Is It Legal to Get Cultured Stem Cells in the U.S.?

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This past month, I had a reliable source tell me that two companies offering same-day fat stem cells have begun offering more. In fact, they are providing a culture-expanded stem cell product in the U.S. I’ve since been able to confirm this based on what’s appeared on the website owned by one of these groups and what was presented as part of a public webinar. So I’d like to explore today whether this is legal, illegal, or somewhere in between. While this post is longer than my usual, I’ve spent quite some time digging through various documents and making phone calls to confirm this information.

What Are Culture-Expanded Stem Cells?

All of the procedures in the U.S. that use your stem cells involve an isolation of the stem cell fraction from some tissue. These all occur on the same day as the harvest procedure and usually utilize bone marrow and fat. It’s also possible to grow the stem cells to produce greater numbers through culture, and this is called “culture expansion.” This process is what our licensed site in Grand Cayman has been doing for many years.

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The Regulations on Growing Stem Cells

We began culturing stem cells in 2005, here at our Colorado facility. At that time, we attempted to ask the FDA about whether any particular permits were needed or whether this was considered the practice of medicine and exempt from FDA involvement. The answer that came back was confused at best, so it seemed clear that the FDA hadn’t fully formed its opinion. So we hired a team of attorneys to vet the issue, and the answer came back that this was the practice of medicine and exempt from FDA approval.

Our clinic happily used culture-expanded stem cells for a few years as part of an IRB-approved and monitored clinical study, and by late 2007, we felt comfortable enough in the results to begin charging patients for the procedure. In 2008 we received an “Untitled Letter” from the FDA, claiming that culturing a patient’s cells was considered a prescription drug. Also, this would need FDA approval that would take 5–10 years and cost hundreds of millions of dollars. Once we responded that we had several legal opinions to the contrary, we thought that this would be the end of the issue. However, the FDA stuck to its position. Hence, we eventually agreed to stop culturing and began a legal back and forth in the civil courts to see who was right. After spending about 500K USD in legal fees, we learned the hard way that it’s “tough to sue City Hall.” Meaning that the process was definitely weighted in the direction of the FDA. Hence, we stopped culturing in the U.S. and decided to license that technology to a site in Grand Cayman, where we could take our patients who required this procedure. Here are a few good articles that covered our ordeal:

The Company Now Offering Culture Expansion

The new company now offering culture-expanded cells is American CryoStem (ACS). One of the stem cell networks launching this new program has this to say on its website about the program:

“Cryo-preservation and banking of adipose derived stem cells is possible and can be performed at the same time as your SVF deployment procedure. XXX is the company that handles this process in collaboration with their technology partner American CryoStem (ACS). Autologous lipo-aspirate can be frozen as SVF Stromal Vascular Fraction (contains mesenchymal and hematopoetic stem cells). SVF can be deployed for repeated treatments and also expanded under IRB approval as part of a safety trial providing vast quantities of autologous stem cells that could be used throughout that patient’s life. This will provide patients with their own personal stem cell line that could be used “on demand” for everything from treating stroke, heart attack, serious accident, or even cancer therapy should the need arise.”

So let’s dig into the two highlighted statements above. First, I’ve learned much about regulatory issues, as I was forced to know this stuff backward and forward. I’ve also reviewed these same statements and evidence with my regulatory counsel, who agreed with my assessment.

The first statement in bold relays that since this use of culture-expanded stem cells has an IRB approval for a safety trial, it’s fine. An IRB is an Institutional Review Board. This organization is made up of a group of doctors and other people who can review whether a study is safe for humans. While what’s written above looks sophisticated, it doesn’t hold regulatory water.

First, since our case determined that culture-expanded stem cells are an FDA-regulated drug, their use in this country must follow drug laws, which are very different from the state laws governing what physicians can and can’t do in their clinics. To study a new drug, each and every clinical indication (like all of those listed in the second statement in bold) must have approval from the FDA to perform the study. For cells, this is called a “Biologics License Application,” or BLA.

How hard is it to get a BLA? As an example, the cultured stem cell disc procedure that we offer down in Grand Cayman is going through the FDA-approval process so that eventually it can be used here in the states. By the time the company pursuing this approval gets to start its clinical trial, the company will have spent about 1 million USDs and 18 months on animal studies. Then they must pay another approximately $1 million fee to begin clinical trials. That IRB approval must go through a particular type of IRB, one which has a Federalwide Assurance, or FWA (essentially an FDA-approved IRB). Once clinical safety trials start, they are typically conducted by a university and will cost approximately 1–3 million USDs and last 1–2 years. This clinical-trial approval is only for one indication—the use of stem cells to treat a bulging disc. If the medical indication changes to heart disease, the process must start over. Even if the indication changes from lumbar discs to cervical, the process must start over. Also, full FDA approval will likely take 5–10 years from start to finish and cost approximately 100–300 million USDs.

A key point above is the type of IRB needed to approve a drug study. The right kind is different from the community IRB that’s usually used by many groups to approve same-day stem cell studies. In particular, the right kind is a “super IRB,” which has what’s called an FWA. This certification is sort of an FDA blessing for an IRB that approves drug studies.

Why Would This Company Believe that It’s OK to Use an Unapproved Drug Without Going Through an FDA Trial?

I can’t find any evidence on the agency’s website that American CryoStem has any BLAs on file with the FDA. So on what authority could they claim that they have “approval” to perform the clinical study discussed above on the stem cell clinic website? The company’s SEC 10K filing provides some of those answers. On page 32 they state the following:

“The Company has maintained approvals from the Institutional Review Board (IRB) of the International Cell Surgical Society since 2013 for the Company’s processing protocols for isolating Stromal Vascular Fraction (SVF) or ADSCs from a patient’s adipose tissue; and for culturing mesenchymal stem cells from adipose tissue. These protocols provide validated testing methods necessary to move the clinical investigative process towards uniform disease treatments’ and provide the collection of processing and outcome data required by prevailing FDA regulations and guidance for approval of regenerative cellular therapies, including potency (cell count), contamination testing and cell viability. The Company obtained approval for these IRBs with the Institute of Regenerative Cellular Medicine (IRCM) in 2014, 2015 and renewed the IRB with the IRCM in 2016.”

So we know that the company lacks the most basic approval from the FDA to culture stem cells for clinical use in a trial. Also, this is confirmed by the SEC filing as I can find no reference to any BLA. Second, the IRBs listed do not have FWAs. Hence, they wouldn’t be qualified to approve a drug trial. However, reading between the lines, could it also be interpreted that ACS is only getting approval for a lab process? Hard to tell. I was able to call the IRCM IRB and confirm with its principal that they have been explicit with ACS that their approval was only for lab use and that if the company were to release these cells for clinical use on humans without a BLA, the IRCM would pull the IRB approval.

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Is There Hard Evidence that These Cultured Cells Are Being Used by Doctors?

For this last part, I had one of our employees register for a webinar on the new program being proposed by ACS and the stem cell network. The website and webinar details the game plan for the group to use ACS’s services to culture expand fat stem cells and then use these in patients as part of an IRB-approved study. The doctor involved has to have tests run and has forms to fill out, but the name of this form says it all: “Frozen/Thawed SVF or MSC Expanded Cells for Deployment…” The doctor can order stem cells in as much as 100 million aliquots for his cost of $7,500 (which he then can mark up).

This webinar tied all of the pieces together. There is now a clear trail of evidence from ACS to the stem cell network, and its intent to use these cells to treat patients. The issue is, of course, that no FDA BLA is in place for even a single medical indication, let alone the 5–10 I’ve seen thrown around. Also, there is no IRB approval from an organization with an FWA. In fact, the only IRB approval that exists is to standardize a lab process and not treat patients.

So Am I Excited that Someone Is Again Trying to Open Culture Expansion to U.S. Patients?

When I first heard about this new program sponsored by ACS, I had very mixed emotions. On the one hand, I’d love for someone to take up the mantle of trying to allow culture-expanded stem cells to be the practice of medicine. You never know what could happen in the new anti-regulatory environment of 2017. However, I have no stomach to go there again, so that will require some brave soul willing to pay big money to place his or her head on the proverbial chopping block.

On the other hand, an FDA-regulated tissue processor without a BLA or proper IRB approval working with a provider network to send culture-expanded stem cells in interstate commerce for clinical use is just plain asking for trouble. It is also quite different from a doctor using his facilities to culture expand his patient’s cells. In the former situation, you might as well bring gasoline to a bonfire. In the latter, there was a colorable argument that this is the practice of medicine. As a result, I expect that we’ll see a thermonuclear regulatory showdown between ACS and the FDA.

The upshot? This scheme could be the craziest thing I’ve seen in the last 12 years of performing stem cell injections. While we believe that culture expansion helps some patients, we pushed that rock up the US regulatory hill ages ago, and it was impossible to get to the other side. This ACS-stem-cell-network arrangement requires the physician to be a sub-investigator and sign forms to use a non-FDA-approved biologic drug that has no real IRB approval. IMHO, this places these physicians at tremendous regulatory risk. It’s one thing when you’re just ordering something from a sales rep, but when you’re signing legal forms that discuss you’re participating in a drug study, that’s a different matter. In the latter case, when the FDA shows up, you’re part of whatever comes down the pike.

1/26/17—I was contacted by the IRCM IRB today and told that due to the revelation that their IRB approval for a lab protocol only is being potentially misused by ACS with publicly advertised plans for these culture-expanded cells to be used in the U.S. without a BLA, they have rescinded all ACS IRB approvals.

Chris Centeno, MD is a specialist in regenerative medicine and the new field of Interventional Orthopedics. Centeno pioneered orthopedic stem cell procedures in 2005 and is responsible for a large amount of the published research on stem cell use for orthopedic applications. View Profile

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