unconvinced… that whatever cells they are claiming to be stem cells are in actuality stem cells.) Yet, they also want you to believe that they are not manipulated and that they are being used for functions in line with their origin.
The FDA regulatory considerations also spend a lot of verbiage discussing stem cells isolated from fat. The reason, of course, is that many stem cell clinics use liposuction to isolate fat, from which many of them isolate the stromal vascular fraction, which is considered a source of adipose-derived stem cells. In essence, any use of fat other than moving it somewhere else to be used to do what fast normally does (fill in tissue, to provide structural form and support), in other words, doing accepted procedures that plastic surgeons do, removing fat from one anatomic location and placing it in another, is considered MMM, requiring full regulatory approval. In essence, isolating the SVF and other fractions from fat is considered a drug manufacturing process and subject to regulatory approval.
Basically, there is an exception for surgery. The FDA states:
In sum, FDA’s view is that autologous cells or tissues that are removed from an individual and implanted into the same individual without intervening processing steps beyond rinsing, cleansing, sizing, or shaping, raise no additional risks of contamination and communicable disease transmission beyond that typically associated with surgery. FDA considers the same surgical procedure exception to be a narrow exception to regulation under Part 1271.
Surgery, ain’t it great? It sure is, as the FDA mentions:
For the purposes of the exception in 21 CFR 1271.15(b), procedures that involve an incision or instrumentation during which an HCT/P is removed from and implanted into the same individual within a single operation performed at the same establishment, are generally considered to be the same surgical procedures. Examples include autologous skin grafting, and coronary artery bypass surgery involving autologous vein or artery grafting.
The new regulatory guidance is not perfect, of course. As Paul Knoepfler notes, there might be a loophole based on the same surgery exception that would allow some clinics to keep doing what they’re doing. Read the whole thing, but basically, homologous use and minimal manipulation are two independent determinations, and, under one interpretation of the FDA guidelines, it would appear that long as HCT/P is not processed beyond rinsing, cleansing, sizing, and shaping, homologous use might not be required to fall within the same surgical procedure exemption.
Unfortunately, there is another issue, too. As is noted in the New York Times regarding sports clinics that use fat-derived cells and frequently inject them into joints:
But the message seemed mixed. Dr. Gottlieb and Dr. Marks also said that orthopedic procedures — injecting the fat-derived cells into joints — were of lower priority than treatments that involved injecting or infusing the cells into the central nervous system or bloodstream.
“There are hundreds and hundreds of these clinics,” Dr. Marks said. “We simply don’t have the bandwidth to go after all of them at once.”
In fact, there are hundreds of stem cell clinics out there, ranging from merely the dubious to quack clinics, as Richard Jaffe notes:
The FDA will continue with the administrative process of the high profile clinics which it has recently targeted. I think it will start the investigatory process with a few other high visibility clinics, as time and person-power permits. This will reinforce the message that the FDA is out there and remind the clinics that what they are doing is illegal (according to the FDA).
It will probably take almost a year or two before there is a judicial decision on the validity or enforceability of the guidance document. A safe bet is that the FDA will bring an injunction action against one of these clinics for not, in effect, closing. Injunction cases are tried to the judge, not a jury.
This is consistent with something I’ve been saying all along. The FDA is woefully underfunded and understaffed for what it is expected to do. Under regulation-averse administrations, this is a feature, not a bug, designed to prevent the FDA from going too strongly against drug companies, but quacks benefit too. It’s a zero sum game. The FDA can’t go after all of the quack stem cell clinics out there, even though it now has better regulatory guidelines to do so.