Hello and thanks for listening to the FDA view of musculoskeletal biologics, where are we in 2023? I have some disclosures, none of that are relevant to this talk. So obviously FDA regulations are about exercising, washing, paint dry, and I appreciate that, but if we don't understand them, we can't play the game and we can get in trouble sometimes. So one of the big points here is, is it worth it, and the answer is yes. The market here is huge, you can see 8.8 billion by 2028, so these things are enormous. So how do we define biologics, and like everything else, FDA has a very specific definition with some products that might not seem very similar to orthopedists, for example, vaccines versus blood products, somatic cells, gene therapies, tissues, and recombinant therapeutic proteins. These are generally biologic things, but they don't have to be made by living tissues, and they can come from almost anywhere. So jurisdiction is interesting, I found the hard way at the FDA, in that sometimes biologics are regulated by different departments, for example, vascular supplementation was in CDRH, which normally regulates devices, but in 2018, there was an abrupt turnaround, and they decided they would regulate it based on being a CBER product. Biologics division, or CBER, covers most of these, but some are also drugs, such as insulin, which is now biologic. So what are human tissue, cellular and tissue products, and these are anything that contain cells or tissues that are intended for implantation, transplantation, effusion, or transfer. This became more complicated in 2005, when FDA tried to be a little more specific about how they were going to regulate these products. So there's two broad categories that came out over the course of the next 10 years of guidance, the 361 products that don't need a IND or IDE, and the 351 products that are felt to be dangerous or risky enough that they do require some type of regulation. So here are the criteria, they have to be minimally manipulated, that's the tough one. They're intended for homologous use, so they have to replace the same type of tissue for which they originated from, that's also tricky. You can't combine cells with another article, and it cannot have a systemic effect. So what's minimal manipulation? Well, there's some arguments that it's even homogenizing these or grinding them up. Is that more than minimal manipulation? I think it's been decided by and large it is not. And homologous use, well, for example, using fat cells to replace osteoarthritic cells in the knee. Well, it doesn't sound very homologous to some of us, but the FDA decided that both tissues were structural, and these are homologous. So here's a long list of things, of things that are regulated and things that don't need to be regulated, and you can find all these in the guidances. So many 351 products were legally marketed, but under enforcement discretion until June 1st of 2021. And that's created some problems because these actually were completely taken off the market at this time, but I continue to get emails about them. So you need to also be aware that if you used any of these when they were under enforcement discretion, CMS at least plans to come back and, as they put it, claw back that money. So these are potentially dangerous for providers. You're going to go back to 2020, amniotic, placental, and umbilical cord injectables are the primary callbacks, and they felt they were experimental, they weren't proven to be safe and effective, and they want their money back, and you can't turn around and bill the patient either. So if you used any of these products and bill Medicare, be aware and be prepared. There are some important items to note. PRP is used by a lot of us. It's a blood product. It's not regulated by the FDA at all. The centrifuges are regulated and cleared under the 510K plan. Adipose tissues, the structural tissues we discussed, and as long as you're just grinding it up, it's normally considered to be minimally manipulated. The LipoGEM's 510K clearance showed this to be substantiated in some detail. And you need to understand that if the FDA decides it's a 351 product, it's just like a PMA or an NDA. You've got to be very careful. So what's the problem? Well, FDA has had permanent injunctions and prosecuted through the DOJ people that are not following these rules. They've had injunctions against stem cell clinics, and some of these were well-deserved because not only were they marketed illegally, but oftentimes they weren't even sterile. So here's a short list of some cases where 351 human cellular tissue products were prosecuted. Recognize as of today, if you use the word stem cell in any of your claims online or otherwise, it's going to be an automatic warning letter if anybody finds out. Cardocell and Macy are the only two orthopedic products approved for stem cells. And you need to be also worried about testimonials because testimonials inconsistent with labeling are illegal. FDA is not sufficiently funded to chase all these people, but they do have a criminal investigations office which can go after these. So another approach, if you don't want to get a warning letter, you can now do an untitled letter. The bar for these is lower and it makes it a little easier for FDA to come after you. And also the warning letters don't say that we're going to prosecute you if you don't cut it out. So you'll see those sometimes too. So why regulate? Here's the point. We can do what we want, right? We're all smart doctors. We know what's going on. Well, you got to read what the FDA is telling patients. All medical treatments have benefits and risks. Unproven cell therapies can be particularly unsafe. They had a workshop in 2016 where they had a patient that was blinded with stem cell injections and they're pretty convinced they got a tumor out of another injection. So there can be other side effects as noted and the cells may not work special and there may be tumors. So FDA also said, even if these are your own cells, there are still safety risks. So these are what your patients are reading. Pew Charitable Trusts in 2021 did a very interesting study recognizing that most of these side effects are not being reported by anybody. And they identified 360 adverse events between 2011 and 2020. Most of these were reported in journals and news media. Only five were reported in the FDA database. So again, another pointing out the problems with the FDA adverse event database or MAUD. So the adverse events, at least of all types, are not rare with these products. So FDA has not been happy about it. Peter Marks, we know mostly for his newsworthiness in the COVID era, but they've had some pretty expensive and harmful stem cell uses, luckily not in orthopedics. So how about some regulatory examples? For me, I'm much better with examples than mindlessly reading FDA regulations. So here's a good one, the Agile C. I was involved with this when I was at the FDA. The PMA for this was ultimately approved in 2021 based on a 24-month pivotal study where 88.5% of patients had their cartilage defects fill on MRI with only 30% of the control group. This took five years to approve, been used in the US since 2011. And it's still having trouble getting to market. So getting FDA approval is only half the battle, sadly. How about Cartofil? This is another very interesting one that's been around for a long time. Cartofil was initially the product where they take cells out. You know about, culture them, put them back in. And these are the indications for use. A cortisol has long claimed that they got hyaline-like cartilage. But we all know between this initial approval, it was used off-label extensively. And off-label is legal. You just need to counsel patients that you're doing it. So it was approved initially in 1995 and got accelerated approval in 1997. But there were no control studies of any type until the post-market START trial 10 years later, which was published in 2016. And by today's standards, that's never going to happen again. One quote from the industry blog that said, and I quote, current cartilage repair technology is facing a more stringent review process in their path to market. FDA developed a greater body of knowledge since the approval of Cartofil. So recognize this is not going to happen again. MACI was more like the now in getting cartilage products approved. And in 2016, they did get a biologic license for the MACI product. It was the first ever green light for this type of third-generation product. Previous cortisol was used off-label with other membranes. But this was the first product using this now on-label with this particular technique. It was approved through the SUMMIT trial. And these are the kind of things we're going to expect in the future with biologics. But there's no headaches here. It was approved in Europe for a long time. Reimbursement issues, however, prevented MACI from even being produced for 2014 when it was drawn from the market. There are similar issues with CONVERT-SELECT. The biggest problem in Europe is many large research-based hospitals improve or provide their own advanced therapeutic medications without EMA approval, which they don't have to do. I'm very familiar with this with a clinic that I work at in Madrid, which is Clinicum Centro. And once again, reimbursement is also the next and sometimes bigger hurdle after FDA approval. So here's the AAOS position statement on the use of emerging biologic therapies. We can all read it. But these are the things the FDA expects you to think about and holds you to when you do biologics. And I think the biggest part of this is pertinent medical facts and recommendations, informed consent, and a frank discussion. So this does not sound like what I often hear, which is the patient wanted it, so I gave it to them without any of the above discussions. So I think informed consent is the key here. They need to be approved and on label. But informed consent is crucial. Patients need to understand many of these don't have hard science yet. We're not sure if they're effective. And marketing these without a good informed consent is never going to be indicated. So in summary, regulation of biologics continues to provide challenges for practicing surgeons. Cell-based biologics are especially challenging. And if you think the FDA is bad, this has only gotten worse in Europe with the changes in regulations that are required under the Medical Device Regulations, or MDR. So what do you do? Keep informed. Obviously, document appropriate informed consent and do it. You have to use approved biologic products, and the AUS has provided the biologic dashboard, which is a good place to check to be sure that what you're using is, in fact, legal. Because the reps and the companies will sell you stuff that's illegal and they'll say it's not on them. And I think some healthy skepticism is good with all these products. I strongly believe that at the end of the day, this is going to be the way that we go. And putting metal and plastic in people is not going to happen in 20 or 30 years. But for right now, we're not sure what works, we're not sure how well it works, or for what group it works for. So think twice, at least, and be honest with your patients. There's a lot of places to look. These are just two websites that are quite good. There are many more. And obviously, any questions at all, get back to me. There's my email, and I'm happy to help anybody with making this work better. Thank you very much. I'm early, and with that, I can stop for any questions. And thanks again for putting up with my remote projection of this talk.

FDA regulations

biologics definition

enforcement discretion

patient safety

informed consent