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 a2013 federal court rulingallowing 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.

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.

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 anInvestigational 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 aBiological 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 definesuch 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? TheFederal Food, Drug, and Cosmetic (FDC) Actand thePublic Health Service (PHS) Actgive 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.

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 numberingmore than 20 in the state of Texas aloneand 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 clinicsincluding the Texas stem cell clinic Celltex, which is well-known for having treatedGovernor Rick Perry.

Strangely the FDA tookno regulatory actionregarding 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 (seehere,here, andhere) 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.

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 calledstromal 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.

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 includingmyselfhave 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 asstromal 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 believethe 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 manufacturers 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 througha possible FDA exceptioncalled 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 inone of the 2014 draft FDA guidancesmentioned 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.

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 (seehereandhere) and thenraised 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 cant be characterized) in a surgical procedure (cant be approved by the FDA theyve never approved a surgical procedure). If the FDA cant 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 Networks 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 menuhere). 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? Isnt 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 surgeons 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.mdis 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 agothey 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 ofthe recent case wherestem 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.

A relatively newer, but important issue related to stem cell clinics is the listing of their stem cell interventions on the official US governments clinical trials website, ClinicalTrials.gov. I recentlyinterviewedthe 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.govin 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 of3,000 patientsand 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 accessNew England Journal of Medicinearticleby Dr. Zarin. Comments on proposed changes including suggestions such as mine can be submitted in response tothis NRPM, but only until February 19th. I encourage you to submit comments and I have dug through the websites to find thisdirect linkthat allows you to do so quickly and easily.

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 andphysician 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 ofbone in an eyeandnose tissue in a spinefrom stem cell treatments that went awry. Some patients treated at stem cell clinics have died, including inthe US,Germany, and elsewhere.

More broadly in this new stem cell debate, the for-profit clinic argument for stem cell deregulation and weakening of the FDAs 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.

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