Cell Surgical Network Series Part 3: Opinion Piece on Key Concerns

I recently interviewed Drs. Elliot Lander and Mark Berman of the Cell Surgical Network, 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.

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.

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.

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.

Cell Surgical Network Interview Part 2: SVF, FDA, & Homologous Use

Cell Surgical NetworkToday I am posting Part 2 of my interview with Drs. Lander and Berman of the Cell Surgical Network.

You can read Part 1 here, which is an interesting look inside the Network. The final portion of this blog post series, Part 3, is my take on their answers and you might not be surprised that I often disagree with them.

Today, the questions are focused on some very critical issues for the Cell Surgical Network including potential FDA regulatory factors for the Network, the definition of their SVF product (biological drug or not a drug), and whether homologous use (see more on homologous use here) applies to their clinical interventions. In addition, I questioned them about why patients have to pay to be part of the Network clinical trial. I also asked for their vision of the future.

1. There seem to be some divergent views on SVF. On occasion the FDA has indicated that in certain circumstances that SVF is a 351 biological drug not strictly regulated by 361 HCT/P regs, but it seems this is on a case by case basis. On the Cell Surgical Network websites it is stated unambiguously that the Network clinics do not need FDA approval for use of SVF. Why do you hold that view? Have you received guidance from the FDA that your SVF product is not a drug? Have you met with the FDA to talk about these kind of issues and if so, how’d that go?

Lander/Berman: I asked Dr. Berman to weigh in on this and here are some of his comments…It seems everyone seems to ignore or forget the PURPOSE of 21 CFR part 1271 – namely to prevent the transmission of communicable disease.  The only reason the FDA can claim that HCT/Ps are a drug is if they are being processed in a laboratory manner or have the potential of transmitting communicable disease.  Once you use a laboratory to process the cells you are under FDA jurisdiction and they have a list of validation procedures they require all facilities to meet.  It’s rare that a physician with a laminar flow hood or a laboratory actually meets these validation standards.  If they don’t meet these standards, then the FDA asserts that there is risk of disease transmission and as such claims authority and requires an IND.

California Stem Cell Treatment Center  and all members of the Network use a completely closed sterile surgical procedure to isolate SVF (not pure stem cells).  There is no laboratory processing of the cells.  All supplies, devices and drugs are already FDA approved though not specifically for SVF / stem cell production.  As is typical of many surgical devices and drugs, it is completely legal, ethical and appropriate to use approved products “off-label.”   While we have followed the FDA exemptions listed in part 1271, we are not really under the FDA jurisdiction as they have NO jurisdiction or ability to approve surgical procedures – just devices and drugs.  Since we do not use a laboratory method to produce SVF, only a surgical method, then there is nothing for the FDA to validate in our process.  There is simply no risk of transmission of communicable disease.  Arguably, Ceteno (sic), Celltex, Intellicell and others all have laboratory involvement that didn’t meet FDA standards for GMP production of HCT/Ps.  The FDA mandates are based on the Congressional desire to prevent organ donors from transmitting disease – so it isn’t a question of mass numbers (as one sees with most drug productions), just a question of validating one’s laboratory procedures.

We produce SVF (over 40 ingredients and can’t be characterized) in a surgical procedure (can’t be approved by the FDA – they’ve never approved a surgical procedure).  If the FDA can’t approve a surgical procedure, why would we possibly request them to approve this procedure?  Also, since the FDA is concerned that they could be responsible for any drug they approve, it’s unlikely they would approve anyone by written request as it would leave them liable without having done their “due diligence.”

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.

2. Your website & clinical trial page indicate that the Network treats perhaps as many as a few dozen different conditions with SVF (http://www.stemcellrevolution.com/currently-studying/). What is the evidence to support such diverse, seemingly in many cases non-homologous use of SVF?

Lander: We do have many conditions that we are looking at and in choosing them we have attempted to exploit either the regenerative, immuno-modulatory, or anti-inflammatory properties of SVF. Although SVF is used in all of our protocols, our deployment techniques vary considerably. I think the term homologous has been used rather loosely and in the field of regenerative medicine, a new paradigm defies simplistic categorizations of cell types. After all, what type of tissue is an undifferentiated progenitor cell? Can it be homologous? Isn’t it potentially everything? For example, if it forms cartilage then could it have ever been anything other than a cartilage precursor? Our comfort zone is that we are surgeons performing a type of surgical tissue transfer procedure. There is no difference than when we replace a bladder with ileum or a coronary artery with a saphenous vein from an extremity. At the end of the day, the ability to use various tissues to treat human disease is within the realm of a surgeon’s domain.

3. In terms of mechanism, how do you believe the SVF therapy works to help patients with specific conditions? Is the mechanism more of a “cell therapy” approach where the cells engraft and help heal a tissue or is it more of a trophic/growth factor mechanism where SVF stimulates existing tissue and cells to become healthier? Both? Depends on the condition?

Lander: Our SVF is essentially uncharacterized but we do know that it contains a rich broth of cells and growth factors. Although there may be conditions of engraftment and transdifferentiation of cells, the autocrine and paracrine effects of the growth factors play a major role in the healing effects we are seeing. This may explain, for example, why it is possible to treat neurologic diseases by mitigating nerve damage using cells that may not easily form nerve tissue.

4. In the Network clinical trial (http://clinicaltrials.gov/ct2/show/NCT01953523?term=cell+surgical+network&rank=1) do the participants have to pay to participate and if so why and how much?

Lander: Our project relies on patient funded research. We are very transparent about the fact that we are a research organization but also a business entity. Treatments are generally 6 to 9 thousand dollars but that can vary. We set fair prices back when we started in 2010 and thereby provided an alternative for patients who at that time were going overseas and paying 30-90 thousand dollars for nebulous treatments. Most government grants mandate that we apply for an IND investigational new drug application with the FDA. Pharmaceutical companies may not perceive value in our research because it is hard to monetize and commercialize autologous cells.  Charitable sources are difficult to obtain and so we have turned to our patients. This is a reasonable approach yet we are always reminded that our consent process for paid investigational procedures must be very specific and comprehensive.

5. How did you first get interested in stem cells and what excites you the most about stem cells looking to the future?

Lander: The serendipitous identification of large numbers of readily accessible adult mesenchymal cells in fat has offered a unique opportunity for physicians to help their patients treat disease. Physicians take the Hippocratic Oath which mandates that we must do everything in our power that is safe to help our patients. Clinicians need to collaborate closer with basic science researchers to move the translational ball along farther. Our safety data is excellent so far. We hope to provide placebo controlled trials using cryo-preservation of SVF in the near future.  Physicians from different specialties will be bringing their expertise to our organization and we are watching our database grow. The future has so much potential as we learn to define which cell types, deployment methods, and combination of growth factors work best for specific diseases enabling us to distinguish optimal treatments.

Elliot Lander & Mark Berman Interview Part 1: A Window into Cell Surgical Network

Elliot LanderMark BermanThe Cell Surgical Network is a large and growing group of affiliated stem cell clinics across the US.

The Network providers use stromal vascular fraction (SVF) interventions for a host of conditions on a for-profit basis. Drs. Elliot Lander and Mark Berman lead the Network.

They agreed to do a Q&A interview with me. Below is Part 1, which delves into the Network itself.

Part 2 on SVF, the FDA, and issues of homologous use can be read here.

Part 3 of this series is my reaction to the interview and to Drs. Lander and Berman’s specific answers.

Here is today’s part of the interview.

1. The Cell Surgical Network is very novel as a linked group of stem cell clinics across the US and some abroad. What is its history? How did it come into being?

Lander: In early 2008, using equipment designed by Dr. Hee Young Lee in South Korea, Dr. Mark Berman, a cosmetic surgeon and an international expert in fat transfer, began isolating concentrated fat for cosmetic uses.   With Lee’s technology and further consideration after visits in Japan with Dr. Katoro Yoshimura and others, he quickly realized the therapeutic potential of SVF for degenerative diseases based on extensive animal studies and clinical work in the US, Europe and Asia. Dr. Berman, in collaboration with Dr. Tom Grogan, a Los Angeles orthopedic surgeon, began empirically using intra-articular injections of SVF for various orthopedic uses and found that their experience matched the positive outcomes described in the literature. I became intrigued with their positive results and we began collaborating to develop research protocols to test for safety and efficacy of various methods of SVF deployment for several degenerative conditions. We formed a multispecialty team and developed protocols to treat orthopedic, urologic, cardiovascular, pulmonary, auto-immune, wound care, and several other disease entities.

It became apparent that to achieve the kind of numbers we need to establish safety and efficacy; we would need a multicenter trial performed under the auspices of an IRB. You can find our study on www.clinicaltrial.gov registered under #CSN111. We were interested in teaching our closed surgical procedure to selected physicians around the country and we created the Cell Surgical Network™ to accomplish this in a high quality and standardized fashion. We also employ a full time clinical research coordinator and support a university quality online database to collect valuable outcomes and safety data. Our Cell Surgical Network™ has treated more than 1000 patients with autologous SVF without any serious complications.

2. What is the current status of the Network today? Is it continuing to grow? How do you evaluate clinics that are interested in joining? Do you sometimes turn down applicants and if so, why? Where do you see the Network say in 3-5 years in the future?

Lander: Our network is growing organically and we do not solicit our doctors. Most of them reach out to us based on word of mouth or referral and we select physicians based on reputation and interest in regenerative therapeutics. We have a credentialing process and a standardized and thorough training program to ensure that our affiliate physicians are performing surgical techniques properly and that they are focusing on education and avoiding claims in their interface with the public. We encourage our affiliates to use their multispecialty team members to carefully evaluate applications for SVF deployment to make sure that patients receive appropriate treatment and it is routine for us to decline at least 25% of the patient applications we receive and we often offer free treatments for new diseases if we are attempting to learn more about them. Our goal is to have regenerative therapies available everywhere in the world where surgeons can use patient’s own tissues to help them contend with disease. It is our hope that our Network will play at least a minor role in that vision coming to fruition over the next few years. We certainly will be providing vast amounts of clinical data to the field of regenerative medicine as we accumulate outcomes and safety data and we hope to contribute to improvements in deployment techniques that may be helpful for both autologous and other cell based therapies globally.

3. What are the uniting elements that link the various Network clinics together? A shared philosophy? Do the clinics share methods and apparatus?  Do the clinics share an IRB? If so, what is the IRB?

Lander: Our clinics are all independently owned but share our ICMS IRB and use the same training, methods and equipment. In order to provide meaningful data, it is imperative that we are all doing the same protocols. We share the same online database and we share the same mission statements, commitment to ethical practice, and vision of advancing our field and making cell based therapy readily available.

4. An Internet search suggests you use the Lipokit by Medikan to produce stromal vascular fraction (SVF)?. Why did you pick that approach and how has it worked for you & the Network clinics?

Lander: We use the MediKan equipment – now branded as the CSN – Time Machine™ because my partner, Dr. Berman originally obtained this equipment in 2008 and then upon visiting Japan and watching Dr. Kamakura with the Cytori machine and Dr. Yoshimura with the same MediKan equipment made an obvious decision.  If it was good enough for Kotaro  Yoshimura, arguably one of the top SVF / fat specialists in the world, it was good enough for us.  We just needed a safe GMP grade enzyme – which came along in July 2010 thanks to Roche Laboratories. We just had to refine the system so that it was completely closed, sterile and provided filtered cells. This has allowed us to reliably produce excellent quality SVF and no culturing or cell manipulation is required. There is no laboratory aspect to our SVF procurement.

Stay tuned for Part 2.