I recently interviewed Drs. Elliot Lander and Mark Berman of the Cell Surgical Network. It’s an affiliated chain of clinics selling stem cell interventions for more than a dozen medical conditions. You can read Part 1 here and Part 2 here of the interview where we cover 10 important questions.
Today is Part 3, where I explain why their answers deeply trouble me.
Cell Surgical Network
First, let me answer a question myself: why interview the leaders of the Cell Surgical Network, especially if I felt going into it that I would likely disagree with them on many things?
It is important to catalyze dialogue in the stem cell field; that is one of the missions of this blog. As I’ve said before, it is easy to talk to someone with whom you agree on most everything, but it is much harder and yet nonetheless probably more rewarding to dialogue with those with whom you disagree.
Further, I specifically see value in shedding light on how the Cell Surgical Network conducts stem cell interventions and on their views on the regulatory landscape.
Why?
Because they are a group of dozens of clinics (see their map above) potentially doing interventions on hundreds or thousands of patients collectively. I’m concerned about risks for those patients and possible future patients. Many physicians who are relative newbies to the stem cell field who are part of the Network could be putting their careers at risk too. Therefore another part of the rationale for this blog post series was educational.
Dialogue
One of the deepest differences that I have with Drs. Lander and Berman is related to my core belief in evidence-based medicine. I believe in having compelling pre-clinical evidence before you start to do a specific kind of new or experimental medicine on human patients. To my way of thinking, for example, prior to getting even one patient involved with an experimental medical approach you should do pre-clinical studies on animals for a given medical condition with the specific medical intervention in question. Then you collect data on safety and efficacy. If these studies are convincing to you, to regulators, and to your community (via peer review and publication) you start the process of possibly doing clinical studies in patients. To my knowledge this has not been the path taken by Cell Surgical Network. If I am mistaken about that, I hope that they correct me. Perhaps they do not define their interventions as experimental, but they are doing a clinical trial and to me at least their work seems like experimental clinical research.
Another concern pertains to whether Cell Surgical Network’s way of doing things would be considered compliant to the FDA. The Cell Surgical Network said the following of the FDA in the interview with me:
Finally, the FDA has audited our IRB approved protocol and there was never any communication indicating that it wasn’t appropriate. Out of the 29 protocols from the ICMS IRB reviewed, only one was rejected by the FDA (not ours). That, in itself, is an indication that we are not in any violation of FDA regulations.
My understanding is that the FDA audited the International Cellular Medicine Society (ICMS) in general. ICMS is an organization that administers a host of IRBs, only one of which was the Cell Surgical Network IRB at the time of the FDA audit. As a result, I disagree with the characterization that the recent FDA ICMS audit results are specifically an indication that the Cell Surgical Network is compliant with FDA regulations.
Cell Surgical Network device
Another issue is the device used by the Network. As Alexey pointed out in the comments on an early part of this blog series on the Network, it seems the Medi-Khan column used by the Cell Surgical Network to make their biological SVF product is not approved by the FDA for that specific application. This could be a very serious problem.
The Cell Surgical Network also argues further that their SVF product is not laboratory prepared, but rather is surgically prepared and is hence not subject to FDA biological drug regs. I’m not convinced by that argument. The use of collagenase and then centrifugation of a fat product through a column would seem to me together to be a laboratory procedure. I believe that the FDA public guidance in this arena that is relevant to how the Cell Surgical Network prepares their product strongly indicates that it is in fact a biological drug as defined by FDA. This is a crucial point as to my knowledge the Cell Surgical Network does not have FDA approval to use a biological drug.
An additional problematic area in my view is the issue of homologous use. In this area, Lander and Berman seem to argue that their SVF product is a progenitor/stem cell like product that defies non-homologous use categorization because it can in essence turn into almost anything in the body due to its cellular potency. I don’t buy this argument. SVF contains a complex mixture of many components some of which are stem and progenitor cells, but it is nonetheless still an adipose derivative. In my opinion an adipose derivative is not pan-homologous to any other tissue such as the nervous system or many others for which the Cell Surgical Network treats many patients.
Pay-for-play
Regarding my question to Drs. Lander and Berman about patients having to pay the Network for participation in its clinical trials, I also philosophically disagree with them. I do not personally believe in collecting millions of dollars from patients for interventions that are still arguably, in my opinion, experimental.
I also am concerned with such a big group of clinics that the Network may be enabling inadequately trained physicians to conduct SVF-based therapies, potentially putting a large number of patients at risk. Physician training in stem cell and cellular medicine therapies is a top priority for me.
In the end, you can see I have many concerns about how Cell Surgical Network answered my questions and how they do interventions with patients. I welcome more dialogue with them and readers of this blog.
Disclaimer: the statements in this opinion piece are solely my views, not facts, and I certainly expect a spectrum of opinions on these important topics.
Note: Since this piece was published, Mark Berman died in early 2022, apparently of COVID-19.
This Comment is from Dr. Berman of Cell Surgical Network in response to this post. – Editor.
April 8, 2014
This is a revised version of my response to Dr. Knoepfler from December 27, 2013. A few issues have come up since then that I have taken the liberty of adding.
This note responds to specific comments made in an earlier critique from Dr. Knoepfler.
First, Dr. Paul Knoepfler (PK) states “I believe in having compelling pre-clinical evidence before you start to do a specific kind of new or experimental medicine on human patients.” I suggest that Paul would be waiting around a long time before he ever got a dose of antibiotics or had a lifesaving surgical procedure performed upon him. Most advances in medicine have been empirical. If appropriate, we back up our empiric findings with evidence based studies. Many studies, however, rely upon outcomes evaluations to deliver empirical data. Not every study is based upon placebo trials. Unfortunately, surgical procedures are not always easily or ethically able to apply double blind placebo testing. It’s not uncommon that we rely on outcomes studies. That doesn’t always mean they are correct. In my own specialty of cosmetic / plastic surgery, there is no shortage of surgical procedures that have been published in excellent peer-reviewed journals only to be discarded for lack of efficacy or inability to recapitulate by others. Nonetheless, when large numbers of doctors do recapitulate information based upon effective interventions, then a significant degree of validity may come out of that. Ideally, one could then go back to the lab or develop an evidenced based protocol that could be ethically carried out to prove “why” the outcomes are actually effective. And, while that may be the ultimate way to prove that a surgical procedure or a medical treatment truly works, we’ve been doing that in the lab for many years without much to show for it. By doing empirical studies and recapitulating the findings among a multitude of physicians, we will have sufficient data that will allow us to set up proper hypothesis to prove our findings. PK wants to prove everything before trying it. That’s a new concept compared to the practical and normal evolution throughout the history of medicine.
Further, there are reams of evidence throughout the world that adipose derived SVF works and is safe. Further, we have doctors in the USA, such as Dr. Centeno, who have provided efficacious treatments with bone marrow derived cells for many years. When we started the study the major criticism was that you don’t know if it’s safe, so consequently, we made the primary objective to look for any adverse events, thus making safety the primary concern. If it’s not safe, then the project would be discontinued. A properly informed patient should have the right to make the decision to participate – and they do.
Next, Dr. Knoepfler discounts our initial ICMS IRB audit. IRBs are under the jurisdiction of the US Office of Human Research Projects but the FDA has the
right to audit IRB approved protocols to make sure they are in compliance with FDA regulations. While I don’t think the FDA would approve any of our procedures (they can’t because they are surgical), they did indeed audit 29 protocols and found only ONE non-compliant because they had previously applied for an IND. They saw our protocol and could have easily contacted us, reviewed us, recommended discontinuation of our program, etc. They did none of those things. We would never claim that makes us FDA approved. The FDA can’t and never will approve us just as they don’t and can’t approve any surgical procedure. The FDA approves drugs and devices.
It should be noted that our original IRB approval was gained through ICMS. We have had some differences with ICMS and have mostly parted ways. We have IRB approval for our investigational deployments through the International Cell Surgical Society IRB which like ICMS; IRB is regulated by the Office of Human Subjects Research (OHSR) which is a division of the Department of Health and Human Services (HHS). We currently have at least eight approved IRB protocols – hardly representing an organization trying to fly under the radar.
Next, Dr. Knoepfler has issue that our devices are not specifically approved to produce SVF. The device is simply approved for collecting and condensing fat. Nonetheless, there are a plethora of approved devices and medications that have very limited approval and are commonly used “off-label.” There are a number of reasons this occurs, but frankly, it has always been up to the surgeon/physician to determine the best use of devices and drugs once they’ve been approved. There are simply countless numbers of devices that have approval for one or two uses yet are implemented in a variety of ways not included under the FDA approval. For obvious reasons, no drug or device company could possibly get approval for every use that doctors ultimately conjure up. There are a plethora of examples and I’d gladly provide plenty if deemed necessary.
Next, collagenase is ONLY an issue because it has largely been produced as a bovine byproduct and may carry TSEs. Medical grade collagenase is available for medical use already so a doctor that wants to use it can anyway they want to use it. In fact, one company has approval for direct injection of collagenase for Peyronies and Dupuytren’s Contractures. Clearly, the FDA has no issue with the presence of collagenase in a body. Thus, this no longer becomes an FDA issue, but rather a medical board issue. Once a drug has been approved, then it’s up to the state medical board to determine it’s not being used in the patient’s best interest. If I worked at the FDA and had to respond to any of these letters of inquiry from different doctors asking if it was okay to use collagenase to produce stem cells, I’d give the same response as the TRGs. Why should the FDA give approval of anything in writing without seriously evaluating it? There’s no benefit to the FDA to do such. Not giving such approval does not equate with making such a practice illegal or even unethical. None of the letters to the FDA ever specifically discuss the exact kind of collagenase they intend on using. Cytori
made a point for quite some time that their system had the only “proprietary approved enzyme” approved by the FDA. That’s no longer the case, as GMP collagenases are now available elsewhere.
Also, as noted previously, it seems EVERYONE, including Dr. Knoepfler, neglects the very first part of the FDA regulation (21 CFR, part 1271) – namely, the purpose is to “prevent the transmission of communicable disease.” This is why the FDA has jurisdiction over any of us, but laboratory procedures in particular. We do not utilize any laboratory equipment or personnel to produce SVF. Once you use even a laminar flow hood, the FDA has a list of compliance issues necessary to be followed. Because our procedure involves only single-use disposables or sterilized surgical supplies and has been set up as a completely closed sterile surgical procedure, there is no risk of transmission of communicable disease and nowhere for the FDA to search out problems. As a surgical procedure, we indeed validate sterility – by our technique and by our autoclave processes (daily logs, spore testing, and regular maintenance). The use of collagenase to change characteristics of the cells is not really an issue. Collagenase is an approved drug already. It breaks down collagen and doesn’t enter a phospholipid cell membrane. We did evaluation studies to further prove that we effectively wash out or dilute all practically detectable levels of the collagenase from our SVF specimen. Besides, if the FDA has approved it for direct injection into a body, what difference does this even make? It’s simply a non-issue under our circumstances.
Oh, and while everyone is all excited about us using collagenase in a completely closed sterile surgical system that revolves around the FDA mandate from the US Congress to prevent transmission of communicable disease, what should surface other than now it appears some 261 stem cell strains developed by our friends in the lab have not been validated to be developed for therapeutic use.
(http://www.thescientist.com/?articles.view/articleNo/39110/title/Stem-Cell-Lines-Not-Fit-for-Clinic/)
From this article: “As of today, the NIH registry contains 261 stem cell lines eligible for federal research funding. Most of the originating donors of the cell lines did not undergo screening for a number of diseases as required by FDA guidelines. This has been described as “a major roadblock on the path from laboratory to the clinic.”
Next, are you really concerned about the issue of the cells being homologous? In surgery, we use cells and tissues for non-homologous purposes all of the time. The FDA cannot stop a heart surgeon from using a vein graft in coronary artery bypass surgery. Nor can they stop us from using cells in surgery for non-homologous purposes. We have been using fat cells (loaded with stem cells) as homologous and non-homologous grafts since the late 1980’s. We now know that a fat graft only survives because it is also a stem cell graft (Yoshimora), but
as a surgical procedure the medical community and the state medical boards are the only ones that can tell us to stop using fat grafts. Since a fat graft is loaded with stem cells, why haven’t you been telling us that it may be unsafe and we should do evidence based studies before we use them. Nearly thirty years has gone by and fat grafting has grown in popularity largely because of empirical findings. Arguably, it certainly must lend some proof that adipose derived stem cells when transplanted elsewhere are safe. If they could cause cancer or some other serious problem, you would have already seen it with fat grafting.
Finally, as far as payment, we are privately funded. This is completely acceptable and so noted on the FDA website. During the recent (1992-2007) moratorium over silicone gel breast implants, gel implants were only available as part of a large clinical trial. There were no evidence-based studies, rather a huge outcomes study from throughout the USA. Indeed, Mentor and Allergan (formerly Inamed), were making in excess of $300 million dollars annually while conducting this study.
In our particular study, we recognized that we are likely doing a great service based upon the large number of acceptable programs throughout Eastern Europe. We know that patients are currently paying $30,000 and up to $80,000 USD for treatments abroad. We believe our pricing is fair and we are rather flexible throughout our entire network. We’ve treated many patients for free and many at significantly reduced prices. We often see patients that may benefit, but we have no idea how they’ll do, we discuss the risks and then treat them at no cost. We’ve learned a lot from this. Ultimately, we will be able to appease the naysayers with evidence-based studies, but our empirical data is extremely important and shouldn’t be minimized by so many “special interest groups” that appear to be more self-serving than really caring about our patients. Further, we have always freely disseminated our knowledge so that other doctors could try for themselves. The fact that we’ve grown a network is simply because our colleagues see benefit in being part of this larger group and sharing in our huge database. Finally, we have medical mal-practice coverage for all of our members with at least two major insurance companies willing to provide coverage. Since when do insurance companies back “dangerous” causes?
One other note about the ethics of private funding – we aren’t taking money from anyone other than our patients who are fully informed. A properly informed patient should have the right to do as they please with their money. However, what is the ethical basis for government backed programs like CIRM, that have already spent in excess of $1.6 billion USD giving money to hugely prestigious universities to build huge offices and laboratories when many of these universities have endowments far in excess of the millions they receive as free government grants. Frankly, I find that outrageously egregious violation of ethical behavior. Our tax dollars have funded numerous programs already rich beyond imagination. That, I contend, is far more unethical than our program that has grown on its own merit.
Finally, it’s simply our duty as physicians to help our patients if and when we can. We have a good mousetrap available now. Indeed, a better one may come along, but in the meantime, we are helping our patients while we gather useful information. So far, we are learning this is safe and there are growing trends in our outcomes to indicate when and where we will get largely positive results. We value the work of our colleagues in the lab and know there are many breakthroughs on the horizon – in the meantime, we have patients that can be cared for effectively even if not in the absolute most optimal way.
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I have read with interest the criticism with regard to use of certain enzymes in extracting SVG or used in the processing fat and extracting the stem cells. I especially take issues with the concept that this is manufacturing of a biological drug. My thought is that the physicians here appear to be in specialties other than Plastic Surgery or non clinicians, research Phd’s. It is understandable that these criticisms of the Cell Surgical Network are because they may not be familiar with what has been common CLINICAL practice in plastic surgery and actually has increased currently with the use of cosmetic wrinkle fillers. That is the injection of Hyaluronidase, Collagenase and others directly into patients tissues (in vivo) to enhance liposuction, dissolve plantars facititis and dupytrens contracture, burn scars and more. Most recently these enzymes are used to dissolve excess fillers such as Juviderm as well as Restylene lumps etc by direct injection, which is done daily around the world. As far as I know there are not extensive clinical trials or pre clinical studies done for this use , but it was found empirically and is indeed a clinically accepted practice. So logically, if your going to inject these enzymes directly into patients tissue, then according to the argument against the Cell Surgical Network, the many thousands of physicians who do this routinely are manufacturing drugs not in a lab, but in the patient themselves. So the FDA should regulate this common clinical practice ? Just a thought, but this in some form has been going on for many years clinically long before stem cell extraction was being done or considered.
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