Should a Medical or Scientific Standard Be Used for SVF Regulation: A Review of the Bernal Decision
The recent Bernal decision on the use of Stromal Vascular Fraction (SVF) by California doctors has thrown the whole cell therapy industry into disarray. In particular, there have been many scientists commenting online or in press releases that the judge got it wrong. So this morning let’s delve into the science behind the decision and look at that from both sides-as a scientist and as a physician. Let’s dig in.
SVF, FDA, and the Bernal Decision
Several weeks ago, a long-awaited court decision was released on the use of stromal vascular fraction (SVF). This is created by taking fat tissue via liposuction and digesting it with an enzyme to break down the collagen which releases many different cell types. A small percentage of these cells are mesenchymal stem cells, so if you centrifuge the remaining product, that can be used as an injection similar to how we use bone marrow concentrate. There is an emerging research base that this SVF can be used to treat orthopedic problems and other issues.
The FDA had taken the position that when a doctor created SVF in their office this constituted the manufacture of an unapproved drug. Their position was that this processing was more extensive than they permitted without drug approval and that the normal physician exemption didn’t apply because the cells that came out of the process were different than those harvested from the patient.
The FDA had previously won two prior attempts to challenge this regulatory concept that doctors could be manufacturing drugs through processing the patient’s own cells (autologous). However, the third attempt at shutting down physicians who were creating SVF in California didn’t bounce in their direction. Judge Bernal in the California district court that serves the LA metro area sided with the doctors. His position was that their autologous fat processing was the practice of medicine and off-limits from FDA regulation.
The Shockwaves From the Bernal Decision
Given that we have many companies pursuing FDA drug approval for autologous cell drugs and at least four companies that are in the midst of expensive FDA-sanctioned clinical trials to use SVF for orthopedic problems, you might imagine that the cell therapy industry is not happy about the Bernal decision. Basically, if upheld, Bernal would mean that companies and their investors would stand to lose billions trying to get FDA approval. In addition, the organizations that have sprung up to support this upcoming cell-drug industry would now find themselves rudderless. Finally, legions of scientists at major universities who have licensed their discoveries to these companies would suddenly find their patents hard to enforce and worth little.
Because of the above, there has been a steady stream of criticism of judge Bernal’s decision in the media, science blogs, and in press releases. For example, here’s one from the ISCT:
“Firstly, the ruling made several statements concerning stromal vascular fraction (SVF) that are both inaccurate and unsupported by current scientific knowledge. The ruling mistakenly claims the production of SVF is essentially equivalent to surgery…”
In reading many of these published pieces online, the beef that the cell therapy industry is taking with the Bernal decision can be summarized as follows:
“The act of creating SVF changes the cells into something new in a way that surgery does not, meaning judge Bernal was in error when he stated that creating SVF was no different than surgery. Hence we need drug regulation to protect the public from this new product.”
Before I dive into this scientific argument, I am very much in the middle of this decision. Regenexx has licensed a commercial drug candidate to treat low back disc bulges and that company has obtained FDA IND approval for a phase 2 clinical trial. Hence I stand to gain financially if Bernal is overturned. We have also licensed a second drug candidate which is not autologous and that wouldn’t be impacted.
Having said the above, I’m a practicing doctor, so if SVF became legal nationally to use (it is only permitted right now in the LA metro area), my patients would be the beneficiary of that decision. Meaning as a physician, I would have more cell therapies to offer my patients. That of course would financially benefit my practice and likely Regenexx.
The Case For and Against Attacking the Science Behind the Bernal Decision
The argument being used for and against Bernal all depends on the size of the magnifying glass and how that information is applied. What I mean is that you can easily show that any type of processing changes certain characteristics of the cells being processed, you just need to look very closely. However, the problem with the cell therapy industry’s position is that using that same level of scrutiny on the cells that make up surgically transplanted tissues will also show that the cells are changed by simple manipulation.
On the flip side of this argument, the credibility of the physician’s position also depends on not scrutinizing the tissue too closely at the cellular level. For example, if the cells processed using SVF are not meaningfully different from a clinical standpoint, then functionally they are the same cells. This is the direction that Judge Bernal’s argument took. In favor of the physician’s argument is that if the cell therapy industry wants to use a big magnifying glass then they have to apply that equally to SVF and the tissue moved around the body during surgery.
What is the Magnifying Glass?
Over these past few decades, our ability to easily measure the microscopic characteristics of cells has exploded. We can now routinely look at things like cell surface markers and gene expression. We can accurately measure the chemicals secreted by cells hundreds or thousands at a time. In one respect that’s great because it allows us to follow cell processes down an infinite number of rabbit holes with some of those investigations leading to new discoveries that help patients. On the other hand, it’s sometimes analysis paralysis that ends up confusing and obscuring discoveries that help patients. Meaning while artificial intelligence systems may one day be able to make sense of all the data we can gather about cells in real-time, our human brains are generally not intelligent enough to make sense of it all so it usually looks like noise.
The Position of the Cell Therapy Industry
Making SVF Changes the Cells
These publications support that the enzymes or processes used to make SVF changes the cells:
- Collagenase (the most commonly used SVF enzyme) changes the cell surface markers on mesenchymal stem cells (MSCs) (4).
- When comparing the mechanical separation of cells from fat to SVF using an enzyme, the SVF cells expressed few stem cell markers and had different gene expression (5).
- While mechanically separated MSCs are similar to those that are obtained by SVF, they are not the same (6).
The Position of Physicians
Surgery Changes the Cells
Here are publications that support that the routine surgical manipulation of fat changes cells:
- In breaking down fat surgically so it can be injected (creating nanofat) the decreasing diameter of the holes used to do this changes the ability of the cells to make new fat cells and promote new blood vessel growth (adipogenic differentiation and angiogenesis). (1)
- Liposuction using a water-assisted FDA-cleared device changes the cell surface markers and gene expression of the isolated stem cells versus routine manual liposuction (2).
- Gene expression in the isolated stem cells is different when using a biopsy to obtain cells versus manual liposuction (3).
There’s much more published, but suffice it to say that if you use a big enough magnifying glass, anything you do surgically impacts cells in some way. Things like the ability of cells to differentiate, express specific genes, and which markers or receptors appear on the cell surface are dynamic and constantly changing, so the concept of a specific FDA-approved process only producing one static cell like a chemical drug is a myth. It’s also a myth that you can differentiate SVF from surgery based on how one process changes the cells and the other doesn’t.
Who Wins this Argument?
At this point, the published data would tend to support judge Bernal’s overall argument that you can’t differentiate the creation of SVF from surgery. However, the scientists are right in that this statement in his decision is clearly not scientifically accurate:
“The SVF Cells are not altered, chemically or biologically, at any point during the SVF Surgical Procedure. There are no genes added to or removed from the SVF Cells during the SVF Surgical Procedure. The SVF Surgical Procedure does not change the size or genetic makeup of the SVF Cells. The procedure does not alter the biological characteristics of the SVF cells, nor does it affect their ability to proliferate.”
The process of making SVF does change the cells. This statement in his decision is also interesting:
“Unlike manufactured drugs, the SVF Surgical Procedure does not create any cellular or tissue-based product that did not previously exist within the patient.”
On the one hand, since the cells are changed by making SVF, this is not a 100% scientifically accurate statement. On the other hand, if one compares creating SVF to surgery, both change the cells, so the overall concept is accurate. Judge Bernal went there with this argument:
“The line between “drug” and “procedure” is especially muddy when licensed medical doctors enter a patient’s body, extract that patient’s cells, and reintroduce those cells to that patient after some amount of cellular processing. The United States argues that this scenario constitutes the production of FDCA drugs. Defendants argue that this is mere surgery, the exclusive province of the medical practitioners, and not something which the FDCA may regulate.
The Court concludes that neither Defendants’ SVF Surgical Procedure nor its Expanded MSC Procedure are “drugs” within the meaning of the FDCA.”
The Expanded MSC Procedure
Nothing about my review above applies to ht idea that expanded MSCs are drugs or not drugs, which is something the judge rule don as well. That’s a MUCH more complex issue that I may review separately at some point.
The US and the EU are WAY Behind on the Practical Use of Cell Therapies
(1) Qiu H, Jiang Y, Chen C, Wu K, Wang H. The Effect of Different Diameters of Fat Converters on Adipose Tissue and Its Cellular Components: Selection for Preparation of Nanofat. Aesthet Surg J. 2021 Oct 15;41(11):NP1734-NP1744. doi: 10.1093/asj/sjab146. PMID: 33769461.
(2) Lauvrud AT, Gümüscü R, Wiberg R, Brohlin M, Kelk P, Wiberg M, Kingham PJ. Water jet-assisted lipoaspiration and Sepax cell separation system for the isolation of adipose stem cells with high adipogenic potential. J Plast Reconstr Aesthet Surg. 2021 Oct;74(10):2759-2767. doi: 10.1016/j.bjps.2021.03.025. Epub 2021 Mar 29. PMID: 33994109.
(3) Gnanasegaran, Nareshwaran & Govindasamy, Vijayendran & Musa, Sabri & Noor Hayaty, Abu Kasim. (2014). Different Isolation Methods Alter the Gene Expression Profiling of Adipose Derived Stem Cells. International journal of medical sciences. 11. 391-403. 10.7150/ijms.7697.
(4) Taghizadeh RR, Cetrulo KJ, Cetrulo CL. Collagenase Impacts the Quantity and Quality of Native Mesenchymal Stem/Stromal Cells Derived during Processing of Umbilical Cord Tissue. Cell Transplant. 2018 Jan;27(1):181-193. doi: 10.1177/0963689717744787. PMID: 29562771; PMCID: PMC6434486.
(5) Tiryaki KT, Cohen S, Kocak P, Canikyan Turkay S, Hewett S. In-Vitro Comparative Examination of the Effect of Stromal Vascular Fraction Isolated by Mechanical and Enzymatic Methods on Wound Healing. Aesthet Surg J. 2020 Oct 24;40(11):1232-1240. doi: 10.1093/asj/sjaa154. PMID: 32514571.
(6) De Francesco F, Mannucci S, Conti G, Dai Prè E, Sbarbati A, Riccio M. A Non-Enzymatic Method to Obtain a Fat Tissue Derivative Highly Enriched in Adipose Stem Cells (ASCs) from Human Lipoaspirates: Preliminary Results. Int J Mol Sci. 2018 Jul 15;19(7):2061. doi: 10.3390/ijms19072061. PMID: 30011969; PMCID: PMC6073668.