‘Are fat stem cell clinics selling unapproved drugs?’ reporters ask in talking about our new paper

Our new paper in the journal Cell Stem Cell on the large stem cell clinic marketplace in the U.S. documented a wide range of different kinds of clinics, stem cells used, and conditions claimed to be treated, but here I want to focus on the fat stem cell clinics in this post. I’m going to try to address one of the major questions I’ve been getting in the last few days since our paper came out:

Are some fat stem cell clinics selling unapproved drugs?SVF

Fat stem cell clinics typically sell therapies based on a product extracted from their customers’ fat tissue, even though there’s no conclusive data that these are safe or effective.

Sometimes this liposuction product after further processing is simply called “fat stem cells” or “adipose stem cells”, while other times it goes by the name “stromal vascular fraction” or SVF.

Regardless of what anyone calls it, the adipose cellular product (for simplicity from here on out in this post I’ll call it SVF) is substantially different than the original fat. The FDA calls this kind of significant processing by the name “more than minimal manipulation” and it means that the resulting “stuff” is almost certainly a drug requiring FDA approval before use.

In fact in one of its draft guidances in 2015, the FDA used SVF as an example of what they often are going to define as a more than minimally manipulated drug. Definition of SVF as a drug makes sense to me as a scientist because the process to make it is fairly involved including in most cases an enzymatic treatment (see my illustration above). I’m not aware of fat stem cell clinics having FDA approval to sell SVF. Therefore, in that sense it seems likely the answer to the reporters’ question about the selling of unapproved drugs is often, but not always “yes”.

Here is the actual FDA guidance language, which is as clear as the FDA has ever been on this particular point on SVF as a drug (emphasis mine):

“Example 10-1: Original relevant characteristics of adipose tissue, a structural tissue, to pad and cushion against shocks generally include its bulk and lipid storage capacity. A manufacturer recovers adipose tissue by tumescent liposuction and processes the adipose tissue to isolate cellular components, commonly referred to as stromal vascular fraction, which is considered a potential source of adipose-derived stromal/stem cells. The HCT/P generally is considered more than minimally manipulated because the processing breaks down and eliminates the structural components that provide cushioning and support, thereby altering the original relevant characteristics of the HCT/P relating to its utility for reconstruction, repair, or replacement.”

As I’ve written before, a “more than minimally manipulated” human cell/tissue product  is usually going to be a biological drug requiring prior FDA approval before use in patients.

Further, in a warning letter sent to three jointly owned fat stem cell clinics, the FDA also seemed to refer to those clinics’ version of fat stem cells as a drug product too in December 2015. Some owners of fat stem cell clinics, however, have argued that their products are not drugs because in their view in each case it is minimally manipulated.

In the context of our paper showing such a large overall stem cell clinic industry, what this all means is that the fat stem cell clinics (a large slice of the general stem cell clinic pie) in the US are very likely in many cases administering unapproved biological drugs to large numbers of American patients each year. However, the FDA has been slow to act leaving arguably some room for debate. Absent action or more finalized guidances, there’s an uncomfortable gray zone. A big fat one in fact.

Another major issue that could lead to defining SVF as used by many clinics as a drug is something called “homologous use” (a primer on that term here). By this the FDA is thought to mean that for any given biological product, its origin is homologous (substantially similar to) the target tissue. For instance, if you use bone marrow stem cells as a treatment, the organ you are treating should have some similarity to that product such as a joint, a bone, etc. That often does not need FDA drug approval. This is using apples for apples if you will by analogy, rather than apples for oranges, which would be non-homologous use.

What the homologous use rule means for fat stem cell clinics is a potential big regulatory challenge because to qualify for homologous use they could in principle only treat fat-related medical conditions (again, by analogy using apples for apples). Most offer fat stem cells for conditions having nothing to do with fat (apples for oranges). This sure raises questions about non-homologous use. There may be some instances where fat stem cells are used for fat-related cosmetics conditions, making that homologous use, but these are not as common as other uses that are marketed.

Again with just the one exception of the warning letter mentioned above, there has been no apparent recent FDA action on fat stem cell clinics. It’s possible the FDA is waiting to do more until after its public meeting on stem cells in September or maybe it will never take any large-scale substantive action. Some of the clinics have told me essentially that absent FDA action they think they’re right to view their clinical practices with fat stem cells as outside the scope of FDA regulation. Could they be right? Why did the FDA issue that one warning letter, but not other ones for all those other clinics? Why hasn’t the FDA done more in this area to make things clearer? Has FDA inaction contributed to the mushrooming of the US stem cell clinic industry?

In future posts I’m going to discuss the bone marrow stem cell and amniotic stem cell businesses. Some of the same issues arise there, but also some interesting, unique ones as well.

18 thoughts on “‘Are fat stem cell clinics selling unapproved drugs?’ reporters ask in talking about our new paper”

  1. “Homologous use” is a concept being applied by the FDA to, by definition, classify almost all autologous stem cell treatments as drugs. The whole purpose of this guideline is to classify autologous stem cell treatment as drugs. So using it to explain why autologous stem cells are drugs doesn’t really answer the question unless the answer is, “because the FDA’s says so”.

    Can MSCs migrate from the bone marrow into the bloodstream? Can pericytes on blood vessels in fat and other tissue migrate into the bloodstream? If the answer is yes, then why are these drugs as soon as one takes them from tissue or bone marrow and places them into the bloodstream?

    PS – Japan just approved Cytori SVF treatment for osteoarthritis under its new law, which requires the demonstration of safety, at least to the satisfaction of the Japanese government.

    1. @Bill
      You asked, “Can MSCs migrate from the bone marrow into the bloodstream? If yes, then why are these drugs as soon as one takes them from bone marrow and places them into the bloodstream?”
      They aren’t – BM stem cells have been used in transplants for decades and are not classified as drugs.

      But if they are subject to “more than minimal manipulation” then they are classified as drugs. So what is more than minimal manipulation? Currently, everything from extraction from the natural tissue context of the stem cell, to the addition of transgenes. This covers such a wide range of “manipulations” and is an unsatisfactory criterion. It will remain so, even if regulators come up with better definitions – they are only paper definitions.

      What is needed are appropriate preclinical and clinical safety tests for each type of “manipulation”. Given that there is clearly existing data in some clinics who are treating thousands of patients with well kept records (especially orthopedics), this data needs to be included, and a decent statistician could extract some value from it, despite its n=1 character.

      1. @Jeff Muggles – My question was rhetorical. According the the FDA drafts, in most cases, including intravenous administration, stem cells harvested from bone marrow will be classified as drugs. “Minimal manipulation” is another way the FDA has chosen to, by definition, make almost all autologous cell therapies qualify as drugs, which they can then regulate.

        1. There are no FDA drafts stating that the established methods of intravenous administration of bone marrow stem cells, a.k.a. “bone marrow transplantation” will be classified as drugs.

          1. @Jeff, Yep, you are right. As quoted from my recent CSC paper, “However,
            According to 21 CFR 1271.3 (d)(4), minimally manipulated bone marrow for homologous use
            does not require pre-­‐marketing approval by the FDA.” Paul

            1. @admin – So, you are saying that under the new draft guidelines, it will be legal to harvest bone marrow, centrifuge it and then put part of that back into a patient’s bloodstream via IV = homologous and minimally manipulated?

              1. @Bill,
                Nope, not across the board.
                This may or may not be a drug.
                To my knowledge it would generally be minimally manipulated, but not necessarily homologous use. Many clinics use BM and/or adipose products for what appear to be non-homologous uses.

                1. @admin – I would say that in most cases, if not all, intravenous, intramuscular and intrathecal administration of bone marrow cellular products, even if only centrifuged, will not be allowed. I expect the FDA to define most everything as a drug one way or another. Enforcement will be another issue…

                  1. @Bill, I guess we’ll see what happens.
                    I don’t see how, by the way, that intramuscular or intrathecal administration of BM products could be homologous use.
                    Yep, enforcement is another issue and not one that the FDA has excelled at.
                    Some of the stem cell clinics themselves have said to me (to paraphrase), “Paul, you can quote FDA stuff to me and worry about hypothetical non-compliance, but we’ve been at this now for years and since they’ve never contacted us or really done anything about this, practically speaking we believe that’s a green light”.

  2. Hi anybody can tell me whether stem cell can help my condition m suffering form bulbar motor neurone tks so much for your info
    don ng

  3. @Paul Does it make any sense to call unclultured SVF a drug while uncultured bone marrow derived cells, in most cases, are NOT considered a drug? MSCs come from many tissues in the body and the FDA has drawn a line in an arbitrary manner. The FDA’s arbitrary definition is illogical because it implies that BM derived cells are somehow safer than an autologous adipose derived stem cells. This is nonsensical. The question of efficacy is a legitimate one though for any treatment that was not properly tested in an placebo controlled trial.

    1. @WST, There are several reasons this makes sense.
      Bone marrow has been around, used, tested, etc. for decades, while SVF is relatively new. Admittedly some applications of bone marrow are relatively new, but there’s way more known about bone marrow than SVF.
      Another reason for SVF being a drug is that it goes through substantially more processing than bone marrow typically does prior to usage. SVF is by no stretch of the imagination a naturally occurring thing. It’s a man-made concentrate of perhaps dozens of kinds of cells that normally are scattered throughout fat tissue far away from each other.
      Thirdly, non-homologous use also comes into play for SVF-like products. How many truly homologous uses are there for SVF? Very few that I can think of and if one looks beyond cosmetic applications, is there anything that SVF is really even remotely homologous to? Keep in mind that bone marrow products also become drugs when used in a non-homologous manner, which happens fairly often in the clinic world. Paul

      1. I get your points @Paul but is there any evidence whatsoever that adult stem cells extracted from fat are unsafe? I believe that the focus by the FDA should be on the protocols, technologies and safety of the enzymes used to extract and purify SVF. Once these guidelines are set, the cells should be allowed under the practice of medicine. Insurance companies won’t pay for this but at least it will provide options to patients while at the same time increasing the safety level from less safe practices.

        1. @WST, there are a lot of views on the best way for the FDA to handle this arena and especially with the FDA not taking much action, there’s plenty of gray zone.
          As to proof that fat stem cells are unsafe, that’s not the way biomedical science works. It’s the other way around. Those wanting to sell fat stem cell treatments have to prove it is safe and they should do so in a non-profit, rigorous setting. instead for the most part they are already selling it. Of course if there were data suggesting a lack of safety that would be worth discussion and especially for the hundreds of clinics out there there’s just no data.
          And just because one group’s fat stem cell prep might be safe, doesn’t mean that another’s is too. There’s so much chaos and heterogeneity out in that market.
          Then of course there’s the big issue of efficacy.

          1. @Paul:”And just because one group’s fat stem cell prep might be safe, doesn’t mean that another’s is too. There’s so much chaos and heterogeneity out in that market.”

            That is exactly my point. This is where the FDA focus should be with regard to giving patients’ options in the U.S.. In fact, if the pressure to make these therapies available continues I could see a compromise where autologous, uncultured fresh SVF could be allowed if the extraction method / equipment is approved. However, you are correct that this would prove nothing about efficacy and that will mean that many are wasting their money. Although those who are in a desperate situation will be given hope where non currently exists. Unfortunately, there are many FDA approved procedures that haven’t proven to be efficacious. Meniscus surgery is an example: http://www.nejm.org/doi/full/10.1056/NEJMoa1305189#t=article It doesn’t work. @Paul, should meniscus surgery still be allowed while a shot of one’s own SVF into the the knee is illegal?

Comments are closed.