The stem cell wild west continues. In the past 18 months, we’ve seen an explosion in companies stating that they are selling vials of millions of stem cells but are really selling vials of dead tissue. In the meantime, a new twist has emerged. We now have some companies selling exosomes. So what are exosomes, why would someone want to use them in patients, and are they even legal?
In short, an exosome is like a guided missile sent out by a cell to influence another cell. In the case of growing stem cells, it’s been known for a long time that you can take the media in which the cells grow and use this as a regenerative agent and this cocktail without cells will have some benefit to tissues. Meaning, the stem cells are giving off something that can help damaged tissue. One of these things being secreted by the cells is called an exosome.
Stem cells detect what’s in their environment and use these clues to see what tissue to repair or how to behave. In the case of exosomes, these are “fired” from the stem cell at another cell and have a distinct payload. For example, the exosome may carry some RNA that can force another cell to make a specific protein. To learn more, see my video below:
Another way to look at exosomes is that they are like the arms and hands of a stem cell in that they are what the cell uses to influence its environment and other cells. Hence, you need the cell to figure out what to do with the arms. So, for example, if you chop off your arms, they’re not much good by themselves! Meaning, your hands and arms require the intelligence of your brain to work well and to know what to do. Exosomes are no different. Healing takes many stages, and different cells are needed at each stage. Stem cells act as a general contractor to bring in the right cells at the right time. So different types of exosomes are sent by stem cells at different times, and this dance of cells is a complex symphony of activity. To use another example, if we remove the arms from the conductor at the symphony and take away the body and brain, does Beethoven’s 9th sound as good?
The easiest way to make exosomes is simply to grow stem cells and to bottle the media from the growing cells. You can also perform some isolation steps. Again, the problem is that what you end up with is a soup of exosomes that may have been created for a number of purposes, but nothing specific to the timing needed to produce a great symphony of healing.
Having answered the questions, what are exosomes and how are they harvested, the important question is, are exosomes legal? Since producing exosomes requires more than a minimal manipulation of cells, this crosses the FDA’s line in the sand between a simple registered tissue product (361) that requires only a free, quickie online registration into the world of a drug that needs to be formally approved through extensive and costly clinical trials. Despite this, we have companies producing exosomes and claiming that they are operating in a regulatory gray area and don’t need FDA approval. In fact, I thought it would be instructive to show you an exchange I had with a random sales rep who doesn’t know what he doesn’t know about FDA regulation. Why? This will help you (and hopefully him), better understand the regulatory status of this unapproved drug.
First, as is common, the rep was told by the company that they had met with the FDA. Here’s what he told me: “I have been told that they have met with the FDA and received marketing clearance.” As someone who has had meetings with the FDA, has worked with regulatory counsel for 14 years, and is now pursuing several FDA approvals for cell drugs, I can tell you this statement makes no common sense. Why? The FDA doesn’t generally provide “clearance” after a meeting. They may decide not to regulate something, but the term “clearance” is specific in FDA parlance. In fact, the rep is likely using it here because that term is associated with physical devices the FDA regulates through the 510K pathway. In that case, they review a device to see if it’s similar to an existing device (called a predicate) and then decide to “clear” the device if it is similar. There is no predicate for exosomes, so no clearance is possible.
Second, came this statement: “I have no plans of selling anything until I have the FDA registration which clearly states the product name and AATB tissue license in hand. Once I have that than the product will be legal to sell.” Now the sales rep is mixing regulatory pathways without even knowing it. The phrase “FDA registration” in this context refers to a 361 tissue. This is a free, 45-minute online registration. The FDA does not clear or look at these in any way, as this pathway was created for tissue vendors who sell things like bone or tissue grafts for surgery. The FDA can and will inspect these sites to make sure that they are using good tissue practices in processing the tissue. However, this is an “honor system” where the onus is on the tissue vendor to correctly classify the tissue. In this case, we have an allogeneic tissue (from a donor) that has been created through more than minimal manipulation of cells, placing it squarely outside of an FDA 361 tissue registration. That makes this product a misbranded and adulterated illegal drug product, despite its 361 registration. The AATB is the American Association of Tissue Banks and doesn’t regulate tissue, but it does promulgate lab standards and can certify a site where tissue is stored or processed.
So those two statements by the rep tell me everything I need to know. He has no idea what’s legal or illegal, and he knows enough to be dangerous. This is not unique to this sales rep, as you can say this about any number of health care providers who believe what sales reps tell them about the regulatory status of any number of products.
The upshot? Exosomes are not something I plan to use at this point. We can use same-day stem cells and can also use culture-expanded cells at our licensed advanced cell therapy site in Grand Cayman. Why would I want to use what these cells produce when I can use the cells themselves, which can then produce the exosomes specific to the local situation into which they’re injected? In the meantime, we have sales reps and doctors out there who are being told that these products are being legally marketed. When I asked a trusted regulatory attorney about this issue, he didn’t hesitate to make it clear that these were illegal drug products. Hence, IMHO, it’s a matter of when, and not if, these companies will be shuttered by the FDA.
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About the Author
Christopher J. Centeno, M.D. is an international expert and specialist in regenerative medicine and the clinical use of mesenchymal stem cells in orthopedics. He is board certified in physical medicine as well as rehabilitation and in pain management through The American Board of Physical Medicine and Rehabilitation.…