Well, thanks for coming. My name's Eric Latzke, and we're going to be talking today about the regulatory landscape of orthobiologics. The title is, If I'm Confused, You Must Be Too. And the reason I wanted to talk about this topic is because a year ago we put together a curriculum committee on orthobiologics for the AAPMNR, and these were the members. And every member had a different topic that we were going to be going over, and my topic was federal regulations and ethics. And I was like, yes, I got the easy topic. This is going to be, well, this will take me a week. And it took maybe three months of reviewing all of these documents to figure out what was going on. And when we sat down, nobody else knew most of this. Some people knew a little bit, but Dr. Borgstein was kind of the overseer of this committee. And then, so, Dr. Oriema and Dr. Gruner will also be speaking today with me. This is where we train. We kind of have a combination of, you know, various residencies and fellowship programs, but we all have similar backgrounds in our physiatry training, in our accredited sports fellowships, and our kind of orthobiologic beliefs and how we treat patients. I've been at the University of Washington for nine out of the last 10 years, where I did my residency and worked as an attending physician, but recently moved to Boston and am now working at a private practice called Boston Sports and Biologics. I have no disclosures other than that. Dr. Oriema has no disclosures, but Dr. Gruner is the co-founder and CMO of Limber Health, and he's the advisor to companies including Tempida and Alfie. So, Dr. Oriema is going to get us started looking at the history of orthobiologic regulation and basically how we got here today. Dr. Gruner will then talk about where we are today, what the regulations are, what matters for you, and I'll end the talk with the debates that are still out there after reviewing all this regulation, and there are a lot of them. All right, good afternoon, everyone. I'm Mike Oriema, and I have the honor of leading off this presentation. Before we get started, I'd like to recognize Dr. Latska for all the time he put into spearheading this lecture. He really put an incredible effort into this, and he deserves recognition for all of his hard work. So in this first lecture, I'm going to meander through time to highlight some important legislation, executive orders, publications, lawsuits, and judicial rulings that have impacted the orthobiologic regulatory landscape. In essence, this will be a little bit of a history lesson that will hopefully help set the table for both Dr. Gruner and Dr. Latska's lectures. Regarding Dr. Gruner and Dr. Latska's lectures, I view them as more of the meat and potatoes of this presentation, whereas mine is more of the appetizer. Still delicious, but not the main course. And in my preparation for this lecture, I considered different ways in which I could possibly present this material. And since we're in New Orleans, and I'm reviewing history, I thought it might be fun to go the route of this old Comedy Central show. However, the Academy clarified that the New Orleans open beverage carry policy did not necessarily extend to the presenters during their actual lecture. Thus, I've been encouraged to take a little bit more of a PG approach. So away we go. This will be a bit of a bumpy ride. However, a quick disclaimer, by the end of this, you very well may feel like you need a drink. So our journey begins back in 1944 during the time of World War II. During this time, the war resulted in heightened concerns regarding multiple public health related issues, including the control of malaria, the spread of TB, and the risk of epidemics due to soldiers carrying home strange and exotic diseases from tropical locations. This resulted in the passage of the Public Health Service Act of 1944, which was aimed at preventing the spread of communicable diseases in the U.S. This act clearly established the federal government's quarantine authority for the first time, and it identified the U.S. Public Health Service's responsibility for preventing the introduction, transmission, and spread of communicable diseases from foreign countries into the United States. The important legacy of this act, as it pertains to orthobiologics, is that it also provided the basis for regulation and enforcement of public health services. Following the passage of the PHS Act of 1944, we then have to jump ahead almost 50 years to congressional hearings that were held in 1993 before we encounter another major regulatory landmark pertaining to orthobiologics. But why such a long time? What triggered the end of this relatively quiescent period? Well, it was the HIV-AIDS epidemic. And in particular, there was an event that occurred in 1991 that traced its origin to an event in 1985. In 1985, a 22-year-old male named William Norwood was tragically shot and killed during a late evening holdup at a gas station. His family, seeking a positive from the tragic loss of their son and brother, agreed to donate his organs to help others. Six years later, in 1991, it was unfortunately discovered that Mr. Norwood had been HIV-positive, as six of the donor recipients were ultimately diagnosed with HIV. And three of these six ultimately died from AIDS-related causes. Now, you would think that as horrible an outcome as this would serve to trigger legislative action. But what it really seemed to take was some guy named Tom Hanks, two years later, playing the role of a character with AIDS to ultimately get Congress to act. That act in 1993 was a subcommittee hearing on the regulation of human tissue banks spurred by a desire to improve donor tissue screening. Chairing that hearing was Representative Ron Wyden, who cited the importance of preventing the transmission of HIV, hepatitis C, and Creutzfeldt-Jakob biotissue transplantations. This hearing resulted in the Human Tissue for Transplantation Act. Though this initial act did not pass, it served as the nidus for the FDA publishing an interim rule that same year for the governance of human tissue intended for transplantation with a goal of improving public safety. We next jump ahead one year to 1994, when the NIH issued a report on human embryo research. This research panel recommended that funding be made available for human embryo research using oocytes fertilized specifically for research purposes. And of course, this recommendation was met by widespread support and agreement. Just kidding. Obviously, a topic as sensitive as the creation of human embryos strictly for research purposes would be met with caution and concern. In fact, this NIH report was first met with pushback by President Clinton, who did not believe that federal funds should be made available for the support of the creation of human embryos specifically for research. Two years later, legislation was passed by way of the Dickey-Wicker Amendment, which officially curtailed federal funding of the research involving human embryos. Specifically, the amendment prohibited federal funds from being used for the creation of human embryo or embryos for research purposes, or research in which a human embryo or embryos were destroyed, discarded, or knowingly subjected to the risk of injury or death. Due to this amendment, human embryo research would require funding by the private sector. One year after the passage of the Dickey-Wicker Amendment, the FDA determined that there was a need for a much more comprehensive set of regulatory requirements regarding human tissue transplantation. In March of 1997, the FDA announced the availability of a document entitled, Proposed Approach to the Regulation of Cellular and Tissue-Based Products, which later that same year was finalized as Title 21, Code of Federal Regulations, Part 1270. 21 CFR 1270 sought to clarify and modify the provisions from the previously discussed 1993 interim rule. Key features included the creation of a tiered approach to detailed regulation of a cellular and tissue-based products based upon risk, as well as the necessity for certain infectious disease testing, donor screening, and record keeping for the prevention of transmission of diseases through human tissue used in transplantation. The very next year saw an incredible scientific breakthrough when James Thompson and colleagues became the first to derive human embryonic stem cells from isolated embryos. Remember, due to the Dickey-Wicker Amendment, this research was all privately funded. Thompson's research led to the isolation and culturing of five different embryonic stem cell lines. Needless to say, the scientific and medical community was ecstatic about the therapeutic potential this research appeared to pave the way for. Over the next several years, the embryonic stem cell debate continued to build. On one end, there was the immense biomedical promise of developing new treatments for various diseases and conditions. On the other, there was the ethical concern over the origin of these cells. As one would expect, this issue became intertwined with the abortion debate. Ultimately, President Bush was confronted with this issue during his first year in office. First, 80 Nobel laureates sent him a letter urging federal funding for embryonic stem cell research. Soon after, Nightlight Christian Adoptions filed a lawsuit to block such funding, citing the Dickey-Wicker Amendment. After a substantial review, President Bush, in August of 2001, introduced a ban on federal funding for research on newly created stem cell lines. However, he did recognize the biomedical promise of embryonic stem cells and, therefore, allowed federal funding to be used on the previously available lines, the five lines from Thompson's research. Thus, moving forward, federal funds could be made available for research on a subset of embryonic stem cells. Later in his presidency, Congress attempted to pass an amendment that would allow for even greater federal funding of human embryonic stem cell research. Namely, Congress sought to support research using human embryonic stem cells, regardless of when they were derived, so long as they met a few criteria. They had to be donated from in vitro fertilization clinics. They had to be created originally for the intended purpose of fertility treatments. They had to be in excess of the needs of the individual who produced them. And they had to be otherwise in line for being discarded. Also, the embryonic stem cells would have to be donated with written informed consent and without any type of financial inducement. President Bush, however, vetoed this amendment. This proposed expansion would remain on the back burner for a few more years until President Obama took office in 2009. In March of 2009, additional relief was brought to researchers by way of an executive order that further expanded the number of embryonic stem cell lines that federal funds could be used for research on. This executive order followed recommendations from Congress from 2006, which President Bush had vetoed. Now, even though this executive order went into place, federal law to this day still prohibits the federal funds being used for the creation of human embryos strictly for research purposes or for research in which a human embryo or embryos are destroyed, discarded, or knowingly subjected to risk of injury or death greater than what's allowed for current research on fetuses in utero. Jumping back now to that 2001-2004 time period, the FDA published three additional rules adding to the 21 Code of Federal Regulations Part 1270. These new rules were ultimately codified as Title 21 CFR 1271. Important features of these rules included the attempt to better define human cells, tissues, and cellular-based products, and to establish a unified system for registering new HCTPs. Understanding these rules is a necessity for orthobiologic regulatory compliance and will be further discussed in Dr. Gruner's lecture. Getting back on track with our chronological time frame, it's worth noting that in 2007 there was another major scientific breakthrough when two independent labs both published on the ability to induce pluripotent human stem cells from somatic cells, thus obviating the need for the destruction of human embryos. This discovery provided a workaround option for researchers seeking federal funding as embryonic stem cells could potentially be avoided completely. We now turn our attention to the first major court case regarding the FDA guidelines pertaining to the clinical use of orthobiologics. This case involved Regenexx and spanned a six-year period. It began when the FDA sent a warning letter to Regenexx regarding the use of cultured stem cells in clinical treatments. The FDA contended that the use of cultured stem cells did not align with their published guidelines. Regenexx countered by suing the FDA, claiming that the use of culture-expanded stem cells fell under the practice of medicine. The FDA ultimately filed for an injunction in 2010. Finally, in 2014, the U.S. Court of Appeals rendered a verdict in the favor of the FDA. The court ruled that the stem cell mixture being used that was a combination of or that consisted of isolated culture-expanded stem cells was consistent with a 351 product or drug and should be regulated as such. They also ruled that Regenexx had violated federal laws regarding manufacturing and labeling of drugs and biologic products. In response to this decision, Regenexx stopped producing or stopped offering culture-expanded stem cells in their U.S.-based locations. Following the court decision in 2014, the FDA went on to issue additional draft guidance documents regarding the regulation of orthobiologics. These documents aim to further explain the concepts of minimal manipulation and homologous use as well as the same surgical procedure exception. A detailed discussion of these concepts will be the focus of Dr. Gruner's lecture. While those guidance documents aim to tighten regulation, the following two years saw Congress and the Senate pass laws that were aimed at slightly loosening regulation. The first of these laws was the 21st Century Cures Act, which included the establishment of the Regenerative Medicine Advanced Therapy, or RMAT, designation. The intention of this law was to accelerate the process of bringing new regenerative treatments to market so long as the products met RMAT designation criteria, including products that treat, modify, reverse, or cure serious or life-threatening diseases or conditions. An additional requirement is the existence of preliminary clinical evidence that the product has the potential to address unmet medical needs for such a disease or condition. In 2018, the FDA identified osteoarthritis as a serious disease with an unmet treatment need, thus making cell-based OA therapies eligible for RMAT designation. Jumping quickly back to 2017, the Right to Try Bill was passed, which granted terminally ill patients access to experimental therapies not currently approved by the FDA. Since that time, legislation has been adopted in most states for other serious diseases as well. Also in 2017, the FDA further expanded upon their previous guidance documents. They also announced a three-year period of enforcement discretion. In other words, practices were expected to conform to the FDA's rules governing the use of orthobiologics or come to the FDA to pursue proper registration of products that were deemed drugs. At the conclusion of that timeframe, practices still running afoul would be subjected to penalties. This discretionary period was ultimately extended to May 31, 2021 as a result of the COVID pandemic. At the conclusion of that discretionary period, the FDA took multiple actions. They substantially increased the issuance of warning letters and lawsuits, primarily targeting practices offering treatments with umbilical products, stromal vascular fraction, and systemic treatments, as well as for advertising fraud. They also posted additional guidance regarding regenerative medicine therapies, this time directed directly towards patients and consumers. In this post to consumers and patients, the FDA attempted to warn patients and consumers that regenerative medicine therapies require FDA licensure or approval to be marketed to consumers. For approval, these products require FDA oversight in a clinical trial. They went on to identify stem cells, SVF, umbilical cord blood and or umbilical cord stem cells, amniotic fluid, Wharton's jelly, orthobiologics, and exosomes as unapproved products. The FDA also made a point to emphasize that regenerative medicine therapies have not been approved for the treatments of any orthopedic condition, such as osteoarthritis, tendinitis, risk disease, tennis elbow, back pain, hip pain, knee pain, neck pain, or shoulder pain. As our history tour inches closer to present day, let's briefly review a few notable lawsuits. First, in 2019, US Stem Cell Clinic, based in Florida, lost their case against the FDA regarding the use of SVF, or stromal vascular fraction. This practice had been marketing the use of SVF for the treatment of conditions such as Parkinson's, SCI, stroke, and TBI. The US Stem Cell appealed this decision, however, in 2021, the decision was upheld by the 11th Circuit Court. The court's decision seemed to hinge on the belief, as argued by the FDA, that the tissue and or cells removed were different from the tissue and or cells replaced. The court further supported the FDA's position that this treatment, as evidenced by the US Stem Cell's marketing, did not conform with the homologous use requirement. In 2021, another verdict was handed down that ruled against the medical practice. This time, it was the New York State Supreme Court ruling against Park Avenue Stem Cell. In this case, Park Avenue Stem Cell was found to have committed fraudulent and illegal advertising, misrepresentation of FDA approval, and misrepresenting that patients were participating in a research study. A $5.1 million judgment was secured, and the practice ultimately closed. Our next case saw its decision rendered in 2022. In this case, the FDA sought to stop California Stem Cell Treatment Center from performing treatments with SVF. The FDA's position was that the process of obtaining SVF exceeds minimal manipulation, and thus SVF should be treated as a drug that requires FDA approval prior to being sold. The FDA further argued that SVF was not eligible for the same-day surgical exception, essentially because the tissue being removed was different from the cells being reinserted, similar to their argument in the previously highlighted 2019 case against U.S. Stem Cell Clinic. The defendants, on the other hand, argued that the cells being reinserted were fundamentally the same as those being removed. Interestingly, in this case, the court accepted the defendant's position and rejected the FDA's arguments, primarily on the basis of the same-day surgical exception. The judge ruled that the target of tissue being removed is the cells, and they are minimally manipulated. The judge further ruled that the procedure did not fundamentally change these cells, and thus SVF is not considered a drug and, therefore, not subject to regulation by the FDA. Further, in the same ruling, the judge actually ruled that culture-expanded stem cells were also not drugs and therefore not subjected to FDA regulations, so long as there was a third party that was responsible for expanding the cells. This ruling is now at clear odds with all prior court decisions, including the 2021 ruling against U.S. Stem Cell Clinic in Florida. The FDA filed a notice of appeal in October of 2022, and we're still awaiting the ruling of this appeal today. If not overturned, this will leave us with opposite rulings by the 11th and 9th Circuit Courts, and thus likely there will be an advancement to the U.S. Supreme Court. Of note, following this decision in 2022, the International Society for Stem Cell Research filed a brief in support of the FDA's position. While the previously highlighted cases have focused on verdicts pertaining to allowable procedures and monetary penalties, it's important to note that there have also been some instances where physicians have lost their medical license over such cases. In one instance, a cardiologist in Florida had his license revoked after two patients died following the IV infiltration of BMAC. In a second instance, a psychiatrist in California lost his license due to negligence, professional misconduct, and false advertising. Finally, and probably most prominently, an assistant physician, who was also an elected state representative in the state of Missouri, lost her license and was sentenced to six years in federal prison related to fraud charges pertaining to purported COVID-19 treatments. So there it is, a summary of the important events over the last 30 years that have contributed to regulatory swings both in the, that have contributed to regulatory swings regarding the use of orthobiologics. Further changes are sure to come, and as practitioners in this space, it's vital for us to remain up to date on these changes. I thank you for your attention, and I will now cede to Dr. Gruner, who will spend greater time describing the current regulatory guidelines. Thank you. Hopefully the big topic for what I'll focus on right now is just the basic rules and the take-home points for you guys to remember, and then we'll finish off with Eric, who's really going to bring this all together and explain different details of what is the best use of biologics in your practice. So the first thing, you see there's many different rules here that have existed, but I really want to break it down to three pieces of regulation that is really important to know. And one of them is 1271, and then the second one is the FDA guidance document, and then the third one is the same surgical day exception. So if you can remember anything from today's talk, these are the three crucial pieces of information that you should know. So we're going to go over 1271. We're going to explain what PRP, BMAC, and other orthobiologics are, and then we'll go over FDA approval, FDA clearance, and the 510K exemption, and just explain some of the FDA guidance. So first, there are four or five products that are used for orthobiologics. The first one is PRP, which is called platelet-rich plasma. The second one is BMAC, which is called bone marrow aspirate concentrate. The third one is MFAT, which is called microfragmented adipose tissue. The fourth one, as Mike was talking about in one of the California studies, was stromal vascular fraction, so that's adipose tissue where they use collagenase to break down the adipose. And the last one is birth tissue, which can be placental or fetal tissue. So one of the most important pieces of regulation that you should know about is Title 21. And what Title 21 really focused on was defining human cells, tissues, and cellular-based products and articles containing them, and how they should be used for implantation, transplantation from one tissue to another, infusion, or transfer into a human recipient. And this flowchart really is something that, if you can try to remember this flowchart in your brain, I think it's a really helpful way to think about how you should consider orthobiologics in your practice. First that you should know is that if you apply for the same surgical day exemption, that you do not have to follow Title 21. And Title 21 applies for people who do not fall into the same surgical day exemption, and they have to follow four criteria, and those criteria will go over in a little bit. And if they do not follow those four criteria, then they're considered a drug and are regulated by the FDA as a drug. So going through those four criteria, the first one is minimal manipulation. So for structural tissue, that is like adipose tissue, and it's specific tissue that cannot be manipulated or reconstructed or repaired or replaced from its original form. For cells or BMAC, this means that they can't alter the biological characteristics of that tissue. So an example of minimal manipulation is culture expansion. You can't take stem cells, grow them in a lab, and inject that into the same tissue. So that is one reason why, or it falls under minimal manipulation. The second criteria is homologous use. So that means that you can't repair, reconstruct, or replace that tissue that performs the same basic function of what it does in a donor. So a good example of homologous use is you can take adipose tissue and put it in the fat pad of the foot because it's providing the same use. But if you put adipose tissue in another part of the body, that adipose tissue is not there, that's not providing the same functional use. Then the third piece of information that's important to know is you can't combine things together with other drugs. So an example of this was combining hyaluronic acid and a orthobiologic in the same tube at the same time. And then the fourth criteria is systemic use. So you can't provide IV stem cells that are going throughout the entire body and have systemic use of that function. And so those are the four critical criteria that you should know, which is part of 1271. But in addition to that piece of regulation, going over the same surgical procedure exception is also important to know. So the same surgical procedure exception means that that procedure was performed on that day and that incision or instrumentation was used and it was taken from and implanted in one single operation. Additionally it means that it must be in the same original form and that you can rinse it, you can clean it, you can store it temporarily, but you can't alter it other than that. And what's really important to know is that the same surgical procedure exception is not required. If you do not follow the same surgical procedure exception, you have to comply with 1271. But if you do follow the same surgical procedure exception, you don't have to comply with 1271. So in addition to those two pieces of information, there's another regulation that you should know about, which is current good tissue practice, which applies to all tissues, and it's not regulated by Title 21. And that means that you're just using a sterile environment, that you're following good tissue practices, and that there was a guidance document written for that. So now we'll move away from those three pieces of information that I really wanted you guys to know about to understand the FDA devices. I've spent some of my career working with FDA medical device, and so we'll talk about the 510K pathway. So the 510K pathway is for any submission for a moderate or high-risk device, and they have to find an equivalent product, and they have to go through this regulatory pathway and submit it to the FDA. And that is an important piece to be an eligible product to be FDA cleared. And this diagram really goes through some of the examples. So as you can see to the far left here, Class 1 is low-risk, and that means that it can be exempt, but you still have to register that product or list it with the FDA. Or in some situations, if you want to fall under Class 2, that would fall under the 510K product and you can be FDA cleared if there was a predecessor product. For a Class 2 product, you can be exempt or have to go through the 510K process. And then for a Class 3 product, which is high-risk, you have to go through three different processes. You either have to have a predecessor and go through the 510K, and you're considered FDA cleared, or you go through many studies and you show that those studies connect a condition to treat that area for that product, and you can become FDA approved. Or you have to go through the de novo product creation. So to sum that into two pieces a little bit easier, so if you're going to be clear, which there's a lot of orthobiologic products that are cleared because there was a predecessor that just explains what that product does, doesn't treat any condition, but it provides that basic idea of what that product does, then that would be considered FDA clearance. For FDA approval, you need to go through many studies and you need to show that the benefits of that product outweigh the risk. And there are currently no orthobiologic devices that are approved for in orthopedics that are FDA approved. But what we should know about orthobiologics is that even though they're not FDA approved and they're being used off-label, in physiatry we use a lot of things off-label. In fact, the most common medications that we use, including gabapentin, duloxetine, amantatine, trazodone, which we use every day, are all being used off-label. So those are just some pieces of information. I'm still confused. I hope you guys are. So I'll pass it over to Eric, and he'll talk about how to clear up some of the confusion that we all are confused in this room about. Thanks, Mark. So some of the questions after, you know, reading all of these papers and listening to these lectures, these are the questions that I still have. Is PRP HCTP? Is BMAC an HCTP? Is BMAC homologous? Does it need to be homologous? Is MFAT homologous and does it need to be homologous? Is SVF allowed? Are various products approved via the 510K pathway? And what can or can't I put on social media or advertise on my website? You guys may have other questions and we can ask those at the end too, but those are just some of the ones that come to my mind. So first is PRP and HCTP. And the answer to that is pretty clear from the FDA that it is not. So they have written that PRP is not an HCTP because it is a blood product. Therefore, the compliance and enforcement policies do not apply to PRP. So what does that mean for our practices? Well, it's not regulated by the FDA. It does not require, it only requires current good tissue practices. It's neither subject to registration nor annual reporting, which are required of 361 products. It's not subject to the preclinical trials, pharmacology studies, investigational new drug approval or biologic license applications that are required of drugs or biologic products. Next is BMAC and HCTP. This is a confusing one, so just prepare to, you know, you'll still be confused at the end. Well, the FDA has written that minimally manipulated bone marrow for homologous use and not combined with another article is not considered an HCTP. However, if it is more than minimally manipulated or used for a non-homologous use, then it does meet the definition of an HCTP and is subject to those regulations. So when I read that, I could not figure out what that meant because they're saying that it's not an HCTP if it meets the criteria used to regulate HCTPs. I know it's hard to see the flow chart. The second box, it says, are the four criteria that Mark talked about that all 361 products, all HCTP products that don't meet the same surgical procedure exception have to qualify under. So that was my first problem with trying to answer is BMAC and HCTP. It is if you regulate it as an HCTP or it isn't if you regulate it as an HCTP. So maybe is my answer. And what does that mean if it is or isn't? Well, if it's minimally manipulated and homologous, then you can basically treat it like PRP, meaning it's not subject to registration or annual reporting. It doesn't require all of that process to go through that a new drug would. Is it homologous? This is another good question. So the FDA writes, we generally consider an HCTP to be for homologous use when it's used to repair, reconstruct, replace, or supplement one of the following two things. And the first recipient cells or tissues that are identical to the donor cells, it doesn't really fit that. You know, we're not injecting BMAC into BMAC. We're not injecting bone marrow into bone marrow. You can make the argument maybe for subchondral injections, but that would be the only one that might be able to make that argument. So we have to go with the second definition that recipient cells or tissues may that may not be identical, but perform one or more of the same basic functions as the recipient cells or tissues in the donor. So is it performing the same function? Well, what is the function of bone marrow? What are we getting from bone marrow? The FDA guidance statements really only, they never address mesenchymal stem cells. They address hematopoietic stem cells. So if you, in their text, it says that relevant biologic characteristics of hematopoietic stem cells generally include the ability to repopulate bone marrow by self-renewal and by differentiating along myeloid and lymphoid cell lines. You know, those basic functions are not the functions of cartilage, tendon, muscle. So in that case, you would say no. But they don't really talk about mesenchymal stem cells. And you could make the argument that mesenchymal stem cells do, you know, save same, serve the same basic function to repair cartilage, bone, muscle. So the answer is still maybe, I think. And what does that mean for your practice? Well, if you believe and want to make the argument that it is homologous, then it's not an HCTP and it is not regulated. And you can treat it just like platelet-rich plasma. If you believe that it isn't homologous, well, then it is an HCTP and it needs to be regulated and meet the four criteria that Mark addressed. But it doesn't meet them, right? So that means it's either not regulated at one end of the spectrum as a blood product like PRP, or it jumps to the other end of the spectrum where it is regulated as a drug or biologic product. And there's no argument you can make that it falls under a 361 product, which is just kind of silly. But so what does it mean for our practice? Well, then we get to the same surgical procedure exception. What about that? And this is where the circular thought process just got me reading document after document and never really getting an answer. So we start with, let's go back and say BMAC isn't an HCTP. It's unregulated, just like PRP. Well, if someone says it's more than minimally manipulated or it's not homologous, now it is an HCTP and it's regulated. Well, then you can argue, what about the same surgical procedure exception? Okay, it's an HCTP, but now it's not regulated. And you can go in this circular loop over and over again. And I think most people out there who are doing bone marrow injections are, you know, in my opinion, and, you know, I don't think that will hold up in court if you don't quote this lecture to defend your case in the future. But in my opinion, you know, the same surgical procedure exception is probably the most, the one that can be argued for with the best argued for if you're going to continue to do bone marrow injections for orthopedic indications. Is MFAT homologous? Well, this is pretty clear, at least per their text. It says, an HCTP from adipose tissue is used to treat musculoskeletal conditions such as arthritis or tendonitis by regenerating or promoting regeneration of articular cartilage or tendon. This is generally not considered a homologous use because regenerating or promoting the regeneration of cartilage or tendon is not a basic function of adipose tissue. So the FDA seemed to be pretty clear that MFAT is not a homologous use. But again, the same surgical procedure exception exists and if it meets these criteria, then it doesn't need to be homologous. So that is, again, how most people are justifying the continued use of MFAT injections for orthopedic indications. And this is some more text from the FDA saying that MFAT is, is, does, I guess the MFAT does fall under the same surgical procedure exception. So what does this mean for our practices? Well, if we assume it qualifies for the exception, then going back to our flowchart, it doesn't fall under the 1271 requirements. It's treated just like PRP, if you believe the exception applies. And then it, as well, is not regulated. Now back to SVF, which we talked about a lot. The FDA is very clear that SVF is not allowed. The 11th District is clear that it's not allowed. The state of Florida is clear it's not allowed. A judge in California disagrees, and that is currently up for appeal. We don't know. And then, like Mike said, this will likely go to the Supreme Court if the decision is unchanged. And then the question about various products. I hear this question from people all the time. It came up in our review in the Orthobiologic Curriculum Committee. Isn't this product approved via the 510K pathway? Well, the 510K pathway doesn't approve products. It clears them, number one. And then, number two, it only clears the devices, not the products that they produce. So I'm not sponsoring any devices here, but I'm just going to use one as an example. LipoGEMS is a device that is FDA cleared through the 510K pathway. The product of LipoGEMS is MFAT. That product is not approved for any orthopedic indication. That use would be off-label. And the same goes for PRP kits. Any PRP manufacturer and their kits, those kits have been FDA cleared, most of them through the 510K pathway. The PRP that is produced is not approved for any musculoskeletal or orthopedic indication. All of its use is off-label. And those things should be disclosed to patients if you're doing these procedures. So what can't you put on your social media or on your website? This is more regulated by the Federal Trade Commission than the FDA. And they have been pretty clear that the word stem cells, in particular, if you put that on your website as a treatment for a systemic issue, that will get you flagged first. You know, people treating for multiple sclerosis, for CP, for cardiac issues, those are the ones that they're going after. Again, though, they say you can't use it to treat specific orthopedic or musculoskeletal issues. So if you say you're using stem cells to treat an orthopedic issue, that's going to be flagged and you're going to get a warning letter. Now, you also can't write that you are using an orthobiologic treatment, PRP, MFAT, BMAC, as a treatment for a systemic issue. You can't write that you're using them to treat a musculoskeletal or orthopedic issue, which is surprising to a lot of us because I'm sure we all see all the time websites and social media accounts saying, I did this PRP to treat this problem, arthritis, tendon partial tear, what have you. But by the letter of the law, you're not supposed to do that. The other thing you can't put on is patient testimonials, and this comes from a document I think from 2010. You can't put patient testimonials of atypical outcomes without disclosing the typical outcome. So if you have a patient that did really well and you have an MRI showing that their cartilage regrew or their ACL regrew after your stem cell injection, that is an atypical outcome. And if you were to put their testimonial and their pictures on your website, you could get, you could have the next $5.1 million lawsuit, right, that Park Avenue Stem Cell had. So what you need to disclose is this patient's cartilage regrew. That is not expected. That is an atypical outcome. Great for them, but what you should normally expect with this injection is not for your ACL to regrow, not for your cartilage to regrow. Maybe we see improvements in pain and function, but this, you know, based on these images is not the case. That leads us to what can we put on social media, what can we put on our websites. You can put, you can have a list of all the procedures you do, BMAC, you can put MFAT, you can put PRP, but you can't say that those procedures are used to treat these diagnoses. That has to be separate. You can have a separate list of all the diagnoses that you see and treat, but you can't connect those diagnoses to these orthobiologic treatments. You can have a blog where you discuss literature and talk about the evidence for and against stem cells, but really that's the only way you can write the word stem cells on your website and not be flagged by the FDA, mostly because, you know, these injections aren't really considered stem cell injections in the United States. We are not allowed to culture expand them. The stem cells that are in them are a minority of that injection and of that product. You can put patient testimonials with typical outcomes that are supported by literature, or like I said before, you can put an atypical outcome as long as you're clearly disclosing the typical outcome. Even after that, I'm sure there's still questions. I still have questions, and future questions will come up because there's new things every day every year. Don't ask me about exosomes. I don't know. There's probably other people in this room that know more. I have not read those documents yet. So if you have those questions, these are some of the places you can go to to get the information that I got for this lecture. Some specific questions, like is X a blood product? Is it an HCTP that's regulated as a 361 product? Is it a biological product that's regulated like a drug? Well, that's a question for the Tissue Reference Group, and their website is linked. If you have a question about starting an IND process for a product that you know is going to be regulated like a drug, that's a question for the Division of Regulatory Project Management and their phone numbers here. Thanks to my mentors and to family, who let me spend all this extra time reading all these crazy documents. And we definitely wanted to leave enough time for questions. So feel free to approach the mics. Or we can just discuss some of the questions and things that have come up just in conversation. Great talk, great title. Do you think the verbiage on the website matters if you say orthobiologics as a treatment versus a management to manage pain and function? A lawyer might, yeah. I think it could still get you, you know, flagged, but then there might be a difference when you get to your case. Awesome. Yeah, I think one of the things that I think is important is separating your conditions that you treat and orthobiologics and having those in separate areas when you're thinking about marking this. Great talk. Oh, sorry. So for the cases that are targeting practices specifically, are these like attorney generals of states? Are these the FDA? Is this a civil lawsuit of false advertising? It's a mix of all of that. Okay. So there have been various, you know, individuals who have spearheaded those lawsuits at those different levels. One of the themes that should carry through if you're trying to read the details on the slides as I was talking is that particularly when these cases come from the FDA, it is years and years and years before that case is closed. So look, in another year or so, we might have a very different situation based off whether or not the current appeal is overturned or it stays. But you don't want to find yourself in one of these lawsuits because even if you feel that you truly are in the right, the financial ramifications of fighting that for years and years is just extensive. And even in the case that currently has favored the defendants, the judge ruled that the FDA was not liable for reimbursing the practice for their legal expenses because they ruled that the FDA still had the right to question this. We're just ruling in your favor at this time. Thank you. And to that, one thing we didn't touch on were state licensing boards. So the doctors who lost their licenses, that decision is always made at a state licensing board level. Your license can't be taken away by the FDA, by the FTC. You can be fined by the FTC. You can have an injunction filed against your office and that office closed by the FDA and or the attorney general, but your license is a state decision. And most of those state licenses, those doctors were doing things that were pretty egregious or very harmful to patients. So as long as you follow the warning letters and make changes, you're unlikely to lose your license, if you at least adhere. Hi, thanks. Great talk. So for the separation of the orthobiologics with the to heal or like to say, can you ever say you can't use this to heal X? It has to be just writing an article on orthobiologic and say, hey, oh, we treat joint pain. Is that what you're saying? It can't be intermixed at all? Okay. Yeah. And I think, you know, anyone who's using orthobiologics, the best way to be very safe and to be honest with your patients, and I think the latest literature talks about improving pain, improving function, as opposed to regrowing that tissue. And that is, you can be very safe. Your patients can feel very comfortable with, you know, some of the knowledge that you're giving them when you say those types of claims. But those laws are regarding advertising. They aren't regarding the practice of medicine. You are allowed to have that conversation with the patient, you know, that you have, you can talk about what the evidence is for these orthobiologics when they are used to treat or manage these diagnoses. That is a conversation you can have. That's practicing medicine. They don't regulate that. How about if you write, like, an article, let's say, about it? Because we were, I think, trying to write a magazine article because we were going to start doing it in our practice. And I was like, oh, my gosh, we can't write to heal or to this. We can do it for pain or function. So I was being very picky on the verbiage because of it. But do they knock down on, like, just, like, hey, we're going to start doing this to potentially treat? Yeah. That's a good question. Yeah. I don't know is the answer to that. Yeah, that was tough, for sure. Yeah. I think it's always going to be better to lean on the conservative side than the uber-aggressive side with that. I think, you know, you can cite, you know, what is the most up-to-date science in terms of how we believe these products work? How does that differ when we're talking about the treatment of soft tissue pathology versus intra-articular pathology? You can cite studies that have shown biologic changes, but you don't want to oversell and overemphasize that. I mean, it comes back to we treat the person, not the picture. We're trying to improve functionality, and I think that should be what is most highlighted. Thank you so much. One other thing I'll add is I think Dr. Laska did a great job of elucidating the difference between how are you advertising versus what are you permitted to have conversation-wise with a patient in the room. An element in between the two of those would be your consent form before this procedure, and you're talking about the risks, the benefits, the alternatives. For the benefits, I think you should be very careful about what that language says, that you're not necessarily healing their tendon or curing their arthritis. You're talking about the pain amelioration and the functional improvements. Yeah. I just wanted to clarify something, too. A lot of my patients work at the NIH. I work in Bethesda, Maryland, and I'll say that one of the most important things that I'll do is provide level one studies, and there are some level one studies for how it improves pain and function for a year for mild to moderate knee arthritis. I think that could be a helpful tool to give patients. There are several studies out there that you can provide patients for. Also, there are some consensus statements out there now. The MBA has come out with a consensus statement in support of PRP for mild to moderate knee arthritis and patellar tendinopathy. Then there's also the American Academy of Orthopedic Surgeons that have come out with a technical review going over studies for PRP. And the AAPM&R will have a technical review hopefully published by next summer. And all those studies would be okay to put on your website? You can put any study on your website, and, I mean, you're not advocating whether you agree with that study or not. You might in a blog, right, but there's nothing against putting a study on your website. We just need you to come up to a mic because it's being streamed, okay? It's more for the streaming. Just curious. Do you think the recent published study, Nature Medicine, FDA approved five sites by Ken Markner would impact the regulatory landscape? How would it impact the regulatory landscape, if it will? He's asking about the study published November 1st in Nature by Dr. Markner, which was a four-armed randomized control study looking at steroid versus SVF versus BMAC and MSBAT. No PRP arm. And it showed equal outcomes among all four arms at one year. So that's a study that is, you know, not going to support the use of most of these biologic products. However, I think most of our patients and most of us have had steroid injections, and this is probably the first study I've ever seen that shows benefit out to a year with steroid. So the argument I would make is most of my patients have tried steroid injections before they're willing to spend thousands of dollars on one of these products. And am I going to cite this study and say, look, this study says you can have a year of improvement from the steroid injection? Well, it's not working anymore. What else do we want to try? And so we have to be able to talk about all the studies and the whole body of evidence and also know that people are people and they're not just going to want to be treated because of one study. It's a great study and it's very well done. One surprising, I think, treatment arm, in my opinion. Yeah. I want to say that study was very well done and we should acknowledge that it was a well-done study. First of all, that's, you know, I think a lot of the things that we argue in some of the other studies, it was just a well-done multi-site study. One did improve in all four arms and they did improve surpassing the minimal clinical important difference in some of the categories. So that's important to note. So I know they're going to do some follow-up studies to see how long several years later. But you know, I think that's an important study for us all to reference and use it as one of many studies that are needed to, in this work, to expand some of the research being done. You have to be able to cite the studies that support your treatments and the ones that don't. I think if you're not talking about both of those with your patients, you're a salesman and not a doctor. Yeah. The interesting thing I found about this, I mean, apart from the clinical side of it was that it was FDA supervised and approved as well. So FDA kind of like was partly, as I understand, was involved in it and that kind of thing. So how would that impact? One of the elements that would have required the FDA's approval for that was the involvement of SVF. So again, SVF is currently, it falls outside of what the FDA deems compliant with the current guidelines, with the exception of Los Angeles County for the time being. Perfect. And just a last million dollar question. So is BMAC STCP or is it not? Is BMAC SVF or is BMAC an HCTP? HCTP. I would say the same surgical procedure exception says it isn't. All right, thanks. Or it says it is, but it's not regulated as a 361 product. Thank you all for coming. I'm sorry. I forgot about the streaming questions, if you guys want to stick around for these, you can. There are three questions from people watching online. Let's see. There are sleazy clinics advertising stem cell treatments. What is the best approach to turn them into regulators? So I still see, I mean, I've had at least three patients since I arrived in Boston that have told me that they saw someone who recommended a birth tissue stem cell injection. That is probably the most clear thing that you can't do right now, according to the FDA. I'm not turning people in, but the FDA has websites where they instruct patients on how to do that if needed. The post that I referenced in my arm of the talk that was directed right to consumers. If you guys could hold the conversation for outside so the people online can hear the answers to their questions, thanks. The post that I cited in my arm of the talk regarding, I think it was 2020 or 2021, that the FDA sent or posted an announcement directed at consumers and patients, it gave them a link to click on there in terms of if you're being offered these treatments, please notify us of that. Now that post was also very ambiguous because they include in one of those products orthobiologics and PRP is clearly an orthobiologic and per the FDA's guidelines, PRP is clearly exempt from these guidelines. So there's a lot of ambiguity, but they did put in there an ability for patients or consumers to directly reach out to them. The second question is, any feeling on where the next rulings or updates may come from? The next one will come from the ninth district and then depending on what they rule, possibly the Supreme Court. That's all. Thank you.

regulatory landscape

orthobiologics

confusion

PRP

BMAC

MFAT

FDA

manipulation

transparency