Dissecting the FDA’s big, fat stem cell dilemma


fdafatstemcell_smRight now the FDA has a big fat stem cell conundrum on its hands. The agency is faced with a tough dilemma as how to deal with fat (adipose) stem cell products and the large number of businesses who sell them.

Are fat/adipose stem cells a drug or not?

If yes, what does the FDA do about the hundreds of clinics currently marketing them without approval?

If not, then how does the agency reconcile that with its past statements and even words this year under new Commissioner Scott Gottlieb indicating that the cells are a drug?

Under Gottlieb’s leadership, the FDA recently took decisive action in two cases related to the use of fat stem cells. There was a “raid” here in California (StemImmune and California Stem Cell Treatment Center, working in collaboration on an anti-cancer approach drew FDA action on a stem cell-vaccine combo drug product) and a strongly worded warning letter to a clinic in Florida, US Stem Cell Clinic, Inc., which is part of the publicly-traded company US Stem Cell, Inc. ($USRM). Gottlieb also issued a very bold, broader public statement on stem cell clinics, indicating the FDA is very active on oversight of this commercial area.

These developments are encouraging to me in the sense that the FDA now both appears to be more active and clearer in its statements. It is addressing a growing stem cell clinic industry that markets what seem to be unapproved biological drugs without any FDA approval. The clinics also most often lack rigorous data from properly controlled studies to back up what they are selling.

In contrast in the recent past the FDA and its CBER branch, the one specifically tasked with regulating biologics like stem cells, hadn’t seemed to be keeping up with the growing stem cell clinic industry. In the past couple years under Obama, the FDA and CBER took near zero apparent action on an industry built selling stem cells without FDA approval and one proliferating at a rapid pace. Now the agency under the new administration seems to be signaling a major change in course on stem cell clinics and a willingness to be bold.

For example, in that warning letter to US Stem Cell Clinic, the FDA indicated unambiguously that a fat stem cell product (similar or identical to that used by many clinics) can be a biological drug that businesses cannot use on patients without prior FDA approval and proper licensing such as a BLA. Presumably this is not a one-time kind of statement about fat stem cells being drugs given consistent past FDA draft guidance.

Where does the FDA go from here?

If the agency wants to be consistent doesn’t it need to do something related to the hundreds of other clinics selling fat stem cell products for a whole medical dictionary’s worth of health problems? On the other hand, does the FDA have the will and the resources to take such large-scale action?  Does anyone recall the agency ever taking action on hundreds of businesses at once in any field of foods or drugs? Even scores or dozens?

Let’s say for the moment that the FDA wants to be consistent on fat stem cell and other stem cell products that are drugs and doesn’t want a huge number of businesses marketing what it views as unapproved drug products, which undermines the agency’s credibility. If so, does it need to inspect every one of those businesses first, issue hundreds of 483 inspection reports, and then potentially draft and issue an equally large number of warning letters? Or can it just issue the potentially hundreds of warning letters without individual inspections, perhaps based on marketing? Each of these scenarios seems relatively unlikely. Also, my understanding is that many if not most warning letters must get cleared by FDA attorneys too before being issued. Overall, this would be a colossal undertaking.

If the FDA cannot do that, does it instead issue a smaller number of letters (warning or untitled) to a smaller number (perhaps 8-12) stem cell clinics, rather than hundreds, picking the specific businesses that it views as the highest risk? If it takes that course of action, do the tons of other clinics take the hint and stop being non-compliant? Or do they instead just keep doing business as usual and hope that being just one lost in a crowd of hundreds of businesses means the FDA won’t take any further steps specifically with them?

In yet another non-mutually exclusive scenario the FDA doesn’t take dramatically more concrete action, but in one of the expected upcoming policy/guidance statements it sends a strong message. For instance, in this scenario perhaps the agency announces unambiguously that fat stem cell products cannot be marketed without approval (perhaps with one or more potentially new exceptions such as for breast reconstruction) and in this way it essentially indirectly signals to the large number of businesses to whom this applies to collectively stop marketing unapproved stem cell drugs. Would such a blanket statement be effective without much action or would the stem cell clinic industry instead just continue to grow fatter at the expense of the bank accounts and potential health of consumers?

Finally, the FDA could back off on the notion of widely classifying adipose stem cells as biological drugs, leaving the big clinic industry largely free to continue business as usual when it comes to adipose stem cell marketing. While this is formally possible, again the recent words and actions from the FDA make it relatively unlikely. What about amniotic stem cell clinics and those businesses marketing bone marrow stem cell treatments that are drugs (e.g. via non-homologous use)?

I asked Patricia Zettler, Associate Professor at Georgia State University College of Law and a former FDA associate chief counsel about the different scenarios for what might happen next with fat stem cell and potentially other noncompliant stem cell commercial outfits. She is one of the most knowledgeable people I know about FDA matters on biologics. Here’s what she said:

Professor Patricia Zettler

“As you point out, the FDA almost certainly does not have the resources to immediately inspect and issue warning letters to the hundreds of stem cell clinics that may be illegally marketing therapies.  But the hope, I think, would be that sending warning letters to some may bring both the recipients into compliance as well as deter some others from marketing illegal therapies.

Another possibility, I suppose, is sending letters that are not warning letters but that say something like “it appears that the stem cell therapy that you are marketing is an unapproved drug; if you believe that approval is not required, please provide us with the basis for that determination.”  FDA did something similar with some DTC genetic testing companies back in 2010.  This might be a way for the agency to get more information about what products are being offered while at the same time signaling to stem cell clinics that they are at risk of a warning letter or other enforcement action if they do not come into compliance.”

These make good sense to me as possible developments to come.

Several law firms are keeping a close watch on this fat stem cell – FDA situation as well. You can see one example here.

It’s not entirely clear how the FDA will approach the stem cell clinic industry overall or the adipose segment, but there is an expectation in the wider community of more FDA action and clearer guidances to come soon.


  1. Thank you, Paul, for keeping this important issue front and center. If companies use fat stem cells inappropriately, with potentially dangerous side effects, it could do damage to the field as a whole.

    • Side effects?
      This is an autologous procedure.
      Those cells are living and was made it by the same organism even allogenics SC procedure are safe.

      • ….just because a procedure is autologous does not mean it is safe and there can be side effects for sure….the adipose or even the blood or marrow….still leaves the body and after a process is put back into the body. There are many steps that could be done along he way that would make an autologous product distinctly NOT safe from the processing (ie. enzymatic production of SVF from adipose) to the delivery process. If a product is more than minimally manipulated, even an autologous product…..there is a definite increase in the potential for side effects…..thus the FDA interest and current section 351 regs on autologous tissue that is more than minimally manipulated being a drug.

        • Sure. Just because heart bypass surgery is a fairly common cardiac procedure in which a body part (the saphenous vein) is removed from one area of the body and placed into another (non-homologous use???) doesn’t mean that it is safe either. The practice of medicine is not perfect. Very few people would say that it is. I’m fairly certain that you could document a number of clinics nationwide that practice accepted medical procedures like this and many others. It’s likely that you could discover a number of adverse patient incidents in these clinics or hospitals, to include death, to otherwise fairly common procedures as well as to accepted medications. But the practices and procedures are accepted not because they are perfect but because we’ve decided that the benefits outweigh the risks. Decades ago medical professionals and others forged forth with what are today accepted medical practices. I don’t think they gave much thought to endlessly and incrementally testing in clinical trials and the lab bench the exact mechanism by which all medical practices & procedures worked for some people but not for others. If they had, few would have been treated and mortality likely would have increased. That’s a problem with all this research. The paradox being that the more questions you answer in research, the more questions that are raised. In a literal sense, research of this sort is endless. Now, this can be a good thing for the researcher in that he/she can keep writing papers, applying for grants, hiring more people and building more corporate and university laboratories. (And all the while boasting to those in the media about the “promise” of their work and how “excited” they are about the latest “breakthrough” or “revolutionary discovery”). In the meantime, they have nothing of use to show for it nor do the medical professionals. Practical applications are always years or even decades away. That day never seems to arrive.
          I have arthritic knees and have received Platelet Rich Plasma treatments for them which has helped a tremendous amount. Still Platelet Rich Plasma is not the accepted Standard of Care. (Grrr!) Injections of this sort are not exactly a pleasant experience and there are risks. But, if I had the cash, I would gladly submit to autologous stem cell injections into my knees. If you had my condition, it would be your choice though. Invasive knee replacement surgery in 5-10 years (a common medical procedure despite the risks) or a far less invasive, probably less risky, non homologous but autologous injection of your own body parts or cellar materials. (Not Drugs!) I cannot speak for others on this blog, but for me the choice appears, not entirely, but fairly obvious.

          • So Doug,
            I have two problems with your assertion about PRP and stem cells:
            First, arthritis goes through active and quiescent stages. I am 61 years old and my right knee had osteochondritis dissecans when I was 16. I have had 3 arthroscopic surgeries in my life, and the last flare up of symptoms was about 5 years ago. I treated that flare with 3 steroid injections about 6 months apart from each other, and prior to the second one my symptoms were bad enough that I started talking to one of my partners about knee replacement. However, after the third, things settled down and today I am still doing fine. I don’t run, but I exercise, ski, snowboard ( I coach a snowboard team and also race myself), hike and do other activities. My X-rays look like crap but my knee is still hanging in there.
            Second: we know very clearly from good research that steroid, PRP, and stem cells all have anti-inflammatory properties and provide temporary relief of pain. I think it is horribly foolish to think that randomly injected interstitial fat cells have any possibility whatsoever of magically turning into articular cartilage, and I think it it criminal that plastic surgeons, anesthesiologists and other charlatans are making millions of dollars a year off of poorly educated patients who are tricked into thinking that $7000 is going to magically restore their knee or somehow delay the progression of their disease. They would benefit as much from much cheaper, scientifically based treatment, and it boggles my mind that we haven’t put these providers in jail already.

            • Paul, I agree that if a physician/clinic portrays their treatments as a ‘cure all’ or ‘rejuvenation’ then they are taking advantage of a susceptible population. However, I do not agree with your equation of steroids and PRP.

              Both certainly have anti-inflammatory effects, however, to this point, PRP has not been shown to have deleterious effects on tissues, whereas, steroids have a long history of such. Injecting tendon insertions for pain (ie tennis elbow) was a mainstay for many in medicine, however, the risk of tendon rupture after injection increased significantly. To this point, I have seen no evidence that this is the same for PRP.

              I HAVE seen some awful PRP injections… done by physicians, who don’t have a clue what they are really trying to accomplish. Injecting PRP into an Achilles tendon tear… and adding Betamethasone to the injection?!?!?! The tendon ruptures, and the PRP is blamed.

              I am not disagreeing with your assertion of the MANY charlatans hocking the treatments in a bogus fashion. In all actuality, it is this black eye which concerns me most about Regenerative Medicine. But when you understand the theory, the biochemistry, and process, I believe that there is a real future for Regenerative medicine. Not as it is often currently administered, but as it will be when these charlatans are pushed to the wayside by solid evidence.

  2. Dear Admin:

    It doesn’t really matter whether or not preparations thought to contain beneficial tissue stem cells (e.g., adipose-derived, bone marrow-derived, or amnion-derived cell populations) are called “drugs”. What matters is that the FDA remain true to its mandate of insuring the safety and efficacy of materials given to patients as medical treatments, whether in private medical practice or FDA-regulated clinical trials.

    FDA officials must step away from the rhetoric and conventional thinking of clinical trial alarmists who imagine that what they are doing in their FDA-authorized stem cell clinical trials is completely superior to the treatment efforts in all private stem cell clinics. Such sentiments are biased conjecture that is not based on informed data about the general nature of stem cell treatments in the estimated 500 or more private stem cell clinics now in operation in the U.S. Critics take a few poorly understood incidences of apparent treatment-induced patient injury to suggest ill will on the part of hundreds of physicians who may have the best intentions for helping their patients.

    Critics object that private clinics require that patients pay for experimental treatments that are not yet FDA-approved for marketing, as in the case of drugs. Yet, many approved drugs do not work for every paying patient who is treated with them. This is one of the fundamental limitations of current medicine. What is more important is that patients are well-informed of this specific aspect of the treatment, just as they are informed by responsible physicians that every drug that they pay for to take for the first time is not guaranteed to work for them, per se, either. Let the informed ailing patients decide what risk they wish to take with the possibility of no efficacy, given that these treatments have proved relatively safe in clinical trials.

    The first goal of the FDA should be to gather real data on the nature of treatments in private stem cell clinics. As an enforcement authority, FDA can require that clinics provide such documentation as well as allow spot audits to begin to define better the distribution of treatment quality, patient experience, and treatment outcomes. With such data, the FDA can make a fact-based assessment on whether, and to what extent, clinics may be harming patients (including physical injury and setting false expectations), as well as whether the experience of these clinics can be guided, organized, and reported in a manner that advances stem cell medicine for all.

    Such an informed approach will expose fraudulent and dangerous clinics that may exist; but more importantly will allow the many more well-intended clinics to come out of the dark and share their experience, expertise, and knowledge towards overall safer, efficacious, and responsible patient care in this erupting new discipline in medicine. Current estimates indicate that in the U.S. each year, hundreds of thousands of patients are now obtaining “stem cell” treatments in private clinics primarily for chronic pain conditions, joint disorders, and wound healing. These treatments constitute a research incubator that dwarfs the number of patients evaluated in FDA-authorized clinical trials that more often address more complicated conditions like heart disease, stroke, and neurological disorders. By guiding the treatment quality, documentation, and reporting of private practices, the FDA could garner a wealth of useful data to drive advances in all areas of stem cell research and stem cell medicine.

    So, let us try to open our minds to a new era of crowdsourced medical treatment research. The FDA is ideally configured to lead the way; and private clinic stem cell therapy is an ideal first test case.

    James Sherley, M.D., Ph.D.

      • Dear Admin:

        Not a single one, yet. However, it is widely known that Asymmetrex does aspire to have everyone and anyone (including private stem cell clinics, public medical centers, and FDA-authorized cell therapy clinical trials) who is putting “stem cells” into patients (human or veterinary) to employ its new AlphaSTEM Test^TM technology to determine the dose and tissue renewal quality of their treatment preparations. We also want tissue stem cell investigators to employ the technology to advance to quantitative cell experiments; and cord blood banks to determine the hematopoietic reconstitution potency of stored treatment samples; and pharma and biopharma companies to employ it to identify stem cell-active drug candidates (e.g., stem cell-toxic ones cause chronic organ failure); and commercial suppliers of mammalian cells for research (e.g., ATCC) to determine the tissue stem fraction of their supplied cells; and suppliers of uncultured therapeutic stem cells (e.g. amniotic) to report the number and tissue renewal quality of stem cells delivered; and producers of therapeutic stem cell to monitor their production process to optimize the percent (though treated as homogeneous, all of these preparations actually have very low fractions of tissue stem cells) and quality of tissue stem cells supplied to cell therapy clinical trial companies. These commercial goals are disclosed in our blogged and peer-reviewed publications, as well as our effort to get the FDA to include the availability of our technology in its new guidances for insuring the highest quality of approved and experimental stem cell treatments, wherever they occur.

        James at Asymmetrex

        P.S. Tsk, tsk, tsk, Admin!

  3. Is the stem cell clinic industry using an enzyme to clean up the fat stem cells before injecting back into the body? If they are not why are they going after these clinics?

    • Most stem cell clinics utilizing adipose stem cell preparations do use enzyme, making the product in all likelihood more than minimally manipulated. On a 2nd level, the adipose drug products are used most often in ways that are likely to be non-homologous use, also triggering a drug product classification. For instance, if you use fat stem cells to treat a non-fat related condition (e.g. say a respiratory problem, heart condition, etc.) then that product must receive pre-market approval as a drug.

  4. I am still not clear what are these adipose tissue stem cells. Has anyone reported them at single cell level and characterized them? Are they pluripotent or multipotent?

  5. I had a successful adipose stem cell treatment in March for an OA knee. I just returned from biking in the tetons.

    1. Does there need to be a standard approved process to collect and process stem cells, yes. There is already is.

    2. Is the FDA the right agency to monitor, hell no.

    3. Is big pharma interfering with the use of stem cells, they dam well are.

    4. Mayo is just starting trials for all this, they are 5 years behind.

    5. My next treatment with be a cultured expanded version of adipose stem cell. If I have to go outside the country I will be mad as hell.

  6. You’ll have to leave the country for this sort of treatment, Terry if you live in the U$A. The FDA consider the expansion of your stem cells by way of culturing them to be tantamount to creating a drug. Sorry. But if you’ve got the cash, more power to you. I wish you well.

  7. My issue with calling ‘STEM CELLS’ a ‘drug’ is the inability to realistically evaluate them in the classic ‘drug’ sense.

    If I as a research entity, wish to develop a true ‘drug’, it can be patented. Making the massive investment in ‘drug’ evaluation reasonable. I don’t WANT any Stem cell related entity to be patentable, because of the massive implications concerning their global use and ultimate cost. I DO want there to be good solid standards and I absolutely DO want there to be solid research backing them.

    But for a physician or group of physicians to do research on them as a ‘drug’ how would you go about it? The research of their use and BEST use would be easy, but ADSCs by definition, are going to be procured from each individual (at least as we are discussing them) and will be enzymatically treated, expanded, and reinjected. Where is the ‘drug’ in this? I understand the definition per the FDA, but this is the problem and why I believe so many people are doing an end run around the FDA, on this issue. There is nothing clear about how this could be a drug, other than a definition which makes no reasonable sense. As soon as the research came out, everyone would be doing it.

    Minimal manipulation is a junk term. My minimal might be your maximal. But this is still not the main issue. It is , that if there was absolute solid evidence that ADSCs could treat a disorder with good solid results, and do it safely… how would it be a drug? It would still simply be a physician taking fat, ezymatically treating it, perhaps expanding it, then reinjecting. There is nothing in this sequence which will allow the type of ‘research’ required concerning FDA ‘drug’ approval requirements.

    I don’t want to come across as anti-research. In fact, I am absolutely PRO-research and standards. However, the FDA needs to completely revamp their view on this issue and come up with a different protocol for biologics. If I were to invest the money to ‘prove’ the ADSCs I obtained were safe and effective, everyone would still be able to jump on my work and use it, because there is nothing about it, which is specific to ME or MY PROTOCOL. It would simply be to ‘prove’ that what is being done is OK with the FDA. (I am not a ADSC user, this is just an example.)

    It also isn’t a financial issue, although that IS the major hindrance to research in this field, I believe. Since there is nothing to ‘patent’ thereby protecting the research investment, there is little reason for people to do the research. I don’t like this fact, but I believe it is why so little research exists and that which does, is of very poor quality. Recently there are a few studies which hold up to some reasonable standards. But still, these are just ‘does this work’or ‘is this safe’ type studies.

  8. So, another round of comment. Shane, every drug/material/fluid/substance used in medical treatment has potential complications and adverse effects. To somehow believe that this is not true for injection of autologous insterstitial fat cells or bone marrow is simply just foolish.
    Steroid injection has potential risk, however, used judicially and properly (1-2 injections per year in the same site), the risks are low, and are certainly less than the risks of surgery, or perhaps even less than the daily ingestion of NSAIDS.
    Injection of autologous tissue also has risks. Infection, adverse reaction, tissue damage can all occur. We also have reports of soft tissue tumors developing with stem cell injection into tissue(not joints).
    My main issue is the snake oil marketing of these treatments to patients who are easily swayed by sports heroes and celebrities who help promote unproven and unsubstantiated claims of efficacy for treatments that cost 10-100 times more than well studied and time oroven FDA approved treatments for the same condition.
    I read the literature. I follow the stem cell industry and PRP literature. Show me one research study that shows clearly improved results for the treatment of arthritis or even tendinitis with stem cells or PRP. At best they show improvement over placebo, and do not show benefit as compared to corticosteroid. None show regression of disease.
    I think it is criminal to advertise that these non-approved treatments are allowed to continue, though I suppose the government is no more responsible for controlling it than they were with the snake oil salesmen of the 19th century.
    Paul Schwartz MD

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