Are fat stem cells a drug? Today the FDA definitively indicated “yes” without leaving much of any room for exceptions on this question.
This morning the FDA made a major announcement on stem cell policy regarding its current thinking on oversight of regenerative medicine and issued four guidances, including two each in final and in draft form. There will be a 90-day comment period for the latter. Are today’s developments a good thing overall? I’d say “yes”, although there are still some ambiguities and a more accurate answer might be “Yes, but it’s complicated.”
Overall, the FDA’s goal is to establish a clear and “modern” framework, as they put it, for oversight of the regenerative medicine arena including related to the 21st Century Cures Act provisions. In this post I’m mainly going to focus on the two finalized guidances and then the two draft guidances will be covered in more depth in a later post. FDA Commissioner Dr. Scott Gottlieb also issued a statement today again highlighting the importance of differentiating between good citizens in this arena and as he puts it “bad actors”. This follows on some action and a bold statement a few months earlier from Gottlieb and his agency.
The first of today’s newly released, finalized guidances relates to the so-called “same surgical procedure exception” and clarifies when an exemption is likely to be in effect and when it isn’t. There’s a ton to read through in all these guidances, but on my initial run through, practically speaking one of the most important stem cell policy elements of this particular finalized guidance (entitled “Same Surgical Procedure Exception under 21 CFR 1271.15(b): Questions and Answers Regarding the Scope of the Exception”) is the clarification that fat stem cells are not going to be exempt from oversight as a drug even in the context of a same surgical procedure. Why? Because they wouldn’t qualify as what the FDA calls “such HCT/P” since they are by definition more than minimally manipulated. The take home from this in my view is that production of what is often called “fat stem cells” (or stromal vascular fraction) as is done by hundreds of for-profit clinics in the U.S. is a drug manufacturing process generally requiring FDA approval, which most of these clinics do not have. Given the apparent conflict between the industry reality of all those non-compliant clinics at the moment and the words in the finalized guidance, many of us are very curious as to what happens next.
The FDA also issued a second finalized guidance entitled “Regulatory Considerations for Human Cell, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use.” It includes a hand-dandy flow chart for figuring out how to apply all the complicated criteria. This 27-pager has a lot to take in, but I’ll try to summarize my initial impressions even as I’m hoping to do a deeper read in coming days.
The main areas of focus in this guidance are as you probably guessed from its title, the issues of minimal manipulation and homologous use. As to the former, the FDA now seems to consider something by default to be more than minimally manipulated if there isn’t data to prove otherwise, with some exceptions of course. There are some other notable points in this second guidance. As to the various amniotic materials often marketed by clinics as “amniotic stem cells“, my impression is that most of what is being sold in such cases are now defined as more than minimally manipulated and hence a drug product based on this FDA guidance. In contrast, amniotics are only minimally manipulated, it would appear, if they are preserved and used a “sheet”. Also, in this guidance (e.g. in answer to question 15) the FDA again clarifies as in the first guidance that adipose cell therapy products are more than minimally manipulated and hence drug products.
This second guidance also touches on homologous use, which basically means using a like product therapeutically only to treat a like target tissue or organ (e.g. fat only to treat a fat-related health condition, skin for skin, blood cells to treat blood or immune conditions, cardiovascular for cardiovascular, etc.) Here the FDA makes an interesting point, “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 would seem to be directed at for-profit stem cell clinics. The statement in my view is an indication that stem cell clinics offering panaceas or making wide marketing claims, such as via large menus of health conditions supposedly treatable with one stem cell type such as adipose or marrow cells, are often going to be in “non-homologous use” territory and their offerings are going to be drugs, requiring pre-market approval. Again, clinics generally do not have that approval.
In example 19-6 in this guidance, the FDA yet again indirectly indicates how frequently adipose stem cells are going to be drugs because in this case they are most often used in a non-homologous manner. Other than for use in filling tissue voids or breast reconstruction, pretty much all the other uses of adipose tissue or cells such as for orthopedic or neurological conditions are non-homologous.
The example in Part (c.) quoted here is key:
“An HCT/P from adipose tissue is used to treat neurological disorders such as multiple sclerosis by limiting the autoimmune reaction and promoting remyelinization. This is generally not considered a homologous use because limiting the autoimmune reaction and promoting remyelinization are not basic functions of adipose tissue.”
Many clinics are already marketing fat stem cells for neurological conditions including most prominently MS. Based on this FDA guidance, I see a very large number of clinics now even more unambiguously being non-compliant. While the FDA does not devote as much time to discussing bone marrow stem cells in these finalized guidances, a footnote on page 13 of the second guidance indicates that more than minimally manipulated, non-homologous uses of bone marrow are going to make it a drug as well:
“However, bone marrow that is more than minimally manipulated, intended by the manufacturer for a non-homologous use, or combined with another article with limited exceptions, meets the definition of an HCT/P and is subject to the regulations in 21 CFR Part 1271. “
Things get tricky though, because a lot of clinics would appear to be using minimally manipulated bone marrow but in a non-homologous manner. How is the FDA going to few that? Are they eligible for same surgical exception? The flow chart isn’t so clear on this. The guidance text also isn’t clear here. I’ve got a question in to the FDA about this and about more broadly whether firms need not worry about non-homologous use of minimally manipulated products meeting the same surgical exception. This could be a problematic loophole…or not. We’ll see.
The FDA in some cases is going to give firms time to adapt to this overall new regenerative medicine framework and stem cell policy depending on the risk profile:
“Under the new policy, in order to allow manufacturers of products time to comply with the requirements, for the first 36 months following issuance of the final guidance document the FDA intends to exercise enforcement discretion for certain products that are subject to the FDA’s premarket review under the existing regulations, but are not currently meeting these requirements. The FDA does not intend to exercise such enforcement discretion for those products that pose a potential significant safety concern.”
As to that last statement, it’s unclear if the FDA views the offerings of many stem cell clinics, including apparently unapproved drugs consisting of fat stem cells, as posing significant safety concerns or not. Three years is a long time for potentially non-compliant clinics to still be raking in the dough from patients.
Finally, as somewhat of a disclaimer, again there’s a huge amount here to digest overall (not using collagenase, of course) from the FDA and the above are just my initial takes on the two final guidances. What do you guys think of all of this? I have to say that despite some remaining gray areas, I strongly appreciate the FDA’s clarity and directness in these finalized guidances.