I periodically get e-mails from medical colleagues asking my opinion on whether an orthobiologics technology is for real or hype. This week I got one from a university-based physician who wanted to know about advertising materials he received for an amniotic fluid called FloGraft. Given that the IOF had tested Flograft and found that it was all dead tissue, this one was easy to answer: “Everything that suggests live and functional stem cells in this marketing collateral is likely false”. However, while the company did a nice job of quantifying what’s in each bottle, the sales rep that was “on the edge” of legal (or perhaps over it). Let me explain through a thorough review of the highlighted product: FloGraft Freedom.
Understanding that a 361 Tissue Registration is Not “FDA Approval” of Anything
Doctors and patients alike usually get confused by the alphabet soup of FDA registration and approval types. For cells, there are two big ones that matter: 351 and 361. A 351 FDA approval is for cell drugs. These are cells that are “more than minimally manipulated”. This means that they require more processing or things like culture expansion and as such, are considered a prescription drug that must go through rigorous, expensive, and time-consuming clinical trials. Once approved, the company is free to market the product for a specific medical indication. There are no 351 approved stem cell products in the US for orthopedic use.
Next up, is a horse of a very different color, a 361 tissue registration. This means that the company has merely filled out a form on-line to classify the tissue and listed it’s address so that FDA can inspect the facility or the product claims. There are NO clinical trials and NO approval processes. Hence, all the company is allowed to claim is that it sells tissue X and that this is what’s in that tissue (i.e. growth factor content). What it’s not allowed to do is to produce any patient materials that claim that the tissue can treat any specific disease. In addition, if the tissue has live cells, it’s automatically classified as a 351 drug and is not allowed to be registered as a 361.
FloGraft’s Claims of Viable Cells
My colleague sent an e-mail from the sales rep as well as three different product brochures. One of these was focused on the product characteristics, one on how the company determines product potency, and the last was meant for patients. Let’s review what was sent:
From the email sent by the sales rep: “The surgical grade of FloGraft is more concentrated and contains 2 million viable cells/cc as opposed to the 750,000 viable cells/cc contained in FloGraft Freedom.”
IS THIS TRUE? The IOF, a 501c3 non-profit tested FloGraft and found NO EVIDENCE OF ANY VIABLE CELLS. See below for the results of those tests by clicking on the thumbnail:
Now let’s take a look at what’s on the product brochure PDF sent to my colleague:
“To facilitate product formulation and end-user application, FloGraft® is standardized by total cellular count as shown in Table 1 prior to cryopreservation. Product potency is guaranteed if correct thawing protocol is applied by end-user (see product information sheet for specific thawing instructions).
Table 1: Standardization Cellular Counts for all FloGraft® FloGraft® FREEDOM SPECIFICATION
Standardized Cellular Count:
750 Thousand cells / mL”
Hmmmm…. This is important for what’s carefully not said to make you think that they said it. The company is saying that it standardizes how much to put in the bottle by making sure that they have 750K total nucleated cells (NOT STEM CELLS which would be only 1-2% of that number). Curiously, “Product potency” is guaranteed, but notice how nothing is said here about viable stem cells. There is a reason for that omission as if the company claimed there were viable stem cells, the product is no longer a 361 tissue, but instead a 351 cell drug.
This statement, of course, begs another question. How is potency established? There is a white paper attached to the email that basically says that potency is established by looking at the product’s growth factor (GF) content and performing a biologic assay. For the former, the company measures the GF content via ELISA and for the later, it looks like they perform an in-vitro cell proliferation assay. While I certainly have to applaud the company for taking these extra steps (most amniotic companies are not doing this), there is no mention of the “potency” being measured as a certain number of viable cells. This again is because if the company places this in writing in a document that is shared with physicians or consumers, it’s violating FDA regulations. In addition, the IOF testing showed that the product had no viable and functional cells, so there is a good reason to keep this out of product brochures. However, notice how the rep selling the product on behalf of the company freely violates these FDA regulations.
How Big a Deal are the Growth Factors in FloGraft?
First, I do want to say a second time that I really applaud this company for doing a great job of quantifying growth factors in its product. However, as a clinician, I now need to decide how important these are relative to what I know from common everyday experience. The best way to do that would be to compare the growth factor levels to a simple Platelet Rich Plasma (PRP) prep. Another helpful tool would be a biologic assay. So how does FloGraft stack up?
Well, the white paper that lists the growth factors present in FloGraft skips the big ones commonly measured in orthopedic products, which are VEGF, FGF, TGF-beta, and PDGF. Others are listed, the most important of which for orthopedic clinical effects would arguably be the TIMPs (TIMP 1 and TIMP 2). Why? These are anti-breakdown molecules that can turn off cartilage destruction (anti-catabolic). So how much TIMP is in this stuff compared to say just a basic PRP without any concentration? Not much. The IOF measured TIMP levels in 1X PRP as in the 22-24,000 pg/ml range. The TIMP levels listed for FloGraft are 1,500-4,000 pg/ml.
What other GFs listed as in FloGraft have been well studied as being major players in orthopedic tissue repair? You could make an argument that “Angiogenin” (a growth factor that helps build new blood vessels much like VEGF) could be helpful. FloGraft has 300 pg/ml compared to the 143 pg/ml measured in a 1X PRP sample. So while FloGraft has more, you could easily get to 300+ pg/ml by concentrating PRP into the 3-5X range which is typically done in the clinic. In addition, PRP is very rich in VEGF, but these levels aren’t listed for FloGraft.
A Biologic Assay
Measuring absolute values of growth factors and translating that to clinical effects can be difficult. This is because it could be the pattern (secretome) of GFs that is more important than absolute levels. Hence, a biologic assay can get closer to determining if the product may help repair orthopedic tissues in-vivo. What’s that?
A biologic assay is when a live cell population in culture is exposed to a product while measuring the proliferation (growth) of the cells. If the product makes the cells grow like gangbusters, it may help real patients. The biologic assay results comparing FloGraft to commonly used controls aren’t in the company whitepapers. However, not worry, the IOF has already compared FloGraft’s cellular effects using bone marrow derived, mesenchymal stem cells.
How did FloGraft do? Not well. It was able to stimulate MSC proliferation about as well as the serum free media control. This would be the least effective way to grow cells in culture. It was blown out of the water by the “Complete Culture Medium” which included fetal calf serum, which is the usual way cells are grown in culture. This means that it actually performed less well than one of the controls. The data is to the left. Click on the image to make it bigger. For reference, a 20% solution of the growth factors derived from blood platelets generally blows away the complete culture medium.
The Patient Brochure Says What?
So far the performance of what’s in each bottle of FloGraft there hasn’t been all that impressive just compared to much cheaper PRP. However, never underestimate the laziness of some physicians who can’t be bothered with the arduous task of drawing the patient’s blood to make PRP, so for those physicians, at least FloGraft may offer an easy, off the shelf, weak PRP like injection. However, the wheels come off the FloGraft marketing bus when you get to the patient brochure, which is really risky from a regulatory standpoint.
The patient brochure sent by the company says:
“Biologic Augmentation for Clinical
• Joint Pain
• Partial Thickness Tendon Tears
• Inflammatory Joint Effusion
• Orthopedic Strains/Sprains
• Other Orthopedic & Soft Tissue Applications
• Chronic Non-Healing Wounds”
Yikes! 361 FDA registered tissue processors are strictly prohibited from creating advertising material aimed at physicians or consumers that make product claims regarding the use of the tissue. Here the company suggests that the product can be used to treat joint pain and effusion, tendon tears, sprain/strains, and other orthopedic and soft tissue diagnoses. In all of the years I have been tracking the birth tissues industry, I have never seen a tissue company list medical applications for its product in a patient focused brochure.
The upshot? FloGraft does not have viable stem cells. While the company is smart enough to avoid talking about that in its marketing materials, the sales rep seems to have not gotten the memo that by sending an email to a doctor claiming that it has live cells, she’s violating FDA regulations. On the positive side, the company did an excellent job of quantifying and standardizing what goes in each bottle. On the negative side, what’s in the bottle is likely inferior from a clinical standpoint to a cheap PRP shot. However, there’s really no way to tell for sure how well FloGraft performs in real patients versus an inexpensive PRP shot until someone does a head to head clinical trial. So far, no clinical data on FloGraft has been published.
On a practical note, it took 4 hours this morning to dig into, evaluate, and write up what the company was claiming. That was with the IOF data in front of me, which itself took hundreds of man hours to create. Physicians have no to little training to help them evaluate the claims of amniotic manufacturers nor do they have access to the sophisticated labs that can cross check those claims. Hence, you can easily see the main problem we all have. It’s easy to throw marketing collateral at physicians laced with fancy scientific terms that fly over their heads and it takes significant time to evaluate whether what’s in those materials make any sense. So buyer beware! In my experience, it’s more likely that what an orthobiologics sales rep is telling you is incorrect than correct.