Good evening. I first want to thank all those who attended tonight. My name is Shannon Strader and I'm a PGY-2 at the University of Louisville. I'm also the moderator and creator for the AAP and AR3T Orthobiologics and Regen Med Series. The goal for the webinars is to provide comprehensive education for physicians in training and physiatrists interested in regenerative rehabilitation. While reducing stigma, misinformation, and encouraging responsible advancements for the regenerative field. AR3T is offering certificates for those who attend eight webinars this year. If during the session you have a question, please write in the chat box and we'll answer as many as time permits. It gives me great pleasure in introducing our very intelligent speaker tonight, Dr. Turner. Dr. Turner is a professor at the University of California, Irvine. Turner's current research addresses ethical, legal, social issues related to stem cells and regenerative medicine products. In particular, he uses approaches from bioethics and the social sciences to examine clinics engaged in direct to consumer marketing of unproven and unlicensed cell-based interventions. He also studies ethical issues related to crowdfunding for medical care, cross-border health-related travel, and other topics. Turner is a co-editor of Risks and Challenges in Medical Tourism, Understanding the Global Market for Health Services, and The View from Here, Bioethics and Social Sciences. Thank you so much, Dr. Turner. Great, thanks very much for the chance to be part of the seminar series, and thank you, Dr. Strader, for the invitation. So yes, I'll just jump into things here. You should probably see me with a blurred background. I was mentioning that I've just moved to UC Irvine, and so there's all the kind of messiness surrounding me that comes with moves. So I'm not used to the blurred background, but there's a functional reason for it. So I'm going to get started here and just try and give you a sense of some of the research that I've been doing, but also I think some of the issues and challenges that it tosses up. And as Dr. Strader mentioned, I'm going to be focusing on the U.S. marketplace in which a great many businesses and clinics have emerged, put out a shingle on the Internet, and market stem cell interventions for a wide variety of indications. Just a second here. So I thought it would be helpful to have a disclosure statement at the very beginning. I don't want to spend a lot of time on it now, but we can always come back to it if anybody wants to. Just to mention some paid and unpaid work. So I'm an expert witness, paid in one case, unpaid in another for a civil suit and a criminal case involving the U.S. government. I'm a member of ISSCR and a member of the International Society for Cell and Gene Therapy. I serve on their committees. It's unpaid, but I just want to acknowledge that. I've just moved here, and the Stem Cell Research Center here graciously contributed to the recruitment package to build a biotech center that I'll be leading. And I have funding from Pew Charitable Trusts to study businesses that are engaged in marketing stem cell-based interventions or purported stem cell-based interventions. I don't know that that's a conflict of interest. I mean, that's the exact focus of my talk. But it is funding, and so I thought I would mention that here. I also wasn't planning on mentioning this because I didn't know that there was going to be an announcement today, although there's certainly been some details swirling in the background. But just to kind of jumpstart today's presentation, I thought I would mention that earlier today, the Federal Trade Commission and the State Attorney General, the Attorney General of Georgia, put into the public domain a press release, but also a complaint that they filed in court where they're suing Stem Cell Institute of America and its co-founders for what's characterized as deceptive joint pain accrual marketing scheme. And if you go down to the paragraph that I've highlighted, they point out that they've launched litigation. They're suing them. And it's because of this business's marketing of purported stem cell therapies, predominantly to seniors using what the FTC characterizes as bogus claims, that the stem cell products they're advertising are effective in treating arthritis, joint pain, and other orthopedic ailments. Earlier today, I tweeted out this announcement and the complaint itself is now available online. So if you're interested in additional details, you're welcome to take a look at the complaint. But I mentioned this just to sort of suggest that I think today's focus is fairly topical. It's timely. And I'm hoping to provide, you know, not just a kind of a quick press release version of things, but a bit of context so that you can sort of see the larger economic, social, ethical environment in which something like this emerges. So there's a common way of addressing this topic. And I think if we were having this gathering, you know, some time ago, many of you may have heard the language of stem cell tourism. And there's kind of this baked in assumption that if Americans are gaining access to unproven stem cell interventions, then they're probably leaving the United States and they're going to clinics in other nations. Maybe it's Mexico, India, China, Russia, Ukraine. But that was a kind of a common framing. And it wasn't just a kind of narrative device. It was because researchers doing empirical research around 2017, 2018, when they did sort of global surveys trying to figure out where these businesses are, that's what they found. But it didn't take very long after those studies first appeared for it to become apparent that there were comparable businesses operating here in the United States. And in time, it went from just a kind of a modest number of these businesses, advertising purported stem cell therapies for, you know, ALS spinal cord injuries and on and on. But it was actually occurring, you know, at scale, at a large scale. And this is something that I've followed this marketplace since around 2012, trying to track individual businesses, began by writing a number of letters to the FDA, urging them to investigate various businesses and then try to take a more, you know, I think what I could describe as a more rigorous, systematic, comprehensive approach to looking not just at discrete businesses, but at the larger marketplace, if we can call it that, in which they operate and that they constituted. I did a piece, a first empirical study along these lines in 2016 with Paul Knaupfer, also in the UC system, but at Davis. And this was a piece that came out in Cell Stem Cell. And we found for this article, I'm not going to get into a lot of details about research methods, but there's hopefully going to be Q&A. We can talk about that later if people want. But, you know, we found what to me is just like sort of this eye-popping 351 businesses operating in total 570 clinics that were involved in this direct-to-consumer advertising of purported stem cell interventions. And these numbers really seem staggering, even to me, someone who'd been following this for some years. I did not know at the start just how many there were. And I think it probably would have seemed a much more intimidating project if I'd known, because that's a lot of businesses to track down and analyze and, you know, write up. It was a fairly labor-intensive effort. We also did a subsequent study where we tried to figure out, you know, when did these businesses first hop into the U.S. marketplace? When did they start advertising purported stem cell treatments? And what we found is that in the data set that we had, so this is from the 2016 study, we tried to figure out, you know, when did the web pages start popping up where they began making these claims? We found the first claims occurring around 2009, as you can see, just kind of like a burbling of activity. But by 2014, 2015, you know, there were over 150 clinics pouring into this marketplace. It looks as though there's a drop down in 2016, but that's just because when we did this study, we only did it for two months into 2016, so it looks like a drop. The actual projection is higher, and empirical research that I've done since then would suggest that they've continued to pour in, you know, at scale on a very rapid basis. Again, I'll provide some details about that in a little bit. But in other words, so there's a story here, and it's a story that goes for, you know, in some sense, a decade with the businesses that we found. But if you're really interested in doing a kind of a genealogy, it is possible to find some earlier activity back before 2009. These just weren't ones that continued to operate in 2015, 2016, which is why they weren't part of our data set. But they were present. They were advertising, you know, placental stem cell interventions, therapies, or placental stem cell treatments, or other kinds of products. And then, you know, they ended up exiting the marketplace at some point. So it turns out that, you know, businesses that are involved in this kind of activity, they're often very savvy when it comes to digital activity, digital advertising, online marketing, because, of course, they're interested in finding a client base. So they have, you know, they'll often have YouTube accounts. They'll put out a lot of YouTube videos, testimonials, maybe have a Twitter feed, have an active Facebook presence, and, of course, they have their own company, you know, business website. All of this activity means that, you know, there's a lot of grist for the mill for anyone who's interested in, you know, looking into the kinds of advertising claims, the marketing representations these businesses make. And if you look at enough of them, you can start to get a sense of what, you know, what's going on in this broader marketplace, because you can step back, you can kind of add up what's going on at individual businesses and come up with tallies, giving you a sense of what's taking place in this marketplace as a whole. It doesn't mean that you, you know, captured all possible businesses, but I think it gives a sense of at least what can be detected using various research methods. So you can find, you know, the names of these businesses, how do they package themselves? Are they orthoclinics? Are they pain management clinics? Do they bring themselves as stem cells or genetic medicine clinics? You can look into a question like that. You can figure out, you know, where they're located. If there's a business that operates the clinic, does it operate one clinic, three, ten? Sometimes they'll run business clinics across a number, you know, a number of different states. The map that I have here to the right is from the piece Paul Knopfler and I did, and it gives you a sense of sort of the geographic clustering that occurs. You can figure out what kinds of purported stem cell-based interventions they claim to administer to people. You can see what kinds of representations they make about diseases, injuries, you know, what exactly do they claim to treat. They'll often provide details about safety and efficacy claims. Very few of them will provide much insight into cost, but you can pick it up here and there. And as I mentioned, you can gain some insight into, you know, when these web pages first went up. So in other words, there's a lot out there. And if you're patient and have time and are interested, you can gather a lot of interesting information. As I mentioned, I'm not going to get into a lot about methods for doing work like this, but there are some important distinctions that I think need to be made. If you're focusing on business involved in, you know, directly advertising to patients or consumers to use that language, I think it's important to ask, you know, are you looking at evidence-based interventions, interventions, you know, lacking evidence of safety and efficacy? Are you looking at ones marketing FDA approved products, not approved? So the work that I'm going to be talking about are ones where, you know, these are not FDA approved stem cell-based interventions. I would say that they're not supported by convincing evidence of safety and efficacy from controlled clinical trials. You know, what exactly constitutes a proven or an unproven intervention is, in some sense, a contested subject. And that's something we might want to discuss. These are businesses that do not have FDA cleared investigational new drug applications into effect. So these are ones where they haven't, you know, submitted a research protocol to an IRB, obtained IRB approval and gone to the FDA and also obtained clearance from the relevant FDA center. They may have IRB approval, but they don't appear to be, there doesn't appear to be any record of FDA clearance. And they market purported stem cell interventions that fall outside, you know, the current standard of care. So this gives some sense in terms of, you know, what I on my own and with coauthors like Paul Moffler have tried to use as, you know, inclusion and exclusion criteria when looking for businesses of this kind. So just to emphasize that, you know, there are some, some cell-based interventions that are FDA approved. So if you go to the FDA's website, as I did earlier today, you can find 22 of them. I think we could have a discussion, maybe a disagreement over how exactly they should be characterized. Are they, are they stem cell therapies? Are they cell-based therapies? Are they gene therapies? These are kind of challenging topics in their own right. But if you just go to the FDA's page, you'll find 22 of them listed. There are also, sorry. No, there are also some stem cell-based interventions that I think we can fairly described as back by years or decades of safety and efficacy data, even though they don't have FDA approval and in fact do not require FDA approval. So, you know, for many of us, if we know someone who's had a stem cell transplant of some kind, it may be a family member or a neighbor or a friend who's had a blood related cancer of some kind, maybe leukemia, multiple myeloma, other cancers of the blood or bone marrow. And they've ended up having a stem cell transplant as a treatment. In many instances, these are not approved by the FDA, but they can be fairly accurately described as evidence-based interventions. This isn't meant to kind of cover all of those, but I think it gives us a sense in the sampler of them. So to move on from that earlier study, I'm going to provide a bit more data about a follow-up piece. Although this is something that I've continued to work on, I'll provide a little bit more recent data near the end of my presentation. So I did a piece first as a presentation, the National University of Singapore, and then in Perspectives in Biology and Medicine to try to take that data analysis process forward into 2017. And in this case, you know, trying to figure out how many businesses in the United States were operating in this marketplace found 432 businesses and 716 clinics. And so this is, if you go back to that earlier work doing global analyses, these are numbers that basically were exceeding the totals for what at one point were described as the global marketplace. So just to sort of get to the point, I mean, you know, this is a lot of commercial activity, a lot of marketing activity taking place just in the United States. Now there are still some individuals in the U.S. who will travel abroad and go to other countries for these procedures. There is still outbound travel, but there's also it's clear a fair bit of inbound travel where individuals from Canada, Europe, New Zealand, Australia are now coming to U.S. based facilities to have what's advertised to them as stem cell treatments or stem cell therapies. And it's really not surprised that the arrows come into the United States given the, just the sheer number of volume, volume of businesses that are now here. This is just to give you a quick sense of what I've seen in, in all of the empirical studies that I've done, there's a kind of a big three and a top five and in red there you have, you know, the big three, there seems to be, you know, an awful lot of these businesses cluster in, in three States. And that's California out in front with 125 of these clinics for this study event in Florida with 116 in Texas with a hundred and then Arizona and Colorado coming up in that next category. So when you actually look at these, you know, these five States, it's a pretty sizable portion of this entire marketplace. And what's interesting to me is that, you know, one, there's been a fair degree of consistency that these seem to be the States that pop up year after year, when you're trying to do empirical analyses like this. And the other thing is that, you know, while there is some matching that, you know, these, the first three, for example, are larger States with large population. But if you actually look across the United States, it doesn't appear to be strictly a story of, of, you know, the, the population, the number of individuals in any given state that available evidence suggests that, that whatever explains clustering, it's more complicated than that. And so it could be, you know, demographics, for example, it's not just how many people are in a state, but, but you know, their age, the number of morbidities, comorbidities they have, it can be things like a backtrack number of, of cosmetic surgery clinics. It can be perhaps comparatively lax medical boards overseeing the practice of medicine relative to other States. There may be a number of factors at play and no one has really quite succeeded in teasing out all, all of the factors that may explain this kind of clustering. What do they advertise? Well, in this study, you can see some specific numbers, but I would say that the, you know, the perhaps the more important point is the general trends and the general trend seems to be that when we're talking about us businesses that are marketing on a direct consumer basis, purported stem cell therapies, you tend to see a couple of main claims. And so these are businesses that will typically say that they perform liposuction. They take fat from someone, process that fat, and then put it back into that person as a fat autologous adipose derived stem cell treatment. Another common claim is to make the assertion that, that basically set up that, that bone marrow is used. So bone marrow aspirin is used again, this is an autologous procedure. It's taken from someone processed by a medical device and then put back into that person. So these are autologous interventions from someone back into that person. And then even in this earlier study, it's possible to see the emergence of a different kind, a different side of this marketplace. And this is what I think of as the kind of the businesses that advertise allogeneic birth tissue derived stem cell products. And so this is where you have businesses and clinics that, that will make claims that they are offering, you know, amniotic derived stem cell therapies, placental derived stem cell therapies, umbilical cord or umbilical cord blood derived stem cell therapies. And that's the language, the kind of language that you'll typically see it's treatments or therapies. So, you know, autologous is a part of this space. Um, the allogeneic birth tissue, birth birth tissue related products is another part of the marketplace. And that latter category seems to be expanding over time. So that it seems to be coming more significant, more prevalent in this marketplace. So for example, if you find businesses that are, you know, podiatrists. It's birth tissue derived sources of what they're advertising is stem cell products. What about the marketing claims that they make? You can, you know, the dominant kinds of advertising claims really do seem to cluster in terms of businesses that will claim to offer orthopedic related procedures or pain relief, pain, pain reduction, pain management, minimization. There are a lot of businesses that claim to use stem cells to treat sports injuries of various kinds. So that's, you know, over on, on the left here, you can see those three popping up with the, with larger numbers, but you can also see this kind of spread or spectrum of advertising claims. And it's across that spectrum that you can see businesses claiming to treat, you know, neurological conditions, respiratory, cardiovascular, cosmetic, you know, urologic skin disorders, some, some it's sort of unclear that they would describe themselves as treating diseases or injuries because it's more, you know, claims like they can reverse aging or, or use stem cells for purposes of rejuvenation, you know, reversing aging. So, you know, kind of quite a wide breadth of claims that are, that are being made here. If we, if we were to talk about this in detail, I mean, you know, we might come to the conclusion that some of these interventions, if you were to sort of track the marketing representation and say, well, what about in period scholarship, we might find kind of, you know, more compelling evidence basis for some claims relative to others. That ortho space could be one of them, but I would emphasize, there is a difference between the kind of current state of stem cell research taking, you know, peer review publications into account and the actual evidence that any, any particular business has. So many of these facilities, businesses or clinics are not active contributors to peer review scholarship. They don't have individuals involved in actually conducting stem cell, stem cell research. In many instances, there's no record of all of any kind of, you know, meaningful engagement with stem cell research. It's more just kind of making marketing representations, putting out these claims without having any real evidence themselves to back up those assertions. A lot of the activity that I've described focuses on marketing to adults, but it is also important to understand that some of these businesses appear to target children or parents, guardians of children. So just to mention that you can certainly find even here in the United States businesses that will make advertising claims about administering stem cells for cerebral palsy, autism, muscular dystrophy, juvenile diabetes. So I think it's important to understand that, you know, I'm going to talk later about the very problematic advertising claims. Many of these businesses make, but I also think it's important to understand that in some cases they have their targets, their clients don't necessarily have decision-making capacity, may have diminished decision-making capacity of some kind. And so we need to kind of acknowledge those complexities when we discuss this commercial activity. So what do businesses like this do to kind of peddle their wares, to make persuasive advertising claims? If they had FDA approved stem cell products to market, they probably have an easier time of it. If everyone recognized that what they were promoting was solidly evidence-based and it fell within the current standard of care, I mean, this wouldn't be as troubling, it wouldn't be as concerning, it'd probably be easier for them to persuade people to come in the door, but they don't typically have that. So what they do is engage in a variety of marketing strategies, rhetorical strategies that I think of them as these kinds of exercises in persuasion. So if you look at the marketing claims made by many of these businesses, whether on their websites or on Facebook or other sources, often they'll use marketing material that contains really quite scientific seeming claims, even though you begin to realize that if you're looking at references to peer-reviewed scholarship, it's not done by anybody at that business, it's maybe a team at an academic institution somewhere else that is using a mouse model or a rat model and it hasn't even moved into human beings yet, or if it does involve human research participants, it's often early phase one studies, for example, where the researchers themselves are nowhere near commercializing their product, it's very early days and it's not clear where their research program is going to go, but that's used as a rationale for defending commercial activity, as though kind of the science is already there. One particularly concerning tactic is to register purported studies, what I think can sometimes be described as junk scientific studies onto clinicaltrials.gov and basically repurpose a valuable public registry and database and use it as a kind of a marketing platform. Some of you may have seen businesses that will use athletes, celebrities, personalities, individuals with a profile to kind of promote the interventions they're marketing. And there are a number of tactics that are outlined here, sometimes it's filing patent applications or claiming that they've got accreditation of some kind and it could be some sort of like self-selecting group that decides to accredit themselves. But these are some of the different kinds of approaches businesses will use to add a veneer of legitimacy and credibility to what they're doing. There are also businesses that will, I think, in a way, try and take advantage of some regulatory exceptions that exist when it comes to federal regulation of stem cell products. So there are a great many stem cell products where it's pretty easy to come to the conclusion that they require approval by the FDA, but there are some credible, legitimate exceptions that are identified in US federal regulations like what's known as the same surgical procedure exception. There's another category that involves the administration of autologous, minimally manipulated homologous products that aren't combined with other articles or products that might increase the risk. There's use of minimally manipulated bone marrow for homologous use. All of these are concepts or categories that really require a lot of unpacking. But what I would suggest is that when you look at some of these distinctions in federal regulations and the white papers and policy documents, many of them are quite well defended as these sort of special categories that don't require pre-marketing authorization by the FDA. The problem is that while they are reasonably defended as a matter of science, as a matter of law, they can be exploited, they can be taken advantage of. People kind of have their elbows out and make them wider and broader than they're meant to be. And so in some sense, we could say there are these gray areas or zones or gaps that can be taken advantage of and often are taken advantage by businesses that will say that they're engaged in practice of medicine or they're operating in these categories of exceptions when it doesn't take much of a background in relevant law and regulations to realize that their products don't really fit in those exceptions. And in fact, they should have conducted rigorous clinical studies and sought pre-marketing authorization because that's the category their product falls into. The FDA to its credit has I think done a good job of trying to clarify these concepts, amplify them, provide information in terms of how the FDA interprets them and how it applies these concepts. So I'm thinking in particular of the same surgical procedure exception and providing definitions and explanations of what constitutes minimal manipulation of cells and tissues and homologous use of cells and tissues. I don't mean to suggest that the guidance documents put out by the FDA in 2017 can't be criticized. I think they can be criticized, but I do think they're valuable in terms of bringing clarity and detail to an area where clarity, detail, certain kind of crispness matters. But I also want to say the FDA, just as it put out these guidance documents, making it clear when particular products require pre-marketing authorization by the FDA and when that's not the path that's required, they did something that I think, I mean, you could say if that's what they did, then this marketplace must have emptied out because a lot of businesses must have realized that they did require pre-marketing approval from the FDA. They would have to do preclinical research. They'd have to do clinical research. And so you might think, oh, that's the step that resulted in everybody jumping out of the pool. But in fact, that didn't happen because in part with these guidance documents, the FDA indicated that when the finalized guidance documents went out, the FDA was going to exercise the enforcement discretion, and they would do that for a three-year period. And what this means, and just to sort of boil it down, is that the FDA said it would take this risk-based approach to enforcing regulations. And so if they saw a particular business really putting patients at significant risk, they could step in and enforce the law. But if they saw a commercial activity, advertising activity that they thought didn't pose significant risks of that kind, they could choose to exercise enforcement discretion and not enforce laws that they, by law, could choose to apply to these businesses. Now, the idea here, I think there was a good intention behind this effort. And the good intention was to basically kind of give a heads up to businesses and say, look, we're giving you time to get in touch with us here at the FDA, to check on the regulatory status of whatever it is that you're advertising, to stop selling products that are non-compliant. And if you want to get into the activity of actually conducting clinical research and generating evidence for what you've been advertising, you can start to engage in preclinical and clinical research and submit IND applications to us, and we'll review those. And maybe you'll wind up doing a clinical study that's been cleared by the FDA and approved by an IRB. So it was meant to provide that kind of meaningful opportunity for businesses to kind of recalibrate and come into compliance. A couple of problems there, and that is that one, there's that three-year period. That's a lot of time. And a lot of businesses just decided to kind of jump into this marketplace and market what appear to be non-compliant products. The other problem is that a great many businesses didn't take this as a stop sign or red light. They didn't even take it as a yellow or amber light. They just kind of kept rolling along, continuing to make their advertising claims. And it turned out that a great many other businesses decided to join them. So as a result, the directory super marketplace at present is much larger than when the FDA put out these guidance documents. So I think this is an idea of how kind of, you know, an example of how good intentions can sometimes have bad outcomes, because now when it comes to enforcement, the FDA, I would say, faces a much larger regulatory challenge than it did back when it put out the guidance documents in 2017. So just to put some numbers on that, this is unpublished data, but back in a study, I tried to bring it up to date to 2019 in April. At that point, there were 748 businesses and 1,263 clinics. So over a thousand of these clinics, and of course the marketplace, there has been attrition, but there's been a lot more businesses coming in. So these numbers are even bigger today. So the FDA would say that at the end of May, the period of enforcement discretion came to a close, and they are now kind of, you know, engaging in enforcement of federal regulations that apply to these businesses. I would say, you know, it's possible that what's happened is we have now entered a new era of enforcement discretion, where there are so many businesses, so many clinics operating in this space that the FDA acknowledging its finite resources, acknowledging, you know, the challenge of preparing untitled letters, warning letters, the effort that goes into that, seeking primitive injunctions, you know, the FDA may still have to kind of exercise discretion in the sense of picking its targets, being selective, and not really getting to this much larger, much broader marketplace. Now, I think you always want to exercise good judgment and think in terms of risk when you're deploying regulatory resources. But if you've got a small amount of human resources, staff members at your disposal, and a very large marketplace that you're supposed to enforce and patrol and regulate, you've got a problem on your hands. And I think the FDA has a big problem on its hand, and not just the FDA. I'll get to that later. You know, what about ethical issues? I'm going to kind of keep this brief, but I think this is a marketplace where there are a great many ethical issues, a great many problems in terms of marketing representations, clinical practices, products given to people. Part of it is that we're talking about commercial activity where businesses routinely make non-evidence-based claims, and they'll frame that in terms of the stem cell products that they're offering are framed as, you know, likely to benefit individuals, probably going to benefit individuals, and have either little risk or no risk of complications of any kind. And I think these are quite often real misrepresentations that mischaracterize the current state of stem cell research, but certainly what the specific products these businesses are marketing, where they don't have convincing scientific evidence, then what they're advertising as a treatment or as a therapy is truly safe and efficacious. So there are problems with the marketing representations, and when you have inaccurate, misleading, and deceptive advertising claims, you create enormous problems when it comes to informed consent processes, for example, because you're providing a kind of an information envelope or, you know, information about risks, benefits, alternatives that's not reliable, it's not robust, it's not accurate. And so people will end up making decisions that are based on inaccurate information, which may pull them into paying for these procedures, but aren't good in terms of making what can be very consequential health-related choices, financial choices. And so, obviously, a basic element of informed consent is making sure that people are given, you know, reliable, honest, accurate, credible, trustworthy information. And so this is a fundamental challenge to informed consent models. It's easy to think of this in terms of individual businesses engaged in misrepresentations, making misleading claims that affect individual patients. But I think we need to step back and realize that when you move from a handful of businesses to this kind of marketplace operating at a large scale, you end up with this kind of, you know, rampant circulation and misinformation, where it's not just individual patients, but entire publics, you know, us collectively, can find it very difficult to make meaningful distinctions between what we could describe as evidence-based, stem cell-based interventions and investigational or unproven products, because that line is being routinely blurred, often deliberately, by these businesses. How do people manage to navigate their way, you know, in an environment where there are so many widespread, you know, misrepresentations out there? And sometimes those misrepresentations extend not just to the products themselves, but to what I think of as often misleading accounts of the role of the FDA, the role of state medical boards, and what, you know, regulations and laws actually mean. And so I think this can play a role in diminishing public understanding, trust in important institutions. So misinformation can take a variety of forms, all of them quite problematic. And it's not just misleading advertising, it's often the way it's done, which is, in many instances, it's done in a very kind of aggressive, hard-sell manner that's used to close the deal in the way that someone might try and, you know, sell a timeshare in Florida, or sort of some other statistics that we have of really aggressive sales tactics. And so, again, we have people making what can often be quite consequential life choices, health choices, financial choices. And sometimes it's being done by parties that are trying to close the deal, clinch the sale, and recommending steps that aren't necessarily in the best interest of that individual. Just to tie it to the pandemic that we're in the midst of, some of this kind of, you know, misleading advertising and aggressive activity is responding to the pandemic that we're living through. So you can find some of these businesses that are claiming to have stem cell treatments for COVID-19 or preventative interventions that will reduce the likelihood that someone will end up with COVID-19. Often this is framed in terms of stem cell treatments playing the role of immune boosters. And so when it comes to, you know, the sort of this mixture of desperation, hope, anxiety, and suffering, it is this kind of, you know, larger constituency, which is, you know, many of us may fall in this category of feeling rather anxious during the pandemic, looking around for something that might help protect us and our family. And these businesses, some of them at least, have very quickly pivoted and taken advantage of this and are now advertising so-called treatments that I think are very far from deserving that name. What happens when you have businesses that have a lot of hype, a lot of marketing froth, and don't have good safety and efficacy data behind them? Well, one thing is that they expose their clients, patients, to unnecessary risks because they're selling purported stem cell interventions where there isn't an adequate, there may be non-existent evidence of a positive risk-benefit ratio. They may have no data at all. And so some of you may have seen this New England Journal of Medicine article where a number of elderly women with age-related macular degeneration went to a clinic in Florida, hoping that they could improve their vision and ended up suffering severe vision loss or blindness. It was not really shocking when it's basically marketing representations that aren't backed by any evidence or scientific data behind them. It's not just the lack of evidence, the lack of research. It's also common in this marketplace to see a lot of clinical activity where it's very clear that the individuals who are operating at these clinics, practicing in these kinds of environments, it's not just that they're involved in the sale and administration of unproven and unlicensed stem cell-based interventions. It's that they're operating well beyond what we might think of as any kind of reasonable scope of clinical practice that's connected to people's training. Now, there's a bit less of this in the ortho space than in many other domains, but I would try and emphasize that in some cases, what we have is kind of risk piled on top of risk on top of risk, where it's not just the products themselves, it's also people who really shouldn't be involved in administering these products. And so it's easy to kind of focus on naturopaths and chiropractors and podiatrists, but there are plenty of licensed clinicians who are in this space, but are treating individuals who have diseases and injuries that are well beyond the expertise of the licensed clinicians. And this is very problematic activity from a professional and from a moral standpoint. There are also products that are in circulation that have gone through inadequate manufacturing, testing and quality control processes. And so this is a report from Mortality and Morbidity Weekly Report, where basically in this case, 12, there were more of them, but 12 were captured in this report, ended up being given contaminated, umbilical derived stem cell products. And these products ended up resulting in infections and hospitalization. And if you look to the right, some of those hospital stays were quite lengthy. One of them, for example, being nearly two months. So when someone has not adequately tested their so-called stem cell product, when they are manufacturing it in inadequate substandard facilities, when they aren't properly testing, when they don't have quality control processes in place, when they don't have any kind of quality control officer in place, things can get very easily go wrong. And they sometimes do. And there can be extremely serious consequences from individuals who have paid $5,000 or $8,000 because they think they're getting a stem cell procedure that's going to help them make their lives better, even if it hasn't been advertised as curing them. And this happens. So there seem to be more case reports in terms of individuals who've suffered, you know, vision loss or blindness. Those are some of the earliest case reports in case series that I come across. But for anyone who's interested in looking into, you know, the orthophysical medicine space, you can certainly find case reports in case series there. And so this is one that came out of the Mayo Clinic where they treated a couple of individuals who'd gone to facilities and had paid for purported stem cell procedures and ended up having these complications. The authors of this piece, you know, kind of refer to this as, is this kind of, you know, a modern day kind of form of snake oil salespeople who are involved in this activity that ends up causing harm. My colleagues at Pew Charitable Trust recently put out a report where they've kind of done an overview of case reports, case series, news media, social media, and come up with a pretty lengthy list of complications that have occurred. Now, we don't know a lot of important information. I mean, how many individuals, for example, would say that they had no complications and clinicians could look and come to that conclusion as well. How many people would say that at least their self-perception is that they benefit, you know, this would be valuable information to have, even though it too is limited in some respects. But one big problem is these businesses themselves tend not to report, tend not to disclose, often for self-interested reasons when complications occur. But if you actually look at people who had to treat these individuals, you can begin to see the carnage, the wreckage, the suffering starting to pile up. And so it may be that we often kind of underestimate, undercount these complications just because it's so routinely under-reported. There's also a problem here. You know, it's easy to focus on individuals being scammed financially, being taken advantage of, sold something that's useless, doesn't work, and maybe people have a brief placebo effect and then as soon realize their lives haven't changed for the better. It's easy to understand the harms that occur when someone has a procedure that they think will help them and then they end up, you know, being blinded or suffer a pulmonary embolism or a stroke or otherwise have a very serious complication. But there is a kind of a larger collective problem here. And that is that, you know, when you have hundreds or thousands of clinics that people can go to that are advertising purported stem cell treatments and therapies, I don't think we know the full effects, but it certainly seems plausible to think that this could have a real effect in terms of people involved in trying to conduct credible, careful, rigorous clinical studies because there's a cohort out there who are going on this direct-to-consumer basis who in all likelihood, you know, can't ever be included in clinical trials because they're going to be excluded because they've had a prior unproven unlicensed stem cell intervention. And even if you change that inclusion exclusion criteria, you might find these individuals aren't interested in participating in a clinical trial anyway, because they might end up being randomized, they might end up being blinded, they might get a sham surgical procedure or a placebo, and they've been convinced and persuaded that they can get access to a stem cell treatment if they go to one of these businesses. So it's going to be very hard to convince them to actually participate in something like a randomized control trial. So I think, again, there are individual harms and those are often easier to spot, but there are collective harms caused by this kind of marketplace as well. I think some of those collective harms really can affect the actual conduct of stem cell research and credible efforts to, you know, advance preclinical and clinical research in regenerative medicine. It may be more difficult to spot those harms, but I think we should be thinking about that as not just individual harms, but kind of, you know, collective harms that a marketplace like this may play a role in causing. Now, there have been a variety of responses to the commercial and clinical activity that I have described, and I was asked to provide a bit of information. The International Society for Stem Cell Research recently, this spring, put out guidelines or updated guidelines having to do with, you know, accountable, responsible, clinical translation of stem cell research. They also, as they've done for many years, addressed and shared the society's concerns about businesses involved in administering, you know, unlicensed, unproven products. I am not going to go through that entire report. That would take a lot of time and be well beyond the scope of what I plan to discuss, but I'm just mentioning it here if you're interested. Some of you probably know it very well. A few details, and that is that, as they have done, you know, for over a decade now, ISSCR places tremendous emphasis, supports, you know, very rigorous, robust testing of investigational stem cell-based interventions, and, you know, urges that this be done in well-designed, properly regulated clinical trials, all with the point of trying to generate robust, reliable, trustworthy safety and efficacy data. And that that's kind of the route that if we want to have stem cell therapies, that's the way to get to them. It's the rigorous, difficult, sometimes costly hard work of getting there, not just putting out a marketing shingle and making bold claims until an FDA inspector or someone from the state medical board someday comes along. And so the ISSCR as it has in the past condemns, criticizes what I think we could describe as premature commercialization of purported stem cell treatments that are not backed by substantial evidence of safety and efficacy. And this is something the FDA and counterparts of the organizations have tried to kind of make these distinctions for many years now. ISSCR, when you look at the kinds of exceptions they recommend, there are a lot of points of overlap with federal regulations here in the United States, acknowledging the value of a kind of same surgical procedure exception. For example, acknowledging that there are distinctions that can be made for stem cell products that have been minimally manipulated and used in a homologous manner. I know these are technical terms and I'm glossing over it. We can come to that later if you're interested. But to really kind of think about that in a confined way so that in general, it's important to generate credible, convincing safety and efficacy data. And that becomes the rationale, the scientific basis for then claiming that you actually have a stem cell therapy is the data that provides the rationale. It's not the marketing fraud. In this report, in this guidelines, ISSCR also points out the many different problems associated with what are sometimes described as pay to participate stem cell studies. And you can find businesses in this marketplace that sometimes they'll use the language of stem cell treatment, stem cell therapy. Other times they'll say they're conducting a study of some kind that you need to pay to participate in. But when you actually start getting into the details of those purported studies, they often have, you know, really serious problems. And it can be things like, you know, problematic eligibility criteria, phase one safety studies with a plan, 3000 research subjects, all of whom will pay and all of them thinking they're getting a stem cell therapy. Problems with selection bias because people have to pay to get into them. Misleading language that makes it difficult to distinguish like, is this a study in which someone is getting an unproven investigational product or are people getting a therapy or a treatment? Because if you're using that language as well, it becomes unclear what exactly is being offered. And so the guidelines try and address studies of this kind and suggest, you know, many instances when they should not be done in very narrow circumstances when if they are done at all, the circumstances that they should be restricted to. ISSCR also touches on patient registries. Some of these businesses really kind of put forward patient registries as an alternative to the conduct of randomized controlled trials. And in the guidelines, if you're interested, you can see the ISSCR is supportive of patient registries, sees them as being valuable in terms of monitoring adverse events, for example, collecting different kinds of data, developing information on endpoints and biomarkers, but challenges any effort to kind of use patient registries as a substitute for the conduct of randomized controlled trials. And so I think that's a valuable contribution as well as there seems to be a shift to advocating for patient registries instead of running RRCTs. Many businesses operate in this space. This is kind of an argument they make. And it's a problematic one, I think. If you're interested, the guidelines themselves are a great place to turn to. If you're looking just for kind of a quick, brief overview of the guidelines as they apply to unproven unlicensed products, I did a little piece for Stem Cell Report that tried to kind of capture some of the key features of the guidelines. You can check them out in Stem Cell Reports. And let me just end by mentioning some other developments that have taken place in response to the marketplace I've described. So to be fair to the FDA, compared to say 2012, 2013, I think we can see the FDA is clearly being more responsive to this marketplace in terms of issuing warning letters, untitled letters, letters of concern, and then the much more challenging work of seeking permanent injunctions in federal court. They have obtained one against one business in Florida. They are pursuing another one here in California. We don't yet know the outcome of that case. It's still before the federal court. But these are labor intensive, challenging activities and the FDA has taken us on. I mentioned at the start of my talk that the FTC had taken a meaningful step today in terms of filing a complaint against the business in Georgia. A couple of years ago, they did the same thing to two businesses operated by the same clinician here in Orange County. So that's an interesting court case. I think there's probably a lot more the FTC could and should do in this space, but to give them credit, I mean, they haven't been entirely on the sidelines and during the COVID-19 pandemic, they've issued a number of letters where I think it showed they've kind of up their game, engaged in much more activity in response to these misleading claims about businesses offering supposed treatments for COVID-19. So I'm trying to offer critiques to some of these businesses while also trying to do justice and be fair to the meaningful efforts they have made. Now, there's been activity in terms of state legislatures, California first, but you can also find the state of Washington and more recently Vermont passing state legislation where they have recognized this kind of commercial and clinical activity as a problem in terms of, again, financial scams, risks to patients. And so they passed legislation where anyone who's trying to sell an unlicensed stem cell product, marketing it as a treatment, must now disclose to individuals that this has not been approved by the FDA. I don't think we know a lot about how people interpret that. I don't think we know how effective this is in terms of kind of protecting people from misleading information, but at least it's an attempt to get these businesses to be more transparent and a bit more accountable and make it clear that these are not FDA approved products. There has certainly been a flurry of civil litigation. And I mentioned during my disclosure statement that I have a kind of a minor role to play as an expert witness in one of them, but because of alleged harms, physical injuries, misleading claims that have ended up resulting in people spending money, this is people basically alleging harms. And so civil litigation has been one route. I don't think to respond to this title, I don't think civil litigation can stem the tide of businesses involved in this activity, but I think it is one meaningful response, particularly when individuals are left to their own devices and federal regulators and state regulators have not responded. In this case, in some respects, civil litigation can become the court of last resort, the court of only resort. The larger problem here to bring things to an end is that there are a lot of financial incentives in place for businesses to engage in the very activity that I described, that a business can have no preclinical research and no clinical research, just start marketing purported stem cell therapies. And the odds of getting a warning letter or an untitled letter are very low. Likewise, the likelihood that a healthcare professional or anyone else in this marketplace will end up dealing with criminal charges or loss of licensure or suffer financial penalties are pretty low. So I think some people decide to kind of play the odds and think they can make a lot of money in a space like this and the chance of something bad happening to them is pretty low. So I would say we've got a problem when we let businesses make their own decisions about the regulatory status of their products. I think we probably want to reframe this because the existing system is just too easy to game. That is the model that we have in place right now. And I think as long as that is the status quo, we need to stop talking just about the FDA and realize that when it comes to predatory commercial activity, misleading advertising claims in businesses, selling in many instances, unsafe products, we don't want to have just one agency tasked with dealing with this. There are many other players that could be responsive to this marketplace. And I've listed a few of them here, but I think, as I said, it's a multilayered problem and multilayered problems require multilayered responses. So I see a role for many different actors in this place in terms of trying to better protect patient safety and better protect public good, public understanding and the public interest. So I'll stop there and very much appreciate the chance to discuss these issues today. Thank you. Thank you so much. That was wonderful. If you guys have any questions, you can put them in the chat now, but I had a question myself. I've thought of how, I guess, physicians in general could be better at explaining and promoting because it seems like we're one of the big factors that are causing these issues. And having a fellowship, a legitimate fellowship with the board or accreditation would be, I think, the best way to go about it. And doing research, I know there's been several literatures saying there needs to be a fellowship, but there hasn't been an actual legitimate fellowship that's offered right now. And I know there's two, I think there's two right now in the nation that's academic, in the nation that's academic cellular therapy fellowships. Otherwise there's not really like a regenerative specific understanding the ins and outs of it. Do you have any thoughts? Yeah, I do. I mean, I think there's a lot that can be said for having fellowship programs, fellowship opportunities like the one you described. I mean, I think of that as a kind of a program that would make for more circumspect marketing claims, would promote credible research, would promote translational research. So I think there are all kinds of reasons why clinicians, clinician investigators could benefit from fellowship training opportunities like that. I don't think it would play a big role in terms of dealing with the marketplace like this, just because I think for many individuals, they don't have much of a background, they don't necessarily have much training anyway, they're not necessarily that interested, they're not gonna go through years to kind of have a better understanding. So I think of it in terms of the conduct of robust, carefully designed, credible clinical trials in terms of meaningful clinical translation, I think that what you're describing is really important. In terms of a marketplace like this, it would be great if individuals at the businesses I mentioned decided to take program like that and then scale back on some of their current activities. I'm afraid the people who would most need a fellowship opportunity like that, perhaps would choose not to do it. And instead they would go to the Bellagio in Vegas and spend a weekend learning about how to do stem cell procedures. So that would be the beginning, middle and end of the depth of their knowledge. Exactly, I just foresee in the future, because if you're trained in GI and do a fellowship to become a gastroenterologist, you can't suddenly work as a hemo-oncologist. And I guess that ideally, because that's obviously illegal in two patients, it's more, I guess, societally known. So I just perceive that would be a really nice way to go. Okay, I'll go into the other questions. Are you aware of any credible practices, clinics in particular, that provide SCBIs that can serve as an ideal model for the industry? Possibly practices that the FDA can base and future guidance regulations around. Yeah, that's a really interesting question. I don't know that I wanna identify any particular business, certainly not by name. I mean, I think the way that I would respond to that is that I would say that it's easy to kind of put all these businesses and clinics in one box. And I think we probably do wanna take a more differentiated approach and understand, some individuals have a more credible background, some facilities, it's an orthopedic clinic and it does confine itself to making claims related to treating orthopedic diseases and injuries. That may play a role in kind of reducing risks. Some places may be much more careful in terms of where they source or procure anything they administer to individuals. So I think there are differences in terms of the degree of risk patients probably face when they go to some of these businesses. I'm just not sure, I'd have to think carefully about a question like that. It's an interesting question, it's a good question. The Federation of State Medical Boards has done some work in this space in terms of individuals involved in advertising and administering stem cell-based interventions. And I would say that that's maybe one place to go to in terms of thinking through, when this is being done in terms of clinical practice, what kind of standards do we wanna have in play? What kind of practices do we wanna have in play? I don't recall there being a long sort of checklist available there, but I think of that as maybe one touchstone to turn to when beginning to give a meaningful answer to it, but I think it's actually quite a challenging question. A very interesting talk, are any US news type ranking systems that take into account safety, evidence-based, et cetera, that is either available to the medical community or even interested patient community? Yeah. I'm not aware of any kind of meaningful, credible, reliable ranking of businesses like the ones that I've described. I mean, you can find things, there's more like sort of the Yelp review equivalent of some of these small practices, but I don't think that's the question that's being asked here. But I mean, that's an example of where, if you kind of drill down on the kind of businesses that I'm interested in looking at, you can find some where people will talk about being very pleased by the procedure they've had, and they're doing better after having it. Other people will post comments and claim, express concern that they've been scammed or taken advantage of, or they have complications. So, I mean, there's feedback on social media sites, there's responses on social media sites. On the other hand, when you take a look at litigation in this space, there also appear to be some businesses that are basically part of their marketing activity involves posting positive reviews for themselves. So we're gonna have to ask the question when it comes to claims online, we have to ask, is it some actual patient? Is it just a kind of, is this kind of a fabrication by the business itself? It's just kind of another form of marketing. So, that's some of what's out there. But as I said, it's more of the kind of Yelp review sort of activity, not what I think is being proposed in terms of, kind of meaningful third party accreditation. You can find a couple of facilities that will make some kind of claim of having accreditation from the joint commission, but it's often just based on kind of filling out of a survey and I don't think it's particularly valuable or insightful or really something that anybody should be making decisions on. Next question, what are some of the more legitimate uses of stem cells that you see in use in clinics or in trials? Yeah, I mean, that's another one that it will take a long time to really kind of give a meaningful answer to that question. I mean, when I think about sort of, most evidence-based interventions, I mean, I don't know this is exactly the question that's being asked here, but when I think about cancer centers, for example, doing performing hematopoietic stem cell transplants for individuals with various cancers of the blood, I think of that as something that, it's evidence-based in many instances, there's decades of research behind it. And so, that's why at the very beginning, when I talked about inclusion and exclusion criteria for kind of doing social science work in this area, I think it is very important to not be sweeping up cancer centers, for example, or cancer facilities that are marketing stem cell transplants when what they're doing is evidence-based, it's rigorous. I also wanna emphasize that, and I don't think my presentation did this well enough, effectively enough, but in many instances, we have this kind of marketing hype, marketing froth, a lot of activity in the commercial marketplace, but we also do have well-designed, credible, rigorous clinical studies taking place, but just kind of in a different sphere. It's not by individuals that are typically charging on a for-profit basis, it's not commercialized, but certainly when it comes to orthopedic interventions, I mean, we have credible clinical research that's taking place, studies get published in peer-reviewed journals. And my response to that is probably like many other individuals who read those articles, which is that with some cell-based products, the safety profile looks encouraging. If it's a phase one study, there's sufficient evidence to proceed to phase two, and hopefully there'll be rationale to proceed on to phase three. So I would emphasize that when it comes to peer-reviewed scholarship, there's plenty of encouraging activity taking place. It's just that in many instances, that world, that realm of rigorous, careful research isn't really backing the kind of commercial, professional activity that I'm describing here. But I do wanna emphasize, I don't wanna make it seem as though I'm giving a presentation where everything to do with stem cells, it must be a scam and people are taking advantage of it, it's all predatory activity, you know, far from it. There are all kinds of rigorous, careful studies in the ortho space and in many other domains as well. There's been a lot of kind of news media coverage the last few days about Selma Blair and her stem cell transplant for MS. And, you know, I think some of the news media coverage has not been particularly valuable, but I would say that's another domain where there are a number of studies right now suggesting that at least for some individuals with the most aggressive form of MS stem cell transplants, you know, may well be something to become standard of care in that area for at least a subset of individuals with MS. And this is not just businesses claiming to treat MS, you know, you can find a kind of growing body of research clinical trials, testing different kinds of stem cell interventions for individuals with MS. So that would be another example kind of beyond the ortho space. That's kind of a rambling response, but to just try and emphasize there is certainly a lot of careful research that we need to make sure is part of this conversation as well. One last question. Any particular international groups or government regulators that are indexing credible SCBI? Sorry, that are indexing credible SCBI? I mean... Yeah. Yeah. ISSCM. Yeah, sure. Um, I guess what I would say is that, let me respond to that maybe a little bit differently than the person intended. And I would say that there is quite a bit of important activity going on at the international or transnational level. So, you know, organizations like the International Society for Stem Cell Research, the International Society for Cell and Gene Therapy. I mean, they are two of a number of organizations that I think are doing a good job of trying to support credible clinical research to challenge problematic forms of direct consumer marketing of unproven, unlicensed products to play a meaningful role in terms of promoting patient education and promoting public understanding. So I think scientific societies, medical societies and associations, you know, do have a role. And many of these are, they're not strictly US-based. They are transnational. They pick up members from around the world, but there are challenges. You know, organizations like that, typically when it comes to enforcement activity, they can boot someone out. They can make someone cease to be a member, but that's kind of the extent of their enforcement capabilities. There have been some arguments that have been made in a recent article in Stem Cell Reports, for example, in a submission to the World Health Organization that it would be helpful to have, you know, a more active involvement of the part of the World Health Organization, both in terms of dealing with problematic markets, not just in the United States, but, you know, in countries around the world. And also in terms of trying to help promote patient awareness, patient understanding, public understanding, making meaningful distinctions between, you know, where do we have evidence-based stem cell interventions and where are we really talking more about unproven ones or investigational products? So I think that we need to think in terms of multiple layers of oversight and multiple layers of analysis. National entities like the FDA and the FTC matter and have important roles to play. At the state level in the United States, state medical boards in a place like Canada, colleges of physicians and surgeons have important roles to play that are not the same as federal regulators. And I also think there are valuable roles that can be played by international and transnational bodies, both in terms of, you know, promoting understanding and good scientific communication, but also perhaps in terms of having, you know, regulatory mechanisms of some sort that go beyond national boundaries, because there is still trans-border activity here. You know, patients flowing across borders or businesses that span nations. So I think that kind of international, transnational layer is an important complement to more nationalistic ways of approaching this topic. Great. Thank you so much, Dr. Turner. Greatly appreciate it. Thanks very much. I'm really glad to be part of your series and appreciate the questions I got and so appreciative for the chance to be invited by you to be part of this. So thank you very much, Dr. Strader, for the chance to be with you this afternoon or evening, I guess, out east.

stem cell interventions

misleading claims

safety and efficacy

FDA approval

ethical issues

informed consent

increased scrutiny

regulation

challenges of informed consent

reliable safety and efficacy data