Stem cell myth: they are homologous to everything

Some stem cell clinics sometimes use questionable ideas to bypass FDA regulations and I’d go far as to say some of these are outright stem cell myths. One such argument that seems like a myth in my opinion relates to the idea of “homologous use”, which is one of the hottest issues in stem cells in the clinical arena right now.

So what is homologous use and what is the clinic myth?

spackle stem cells

Image from web labelled for re-use

The idea with homologous use goes that a stem cell product fitting that definition is similar to the tissue or organ in the body that a provider seeks to treat. For instance, bone marrow used to treat a blood or immune condition is definitely homologous. There’s an undeniable similarity there between the product and the target tissue. It seems so far that the FDA has accepted the notion that marrow cells are homologous to joints too.

In contrast, bone marrow stem cells used to treat the brain would be definitely non-homologous.

Why?

Nerves, glia, and other cells in the brain are not at all similar to bone marrow.

The same is true of using fat stem cells to treat the brain because these cells have nothing in common in terms of origin and function with the nervous system.

Another example is that neither blood nor fat stem cells have anything in common with lung tissue. The list goes on and on.

In fact, many stem cell clinics market entire menus of non-homologous offerings. It’s common to find claims, for instance, that one type of fat stem cell product can treat the brain, the lungs, the kidneys, the eyes, the GI tract, sexual dysfunction, and more. All of these are non-homologous uses in my view and this is important because that means that these clinics legally must have FDA approval in advance, but of course they don’t in almost every case.

So how do the clinics handle this?

Some of them just ignore this situation and I guess hope for the best on the regulatory front, but others make a remarkable claim that stem cells are by definition homologous to everything so there never could be a non-homologous use.

This is called “pan-homology” and as a scientist I think it is a myth.

It reflects a fundamental misunderstanding of cell biology. While stem cells are “potent” meaning that they can differentiate into some specialized cell types, this doesn’t make them the same across the board to anything and everything tissue wise.

Why care about non-homologous use?

It makes experimental therapies have higher risk. You can imagine that injecting stem cells of one type into a tissue of a totally different type could lead to trouble. For example, fat stem cells just don’t belong inside the nervous system or in the lungs or in the eye.

But some clinics tout stem cells almost like some kind of universal “fix it” putty that can spackled anywhere with no problem. Spackle it on your face, in your brain, into your lungs, kidneys…it’s all good no matter where you put it and no matter what type of stem cells it is.

I believe that the myth of pan-homology is bad for patients and for the stem cell field.

New FDA Interview on April stem cell meeting & draft guidances

FDA draft guidanceBelow is a my interview with an FDA spokesperson on the upcoming April public meeting on the four recent draft guidances related to the regulation of HCT/Ps, including stem cell treatments.

This meeting and the draft guidances could have substantial impact on future regulatory frameworks for stem cell treatments so I thought it important to reach out to the FDA to clarify the process.

  • PK: When the FDA issues draft guidances is it a standard approach to have a public meeting of the kind that will be held in April on the four stem cell-related draft guidances?
  • FDA: No, this is not typical. But with these there has been such strong public interest that we decided to have a Part 15 hearing. This will allow us to hear from interested stakeholders. So for these draft guidances we will both have the docket (the opportunity for written public comments) and the public meeting.
  • PK: Does the agenda include everyone who requested to speak and is that why each speaker gets only about 3 minutes?
  • FDA: We have tried to accommodate everyone who expressed interested in speaking in person at the meeting. Time is limited as a result of the interest.
  • PK: What happens after the meeting and when the written comment period ends?
  • FDA: We will take into consideration and review all the comments as we finalize each of the four draft guidances.
  • PK: Once finalized, what happens next?
  • FDA: These finalized guidances will then reflect the FDA’s current thinking, but the guidances are recommendations and are not binding. Even after we finalize guidance, it can undergo future revision.
  • PK: How do you collate all the comments both in writing and at the meeting, along with the FDA’s own research on the matters at hand? I imagine it could be quite the task with hundreds of potential viewpoints from stakeholders.
  • FDA: Regulatory and policy staff go through all the comments, which is indeed a lot of work. For instance, on the recent review of blood donation deferral, we got something like 700-800 comments that were roughly equally divided. With the four draft guidances related to stem cells, our goal is to provide clarity through the guidance, which we hope will lead to development of safe and effective products.
  • PK: We’ve recently seen a change in Japan as relates to the regulatory scheme for review of stem cell and regenerative medicine products. This has been predicted to speed things up there, but there will be less review before products go into patients. Does the FDA take into consideration paradigms in other countries?
  • FDA: In general we work closely with our regulatory counterparts in other countries.
  • PK: Can you predict a timeline for finalizing these four draft guidances?
  • FDA: I can’t predict the timing. These are a priority though.

More tough FDA draft guidance on stem cells…still no action

FDA logoThe FDA released more draft guidance with strong relevance to the stem cell field.

This October 2015 new draft guidance follows about a year after three other previous draft guidances that made it clear the current FDA thinking on various issues including stromal vascular fraction (SVF; fat stem cells) was much more restrictive than generally thought in the for-profit stem cell clinic field.

“Industry” apparently hasn’t been happy about this.

For instance, December 2014 FDA draft guidance very clearly indicated that fat-related stem cell products like SVF are more than minimally manipulated and hence are drugs requiring pre-approval and licensing. Another draft guidance on the same day surgical exemption issued a few months earlier also seemed (appropriately) to point toward more stem cell products being drugs requiring pre-marketing approval.

Still, to my knowledge the FDA has not actually finalized these guidances or taken any action based on them.

The new 2015 draft guidance aims to provide clarity and answer questions on the issue of homologous use. My sense is that this draft guidance, if ever finalized, would limit the unapproved uses of specific human tissues including amnion.

One particularly telling phrase from the new guidance stood out to me:

Generally, 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.

This sure sounds like how hundreds of stem cell clinics are using unapproved adipose and amniotic “stem cells”. Thousands of patients are spending millions of dollars right now on interventions violating multiple FDA perspectives mentioned in the various draft guidances.

Yet despite all this “tough talk” in draft guidances, by all accounts the FDA seems to be doing nothing to back it up in the way of actual actions on stem cell clinics violating these proposed rules or via finalized guidances. For instance, the CBER branch of the FDA suddenly stopped taking actions on stem cell clinics almost 2 years ago and since has done little if anything.  In the same period of time the number of stem cell clinics has roughly doubled. That is an equation for trouble and risks to patients.

What gives with the FDA?

In part I think they are just unbelievably slow in how they take steps on things, but that glacial slowness isn’t working to protect patients in the context of the warp-speed stem cell clinic world. They may also be getting political pushback on what seems to be emerging as a firming up path to regulating adipose stem cell products as drugs.

A big HT to Alexey Bersenev for pointing out the new draft guidance (see #5 in his post and another post). I recommend reading his post for another valuable view on this. He also points out that stocks have dropped for some companies related to this draft guidance and the FDA will hold a public hearing next year on these new draft guidances.

At this snail-like pace from the FDA we can expect these guidances might be finalized (assuming they ever are) in some revised form in…about 2-3 more years. By then there will probably be more than 1,000 stem cell clinics in the US selling unapproved stem cell drugs…

I’m all for public engagement by the FDA and responsiveness to feedback, but the FDA doesn’t have time to move so slowly.

Stem cell clinics, FDA, and giant, unapproved for-profit human experiments

When I started blogging in 2010 the stem cell arena was a very different place.

Back then the hot topic was the battle over the legality of federal funding of embryonic stem cell research. That battle is over, or at least in hibernation, with a 2013 federal court ruling allowing such funding to continue. The stem cell debate of today, which in its own way is just as fierce as the old one, is focused on how best to regulate the clinical translation and commercialization of innovative stem cell technologies.

The stakes in this new stem cell battle on the regulatory front are very high both for the stem cell field and for patients. Too little regulation could lead to harm to patients and damage to the stem cell field at a crucial juncture in its history, while too much regulation could stifle stem cell and regenerative medicine innovations.

Stem cell clinics should be better-regulated than a Starbucks

The goal of stem cell advocates, including myself, is to find a regulatory sweet spot where science-based, innovative stem cell medicine can advance expeditiously. On the other side we have largely physicians and lawyers along with some patients arguing for drastically-reduced regulation and acceleration of for-profit stem cell interventions to patients, even without concrete data supporting safety or efficacy.

The latter group is a key part of a rapidly-proliferating stem cell clinic industry in the US. It consists of for-profit stem cell clinics that collectively have already conducted stem cell transplants on potentially thousands of patients without federal regulatory approval. These clinics have in effect thrown down the gauntlet to the US Food and Drug Administration (FDA) with their use of non-FDA approved stem cell products on patients. 

Role and authority of the FDA

The FDA is the regulatory body legally empowered to regulate biologic products and hence stem cells in the US. However, the clinics generally argue that they and their stem cell products should not be regulated by the FDA because they believe that the products are not drugs and they as the physicians transplanting the stem cells are just conducting “the practice of medicine”. FDA guidance over the years has consistently conflicted with this view and indicated to the contrary that these clinics are generally producing a stem cell product that is a biological drug. Even so the clinics at this time do not have FDA approval to make and use stem cell biological drugs. Such approval can come in response to what is called an Investigational New Drug (IND) application. The clinics do not have IND approval from the FDA for their stem cell products or devices and do not have the licensing (called a Biological License Application or BLA) needed to produce and administer biological drug products such as certain types of stem cells. Collectively, for these reasons (absence of BLA and INDs), I define such clinics as “unlicensed” and their products as “unapproved” or “unproven”. Note that the physicians practicing at such clinics generally do have medical licenses from state medical boards, so they personally are licensed in that sense. These clinic physicians frequently further point out that doctors themselves can only be directly regulated by state medical boards and not by the FDA.

Where does the FDA get its authority to regulate stem cell products and clinics? The Federal Food, Drug, and Cosmetic (FDC) Act and the Public Health Service (PHS) Act give the FDA the legal authority and responsibility to regulate biologics including human stem cells. Therefore, barring a federal court specifically overturning a particular FDA decision, FDA regulations are essentially law when it comes to clinical use of stem cells in the US. The FDA is given certain authority over stem cell biological products and procedures more specifically under several regulations including “21 CFR Part 1271.10“, modified by “21 CFR 1271.15“, which details exceptions to its regulatory requirements. A key term to know before trying to decipher the verbiage in these regulations is “human cell and tissue products” or “HCT/Ps”, which basically means human biological products including human stem cells.

The state of the market

Both individual doctors doing stem cell transplants and chains of dozens of stem cell clinics have sprouted up from coast to coast in the US in the last few years. These clinics, collectively numbering more than 20 in the state of Texas alone and more than 100 across America, are administering stem cell transplants of one kind or another to growing numbers of patients each year, potentially generating millions of dollars in income, all without FDA approval. In doing so many of these clinics, even absent litigation against the FDA, are operationally challenging and undermining the authority of the agency by acting as medical providers using stem cell products without FDA approval or licensing. They are also a direct challenge to science-based medicine more generally. To put it more bluntly, I believe these clinics are in essence collectively doing a huge, unapproved human experiment for profit.

The FDA has issued a steady stream of regulatory guidances, supported in some cases by court decisions (e.g. US v. Regenerative Sciences Inc.), painting a clear picture that stem cell clinics in a general sense (as well as their products, devices, and procedures) are within its regulatory domain and their products can be defined as biological drugs. Furthermore, in 2012 and 2013 the FDA took numerous actions related to stem cell clinics such as warning letters issued to a number of clinics including the Texas stem cell clinic Celltex, which is well-known for having treated Governor Rick Perry.

Strangely the FDA took no regulatory action regarding stem cell clinics in 2014, at least none that is evident in the public domain, but the FDA did issue important new draft guidances related to stem cells (see herehere, and here) that I predict will be the basis for future action. One part of these guidances focuses on “minimal manipulation“, which is a key term in the stem cell clinical world and more broadly the world of biologics. If a biological product is defined as more than minimally manipulated it automatically leads that product to be defined as a biological drug subject to the full spectrum of drug regulatory oversight by the FDA. While stem cell clinics frequently argue that their products are less than minimally manipulated, it is becoming clearer that a large fraction of (but certainly not all) stem cell products sold by various clinics are likely to be viewed by the FDA as more than minimally manipulated.

The FDA and the stem cell therapy industry use numeric names for products that are minimally manipulated (361) or more than minimally manipulated (351), so these can be important to know as one navigates this arena. The for-profit stem cell clinics generally argue that their products are 361s, but I believe that FDA guidance indicates instead that a large number of these products are 351 biological drugs.

Treatment types, guidance and loopholes

It is also valuable at this point to talk about the different kinds of stem cell “treatments” sold by dubious clinics. The most common stem cell product transplanted into patients is something called stromal vascular fraction or SVF, which is a product manufactured from fat tissue. While various clinics use other stem cell products including cells isolated from bone marrow and other tissues (some of which may be 361s, while others are 351s), SVF is by far the most common stem cell product sold by clinics.

 Stromal vascular fraction, an extract of cleaned, centrifuged stem cells derived from body fat.

Amongst other things, the new draft FDA guidances explicitly single out SVF for attention and define it as a biological drug. This is particularly notable because many stem cell clinics have argued that SVF is not a drug and hence is not subject to drug-related FDA vetting. While many including myself have asserted in the past that SVF is almost certainly a drug and needs FDA approval before use, these new guidances from the FDA articulate, far more specifically and unambiguously than in the past, how SVF is by definition more than minimally manipulated and hence a drug (emphasis mine):

Example A-1: Adipose tissue is recovered by tumescent liposuction. The adipose tissue undergoes processing or manipulation (e.g., enzymatic digestion, mechanical disruption, etc.) to isolate cellular components, commonly referred to as stromal vascular fraction, which is considered a potential source of adipose-derived stromal/stem cells for clinical therapeutic uses. This processing breaks down and eliminates the structural components that function to provide cushioning and support, thereby altering the original relevant characteristics of the HCT/P relating to its utility for reconstruction, repair, or replacement. Therefore, based on the definition of minimal manipulation for structural tissue, this processing would generally be considered more than minimal manipulation.

Because of these new FDA guidances, I believe the fat stem cell clinic industry could be subject to future FDA action. However, the FDA is slow and cautious in how it proceeds with even what seem to be relatively straightforward regulatory actions that could even be viewed as neutral such as simply visiting a stem cell clinic to obtain information on its practices, products, devices, and such. It is important that the science-based medicine community advocate for appropriate, expeditious FDA action.

Another key term in the stem cell clinical arena is “homologous use“. When applied to an HCT/P product, it means that the clinical use of that product must be highly consistent with (i.e. homologous to) the properties of the original tissue from which the product was made; if it is not homologous, even if minimally manipulated it will automatically be considered a 351 drug product. An example of homologous use would be the transplant of hematopoietic stem cells to treat a hematopoietic disorder. In that case, a blood-related product is used to treat a blood-related disease.

An example of non-homologous use would be the transplant of SVF (again, a fat tissue derivative) as an intervention for a neurological disorder, as fat is not homologous to the nervous system. In this regard, it is important to point out that many stem cell clinics offer up their stem cell products (most often SVF) to “treat” a whole menu of human diseases manifesting in tissues that having nothing to do with fat or with the other tissues of origin of the various types of stem cells.

In an example given in the new draft FDA guidance in the section on homologous use, the agency points out that use of SVF to treat a bone or joint disease is non-homologous use (emphasis mine):

Example B-2: Adipose tissue is recovered and processed for use, as reflected by the labeling, advertising, or other indications of the manufacturer’s objective intent, to treat bone and joint disease. Because adipose tissue does not perform this function in the donor, using HCT/Ps from adipose tissue to treat bone and joint disease is generally considered a non-homologous use.

Another way that clinics try to get around having their products defined as biological drugs is through a possible FDA exception called “same surgical procedure“. The idea here is that if a procedure involving biologics such as stem cells is done in an autologous manner (the patient is both donor and recipient) and is completed in a single surgical procedure, then the biological product in theory might not be defined as a biological drug. It might be exempt from that designation because such procedures may have relatively lower risks. Many stem cell clinics have made the assertion that because in some cases they use stem cells in same surgical procedures that it means that they are not subject to FDA regulation of their product as a drug even if the product is, for example, SVF. However, the reality appears to be that the “more than minimal manipulation” and “non-homologous use” definitions trump the same surgical procedure exemption, discussed further in one of the 2014 draft FDA guidances mentioned earlier. What this means is that if your product is more than minimally manipulated or it is used in a non-homologous manner (either of these is enough), it is still automatically defined as a biological drug even if you use it in a same-day surgical procedure.

Stem cell clinic chains

The point of these FDA biologics regulations is to protect patients. It is logical that products that are more than minimally manipulated or used in a non-homologous manner pose higher risks to patients. As a result there is an appropriately higher requirement for evidence to support the use of such products in human patients. It is therefore of substantial concern that so many stem cell clinics in the US and around the world are going ahead and using experimental stem cell drugs as the basis of for-profit interventions without evidence that such products are safe or effective.

The stem cell entities in the US that concern me the most are chains of stem cell franchising clinics. These are rapidly-growing chains of affiliated clinics selling mostly fat stem cell-based interventions without FDA approval or licensing. Two examples of such chains are Cell Surgical Network and Stem.md.

Cell Surgical Network

Cell Surgical Network is a Beverly Hills-based chain of upwards of 50 stem cell clinics around the US that share philosophies, institutional review boards (IRB), procedures, devices, and malpractice insurance. They offer up SVF-based interventions for a wide range of medical conditions. I interviewed the leaders of Cell Surgical Network, Drs. Elliot Lander and Mark Berman, on my own blog last year (see here and here) and then raised my concerns about their operations, including my view that their SVF product is likely more than minimally manipulated, that they use the product in what I view as a non-homologous manner, and that the device they use is not FDA-approved for this application. Their device is a column, which is a laboratory tool used to separate cells from the rest of the components of tissues, manufactured by a company called “Medikan”.

In response to my question regarding the possibility that the Cell Surgical Network SVF product is a 351 biological drug (and one for which they do not have FDA approval such as an IND to use it clinically), Cell Surgical Network responded in part by invoking the same-day surgical exemption, which again to my knowledge does not apply in this case with SVF:

We produce SVF (over 40 ingredients and can’t be characterized) in a surgical procedure (can’t be approved by the FDA – they’ve never approved a surgical procedure). If the FDA can’t approve a surgical procedure, why would we possibly request them to approve this procedure?

It is worth noting that although arguably the FDA cannot directly regulate doctors or surgical procedures, the FDA can and does regulate drug products, biologics production procedures and devices in a general sense, which largely challenges the Cell Surgical Network’s argument as well.

I also asked Cell Surgical Network about the issue of their arguably non-homologous use of SVF to treat diverse non-fat related conditions (see their menu here). I found their response to be rather creative, but one with which I disagree:

We do have many conditions that we are looking at and in choosing them we have attempted to exploit either the regenerative, immuno-modulatory, or anti-inflammatory properties of SVF. Although SVF is used in all of our protocols, our deployment techniques vary considerably. I think the term homologous has been used rather loosely and in the field of regenerative medicine, a new paradigm defies simplistic categorizations of cell types. After all, what type of tissue is an undifferentiated progenitor cell? Can it be homologous? Isn’t it potentially everything? For example, if it forms cartilage then could it have ever been anything other than a cartilage precursor? Our comfort zone is that we are surgeons performing a type of surgical tissue transfer procedure. There is no difference than when we replace a bladder with ileum or a coronary artery with a saphenous vein from an extremity. At the end of the day, the ability to use various tissues to treat human disease is within the realm of a surgeon’s domain.

In this line of argument then, would anything stem cell-related be considered “pan-homologous” to every other tissue and could never be used in a non-homologous manner? That seems like a rather radical notion and one not consistent with FDA guidance. Further, can a surgeon pretty much do anything they want? That seems to be a rather extreme idea too.

Still, despite these concerns, to my knowledge the FDA has so far never taken any action related to Cell Surgical Network. Therefore, a reasonable question to ask is why, if from my perspective the FDA would view Cell Surgical Network as likely being non-compliant in its use of stem cells, has the agency apparently done nothing about it? The frank answer is that no one except the FDA knows why or why not they take specific actions and they do publicly discuss specific situations.

Stem.md

Stem.md is a similar group of stem cell clinics, but one that sprouted up on the East Coast. Stem.md has dozens of clinics too, including some using SVF as well as other types of stem cell products. While the Stem.md website frequently has changed over the years, as recently as a year ago they made some rather bold claims for their stem cell transplants including the remarkable statement that they “provide a treatment for every condition”. Sounds like a panacea, right? They also at one point claimed their “advances” were FDA-approved, although they took down that claim when I pointed it out to them as being incorrect. Like some other stem cell clinics, Stem.md has made a big deal out of treating pro athletes, including in their case former Yankee Bartolo Colon, which might remind you of the recent case where stem cell clinics Stemedica and Novastem arguably could have benefited from a free stem cell intervention performed on hockey legend Gordie Howe as a public relations opportunity.

Some of the same nagging issues come up with Stem.md as with Cell Surgical Network, including potential non-homologous use and more-than-minimal manipulation. However, as with Cell Surgical Network, to my knowledge the FDA has not taken any regulatory action related to Stem.md.

While the recent FDA draft guidances are a step in the right direction of increased clarity, if the FDA takes no action, or waits years to enforce its finalized guidances, the end result is that the FDA is undermining its own authority and I believe putting patients at increased risk. In principle, in the absence of FDA action, stem cell clinics can effectively argue that if their practices did violate FDA regulations then the FDA should have done something about it by now. In the absence of regulatory action, there is always the possibility that the FDA could view the clinics’ use of stem cell products as compliant. I would also note that my views presented in this article, of course, do not necessarily reflect those of the FDA, and the stem cell clinics view FDA regulations quite differently.

The role of ClinicalTrials.gov

A relatively newer, but important issue related to stem cell clinics is the listing of their stem cell interventions on the official US government’s clinical trials website, ClinicalTrials.gov. I recently interviewed the Director of ClinicalTrials.gov, Dr. Deborah Zarin, to ask her about key issues including specific questions related to stem cell clinic listings. I was concerned to find out that ClinicalTrials.gov largely operates on the honor system in terms of deciding whether to list trials submitted to it for consideration. For example, there is neither specific vetting of US trials (keep in mind that ClinicalTrials.gov lists trials from all over the world) for FDA compliance nor a requirement that trials list specific IRB or other key information. Trials listed on the database can also be of a for-profit nature (i.e. patients are charged simply for participating in the trial before there is concrete evidence that the product or procedure in question is safe or effective) and based on the information in the trial listing, there is no straightforward way for patients to know that reality. I believe that this situation puts patients at added risk and also puts the valuable mission of ClinicalTrials.gov in jeopardy.

The end result of this situation is that many for-profit stem cell clinics have trials listed on ClinicalTrials.gov and some use that listing as a marketing tool. What kind of money is involved here? Cell Surgical Network has a clinical trial listed with a projected enrollment of 3,000 patients and hypothetically if the organization makes $5,000 profit per patient that would add up to $15 million, again before the SVF product in question is even known to be safe or effective for the particular condition in question and without FDA approval or licensing.

I believe that a number of changes are needed at ClinicalTrials.gov including a requirement that for-profit trials be labeled clearly as such near the top of their listing page, that the listing of a given trial on the site should be prohibited from being used as a marketing tool by the entity responsible for the trial, and that the ClinicalTrial.gov team vet trials located in the US for FDA compliance and as needed consult with the FDA on this matter.

If you feel likewise, this is one case where you can easily take positive action during a specific window of time. ClinicalTrials.gov has issued a Notice of Proposed Rule Making (NPRM), detailed in a very recent open access New England Journal of Medicine article by Dr. Zarin. Comments on proposed changes including suggestions such as mine can be submitted in response to this NRPM, but only until February 19th. I encourage you to submit comments and I have dug through the websites to find this direct link that allows you to do so quickly and easily.

Conclusion

The overall bottom line with most stem cell clinics in the US is that collectively they could be viewed as conducting a huge, unapproved and for-profit stem cell experiment of a sort, on thousands of vulnerable patients who are often desperately looking for hope. At the very least these patients are spending money that they can ill afford to lose on stem cell transplants that probably do not help them. It is also quite possible that some of these patients are being harmed. Stem cells do not always do what we might hope and their power to potentially help patients is equaled by their potential to do harm, especially when not backed up by rigorous science and physician training. For example, fat stem cells are typically a heterogeneous mix of a variety of cell types with variable multipotency – meaning that they can not only form mature fat tissue, but also potentially blood vessels, bone, cartilage, or others. The growth of an undesired tissue in the wrong place could be a major adverse outcome. There is evidence of potential for patient harm including growth of bone in an eye and nose tissue in a spine from stem cell treatments that went awry. Some patients treated at stem cell clinics have died, including in the USGermany, and elsewhere.

More broadly in this new stem cell debate, the for-profit clinic argument for stem cell deregulation and weakening of the FDA’s role in regulating stem cell products is a direct challenge to our system of science-based medicine. Furthermore, while to those of us in the stem cell field it may often seem clear where we can place a dividing line between the dubious clinics and the ones who follow the rules, that line is at best fuzzy for the wider community (including patients). For this reason the ever-growing unapproved human stem cell experiment poses a grave risk to the legitimate stem cell field as well. Governmental entities such as the FDA and ClinicalTrials.gov perform important services in this arena, but can and should do better to reign in the “wild west” mentality of the stem cell clinic industry in America today. Advocates of science-based medicine have an opportunity to make a positive impact here as well via educational outreach, participation in the FDA guidance comment process, and advocacy for responsible clinical research.

Note: a version of this piece was first posted at Sciencebasedmedicine.org.

FDA to Put Mushrooming Fat Stem Cell Clinics on Crash Diet?

Is it the beginning of the end for dubious American clinics that sell transplants of unproven and non-FDA approved fat stem cells?

As the year of 2014 was winding down, the FDA issued two key new draft guidances (see here and here) that could prove to be crash diets for these burgeoning fat stem cell clinics.

These new FDA guidances indicate that the stem cell products used by scores of dubious stem cell clinics in the US are almost certainly drugs for which pre-marketing approval and licensing (biological license application or BLA) from the FDA are required in advance of use on patients.

The clinics don’t have that licensing or approval, but they are transplanting stem cells into thousands of patients a year any way and making millions doing it.

In 2012 I imagined in a cartoon (below) a possible future if the stem cell clinics got their way for extreme deregulation. These new 2014 draft guidances are a strong signal that appropriate regulation of the stem cell clinic industry is not going away.

Stem cell cartoon

In fact, these new FDA guidances more squarely put scores of such dubious stem cell clinics in the US on a regulatory collision course with the agency.

Could the clinics win out in such a conflict?

It’s very unlikely.

The regulatory path may be a slow one and these are so far just draft guidances, but the eventual outcome is not in much doubt. It is not a question of if, but rather when.

These clinics and their doctors cannot continue with their status quo of using patients as guinea pigs for profit now without serious legal risks to themselves. Indeed, the one thing that could alter the impending collision is if the clinics change course and mend their ways to be compliant in a regulatory sense. It’s hard to imagine that happening, but it is possible that some will try. I hope so.

I suppose the clinics could also try to sue the FDA, but that would likely be a huge waste of money as the FDA would almost certainly prevail in court given legal precedent.

SVF

The newer of the two FDA guidances that came out at the end of the past year is specifically all about fat (or adipose) stem cells.

Fat stem cells are the stem cell product of choice for most dubious clinics in the US today. Their fat stem cell product is most often called “stromal vascular fraction” or SVF, which is made by enzymatically liquefying the fat tissue and spinning it through a column to isolate just the cellular “stem cell” part of the fat.

You can see a diagram that I drew of the method to make SVF from my book on stem cells. It’s hard to imagine the stem cell clinic argument that the SVF (cell pellet at the bottom of that tube) is the same thing as the starting fat tissue.

The new FDA guidance makes it crystal clear that regardless of other circumstances, if a clinic makes SVF it is a biological drug legally requiring pre-market approval and licensing by the FDA before you use it on patients.

Again, to my knowledge 100% of these clinics do not have such FDA approval.

The top rationales put forth by the clinics for why they do not need FDA approval seem even more outlandish today after these new guidances.

For example, clinics often claim that the fact that they transplant the fat stem cells in a “same day” surgical procedure makes the fat stem cells not qualify as drugs. The new guidance says that reasoning is invalid if the product is more than minimally manipulated and to be clear it says that fat stem cells are more than minimally manipulated.

Another important issue is non-homologous use of fat stem cells. The clinics often sell fat stem cell transplants to supposedly help a surprisingly wide array of conditions that generally have nothing in common with fat. For example, the clinics sell fat stem cells to treat neurologic or orthopedic conditions or for sexual dysfunction. The FDA draft guidance says that such non-homologous use automatically means that the fat stem cells are drugs regardless of other circumstances.

There is a compelling logic to the FDA guidance here. Fat is fat. It is not nerve or cartilage or other kinds of tissues. This doesn’t mean that fat stem cells cannot ever be used to treat other kinds of conditions, but rather it just means that there is an appropriately rigorous requirement for scientific data in advance before such use should occur.

What should the fat stem clinics do now? Given these new guidances, if I were such a stem cell clinic doctor, I would be stopping my clinic operations right away at this point so as to avoid serious legal ramifications. Otherwise there is a good chance in the future that you will receive a visit from the FDA, perhaps a warning letter, and they may shut you down. Such FDA action may also be a sound legal basis for patients to sue you for malpractice as well.

Below are some key quotes from the newest FDA guidances, which could give the clinics operators some sleepless nights because they sure seem to directly indicate that what the clinics are doing is making and using unapproved biological drugs, which is almost certainly contrary to FDA regulations and hence the law (emphasis mine):

“Example A-1: Adipose tissue is recovered by tumescent liposuction. The adipose tissue undergoes processing or manipulation (e.g., enzymatic digestion, mechanical disruption, etc.) to isolate cellular components, commonly referred to as stromal vascular fraction, which is considered a potential source of adipose-derived stromal/stem cells for clinical therapeutic uses. This processing breaks down and eliminates the structural components that function to provide cushioning and support, thereby altering the original relevant characteristics of the HCT/P relating to its utility for reconstruction, repair, or replacement. Therefore, based on the definition of minimal manipulation for structural tissue, this processing would generally be considered more than minimal manipulation.

 

“Example B-2: Adipose tissue is recovered and processed for use, as reflected by the labeling, advertising, or other indications of the manufacturer’s objective intent, to treat bone and joint disease. Because adipose tissue does not perform this function in the donor, using HCT/Ps from adipose tissue to treat bone and joint disease is generally considered a non-homologous use.

 

“Example A-2: Adipose tissue is recovered by tumescent liposuction. Stem cells from the lipoaspirate are then isolated. Cell isolation would typically cause the adipose tissue to no longer be “such HCT/P.” Thus, even if this processed HCT/P from adipose tissue is injected into the same patient from whom it was removed during the same surgical procedure, the establishment would generally not be considered to qualify for the exception under 21 CFR 1271.15(b).

 

In order to lawfully market a biological product, a biologics license must be in effect (42 USC 262(a)). Such licenses are issued only after a determination by FDA that the establishment(s) and the biological products meet the applicable requirements to ensure the continued safety, purity, and potency of such products (21 CFR 601.2(d)).

 

In the end, this new FDA guidance is appropriate and when finalized will further protect the public from dubious stem cell clinics that today are making big bucks off of vulnerable patients via unapproved as well as potentially harmful and ineffective stem cell “treatments”.

Some helpful background posts and FDA links: