to understanding the science, we need to understand what the regulatory issues are because they're not insignificant. So, no disclosures of note. So, in fairness to me, this is a little bit like watching paint dry, and I apologize for that, so if you need an extra coffee, feel free to walk out for a couple minutes while I'm getting started with this talk. Obviously, this is a big deal, and this is what we call the money slide, which just shows you how much money is involved with these orthobiologics. This is in the billions of dollars, and money sometimes makes people make decisions that maybe aren't entirely backed by the science and what's good for our patients, so we need to be aware of that. What's a biologic? Well, even the FDA isn't entirely sure. This is off one of their websites. It's a wide range of projects. It could be a vaccine. We don't do that very much. Blood and blood projects, allergenics, somatic cells, gene therapy, tissues, and recombinant proteins. But basically, they're things that we kind of think are biologic in nature that come from some type of a biologic source. So, where do these things go in the FDA? And anybody that's worked in the government knows that that can be a crazy place to work. Biologics can go to the Department of Devices, CDRH, and for it, interestingly, all the viscose supplementation products were, in fact, regulated as devices until 2018, and then they abruptly switched to biologics for no apparent reason, when I was there at least. Most of the biologics come from CBER, the Center for Biologics Evaluation and Research, but some are evaluated as drugs, and some get stuck in two centers, which means you get the worst of both worlds. So, what are these human tissue products? And this is important, and this is where the paint really starts to dry, because it's very difficult to understand exactly what's in and what's out. FDA looked at 2005, starting to try to regulate these. They've had numerous guidances and rules passed since then. But basically, what they're trying to decide is, what can you use in your office, and what do you need FDA approval to use? So, there are two categories. The numbers refuted to documents in the Congressional Register, they're not specific to anything, but the 361 products, you don't need an IDE, you don't need a premarket approval, you can use these with your own judgment. In contrast, the 351 products, you have to have an IDE. If you don't do it, it's illegal, and they're increasingly enforcing this, so you need to understand how these work a little bit. So, here's the wonderful 21 CFR 1271, which tells you how these things are regulated. And basically, you can use it in your office if it is minimally manipulated. Well, what's that mean? If it's for homologous use, and it has to be autogenous as well, you can't put somebody else's anything into somebody without a IDE or IND. And you have to not mix it with much. So, this is what the FDA is thinking, basically, for you to use it in your office. So, what's minimal manipulation? You can't alter the relevant structures, and when I was at FDA, there were some arguments, well, if you homogenize this stuff, is that manipulating it? If you spin it down, is it manipulating it? And for the most part, the answer to both of those has turned out to be no. But you can't alter the relevant biologic characteristics of the cells, and that's really what they're looking at. So, homologous use, it has to be kind of asking it to do what it did before you took it out, basically. And that was an argument. If you're using fat and you put it into a knee, is that a homologous use? Well, they've decided it probably is. So, these are examples, busy slides, but it kind of gives you a basic idea of what the FDA says you can use in your office and what you can only use with some type of marketing application. So, things changed. The industry and orthopedists understandably pushed back a little bit and said, look, we need some time. We can't just do this immediately. So, for a few years, the FDA had enforcement discretion, and they said, we're going to let you use these 351 products for a period of time while we sort this out. Well, there was a hard stop to that on June 1st, 2021, and after that, it's not discretion, it's illegal. And these are the things that are illegal to use in your office without an IND. Stem cells, stromal vascular fraction, adipose tissue, exosomes, wort and jelly, and basically any type of amniotic product. So, you need to realize, if you're using these, you need to stop. It's illegal. If you built CMS for these products at any time, understand that CMS plans to go back and do what they call claw back the money that you charge CMS to use these products and be aware. And they are prosecuting orthopedists that don't refund it. So, how do you know? Most of us are not like Jason and know this stuff backwards and forwards, but the AOS has created this biologic dashboard to help you look at it and say, is this legal for me to use or not? And you need to know that and don't trust the rep because they're not going to be straight with you. And it's on you. You can go to the Department of Justice and tell them that the rep said it was okay, all you want. It's not going to work. So, some specific things to note, a lot of things about PRP. It's generally used as a blood product, so it's not regulated by the FDA. The centrifuges are, and those are regulated, as we pointed out earlier. Amniotic fluid is not a human tissue product either. Adipose tissue is a structural tissue. As long as you don't do more than minimally manipulate it, you're okay. And again, most of these things are done with precedence. For example, the LipoGem 510K was quite clear to say you can use their device as long as you do not do any additional manipulation. So, why are we interested in it? Is this just some kind of a parlor game? The answer is no. FDA has sought permanent injunctions against people that are injecting stem cells. And they're going after people. They don't have the manpower to do this most of the time, but they are going to go after people, and it's not pretty when they do. And you have to recognize, it's not the FDA that's searching things and finding this out. When I was at FDA, 90% of the people that got turned in were turned in by other people in their town that resented the fact that they were doing it. So, it's not going to come from FDA, it's your local competition. And so, they're doing big time injunctions against these stem cell clinics. And a lot of them are really bad. It's not just that their stem cells are not approved, the stem cells that are prepared are not even sterile. So, there's some bad stuff out there. These are cases, just a short list of the ones that have been prosecuted up until 2017. They can do warning letters, which is a letter that says, if you don't cut it out, we're going to report you to the DOJ. Or they can do other types of letters we'll talk about in a minute. As Jason pointed out, if you do anything in your claims on your office website, your letterhead, whatever, that uses the word stem cell, you're probably going to get a warning letter at this point. The only two procedures in orthopedics are Cardozole and MACI. The testimonials are inconsistent with labeling, and it's illegal. And so, they need to be aware of all of this and start thinking about it. Also, you can get an untitled letter. This one doesn't involve the DOJ, but it just says, you really need you to stop. So, and these have become more common, I think, because the FDA recognizes there's a little less legal risk for them. So, why regulate? Why are we stepping in? These are good products, we should just all do them. There have been problems with stem cells, and some of these are not in our area, but they've had a patient blind to do a stem cell injection. They've had a probable tumor from a stem cell injection. You can certainly get infections and other things, and FDA has put it clearly, even in stem cells of your own cells, there are still significant safety risks. So, this is what our patients are reading when they look at this on the web. How about Pew Charitable Trust? They looked up 360 adverse events with stem cells in the last decade, and this is just the ones that are reported. There's no requirement to report anything. So, they're not insignificant, and some of these have been real disasters, like this article written by Peter Marks, we all know of vaccine fame now, talking about stem cells for breast cancer, where they were widely used, ineffective, costly, and risky. So, I want to go over some examples, just so you can get an idea of how this is working, because that sometimes helps the best. One product that I was involved with the FDA is the Agile C product. This is a calcium carbonate, or an argonite product. It took five years to get through. A 24-month pivotal study did work based on MRI follow-up, but it's been used in Europe since 2011. So, in fairness to beating up the FDA, that's going to change in Europe as they bring in what they call MDR, and in the next two years, it's going to be much harder to get any of this done in Europe than it is here. Another one, we all did Cardocell. Cardocell indicated for symptomatic cardiac defects of the femoral condyle caused by acute or repetitive trauma in patients having inadequate response. So, this product was used, as we all know, extensively off-label, and we did it in our practice. We're not innocent of that either. So, initially got approval. It's unregulated self-therapy in 1995. Genzyme, who was marketing this at that time, got approval in 1997. There were no controlled studies at all until the STAR trial ten years later, which was published in 2016. And the point of the article by Plyth et al. was that cartilage repair technologies are never going to get authorized like this again. They're going to be very stringent, and they're going to require prospective randomized trials with some type of control. So, MACI, another good product. I don't have any personal experience with MACI. Some people in the audience do, I'm sure. This is the second and only third generation cell product that was authorized in the United States. It's been used with membranes off-label, but this was first used in the U.S. in 2017. And this was because of the summit trial that was a phase three, two-year prospective randomized trial. And that's the way it's going to have to go. As always, though, getting it through the FDA is only the first step, and there are other issues. MACI's been around forever in Europe, but reimbursement issues in Europe caused this to be withdrawn from the market. And their problem, largely, was that hospitals in Europe could make these stem cell products on their own. There was no reason for people to go to the MACI people. And so, we'll see whether reimbursement's going to be an issue with many of these products, even after they're approved or cleared by the FDA. So, I'm winding up here, I promise. This is the AAOS statement on emergent biologic therapies, and it's our guideline for ethical use of these products. And you need to disclose what you know. You need to disclose if there are problems. And you certainly need to disclose if these are off-label or if there's anything in the way you're using them that doesn't meet the FDA requirements. And to me, what I usually hear is the patient wanted it, so we gave them PRP. And that's not going to work within the current ethical standards of using these products. So, the big thing, it covers most of what we do is informed consent. Talk to your patients, be sure they understand, don't paint this great picture, and be honest with them of the science, both risks and benefits. So, in summary, these are challenges. We've got to understand what's going on here. Before enforcement discretion, it was easy. It's not anymore. Cell-based biologics are especially difficult. It's going to get worse in Europe. That's for sure. Informed consent is the key. Look at the dashboard to be sure what you're using is approved. And be skeptical. Don't be the first, and don't be the last. Here's some additional information. If you need to talk to me, feel free to email me. We'll be around for questions. And thank you very much.

regulatory issues

biologics

orthobiologics

healthcare providers

FDA regulations