Two new FDA inspection reports called 483s provide fresh insights on a stem cell clinic, the network of clinics that it belongs to, and adverse events in patients.
These reports detail issues the FDA found at the stem cell clinic California Stem Cell Treatment Center and its parent chain of clinics, Cell Surgical Network. The latter is an affiliated group of dozens of stem cell clinics across the U.S. generally marketing experimental adipose (fat) stem cell therapies, sometimes called “stromal vascular fraction” or SVF). As far as I know California Stem Cell Treatment Center was the founding clinic of Cell Surgical Network.
For background, this summer the FDA took action on a Florida stem cell clinic and two stem cell businesses here in California, including California Stem Cell Treatment Center and another company called StemImmune that it was collaborating with on a new experimental cancer treatment. The FDA reportedly seized an unapproved product from at least one of the firms here in California, apparently consisting of a combination of adipose stem cells and a smallpox vaccine.
What’s the scoop on these two new documents?
The FDA issued two separate, but related 483 reports: one to just California Stem Cell Treatment Center and the other to both that clinic and the Cell Surgical Network. I’m still reading the documents so it’s not 100% clear to me why two separate (although sequentially numbered) reports were issued, but it may be that two different locations were inspected as each inspection report lists different firm addresses.
Some sections of the FDA inspection reports are redacted and such reports don’t tell a full story yet so there is more to learn about this situation and surely things we don’t now know. Plus, the businesses (and their founders/leaders Elliot Lander and Mark Berman, see screenshot from the network’s website above) have their own perspectives too.
I emailed Drs. Berman and Lander yesterday for their response to these 483s and I’ve posted Dr. Lander’s email reply in verbatim at the bottom of this post. Overall, they strongly disagree with a number of things in the 483s. Some of the differences may stem from a fundamental difference of opinion as to whether SVF is a drug or not (more below).
Berman, Lander, California Stem Cell Treatment Center, and Cell Surgical Network have been mentioned in posts on this blog before and I’ve done interviews with them as well (for past posts see here). Even though Drs. Berman and Lander see things very differently than I do on many aspects of the stem cell clinical arena, I regularly reach out to them and include their perspectives to catalyze more exchange of information and diverse discussion.
The first 483 report on just California Stem Cell Treatment Center alone includes “observations” by the FDA of numerous issues: QC, training, documentation, sterility, product safety determination, and the list goes on. The FDA also refers to the fat stem cell product of California Stem Cell Treatment Center as a “drug product” throughout the 483 and I’m not aware of the firm having FDA approval for such as a drug such as a cleared IND. However, the FDA does not explicitly mention, at least that I saw on my first look at these reports, that the products are unapproved drugs and/or not subject to exceptions. Hypothetically, it may be that if the FDA were to make such a statement of product determination it would not come in a 483, but rather in some other communication. For instance, the FDA warning letter to U.S. Stem Cell Clinic, Inc. mentions that in that case their SVF is a drug.
Importantly, this 483 to California Stem Cell Treatment Center says that the firm “failed to establish written procedures for handling reports of adverse drug experiences” and gave four examples of “serious adverse events” in patients who apparently received stem cells there (note that Lander in his email to me pasted at the end of the post has something to say about adverse outcomes):
- Patient retinal detachment
- Patient hospitalization for confusion and headache with other symptoms worsening at the hospital
- Patient “severe infection” from SVF
- Patient hip pain and hip infection
The FDA says these events in patients were in each case “not investigated and not reported to the FDA”.
The other 483 FDA inspection report, the one addressed to both California Stem Cell Treatment Center and Cell Surgical Network, also raises issues, some of which overlap with the first 483. Two more adverse events are mentioned in this letter: the death of an astrocytoma patient and a COPD patient who apparently passed out, was resuscitated, and then hospitalized after receiving an SVF product both by IV and nebulization.
More broadly, the number of known or alleged adverse events in American patients who were customers at a stem cell clinic continues to rise in the past year, and includes a spinal tumor, the reported blinding of at least three women, and other allegations of blindness. Is the incidence of such adverse events rising or is it just that there is more awareness lately?
Getting back to the current situation with the stem cell clinic California Stem Cell Treatment Center and Cell Surgical Network, the two 483 reports also indicate that the SVF fat stem cell product was administered to patients in many different ways that each could have their own potential risks in addition to possible risks of the product itself: (1st 483) intravenously (IV) or IV combined with “intra-articular, intrathecal spinal injections, intravitreal injection, intramuscular injections, spinal taps, nasal nebulization”; and (2nd 483) additional locations including “into soft tissue” and “intra-cerebroventricular injection”. That last phrase stands out as it suggests direct administration of stem cells into the brain of one or more patients at the stem cell clinic. How was that done and would that be safe to do in this context?
There is much more in these 483s than I mentioned in this post, but the above points are the things that struck me as important on first reading. I’ve included my sense of those and initial opinions. Again, other stakeholders such as those who run a stem cell clinic are likely to see things differently than me and disagree on certain points.
From Dr. Elliot Lander, co-Founder of Cell Surgical Network, in reply to my inquiry on the FDA inspection reports:
“The FDA did not “randomly” find 4 complications during their inspection. We shared with them our CSN database transparently demonstrating EVERY adverse event for the entire country. Our online database collection of adverse outcomes data covered nearly 7000 patients. What surgery do you know of where there are only 4 complications out of 7000?
They were not “reported” to the FDA because your autologous SVF is not a drug and does not have to obey approved drug reporting rules. However, they were all reported to the IRB and fully investigated. The macular degeneration investigation resulted in an immediate moratorium on intravitreal injections. This protected any other future patients from eye injury and was prudent since we now know that SVF inside the vitreous chamber can be harmful. A second patient had meningeal irritation after central nervous system deployment but no infection was detected and the patient promptly improved. A third had reported knee infection subjectively but laboratory and orthopedic evaluation demonstrated no evidence of infection. A fourth had a hip infection but the IRB investigation determined that it was not due to the SVF product and instead to a skin contamination incurred upon injection.Our investigational work stands on its own. Our SVF system is safe. Our database is robust. Our results are excellent. SVF has amazing clinical qualities.
We wish to fully cooperate with the FDA’s efforts to make sure products given to humans are safe and sterile. We have been in close contact with the FDA regarding the application of GMP manufacturing rules in the operating room for the evaluation of procedures performed by physicians on a person’s own personal cells and tissues. A GMP laboratory would never produce adipose derived SVF for a “contaminated” patient if they had HIV or hepatitis, but physicians do it every day in the operating room. Are patients with chronic viral illnesses less entitled to the benefits of SVF? Surgical sterility can protect patients receiving their own personal cell product. GMP is needed for products that are mass distributed.
We hope to help the agency understand the unique regulatory needs of autologous biologic products as this area of medicine moves forward rapidly.
Personal medical access to one’s own healing cells is a BASIC HUMAN RIGHT which transcends arbitrary regulation of those tissues as a “manufactured drug.” We must find ways to protect patients from exploitation while at the same time protecting the science and innovation. Criminalizing SVF personalized medicine is a bad place to start. Rather than legally restricting access to certain autologous cell therapies, we propose an online registry for efficacy and safety for all physicians involved in regenerative medicine using any autologous non engineered cells. This would give us real time information on what works and what is not effective or safe. Participating physicians would be expected to avoid misleading or irresponsible claims and transparently collect data. There is a lot of support for such a concept from both industry and academia as well as clinicians. That is the future. “
So Cosmetic surgeons who specialize in facelifts and boob jobs are now performing intra-cerebroventricular injections on patients with neurodegenerative disease?
What could possibly go wrong.
The registry is for all physicians company wide. Not just Beverly Hills. Also it does not say that they didn’t bring in a neurosurgeon to perform the operation. You are just speculating.
Paul, two 483’s were issued since there were two different inspection teams on different dates. Also, the inconvenient truth is that CBER / FDA has opined that SVF do not meet the requirement of being “minimally manipulated”, which may impact their “normal” biological activity. Basically, much more complex than an organ or tissue transplant. This puts SVF in the same category as “drugs.” And to the claim that these are now “mass produced” drugs, 7,000 doses sounds like mass production to me. That said, I agree that the water is still murky here and definitions of what is “minimally manipulated” are likely to change, but that’s the line in the sand that CBER has drawn.
Dr. Berman used the words “Mass Distributed” in his above statement and it’s a good point which I think is being misread. Specifically, “GMP (Good Manufacturing Practices) is needed for products that are Mass Distributed”. He did not say “Mass Produced”
The SVF in these instances were being administered in a one to one fashion from the very patients it was derived. In other words…Autologous. Furthermore, it was not being transported across state lines to be distributed ultimately to 7000 other patients.
The, FDA needs to involve itself in matters involving Mass Production for Mass Distribution across state lines (interstate commerce in other words) ultimately for Mass Consumption. The treatment in question (SVF) was returned to the very same patients from whom the SVF was derived at essentially the same membership facilities…(Cell Surgical Network.) These treatments were Autologous only for each of the 7000 SAME patients. These procedures were not Allogeneic or one to 7000 OTHER patients. If they were then the FDA might have some cause for concern.
@Douglas,
I don’t know of any requirement for “mass distribution” or large scale production in order for the FDA to have oversight or for GMP to be required.
For interstate commerce to be triggered, all that is required is that some component of the production process has crossed state lines.