 Good afternoon, everyone. Thank you for coming to another in the series of NeuroEthics seminars. I'm Toss Cochran. I'm the director of NeuroEthics at the Center for BioEthics here at Harvard Medical School. And we've got a topic tonight that we have touched on in other contexts earlier in the series when we talked about the brain stimulation and a little bit when we talked about brain enhancement. We're going to be talking about innovation in neurosurgery. Neurosurgical innovation is not a new topic in the world, as some topics in NeuroEthics are. But with the accelerating case of technological change, there is probably more and more opportunity for neurosurgical innovation. And because you're not picking me up well enough. OK. I'm going to get the headphones. OK. That looks like I'm projecting. So we're going to be talking about the ethics of neurosurgical innovation. And we will probably also be touching on the legal considerations that come into play. And we're lucky to have a couple of prominent neurosurgeons here with expertise in not only neurosurgery, but ethics and the law to talk about their experience and their knowledge in the field. Before we start, I'd like to mention that, as always, after the formal portion of our presentation, there will be some dinner served here. And everyone here is welcome to stay and join in a slightly less formal conversation with our speakers. And I'd also like to thank the groups that help us fund the seminar series, most particularly the Harvard Brain Initiative and the International NeuroEthics Society, which allows us to webcast this. We do I'm told that we do have a class at the undergraduate campus who's joining us. So welcome to you and thank you for joining us. Feel free to tweet questions to us at HMS Bioethics. We will try our best. We don't have our usual Twitter feed monitoring person here with us. But I will try my best to monitor the Twitter feed. So if you've got a question, feel free to send it to us during the Q&A session. We've got a number of co-sponsors who are shown here who made it possible to organize this and help us come up with a series of topics. So let me introduce our two speakers. Our first speaker is going to be Dr. Joseph Madsen, who is the director of epilepsy surgery at Children's Hospital Boston. He's very well known in the field. And as you might imagine, his expertise in epilepsy surgery and in pediatric neurosurgery means that he's frequently finds himself at the interface of what's known and what's not known about neurosurgical interventions. And our second speaker is Marika Brokman, who is a neurosurgeon also from the Netherlands. She is at the University of Utrecht. And she is also the president of the Ethics Committee of the European Association of Neurosurgical Societies and a member of the Ethics Committee of the World Federation of Neurological Surgeons. As you can see, she's an MD, PhD, JD. So she's got legal and ethical expertise and is a neurosurgeon. And so we're very lucky to have her here. We're taking the opportunity to speak to us as a community while she's here in the States. So please join me in welcoming our speakers. And we'll get started. Thank you. And how do I advance? OK, great. Well, welcome, everybody. It's great to see a lot of people here live. And I don't know the last time I was on the World Wide Web live, so I have to try to do careful what I say. My name is Joe Madsen. I am a pediatric neurosurgeon. And I never thought I would be asked to give a talk on the ethics of innovation. And it's really interesting to have this opportunity because I had to sort of think about it quite a bit. My email address is there, if you would like to follow up with questions on things. Well, I've never talked about ethics of innovation. I do sometimes talk about the nature of innovation in surgery and specifically the idea of inventorship and innovation. The act of doing surgery puts a person in confrontation with unexpected challenges every single time. So every surgeon is innovating a solution to a particular problem for a particular patient every time she or he does any work, basically. The surgery is also a fairly mechanical area of medicine, meaning we deal with structures, or the pair of structures that are broken, and we use a lot of devices for that reason. So the idea of making devices as a way of solving problems in human health is really something that just comes with being a surgeon. In fact, I've sometimes wondered why so few surgeons do not actually get patents and advance their ideas. And that's what I'm usually talking about, is to convince surgeons that basically they're all inventors anyway. And those of you who are not, I see a lot of surgeons in the audience here, those of you who are not, I would give you the same word of advice. It is a fun thing to do, and it's very interesting. From the point of view of this lecture, then, let me just make a few disclosures in our usual Harvard Medical School disclosure format. First of all, this entire talk is basically a long kind of disclosure of the way I think about things. The one sort of financial disclosure that I'm required to make that is relevant to the talk is that I'm a scientific advisory board member and consultant for LC on life sciences that is producing one of the devices that I'm going to be talking about. I'm going to be telling a story about my friend Ben Worf, and I want to disclose that he and I go back a very long way since he was a medical student, and I was just fresh out of internship and hadn't started full neurosurgical training. And he went on to become the first fellow in our fellowship training program at Children's Hospital to become a pediatric neurosurgeon. And what happened after that is the story that I'm going to be telling you. Also relevant to this talk is that I did spend time on the IRB at Children's Hospital for four years, and it was a pleasure to be an extremely interesting and educational time period. And I'm currently a member of the Conflict of Interest Resolution Committee, which is almost as interesting as the IRB. But this will come into play on some of the topics that we raise as we talk about the ethical issues in neurosurgery. So I was having dinner with a friend who is a psychiatrist, Ben Simon, the other night, and saying, so he had heard that this talk was going to be happening. And I said, this is kind of interesting, because what I'm going to be talking about is not necessarily the same thing that other people in a series on neuroethics would be discussing. In other words, if I think about neuroethics, I would think about the neurobiology of decision making and whether a device that changes the way we treat mental health or something like that is fundamentally ethical. But what I'm going to be talking about here has to do with the ethics of virtually any kind of innovation in medicine, but particularly any kind of device innovation in surgery. So I was a little worried that this maybe wasn't the right thing to be talking about. I've been reassured that this is an OK topic. But this isn't really so much about the neuroethics of neurosurgical innovation. This is really about the ethics, ethical problems that arise with anybody trying to make a new innovation in any area of medicine, really. But he pointed out to me the title of this book by Valenstein about the history of psychosurgery in the late 40s and early 50s, particularly between the time of its invention by Moniz, who was a neurologist, and its widespread practical application in the United States by a neuropathologist named Freeman. And there was a neurosurgeon involved in this for a while, but he dropped out. So this is really a big change in surgical practice that happened for a short time. And so the title of the book is Great and Desperate Cures. The part of what makes the topic interesting to think about how innovation works in neurosurgery is that the conditions that we are treating can be so dangerous and deadly that to not innovate may be unethical. But you could turn around and say, well, but these guys came up with a theory of how to improve behavior that really turned out not to be so scientifically justified and turned out not to be such a great idea. And probably hurt a lot of people. And so this is, we are in the shadow of the great and desperate cures. They know. Well, I can see my slides. One of the things that we, the reason that we wanted to talk about some things that were device related, but some things that were not particularly device related, like just how do you invent a new operation, is that particularly with devices and particularly in the United States, there is a feeling that almost anything you do that has to do with coming up with some change in clinical practice and certainly for a device and certainly anything that's going to be sold or marketed, there are a lot of guardians out there to be sure that there is a rulebook that tells you what you have to do at every step of the way. And so I think of these as we're, when we talk about the ethics of making a new innovation, there are a number of borderlands of the area of ethics, per se, which are regulated by certain of these groups. So the first is the institutional review boards for protection of human subjects. So we have an idea that you're going to have a group of your peers that makes sure that what you do to an individual patient is reasonable. So that's the IRB. Then you run into the question, well, what are my conflicts of interest as an investigator and innovator? How do I am I at risk of making a decision that is a bad decision because I am going to benefit financially from it? And so that's where the whole idea of conflict of interest committees come from. And incidentally, Harvard Medical School is undergoing a big review of its conflict of interest policies, which is really quite fascinating. There used to be things that were totally forbidden and how you could interact with a company that were going to become more and more allowed. But that is the idea of conflict of interest. And could you do bad research that could hurt people because you had an interest that was not in the patient's interest? And finally, the Food and Drug Administration as the regulatory board is extremely important, because we sort of have the feeling that if you can get through this hurdle, then you are at least legally allowed to sell something. But all of these become important if you are trying to be a surgeon that says, I have an idea for a solution to a problem. I would like to make it a general solution. In other words, I can always solve it for just one patient at a time. That's what most of us surgeons do. But if I want to say, I think of a way that I could treat a disease that is not being treated well, that needs a new time to cure it. How do I go at it? Well, you're going to have to work with all of these different regulatory and advisory boards. A lot of people, I think, back off just because of that. They say, well, there's no way that I'm going to do all of this. But I think what I will be making as a point in the talk today is that it's important to not confuse being in the following the rules of the Harvard Committee on Conflict of Interest with ethical behavior. It's important to understand that there is a difference between being approved by the IRB and being sure that what you're doing for patients is ethical. And there are going to be gray zones no matter what happens with all this. It's interesting. I understand a lot in many European hospitals and where they call the IRB, what we call the Human Psychic Committee, is called the Ethics Committee. We've got ethics approval to do this. And they are adjacent, but not synonymous. I could almost turn one of these around here and show if it might work. It's going to take a little while. We just paged them. OK, good. Well, these next few slides are just sort of setting the both of them. I'm going to tell you three stories, three cases of different types of innovation that will really serve as a question for Rika and the rest of us to discuss afterwards, or at least try to stimulate the talk. And in addition to working on epilepsy, one of the other areas that I've worked in a lot has been hydrocephalus, or the buildup of fluid, buildup of pressure, and how to treat that. And those are two of the most common conditions treated by pediatric neurosurgeons. And both of them are areas that are probably not adequately understood in every sense that they should be. So a patient with hydrocephalus, a child to simplify things so that we're on the same page, has a buildup of fluid in the head, usually under pressure. And one of the ways to treat this that became very popular in the 1950s when a man who was a machinist had a child formed with hydrocephalus and needed a shunt. And the surgeon said, if only we had some kind of valve so we could put in tubing to drain this. And Mr. Holter, this machinist, went home and built a valve. And the valve was later used to treat his son. And later this became the Holter Shunt Company, one of the big innovations in treating hydrocephalus at the time. But the problem with shunts is it is a piece of tubing. It is mechanical, and they plug up. And if they plug up, they can cause headaches. They can cause symptoms. And in certain cases, a bad shunt malfunction could cause death if the patient is very dependent on the drainage of the fluid. So two ideas of things that we might try to do to help with it to make shunts better would be, number one, can we make a self-cleaning shunt? Could we make a shunt that when it starts to get plugged up by the material that plugs it up, without doing surgery, you open it up and clean it? Thank you very much. Number two, how about if we could figure out ways to treat patients without using a shunt at all? If you don't have a shunt, you can't have a shunt malfunction. So those will be my first and third stories that we'll talk about. The second story is going to talk about the surgical treatment of epilepsy. And one of the things we do is to expose the brain, put on electrodes in order to find out where the seizures are coming from. And then you have to wait for a seizure to happen. And the problem is, of course, you don't know when a seizure is going to happen. Is there a way that we could understand the network well enough without waiting for a seizure and do the surgery sooner? So those are the three things that we're going to talk about just for, to name these, we'll call one the fail-safe shunt, the shunt that can clean itself. We're going to talk about granger causality to find the seizure focus, which is the mathematical approach. And the third one is going to be the invention of a new procedure for hydrocephalus by Ben Worf, who I mentioned, who was a medical missionary in Uganda at the time. So this is back to the story. As I was setting it up, this is a schematic picture of the fluid space in the ventricles, a shunt that drains the fluid, the valve that keeps the flow going one way. And that's a common thing. Used to be this was the most common procedure that we did at Children's Hospital. And it's been taken over by a different procedure that we'll come back to in the good story. But the problem with this is that the tissue that's lives in the ventricle and floats in there and kind of beats back and forth like seaweed, if you look at it, through a scope is pushed into the little holes that are draining the shunt. And this tissue called the coreyplexus gets into the holes, gets impacted there. And that's what causes the shunt to fail. Most of the times, they fail. They can fail for other reasons, too. That's a very major cause of shunt failure in children. So this is the need. And by the way, the half-life of shunts to fail is about five years. So for somebody with a shunt in, they are kind of waiting for a shunt malfunction all the time. How can we think of ways to improve that? And this is actually an idea that I had been thinking about and sketching for a long time. It was actually presented at engineering classes for medical device design at both MIT and Harvard. And these were the kind of classes where the students would form teams and then they would get $5,000 to build the device. And it was very exciting. And it was great fun presenting to them. I was voted off the island both times. I did not get to organize a team, despite the fact that I thought I gave a very charming statement of the problem. And it would have been fun. We tried to get the solution funded through an SBIR grant. And that grant was not funded. And then it happened that an entrepreneur who was interested in talking with me, who had a company already making other devices, even said, we'd really like to get into the Hygienescephalus market. Do you have anything we could make pretty quickly? And I said, well, I do have some drawings, sketches, and a pitch for this device. And so this is this company called Alcyon. And this is the device. So let me explain what it does. There are two new parts of this device. One is a special kind of flusher that should be sort of designed to make sure that all of the flow goes from the head out of the head. And that's part of what causes the cortex to get stuck. If you breathe something into your windpipe, if you get something in your pharynx, you get something in your trachea, you have a very strong reflex that tells you to build up pressure and then release it. So that's a cough. You cough or through your throat, that's how you do it. That's the biological inspiration. So the idea here is that this surface, when you push on it, builds up, first of all, closes off the flow temporarily going down. It builds up a small volume under high pressure and then can sort of do the Heimlich maneuver to open up the holes up here. So for many kinds of impending shunt malfunctions, yes, that might work as a way of solving it. Second idea is to have a membrane here in the shunt that is normally closed. So as far as the core plexus knows, the only holes are here. There's an opening here that the core plexus won't stick to because as far as the core plexus sees, that's just a part of the tubing. And we know the core plexus doesn't stick to the rest of the tubing, but if you pump this and these holes are completely blocked, it'll open up a new hole there. So you could imagine someone coming in with a completely blocked shunt. You massage this device, you activate this device, it pops open and they now have a working shunt. And what you do next may depend on, they may be different things you could do clinically. You change, this becomes like an airbag. You wanna know if it's been deployed or not and you might want to change the catheter to like that. But that's the device. So, and then this is just sort of showing a cartoon showing how that would work. This is the clogged system and you pump that in it and it pops back open. The interesting thing about this is that, so I did everything here the way we tell people they should do it. If you're in an academic center and you're trying to get a new device going, the devices has a patent file through our translational office, the technology and innovation development office or TDOs is called the Children's. We declared everything to our conflict of interest people and we, who just came just at the right moment to make sure that everything I'm saying is correct. And this kind of relationship with a company then, which was really based on our idea, we couldn't have gotten this going without a company. Now there's suddenly a whole book of rules of things that we are allowed to do and not allowed to do. How much consulting I am allowed to do to tell the company things about this device if I want to do various kinds of research, et cetera. These are the rules that the Harvard Conflict of Interest Committee is now overhauling and reviewing. So, rather than going to the rules and so the thing that's interesting is, they all come down to dollar amounts. So it is considered that you probably won't have a conflict of interest if you are under X number of dollars per year. But if you go over that level, then you're not allowed to do other things because that would be too large an apparent conflict of interest. And one of the practical things that we've seen from this, which is really a matter of navigating inherent conflicts of interest to understand and employ a new device, is that I'm not allowed to be an investigator on this device, but I can be kind of a cheerleader. So I'm the only one who really cares if the device gets tested. We're now in a stage where we are able to actually do some clinical testing in the operating room of the device. I can't do it, but I can exert whatever force of will I can to try to get other people to do it. And so Ben Worf is the principal investigator of the program, of the clinical part of the program. But there's a lot of these rules that come into play and the problem of how do you get other people to do the things that basically I may understand the device better than anybody? How do we find the level where the innovation still takes place and yet we're not tempted to do something wrong? Okay, but that's a device. So all of those, that big legal rule book about devices, the FDA, the IRB, et cetera, clearly apply and it's very clear how that applies. The next case is a little bit more, a little bit trickier in some ways. I think the point of view of figuring out what the rules should be. This has to do with treating medically refractory epilepsy. The idea of epilepsy surgery is if you can find the place that's causing the seizures that is different than the rest of the normal brain and remove it, that's the one way that you can cure epilepsy. So you can take somebody that has seizures every day, remove this and they may never have another seizure in their life, they may not have to take medicines. So it's a wonderful thing to do. One of the challenges is that to find this area you have to actually see seizures happening most of the time. So there's the electrical activity that you might read in EEG gives some indications of where a seizure will happen, but it's not considered nearly as good as actually seeing a seizure. You can see sprites and funny things that you can read that may come from elsewhere, but seeing a seizure is a real seizure. So what we sometimes do is put these electrodes on and I'm gonna have a picture of a couple here in a second, but then you have to wait for a seizure. So what that means is you have to do two operations for some of these patients. You open up, put the electrodes on, bring the wires out, close up, send them to the floor, hooked up to a machine waiting for seizures to happen. You hope that this is the one time in their lives you really hope a seizure happens today and then you record it, this helps us find it and then you move on. But if the argument is if we're operating on a network to try to stop the seizures, if we could identify the network, we could solve the seizure problem faster. So if we can get rid of the costly waiting, this is, here is the brain where we're putting on one of these sets of electrodes and here is the brain with a large grid and some depth electrodes going into it. And this ended up being a very successful operation, but the patient had to sit with that much hardware in their head with everything closed up, unfortunately, in order to get to that point. So wouldn't it be wonderful if you could just record something from this network, say, ah, I see how the information is traveling from point to point here. I can estimate from data when a seizure is not happening, where it will be if a seizure is happening. So this is kind of the standard thing and the inter-ecodata from these is a very rich and very confusing and unreadable amount of digital information. And so what we decided to do, Sunyoung Park in my lab and I started taking this digital information and applied a mathematical algorithm for which Sir Clive Granger won the Nobel Prize in Economics in, I think, 2009. And the idea is Granger was interested in the nature of causality. So how do you know if one thing is causing a lot of data, and it's sort of like, if you think of all these as economic indicators and you said I don't really know, how do I predict what's going to happen next or if something bad happens, where is it going to happen? Can you get it from the interactions between all of these very complicated nodes? And basically the idea was that if knowing the data in any one channel gives you additional information on predicting the future of another channel, that is causality, according to this mathematical definition of causality. The analogy which he used, which he used even in his Nobel acceptance speech was if there are, if you see a person making an apparent random walk and you have that trajectory coming out of a tavern, you might assume that possibly they were intoxicated. But if there's two of them and you find out that one of them actually is making a random walk, the other one is following at a safe distance. Could you figure out which one was the follower and which one was the drunk? And the answer is you could, because you use this technique to see who was leading. So if you use that, it turns out that the causal areas turn out to be very similar to, in many of the patients, to what are actually the seizure onset zone areas. And we ran a series of 20, so here and here, and if you just even line these up by their rank order, it turns out that it's very unlikely that you could get this result by randomness. And this worked in most of the cases, but not every single time, so these are probability values. And if you look at that, most of them are P is less than 0.05, but these are for individual patients. The odds of getting this much similarity between the interictal data and the ultimateictal data, as read by experienced neurologists, is something like one in 10 to the eighth. So it's something that works most of the time, and it would be additional information, and it would be good to have. So we've continued to develop this. We now have it at a computational point where it can be done in close enough to real time that we get data back in the operating room while you're looking at that electrode. Question is, how and by whom do we take the next to eventually use this information? And that's an interesting question. So the more general version of this is how do we introduce a new way of thinking into surgical practice? And can a surgeon use new information that is coming out of a source and get the best him or herself from the conflict brought on by the risk of novelty? So we don't really know how good this is, but at some point we wanna start using it. Now we actually have a lot of experience with this in epilepsy mapping and epilepsy surgery because there are a whole variety of new things that have come along recently, like different kinds of imaging, magnetic imaging and so on. And we're really looking for a concordance of information. So I think this is actually something that is solvable, but this is not something that is clear how you properly solve it with respect to almost anyone. The FDA can't exactly answer this question for us. The IRB can't exactly answer the question for us. The conflict of interest can only care if I try to get money off of it, which I'm not gonna try if it's okay. So that's the second one. Now the third story is perhaps is a, so both of those ideas for innovation or just things we're working on, they're in progress, they may never make it to the light of day. This story has made it to the light of day and has become an extremely important story. So I've mentioned to you Ben Worf, my long-time friend, and he, after studying with us to become a pediatric neurosurgeon, went back to Kentucky for a few years, and then one day surprised us all by saying, I have received a religious calling to go and treat children in Africa who are not being treated. Everybody said, wow, that's, and I'm taking my whole family, here's his whole family, and I'm gonna homeschool them in Africa. They ended up in Uganda. They built a hospital. And the patients that they saw primarily were patients with very bad hydrocephalus. So these were kids that came in the very large house. He, here he's with a whole line of mothers with their babies with enormous heads. Many of these people are living in small huts that we may come back to with animals and animals. But the amazing insight that he had was, if I put those shunts in, the ones that we told you were always plugging off and can cause death, and send them back home, they may never make it back to me if they get sick. This is not a reasonable thing to do. But the problem is that the conventional wisdom was if you treat anybody under about a year of age with the alternative procedure, which I'll explain in a second, it almost never works. For the alternative procedure to shunts, we talked about shunting as a way to treat hydrocephalus. The other technique is to use an endoscope or a video telescope that goes, can be put into a small hole and go into the ventricle and see what's going on. And then to make a hole in the floor of the third ventricle of the brain which allows the fluid to escape. And that was considered a good treatment for a very narrow selection of patients who had a clearly blocking blockage. And it was thought that it basically never worked under a year of age. And so don't even try. Ben said, I'm gonna add something to that which is to cauterize the corey plexus and to go through and burn the corey plexus. And with doing that, he found that he could treat younger and younger children and he got them through without shunts. And I tell you this story because at times when I would tell it to various hydrocephalus on the patient's parents and people like that, they would say, wait a minute, he, so he just started doing an operation that had never been done before. I said, well, technically it had been done by Walter Dandy, but it never really worked when he did it. So yeah, basically no one was doing this. This was a new operation. It was a time when a great and dangerous cure was needed for these children. He started with these kids with enormous heads. This was palliative, but now he starts treating them at a younger and younger age and they get by without shunts and they grow into neurologically normal children. So he ended up treating 3,000 of these children before he finished his seven years in Africa and brought his family back eventually to rejoin us. But that hospital that he established became the training grounds where pediatric neurosurgeons and others have come from all over the world to learn to do this procedure in Uganda. The people they have trained at that hospital in Uganda have done over 17,000 of these operations by this point. And the prevalence of putting shunts in at Boston Children's Hospital has been dramatically declining as the number of endoscopic dermatolostomy and CPCs has gone up. And then went on to win a MacArthur Genius award for this work and probably will someday be promoted to full professor, which is even harder at Harvard. So that is the story of someone who really innovated a whole new surgical strategy, a whole new operation. And the point being just to come back to where we started that surgeons have to innovate every day, it's the difference between what is a practical solution to something for one patient that is what you're paid to do and what becomes clinical research or something that has to be identified as innovation and regulated in some way is an interesting question, I think, to try to sort out. So that's all I have to say. Thank you very much for letting me post some questions. Thank you. So it was a great presentation. Thank you. So that's really some of the things that I'll be talking about in a bit. So today we'll be talking about the ethics of surgical and neurosurgical innovation. So why is it important to talk about this? Because without innovation, medicine wouldn't be where it is today. Neurosurgery would be completely different, but it comes at a price. So these are the numbers of the Netherlands. If we continue to spend as much money on healthcare as we have done over the past 10 years, in a couple of years we will be spending around a quarter of our GNP on healthcare. Well, that's not sustainable. So which way you see it, there is some sort of scarcity in healthcare and you have to find ways to deal with it. So you can either put more money and invest more in healthcare. You can work more efficiently. You can also start selecting patients. And you can also carefully evaluate and select your treatments. So evaluating your treatments, why is it important? Well, some controversies could teach us that. In Europe a couple of years ago, well, the same here. For a matter of fact, there was a huge scandal about the sports hip, the metal hip implants. So it's not really neuro-related, but it clearly demonstrates a problem. FDA had approved this hip that could be used for patients who wanted to lead an active life. European agencies had approved this device and many orthopedic surgeons really liked the theoretical idea of having this hip that could give people a more mobile life than they would have with a different form of implant. And basically everyone started this implant in those hips. And then it went wrong because it was metal on metal. Small metal particles could come off and could enter the bloodstream and the muscles. Well, there were lots and lots of complications. So there was approval, but people in the British Medical Journal called it a very large, uncontrolled experiment exposing millions of patients to an unknown risk. Wow. And it had a full out all the rules for medical implants. Another controversy, closer to home. One of our colleague neurosurgeons implanted bacteria in recurrent GBM patients. GBM, glioblastoma, not firm, is the most devastating form of brain cancer. People with this disease die usually within one and a half years with extensive treatments. Once this tumor recurs, there are not that many options or there are options, but there's like no golden standard and really where are the loss? Once this tumor recurs, well, every person involved in the care of the patient usually feels the need to do something. This neurosurgeon based on evidence in literature indicating that it could be beneficial to have an infection if you have a tumor. So thought, well, it might be a good thing to actually give these bacteria to patients. So after he took out the tumor for a second time, he placed some bacteria and then closed up. For the first patient he wanted to do, he asked the IRB, do I need to get some sort of approval for this? Well, there was no need for approval. It's sort of compassion use is one case. He could do it, it's not research, it's care. You can go ahead for this one patient. Then he started doing more and more cases when it went horribly wrong, unfortunately. So the patients did consent to the procedure and he followed most of the rules that we set forth. These are ethical guidelines without the approval of the IRB. So this raised a lot of questions all over the world about so if you have to select treatments, how do you do that? How do you manage care for these patients? If you wanna do something, how can you innovate within an ethical manner? So if you think about drugs, if you are a company making this new drug for a headache, well, you know exactly how to do it. There's lots of oversight, there's a lot of regulation. Well, you have to undergo this RCT. There's usually a lot of golden standards you can refer to, but surgery is different. And I think Dr. Metzen explained it very well. For every patient's different, every situation is different. And so there's for clinical introduction of novel therapies or implants, there's actually not that much oversight and there are not that many regulations. And if there are regulations it's really hard to, well, to somehow make sure that they're being followed. Is this a bad thing? Well, some people would say no. This is called the more the surgical exceptionalism because surgery, you have to invent every day. You have to invent for every patient. It's impossible to really measure a technique. It's easier to do with pills. You can control for things, et cetera. It's harder for surgical procedures. It's harder to really reproduce it because if I were to do the exact same procedure as Dr. Metzen, we would do it in a slightly different way or it might take me longer or it might have the difference or my team works in a different manner. So it's really hard to reproduce the exact same procedure. And well, is it really possible to do a randomized controlled trial, especially in patients' rear treating, high complex cases usually, and small volume cases? Can you do an RCT in situations like that? So if you think all these things, well, yes. So it's basically impossible. So perhaps surgery, well, you saw the traffic light but perhaps you should be on green if you have a novel idea, well, go ahead and test it. I think the controversies, well, and I have plenty more examples of that show something different. But the most difficult question is, so when do you call it research? When is it research and when is it actually care and when is it innovation? That's actually a super difficult question. So we all see you at some point when it's research. That's somehow clear. It's when you want to generate knowledge that can be generalized to a larger population of patients. When you're really at the clinical acropoise, when you don't know, really don't know what's better, well, then you should have some form of IRB review and well, preferentially you do like a really good trial and you should, well, find your answer. It's research. Examples include like if you wanna compare like two implants to each other or to do this procedure for another procedure. Innovation is difficult because it's usually, it starts in the individual patient. Before coming here, I was on call and I had to, I did a hemorrhage nectomy for acute subdural hematoma. What you do then is you make super large incision in the skin, you take out the bone, you open the dura and then you see a big clot. You take it out. But what happens in many cases, the brain starts swelling by that point. So we have now tricks to close the dura. None of them tested in the trial or whatever, but you have ways to close the dura. That's been sort of accepted in our field. But then I couldn't close the skin. I was like, oh, because we didn't have like off the shelf something to replace the skin. So I was just asking the nurses everyone, so what do you think that I can use some sort of plastic? And we ended up with Teflon and it worked and the patient survived without an infection. It's like, hey, this could be used. Well, this is really care, it was innovative care, but you need individual patients. You can't do an RCT for a case like this. And well, I really believe this was superior to leaving the skin open. It's unclear if there should be some form of oversight because who's coming in the middle of the night to the OR check on me closing the skin in a certain way, no one. And well, it's really, you can't do an RCT. So this was a difficult question. So what's really innovation in neurosurgery? Another example that triggered me to study this further. In my hospital, I do the away craniotomies for tumor and I do for, and I went, when I learned how to do this, I visited several places in Europe where other surgeons do this procedure. And visiting one of my colleagues, I noticed that instead of, he would take out the lesion that would be typically located in the temporal lobe. But if the patient would have epilepsy, he would take the amygdala and hippocampus as well, even though there was no tumor there. Because he thought, well, amygdala hippocampus to me works for epilepsy. This patient has epilepsy. I'm nearly there anyway, let's take it out. And he started doing this and after a couple of cases he published this. But is there someone in his OR really checking what he's doing? No, did he add like informed consent? Well, I'm not sure. Was there, you know, other things? So I felt this is highly innovative, but it felt not perhaps how you should perform innovation. So was this research innovation care when you do your first patient, when you do your 10th patient? So this triggered me. So what's surgical innovation and what are the teams that you should pay attention to if you're interested in this topic, if you want to innovate in surgery? So how to go about this? So I teamed up with one of my close friends. She's an ethicist and member of parliament for that matter and hopefully she'll be here in the summer. And she said, well, if you want to know what the questions related to innovation are, well, start with the review. So that's what we did. We did perform the systematic review of the literature. You can't really read this, but the slide says that we looked into search engines and checked multiple keywords. And what you get then is that you filter out the ones that you found in both search engines and then you select on title, abstract and then you go full text screening. And then we selected 64 papers that described not only that ethics are important in innovation, but really we're more normative papers and we studied those 64 papers. So what did these papers teach us? Well, if you want to innovate a surgery, there are four things are super important. Oversight, informed consent, learning curve and special groups. So regarding oversight, there were 33 people papers reporting about this, but basically no one agreed what sort of oversight there should be. You know, some people would say, why should there be oversight? It's a surgery, it's unique and because of its unique nature, please let the surgeon do his or her thing. Well, you can say, you know, in the middle of the night, if you can't close the thing and you have to skin and you have to come up with something, well, you can see how that could be sort of okay. There are authors arguing for, well, we should really establish like a new committee. So that's not only like the ethics committees in Europe, especially, you know, if you want to compare two types of drugs, no, but a committee specifically for surgical procedures and surgical devices. There are people who say, well, it could be the IRB like it is, it's well positioned to do this. Others say, well, actually, perhaps someone's peers would know better if something would work or not and these peers could be internal and the chief of surgery could perhaps ask about this, but you can also ask your external colleagues. For instance, in the case of my colleague who did make the hippocompactomy, you know, he could have asked like epilepsy surgeons or other functional neurology surgeons and you know, what do you think? And do you, well, something like that. Informal consent, obviously important and it does not replace oversight. 28 pay papers reported about that. What should be in the informed consent? Well, you should perhaps tell your patients that you're doing something innovative. You should say that, well, we don't really have evidence for this. You should discuss the risks and the benefits as well, but you know about them. Interestingly, many patients said, yeah, I would love to know the technical details. Most doctors said, well, I don't think it's really necessary for a patient to know the technical details and I discussed this with my colleagues in Utrecht and some were done, yeah. If a plumber comes to my house to fix the plumbing, well, I don't need to know how that works, just fix it. So, well, that's an interesting discrepancy between the view of the doctor versus the patient. How you should get informed consent? Well, there are some papers about that too. Some people say, well, it can't be the innovator asserting itself. It could be a really third party. Some people say, well, use like multimedia, some people, YouTube clip, something like that. Learning curve, it's a surgical procedure. Well, some innovations will be so close to what you've always have done that it's or it's like a new indication for the same procedure that it's not really, there won't be much of a learning curve, but in many cases, for instance, if you start to want to use robots for surgery, well, surgeon, you have to get, well, trained to do that. So how do you deal with a learning curve? Well, you can use cadaver, you can use animals, but you can also have a tutor present to say, okay, well, together we're going to do this. Some people say there could be like an institutional committee and they should like sort of pre-define when you're good enough. And some people argue that it could be this accreditation system that you get, okay, now you've earned enough points, now you can do this in all the procedure. For some things, it actually might work, but if you're doing something in Uganda, something that's so innovative, where there are no fears around, where you can't ask, okay, how well, do I have enough experience now? It won't work. So it's really depending on the situation, but also the type of innovation. And then, of course, if you innovate, you have to be aware that there could be special groups that need more or different attention. So in the emergency case, you have to do something. So you come up with something. Well, you can sort of get a waiver of consent for those emergency cases where you can't get consent in the community of patients from the patient itself. Children, if you wanna innovate in children, you should really, so why children? Why not adults who can consent themselves? You really, well, it's a more precious group. And if you wanna innovate in children, most adults agree that you should get consent of both the parents and the child. So back to question one, so what is surgical innovation? Well, we read 64 and a little bit plus papers. No one gave a clear definition. It's really, really hard. It's clear when it's really individual case, no other way around it's innovation. And it's clear when it's research, but everything in between, it has usually elements of both. So we came up with like four types of surgical innovation based on all the literature we've read. So you could have minor modification of the standard procedure, innovations that are new to your institution, but they're being done elsewhere. For instance, if you, with the third materialistomy, if you know that it's being done so often in that center, well, it's different from them where you're really, really diverse. Well, you have this technique which you use now for a different application and you have major modification of an established technique or super new, radically new innovations. The last one is really clear. It should perhaps be a little bit more oversight, but sometimes minor modifications of the standard procedure while you should question how much oversight and regulation you need for that. We started using, for instance, a laser from an angioma surgery and it was such a minor modification. We had this super long discussion in our department. Is this not something we should like call the ethics committee or get approval and then, well, we started doing it. And that's often how innovation happens. We think that these, every type of innovation needs a different form of oversight and regulation. So how to proceed? I think we can't do neurosurgery without innovation. It would be super bad for our patients of the future if we should just stop innovating. If you regulate too much, well, there won't be any innovation anymore. But if you don't evaluate your treatments, it could have really bad outcomes for your patients, but as society as a whole as well. And therefore, we should really discuss what type is when, what type of oversight and regulation is when appropriate. So how to proceed? Just a couple of more slides on what we did next. We, there is this ideal collaboration. It's a mainly European effort of surgeons from different specialties who developed a model for stages of innovation in surgery. And recommendations for each stage. So ideal is idea, you start with an idea. It's usually one person, not a lot of oversight. You can publish this in the case report and then you develop. Usually more people get involved, more patients. You start perhaps needing some sort of ethics oversight if you do that. Especially when you start exploration phase that more people are enthusiast, the early adapters, they jump on board. They, you want to really publish your data so that it's really no, and look at not only the, is it feasible, but also what are the safety issues. Assessment, that's the fourth stage, usually, well, preferably according to ideal that should be in some sort of our RCT, randomized control trial. And long-term follow-up and the recommendation would be like to really assess long-term outcomes. You can use registries, et cetera, for that. So I would really refer you to their website. It's great, it's a great resource if you're interested in innovation. So basically, well, this slide is, I took it from their website, and it really shows that there are, given, depending on the phase of innovation, there are different recommendations and they varied from the idea phase to the long-term study phase where there are like, everyone's doing the procedure and you just really want to make sure that it's doing, you know, that in a long-term, there are like rare or rare events or that the quality remains good. So this is a model of how surgical innovation could or perhaps even should take place. What did we do? Well, we looked at, we took an example of neurosurgical practice. So for arterial skull-based meninjomas like this, traditionally, people would approach this via craniotomy, that means, well, open. You make an incision, you make a bone flap, open the dura and then, well, or not, and then you, well, try to get it out. And so this was the traditional approach, but as people have been using scopes more and more, for instance, for pituitary surgery, people started using a different approach using an endoscope. And if you use an endoscope, you can, well, you can perhaps approach it through the nose because that gives an excellent route as well. And so we were just, we saw how this, well, evolved and we started doing in our center a case like this. And, well, I thought, well, this is a good example of something that's clearly innovative. I mean, well, it's, you know, patients don't have a scar anymore. It's a really different approach, a surgical technique. So how was this introduced? Again, we did a systematic review to identify all cases that, to identify all cases of an nasal approach of these arterial, skull-based meningioma and we include those that really said how, what they did and what their outcomes were, et cetera. So these, we found 24 papers discussing what we were interested in. We found what typically happens in our field that there are like two cadaver studies. So two people report on, hey, we did try this in a cadaver. And then basically you see a lot of retrospective case series and these were the complications we have had. So there were a couple of case reports, so really diverse people to do this in humans. And then all stage two retrospective studies, these were the things we did. And these were the complications we had. So it did not really follow the stages, specifically if you would look at the order, the time order of the, in which they appeared and you're like, okay. So basically what happens, someone did a case report, then you see a cadaver study and then you see all the complications series. So in neurosurgery we don't naturally tend to innovate according to a roadmap like the ideal. If you look at some of the recommendations and I realize it's hardly legible this table, but if you look under ethical approval because after the first patient you did, you sort of need the recommendation is that you need some sort of ethical approval. So basically everything from stage one or two on you need some sort of ethical approval. Well, you don't see a there. So none of the studies reported on having ethical approval to do this procedure, even though they report in their papers we're the first to do this and they were definitely the first in their institution often in their country. None of the authors reported on informed consent. So none wrote and we got informed consent for our patients. We didn't. So basically probably didn't ask her, well, we don't know what happened, but well, they all described the procedure, they all described the outcome, but none of the studies were really prospectively designed and really looked at, okay. So is this really better than the open approach? Is this new approach? Is there, you know, how are the long-term outcomes, et cetera? So these things really stand out. And this is just a random example in neurosurgery. So if you look at how we introduce novel techniques in neurosurgery, well, we can do better with asking informed consent. Same sometimes for ethics approval, but like I said, it's really different if you see it as a minor adjustment of an existing technique. If you say, well, it's just a different pathology than the pituitary tumor, then it's perhaps a minor modification. But if you see it as a radically new thing, then well, you should, well, there, well, I think you can argue that you could, not weird to think about some sort of oversight. And lack of perspective says, yeah, we can do better. And they don't, I think it's not really feasible to do an RCT, as I do recommend. And there are multiple reasons, but so I think we have to look for alternative trial designs. We have to look for how can we really monitor outcome in a way that doesn't have to be an RCT, but you should think about registries. You should think about different design trials, et cetera. Because there are too many hurdles for an RCT. It could be that if you start doing this through the nose, you really believe that this is better. So well, how are you going to treat people open? But it also that there are so small numbers and there's many people who don't feel they're really clinical equipoise. So there are many reasons why an RCT is not perfect for cases like that. So I really think we should focus on how can we better monitor outcomes and how can we innovate in an ethical sound manner. One of the things, and that's one of my last slides, I think it's a very interesting initiative launched by the Institutes of Medicine 2006, the Learning Healthcare System. A system in which knowledge is so embedded into the core of practice of medicine, that is a natural outgrowth and product of the healthcare delivery process. And this will lead to continual improvement in care. So everything you do, you can and should learn from as a doctor. And there should be an ongoing interactions between scientists, doctors, patients to learn from each other. And especially for innovation in neurosurgery with highly complex cases where the outcome can be so different be one between two patients while the scan looks the same. I think this could be a way forward. Two aspects, there's the integration of research and care, I said, and the moral emphasis on the learning activities. I think this is something really, really potentially powerful for innovation in surgery. For that, we need to be open to our patients. We need to be open to, well, to acknowledge your mistakes. And it could be that there are some cultural changes, that we need some cultural changes so that we can be more vulnerable as a doctor but at the same time that patients tell us more even about how they perceive their outcomes. So it could be that before we get to a system where we evaluate our innovations in an ethical sound manner, we might need cultural changes. So I mentioned this afternoon that in certain innovations, it's innovation, there are four things super important according to what we found in literature. Oversight, informed consent, learning curve, and a vulnerable patient group. If you look at how we introduced neurosurgical techniques, well, they're not always according to a predefined roadmap. Some things, well, it's just the nature of our profession, but some things we could do better. We could try and get at the core approval. We could get this informed consent of our patient and we should focus on prospective studies and studies with an alternative trial design so that we really evaluate what we're doing. So learning healthcare system could be an interesting alternative because of this moral emphasis on learning and integration of research and care, but perhaps we need some cultural changes. Like I said, this is teamwork and I would like to acknowledge the people on the slide. They've worked on the projects. Amelie, well, she's the medical ethicist I work with a lot and who's been, well, she was really crucial for these projects we did. Michelle and Ivor are the students who did great work with all the search and et cetera. And Anna is epidemiologist who knows a lot about trial designs. And the people here, Dave, and I hope you, and Tim, I hope both of you will stay involved in this topic so that we can continue to improve innovations in surgery. Thank you. You can trade it back before. Yeah, I think if you speak up, the mics are probably good enough. So thank you both very much for a really fascinating conversation about a tough topic. Dr. Madsen, I'm really grateful that you brought Dr. Worf's example to the table because I find it one of the more challenging ones. When Marika talks about striking a balance between innovation and regulation, it makes all the sense in the world in a third world environment where you've got lots and lots of people thinking about the problem and you have all sorts of resources to come to bear and you can sort of think about the right balance to strike. Whereas Dr. Worf was facing a different type of problem and he didn't have lots of people to consult or people who are used to providing ethical oversight who he could turn to. And so the question as an ethicist that's going through my mind is, well, what do I think of how he approached the problem? Was what he did an example that others should follow when faced with similar problems? And the answer that I've got right now is I don't know. And the reason is you can't use the fact that it turned out really well as a ratification of what he did, right? Because it could have just as easily gone badly and then we would be using him as a cautionary example of what not to do when you're faced in a, when you're operating in a resource poor environment. So the things that I would wanna know about how he approached it are things that have to do with how thoughtful the approach was and how respectful of the patient population and the families, the behavior was. So you may or may not wanna share a ton of detail about that or you may not know a ton of detail about that, but I wonder if you've had any conversations with him about the thinking that went into this innovation that he did before he went ahead and did it? Yes, he actually tried a few different things and included using less expensive shunts and there were a number of solutions. He had the problem that came up immediately. But he was right from the get go, very concerned about the problem of follow up and finding out where these patients were and ended up having nurses that would drive out in jeeps and find the families and see what happened with the children. This has the system that he ended up getting for collecting data in Uganda, it may be better than some of our follow ups and outcomes research on some of our patients here actually. And the other really amazing thing that came out of this is that the technique that he came up with actually led to additional scientific discovery. So what he found looking in with the endoscopes was a previously undetected infection that was causing all of these hypocephalus and using that did not grow anything out of culture, but with PCR you could find out that this was an acenida bactra which they eventually found in that picture of how people were living was in the animal dung that was used to seal the housing that they had. So there's kind of a huge public health effort that went in to it along with this, but I think that is a good point. He was, you know, when we do these innovations, all this, you kind of ask your chief, you ask the person above you, he was called to this by God, you have to remember. I mean, this was, he was doing this very, very seriously. So the contrasting anecdote that you gave of the surgeon who was, I guess, surgically removing seizure centers and also removed the amygdala and the hippocampus, do you have any further information about the thought that went into that? I mean, I have to say I'm kind of shocked. I'm not a neurosurgeon, I'm not a neurologist. I have only the barest appreciation of what the amygdala and hippocampus do, but I can't quite imagine cavalierly. It's perhaps wasn't cavalier, but it sounds almost cavalier to have taken them out and you used a sort of plumbing analogy, but surely any homeowner who hired a plumber would want to know if they were gonna take out the heater or, you know, some other critical part of the infrastructure one's home. So do you know more about that anecdote, which would be more of a cautionary tale? So his rationale was that this is a procedure that's often performed for certain types of epilepsy, well, in specific indications. That's something you do. Well, it's one of your workhorses. It's regularly performed for epilepsy and epilepsy surgery. You take out the amygdala and the hippocampus. But these patients were not, they were not the same. So it's just this reasoning work for this condition. Oh, it could work for epilepsy in this condition as well. Yeah, I can't, well, that was his rationale. And indeed, if you take out a structure like that, well, wouldn't you wanna know as a homeowner? Of course. So I think there, the four aspects I spoke about, well, I think this is something well, you need to inform consent about this. You need to explain that this is innovative, that this is really not what the rest of the world is doing and that you're basically trying. And because you're not really trying is one patient that you feel so sorry for, but actually several in a row, well, I think it starts to be researched so that there should be some form of oversight for things like this. But well, the fact is that there wasn't oversight. Well, you can just do this apparently. So that's also the unique nature of surgery. So we can just only make things like, discuss things like this so that my residents don't start to do the same so that I can teach them. So guys, this is not the normal way to do it. And hopefully we can change the culture by that because that's actually all we can right now in cases like that. So Marike, I just, I met Bill Gramlein, one of the neurosurgeons. If you think about it, it sounds terrible. One of the most successful surgeries that we do is something called a microvascular decompression where people come in with terrible trigeminal pain. We go in and we take a vessel off the pain, off the nerve and we put a piece of cotton. The way we got to that was that subsurgeon was taking out tumors in the region and happened to notice that all these patients with pain had a blood vessel. So he said, how about if I just start taking people who show up with pain, but with no tumors and just go to the OR? And maybe they have a blood vessel on it. Maybe they don't, but I'll just try that. That is to this day, the most successful neurosurgical intervention we have tried over 35 years. So there is something about innovation, which is, it is scary. It has to be watched, but I think that the moment we say, you can't do it on a hunch. You can't do it with the information you have. We stop progressing. And so I would be cautious to say that one-offs don't count. One-offs, and I get the problem, I get the difference between a plumber and a neurosurgeon. One-offs in Silicon Valley have created all of our progress. One-offs here will create it too. And I think that the moment we over constrain the thought process, we get ourselves into a non-mobile medical community. I fully agree with you. And I think that especially the idea phase, and you have to do something and critically look at what you're doing, it could be innovative. So that's, I think, a little bit what happens with the endoscopic and the nasal approach that we realized in hindsight, oh wait, this was kind of an innovation, actually. So I think we should culture the idea phase and we should nurture it and have people come up with as many ideas as possible. But I think we really need to keep discussing how to translate the ideas like that into clinic. And I think it's really good. So I learned in medical all-case reports, you should never publish, but I'm a huge proponent of case reports because especially from those things you learn, what worked for other people in a rare situation, but you can, it's a way to share knowledge about this one individual patient. And I should even encourage people, well, we tried this and didn't work because that's the whole point. If it works, then it's great to have the idea and to move on. But well, you don't want people, everyone to try something that won't work anyway. So I fully agree, but we have to think about a way to really take this idea to the clinic because that's a big difference with Silicon Valley. Company fills and I think, what was it? One out of 10 only succeeds or something while the other one, well, yeah. But neurosurgery is a bit different. If we fill nine out of 10, well, we're not doing such a great job. I think we've hurt. Yeah, hurt. She's been hurt. We may not have helped. I don't mean to sound from Pesk, but there is a space for trying things that seem logical and novel. Now sticking a tumor with stool is probably not a great idea, right? There are limits to how much we can do, right? But I do think that 10 neurosurgeons should around say this is a great idea. Yeah. Probably try it. Right, well, so I think the example of asking 10 neurosurgeons is an example of a type of oversight, right? So I think you would agree that if there wasn't even a very good rationale for trying that, right? If he just had the idea one day, wasn't based on any rationale, didn't really ask anybody, didn't explain to the patients why he thought this would work and that this was novel. Even if it worked out, then you'd be critical of it, right? You'd say, really, you should have asked your colleagues. At a minimum, you should have asked your colleagues for a little bit of input before you tried this. And maybe at a minimum, you should let the first patients that you do this on know that this is a brand new innovative thing, right? So there's a middle ground between saying, oh yeah, if you've got a good idea, you should try it and know everything needs to go to an IRB, right? Like there's gotta be some middle ground, which I think is what Marika was trying to sketch out was like a graded approach to oversight in these situations. Chris, in terms of the way this is formally done, at Children's Hospital now, it's just of interest once it was realized that people started to bring some of these innovative surgical advances like multiple organ transplants at the same time hadn't been done in this population. We wanted to try to do it. And the IRB said, we don't really have exactly the right expertise to evaluate that. I mean, how do we know whether that's a good idea or not a good idea? We are not the right ones to do that. On the other hand, the members of, and by the way, the IRB is one of the committees in the hospital that is federally sanctioned. So everything the IRB does is carefully documented. They have to do everything by very clear legal rules. But what has happened at Children's, and I believe this is still the case, is that there is a second, there is a different committee which has a lot of the same members. So the people who are on the IRB actually have a lot of experience in evaluating risk benefit issues for individual patients and written protocols. But situations that are presented to this committee, also the committee gets ad hoc, some members who are under surgeons in a similar area, some clinicians who are outside of the area, different stakeholders to look at it. And basically what they do is they give an advisory opinion on what is reasonable to do. And I think if in the case of, when Dr. Genetic got the idea to do microvascular decompression, probably that is what at our hospital would have been recommended to say, I see you're now operating on people who don't have tumors, but it sounds like you have a pretty good reason for doing it, but let's have this committee review. And this is some language you should probably include in your surgical informed consent, not a research informed consent, a surgical informed consent. My name is Dave, I'm a first year medical student. My question maybe relates more to what Dr. Brokaw was asking about, but Dr. Mezzan, I'd love to hear your thoughts as well. One of the things I'm curious about is patients who are extremely vulnerable. So near the end of their life with, like you mentioned, glioblastoma or an end state neurological disease like ALS or something like that. We often talk in ethics that they sort of need more protection and that the standards for informed consent and things like that need to be maybe a little bit higher. What I'm curious about though is sometimes when we talk about surgical innovation, it seems like we may be restricting their right to choose their treatment. And what I'm thinking of specifically is sort of the example that you gave of the surgeon who gave patient with GBM the bacteria to see if it would work. I can imagine a situation in which a patient who is extremely ill and near death sort of wants a very experimental treatment like that on the very, very off chance that may work for them. And so that as they die, they maybe could be contributing in some way to further scientific knowledge and things like that. How can we balance sort of the desires of these patients with sort of our societal level protections of people that we consider to be somewhat vulnerable in the context of neurological disease? This is an extremely good and important question. So I treat mainly people with brain tumors. So I treat a lot of those patients that have recurrent GBM. And many come to me and my colleagues at Neuron Collegy and asking about all forms of experimental treatment. And well, how do you advise them as a doctor? So there are multiple aspects. Well, in Europe they can fly, for instance, to Germany or drive to Germany and there are a couple of clinics offering all these alternative therapies as long as they're willing to pay. So I could say, well, you should just go there and get your experimental therapy. However, I'm not sure that's the best way to protect my patients. And why do you want to protect them? Because you want them the last time, the time they have with their families to be of as high quality as possible. And you don't want to expose them to unnecessary risk. So I usually, what I usually recommend is I work with them and the Neuron Collegy and see what are the open experimental trials. And then you really look at phase one trials as well because I know that if a patient enrolls in a trial like that, they don't have to pay money to be enrolled. The data that will be generated will be used for future patients because the goal of such a trial is really to create generalizable knowledge. If they go to this clinic in Germany and get some stem cells injected, for instance, well, no one will know if it worked or not. So that will be important. So you should, I want to, if they really want to make this contribution to other patients, well, it should be in some sort of trial that it's being reported about. It's really good if like an independent committee looked at the protocol to see, okay, does it make sense? Will this answer questions that can help future patients and doesn't it put the patient at too much risk? So that's what I usually do. However, more and more people go on the internet and find all these really extreme forms of alternative treatment options, surgically or non-surgically. And more and more people ask about that. So it's a question that's becoming more and more urgent. And I think it's important to, so for any patient, you, well, what's the goal? Why do they want this? Because they want as much time as possible with the family of the best quality possible and they want to help future patients. So you have to make sure that if you advise your patients, so that's what you will be getting. So with respect to the informed consent, I don't think it should be for patients like that, even it should be really different from patients that are, you know, that get like a spinal implant or something. Well, I'm not sure how that should be really different. If you talk about people in a coma or children, et cetera, and you want to do something of it as well, I think you do need to change your informed consent procedure. So we're right at six o'clock. We will have an opportunity to continue the conversation and the question about whether patients have a right to access to experimental therapies is maybe an excellent topic for a conversation there. Anyone who likes to stay is welcome to stay and join us for that dinner and conversation. But let's all thank our speakers for an excellent conversation. Thank you.