So, I have some disclosures, but nothing that's making any money from this talk, at least. So, the regulations are really confusing, and this is from a guy that worked at the FDA for half a decade. But the FDA has decided that many of these biologics are potentially dangerous, and there's no doubt about that. So they've broken these into two categories. Whoops, this keeps walking through without my permission. The 361 products are felt to be pretty safe and effective, and the 351 products basically require an IND, and that's the rules that we're dealing with as of 2021. Here's your beautiful 21s Congressional Federal Regulation, which is what they do, the 361s, and if you read through these quickly and think that these might be a little bit vague, you are not the only one. Obviously, what does minimally manipulated mean? Some of the FDA regulators that I have talked to suggested that if you simply use a shaver and homogenize the tissue, that it's no longer minimally manipulated. Homologous use, and I still struggle with what that term means exactly here, but in general, as Jason pointed out with the amniotic fluid, if what you're putting in, it doesn't normally make what you want, then it's not homologous. The manufacturer is very strict, and you can't leave it out of the body for a while, and it can't change sites, so these are all pretty strict, and as Scott pointed out, when you follow these rules for a 361 product, you don't get a lot of cells, so you need to be aware of that, and again, there were a lot of biologics on the market that don't fit this criteria. So here's your minimally manipulated from the law, and like I said, the paint drying part is getting more like paint drying all the time, but you can't alter the original relevant characteristics of the tissue, and so they really don't want you messing with these things, and even some of the stuff that looked on label, I think Jason did a pretty good job. It's not black and white. There's a flow chart here, and you want to be sure that you're staying on the right side of the flow chart. So here are some examples. The 61s, obviously bones, stuff, skin, these are all minimally altered things that you're allowed to use, and the 351s, you can use them, but you have to do them under the auspices of an IND, and those are good examples from the FDA guidance, and these things are all publicly available. You can pull up the FDA guidance. The latest one, I believe, is from 2019, but this is in flux because, admittedly, the regulators don't know what to do either. So they've done some warnings and prosecuted clinics, and the truth of the matter is the FDA, especially in COVID, is simply not equipped to go after everybody, but I can tell you how this works, having been at the FDA. You're doing something that your partner or buddy down the hall thinks is a little shady, and he turns you in, so that's the mechanism for this. The FDA is not looking at newspaper ads and things like that, but when, you know, Bill Smith, the orthopedist down the road, doesn't like what you're doing, they anonymously turn you in, and it's not fun getting turned into the FDA. The first thing you'll get is a cease and desist letter, and the second is a statement of prosecution from the DOJ. So we talked a bit about enforcement discretion. When this came out a couple years ago, the industry was up in arms, understandably, and they said, okay, we're not going to do anything about this for a while. We're going to not enforce these rules. So it was December of 2020. It got pushed off until May 1st, but Peter Marks, who most of us have seen on TV talking about vaccines, did get on TV again and talk about enforcement discretion, and it's over. May 1st, if you don't meet these rules, and the guy that doesn't like you down the hall turns you in, then you're going to get a warning letter. So this is a new approach that I hadn't seen very much of, is rather than a warning letter, they send you an untitled letter, and you might say, what does that mean? Well, it turns out, from a variety of regulatory issues, these are much easier to generate, but they have the same power. This is the same kind of letter as you'd get with a warning letter that's telling you, if you don't cut it out, your next thing is going to be a letter from the Department of Justice. So why do we regulate these things? I mean, should patients have rights, they should get whatever they want, right? And the problem is, as was pointed out, some of these things are just flat-out unsafe, and some are unsafe for reasons anybody in this room would know. There have been multiple septic joints from stem cell injections from clinics, where, when the FDA went to look, the stuff they're putting in is not even sterile. There have been problems, site reactions. There have been a couple cases of potentially stem cell-induced cancers. So the FDA website's pretty clear, even with your own cells, there can be risks you need to check, and you need to go talk to your doctor about what the risks are. So there are some really bad track records. This one is the most common, using autologous stem cells to treat metastatic breast cancer was ineffective, costly, and risky, no benefit. So it's out there. And there have been injunctions. Some of these people that ignored their warning letters did get fined. Again, the FDA doesn't have the manpower to chase everybody down. That's the truth. But the way I've seen this in my experience at the FDA, it's not the FDA that gets you, it's the guy down the hall. So this is an example of one U.S. stem cell clinic. In fairness, these guys do this. They get their warning letter. They change their name and keep doing what they were doing before. So it's not easy. So again, some items to note, PRP generally has been regulated as a blood product. So therefore, it's not regulated in any fashion by the FDA. Amniotic fluid is not considered a human tissue product. And as you heard, almost all of these amniotic products have chosen not to take the high road and get an IND. So they're off the market until they get an IND. They just have said, by and large, we're not going to do it. There are some companies that are trying to do it. But adipose tissue is a structural tissue. So processing more than minimally manipulated changes the way these things work. And you've got to be careful. And the bottom line, again, is what's minimally manipulated? And it's really not entirely clear yet. So AAOS has their own position statement. And they're basically saying, you know, put on the brakes. Think about this. So once again, if you're going to get towards the bottom of that gray zone where it may not be entirely clear in treating your patients, you need to be aware that neither the FDA or the AAOS is going to back you up. And again, I have a lot of trouble with this. The justification I hear for some of this really off-the-wall treatment is the patient wanted it. And this is COBE going to Germany to get special PRP. But the point is, I don't think that's a reasonable excuse. Our job when patients want stuff that's not effective is to caution them that it's not. And that's where informed consent comes in. And it's really important that these people get a rigorous informed consent, especially if you're down towards the darker area of that gray curve in terms of the FDA authorization. So there's a lot of places to get information. It's well done. Peter Marks was the lead author on one of these. And regulatory conditions for cells. These guidances, they're hard to read, I admit. But the flip side is, if you're going to do this stuff, you need to know the rules. Because the party's over in terms of not enforcing. So now that the paint's dry, I'm going to let someone really interest you and get Lou up to the podium.

biologics

FDA regulations

361 products

351 products

non-compliance consequences